Pharmacology

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 Index

Antirheumatoid Drugs 1-6

DRUGS USED IN GOUT 6-11
Antiretroviral agents and Treatment of HIV 12-19
infection
ANTIMALARIAL DRUGS 20-31
ANTILEPROTIC DRUGS 32-38
ANTIHELMINTIC DRUGS 39-47
ANTIFUNGAL DRUGS 48-59
ANTICANCER DRUGS 60-80
Antiamoebic & other Antiprotozoal Drugs 81-88
ANDROGENS,ANTIANDROGENS & 89-97
ANABOLIC STEROIDS
AMINOGLYCOSIDES 98-105
DRUG INTERACTIONS 106-112
ORAL ANTI-DIABETIC DRUGS 113-125
INSULIN & DIABETES MELLITUS 126-148
CORTICOSTEROIDS 149-159
CONTRACEPTIVE DRUGS 160-172
CHEMOTHERAPY OF TUBERCULOSIS 173-181
CHELATING AGENTS 182-187
CEPHALOSPORINS 188-192
BROAD SPECTRUM ANTIBIOTICS 193-201
ANTIVIRAL DRUGS 202-211
Immunopharmacology 212-222
TREATMENT OF DIARRHEA 223-229
PROKINETIC AGENTS 230-233
PHARMACOTHERAPY OF PEPTIC 234-246
ULCERS/ACID PEPTIC DISEASES
247-250
Digestants ,carminatives and gall stones dissolving
agents

TREATMENT OF CONSTIPATION 251-266

Drugs Affecting Calcium Balance 267-273

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DRUGS ACTING ON UTERUS 274-280
Drug therapy during Pregnancy 281-293

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 Antirheumatoid Drugs
Dr. K. Govardhan Reddy
• Rheumatoid Arthritis (RA) is an autoimmune
disease
• Characterized by
- pain, swelling, stiffness in the joint particularly
in the morning, synovial proliferation &
destruction of articular cartilage
• IL-1, IL-6 & TNF-α are the central mediators of active rheumatoid
process
Classification
I. NSAIDs
II. Disease Modifying AntiRheumatic Drugs
(DMARDs) or (SAARDs)
A. Biological agents
1. TNF-α inhibitors
- Etanercept, Infliximab, Adalimumab
2. IL-1 receptor antagonist - Anakinra
3. IL-6 receptor antagonist - Tocilizumab
4. T- cell activation inhibitor - Abatacept
5. Anti B- lymphocyte antibody - Rituximab
B. Non-biological drugs
1. Sulfasalazine
2. Chloroquine, Hydroxychloroquine
3. Leflunomide
4. Immunosuppressants
- Methotrexate, Azathioprine, Cyclosporine
5. Gold Compounds
6. d-penicillamine
III. Adjuvant Drugs
- Glucocorticoids
I. NSAIDs
• These drugs act symptomatically
- relieves pain, swelling, morning stiffness &
immobility
- but no effect on the progression of the disease
Ex: Aspirin, Ibuprofen, Diclofenac
II. DMARDs
“ Drugs which antagonize the effects of
proinflammatory cytokines & arrest or slow

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 down the progression of joint destruction by
modifying the pathogenesis of disease itself,
but non of them is able to halt the long term
progression of the disease”
- Hence the term disease modifying
A. Biological agents
1. TNF-α blocking drugs
Infliximab:
• It binds & inactivates TNFα- prevents the release of IL-1, 6,
collagenases &
metalloproteinases
• I. V infusion, t1/2 9-12 days
Uses:
• RA, psoriatic arthritis, Sarcoidosis, CD, UC
• Infliximab + Methotrxate – reduces new bony erosions
A/E:
• URTIs, nausea, headache
• Activation of latent TB, Opportunistic
infections
• Infusion site reaction
Etanercept:
• It binds to TNF α and TNF β
• Binding to the TNF α - inhibition of TNF α
mediated inflammation
• S.C, t1/2 – 5 days
• Uses similar to infliximab
2. IL-1 receptor antagonist:
Anakinra:
• Activated macrophages & mononuclear cells
produce IL-1
- which activates helper T-cells & induces
production of other ILs & metalloproteinases
• It prevents IL-1 binding to its receptor
• Given S.C.
A/E:
• Infusion reactions, head ache, flu like symptoms
3. IL-6 receptor antagonist:
Tocilizumab:
• It is effective in patients not responding to TNF
α inhibitors

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 A/E:
• Similar to TNF α inhibitors
• Neutropenia, ↑ LDL
4. T- cell activation inhibitor
Abatacept:
• It is a fusion protein of cytotoxic T-lymphocyte antigen-4 linked to
IgG1
• It prevents T-cell activation & lowers serum
conc. of inflammatory cytokines
• I.V
A/E:
Opportunistic infections
5. ANTI-B- lymphocytic antibody
Rituximab:
• Selectively depletes CD20 B lymphocytes –
play a role in the autoimmune response
• Used in cases resistant to TNF-α inhibitors
B. Nonbiological drugs
1. Sulfasalazine
• It is metabolized to sulfapyridine & 5-ASA
• Sulfapyridine is absorbed systemically, active
component in treating RA
• It
- decreases RF levels
- suppress the generation of superoxide free
radicals
- reduce cytokine release by inflammatory cells
• t1/2 6-15hrs
Uses:
• RA, Juvenile chronic arthritis & Ankylosing
spondylitis
A/E:
• GIT disturbances, headache, haemolytic anemia,
Thrombocytopenia
2. Chloroquine & Hydroxychloroquine
• Relatively low toxicity, bony erosions are not
prevented
• They are taken up by macrophages &
lymphocytes
- inhibits phagocytosis & T- cell activation

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 - traps free radicals
- stabilizes lysosomal enzymes & leukocyte
chemotaxis
• Usually remission occurs after 3 months & full effect may take
even after 1 yr
• Long term use – Corneal deposits, Occular toxicity
3. Leflunomide
This immunomodulator is rapidly converted to
an active metabolite
• which inhibits
DiHydroOrate DeHydrogenase (DHODH) &
pyrimidine synthesis in actively dividing cells →
inhibits RNA synthesis & cell growth
• As a result, it inhibits
- T-cell proliferation
- production of autoantibodies by B-lymphocytes
• t1/2 2-3wks
• It also reduces the bony damage
A/E:
• Diarrhoea, raised hepatic enzymes, alopecia,
weight gain, SJ syndrome
• It is carcinogenic, teratogenic
4. Immunosuppressants
• Methotrexate, Azathioprine, Cyclosporine,
Cyclophosphamide
• These agents acts by suppressing the action of both the B & T
lymphocytes
• These agents are toxic, so not preferred unless other agents fail to
produce satisfactory response
5. d-penicillamine
• Copper chelating agent
• Possibly it causes marked reduction in
immunoglobulins, IgM
• Gold like action, toxicity also similar
• The effect takes weeks to start & the desired
response is not seen for several months
6. Gold compounds
• Sodium aurothiomalate (I.M), Auranofin (Oral)
• Use declined because of their toxicity
• Gold alters the morphology & functional

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 capabilities of macrophages
• Suppress CMI
• It prevents joint destruction & induces healing of bony erosions
Aurothiomalate:
- It also reduces lysosomal enzyme activity &
histamine release
- suppress the phagocytic activity of
polymorphonuclear leukocytes
Auranofin:
- It also inhibits the release PGE2, LTB4, IL-1, TNF-α
• Gold salts tend to accumulate in synovial fluid, liver, kidney,
spleen & BM
• t1/2 7 days
A/E:
• Exfoliative dermatitis, stomatitis, hepatitis,
peripheral neuropathy, hypertension, pulmonary fibrosis &
thrombocytopenia
III. Glucocorticoids
• These are used in patients where relief does
not occur with NSAIDs or other agents
• They inhibit the
- Synthesis & suppressing the actions of
inflammatory mediators
- proliferation of TH1 cells
- decrease the transcription of IL-1 & TNF-α
during immune response
• It is used together with DMARDs
- to reduce the symptoms & rate of joint
destruction
• Intra articular injection of Triamcinolone,
Hydrocortisone – when there is one or two joints
are severely affected

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DRUGS USED IN GOUT
Dr. K. Govardhan Reddy
Gout
It is due to hyperuricaemia (normal 2-6 mg/dl)
Primary:
• Over producers or under excretors of uric acid
• Uric acid is a end product of purine metabolism
- MSU crystals precipitates & deposits in joints,
kidney & subcutaneous tissues (tophi)
Secondary:
• leukaemias, lymphomas - when treated with
chemotherapy or radiation
• Drug induced: thiazides, furosemide, levodopa,
pyrazinamide, ethambutol
Classification
I. For Acute Gout
- NSAIDs
- Colchicine
- Corticosteroids
II. For Chronic Gout
A. Uric acid synthesis inhibitors
- Allopurinol
- Febuxostat
B. Uricosuric drugs
- Probenecid
- Sulfinpyrazone
I. Acute Gout
• It manifests as sudden onset of severe
inflammation in a small joint
- metatarso-phalangeal joint of great toe
• The joint becomes red, swollen,& extremely
Painful
1. NSAIDs
• To provide symptomatic relief
• Strong antiinflammatory drugs – naproxen,
piroxicam, diclofenac, indomethacin, etoricoxib
• Naproxen & piroxicam inhibit
- chemotactic migration of leukocytes into the
inflammed joint
2. Colchicine:

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 • Obtained from “Colchicum autumnale”
• It is neither analgesic nor antiinflammatory, but specifically
suppresses gouty inflammation
• It does not inhibit the synthesis or promote the excretion of uric
acid
MOA:
• Precipitation of urate crystals in the synovial fluid, initiate
inflammatory response
↓
chemotactic factors are produced
↓
granulocytes migrate into the joint
↓
phagocytose urate crystals & release a glycoprotein
↓
which aggravates inflammation by
- ↑ lactic acid production - ↑ precipitation of crystals
- releasing lysosomal enzymes causes joint
Destruction
It acts by
• Binding to tubulin, Inhibits the granulocyte
migration into the inflammed joint
Other actions:
• Antimitotic
- causes metaphase arrest by binding to
microtubules of mitotic spindle
• Increases gut motility through neural
Mechanisms
PK:
• Rapidly absorbed orally
• Partly metabolized in liver & excreted in bile
• CYP3A4 inhibitors retard metabolism
Uses:
• Acute Gout – fastest acting, dramatic response
- 0.5mg TID for 4 days
• Prevention of acute attacks of gout
• Prevention of attacks of familial mediterranean
Fever
A/E:
• N, V, watery or bloody diarrhoea & abdominal cramps

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 • In overdose - kidney damage, CNS depression, intestinal bleeding
- death is due to muscular paralysis & respiratory Failure
3. Corticosteroids:
• Reserved for refractory cases not responding to NSAIDs or
Colchicine
• Intraarticular injections suppresses symptoms of acute gout
• Systemic steroids are rarely used
- in patients with peptic ulcer or renal failure in whom NSAIDs are
C/I
II. Chronic Gout
• Characterized by
- persistant pain & stiffness in a joint between
attacks
- hyperuricaemia
- tophi under the skin in pinna, eyelids, nose,
around joints
- urate stones in the kidney
A. Uric acid synthesis inhibitors
1. Allopurinol:
• It was purine antimetabolite for cancer
chemotherapy, but lacked such activity
• It inhibits xanthine oxidase, the enzyme responsible for uric acid
synthesis
MOA:

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 • During therapy, plasma conc. of
- uric acid ↓
- xanthine & hypoxanthine ↑
• Acute attack may increase initially due to
mobilization of uric acid from stores
- Colchicine or NSAIDs are used initially with
Allopurinol
PK:
• Rapidly absorbed orally
• Not bound to plasma proteins
• Short acting (t1/2 - 2 hrs)
• Its metabolite alloxanthine is longer acting (t1/2 24hrs)
• Excreted through faeces
Uses:
• Chronic gout - first choice in patients with gouty tophi or
nephropathy, renal urate stones
• When patients are allergic to uricosuric drugs
• In secondary hyperuricaemia

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 • To potentiate 6-MP or azathioprine in cancer chemotherapy &
immunosuppressant therapy
• As adjuvant to sodium stibogluconate in kala-azar
A/E:
• Acute attack of gout may get precipitated
• Hypersensitivity reaction, SJ syndrome
• Gastric irritation, N, headache, dizziness
• Hepatic or renal dysfunction
D/I:
• Allopurinol inhibits the degradation of 6-MP & azathioprine
• It prolongs t1/2 of probenecid, while probenecid
shortens t1/2of alloxanthine
• Higher incidence of skin rashes when used with Ampicillin
• Potentiate the actions of warfarin & theophylline by inhibiting
metabolism
Precaution:
• Allopurinol & uricosurics should not be started during acute attack
• Initial treatment with these drugs acute attacks are more common
• This period should be given by NSAIDs, or
Colchicine
2. Febuxostat:
• Newer, more potent & selective inhibitor of
xanthine oxidase
• rapidly absorbed orally, high PPB
• t1/2 6 hrs
• It is an alternative for gout in patients intolerant to allopurinol
• Not used in cancer associated hyperuricaemia
A/E:
• N, D, headache, Liver damage
3. Pegloticase:
• recombinant uricase
• Oxidizes uric acid to highly soluble allantoin
B. Uricosuric drugs:
- used to enhance excretion of uric acid
1. Probenecid:
• It is neither analgesic nor anti inflammatory drug
MOA:
• Promoting the excretion of uric acid by inhibiting its active tubular
reabsorption
PK:

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 • Completely absorbed orally
• 90% PPB
• t1/2 6-8 hrs
Uses:
• Chronic gout
- given with plenty of water to prevent
formation of renal urate calculi
• With cidofovir in CMV retinitis in AIDS patients:
- used to ↑plasma conc. of cidofovir & reduces nephrotoxicity by
blocking its active tubular secretion
• To prolong penicillin action by inhibiting renal tubular secretion
A/E:
• Dyspepsia
• Hypersensitivity reaction - rare
• Toxic doses – convulsions & respiratory failure
D/I:
• It inhibits urinary excretion of penicillins,
cephalosporins, methotrexate & indomethacin
• Low dose aspirin block uricosuric action of
probenecid
• Inhibts biliary excretion of R, Z, E
• Inhibits tubular secretion of nitrofurantoin2. Sulfinpyrazone:
• It is structurally related to phenylbutazone
• Neither analgesic nor anti-inflammatory
• It inhibits tubular reabsorption of uric acid, but smaller doses
↓urate excretion
• It inhibits platelet aggregation
• More gastric irritation – less commonly used
3. Benzbromarone:
• Newer & more potent
• Used in patients who are allergic or resistant to other uricosuric
drugs or in patients with GFR < 25%
4. Lesinurad:
• Newer drug
• MOA similar to probenecid

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Antiretroviral agents
and
Treatment of HIV infection
Dr. Pushpalatha C.
• Drugs – Act against HIV (Human Immunodeficiency Virus)
• HIV – infects CD₄ T lymphocytes, macrophages & dendritic
cells
• HIV infection cannot be cured
• Combination antiretroviral therapy
– Prolong life
– Prevent progression of disease
– Postpone complications of AIDS or AIDS related complex
• Clinical efficacy monitored at regular intervals by
– Plasma HIV-RNA assay
– CD₄ lymphocyte count
Antiretroviral agents
Nucleoside reverse transcriptase inhibitors (NRTIs)
- Zidovudine (ZDV/AZT) - Stavudine (d4T)
- Lamivudine (3TC) - Abacavir (ABC)
- Didanosine (ddI) - Emtricitabine (FTC)
- Zalcitabine (DDC)
Nucleotide inhibitors
- Tenofovir (TDF)
Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
- Nevirapine (NVP) - Efavirenz (EFV)
- Delavirdine (DLV) - Etravirine (ETV)
Protease inhibitors (PIs)
- Saquinavir (SQV) - Atazanavir (ATV)
- Ritonavir (RTV) - Fosamprenavir (FPV)
- Lopinavir (LPV) - Nelfinavir (NFV)
- Indinavir (IDV) - Tipranavir (TPV)
- Amprenavir (APV) - Darunavir (DRV)
Entry/Fusion inhibitors
- Enfuvirtide (T-20)
- Maraviroc (MVC)
Integrase inhibitor
- Raltegravir (RAL)
Replicative cycle of HIV and showing sites of
action of antiretroviral agents

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Nucleoside reverse transcriptase inhibitors
(NRTIs)
• Nucleoside analogs
MOA
• Enter cell – undergo phosphorylation – MP → DP
→ TP → inhibit reverse transcriptase → inhibit
production of complementary DNA from RNA →
block replication of viral genome
• Also get incorporated into growing viral DNA &
result in termination of DNA chain elongation
• They differ in their intracellular pathways
Pharmacokinetics
• Rout of admn. – Oral
• Cross BBB
• Cross placenta
• Found in high conc. in male genital tract (ZDV & 3TC)
• Excreted in urine
Therapeutic uses
• Treatment of HIV infection & AIDS
– In combination with other antiretroviral drugs
• For preventing mother-to-child transmission of HIV
infection (zidovudine)
• For post-exposure prophylaxis in health workers
(zidovudine)
Adverse effects of NRTIs
• All NRTIs – Lactic acidosis
- Hepatic steatosis

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- Lipodystrophy
• Abacavir – Hypersensitivity reaction
• Zalcitabine – Peripheral neuritis (PN)
• Stavudine – PN, Pancreatitis
• Didanosine – GI intolerance, Pancreatitis, PN
• Zidovudine – Headache, GI intolerance, Bone marrow
Suppression
Nucleotide inhibitors
Tenofovir
• Acyclic nucleotide analog of adenosine
• Available as tenofovir disoproxil prodrug
• Effective against – HIV-1, HIV-2 and HBV
• Not metabolized by CYPs
• Adverse effects – Headache, GI intolerance, Renal
impairment
• In renal insufficiency – dose needs to be reduced
Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
• Nucleoside unrelated compounds
MOA
• Directly inhibits HIV reverse transcriptase (no need of
intracellular phosphorylation) → inhibit production
of complementary DNA from RNA → block
replication of viral genome
• Binding site near to but distinct from that of NRTIs
• Active against HIV-1 but not HIV-2
Pharmacokinetics
• Routes of admn. - oral
• Metabolized by CYP 3A4
• Nevirapine & Etravirine – enzyme inducers
• Delavirdine – enzyme inhibitor
Therapeutic uses
• In HIV infection– in combination with other antiretrovirals
• In pregnant HIV-infected woman – prevent mother-to-
child transmission (vertical transmission) – Nevirapine
Exposure to even a single dose of nevirapine → resistance
Adverse effects
• All NNRTIs – Rash
- Stevens – Johnson syndrome
- Drug-drug interactions

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• Nevirapine – Hepatotoxicity (severe)
• Efavirenz – Neuropsychiatric & Teratogenic effect
Protease inhibitors (PIs)
• Peptide-like chemicals
MOA
• Inhibit retroviral protease enzyme – prevent proteolytic
cleavage of large viral polyproteins into various
functional components → inhibit HIV replication &
maturation
Pharmacokinetics
• Oral BA – variable
• Metabolized by CYP3A4 (except nelfinavir)
• Inhibit CYP3A4 enzyme (specially ritonavir)
• Boosted protease inhibitor regimen
– PI + Ritonavir (low dose) + NNRTI
– Reduce both drug’s dose & dosing frequency
– Increase systemic conc.
Adverse effects of PIs
• All PIs – Hyperlipidemia
- Insulin resistance & diabetes
- Lipodystrophy
- Elevated liver function tests
- Possible increased bleeding risk in
hemophiliacs
- Drug – drug interactions (Due to CYP 450
inhibition)
• Amprenavir & Fosamprenavir – GI intolerance, Rash
• Atazanavir – Hyperbilirubinemia, PR interval
prolongation
• Indinavir – Nephrolithiasis, GI intolerance
• Lopinavir / Ritonavir – GI intolerance
• Nelfinavir – Diarrhoea
• Ritonavir – GI intolerance, Hepatitis
• Tipranavir – GI intolerance, Rash, Hyperlipidemia, Liver
Toxicity
Entry/Fusion inhibitors
• MOA
– Enfuvirtide – binds to gp41 subunit of viral envelop
glycoprotein → prevents conformational change
required for fusion of viral & host cell membrane

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– Maraviroc – Chemokine receptor antagonist – binds
to host cell CCR5 receptor to block binding of viral
gp120 → inhibits fusion of viral & host cell membrane
Pharmacokinetics
• Route of admn. – enfuvirtide - SC
- maraviroc – oral/SC
• Enfuvirtide - Not metabolized by CYP450
• Maraviroc – metabolised by CYP3A4
Adverse effects
• Enfuvirtide – local injection site reaction
- Hypersensitivity reaction
- Eosinophilia
- No drug interaction
• Maraviroc – Hepatotoxicity
- Allergic reactions
Integrase inhibitors
• Raltegravir – Active against HIV-1 & HIV-2
MOA
• Inhibit integrase enzyme – prevents integration of viral
DNA into host chromosome → inhibits viral replication
Pharmacokinetics
• Route of admn. – oral
• PPB – 83%
Adverse effects
• Well tolerated
• Headache, nausea & fatigue
• Myopathy & rhabdomyolysis
• Exacerbation of depression
Treatment of HIV infection & complications
– Complex & Prolonged
– Very expensive
– Needs – Expertise therapy
– Strong motivation
– Commitment of pt.
– Life long treatment most of the times
– Monotherapy → development of resistance – C/I
– HAART (Highly Active Antiretroviral Therapy)
• Combination of 3 or more drugs
• Rapidly kills 99% virions → a small no. survive in resting
CD₄ cells → relapse

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• High rate of mutation → resistance
– HIV eradication – not possible
Goal of therapy
– To reduce clinical progression of disease
– Inhibit viral replication – to attain & maintain
effective immune response
Initiating antiretroviral therapy
– All cases of symptomatic HIV disease
– All cases with CD₄ count of ≤ 350 cells/mm³
– HIV infected pregnant women
– Pts. With HIV nephropathy
– HIV pts. With concurrent hepatitis B virus infection
• Pts. Interest & potential to adherence to therapy
• Individual risk of toxicity & interactions
Therapeutic regimens
HAART (Highly Active Antiretroviral Therapy)
• Aggressive therapy with 3 antiretroviral drugs
• Should suppress plasma viral load to
undetectable level (˂50 copies of HIV-RNA/ml)
• Choice of drugs based on –
– Efficacy
– Tolerability
– Convenience
– Drug interactions
– Impact on future options
– Cost
• Common initial regimen
– 2 NRTIs + 1 PI
– 2 NRTIs + 1 NNRTI
– 3 NRTIs (in less advanced cases)
• Regimens to be individualized
• NRTI + NNRTI + PI
– Due to high toxicity this regimen used only in
• Advanced cases
• Short life expectancy
• Repeated failure of treatment
• Multiclass drug resistance
Preferred regimens
• 2 NRTIs + 1 NNRTI
– Zidovudine + Lamivudine + Efavirenz

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 • 2 NRTIs + 1 PI
– Zidovudine + Lamivudine + Lopinavir/Ritonavir
• 3 NRTIs
– Zidovudine + Lamivudine + Abacavir
Antiretroviral drug combination to be avoided
• Zidovudine + Stavudine → Pharmacodynamic antagonism
• Stavudine + Didanosine → Lactic acidosis
• Lamivudine + Didanosine → Clinically not additive
Changing a failure regimen
• Change of regimen considered if :
– Persistent increase in plasma HIV-RNA concentrations
after initial suppression to undetectable level (˂ 50
copies/ml)
– Clinical deterioration
– ↓ CD₄ count
• Failure of regimen occur
– Usually due to non-adherence to treatment
– with in one year or successive year with all regimens
• All 3 drugs are to be changed
• For selection of salvage regimen – Pts. Treatment
history & viral resistance testing is recommended
• When NRTIs to be spared
– PI + Ritonavir + NNRTI/Fusion inhibitor (ritonavir- boosted PI
regimen)
Prophylaxis of HIV infection
1. Post exposure prophylaxis (PEP)
– 2 drug regimen for low risk pts.
• ZDV 300 mg + 3TC 150 mg BD for 4 wks
– 3 drug regimen for high risk pts.
• ZDV 300 mg + 3TC 150 mg BD + Indinavir 800 mg TID for 4 wks
2. Perinatal prophylaxis
– Nevirapine 200 mg single oral dose to pt. at the
onset of labour followed by 2 mg/kg single oral dose to neonate
within 3 days after birth – to prevent vertical transmission
TB & HIV co-infection
• Start TB therapy with DOTS
– Rifampin – used only with efavirenz or full dose
ritonavir
– Rifabutin – recommended with nevirapine & other
Protease Inhibitors

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ANTIMALARIAL DRUGS
Dr. Pushpalatha C.
• Malaria
– is coined from the Italian phrase ‘Mal aria’ –
meaning ‘bad air’
– Characterized by – fever with rigor, headache,
myalgia, anaemia and splenomegaly
• Malaria caused by following species of Plasmodium
– P. falciparum → Malignant tertian malaria
– P. vivax → Benign tertian malaria – Relapse
– P. ovale → Benign quartan malaria – Relapse
– P. malariae → Benign quartan malaria
– P. knowlesi – recently has been shown to infect humans.
• P. falciparum – responsible for majority of
serious complications & death due to Malaria
• Infection by malarial parasite occur through
• The bite of a female Anopheles mosquito
• Transfusion of infected blood
• Mother to the fetus across the placenta
• NMEP – National Malaria Eradication Program
started in 1958 – highly successful
• 1970s – come back of malaria
• NMEP was renamed as NAMP – which is now
NVBDCP (National Vector Born Disease Control
Program)
Life cycle of Malarial parasite
Antimalarial drugs classification
I. Quinoline derivatives
a) 4-aminoquinolines – Chloroquine, Amodiaquine,
Piperaquine
b) 8-aminoquinolines – Primaquine, Tafenoquine,
Bulaquine
c) Quinoline methanol – Mefloquine
II. Artemisinin compounds – Artesunate,
– Artemether,
– Artether
III. Cinchona alkaloids – Quinine
– Quinidine
IV. Antifolates
a) Biguanides – Proguanil

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 b) Diaminopyrimidines – Pyrimethamine
c) Sulfonamides – Sulfadoxine, Sulfamethopyrazine,
Dapsone
V. Phenanthrene methanols – Halofantrine,
– Lumefantrine
VI. Naphthoquinone – Atovaquone
VII.Antimicrobials – Doxycycline
– Clindamycin
4-aminoquinolines
• Used in suppressive therapy of malaria
• Also useful in many other conditions
CHLOROQUINE (CQ)
• Most effective & frequently used antimalarial
drug
• MOA
– Chloroquine – gets concentrated in food
vacuoles of parasite – binds to heme –
prevents polymerization of heme to hemozoin
– accumulation of heme & drug-heme complex
– both cause damage to organelles of parasites
–→ causes death of parasite
• Antimalarial activity
– Blood schizonticidal action – highly effective on all 4 species
– Gametocidal action – moderate against all species of malaria
except P. falciparum
• Other actions
– Effective in giardiasis, taeniasis and extraintestinal amoebiasis
– Has some anti-inflammatory, antihistaminic & local anaesthetic
activity
• Resistance
– P. falciparum develops efflux mechanism to pump the
drug out of the cell – shows cross resistance
• Pharmacokinetics
– Routes of admn. – Oral – Rapid absorption
– IM/IV – Given only in severe cases
– Vd – very high (13,000 L) – loading dose is required
– Gets concentrated in – liver, spleen, kidney, lung, skin,
retina & leucocytes
– Plasma t ½ – ~241 hrs.
– Conc. in CNS – 10-30 times the plasma levels

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 – Metabolized in liver to active metabolites
– Oral prep. – Tablet chloroquine phosphate 250mg
contains chloroquine base 150mg
• Therapeutic uses
– Malaria – Prophylaxis & Treatment
• Suppressive Prophylaxis – in persons visiting
endemic area – 300mg (base) once a week – one
week before & continue for 4 weeks after return.
• Treatment of acute attack (chloroquine sensitive
malaria) – chloroquine 600mg (base) orally –
followed by 300mg after 6hrs – then 300mg daily
for next 2 days.
• Chloroquine can be used in malaria during
pregnancy– Hepatic amoebiasis – given only if metronidazole is
ineffective or not tolerated
– Giardiasis
– Chinese liver fluke
– Rheumatoid arthritis
• Chloroquine – Has mild antiinflammatory &
immunomodulatory action – Given as a DMARD
– Lepra reaction
– Discoid Lupus Erythematosus – as an alternative to
corticosteroids
– Systemic Lupus Erythematosus – less effective
• Adverse effects
– At therapeutic dose – after oral Rx of acute attack
• GI upset – nausea, vomiting – due to bitter
taste
• Headache & urticaria
• Visual disturbance
– Prolonged Rx with suppressive doses
• Headache, blurring of vision, diplopia,
confusion, convulsions, photosensitivity,
graying of hair, widening of QRS interval & T
wave abnormalities – reversible
• Haemolysis & blood dyscrasias – rare– High doses in Rx of
diseases other than malaria
• Retinopathy & ototoxicity – irreversible
• Toxic myopathy, cardiopathy (↓BP, arrhythmias),
peripheral neuropathy – reversible

21
 • Neuropsychiatric disturbances
– Pts. receiving long-term high-dose therapy – should
undergo ophthalmological & neurological
evaluation – every 3-6 months
• Contraindications & Precautions
– Epilepsy, myasthenia gravis, psoariasis, retinal &
visual field abnormalities
– liver & kidney disease, neurological & blood
Disorders
• Drug interactions
– Mefloquine → seizures
– Amiodarone or Halofantrine → risk of ventricular
arrhythmias
– Anticonvulsants → ↓ efficacy
– Digoxin & Cyclosporine – ↑ toxicity
AMODIAQUINE
– Properties identical to Chloroquine
– Faster acting & less bitter in taste
8-aminoquinolines
PRIMAQUINE
• Mainly used for radical cure of malaria
together with Chloroquine
• It kills hepatic forms of P. vivax & P. ovale
• Antimalarial action
– Active against hepatic forms of all species of
Plasmodium
– Only drug active against dormant hepatic stage of P.vivax & P.
ovale– Also exerts gametocidal action against all species of Plasmodium
– Weak activity against erythrocytic form
• Mechanism of action
– The exact mechanism is not clear
– Primaquine – its quinone metabolite – generates
reactive oxygen species or interferes with
plasmodial mitochondrial function → antimalarial
action
– Some strains of P. vivax in some areas may show
resistance – high dose may be required
• Pharmacokinetics
– Oral admn. – well absorbed
– Widely distributed

22
 – Plasma t ½ - 3-8 hrs.
– Rapidly metabolized → 3 metabolites
• Possess less antimalarial activity
• More liable to cause hemolysis than parent
drug
– Excreted in urine
• Therapeutic uses
1. Malaria
– Radical cure of acute P. vivax & P. ovale malaria
• CQ therapy followed by Primaquine 30mg/d for 14 days
– Terminal prophylaxis of P. vivax & P. ovale malaria
• Primaquine – 30 mg base daily for 14 days just
after leaving the endemic area – to prevent
relapse– Causal prophylaxis - 0.5mg/kg daily as long as the pt. is in
endemic area – prevent maturation of sporozoites to schizonts in
hepatic cells
– Gamatocidal action
• Single dose of primaquine (45mg base) given
along with CQ therapy
→ gamatocidal action
→disrupt transmission to musquitoes
2. Pneumocystis jiroveci infection(mild to
moderate)
• Primaquine given together with Clindamycin
• Adverse effects
– Well tolerated in therapeutic doses
– GI effects – nausea, epigastric pain, abdominal
cramps, headache – on admn. of high doses
– Haemolysis in G6PD deficiency pts.
– Leucopenia, agranulocytosis & cardiac arrhythmia
- rare
• Precautions & Contraindications
– Pt. should be evaluated for G6PD deficiency &
blood count should be repeated
– In Pregnancy – foetus is G6PD deficient –
Primaquine should be avoided
TAFENOQUINE
– Recently approved Single-dose (300mg) medicine to
prevent the relapse (radical cure) of P. vivax malaria
– co-administered with CQ or ACTs

23
– Long half life – 15 days
– Use – In pts. ≥ 16 years of age with P. vivax infection
Adverse effects
• Haemolytic anaemia in G6PD deficiency
• Methhaemoglobinaemia
• Nausea, vomiting, headache & dizziness
• Psychiatric adverse effects
• Hypersensitivity reactions
Contraindications – same as Primaquine
Quinoline methanol
MEFLOQUINE
• Developed & introduced for the treatment of
resistant malaria
Antimalarial action
• Highly effective blood scizonticidal drug
• No activity seen on
– Early hepatic stages
– Gametocytes
– Latent tissue forms
MOA – mefloquine gets concentrated in plasmodia
→cause swelling of food vacuoles
→inhibits polymerization of Heme
→form toxic complex with free Heme
---------- → toxic to Plasmodia – kills parasite
Resistance
– P. falciparum develops efflux mechanism to pump the
drug out of the cell – ↓intracellular conc. of drug
Pharmacokinetics
– Oral admn. – well absorbed
– Plasma t ½ - 20 days
– Widely distributed including liver & lungs
– Undergoes enterohepatic circulation
– Excreted through gut
Therapeutic uses
• Prophylaxis of Malaria
– Effective for prophylaxis of Chloroquine resistant
P.falciparum malaria
• Treatment of Chloroquine resistant & multidrug
resistant malaria
Adverse effects

24
 • GI tract – nausea, vomiting, diarrhoea, abd. pain & dizziness
• CNS effects – anxiety, hallucinations, sleep disturbance, loss of
concentration, depression, psychosis & convulsions
• CVS effects – bradycardia & arrhythmias
• Others – blood dyscrasias & skin reactions
Contraindications
– Pregnancy, seizures & neuropsychiatric disorders
Drug interactions
– Use with Chloroquine, quinine or quinidine – cause convulsions &
cardiac toxicity
Artemisinin compounds
ARTESUNATE, ARTEMETHER & ARTETHER
• Derivatives of artemisinin – Obtained from the
Chinese plant Artemisia annua
Antimalarial action
• Very potent & fast acting erythrocytic schizonticidal drugs
compared to other antimalarial drugs
– Effective against all Plasmodial species including
Chloroquine resistant & MDR P. falciparum
• Also effective against gametocytes
• Does not effect either primary or latent tissue forms of
parasite
• Cause rapid parasite clearance & fever resolution
MOA – artemisinin derivatives have endoperoxide
moiety – heme iron present in parasite causes
cleavage of endoperoxide bridge – produce free
radicals – cause damage to malarial proteins –→
lysis of malarial parasite
• Also inhibit Ca²⁺ ATPase in parasite
Pharmacokinetics
• Routes of admn. – oral, parenteral
• Absorption – rapid
• Metabolized in liver – form active metabolite
• Plasma t ½ - Artesunate 23 min., Artemether 45
min.
Therapeutic uses
• Uncomplicated Cloroquinine resistant/Multidrug
resistant P.falciparum malaria
– Given as monotherapy – causes relapse
– Artemisinin compound + Mefloquin/Doxycycline

25
 • Severe malaria due to P. vivax
• Complicated severe P. falciparum
malaria/Cerebral malaria
– Artesunate by IV route
• Not used in mild attacks or for prophylaxis (short
half life)
Adverse effects
• Well tolerated & relatively safe
• Nausea, vomiting, loss of appetite & drug fever
• Q-T prolongation
• Neurotoxicity
• Bone marrow depression
Drug interactions
• Should not be admn. With drugs prolonging Q-T
interval
– Eg. Astemizole, antiarrhythmics, TCAs &
Phenothiazines
Cinchona alkaloids
QUININE & QUINIDINE
• Are alkaloids obtained from Cinchona bark
Antimalarial action
• Quinine – mainly blood schizonticide for all species of plasmodia
• It also exerts gamaticidal effect against P. vivax & P. malariae
• Quinidine – used as antiarrhythmic
–also has antimalarial action – but it is
cardiotoxic & shows unpredictable
pharmacokinetics on IV admn.
Other actions – antipyretic, oxytocic, antiarrhythmic,
hypoglycemic action & also ↓muscle contractile power
MOA – same as Chloroquine
– gets concentrated in food vacuoles of parasite – binds to heme –
prevents polymerization of heme to hemozoin – accumulation of heme
& heme drug
complex – kills plasmodia
Pharmacokinetics
– Route of admn. – oral/parenteral
– Well absorbed orally – PPB – 70%
– CSF conc. – low
– Plasma t ½ - 10-18 hrs.
– Metabolized in liver

26
 – Excreted in urine
Therapeutic uses
• Uncomplicated resistant malaria due to P.
falciparum
– Used in Chloroquine resistant & MDR malaria
– Used for termination of acute attack
– Quinine used orally as well as by infusion
• Complicated resistant malaria due to P.
falciparum/Cerebral malaria
– Quinine – given by IV infusion initially – followed by oral admn.
– Other antimalarials (doxycycline/clindamycin/
Pyrimethmine + Sulfadoxine) can be used together
with quinidine
• Other uses
– Nocturnal muscle cramps
– Babesiosis – quinine used with Clindamycin
– Myotonia congenita – quinine ↓excitability of muscles
Adverse effects
• Cinchonism – occurs with large dose
– Nausea, headache, tinnitus, visual disturbances
• Hypotension – occur at high doses/rapid IV admn.
• Hypoglycemia – occur due to insulin release
• Hematological effects – thrombocytopenia,
agranulocytosis
• Skin rashes, flushing, fever, pruritus & asthma
• Black water fever – haemolysis, haemoglobinuria, fever & renal
failure
Biguanides
PROGUANIL (Prodrug)
Antimalarial action
• Slow acting erythrocytic schizonticide
• Acts on primary tissue forms of P. falciparum
MOA – Proguanil – converted to cycloguanil (active
metabolite) – inhibits DHFRase-thymidylate
synthetase in plasmodia – causes depletion of
folic acid – inhibits DNA synthesis
Pharmacokinetics
– Slow absorption from gut, plasma t ½ is 20 hrs.,
metabolized in liver & excreted in urine
Therapeutic uses

27
 • Prophylaxis of malaria due to P. falciparum & P.
vivax
– Given in combination with Chloroquine
• Treatment of acute attack due to Chloroquine
resistant & MDR P. falciparum malaria
– Given in combination with Atovaquone
Adverse effects
• Nausea & diarrhoea
• Vomiting, abdm. pain, haematuria, epithelial
cells & casts in urine – At higher doses
• Safe during pregnancy
Diaminopyrimidines
PYRIMETHAMINE
Antimalarial action
• Slow acting blood schizonticide
• Effective in combination with sulfonamides
MOA – Pyrimethmine + Sulfoadoxine act
synergistically
– Pyrimethamine inhibits plasmodial DHFR enzyme
– Sulfadoxine inhibits Plasmodial folate synthetase
– ---→ reduce folic acid synthesis (essential for
nucleotide synthesis) – inhibit DNA synthesis
Pharmacokinetics
– Absorbed slowly from gut, accumulates in kidneys,
lungs, liver & spleen
– Plasma t ½ - 3-4 days
– Excreted in urine & secreted in milk
Therapeutic use
• Chloroquine resistant P. falciparum malaria
– Pyrimethmine + Sulfadoxine combination used with quinine
• Toxoplasmosis
– Pyrimethmine + Sulfadiazine
• Polycythemia vera
• Adverse effects
– Skin rashes, nausea, anorexia
– Megaloblastic anaemia
– Other sulfonamide related adverse effects – when used in
combination with sulfonamide
Phenanthrene methanol
HALOFANTRINE

28
 – Effective against only erythrocytic stage of all 4
malaria species
– Effective against Chloroquine resistant & multidrug
resistant strains of P. falciparum
– It is not used commonly – due to erratic absorption &
cardiac toxicity (prolongation of PR & QT intervals)
LUMEFANTRINE
– Chemically related to halofantrine but does not cause
cardiac toxicity
– Highly effective blood schizonticide– Slower in onset of action
than Chloroquine
– Long duration of action
– Metabolized by CYP3A4
– Available only as fixed-dose drug combination
with artemether – used in resistant malaria
– Adverse effects – GI disturbances, headache,
dizziness, rash & pruritus
• Halofantrine & Lumefantrine – both are
contraindicated in pregnancy
Naphthoquinone
ATOVAQUONE
• Has activity against – Plasmodia, Pneumocystis
jiroveci & Toxoplasma
MOA – not clear
– Selectively inhibits mitochondrial electron
transport in parasite
• Acts on erythrocytic stage of Plasmodia
Pharmacokinetics
– Absorption – slow, erratic, unpredictable &
increased by fatty meal
– PPB is 99% & Plasma t ½ is 2-3 days
Therapeutic uses
• Mild to moderate cases of Chloroquine resistant
& MDR P. falciparum malaria
– Atovaquone + Proguanil 3 days therapy
• Prophylaxis of malaria – Atovaquone + Proguanil
• Pneumocystis jiroveci pneumonia
• Toxoplasmosis
• Babesiosis
– Atovaquone + Azithromycin

29
 Adverse effects
–Nausea, vomiting, diarrhoea, fever, rash,
headache & insomnia
Antimicrobials
DOXYCYCLINE & CLINDAMYCIN
• Modestly active antimalarials
• Have slower antimalarial action than standard
drugs
• Doxycycline
– Effective against erythrocytic schizonts of all 4
plasmodial species
– Doxycycline + Quinine
• Used in Chloroquine resistant & MDR falciparum
malaria
• Shortens the treatment & better tolerated– Doxycycline alone can
be used for short term
prophylaxis of multidrug resistant strains
– Adverse effects – photosensitivity &
superinfection
– C/I – Pregnancy & children less than 8 yrs. of age
• Clindamycin
– Can be used with Quinine
• For the Rx of resistant falciparum malaria
• In cases where tetracyclines cannot be used
Treatment of malaria
Clinical Setting
Drug Therap
Drugs for the prophylaxis of malaria (in travellers)
• For prophylaxis in travellers – residents of non-
endemic area wish to travel endemic area of
malaria
–Drug therapy – should be started 1-2 wks
before entering the endemic area & should be
continued for at least 4 wks after leaving the
Area
Clinically malaria can be controlled by
following ways:
• True casual prophylactics – drugs that supposed
to destroy the sporozoites prior to their invasion
into the liver parenchymal cells of the human host

30
– No drug available.
• Casual prophylactics – these drugs prevent the
maturation of sporozoites to schizonts within the
infected hepatic cells.
• Eg. Proguanil (against P. falciparum only)
Pyrimethamine (against P. falciparum only)
Primaquine (against all) – 0.5mg/kg daily as long as
the pt. is in endemic area.
• Suppressive prophylaxis – drugs used to
destroy the merozoites released from the liver
so that the development of erythrocytic stage
is prevented (in persons visiting endemic area).
– Eg. Chloroquine – 300mg (base) once a week – one
week before & continue for 4 weeks after return +
in the end Primaquine 0.5mg/kg orally.).
– Mefloquine 250mg weekly orally starting a week
before & ending 4 weeks after leaving.
– Doxycycline 100mg orally daily from 2 days before
travel and till a month after return from the
endemic area.
• Suppressive cure: Extension of suppressive
prophylactic therapy for a longer period. So
that the hepatic phase of hypnozoites (P.
vivax) become extinct or exhausted.
– Chloroquine 300mg weekly is extended for 3
months after leaving the endemic area
• Radical cure: eradication of both
exoerythrocytic as well as erythrocytic stage of
malarial parasite leads to radical cure of malaria.
–Eg. Chloroquine (600+300+300+300mg), Primaquine
30mg base daily for 14 days immediately after
Chloroquine.
• Gametocidal: drugs that kill sexual erythrocytic
stage.
• Eg. Primaquine (for all species)
Quinine & Chloroquine (except for P. falciparum).
-----

31
ANTILEPROTIC DRUGS
Dr Ch.Anil
LEPROSY
• Chronic granulomatous infection caused by an
acid fast bacilli, Mycobacterium leprae related to
tubercle bacilli
• Hansen discovered M. leprae in 1873
• Progress in chemotherapy of leprosy has been
slower because,until recently, it was not possible
to culture leprosy bacillus
• It primarily affects the skin,mucous membranes
and the peripheral nerves
• More prevalent among the lowest socioeconomic
Strata
Types
Paucibacillary Leprosy –Patient has few bacilli
and is noninfectious
TT
BT
Multibacillary Leprosy –large bacillary load and
is infectious
BB
BL
LL
Paucibacillary(tuberculoid) Leprosy
• Anaesthetic patch
• 1-5 skin lesions
• No nerve/only one nerve
involvement
• Skin smear negative at all sites
• Normal Cell Mediated
Immunity(CMI)
• Lepromin test +ve
• Prolonged remissions with
periodic exacerbations
Multibacillary(Lepromatous) Leprosy
• 6 or more skin lesions
• >1 nerve involved
• Skin smear positive at
any one site

32
 • CMI - Absent
• Lepromin test –ve
• Progress to anesthesia of
distal parts,atrophy,
ulceration,absorption of
Digits
Antileprotic Drugs
• Sulfone – Dapsone
• Phenazine derivative - Clofazimine
• Antitubercular drugs – Rifampicin
Ethionamide
• Other Antibiotics: Ofloxacin
Moxifloxacin
Minocycline
Clarithromycin
Dapsone (DDS)
• Diamino diphenyl sulfone (DDS) - Simplest, oldest,
cheapest, most active and most commonly used
• Leprostatic at very low concentrations
• Chemically related to Sulfonamides
MOA: Inhibition of bacterial folic acid synthesis
• Specificity to M leprae – affinity for folate synthase
• Dapsone action is antagonized by PABA
Activity:
• Monotherapy – resistance – MDT needed
• Resistance – Primary(dapsone resistance in
untreated patient) and Secondary(resistance which develops during
monotherapy)
• Resistant bacilli - mutated folate synthase – lower
affinity for Dapsone
• Persisters – drug sensitive bacilli - dormant, hide
in some tissues
Pharmacokinetics:
• Complete oral absorption and wide distribution
(poor CSF penetration)
• 70% bound to plasma protein – concentrated in
Skin, liver, muscle and kidney
• Acetylated as well as glucuronide and sulfate
conjugated in liver
• undergoes enterohepatic circulation

33
Dapsone (DDS)
• Half life >24 Hrs
• Cumulative drug – retention in tissues &
enterohepatic circulation
ADRs: Generally well tolerated drug(100mg/day)
• Haemolytic anaemia (oxidizing property) –Pts
with G-6-PD deficiency are more susceptible
• Gastric intolerance - nausea,anorexia
• Methaemoglobinaemia, paresthesias, allergic
rashes, FDE, phototoxicity, exfoliative
dermatitis,drug fever and hepatitis etc.
Other uses
• In combination with pyrimethamamine,dapsone
can be used for chloroquine - resistant malaria
• Toxoplasmosis
• Pneumocystis jiroveci infection
Dapsone contraindications
Severe anaemia(Hb <7gm/dl)
Hypersensitivity
G-6-PD deficiency
Sulfone Syndrome
• Symptoms: Fever, malaise, lymph node
enlargement, desquamation of skin, jaundice and
anemia
• Develops 4-6 weeks after starting dapsone
treatment/after MDT
• Management:
• Stopping of Dapsone
• corticosteroid therapy
• supportive measures
Clofazimine
• Phenazine dye – Leprostatic & anti-inflammatory
MOA:
– Interference with template function of DNA
– Alteration of membrane structure and its
transport function
–Disruption of mitochondrial electron transport
chain
• Monotherapy causes resistance in 1 – 3 years
• Dapsone resistant M.leprae respond to

34
Clofazimine after 2 months lag period
• PK: orally active(40-70% absorbed).Accumulates
in macrophages & gets deposited as needle
shaped crystals in subcutaneous fat
Half life – 70 days – intermittent therapy possible
USES:
Component of MDT of leprosy
Antiinflammatory property – lepra reaction
Component of combination regimen for XDR – TB
ADRs:
• Skin: Reddish-black discolouration of skin,
discolouration of hair and body secretions
• Dryness of skin and itching, phototoxicity,
conjunctival pigmentation
• GIT: Nausea, anorexia, abdominal pain,weight
loss and enteritis with loose stools
• clofazimine crystals deposition in intestinal
submucosa – late GI symptoms
Contraindication:
• Early pregnancy
• Liver and kidney damage
Rifampicin
• Most potent Cidal drug for M.leprae
• 99.99% M.leprae killed in 3-7 days
• Clinical effects – very rapid
• Renders leprosy pts – noncontagious
• Nasal symptoms subside →2-3 wks; skin lesions
regress by 2 months
• Included in MDT
– it shortens the duration of treatment and
– Prevents development of resistance
• Once a month(600mg) orally - Non toxic & no
enzyme induction
• Multiplication time of M.tuberculosis is 18 hrs
whereas that of M.leprae is 12 days – in leprosy
once a month regime is effective
• Should not be given to pts. with hepatic or renal
dysfunction
• Should not be given with ‘erythema nodosum
leprosum’ (ENL) or ‘Reversal reaction’

35
Ethionamide:
• Significant antileprotic – poorly tolerated
• Hepatotoxicity in 10% pts
• alternative to clofazimine
Ofloxacin:
• Cidal to M.leprae
• Can be used in alternative regimens
– in case rifampin cannot be used,
– to shorten the duration of treatment
– reduce chances of drug resistance
• 400mg/day
Minocycline
• High lipophilicity - penetrates into M.leprae
• Vertigo - serious complication of its long-term use
• Being tried in alternative MDT regimens
Clarithromycin
• Only macrolide with significant activity against
M.leprae
• Less bactericidal than rifampin
• being included in alternative MDT regimens
Multidrug therapy (MDT) of leprosy
Multibacillary
Paucibacillary
ROM therapy
• WHO recommends one time dose for treating a
single lesion of paucibacillary leprosy
Rifampin 600 mg +
ofloxacin 400 mg+
minocycline 100 mg
All taken together
Intermittent RMMx
• Moxifloxacin 400 mg+ minocycline 200 mg +
rifampin 600mg – once a month
Lepra reactions
• Acute exacerbation that occurs during course of
leprosy
• Precipitated by anxiety,malaria,acute infections
and during treatment with sulfones
• Dapsone should neither be stopped nor the dose
be reduced in both types of lepra reactions

36
Lepra reactions
Type I
• Reversal reaction
• In tuberculoid
• Type IV Hypersensitivity
{Delayed hypersensitivity to M. leprae antigens}
• Existing lesion-
↑Erythema.cutaneous ulceration, multiple nerve
involvement with swollen,painful & tender
nerves
Type II
• Erythema Nodosum Leprosum
• In lepromatous
• Type III Hypersensitivity
{Jarisch Herxheimer(Arthus)}
reaction
• Abrupt onset.
Existing lesions enlarge, become red,swollen & painful.
Several new lesions appear.
Fever,iritis,neuritis,arthritis,orc
hitis,lymphadenitis
Type I
• Corticosteroids
• 40 mg/day - Prednisolone
• Tapered over 2-3 months
• Clofazimine
Type II
• Clofazimine - 200mg/day - antiinflammatory
• Severe reaction→ Prednisolone 40 mg/day is
started immediately & continued till reaction
subsides. Tapered off in 2-3 months
• Thalidomide -100-300mg/day
• Chloroquine
• Analgesics
• Antipyretics
• Antibiotics
Leprosy prophylaxis
• Avoid skin to skin contact with LL Pts with open
lesions
• BCG Vaccine

37
• Prophylactic dapsone at half the therapeutic
dose – (close contacts) children of leprotic
mothers

38
ANTIHELMINTIC DRUGS
Dr. Ch. Anil
ANTIHELMINTIC DRUGS
• Drugs used to get rid off the helminths(worms)
• May be
Vermicide – Drugs that kill worms
Vermifuge – expel infesting helminths
Choice of drug based on:
Efficacy
Lack of side effects/toxicity
Ease of administration(single dose)
Low cost
Helminths
Platyhelminths Nemathelminths
(Flat bodied worms) (Round bodied worms)
*Trematodes (Flukes) *Blood/tissue type
*Cestodes (Tapeworms) *Intestinal type
NEMATODES
• Ascaris lumbricoides ( Round worm)
• Enterobius vermicularis (Pinworm)
• Trichuris trichura (Whipworm)
• Strongyloides stercoralis (Thread worm)
• Ancylostoma duodenale & Necator americanus
(Hookworm)
• Trichinella spiralis
OTHER ROUND WORMS
• Wuchereria bancrofti (filariasis)
• Onchocerca Loa loa
• Onchocerca volvulus (onchocerciasis)
River blindness
• Brugia malayi and B. timori
• Dracunculus medinensis (Guinea worm)
CESTODES (TAPE WORMS)
• Taenia saginata (Beef tapeworm)
• Taenia solium (Pork tapeworm)
• Hymenolepis nana (Dwarf tapeworm)
• Diphyllobothrium latum (Fish tapeworm)
• Echinococcus granulosus (Dog tapeworm)
TREMATODES/FLUKES
• Schistosoma mansoni

39
 • Schistosoma hematobium(Blood fluke)
• Schistosoma Japonicum
• Paragonimus westermani(Lung fluke)
• Fasciolopsis busci(Giant intestinal fluke)
• Fasciola hepatica(Liver fluke)
• Clonorchis sinensis(Chinese Liver fluke)
CLASSIFICATION
• For Roundworm,Hookworm,Pinworm –
Albendazole,Mebendazole,Pyrantel pamoate,
Piperazine,Levamisole
• For Whipworm,Trichinella spiralis – Albendazole,
Mebendazole
• For Tapeworms – Praziquantel,Niclosamide,
Albendazole
• For Hydatid disease – Albendazole,Mebendazole
• For Threadworm – Ivermectin,Albendazole
• For Filariasis – Diethylcarbamazine,Ivermectin,
Albendazole
BENZIMIDAZOLES
(ALBENDAZOLE & MEBENDAZOLE )
MOA – Immobilizing and lethal action is rather
slow: takes 2-3 days to develop
• Binds to microtubular protein β-tubulin of
susceptible worms - inhibits its polymerization
• Intracellular microtubules in cells of worms are
gradually lost
• Blocks glucose uptake in the parasite and
depletes its glycogen stores
• Hatching of nematode eggs & their larvae are
Inhibited
MEBENDAZOLE
• Congener of thiabendazole
• Has been used for mass treatment, but need for
multiple doses is drawback
PK: Minimal oral absorption, 75-90% of oral dose is passed in the
faeces
Adverse effects:
• Nausea, diarrhoea and abdominal pain
• Allergic reactions, granulocytopenia,loss of hair
• Pregnancy – contraindicated based on animal

40
Data
Uses:
• Dose & duration of Rx same for children above
2yrs as for adults
• Preferred for multiple infestations
• Round worm,hookworm,whipworm:
100 mg twice daily for 3 days. No fasting,purging
is needed
• Trichinosis
200 mg BD for 4 days
• Hydatid disease
200 - 400 mg BD for 3-4 weeks
• Enterobius
100 mg single dose + repeat after 2-3 weeks(to
kill ova that have developed later)
Strict hygienic measures & simultaneous
treatment of all children in family or class is
advocated to cut down autoinfection & person to
person infection
ALBENDAZOLE
• Congener of Mebendazole
• Broad spectrum oral antihelmintic
Advantage: Single dose administration in many
infestations & is cost effective
• One dose treatment produced cure rates
comparable to 3 day mebendazole treatment for
round worm, hook worm and enterobius
• Trichuriasis – inferior to mebendazole
• More effective against strongyloides
• Effective for tape worms (including H. nana)
ALBENDAZOLE - Pharmacokinetics
• Significant and inconsistent oral absorption
• Fatty meals enhance absorption
(neurocysticercosis & hydatid disease)
• Fraction absorbed is converted to “sulfoxide”
metabolite – potent antihelmintic activity
• Albendazole sulfoxide – widely distributed – exert
antihelmintic activity in tissues as well
• For intesinal worms - given on empty stomach
• For cysticercosis,hydatid & cutaneous larva

41
 migrans – given with fatty meal• No preparation or postdrug
fasting/purging is
required
Uses
• Ascaris,hookworms,Enterobius,Trichuris: single
dose of 400 mg (200 mg for 1- 2 years)
• Tape worm & Strongyloidosis: 400 mg BD for 3
days
• Cutaneous larva migrans: Drug of choice - 400
mg daily for 3-5 days. Kills larvae & relieves
Symptoms
• Neurocysticercosis: treatment of choice – 400
mg BD for 8-15 days
No drug for ocular cysticercosis - blindness can
occur – reaction to dead cysticerci
• Hydatid disease: 400 mg BD for 4 weeks, repeat
after 2 weeks upto 3 courses. Treatment of
choice before and after surgery & inoperable
cases
• Filariasis: with DEC or Ivermectin – adjuvant in
lymphatic filariasis
Used in mass programmes – single dose of its
combination with either DEC or ivermectin yearly
- suppress microfilaraemia and disease
Transmission
• Trichinosis: 400 mg BD for 3 days expels the
adult worm from intestine. Larvae are not killed
but symptomatic relief occurs
Contraindicated in pregnancy – embyotoxic in
animals
Caution – hepatic & renal disease
A/E:
• Well tolerated
• Dizziness, headache, fever, alopecia,jaundice
THIABENDAZOLE
• First benzimidazole
• Roundworm, hookworm, pin worm and
Strongyloides
• Rarely used now due to toxicity
• Replaced by safer drugs like albendazole &

42
Ivermectin
PYRANTEL PAMOATE
MOA:
• Activation of nicotininic cholinergic receptors
• Persistent depolarization - slowly developing
contracture and spastic paralysis – worms are
expelled
• Anticholinesterse action also demonstrated
Uses:
• Used in Ascaris, enterobius and ancylostoma –
single dose(10 mg/kg)
• No fasting, purging or other preparation of the
patient is needed
PIPERAZINE
• Now infrequently used
MOA:
• Hyperpolarization of Ascaris muscle - GABA
agonistic action
• Opening of Cl- channel causes relaxation &
depresses responsiveness to ACh contractile
action– flaccid paralysis
• Worms are expelled alive
Uses:
Round worm infestation
Pin worm
LEVAMISOLE
• Levo isomer of Tetramisole
MOA:
• Tonic paralysis and expulsion of live worms - by
stimulating ganglia in worms
• Inhibition of fumarate reductase enzyme:
carbohydrate metabolism interfered
USES
• Ascariasis and Ancylostomiasis
• Immunomodulator – restores depressed T cell
function
• Adjunt in malignancies, Apthous ulcers, recurrent
Herpes
DIETHYL CARBAMAZINE (DEC)
• First drug for filariasis caused by the nematodes

43
Wuchereria bancrofti and Brugia malayi
• DEC – Microfilaricidal. Clears microfilaria from
peripheral blood in 7 days
• Mf in nodules & transudates (hydrocoele) - not
killed
• Rapidly absorbed from GIT
• Excretion is faster in acidic urine
• Half life of 2-3 hours in acidic urine but 8-10 hrs in
alkaline urine
MOA:
• Acts by sensitising microfilariae so that they
become susceptible to phagocytosis & are
trapped by fixed reticuloendothelial cells in liver
sinusoids
• Muscular activity of Mf & adult worms affected-
dislodged
• DEC – Slowly acting macrofilaricidal
• Prolonged treatment kills adult worms of
W. bancrofti, B.malayi
Uses:
• Filariasis: 2 mg/kg TDS for 10 - 12 days
more than 1 course with a gap of 3-4 weeks
Elephantiasis due to chronic lymphatic
obstruction not affected – fibrosis of lymphatics is
irreversible
Yearly combination DEC(6mg/kg)& albendazole
(400mg) - single dose on mass scale has brought
down transmission of filariasis
• Tropical pulmonary eosinophilia: (2-4 mg/kg TDS
for 2-3 weeks)
Benefit reflects anti - microfilarial action
ADRs:
Nausea, vomiting, anorexia, headache,
dizziness etc.
– Febrile reaction due to destruction of Mf &
adult worms – rash, pruritus, enlargement of
lymph nodes,bronchospasm,fall in BP
– Severe allergic reactions may involve eyes in
onchocerciasis – MAZZOTI REACTION
– DEC should be temporarily withheld and

44
antihistamines and/or corticosteroids are given
– Recommanded to start with a small dose(50mg)
& then increase gradually
IVERMECTIN
• Obtained from Streptomyces avermitilis
• Drug of choice for single dose treatment of
Onchocerciasis and Strongyloidosis and is
comparable to DEC for bancroftian & brugian
filaria
• Microfilaricidal but not macrofilaricidal
• Cutaneous larva migrans and ascariasis
• Moderate action – Enterobius & Trichuris
• Scabies and head lice are killed
MOA:
• Acts through special type of glutamate gated Cl
channel found in invertebrates - tonic paralysis
• Potentiation of GABAergic activity in worms
Uses:
• Onchocerciasis : Single dose of 0.15 mg/kg is
highly effective – given every 6 months
• Lymphatic Filariasis: Single 10-15 mg oral
ivermectin with 400 mg albendazole annually
• Strongyloidosis: Single dose of 0.15 - 0.2 mg/kg
• Scabies & Pediculosis: Effective as single oral dose
ADRs:
• Pruritus, giddiness, nausea, abdominal pain,
constipation,transient ECG changes
• Fever,urticaria,myalgia,edema,tender lymph
nodes – reactions due to degeneration products
of Mf
• Safety in pregnant women & young children - not
Established
DOXYCYCLINE
• Filariae acts as host to endosymbiotic Wolbachia
bacteria
• Growth,reproductin & survival of adult worms
depend on Wolbachia
• Wolbachia lipoprotein - blamed for chronic
disease by provoking inflammatory reaction
• Dying microfilariae release Wolbachia

45
• Doxycycline 200mg/day for 6 weeks – long term
sterilizing effect in bancroftian filariasis
• Macrofilaricidal in onchocerciasis
OXAMNIQUINE
• Active only against Schistosoma mansoni
• Given orally
MOA –
• flukes esterifies drug to produce reactive
metabolite alkylates DNA of flukes
• It intercalates in parasite DNA & cause death of
schistosome by blocking nucleic acid & protein
Synthesis
BITHIONOL
• DOC - Fascioliasis(sheep liver fluke)
Parogonimiasis(lung fluke)
MOA: Uncouples oxidative phosphorylation
Blocks ATP Synthesis
METRIFONATE
• Organophosphorous compound
• Effective against schistosoma haematobium
MOA: Cholinesterase inhibitor
• Potentiates depolarizing neuromuscular blockade
NICLOSAMIDE
• Against tape worms – T.saginata,T.solium,D. latum
and H.nana
MOA:
• Inhibition of oxidative phosphorylation in
mitochondria and interference of anaerobic
generation of ATP by tapeworms
• Injured worms are partly digested in intestine
• But, in cases of T. solium – visceral cysticercosis
• 2 gm OD orally in morning on empty stomach
• Tablet is to be chewed & swallowed with water
ADRs:
• Minimally absorbed from GIT
• No systemic toxicity occurs
• Abdominal discomfort, nausea,loose stools
• Safe during pregnancy
• Infrequently used now due to availability of
Praziquantel

46
PRAZIQUANTEL
• Wide range of activity against Schistosomes and
other Trematodes, cestodes but not nematodes
MOA:
• Rapidly taken up by susceptible worms
• Leakage of intracellular Ca2+ from membranes
causing contracture & paralysis of worms
• Worms lose grip on intestinal mucosa & are
expelled
• Acts against adult worms and larvae
• High conc.– vacuolization of tegument and
release of contents of tapeworms & flukes
followed by destruction by immune mech. of host
• High first pass metabolism
• Crosses BBB and attains therapeutic conc. in CSF
• Phenytoin, carbamazepine,dexamethasone induce
praziquantel metabolism – ↓Bioavailability
USES
• Tapeworms - T. solium & T.saginata - 10mg/kg
single dose
• H.nana & D.latum - 15-25mg/kg single dose
• Neurocysticercosis - 50mg/kg daily for 15-30 days
second choice to albendazole
• Schistosomes – 40 -75mg/kg
NEUROCYSTICERCOSIS
Albendazole is preferred over Praziquantel:
• Short course of treatment(8-15 days)compared to
praziquantel(15-30days)
• High cure rates(75-85% with albendazole) than
praziquantel(50-60%)
• Corticosteroids enhance absorption of
albendazole but lower levels of praziquantel
• Phenytoin & carbamazepine also lower
praziquantel levels
• Albendazole is cheaper

47
ANTIFUNGAL DRUGS
Dr. Pushpalatha C.
ANTIFUNGAL DRUGS
• Fungal infection
– Common as primary or secondary to oral antibiotic Rx
– More prone in – Pts. with Malignancy
- Diabetes mellitus pts.
- Pts. on corticosteroids
- Immunocompromised pts.
• Fungal infections are called mycoses
– Types
1. Superficial mycoses
2. Subcutaneous mycoses
3. Systemic mycoses
1. Superficial mycoses (Commonest variety)
A. Tinea or Ringworm (Dermatophytes)
Infection of – Skin
- Nails
- Hair
B. Candida species – Candidiasis
- GIT – Mouth thrush, Intestinal
candidiasis
- Vagina, vulva
- Moist areas of skin – Under
mammary glands
– More common in special subjects
1. Immunocompromised
- AIDS
- Chronic extensive burns
- On immunosuppresive agents
2. On Antibiotics (High dose) → ↓ Gut flora
2. Subcutaneous mycoses
– Subcutaneous granuloma & Chronic skin
ulcer lesions
Eg. Madura foot
3. Systemic mycoses
i. Blastomycosis
ii. Coccidiomycosis
iii. Histoplasmosis
• Fungal cell

48
– Cell wall
• Rigid & contains more polysaccharides
• No cell wall in mammalian cell
– Cell membrane contains
• Ergosterol in fungus
• Cholesterol in mammals
ANTIFUNGAL AGENTS
I. Systemic Antifungal drugs for Systemic
Infections
1. Amphotericin B
2. Flucystosine
3. Azoles (Imidazoles & Triazoles)
- Ketoconazole
- Voriconazole
- Itraconazole
- Posaconazole
- Fluconazole
- Isavuconazole
4. Echinocandins
- Caspofungin
- Micafungin
- Anidulafungin
II. Systemic Antifungal drugs for Mucocutaneous
Infections
- Griseofulvin
-Terbinafine
III. Topical Antifungal drugs
1. Azoles – Clotrimazole
- Miconazole
- Econazole
- Tioconazole
- Ketoconazole
- Terconazole & Butoconazole
2. Allylamines – Terbinafine
- Naftifine
3. Antifungal Antibiotics – Nystatin
4. Miscellaneous – Undecylenic acid
- Benzoic acid & Salicylic acid
Site of action of antifungal drugs

49
 Amphotericin B
• Antifungal antibiotic
• Obtained from Streptomyces nodosus
Chemistry
– Amphoteric polyene macrolide
– Insoluble in water
– IV preparation (Colloidal suspension)
– Liposomal Amphotericin B (New formulation)
– Lipid associated delivery system
– Less readily bind to mammalian cell – less toxic
– Effective dose with less toxicity – 3-5 mg/Kg/day
Pharmacokinetics
• Oral – Poorly absorbed in GIT
– Effective only on fungi in lumen
• IV – 0.6 mg/Kg/day
– > 90 % bound by plasma proteins
– t ½ - Approx. 15 days
• Excretion through urine – slow – over a period
of several days
• Distribution – widely distributed in tissues
• In CSF – 2-3 % of blood level
Mechanism of Action
– In fungal cell membrane – Amphotericin B binds to ergosterol →
↑ permeability by forming
amphotericin-B-associated pores → leakage of
intracellular ions & macromolecules → cell death

50
(fungicidal)
Adverse Effects
A. Immediate reactions
B. Slow reactions
• A. Immediate Reactions
– Infusion related – Fever & chills
-Headache
-Muscle spasms
-Hypotension
-Vomiting
• B. Slow Reactions (cummulative toxicity)
– Nephrotoxicity – In nearly all pts.
- Renal tubular necrosis
- Hypokalaemia
- Hypomagnesaemia
- Irreversible - if total dose is > 5 g
– LFT – Abnormal (Occassionally)
– Anaemia – Due to decreased production of
erythropoietin
– After intrathecal therapy – Seizures
– Chemical arachnoiditis
– Neurological sequelae
Antifungal Activity
• Action – Broad spectrum
- Candida albicans
- Cryptococus neoformans
- Histoplasma capsulatum
- Blastomyces dermatidis
- Coccidioides immitis
- Aspergillus fumigatus
Clinical Uses
• In life threatening mycotic infections
- Fungal pneumonia
- Cryptococcal meningitis
- Histoplasmosis
- Coccidioidomycosis
– Amphotericin B (DOC) Initial induction Rx regimen →
followed by newer Azole drugs oral admn.
• Systemic fungal diseases – Slow IV infusion 0.5-1
mg/Kg/day (total dose 1-2 g)

51
• CNS fungal infections – Intrathecal therapy
• Mycotic corneal ulcers & Keratitis – Topical drops &
Subconjunctival inj.
• Fungal arthritis – Local inj. directly into joint
• In Candiduria – Bladder irrigation
FLUCYTOSINE (5-FC)
• Water soluble antimetabolite
• Pyrimidine analog
• Spectrum – Narrower than Amphotericin B
Pharmacokinetics
• Dose (Oral) – 100-150 mg/Kg/day
• Well absorbed
• Therapeutic window – Narrow
• Protein binding - Poor
• Penetration into body fluid compartments –
Good
• t ½ - 3-4 hrs
• Elimination – By glomerular filtration
– In renal insufficiency – Peak serum conc. –
Periodically measured – Maintained between 50-
100 µg/ml
Mechanism of Action
• 5FC → Taken up by fungal cells → converted to
5-FU → 5-Fluoro deoxyuridine monophosphate
(FdUMP) → 5-FUTP → Inhibit DNA & RNA
Synthesis
• Given with Amphotericin B – Synergistic effect
– Enhanced penetration of 5-FC through Amphotericin
damaged fungal cell membrane
Adverse Effects
• Bone marrow toxicity (Most common) – due to
its metabolite 5-FU
- Anaemia
- Leukopenia
- Thrombocytopenia
• Derangement of Liver enzymes
• Toxic enterocolitis
• Nephrotoxicity (in AIDS & renal impairment)
Clinical Uses
• Spectrum restricted to

52
 - Cryptococcus neoformans
- Candida species
- Chromoblastomycosis
• Combination therapy in
– Cryptococcal meningitis
• 5-FC + Amphotericin
– Chromoblastomycosis
• 5-FC + Itraconazole
AZOLE DERIVATIVES
• Synthetic compounds
• Relatively non-toxic
• Most extensively used
• Imidazoles – Ketoconazole, Miconazole & Clotrimazole
• Triazoles – Itraconazole, Fluconazole, Voriconazole &
Posaconazole
MOA
• Inhibit fungal cytochrome P450 enzyme (14-α-sterol demethylase)
→ ↓ergosterol synthesis → cell membrane abnormalities
• Imidazoles – exhibit lesser degree of specificity than Triazoles
• Resistance to azoles – by multiple mechanisms
Clinical use
• Azoles (Broad spectrum Antifungals) – used in :
– Candidiasis
– Cryptococcus neoformans
– Blastomycosis
– Coccidiomycosis
– Histoplasmosis
– Dermatophytosis
– Aspergillosis (itraconazole & voriconazole)
– Also useful in – intrinsically Amphotericin resistant Organisms
Adverse effects
• Relatively non-toxic
• GI upset – most common
• Liver enzyme abnormalities
• Clinical hepatitis – very rare
Drug interactions
• All azoles inhibit mammalian cytochrome P450
→ prone to drug interactions
KETOCONAZOLE
• First oral azole (imidazole)

53
 • Well absorbed from gut
• Highly protein bound
• Therapeutic range – narrow
• Broad spectrum antifungal drug
• Metabolized by liver
• Less selective for fungal cytochrome P450
• Greater propensity to inhibit mammalian CYP 450
• Systemic use – less– Interferes with synthesis of adrenal &
gonadal steroid hormones → endocrine effects (gynaecomastia,
infertility & menstrual irregularities)
– Inhibits human cytochrome P450 – causes drug-drug interactions
with phenytoin, warfarin, digoxin,
sulfonylureas & cyclosporine
Adverse effects
• Gastric irritation – nausea, vomiting & anorexia
• Allergic reactions
• Gynaecomastia & Infertility in males
(antiandrogenic effect)
• Menstrual irregularities in females
• Acute hepatic necrosis
Therapeutic uses
• As a topical antifungal agent in topical infections
• In cushing’s syndrome
• Familial testotoxicosis • Prostatic cancer
ITRACONAZOLE
• Most potent available azole
• Exerts both topical & systemic activity
• Oral BA – variable
• Does not inhibit steroid synthesis – less A/E
• Penetration into CNS – poor
• Preferred in infections with
– Cryptococcus
– Candida
–Histoplasma
– Asperlgillus
• Drug interactions
– Inhibits CYP3A4
• Given with
terfenadine/astemizole/cisapride/quinidine
→ ventricular arrhythmias (fatal)

54
FLUCONAZOLE
• Safer & long acting azole
• Antifungal activity – wider than ketoconazole
• Does not inhibit steroid synthesis in humans
• High selectivity for fungal CYP450 – less drug
interactions
• Indications – Cryptococcal meningitis
- Candidiasis (systemic & mucosal)
- Coccidiodal meningitis
- Histoplasmosis
- Sporotrichosis• Oral absorption – 94% – not affected by gastric pH
• Can also be given by IV infusion & eye drops
• Therapeutic index – wide (among azoles)
• Penetration into brain & CSF – good
• Fungicidal conc. achieved in nails, vagina & saliva
Adverse effects
• Nausea, vomiting & abdominal pain
• Thrombocytopenia & alopecia
Contraindications
• Pregnancy & lactating mothers
• With cisapride
Therapeutic uses
• Candidiasis (vaginal) – 150 mg single dose orally
• Tinea infections – 150 mg weekly for 4 wks
• Cutaneous candidiasis
• Disseminated candidiasis – 200-400 mg/d for
4-6 wks or longer
• Cryptococcal meningitis
• Systemic fungal infections
• Fungal keratitis – eye drops
VORICONAZOLE
• Newer azole
ECHINOCANDINS
• Cyclic lipopeptides with a hexapeptide nucleus
• MOA
– Inhibit glucan synthase complex → Inhibit glucan
synthesis → reduce structural integrity of fungal cell
wall → result in osmotic instability and cell death
• Antifungal spectrum
– Candida & Aspergillus species

55
 • Pharmacokinetics
– PPB – 97%
– Penetration into CNS – No
– Lack of renal clearance
– Routes of admn. – IV
MOA

• Adverse effects
– Caspofungin – phlebitis at infusion site
- histamine like effect with rapid
infusion
– Micafungin – mild inhibitor of CYP3A4
• Therapeutic uses
– Deeply invasive candidiasis – for initial therapy
– Invasive aspergillosis – as salvage therapy
– Esophageal candidiasis
– Persistently febrile neutropenic pts. with suspected fungal
infections
II. SYSTEMIC ANTIFUNGAL DRUGS FOR
MUCOCUTANEOUS INFECTIONS
GRISEOFULVIN

56
• Insoluble in water
• Fungistatic – antifungal antibiotic
• Derived from – Penicillium species
MOA
• At cellular level – not clear
• Prevents fungal mitosis
• Deposits in newly forming skin → binds with
keratin → protects skin from new infection
• Administered in microcrystalline form
Use – only in dermatophytosis – systemic Rx
- dose – 1g/d
Adverse effects – Mild GI symptoms, Allergic
reactions, peripheral neuritis, vertigo & Hepatitis
Drug interactions – with warfarin & phenobarbitone
TERBINAFIN
• synthetic allylamine
• Fungicidal
• Keratophilic medication
• Route of administration – oralMOA
– Inhibits fungal enzyme squaline epoxidase
• interferes with ergosterol biosynthesis
• accummulation of sterol sqaline → toxic to fungus
– More effective in onychomycosis than other
agents
Use – dermatophytosis (onychomycosis)
Adverse effects – rare
- GI upset & headache
Drug interactions – not significant
III. TOPICAL ANTIFUNGAL DRUGS
NYSTATIN
• Polyene macrolide antibiotic(antifungal antibiotic)
MOA – similar to amphotericin B
• Routes of admn. – topical only (not absorbed
hence not toxic)
– parenteral – toxic
• Active against – Candida species
• Uses – local candidal infections
» Oropharyngeal thrush
»Vaginal candidiasis
CLOTRIMAZOLE

57
• Effective against many fungi
• For systemic fungal infections – not so useful
• Routes of admn. – Topical only
– Parenteral – more toxic
• Uses – Skin infection (dermatophytosis)
– Vaginal infection
– Oropharyngial candidiasis
• Adverse effects – at the site of application
- Local erythema
- Blistering
MICONAZOLE
• Broad spectrum antifungal drug
• Also has Antibacterial action
• Route of admn. – Topical
• Effective against
- Dermatophytes
- Madurella
- Microsporum
- Nocardia
- Cryptococcus
- Candida
- Blastomycosis
- Trichomonas
- Coccidioides
- In mixed skin infections
• Adverse effects
- Fever
- Allergic reactions
- Chills
- Anaphylaxis
- Nausea
- Local irritation
ECONAZOLE
• Similar to clotrimazole
• Penetrates superficial layers of skin
• Highly effective in
– Dermatophytosis
– Otomycosis
– Oral thrush
ALLYLAMINES – TERBENAFIN & NAFTIFINE

58
• Uses – topical admn. in – Tenia cruris Teniacarporis

59
ANTICANCER DRUGS
Dr Ch Anil
CANCER
• Cancer refers to disease of cells that show
uncontrolled proliferation, dedifferentiation
(anaplasia), invasivesness & ability to metastasize
(spread to distant parts of the body)
• Extent of metastasis & deterioration in metabolic
processes due to cancer leads to death of patient
unless eradicated by treatment
• Selectivity of anticancer drugs is very limited –
cytotoxic to cancer cells & normal cells
• The anticancer drugs either kill cancer cells or
modify their growth
CANCER TREATMENT MODALITIES
• PRIMARY CHEMOTHERAPY - refers to
chemotherapy administered as the primary
treatment in patients who present with advanced
cancer for which no alternative treatment exists
• ADJUVANT CHEMOTHERAPY – Drugs are used to
mop up any residual malignant cells (micro
metastases) after surgery or radiotherapy
• NEOADJUVANT CHEMOTHERAPY – Treatment is
given before surgery or radiotherapy to reduce
the size of primary tumour so that surgical
resection can be made easier & more effective
AIMS OF CHEMOTHERAPY
• Cure or induce prolonged ‘remission’:
Chemotherapy is the primary treatment modality
that can achieve cure or prolonged remission -
Acute Leukemia, Wilm`s tumor in children,
choriocarcinoma
• Palliation: Shrinkage of evident tumour,
alleviation of symptoms and prolongation of life -
Breast cancer, ovarian cancer, CLL, CML
• Less sensitive to drugs but life may or may not
be prolonged - Carcinoma esophagus, carcinoma
stomach, carcinoma pancreas
CELL CYCLE AND CLINICAL IMPORTANCE
• All cells—normal and neoplastic—must traverse

60
before & during cell division
• Anticancer drugs which exert their action on cells
traversing the cell cycle - cell cycle-specific (CCS)
drugs
• Cell cycle-nonspecific (CCNS) drugs - sterilize
tumor cells whether they are cycling or resting in the G0 phase

CELL CYCLE CLINICAL IMPORTANCE

• Information is relevant to mode of action,
indications, and scheduling of cell cycle-specific
(CCS) and cell cycle-nonspecific (CCNS) drugs
• CCS – Effective in cancers with large growth
fraction or those in growth phase such as
hematological malignancies
• CCNS drugs – Cancers with small growth fraction
such as solid tumours. Act against multiplying &
quiescent cells(G0)
CELL CYCLE SPECIFIC DRUGS
• S – Phase: Antimetabolites like Methotrexate, 6
Mercaptopurine, 6 –Thioguanine,Cytarabine
• M – phase: Vincristine, Vinblastine,Paclitaxel
• G1 – S Phase: Etoposide
• G2 – M Phase: Bleomycin
CELL CYCLE NONSPECIFIC DRUGS
• Alkylating agents

61
 • Antitumour antibiotics
• Platinum analogs
GENERAL TOXICITY OF CYTOTOXIC DRUGS
Bone marrow depression – limits the dose
Oral mucosa - susceptible due to high epithelial turnover –
subjected to minor trauma &
breaches(bleeding gums, Xerostomia,dental
caries)
GIT: Diarrhoea, shedding of mucosa,
haemorrhage Nausea, vomiting – CTZ direct stimulation
Gonads: Oligozoospermia & impotence in males, inhibition of
ovulation & amenorrhoea in
Females
Skin: alopecia, dermatitis
Lymphoreticular system: Lymphocytopenia and inhibition of
lymphocyte function – host
defence mechanisms are broken down–
↑susceptibility to infections
Carcinogenicity – secondary cancers like
leukemias,lymphomas
Teratogenicity and
Hyperuricemia
CLASSIFICATION
CYTOTOXIC DRUGS
ALKYLATING AGENTS
• Nitrogen Mustards
– Mechlorethamine, Melphalan, Chlorambucil,
Cyclophosphamide, Ifosfamide,Bendamustine
• Ethylenimine : Thiotepa,Altretamine
• Alkyl Sulfonate: Busulfan
• Nitrosureas
– Carmustine,Lomustine
• Triazines
–Dacarbazine, Temozolamide
• Methyl hydrazine - Procarbazine
PLATINUM COORDINATION COMPLEXES
• Cisplatin
• Oxalipaltin
• Carboplatin
ANTIMETABOLITES

62
• Folate Antagonists
– Methotrexate,Pemetrexed
• Purine Antagonists
– 6 Mercaptopurine, 6 Thioguanine,
Azathioprine, Fludarabine
• Pyrimidine antagonists
– 5 Fluorouracil, cytarabine, Capecitabine,
Gemcitabine
MICROTUBULE DAMAGING AGENTS
VINCA ALAKALOIDS: Vincristine(Oncovin)
Vinblastine
Vinorelbine
TAXANES: Paclitaxel
docetaxel
TOPOISOMERASE-1 INHIBITORS
CAMPTOTHECIN ANALOGS: Topotecan
Irinotecan
TOPOISOMERASE-2 INHIBITORS
EPIPODOPHYLLOTOXINS: Etoposide
ANTIBIOTICS
ActinomycinD (Dactinomycin) Doxorubicin
Daunorubicin Bleomycin
Mitomycin C Mitoxantrone
Epirubicin Idarubicin
BIOLOGICAL RESPONSE MODIFIERS
• Interferons,Interleukins,BCG,levamisole
MISCELLANEOUS
• Hydroxyurea
• Tretinoin
• Arsenic trioxide
• L-Asparaginase
HORMONAL DRUGS
• Glucocorticoids
Prednisolone
• Estrogens
Fosfestrol,Ethinylestradiol
• SERM
Tamoxifen, Toremifene
• SERD
Fulvestrant

63
• Aromatase inhibitors
Letrozole, Anastrozole,
Exemestane
• Antiandrogens
Flutamide, Bicalutamide
• 5-α reductase inhibitor
Finasteride, Dutasteride
• GnRH analogues
Nafarelin, Leuprorelin
Triptorelin
• Progestins
Hydroxyprogesterone
Acetate
TARGETED DRUGS
• BCR-ABL tyrosine kinase inhibitors
Imatinib, Nilotinib ,Dasatinib
• EGF(HER) receptor inhibitors
Gefitinib, Erlotinib,Cetuximab,
Trastuzumab,Lapatinib
• Angiogenesis Inhibitors
Bevacizumab, Sunitinib, sorafenib
• Proteasome inhibitor
Bortezomib
• CD20 inhibitor - Rituximab
ALKYLATING AGENTS
- MECHANISM OF ACTION
• Produce highly reactive carbonium ion
intermediates
• Transfer alkyl groups to cellular macromolecules
by forming covalent bonds
• Alkylation results in Cross linkage/Abnormal base
pairing/ DNA strand scission
• React with nucleic acid bases & inhibit DNA
synthesis
• Cross link DNA strands - Interfere with cell
Replication
• Alkylating agents have cytotoxic and
radiomimetic (like ionizing radiation) actions
• Cell cycle non-specific(CCNS)
MECHLORETHAMINE (Mustine Hcl)

64
• First nitrogen mustard
• Highly reactive & local vesicant
• Very toxic drug
• No longer used – due to marked acute effects
• Hodgkin’s (MOPP regimen) & NHL
• Occasionally used by topical application on
cutaneous T cell lymphoma
CYCLOPHOSPHAMIDE
• Pro-drug and converted to active metabolites
(aldophosphomide,phosphoramide mustard) in
liver
• Prominent immunosuppresant property
• Wide range of antitumour actions
• Popular alkylating agent for solid tumours
• Not a local irritant
• Less damaging to platelets
• Given orally as well as parenterally
• Alopecia & hemorrhagic Cystitis(due to another
metabolite acrolein)are prominent
• Mesna, SH compound is simultaneously given
with it
• Binds & inactivates vasicotoxic metabolites of
cyclophosphamide –prevent hemorrhagic cystitis
• Advised plenty of fluids
USES:
• Chronic lymphatic leukemia
• Lymphoma
• Solid tumours
IFOSFAMIDE
• Congener of cyclophosphamide
• Longer & dose - dependent t1/2
• Less alopecia and less emetogenic than
cyclophosphamide
Uses:
Bronchogenic,breast,testicular,bladder,head &
neck carcinomas
• Dose limiting toxicity - hemorrhagic cystitis
• MESNA( SH group) is mostly given with it
MELPHALAN
• Very effective in MULTIPLE MYELOMA

65
• Used in advanced ovarian cancer
• Orally effective
• A/E: Bone marrow Depression
CHLORAMBUCIL
• Orally effective, very slow acting alkylating agent
• Active on lymphoid tissue,spares myeloid tissue
• Drug of choice for long term maintenance
therapy of CLL (chronic lymphatic leukemia)
• Non Hodgkin’s Lymphoma
Thio-TEPA
• Ethylenimine
• Seldom used in bladder & ovarian cancer – high
toxicity
BUSULFAN
• Highly specific for myeloid elements
• Granulocyte precursors – most sensitive
• Little effect on lymphoid tissue and g.i.t
• 2nd choice drug to imatinib – Chronic phase of
myelocytic leukemia
A/E: Pulmonary fibrosis, Skin pigmentation
NITROSUREAS
• Highly lipid soluble, Cross BBB
Uses: Meningeal leukemias / Brain cancer
ALTRETAMINE
• Alkylates DNA & proteins
• Recurrent ovarian carcinoma – palliative
treatment
TRIAZINES
Dacarbazine
• Acts by methylating DNA and interfering
with its function
Uses: Malignant melanoma,Hodgkin’s Lymphoma
Temozolamide
• Orally acting methylating agent
• Glioma,malignant brain tumours, melanoma
METHYLHYDRAZINE
Procarbazine :
• Methylate & depolymerize DNA
• Inhibit nucleic acid synthesis
• combination regimen for Hodgkin’s,brain tumours

66
 • MAO inhibitor & disulfiram like reaction - alcohol
CISPLATIN
• Platinum coordination complex – given i.v
• Hydrolysed intracellularly to produce highly
reactive moiety - cross linking of DNA
• Inhibit DNA biosynthesis & kills cells at any stage
of cell cycle
• Effects resemble those of alkylating agents &
radiation
• Highly emetic – Prophylactic antiemetics are
given
• Renal toxicity – reduced by normal saline i.v
• Uses
– Metastatic testicular & Ovarian carcinoma
– Solid tumors: lung,bladder,esophagus, stomach
• Adverse effects
– Marked nausea,vomiting
–Dose dependent renal impairment
– sensory neuropathy
– Tinnitus,deafness
CARBOPLATIN
• Better tolerated,2nd gen platinum compound
• Nephrotoxicity , ototoxicity , neurotoxicity – low
• Nausea & vomiting – mild and delayed
Uses:
• Ovarian carcinoma of epithelial origin
• Squamous cell carcinoma of head and neck
OXALIPALTIN
• 3rd generation
Uses: Colorectal cancer
gastroesophageal & pancreatic cancer
ANTIMETABOLITES
• Chemical agent which,by virtue of its close structural
similarity to the metabolite,blocks its actions
• It competitively inhibit utilisation of normal substrate or gets
incorporated forming dysfunctional macromolecules
METHOTREXATE
• Folic acid analogue
• Acts by inhibiting dihydrofolate reductase (DHFRase)
– blocks conversion of dihydrofolic acid (DHFA) to

67
tetrahydrofolic acid (THFA)
• THFA is an essential coenzyme for one carbon
transfer reactions in de novo purine synthesis &
amino acid interconversions
• Cell cycle specific action – S phase
• Inhibits thymidylate synthase – DNA synthesis is
primarily affected
• Synthesis of RNA & Proteins also suffer
• Mtx utilises folate carrier to enter into cells &
transformed to active polyglutamate by FPGS
• Toxicity of methotrexate cannot be overcome by
folic acid as its conversion to THF is blocked
• Since THF is too unstable ,Folinic acid (N5 formyl
THF,Citrovorum factor) is used as Calcium
leucovorin or Calcium folinate which bypasses
the inhibited DHFR
• Leucovorin is used in conjunction with
high dose methotrexate therapy to rescue
normal cells from undue toxicity
(Leucovorin rescue)

PHARMACOLOGICAL ACTIONS
Cytotoxic actions

68
• Predominant on bone marrow
• Inhibit erythropoiesis,myelopoiesis-
granulocytopenia,reticulocytopenia,lymphopenia
• Ulceration of oral & intestinal mucosa
• Crosses placenta interferes with embroyogenesis -
foetal malformations and death
Immunosupressive action - B&T Lymphocytes
Anti-Inflammatory action
• Interferes with release of inflammatory cytokines
IL-2, IL-6,IL-8 & TNF-
USES OF METHOTREXATE
• Choriocarcinoma (curative)
• Induction & Maintenance of remission of Acute
lymphatic leukemia in children
• Soft tissue sarcoma,breast cancer,AML,NHL
• Bladder,head & neck cancers
• Immuno - supressive agent
– Rheumatoid arthritis
– Crohn’s disease
– Transplant rejection
– Psoriasis
• Medical termination of pregnancyA/E:
• Megaloblastic anemia
• Thrombocytopenia,leucopenia
• Mucositis
• Diarrhoea
• Alopecia
• Liver damage
• Nausea & vomiting
• Desquamation & bleeding in GIT
PEMETREXED
• Congener of methotrexate
• Inhibits thymidylate synthase
• Hand – foot syndrome - itching erythematous
rash ( Rx Dexamethasone)
• Folic acid & vit B12 to limit myelosuppression
USES:
• With cispaltin for Mesoepithelioma,Non small cell lung carcinoma
PURINE ANTAGONISTS
• After conversion to monoribonucleotides,they

69
inhibit conversion of inosine monophosphate to
adenine & guanine nucleotides that are building
blocks for DNA & RNA
• Inhibit denovo purine synthesis
• Incorporated into DNA & RNA –dysfunctional
6 - MERCAPTOPURINE
• 6-MP is oxidised by xanthine oxidase – dose has
to be reduced to 1/4 - ½ if allopurinol is given
Concurrently
• Methylation by thiopurine methyl transferase
(TPMT) – additional pathway of metabolism
• Genetic deficiency of TPMT –Toxicity
• Overexpression of TPMT – resistance
Uses:
– Childhood acute leukemia
– Choriocarcinoma
Adverse Effects:
– BM depression
– Reversible jaundice
–Hyperuricaemia - reduced by allopurinol
FLUDARABINE
• Phosphorylated intracellularly to form active
triphosphate derivative - Inhibits DNA polymerase
& ribonucleotide reductase
• Interferes with DNA repair - form dysfunctional
DNA
• Effective in slow growing neoplasms: (Tumour cell apoptosis)
Uses:
– CLL and Non Hodgkin’s recurring after
Treatment
PYRIMIDINE ANTAGONISTS
5-FLUOROURACIL
• Converted to nucleotide 5-fluoro-2-deoxyuridine
monophosphate (FdUMP)
• Irreversibly inhibits thymidylate synthase –
conversion of deoxyuridilic acid to
deoxythymidylic acid is blocked
• Selective failure of DNA synthesis
Uses:
• Solid malignancies – colon,rectum,stomach,

70
pancreas,liver,urinary baldder
• 1% topical solution – superficial basal cell
carcinoma & actinic keratosis
CYTOSINE ARABINOSIDE
• Pyrimidine analog – Used for inducing remission
in AML ,ALL,Blast crisis in CML,NHL
• Triphosphate of cytarabine inhibits DNA
polymerase - inhibit DNA synthesis
• Incorporation into DNA – Cytotoxicity
GEMCITABINE
• Analogue of deoxycytidine
• Used in metastatic carcinoma of pancreas
• Non small cell lung cancer
CAPECITABINE
• Prodrug
• hydrolysed to 5 –FU by thymidine phosphorylase,
expressed in breast & colorectal cancer cells
• Useful in metastatic colorectal cancer in
combination with oxaliplatin
• 2nd line treatment for metastatic breast cancer
with docetaxel
VINCA ALKALOIDS
• Obtained from periwinkle plant ( Vinca Rosea)
• Vincristine, vinblastine,vindesine - alkaloids
• Vinorelbine - semisynthetic
MECHANISM OF ACTION
• Mitotic inhibitors – bind to microtubular protein
“tubulin”, prevent its polymerisation & assembly
of microtubules – anti-mitotic spindle poison
• Disrupt the mitotic spindle & interfere with
cytoskeletal function
• Cell cycle specific – M Phase
• Metaphasic arrest
VINCRISTINE (ONCOVIN)
• Used for inducing remission in childhood acute
lymphoblastic leukemia
Other uses:
• Acute Myeloid Leukemia
• Hodgkin’s lymphoma
• Wilm’s tumour

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• Ewing’s sarcoma
A/E:Peripheral neuropathy,alopecia,ataxia,
nerve palsies,SIADH
• Bone marrow depression - minimal
VINBLASTINE
Uses:
Hodgkin’s disease,kaposi sarcoma, neuroblastoma,
NHL,breast & testicular carcinoma
• BM depression – prominent
• Neurotoxicity & alopecia – less
VINORELBINE
• Non small cell lung cancer
• 2nd line drug - advanced breast & ovarian
Carcinoma
TAXANES
• PACLITAXEL – Obtained from bark of western
yew tree (Taxus brevifolia)
MECHANISM OF ACTION
• Binds to β – tubulin & enhances its
polymerisation to form excess of microtubules -
opposite to that of vinca alkaloids
• Microtubules are stabilized & their
depolymerisation is prevented
Uses:
• Metastatic ovaraian & breast carcinoma
• Advanced head & neck cancer• Small cell lung cancer
Adverse effects:
• Anaphylactoid reaction due to solvent cremophor
• Reversible Myelosupression
• Stocking & glove neuropathy
DOCETAXEL
• Potent congener & long t1/2
Uses:
• refractory breast & ovarian cancer
ESTRAMUSTINE
• Complex of Estradiol with nitrogen mustard,
Normustine
• No alkylating property
• Binds to β tubulin - antimitiotic action
USE:

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• Advanced or metastatic prostate cancer not
responsive to hormone therapy
EPIPODOPHYLLOTOXINS
ETOPOSIDE:
• Semisynthetic derivative of podophyllotoxin
obtained from podophyllum peltatum
• Inhibit topoisomerase 2
• subsequent resealing of DNA strand is prevented
• cause DNA breaks – DNA damage
Uses:
• Testicular tumors
• lung cancer
• Hodgkin’s & other lymphomas
• Carcinoma bladder & stomach
CAMPTOTHECIN ANALOGUES
• Inhibit Topoisomerase I:Inhibit DNA replication
TOPOTECAN:
• Used in metastatic carcinoma of ovary,SCLC
• With cisplatin for cervical cancer
• Major toxicity is myelosuppression - neutropenia
IRINOTECAN:
• Use: metastatic/advanced colorectal carcinoma
• Inhibit AchE – Cholinergic effects - suppressed by
prior atropinization
• Toxicity: Diarrhoea
ANTITUMOUR ANTIBIOTICS
• Have prominent antitumour activity
• Cell cycle non specific drugs
• Derived from streptomyces species
MOA:
• Intercalation between DNA strands and interfere
with template function - Inhibit DNA & RNA
synthesis
• Alters topoisomerase - 2 function
• generation of semiquinone free radicals and
oxygen free radicals
Actinomycin D(DACTINOMYCIN)
Uses:
• Wilms tumor
• Childhood rhabdomyosarcoma

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• Mtx resistant choriocarcinoma
Adverse effects :
• Vomiting,stomatitis,diarrhoea
• Erythema,desquamation of skin
• BM depression
DOXORUBICIN & DAUNORUBICIN
• Anthracycline antibiotics
• Cause breaks in DNA strands by interfering with
topoisomerase 2
• Also generate quinone type free radicals
Doxorubicin:
• Used in solid tumours - breast,thyroid,ovary,
bladder,lung cancers,neuroblastoma
Daunorubicin:
• Use: Acute leukemia in children and AML in adults
Toxicity:
• Both cause cardiotoxicity (Acute - ECG changes,
arrhythmias & hypotension;Delayed – CHF due to
cardiomyopathy)
Treatment: Dexrazoxane - iron chelating agent
• Marrow depression, Alopecia
• Radiation recall reaction - Erythema &
desquamation of skin observed at sites of prior
radiation therapy
EPIRUBICIN – Breast & Gastroesophageal cancer
IDARUBICIN – With cytarabine in AML
Mitoxantrone
• Lower cardiotoxicity
• Uses: AML
advanced hormone refractory prostate cancer
Mitomycin C
• Highly toxic now used only in anal cancer
Combined with 5-FU,cispaltin & radiation
• Intravesical - superficial bladder tumours
• Transformed to a form which acts as alkylating
agent & crosslinks DNA
• Free radical DNA damage
BLEOMYCIN
• Glycopeptide antibiotics
• Chelates copper or iron,produce superoxide ions

74
and intercalates between DNA strands
• Cause chain scission & inhibits repair
• G2 phase of cell cycle
• Minimal myelosuppression
• Can be given by i.v,i.m or s.c
Uses :
• Testicular tumor - with cispaltin + vinblastine
• Squamous cell carcinoma of skin,oral cavity
• Hodgkin’s lymphoma
ADVERSE EFFECTS:
• Pulmonary fibrosis
• Mucocutaneous toxicity
• Anaphylaxis
L-ASPARAGINASE
• Prepared from E.coli
• Leukaemia cells - deficient in L-asparagine
synthase & depend on L-asparagine from medium
• L-Asparaginase degrades L-Asparagine to L-
Asparatic acid depriving leukemic cells of an
essential metabolite & cause cell death
Uses: Induction of remission in ALL
A/E:
• Liver damage
• Allergic reactions
• Hyperglycemia,↑ triglyceride levels
HYDROXYUREA
• Blocks the conversion of ribonucleotides to
deoxyribonucleotides by inhibiting the enzyme
ribonucleoside diphosphate reductase
• Interfere with DNA synthesis
• Exerts S - phase action
Uses:
• Chronic myeloid leukemia
• Psoriasis
• Polycythaemia vera
• Sickle cell disease
TRETINOIN:
• All trans retinoic acid,form of vit A acid
• Acts as differentiating agent
• Used with daunorubicin or doxorubicin for Acute

75
 Promyelocytic leukemia
ARSENIC TRIOXIDE:
• Acts by enhancing reactive oxygen free radicals in Acute
promyelocytic leukemia
Bortezomib
• Boron containing compound - covalently binds to
proteasome and inhibits its proteolytic activity
• By inhibiting proteasome,bortezomib prevents
the breakup and degradation of IκB, so that NFκB
is not released to transcript survival molecules
Uses:
• Multiple myeloma
• Also for refractory mantle cell lymphoma
Radio active isotopes
RADIOIODINE(sodium I131 )
• Emits beta radiation
• acinar destruction
Use:
• Follicular Carcinoma Thyroid - given orally
RADIOPHOSPHOROUS(P32 )
• Beta emitting isotope
• given orally or i.v.
Use :
• Polycythaemia vera
BCR-ABL TYROSINE KINASE INHIBITORS
IMATINIB
• Inhibits specific tyrosine kinase labelled as BCR-
ABL tyrosine kinase and blocks the
phosphorylation of effector proteins
• CML - characterized by t(9:22) Philadelphia
chromosome translocation
• First line therapy for chronic phase Chronic
myeloid leukemia
• Also effective in Gastrointestinal stromal
tumours(GIST) expressing c-kit tyrosine kinase
• Metabolised by CYP3A4
Dasatinib
• Multiple tyrosine kinase inhibitor
• Uses: Philadelphia chromosome positive CML
Nilotinib

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• Tyrosine kinase inhibitor
• Uses: CML cases resistant to imatinib
Angiogenesis inhibitors
Bevacizumab
• Humanized monoclonal antibody that binds
VEGF-A & hinders its access to VEGF receptor
• Inhibits angiogenesis
• With 5-FU used for metastatic colorectal cancer
• Metastatic NSCLC, breast cancer
• Given i.v
Sorafenib & Sunitinib
• Oral multiple tyrosine kinase inhibitors
• Targets VEGFR & PDGFR
• Use: Renal cell carcinoma
EGF RECEPTOR INHIBITORS
Gefitinib
• Inhibit EGFR tyrosine kinase.
• Use: Non-small cell lung cancer
Erlotinib: NSCLC
• Erlotinib with Gemcitabine -
advanced/metastatic pancreatic cancer
Cetuximab:
• Chimeric monoclonal antibody against EGFR
• Metastatic squamous cell ca of head & neck
• EGF receptor +ve metastatic colorectal cancer
Lapatinib
• Oral inhibitor of HER-2 & EGFR-1
• Uses: Metastatic breast cancer
Monoclonal antibodies
• Trastuzumab : Breast cancer (against HER2)
• Rituximab : Non Hodgkin’s Lymphoma, CLL (CD-20)
• Panitumumab : Metastatic colorectal cancer (EGFR)
• Alemtuzumab : CLL(CD52)
• Iodine tositumomab : Non Hodgkin’s lymphoma
HORMONAL AGENTS
Glucocorticoids
• Direct lympholytic effect - ALL in children,
malignant lymphoma
• Effectively counter hemolytic and haemorrhagic
complications(due to thrombocytopenia) in

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Chronic lymphocytic & myeloid leukemias
• Cerebral oedema due to intracranial metastasis
• Control hypercalcemia following chemotherapy
• Dexamethasone – adjunctive antiemetic
AROMATASE INHIBITORS
• Aromatase enzyme is responsible for the
conversion of adrenal androgens and gonadal
androstenedione and testosterone to the
estrogens, estrone (E1) and estradiol (E2),
respectively
• Anastrazole, Letrozole- Non steroidal,reversible
aromatase inhibitor
• Use: ER - positive breast cancer in
postmenopausal women
Exemestane - Steroidal,irreversible aromatase
inhibitor
• Breast cancer
ESTROGENS
• Provide symptomatic relief in carcinoma
prostate which is an androgen dependent
tumour
• Diethylstilbesterol is used
• Superseded by GnRH agonists used with an
Antiandrogen
SELECTIVE ESTROGEN RECEPTOR
MODULATORS (SERMS)
Tamoxifen :
Estrogen antagonistic:
Breast carcinoma cells and blood vessels
Estrogen agonistic:
Uterus, bone, liver, pituitary
• Inhibition of human breast cancer cells –
antiestrogenic action
• Established hormonal treatment of breast cancer
in both pre & post menopausal women
SELECTIVE ESTROGEN RECEPTOR DOWN REGULATOR
(FULVESTRANT)
• Pure estrogen antagonist
• USES: Metastatic ER+ Breast Ca in
postmenopausal women which has stopped

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responding to tamoxifen
MOA:
• Inhibits ER dimerization & prevents interaction of
ER with DNA - receptor degradation - enhanced
• ER is down regulated - more complete
suppression of ER responsive gene function
ANTI ANDROGENS
FLUTAMIDE & BICALUTAMIDE :
• Antagonise androgen action on prostate
carcinoma & have palliative effect in
advance/metastatic cases
• Used in conjunction with GnRH agonists(to
suppress LH & testosterone secretion) to produce
full therapeutic effect
5-REDUCTASE INHIBITORS
FINASTERIDE:
• Competetive inhibitor of 5-reductase enzyme
• Inhibits conversion of testosterone to more
active DHT
• ↓Prostatic size &↑peak urinary flow rate in
symptomatic BPH
• Palliative effect in advanced carcinoma prostate
GnRH agonists:
• ↓FSH & LH release from pituitary - indirectly ↓
the secretion of estrogen & androgen
• Palliative effect in advanced estrogen/androgen
dependent carcinoma breast & prostate
PROGESTINS:
• Temporary remission in some advanced or
recurrent & metastatic endometrial Carcinoma
• Palliative treatment of metastatic breast cancer
DRUGS USED TO PREVENT TOXICITY OF
ANTICANCER DRUGS
• MESNA - Hemorrhagic cystitis
• LEUCOVORIN - Rescue after high dose methotrexate
• AMIFOSTINE – Radiotherapy related xerostomia,
prophylaxis of cisplatin nephrotoxicity
• DEXRAZOXANE - Cardiotoxicity due to anthracyclines
• BISPHOSPHONATES - Hypercalcemia of malignancy
• FILGRASTIM - Neutropenia

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 • ONDANSETRON – Cytotoxic drug induced vomiting Addition of
Dexamethasone/Lorazepam or Aprepitant further enhances protection
against vomiting

80
Antiamoebic & other Antiprotozoal Drugs
Dr. K.Govardhan Reddy
• Amoebiasis is a protozoal infection caused by
‘Entamoeba histolytica’
• Transmitted through faeco-oral route
• Exists in two forms
Trophozoites - present in the intestinal lumen &
in infected tissues
Cysts - develop from the trophozoites within
intestinal lumen
• Extraintestinal amoebiasis is secondary to
intestinal amoebiasis
• In tissues only trophozoites are present not the
Cysts

Classification
I. Tissue amoebicides
1. Intestinal & extraintestinal amoebicides
a. Nitroimidazoles:
Metronidazole Secnidazole
Tinidazole Ornidazole
b. Alkaloids:
Emetine Dehydroemetine
2. Extraintestinal amoebicides
Chloroquine
II. Luminal amoebicides

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(used only in intestinal amoebiasis)
a. Amides:
Diloxanide furoate Nitazoxanide
b. 8-hydroxyquinolines:
Quiniodochlor (Iodochlorohydroxyquin)
Diidohydroxyquin (iodoquinol)
c. Antibiotics:
Tetracyclines Paromomycin
Metronidazole:
• It is a nitroimidazole derivative
• It is the drug of choice in most forms of
amoebiasis except in asymptomatic cyst passers
It is:
• A potent amoebicide
• Effective in both intestinal & extraintestinal
amoebiasis
• Less toxic & cost effective
• Highly effective against
anaerobic protozoa - Entamoeba, Giardia,
Trichomonas & Balantidium coli
anaerobic, G +ve & G -ve bacilli - Peptococcus,
Bacteriodes, Clostridium difficile & H.pylori
Mechanism of action:
• After entering the cell by diffusion, the nitro
group of metronidazole (prodrug) is activated by
reduction by the susceptible organism
• Anaerobic protozoa contain an enzyme,
pyruvate-ferredoxin oxido-reductase (PFOR)
- Which donate electron to nitro group in
metronidazole
↓↓
Reduced 5’ nitro group of metronidazole is active
↓
It is cytotoxic to anaerobic protozoa & bacteria
↓
disrupts replication, transcription & repair process
of DNA
↓
Cell death
Pharmacokinetics:

82
• Completely (80%) absorbed from the small
intestine
- therefore ineffective in the asymptomatic cyst
passers & in chronic intestinal amoebiasis
• Widely distributed in the body
- therapeutic conc. in vaginal, seminal fluids,
saliva & CSF
• Metabolized in liver & excreted through urine
• Plasma t1/2 - 8hrs
• It is available for oral, I.V & topical administration
Uses:
1. Amoebiasis:
• Drug of choice for the both intestinal &
extraintestinal amoebiasis
• It kills trophozoites but not the cysts
• Recommended dose regimen:
Intestinal amoebiasis – 400mg TID for 7 days
Amoebic dysentery & liver abscess – 800mg TID
for 7 -10 days
2. Giardiasis - 400mg TID for 7 days
3. Trichomonas vaginitis – 2 g single dose
4. Anaerobic bacterial infections
- occur after colorectal or pelvic surgery,
appendicectomy
- metronidazole + gentamicin or cephalosporins
(because many are mixed infections)
5. Prophylactic use – in colorectal or biliary surgery
6. Pseudomembranous enterocolitis
- caused by cl. difficile associated with use of
antibiotics
- metronidazole 400-800 mg BD/TID for 10-14
days (less toxic than vancomycin)
7. Acute necrotizing ulcerative gingivitis
(ANUG)/trench mouth
- caused by mixed flora of fusobacteria,
spirochetes & bacteriods
- Metronidazole + tetracycline
8. H. Pylori infection –
- metronidazole + omeprazole + clarithromycin
9. Bacterial diarrhoea – metronidazole + FQs

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 10. Guinea worm infestation
Adverse effects:
• Anorexia, nausea, metallic taste & abdominal
cramps
• Less frequently – vertigo, dizziness, headache,
glossitis, dryness of mouth
• Rashes, urticaria, flushing, ataxia & fixed drug
eruption occur in allergic subjects
• Thrombophlebitis
• Prolonged use – peripheral neuropathy & CNS
Effects
C/I:
• In neurological disease, blood dyscrasias
• First trimester of pregnancy (its mutagenic
potential, no teratogenic)
• Cautious use in chronic alcoholics
Drug interactions:
• It potentiates the anticoagulant effect of warfarin & lithium
toxicity
- by decreasing its renal elimination
• Disulfiram (Antabuse) like reaction, if taken with
alcohol
- metronidazole inhibits aldehyde dehydrogenase
Tinidazole:
• Similar to metronidazole, except –
- slower metbolism
- longer duration of action, t1/2 – 12hrs
- better tolerated than metronidazole, incidence
of nausea, metallic taste is less
Uses:
• Amoebiasis
• Trichomoniasis & giardiasis
• Anaerobic infections - used for prophylaxis of
colorectal surgery
• H. pylori infection
Secnidazole:
• Uses, potency, side effects similar to
metronidazole except -
- longer t1/2 > 20hrs
- post antiprotozoal effects

84
Ornidazole:
• Uses, side effects similar to tinidazole
• Slowly metabolized
• t1/2 - 12 hrs
Satranidazole:
• More potent
• longer t1/2 - 14hrs
Advantages:
- minimal nausea & metallic taste
- Absence of neurological & disulfiram like
Reactions
Emetine & dehydroemetine:
• Alkaloid - from Cephalis ipecacuanha
• Act by
- inhibiting protein synthesis in trophozoites,
which arrest their multiplication & leads to their
phagocytosis
- little effect on the cystic forms
• Given by deep S.C, I.M; because of bitter taste
• As it slowly eliminated in urine, repeated injection
can cause cumulation
• Rarely used where metronidazole cannot be
used; because of cardiotoxicity & GI disturbances
• Dehydroemetine is less toxic & preferred over
emetine
Uses:
• As a tissue amoebicide
• For the treatment of lung fluke & fasciola
hepatica
• Ipecacuanha as an emetic
Chloroquine:
• It is highly concentrated in liver & kills
trophozoites
• Very effective in hepatic abscess, amoeboma &
extraintestinal amoebiasis
• Dose:
- 500 mg BD for 2 days f/by 500mg OD for 21
days
- f/by luminal amoebicide
Diloxanide furoate:

85
 • It is highly effective luminal amoebicide
• It directly kills trophozoites responsible for
production of cysts
• Not effective against tissue trophozoites
• It is hydrolysed in the gut to diloxanide + furoic
acid
- 80-90% of diloxanide gets absorbed systemically,
but has no systemic antiamoebic action, so not
useful in amoebic dysentery
• Unabsorbed diloxanide produce effect• It is given with tissue
amoebicide for complete
eradication in intestinal & extraintestinal
amoebiasis
• Well tolerated, less side effects, flatulence is
common
Nitazoxanide:
• It is a prodrug, converted to tizoxanide, inhibitor
of PFOR enzyme
• Active against metronidazole resistant Giardia
• Also used in Cryptosporidiasis, amoebic
dysentery & T. vaginalis infection
Iodoquinol:
• It kill the cyst forming trophozoites only
• Used in intestinal amoebiasis as alternative to
diloxanide furoate
• Also used in giardiasis, trichomonal vaginitis &
fungal skin infections
• Side effects – nausea, diarrhoea, constipation,
anal pruritis
• Prolonged use – goitre, iodism
• High doses – subacute myelo optic neuropathy
(SMON)
Tetracycline & paromomycin:
• Alternative drugs in intestinal amoebiasis with
luminal amoebicide
• They inhibit the bacterial flora, which is required
for growth of entamoeba
• Tetracyclines have modest direct inhibitory
action on entamoeba
• Paromomycin is active against

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- Entamoeba, Giairdia, Cryptosporodium,
Trichomonas, Leishmania & some tape worms
Chemotherapy for Giardiasis
• Characterized by watery diarrhoea &
malabsorption
Drugs:
• Metronidazole, tinidazole, secnidazole
• Nitazoxanide, Quiniodochlor
• Furazolidone:
- nitrofuron derivative
- active against giardia, trichomonas, salmonella
& shigella
- Alternative for diarrhoea due to food poisoning
& bacillary dysentery
Chemotherapy for Trichomoniasis
• Characterized by vulvovaginitis with frothy pale
discharge
• Male & female partners are treated
simultaneously
Drugs:
• Orally -
- Metronidazole, tinidazole, secnidazole
• Intravaginally -
- quiniodochlor, iodoquinol, povidone-iodine
Chemotherapy of Leishmaniasis
• Visceral leishmaniasis (kala azar) – L. donovani
• Cutaneous leishmaniasis – L.tropica
• Mucocutaneous leishmaniasis – L.braziliensis
Drugs:
Sodium stibogluconate:
• Acts by a specific enzyme present in leishmania
amastigotes, reduces pentavalent-Sb of SSG to
the toxic trivalent form – oxidative damage
• First choice – visceral & cutaneous L.
• I.V or I.M
Miltefosine:
• First orally effective for visceral & cutaneous L.
• It inhibits key enzymes involved in the
metabolism of surface glycolipids in leishmania
Alternative drugs :

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Pentamidine, Amphotericin-B
Chemotherapy of Trypanosomiasis
1. African trypanosomiasis (sleeping sickness) - T.
brucei
• Illness passes through two stages:
Haemolymphatic - suramin, pentamidine
Meningo encephalopathic - melarsoprol
- Eflornithine is effective for both
Suramin:
• Drug-protein complex enter the trypanosome
- drug is liberated – exert toxic effects
Pentamidine:
• It binds to protozoal DNA & inhibits DNA
replication
• Also effective against P. carnii & L. donovani
2. American trypanosomiasis (chagas disease) -
T. cruzi
Nifurtimox & Benznidazole:
• It undergoes reduction to nitroamine radical &
eventually generates free radicals & are toxic

88
 ANDROGENS,ANTIANDROGENS &
ANABOLIC STEROIDS
Dr. Ch.Anil
ANDROGENS
• Substances which cause development of
secondary sex characters in castrated male
• Includes all natural & synthetic steroidal drugs
having musculinising properties
• Testosterone – isolated as testicular hormone –
synthetically prepared by 1935
CLASSIFICATION
Natural Androgens:
• From Testes: Testosterone (5-12 mg daily)
• Part of which is converted in extraglandular
tissues to more active Dihydrotestosterone by
enzyme 5 – α reductase• Adrenal cortex produces small quantities
of
dehydroepiandrosterone and androstenedione
(weak androgens)
• Females - testosterone: 0.25 – 0.5 mg/day
(ovary+ adrenals)
• Androsterone – metabolite of testosterone with
1/10 activity of testosterone
Synthetic androgens:
- Methyltestosterone
- Fluoxymesterone
- Testosterone undecanoate
- Mesterolone
TESTOSTERONE
• Testosterone is secreted by interstitial cells of
testis (Leydig) under the influence of LH from
pituitary
• FSH – Spermatogenesis in tubular (sertoli) cells
• Reduced by 5 α-reductase to the more potent,
Dihydrotestosterone (DHT), which is responsible
for many of the differentiative,growth promoting,
secondary male sexual characteristics
• Also converted to estradiol by aromatase enzyme
in extraglandular tissue (liver,adipose tissue)
REGULATION OF SECRETION

89
90
TESTOSTERONE – ACTIONS
Sex organs and secondary sexual characters:
• Growth of genitals – penis,scrotum,seminal
vesicles,prostate
• Growth of hair – pubic,axillary,beard,moustache
• Thickening of skin – greasy due to proliferation &
↑activity of sebaceous glands – face
• Larynx grows & voice deepens
• ↑physical vigour,aggressiveness,penile erections
• Intrauterine development – male phenotype
Anabolic actions:
• Pubertal spurt of growth in boys
• Rapid bone growth(thickness & length)
• Promotes muscle building if aided by exercise
• ↑protein synthesis &↓ protein breakdown
• Sodium & water retention
Erythropoiesis:

91
• accelerates erythropoiesis by increasing
erythropoietin production & haeme synthesis
MECHANISM OF ACTION
• Testosterone or DHT – bind to cytoplasmic
androgen receptor (AR) and the complex
combines with androgen responsive elements of
target genes
• DNA transcription is enhanced/repressed with
the help of coactivators/corepressors
• Effects expressed through modification of
protein synthesis
PHARMACOKINETICS
• Orally ineffective - high first pass metabolism
• Slowly absorbed esters of testosterone are used
• Highly protein bound (98% - SHBG, albumin)
• Major metabolites: androsterone &
etiocholanolone
• excreted in urine after conjugation with sulfate &
glucuronic acid
• small quantity of estradiol produced from
testosterone - aromatization
TESTOSTERONE PREPARATIONS
• Testosterone propionate IM
• Testosterone enanthate IM
• Testosterone cypionate IM
• Methyl testosterone ORAL
• Mesterolone ORAL
• Fluoxymesterone ORAL
• Transdermal androgen
• Gel formulation - once daily application
THERAPEUTIC USES - ANDROGENS
1. Androgen replacement therapy (ART) –primary
and secondary testicular failure(hypogonadism)
2. AIDS related muscle wasting
3. Hypopituitarism
4. Hereditary angioneurotic edema -17α-alkylated
compounds
5. Ageing
6. Postmenopausal hormonal replacement
7. Idiopathic male infertility

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8. Refractory anemia
9. osteoporosis
ANDROGENS – ADVERSE EFFECTS
• Virilization, excess body hair and menstrual
irregularities in women
• Acne
• Frequent, sustained &often painful erections in males
• Oligozoospermia,testicular atrophy
• Precocious puberty, premature sexual behaviour, and
stunting of stature
• Salt retention and edema
• Cholestatic Jaundice - 17-alkyl compounds
• Hepatic carcinoma
• Gynaecomastia
• Lowering of HDL & rise in LDL
ANABOLIC STEROIDS
• Synthetic androgens – higher anabolic and
lower androgenic activity (3:1 to 10:1 ratio)
• mediated through the same receptor as the
androgenic effects
• Were developed to avoid virilizing A/E of
androgens while retaining anabolic effects
• Ex:
–Nandrolone
–Oxymetholone
– Stanozolol
– Methandienone
PHARMACOLOGICAL ACTIONS
• Protein anabolism:↑muscle mass & body weight
• Anticatabolic effects: Positive nitrogen balance
in individuals on prolonged glucocorticoids
• Progestational effects
• Reduce bone resorption
A/E: Similar to testosterone (androgenic action)
• In pregnancy - virilization of foetus
• Orally active anabolic steroids - cholestatic
jaundice,liver damage
• Sodium & water retention
THERAPEUTIC USES
• Catabolic states: Chronic illness, severe trauma,

93
major surgery, HIV cachexia - to improve appetite
& sense of well being
• Suboptimal growth in boys-hypogonadal children
• Anaemia –Hypoplastic,hemolytic,malignancy
associated
• Osteoporosis
• Renal failure along with protein restriction
To enhance physical ability in athletes -↑ strength
of exercised muscles - Considered illegal
DOPE TEST - included
ANTI-ANDROGENS
• Any compound which antagonises with action of
androgens at tissue level
Androgen receptor antagonists –
Flutamide,Bicalutamide,Nilutamide,Cyproterone
acetate, spironolactone
GnRh anlogues –
Agonists – Leuprolide,Goserelin,Nafarelin
Antagonists – Cetrorelix,Ganirelix
5 α reductase inhibitors – Finasteride,Dutasteride
Androgen synthesis inhibitor - Ketoconazole
Others – Danazol
DANAZOL
• Orally active ethisterone derivative
• Weak androgenic, anabolic, progestational &
glucocorticoid activity
• Labelled as impeded/attenuated androgen -
Induces some androgen specific RNA production
• Suppresion of Gn secretion from Pituitary in both
men & women – inhibition of testicular/ovarian
function
• Results in endometrial atrophy and
Ammenorrhoea
DANAZOL
• Uses:
– Endometriosis
– Menorrhagia
– Fibrocystic breast
disease
–Hereditary

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angioneurotic
oedema
– Infertility in
women
• Side effects: Dose related
• Amenorrhea (High
doses)
• Androgenic effects
- Decreased breast
size, hirsutism,
weight gain etc.
• Hot flashes, night sweating, cramps
CYPROTERONE ACETATE
• Inhibits LH release by its progestational activity
• Lowers serum testosterone( LH inhibition) –
direct antiandrogenic action
Uses:
• Precocious puberty in boys
• Inappropriate sexual behaviour in men
• Acne & hirsutism in women(with oestrogen)
• With ethinylestradiol – contraceptive in women
• Prostatic carcinoma
FLUTAMIDE
• Non-steroidal AR antagonist with no other
hormonal activity
• Active metabolite “2-hydroxyflutamide” causes
competitive block of androgen action on
accessory sex organs & Pituitary
Uses:
• Metastatic carcinoma of prostate along with
GnRH agonist - preferably started 3 days before
the GnRH agonist to block the initial flare up
• Female hirsutism – with Oral Contraceptives
FINASTERIDE
MOA:
• Competitive inhibitor of 5 α-reductase, which
converts testosterone to more active DHT
• Selective for 5 α-reductase type - 2 isoenzyme
• Male urogenital tract – Circulating and prostatic
DHT concentration are lowered

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 Uses:
Benign prostatic hypertrophy
• ↓Prostatic size and↑ peak urinary flow rate
• Beneficial effects delayed – 6 months
• Primarily reduces static component of obstructionMale pattern
baldness
Kinetics:
• Effective orally
• metabolized in liver
A/E:
• decreased libido
• Impotence
• decreased volume of ejaculate
DRUGS FOR ERECTILE DYSFUNCTION
• PDE-5 Inhibitors: Sildenafil, tadalafil,Vardenafil

SILDENAFIL
• Orally active for treatment of erectile
dysfunction
• Inhibits PDE-5 in the corpus cavernosum
• 50mg 1 hr before intercourse• Potentiate nitrate’s hypotensive
activity –(nitrates be
avoided for 24 hrs)
• CYP3A4 inhibitors like ketoconazole, erythromycin,
Verapamil potentiate its action
A/E:
• Headache, flushing, fall in BP, dyspepsia, nasal
congestion,impairment of colour vision(blue-
green discrimination),sudden loss of vision due to
non arteritic ischaemic optic neuropathy(NAION)
• Contraindicated in coronary heart disease
• Caution – liver, kidney disease
• Other Uses: Pulmonary hypertension
• Tadalafil – potent & longer acting congener
• Papaverine/ phentolamine induced penile

96
erection(PIPE) therapy – Injected into corpus
cavernosum
• Alprostadil (PGE1) – Injected into corpus
cavernosum
• Parenteral testosterone esters – ED due to
Androgen deficiency

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AMINOGLYCOSIDES
Dr. Pushpalatha C.
Aminoglycosides
• Effective against Aerobic gram –ve bacteria
• Bactericidal
Classification
SYSTEMIC AMINOGLYCOSIDES
- Streptomycin
- Amikacin
- Gentamicin
- Sisomicin
- Kanamycin
- Netilmicin
- Tobramycin
TOPICAL AMINOGLYCOSIDES
- Neomycin
- Framycetin
- Paramomycin
- Gentamicin
• Natural Products or semi-synthetic derivatives
• Mycins – derived from streptomyces
– Eg. Streptomycin
• Micins – derived from micromonospora
– Eg. Gentamicin
Common properties of aminoglycosides
• Chemistry – they are polycations containing two
or more amino sugars joined in glycosidic linkage
to a hexose nucleus
• Used as sulfated salts
–Highly water soluble
– Solutions stable for months
• Highly polar drugs
–Not absorbed orally
–Do not penetrate CNS or eye
• Excreted unchanged in urine – by glomerular
filtration
• All are bactericidal & more active at alkaline pH
• MOA – Act by inhibiting bacterial protein synthesis
• They show – Concentration dependent bacterial
killing

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 – Post antibiotic effect
• Active primarily against – Aerobic gram –ve
bacteria (narrow spectrum)
• Show partial cross resistance
• Narrow margin of safety
• Exhibit common toxicities
–Ototoxicity
–Nephrotoxicity
–Neuromuscular blockade
Mechanism of action
• Irreversible inhibitors of protein synthesis
• Gets transported through cell wall &
cytoplasmic membrane of bacteria by
– Passive diffusion via porin channels across
the cell wall
– Active transport across the cytoplasmic
membrane by an oxygen-dependent
Process
• Inside the cell, binds to mainly to 30s & also to 50s ribosomal
subunits, 30s-50s interface and inhibits protein synthesis by three ways
1) Blocks initiation of protein synthesis
2) Blocks further translation & causes premature
termination of peptide chain
3) Causes distortion of mRNA codon – misreading
of mRNA – incorporation of incorrect amino
acid in peptide chain → abnormal proteins
• Abnormal proteins insertion into cell memb. →
↑membrane permeability → leakage of ions, a.a & proteins →
bactericidal action
Mechanism of action

• Concentration dependent bacterial killing

–Higher the concentration, greater the rate of

99
bacterial killing
• Post-antibiotic effect
– Residual bactericidal activity persisting after
the serum concentration has fallen below
MIC
– The duration of this effect is also
concentration dependent
• Single dose – more effective ,less toxic & long
duration of action
Mechanism of resistance
1) Inactivation of aminoglycosides by adenylation,
acetylation or phosphorylation (Genes encoding
aminoglycoside-modifying enzymes are acquired
by conjugation & transfer of resistance plasmids)
2) Mutation or deletion of porin protein or proteins
involved in transport – Impaire entry of
aminoglycosides into the cell
3) Receptor protein on 30s ribosomal subunit
deleted or altered as a result of mutation –
↓ affinity to aminoglycosides
Shared toxicities
1) Ototoxicity – Largely irreversible
• Results from progressive destruction of
vestibular & cochlear part – due to drug conc.
in labyrinthine fluid
• Cochlear damage → Permanent deafness
– Due to degeneration of hair cells & neurons
in cochlea → irreversible bilateral high
frequency hearing loss
– High-pitched tinnitus – first symptom of
Toxicity
• Vestibular damage
– Headache, nausea, vomiting, dizziness,
nystagmus, vertigo & ataxia – Recovery (1-2
years) depends on extent of initial damage &
age of the patient
• Ototoxicity worsened by
– Coadministration of vancomycin, furosemide &
ethacrinic acid
• Ototoxicity (early changes) can be reversed by

100
– Calcium (Ca²⁺)
2) Nephrotoxicity – Reversible
• Drug attains high conc. in renal cortex – results
in tubular damage
– Loss of urine concentrating power
– ↓ GFR
– Nitrogen retention
– Albuminuria & casts
– ↓ clearance of aminoglycoside → higher blood
levels→ ↑ ototoxicity
3) Neuromuscular blockade – caused by
• ↓ Ach release from motor nerve endings
• ↓ sensitivity of muscle end plate to Ach
4) Other untoward effects
• Local irritation – At site of injection
• Allergy – Skin rash, eosinophilia, fever, dermatitis,
stomatitis & anaphylactic shock (rare)
• Superinfection with Staph. aureus & Candida
Precautions & Interactions
• Avoid aminoglycosides
– In pregnancy – Risk of fetal ototoxicity
–With ototoxicity drugs – High ceiling diuretics
- Minocycline
–With nephrotoxic drugs – Amphotericin B, Cisplatin
& Cyclosporin
• Given with caution in pts – Past middle age
- With kidney damage
- on skeletal muscle relaxants
• Should not be mixed with any other drug in
same syringe or infusion bottle
• Aminoglycosides frequently used in
combination with β-lactam antibiotics
– To expand spectrum of activity
– To provide synergistic bacterial killing
– To prevent emergence of resistance to
individual agents
Gentamicin
• Isolated from Micromonospora purpurea
• First choice aminoglycoside
– Cheap

101
 – Reliable activity against gram –ve aerobes
• Routes of admn. – Parenteral, ophthalmic &
topical
• Effective against both gram –ve & gram +ve
Organisms
Antimicrobial activity
- Staphylococci
- E. coli
- Other gram –ve aerobes
– Combined with β lactam antibiotics effective in
- Pseudomonas
- Proteus
- Enterobacter
- Klebsiella
- Serratia
Therapeutic uses
1) Urinary tract infection
– Uncomplicated lower UTI – 5 mg/kg IM single dose
2) Hospital-acquired pneumonia - caused by multi-
drug-resistant gram –ve bacteria
– Given in combination with β lactam antibiotic
3) Meningitis - caused by gram –ve organisms
– By intrathecal inj.
4) Peritonitis associated with peritonial dialysis
– Gentamicin diluted in dialysis fluid
5) Bacterial endocarditis
– Gentamicin + Penicillin
6) Sepsis
7) Topical application – Skin & ocular infections, bed sores & burns
infected with pseudomonas
Adverse effects
• Serious toxicity – Nephrotoxicity
- Irreversible ototoxicity
• Topical admn. – Allergic skin reaction
- Photosensitivity reaction
• Less toxic than kanamycin & streptomycin
Streptomycin
• Derived from Streptomyces griseus
• Less potent aminoglycoside
• Routes of admn. – deep IM & IV

102
Therapeutic uses
• Generally used in combination with other
antimicrobial drugs
1) Tuberculosis
– As a second-line drug given in combination with
other drugs
– Dose – 15 mg/kg/day – IM inj.
2) Bacterial endocarditis
– Streptomycin 15 mg/kg/day + Penicillin G
3) Tularemia
– Streptomycin – DOC
– Dose – 1-2 g/day (in divided doses) for 10-14 days
4) Plague
– Effective against all forms of plague
– Dose – 2 g/day in two divided doses for 10 days
5) Brucellosis
– Streptomycin + Tetracycline
6) Enterococcal infection
– Streptomycin + Penicillin G
Adverse effects
• Eighth cranial nerve damage – Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade
• Optic nerve dysfunction – scotoma
• Peripheral neuritis
• Pain at the site of inj.
• Superinfection
• Allergic reactions – skin rash, eosinophelia &
drug fever
Tobramycin
• Derived from strptomyces tenebrarius
• Similar to gentamicin in:
– Antimicrobial activity
– Pharmacokinetic properties
– Toxicity profile
• Routes of admn. – IM, IV, Inhalation &
eye drops
Therapeutic uses
• Similar to gentamicin
• Lower resp. tract infection with P. aeruginosa

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– inhalational tobramycin superior to gentamicin
Amikacin
• It is a synthethetic derivative of Kanamycin
• Broad spectrum aminoglycoside
• Resistant to many of aminoglycoside inactivating
enzymes
• Routes of admn. – IM, Slow IV drip
Therapeutic uses
• Gentamicin resistant gram –ve bacterial infection
• Community & hospital acquired gram –ve
infection
• Multidrug resistant tuberculosis
Netilmicin
• Pharmacokinetics similar to gentamicin &
tobramycin
• Broad antimicrobial activity against gram –ve
bacilli
• Resistant to many of aminoglycoside inactivating
enzymes
• Effective against gentamicin resistant pathogens
except enterococci
Therapeutic uses
• Complicated UTI in adults
• Serious systemic infections
Neomycin
• Broad spectrum antibiotic
Antimicrobial spectrum
• Gram –ve species
- E. coli
- Enterobacter aerogenes
- Proteus vulgaris
- Klebsiella pneumoniae
• Gram +ve microorganisms
- S. aureus
- E. faecalis
- M. tuberculosis
• P. aerugenosa (resistant to neomycin)
• Routes of admn. – Topical & oral
Therapeutic uses
• Skin & mucous memb. Infections – Burns,

104
wounds, ulcers & infected dermatoses
• Preparation of bowel for surgery – as an
intestinal antiseptic
– In combination with erythromycin base
• Irrigation of bladder
– To prevent bacteriuria & bacteremia with indwelling catheters
• Hepatic coma/Hepatic encephalopathy
– Given orally – suppress coliform flora (ammonia
producing bacteria) – reduce ammonia intoxication
Adverse effects
• Topical appl. – Skin rash
• Parenteral prep.– Not available – severe renal
damage & nerve deafness
• Oral admn. – Sprue-like-syndrome
• Irrigation of serosal cavities – Neuromuscular
blockade

105
DRUG INTERACTIONS
Dr. Pushpalatha C.
DRUG INTERACTIONS
• The effects of one drug are changed by the
presence of another drug, food, drink or by
some environmental chemical agent.
• The interactions are classified into:
– Drug - drug interactions
– Drug - herb interactions
– Drug - food interactions
– Drug - lab test interactions
– Drug - disease interactions
DRUG-DRUG INTERACTIONS
• Modification of drug’s effects by another drug
when administered simultaneously or in quick
succession
– Most commonly observed because of:
• Ever increasing number of drugs available over
the counter
• “Polypharmacy” being practiced by the
clinicians
–Drug interactions maybe harmful or
beneficialHarmful Drug Interactions:
- May Increase the toxicity of the drug
- Reduce the efficacy of the drug
- Cause potential organ damage in the body
Eg.
• Tricyclic antidepressants + MAOIs →
hyperpyrexia, convulsions & death.
• OCPs + Rifampicin → Failure of oral
Contraceptives
Beneficial drug interactions:
•Sometimes a second drug is prescribed
intentionally with an another drug
–to enhance the effectiveness
–to reduce the adverse effects of the primary agent.
Eg.
• Probenecid + Penicillin (Probenecid inhibits
renal secretion of Penicillin, thereby prolongs
duration of action of Penicillin)

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• Naloxone for Rx of Morphine overdose.
• Interactions will not necessarily occur in all
patients.
• In most patients, drug interactions may be of
minor clinical significance.
• In some patients, drug interactions can
produce severe adverse effects.
HIGH RISK PATIENTS
• Elderly patients → ↓PPB, ↓ hepatic and renal
clearance.
• Severely ill patients.
• Patients having hepatic and/or renal
impairment.
• Patients with Chronic Asthma, COPD, CHF,
Diabetes, Hypothyroidism, Epilepsy,
Malignancy, Psychiatric illness, AIDS.
• Patient’s susceptibility may be genetically
determined.
• Drug abusers.
HIGH RISK DRUGS
• Drugs with narrow therapeutic Index
• Drugs that are Enzyme Inducers or Inhibitors
(CYP 450 enzyme system)
• Drugs that exhibit Zero order kinetics
• Drugs that are highly protein bound
COMMON DRUGS INVOLVED IN DRUG
INTERACTIONS
–Digoxin
– Aminoglycosides
–Warfarin
– Antiepileptics
– Antidepressants
– Antipsychotics
– Cyclosporin
– Lithium
– Rifampin
– Theophylline –NSAIDs
– Oral contraceptives
– Antihypertensive drugs
– Antiretrovirals

107
– Anticancer drugs
MECHANISMS OF INTERACTIONS
• IN VITRO INTERACTIONS (Interactions
outside the body)
• IN VIVO INTERACTIONS (Interactions
inside the body)
IN VITRO INTERACTIONS
•These are the interactions occurring outside the
body before the drugs are administered into the
body.
Eg.
– Penicillin & Aminoglycosides mixed in same syringe
may get precipitated & the efficacy of the individual
drugs is reduced.
– Diazepam will get precipitated in distilled water.
• No drugs should be added in blood or blood
products.
IN VIVO INTERACTIONS
These are of two types:
1. PHARMACOKINETIC INTERACTIONS
2. PHARMACODYNAMIC INTERACTIONS
PHARMACOKINETIC INTERACTIONS
• One drug altering another drug’s plasma conc.
& intensity of response – by affecting
– Absorption
– Distribution
– Metabolism
– Excretion
• Due to marked individual variability in these
processes – these interactions may be expected
but their extent cannot be predicted.
Drug absorption interactions
– Change in gastric fluid PH:
• Antacids decreases absorption & efficacy of
Ketoconazole
– Effect on gastric emptying & motility:
• Metoclopramide → ↑gastric emptying → enhance
rate of absorption of Paracetamol & Propranolol.
• Atropine → ↓ gastric emptying → delays
absorption of other drugs.

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– Toxic effects on GIT:
• Failure of Oral Contraceptives by Ampicillin due to
change in gut bacterial flora.
– Binding & Chelation of drugs:
• Tetracycline & Fluroquinolones absorption are
reduced by Calcium, Magnesium, Aluminium,
Iron & Milk.
• Absorption interactions can be avoided by
allowing an interval of 2-3 hrs between
administration of the interacting drugs
Drug distribution interactions
–Drugs that are bound to plasma proteins are
potentially subject to displacement from
their proteins by another drug with high
affinity for the same protein.
Eg.
– Sulphonamides displace Warfarin from its plasma
protein binding site resulting in haemorrhage.
– Salicylates displace Tolbutamide from its plasma
protein binding sites resulting in hypoglycemia.
Drug metabolism interactions
– Most clinically important interactions
involves the effect of one drug on the
metabolism of another.
– The liver is the principal site of drug
metabolism; the other sites include gut,
kidney, placenta, lungs & skin.
– Clinically important drug interactions can
occur when the CYP450 isoenzymes are
induced or inhibited.
Enzyme Inducers
• One drug accelerates metabolism and decreases
pharmacological response of co-administered
drugs utilizing same enzymes.
• Enzyme induction – produces clinical response
only after 1 to 2 weeks.
• Most CYPs are inducible but not CYP2D6
Eg.
– Barbiturates, Carbamazepine, Phenytoin, Rifampin,
Chronic ethanol intake, Griseofulvin

109
• Clinical Importance: Enzyme Inducers if taken with Oral
Contraceptive Pills (OCPs) decreases efficacy of OCPs
results in unwanted pregnancy.
Enzyme Inhibitors
• They decrease metabolism and increase action of
co-administered drugs utilizing the same enzymes.
• Enzyme inhibition effects occur quickly.
Eg.
Erythromycin, Cimetidine, Ciprofloxacin, Diltiazem,
Ketoconazole, Metronidazole, Sulphonamides,
Amiodarone, Ritonavir.
• Clinical Importance: Enzyme (CYP450) Inhibitors if taken
with Terfenadine & Astemizole results in prolongation of
QT interval resulting in cardiac arrhythmias (Torsades de
pointes).
• Erythromycin will potentiate Theophylline toxicity.
• If affected drug is prodrug which requires
enzymatic metabolism to active metabolites, a
reduced pharmacological effect may result.
Eg.
– Lansoprazole inhibits CYP2C19 enzyme which
reduces effectiveness of clopidogrel when used in
combination → ↓Antiplatelet activity
• Interactions involving other enzyme inhibitors
Eg.
– Allopurinol inhibits Xanthine oxidase resulting in
decreased metabolism of Azathioprine .

110
Drug Excretion Interactions
• Changes in Renal blood flow: If the synthesis of
prostaglandins is inhibited
Eg. Indomethacin, reduces the renal excretion of Lithium
• Changes in active renal tubular secretion: Drugs
that use the same active transport system in the
kidney tubules can compete with one another.
Eg. Probenecid and Pencillin
• Alteration in PH:
Eg. Alkalinization of urine (with NaHCO₃) increase
excretion of acidic drugs like Phenobarbitone & Salicylates
PHARMACODYNAMIC INTERACTION
• Pharmacodynamic Interactions are those where
the effects of one drug are changed by the
presence of another drug at its site of action,
without a change in drug plasma concentration.
– Additive: 1+1=2.
Eg: Ibuprofen & Paracetamol
– Synergistic : 1+1 > 2.
Eg: Verapamil & Beta blocker
– Antagonist: 1+1 <2.
Eg. Receptor Antagonist: Propranolol & Salbutamol
Physiological Antagonists: Histamine & Adrenaline

111
PREVENTION OF DRUG INTERACTION
• Identify the patients risk factors.
• Document all drugs, including herbal
preparations and OTC and recreational drugs,
that the patient is consuming. Carefully review
this list before prescribing a new medication
or deleting a current medication.
• Many drug interactions can be predicted &
prevented if the pharmacodynamic effects,
pharmacokinetic properties and mechanisms
of action of the interacting agents are known.
• Be particularly vigilant when patient is taking
narrow therapeutics index drugs.
• Avoid polypharmacy to the maximum extend.
• Monitor the therapy given including
Therapeutic Drug Monitoring.
• Consider therapeutic alternatives.
• Educate the patient about the prescribed
drugs.
• Be careful while prescribing new drugs as long
term side effects and interactions are not
familiar.
-----

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ORAL ANTI-DIABETIC
DRUGS
Dr. Sam Pavan Kumar
Professor
Management of Type 2 DM:
Counseling
Life style modification
Drug therapy
Life Style Modification (LSM):
• Diet
• Weight reduction
• Habits/addictions
• Exercise
Diet:
- low-fat
- Minimal trans fat consumption
- low-carbohydrate
- Protein in diet: as part of an optimal diet
- Non-nutrient sweeteners
- Routine supplements of vitamins, antioxidants, or
trace elements not advised
Exercise:
- ADA recommends 150 min/week (distributed over
3-5 days)
- moderate aerobic physical activity
- should also include resistance training
BUT HAVE WATCHFUL EYE ON THE BLOOD GLUCOSE
LEVELS
Exercise has multiple positive benefits:
cardiovascular risk reduction
reduced blood pressure
maintenance of muscle mass
reduction in body fat
weight loss
lowers plasma glucose
Improves insulin sensitivity
CLASSIFICATION OF DRUGS USED IN TYPE 2 DM
1. Sulfonylurea derivatives
1st Generation: Tolbutamide, Chlorpropamide
Acetohexamide, Tolazamide

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2nd Generation: Glibenclamide, Glipizide
Gliclazide, Glimeperide
2. Non-sulfonylureas: Meglitinides
Repaglinide, Nateglinide
3. Biguanides
Metformin
4. Alpha-glucosidase inhibitors
Miglitol, Acarbose, Voglibose
(Drugs used in DM – cont)
5. Thiazolidine-diones
Pioglitazone, Rosiglitazone
6. Incretin mimetics
Exenatide, Liraglutide
7. DPP-4 Inhibitors
Sitagliptine, Vildagliptine
8. SGLT2 Inhibitors
Dapagliflozin, Empagliflozin, Canagliflozin
Drugs by their type of action:
a. Insulin secretagogues / Hypoglycaemic
Sulfonylurea derivatives
Glibenclamide, Glipizide
Gliclazide, Glimeperide
Non-sulfonylureas: Meglitinides
Repaglinide, Nateglinide
b. Insulin sensitizers
Biguanides: Metformin
Thiazolidinediones:Pioglitazone
c. Euglycaemic / Anti-hyperglycaemic
Biguanides: Metformin
Thiazolidinediones:Pioglitazone
Alpha-glucosidase inhibitors: Acarbose
Incretin mimetics: Exenatide, Liraglutide
DPP-4 Inhibitors: Sitagliptine, Vildagliptine
METFORMIN:
• Originally obtained from a guanidine - rich herb
Galega officinalis (goat’s rue or French lilac)
• Metformin, Phenformin and Buformin – were
introduced in the late 1950s.
• Phenformin and Buformin were withdrawn in the
late 1970s because of a high incidence of lactic

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acidosis.
11(Metformin – cont)
Mech. of action of Metformin:
Inhibits hepatic gluconeogenesis
Inhibits glycogenolysis
Increases peripheral uptake of glucose into
skel.muscle and adipose tissue (via Glut 4)
Improves insulin sensitivity, probably via
post - receptor signaling pathways for insulin
also may decrease plasma glucose by reducing the
absorption of glucose from the intestine -
? clinical relevance
• Metformin does not stimulate insulin release
• Does not cause frank hypoglycemia
• Suppresses appetite and weight gain, hence much
preferred in obese diabetics
Pharmacokinetics:
• Metformin is taken orally
• is rapidly but incompletely absorbed
• less plasma protein bound
• is not metabolized
• is widely distributed
• plasma t ½ is about 2-3 hours
• eliminated unchanged in the urine {dose should be
reduced in renal failure}
14(Metformin – cont)
Adverse effects:
- Lactic acidosis
- Inhibits absorption of Vit.B12 and folic acid
- GI: dyspepsia, anorexia, abd.pain, nausea,
metallic taste, diarrhea
to avoid GI effects:
gradually increase the dose
Preferable to be taken after a meal
use a sustained release preparation
Precautions/Contraindications:
• Metformin should not be used in patients with
- renal insufficiency [GFR < 60 mL/min]
- any form of acidosis
- CHF

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- liver disease
- severe hypoxemia
• should be discontinued temporarily prior to the
administration of intravenous radio-contrast
media and prior to any surgical procedure
• stop in myocardial infarction and septicemia
• Dose: 250 mg, up to 2000 -3000mg/day
• Slow onset of action
• Increase the dose gradually once in 2-3 weeks
monitoring blood glucose levels
• effective as monotherapy
- can be used in combination with other oral
agents or with insulin
Uses of Metformin:
1. Type 2 DM
2. Type 1 DM, along with Insulin
3. Polycystic ovarian syndrome (PCOS)
INSULIN SECRETAGOGUES:
a) Sulfonylurea derivatives
• Accidentally discovered from Sulfonamide
antibiotics
• Now used extensively
• These drugs are most effective in individuals with
type 2 DM of relatively recent onset (<5 years),
who have residual endogenous insulin production
(atleast 30% of functional β cells are required for
their action)
Mech.of action of Sulfonylureas:
• causes release of insulin from β cells
• suppress the secretion of glucagon slightly
• stimulate release of somatostatin
• closure of K+ATP channels in other tissues (heart)
• Does not increase insulin biosynthesis
• Decreases blood glucose in both diabetics and
non-diabetics
• Have to be given 20-30 mins. before meal as they
secrete insulin

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20

Mech.of action:
• Enter the β cells of Ilets of Langerhans, bind to the
cytosolic surface of the sulfonylurea receptor 1
(SUR1)
• Binding of a sulfonylurea to SUR1 closes the ATP
sensitive K+ channel, reducing the efflux of
potassium and enabling membrane depolarization
• This opens up Ca++ channels, causing release of
Insulin from storage granules
• Insulin is released : First phase (immediately)
Second phase (10 mins.later)
First-generation sulfonylureas:
Chlorpropamide, Acetohexamide,
Tolazamide, Tolbutamide
- have a longer half-life
- a greater incidence of hypoglycemia
- more frequent drug interactions
are now rarely used.
• Second-generation sulfonylureas
Glibenclamide, Gliclazide,
Glipizide, Glimeperide
- have a more rapid onset of action
- reduce both fasting and postprandial glucose

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Glibenclamide:
• Dose 2.5 – 20 mg/day, in one or two divided doses
• Causes severe and prolonged hypoglycemia
• Contraindicated in hepatic and renal impairment
Glipizide:
• Has shortest half-life (2-4 hrs)
• Dose 5 – 20 mg/day, in one or two divided doses
• Contraindicated in hepatic and renal impairment
Glimeperide:
• Has long plasma half life of 5 hrs., can be given
once a daily
• Dose: 1 – 8 mg/day; may given in divided doses
Pharmacokinetics:
• Given orally
• Well absorbed
• Highly plasma protein bound – drug interactions
• Metabolized in liver
• Excreted by kidney
• Micronized form of Glibenclamide available
• Extended release forms of Glipizide and
Gliclazide available
Adverse effects:
• Hypoglycemia
• Weight gain
• Hypersensitivity reactions
• Flushing when taken with alcohol
• ?? Cardiac adv.effects due to blockade of K+
channels
b) Meglitinides:
Meglitinide derivative: Repaglinide
D-Phenylalanine derivative: Nateglinide
• are not sulfonylureas
• but also interact with the ATP-sensitive potassium
channel, causes release of insulin
• Because of their quick onset of action and short
half-life, these agents are given with each meal or
immediately before, to reduce meal-related
glucose rise
- Incidence of hypoglycemia very less
- Less incidence of weight gain

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- Dose may be omitted if a meal is missed
Thiazolidinediones:
PIOGLITAZONE, ROSIGLITAZONE:
• Are ligands of PPAR-γ (peroxisome proliferator
activated receptor γ) nuclear receptor
• These PPAR receptors are found in muscle, fat,
and liver.
• also have significant effects on vascular
endothelium, the immune system, the ovaries,
and tumor cells
• Decreases insulin resistance by binding to the
PPAR γ
• a major site of Tzd action is adipose tissue, where
the drug promotes glucose uptake and utilization
• promote a redistribution of fat from central to
peripheral locations
• Circulating insulin levels decrease
• Decreases triglyceride levels in plasma

32
Pharmacokinetics:
• Given orally
• Absorbed completely, but food delays absorption
• Rosiglitazone is highly plasma protein bound

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 • Metabolized by CYP 2C8 and 3A4
• Maximum clinical effect is seen after 6-12 weeks
• Pioglitazone: dose 15-45 mg/day, once daily
• Rosiglitazone: dose 4-8 mg/day, once or twice
daily
Side effects:
- Weight gain
- Peripheral edema
- Precipitation of CCF
- Hepatotoxic (LFT monitored)
- increased risk of fractures in women
- Induce ovulation in premenopausal women with
PCOS(good news/beware of unwanted pregnancy)
- Increased incidence of macular edema
Alpha Glucosidase Inhibitors:
ACARBOSE, VOGLIBOSE, MIGLITOL:
• reduce postprandial hyperglycemia
• they do not affect glucose utilization or insulin
secretion
• Do not cause hypoglycemia
Mech.of action:
• These drugs competitively inhibit the activity of
α - glucosidase enzymes in the brush border of
enterocytes lining the intestinal villi
• They bind to the enzymes with high affinity,
preventing the enzymes from cleaving
disaccharides and oligosaccharides into
monosaccharides
• This delays completion of carbohydrate digestion, leading to a
delay in glucose absorption

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Dose:
Acarbose: 25-50 mg with each meal
Voglibose: 0.2-0.3 mg with each meal
Side effects:
- diarrhea, flatulence, abdominal distention
- Hypoglycemia (when used in combination)
should be treated with glucose (dextrose) and not
sucrose, whose breakdown may be blocked
• should not be used in individuals with
inflammatory bowel disease
gastroparesis
serum creatinine > 2 mg/dL
• Can be used in both Type 1 and 2 DM
• Can be used as monotherapy and also in
combination with other OHAs.
Dipeptidyl dipeptidase 4 Inhibitors:
Ex: Sitagliptin, Vildagliptin, Teneligliptin
Incretins:
Glucagon like peptide(GLP-1)
Glucose-dependent insulinotropic polypeptide(GIP)
Cholecystokinin (CCK)
- secreted from the specialised endocrine cells of
the intestinal mucosa
- they are secreted in proportion to the
nutrient load ingested

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- they cause release of insulin
They are metabolized/degraded into inactive
products by the enzyme Di Peptidyl Peptidase 4
DPP-4 is present:
in circulation
attached to endothelial cells of vasculature
in the intestinal mucosa
nactive GLP-1
Increase insulin
release sitagliptin
(-)
Inactive DPP-4 Incretins, decrease
GLP-1 GLP-1 blood
glucose
Exenatide-
GLP-1agonist decrease
Glucagon release
Inhibition of DPP-4 » increases natural incretins »
Increase glucose-stimulated insulin secretion
suppress glucagon
slow gastric emptying
• Do not cause hypoglycemia
• Can be used alone or in combination
• Cause suppression of appetite, and weight loss
• Cause nausea, vomiting, diarrhea
Sitagliptin & Vildagliptin:
• Given orally
• Bioavailability: 85%
• Less protein bound
• Mostly excreted unchanged in urine
• Partly (15%) metabolized by CYP3A4 and 2C6
• T½ : Sitagliptine: 8-14 hrs
Vildagliptine: 1.5-4.5 hrs
• Dose: 50-100 mg
• Given once daily
INCRETIN MIMETICS (GLP1 Analogues)
Ex: Exenatide, Liraglutide
• regulate glucose metabolism
• promote weight loss with a low risk of
hypoglycemia

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Exenatide:
• originally isolated from the saliva of the Gila
monster
• is resistant to DPP - 4 cleavage
• given subcutaneously; twice daily
• half - life 2.5 hours
• Predominantly eliminated by kidney, dose
reduction required in renal insufficiency
• Main side effect is nausea
• May cause diarrhea, constipation, Pancreatitis
Liraglutide:
• Resistant to the action of DPP-4
• Given subcutaneously
• Plasma half life is 13 hours
• Given once a day
Amylin analogues: Pramlintide
• Amylin is a 37 amino acid peptide co - secreted
with insulin.
• It : delays gastric emptying
suppresses post - prandial glucagon secretion
increases satiety
• Pramlintide is a synthetic analog of amylin
• Given subcutaneously
• Duration of action 2-3 hrs
• Adverse effects: hypoglycemia
nausea, vomiting, and anorexia.
Insulin Therapy in Type 2 DM:
should be considered as the initial therapy in type 2
DM:
• in lean individuals
• those with severe weight loss
• in individuals with underlying renal or hepatic
disease before initiation of oral agents
• in individuals who are hospitalized or acutely ill
• Peri-operative
• In severe infections
NEWER THERAPIES:
1. Bromocriptine
2. Bile acid–binding resins - Colesevelam

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Points to ponder:
1. All drugs are more effective than Pioglitazone
and Sitagliptin
2. All are equally effective in lowering A1c levels
(1-2%), except Pioglitazone and Sitagliptin
3. No clinical advantage to one drug/group
4. Not all agents are effective in all individuals with
type 2 DM (primary failure)
5. Biguanides, α-glucosidase inhibitors, GLP-1
receptor agonists, DPP-IV inhibitors, and
thiazolidinediones do not directly cause
hypoglycemia
6. Insulin secretagogues, GLP-1 receptor agonists,
DPP-IV inhibitors, and α-glucosidase inhibitors
begin to lower the plasma glucose immediately,
whereas the glucose-lowering effects of the
biguanides and thiazolidinediones are delayed by
several weeks
7. durability of glycemic control is slightly less for

124
Glibenclamide
8. most individuals will eventually require treatment
with more than one class of oral glucose-lowering
agents or insulin, reflecting the progressive nature
of type 2 DM

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INSULIN & DIABETES MELLITUS
Diabetes Mellitus:
- Described 3500 years ago by the Egyptian
physicians as a disease marked by excessive
urination
- Ancient Indian physicians like Charaka diagnosed
diabetes because ants and flies were attracted to
the urine.
- Sushrutha described it as “madhu meha”- for
honeyed urine
Greek Physician Aretaeus (2nd century AD)
- described it as as “melting down of the flesh and
bones into urine”
- he coined the term ‘diabetes’ – based on Greek
word for ‘siphon’(as if water poured in & out the
body, as if it were a hose)
Galen(129-210 AD) – called the disease “diarrhea of
the urine”
John Rollo in 1809
‘mellitus’ – latin word for honey
Diabetes Mellitus :
is a heterogenous group of metabolic disorders
- characterized by chronic hyperglycemia
- with disturbances of carbohydrate, fat and protein
metabolism
- resulting from defects in:
- insulin secretion
- insulin action
- or both
• Affects 1-2% of population
• Estimated 400 – 450 million diabetics by 2020
• Incidence increases with age
• Incidence similar in both sexes
SYMPTOMS:
- Polyuria, polydipsia, polyphagia, blurring of vision,
weight loss, paresthesias, easy fatiguability etc.
- In severe cases, may present with ketoacidosis or
non-ketotic hyperosmolar coma
- Often symptoms are not severe or may even be
absent (hence diagnosis in early stages is missed)

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 CLASSIFICATION:
- Proposed by ADA in 1997, adopted by WHO in
1999
clinical stages
DM
etiologic types
Clinical Stages:
HYPERGLYCEMIA
impaired
normo Glucose diabetis mellitus
Glycemia regulation
IGT insulin insulin
Not requiring requiring
Requiring for for
Insulin control survival
IFG
- If insulin is required to prevent ketoacidosis, such
patients are designated as “ Insulin Requiring for
Survival”
Etiologic types:
TYPE 1
AUTOIMMUNE beta cell destruction,usually
TYPE-1 leading to absolut insulin
YPE-1β CELL IDIOPATHIC deficiency
DEFICIENCY
insulin resistance with relative insulin deficiency
TYPE-2 SECRETORY DEFECT WITH OR WITHOUT
INSULIN RESISTANCE
OTHER SPECIFIC TYPES
GESTATIONAL DIABETES
Two features of the current classification of DM
diverge from previous classifications.
First, the terms insulin-dependent diabetes mellitus
(IDDM) and non-insulin-dependent diabetes
mellitus (NIDDM) are obsolete – are now Type 1
and Type 2 DM
Second, age is not a criterion in the classification
system.
Other Specific types of DM:
1) Genetic defects of β cell function:

127
MODY 1 – 6
Mitochondrial DNA mutations
Subunits of ATP sensitive K+ channel
2) Genetic defects in Insulin action
Type A insulin resistance
Leprechaunism
Rabson-Mendenhall syndrome
Lipoatrophic diabetes
Other Specific types of DM(cont)
3) Other genetic syndromes associated with DM
Down syndrome Myotonic dystrophy
Friedreich ataxia Turner syndrome
Huntington disease Prader-Willi syndrome
Klienefelter syndrome Wolfram syndrome
Porphyria Laurence-Moon-Beidl syndrome
4) Infections:
Congenital Rubella Cytomegalo virus
5) Endocrinopathies:
Cushings syndrome Glucagonoma
Acromegaly Somatostatinoma
Pheochromocytoma Hyperthyroidism
6) Drug/Chemical induced:
Glucocorticoids Thiazides
Thyroid hormone α agonists
Phenytoin Interferon-α
Pentamidine
7) Diseases of exocrine pancreas
Fibrocalculus pancreatopathy
Pancreatitis Trauma/ Pacreatectomy
Neoplasia, Cystic fibrosis, Hemochromatosis
8) Uncommon forms of Immune-mediated
Antibodies to insulin
Anti-Insulin receptor antibodies
Stiff-man syndrome
17Diagnostic criteria for DM
*Random- without regard to time since last meal
*Fasting - no calorie intake for atleast 8 hours
YPE
TYPE FASTING 2 HOURS POST HbA1C
GLUCOSE

128
DIABETES
MELLITUS ≥ 126 ≥ 200 ≥ 6.5
SYMPTOMS OF DM
+ RBS ≥ 200 -
IGT < 126 140 – 199 -
IFG 100 - 125 - -
Abnormalities on screening tests for diabetes should
be repeated before making a definitive diagnosis
of DM, unless acute metabolic derangements or a
markedly elevated plasma glucose are present
The diagnosis of DM has profound implications for
an individual from both a medical and a financial
standpoint

Acute complications of diabetes:

• Diabetic ketoacidosis (DKA)
• Hyperglycemic hyper-osmolar state (HHS)

129
The goals of therapy for type 1 or type 2 DM:
(1) Eliminate symptoms related to hyperglycemia
(2)reduce or eliminate the long-term microvascular
and macrovascular complications of DM
(3) allow the patient to achieve as normal a lifestyle
as possible.
To reach these goals, the physician should:
1. identify a target level of glycemic control for each
patient
2. provide the patient with the educational and
pharmacologic resources necessary to reach this
level
3. monitor/treat DM-related complications.

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TREATMENT OF DIABETES MELLITUS
• Insulin
• Oral Hypoglycemic drugs
HISTORY OF INSULIN
-1813 – 1878 ; Claude Bernard : Glucose metabolism
-1847- 1888: Paul Langerhans
a medical student, described “Islets” of Pancreas
in 1869.
-1889 : Oscar Minkowski
noticed pancreatectomisd
Joseph von Mering dogs developed DM
-1893: Laguesse
- suggested “Islets” as a gland of secretion
within pancreas
1909 : Jean de Meyer
- suggested the pancreas secretion that was
lacking in the diabetic state should, when
found, be called “INSULIN” to denote its
origin from ‘Insulae’(greek word for Islands)
-Georg Zuelzer (1840-1949)
Nicolas Paulesco(1869-1931)

131
- Reported that pancreatic extract reduced glycosuria in
pancreatectomised dogs
-Frederick Banting (1891-1941)
Charles Best (1899-1978)
- The discoverers of INSULIN
-John Macleod(1876-1935)
James B Collip(1892-1965)
- The discoverers of INSULIN
-Leonard Thomson – the first patient to receive insulin
on 11th Jan. 1922, at the age of 14 years
(the first clinical trial of Insulin)
PANCREAS:
Exocrine – comprise of acinar cells
- contain zymogen granules which
secrete digestive enzymes like
amylases, proteases, nucleases and lipases.
Endocrine :
α cells – Glucagon
β cells – Insulin, Amylin (IAPP - Islet Amyloid Polypeptide)
δ cells – Somatostatin
γ cells – Pancreatic polypeptide
ε cells - Ghrelin
Other cell types of Islets (< 1%):
δ₁ cells – Vasoactive intestinal polypeptide
EC cells – Substance P, Serotonin
G₁ cells – Gastrin
• Pancreas in an adult contain approximately 1.5
million islets
• Contain 200 units (8mg) of Insulin
FACTORS AFFECTING INSULIN RELEASE
* Stimulators of Insulin release:
- sugars like glucose, mannose
- amino acids like leucine, arginine
- hormones like glucagon like peptide(GLP-1)
glucose-dependent insulinotropic polypeptide(GIP)
cholecystokinin(CCK) glucagon
- vagal activity - Ach (cephalic response)
- β₂ agonists
- adepokines like adeponectine
* Inhibitors of Insulin release:

132
- somatostatin - adepokines like leptin
- chronically elevated glucose & fatty acids
- norepinehrine - dopamine - α₂ stimulants
- ghrelin
Glucagon & Insulin secretion are regulated in
reciprocal fashion ie., agents that stimulate insulin
suppress glucagon secretion;
- Exceptions: arginine – stimulates both
somatostatin – inhibits both
• GLP1, GIP and CCK are called ‘Incretins’
- secreted from the specialized endocrine cells of
the intestinal mucosa
- they are secreted in proportion to the
nutrient load ingested
- relay this information to the Islets as a part
of ‘feed forward’ mechanism that allows an
insulin response appropriate to the size of the
meal
• “Incretin effect” – insulin secretion is much
greater when the same amount of glucose is
given orally compared to intravenously
INSULIN SECRETION
• In healthy humans, β cell function is primarily
controlled by plasma glucose concentrations
• Insulin is secreted in phasic manner
- basal: 5 – 15 μu/ml
- meal related surge: 60 – 90 μu/ml
a rise in plasma glucose is necessary for insulin
release above basal levels
other stimuli are ineffective when plasma glucose
is in fasting levels (of 80 – 100 mg/dl)
INSULIN SYNTHESIS
• Initially synthesised as a single polypeptide chain
Pre-pro-insulin(110 AA)
• The gene encoding preproinsulin is located on
the short arm of chromosome 11.
• Preproinsulin is made up of a Signal peptide,
B chain, C peptide & A chain
• Preproinsulin is rapidly(< 1 min) discharged into
the cisternal space of the rough endoplasmic

133
reticulum, where proteolytic enzymes
immediately cleave the Signal peptide,
generating Pro-Insulin
Proinsulin :
- With cleaving of signal peptide, Proinsulin folds, with
development of di-sulfide bonds (containing A & B
chains connected by C peptide)
- is transported to Golgi complex & stored in
secretory granules,
- where prohormone convertases (PC2 & PC3) cleave
proinsulin to Insulin (51AA) and C peptide (30-35AA)
- granules of β cells store insulin in the form of crystals
containing two atoms of zinc & six molecules of
insulin
- and are released in equimolar concentrations by
exocytosis
- a small amount (< 5%) of Proinsulin is also released
SYNTHESIS OF INSULIN

INSULIN:

134
- mol.wt. 5808 daltons
- contains 51 aa arranged in two chains – A, B
- linked by disulfide bridges
- Insulin & C peptide are released in equimolar
amounts
- t½ of Insulin: 3 – 5 mins
C peptide: 30 mins
INSULIN

REGULATION OF INSULIN SECRETION:

- Pancreatic β cells respond to small changes in
extracellular glucose concentrations
- Glucose is transported into β cells via GLUT 2
» glucose is phosphorylated by glucokinase
» formation of glucose-6-phosphate
» enters glycolytic pathway
» ↑ ATP formation
» inhibits ATP sensitive K+ channel
» depolarisation of cell membrane
» opening of voltage dependant Ca++ channels
» ↑ intracellular Ca++
» exocytotic release of insulin from storage
vesicles

135
Insulin secretion on healthy adults are highest in
Early digestive phase of meals, preceding and
limiting the peak in blood glucose
• This pattern of premonitory insulin secretion is an
essential feature of normal glucose tolerance
INSULIN DEGRADATION
- After its release, insulin undergoes absorption
» portal vein
» 60% metabolized in liver
» rest enters circulation and subsequently
removed by the kidney
- C peptide is not metabolized by liver
- all the amount secreted reaches the

136
circulation
- estimation of C peptide levels in plasma is
useful in assessment of β cell secretion of
insulin
GLUCOSE TRANSPORTERS (GLUT)
- Are important in regulation of release and actions
of insulin.
TRANSPORTER
TISSUES
INSULIN RECEPTOR
- Is a large transmembrane glycoprotein consisting
of two α - and two β - subunits which form a
heterotetramer (two hetero dimers linked by
disulfide bonds)
• The Insulin receptor gets activated by three
well-defined ligands:
- insulin
- insulin-like growth factor 1(IGF-1)
- insulin-like growth factor 2(IGF-2)
• All three ligands can bind and activate cell-surface
insulin receptors
• IGF-2 predominates during fetal development,
promotes growth
• IGF-1 present in postnatal life
INSULIN ACTION
Promotes:
• Glycogen synthesis
• Protein synthesis
• Mitogenesis (cell growth & differentiation)
• Transport of glucose into cells

137
TARGETS OF INSULIN ACTION
1. Liver:
a) anticatabolic
- inhibit glycogenolysis
- inhibit conversion of fatty acids & amino acids to ketoacids
- inhibit conversion of amino acids to glucose
b) anabolic
- promotes glucose storage as glycogen
- ↑ triglyceride synthesis & VLDL
2) Muscle:
a) ↑ protein synthesis
- ↑ amino acid transport
- ↑ ribosomal protein synthesis
b) ↑ glycogen synthesis
- ↑ glucose transport
- induces glycogen synthase& inhibits phosphorylase
3) Adipose tissue:
a) ↑ triglyceride storage
- activation of lipoprotein lipase
- esterification of fatty acids
- inhibition of intracellular lipase
USES OF INSULIN
• Type 1 DM
• Diabetic ketoacidosis (DKA)

138
• Hyperosmolar hyperglycemic syndrome (HHS)
• Gestational diabetes
• Type 2 DM - during surgeries/postoperatively
- infections
- ill & hospitalized patients
- initial therapy in lean individuals or
those with severe weight loss
- associated renal/hepatic diseases
- long standing DM (secretory failure)
• Emergency treatment of hyperkalemia, along with
glucose infusion
ADVERSE EFFECTS OF INSULIN
o Hypoglycemia
o Modest weight gain/ ‘Insulin edema’
o Lipodystrophy
- lipoatrophy: immune mediated
- lipohypertrophy: increase in adipose tissue as
a trophic response to insulin, -
can be avoided by rotating the site of injections
o Insulin allergy – immediate type hypersensitivity-
IgE mediated,local rash, urticaria, anaphylaxis-rare
o Immune insulin resistance – due to circulating IgG
anti-insulin antibodies
ROUTES OF INSULIN ADMINISTRATION
- subcutaneous
- intravenous
- intramuscular - rare
SITES OF SC INSULIN ADMINISTRATION

139
TECHNIQUE OF SC INJECTION
• The size of the needles: 6 – 8 mm for non-obese
12.7 mm for obese
INSULIN UNITAGE:
- expressed in international units (as the
preparations of hormone were impure and the
concentration was standardized by bioassay)
- 1 unit of insulin is defined as the amount
required to reduce the blood glucose
concentration in a fasting rabbit to 45mg/dl
*commercially available in: 100 units/ml
40 units/ml
SOURCES OF INSULIN
- Animal: bovine
porcine
- Human: - cadaveric
- “semi synthesis”- chemically converts

140
porcine insulin to human sequence
through substitution of the
aminoacid difference in the primary
sequence
- DNA recombinant
HUMAN vs ANIMAL INSULINS
• The aminoacid structure of animal insulins differ
from that of human by:
- Bovine: 3 AA (position B30, A8 & A10)
- Porcine: 1 AA (B30)
• DNA recombinant technology:
- involves the insertion of the human DNA
sequence into a host cell, usually Yeast or E.coli,
allowing to synthesize the insulin molecule.
- the protein would then be purified via
chromatography columns to achieve a
99.5 – 99.9% insulin purity

141
INSULIN PREPARATIONS
1. Rapid acting
2. Short acting
3. Intermediate acting
4. Long acting
5. Pre-mixed insulins
• RAPID ACTING INSULINS
- insulin Lispro
- insulin Aspart
- insulin Glulisine
• SHORT ACTING INSULINS
- Regular insulin
- Velosulin
• INTERMEDIATE ACTING INSULINS
- Protamine- Zinc insulin
- Lente insulin
- Neutral Protamine Hagedorn(NPH)/Isophane
• LONG ACTING INSULINS
- Ultra Lente insulin
- insulin Detemir
- insulin Glargine
PROLONGING THE DURATION OF ACTION OF INSULIN
• Duration of action of soluble/regular insulin: 5-6hr
• Attempts to prolong the duration of action
» by adding lecithin, oil, cholesterol
» erratic absorption
• Protamine, highly basic protein from salmon fish
added to insulin » slowed absorption(Protamine In)
• PI further stabilized by addition of zinc (PZI)
• Technique refined, Protamine & Zinc added in
stoichiometric proportions, that there was no free
protamine or zinc » Neutral Protamine Hagedorn or
Isophane insulin, with consistent absorption and
prolonged action
• Insulin(without protamine) to which zinc was
added in excess in acetate buffer » resulting in
crystals of relatively insoluble zinc-insulin
complexes, the lente insulins
- By changing the pH:
- Larger the crystals » slowly absorbed » long

142
duration action, Ultra Lente
- Smaller crystals, Semi Lente
- Lente insulin: a preparation containing
70:30 ratio of ultra lente & semi lente
INSULIN IN BODY:
• Insulin circulates as single molecules in the blood
• Insulin in commercial preparations tend to self
associate non-covalently into dimers, tetramers or
hexamers
• The presence of zinc further stabilizes the
hexameric associations
• After SC inj., Insulin hexamers slowly dissociate &
gradually get absorbed across capillary walls as
monomers into circulation
• Accordingly patients are advised to inject soluble
insulin 20-30 mins. prior to meal, so that
circulating insulin levels are optimal at the time of
meal absorption
• The association of insulin molecules into
hexamers can be reduced by specific changes to
the aminoacid sequence of insulin
• Accordingly Lispro, Aspart, Glulisine are available.
INSULIN ANALOGS:
• Are human insulins with slight alteration of
aminoacid sequence/substitution of aminoacid in
structure
• Two types:
a) Rapid acting: Lispro Aspart Glulisine
b) Long acting : Glargine Detemir
INSULIN ANALOGS

143
LISPRO, ASPART, GLULISINE:
• Retain the action of insulin but:
*have less tendency to self associate
*though they exist as hexamers in commercial
preparations, they dissociate into monomers
almost instantaneously following injection
* have rapid onset of action & so can be taken
immediately prior to, or with or soon after a
meal
GLARGINE (long acting)
- pH of 4.0 stabilizes the insulin hexamer
- When injected into neutral pH of subcut.
» aggregation of molecules
» slower but predictable absorption
» prolonged action, ≥ 24hrs (peakless insulin)
- Provides ‘basal’ insulin; given once daily
- Has lower risk of hypoglycemia
- Site of administration & also exercise do not
influence the absorption kinetics
- Should not be mixed with short acting insulins(pH)
- Has higher affinity than Insulin for IGF1R,
? mitogenic
INSULIN DETEMIR(long acting)
• Insulin analog modified by the addition of a
saturated fatty acid to the ε amino group of
LysB29, and B30AA is removed
• After injection, it binds to the albumin via its fatty
acid chain » long duration of action

144
• Given twice daily
• Regular insulin Lispro
Aspart clear solutions
Glulisin Glargine
• All other insulin preparations are cloudy/whitish
PRE-MIXED INSULINS
• Usually – Regular insulin + NPH, 30:70 / 50:50
• Others – Lispro protamine + Lispro, 50:50 / 75:25
- Aspart protamine + Aspart, 70:30
INSULIN DELIVERY SYSTEMS
1. Syringe and needle:
- traditionally used
- allows dosages to be adjusted
- allows insulin formulation to be mixed
*limitations: - good eye sight
- fine motor skills
* available in 40 units/ml gradation
100 units/ml
2) Pen devices:
* became more popular
* replaceable insulin cartridges containing
150 – 300 units of Regular, Aspart, Lispro,
NPH, premixed insulins
* the dose is set & a button is pressed which
releases insulin through a very fine gauge needle
* is convenient, unobtrusive, easy to carry, very
useful for MDI regimens
* Limitation: two insulin preparations cannot be
mixed
3) Continuous subcutaneous insulin infusion(CSII):
- Contains an insulin reservoir, the program chip,
the key pad & the display screen;
- Is about the size of a pager, can be worn on a belt
or placed in the pocket
- Insulin is infused through thin plastic tubing
connected to the subcutaneously inserted
infusion set
- Sites: abdomen, flanks, thigh
- Delivers continuous basal insulin and a
programmed pre-meal bolus

145
- Regular blood glucose monitoring is required
- CSII regarded as the most physiological method of
insulin replacement
- Useful in:
*patients unable to obtain target control with
multiple daily injections(MDI)
*recurrent severe hypoglycemia &
hypoglycemic unawares
*diurnal variations in basal insulin requirements
caused by the Dawn phenomenon
*Pregnancy
*Pts. on steroid therapy(DM+post-renal
transplantation)
- Insulin prepns. approved for use in CSSI:
Aspart, Glulisin, Lispro, Regular, Velosulin
Advantages of CSSI:
- dosing precision
- optimizing post-prandial insulin coverage
Practical issues/Disadvantages of CSSI:
- scarring/lipodystrophy at infusion site
- infusion catheter kinking or dislodgement
- insulin instability in pump infusion system
- failure to change pump reservoir/infusion system
- pump malfunction
INSULIN REGIMENS
1) In Type 1 DM:
- Basal bolus
- pre-mixed insulins, twice daily
2) In Type 2 DM:
- basal only(in addition to oral agents, diet, LSM)
- basal plus(as above + rapid acting insulin prior
to the main meal of the day)
- basal bolus

146
Storage of insulin:
- preparations are stable at room temperature for
30 days
- ? Slight loss of potency if the same vial is used
more than 30 days
- Avoid - extreme temperatures
- excess agitation/shaking of the vial
NEWER ROUTES OF INSULIN DELIVERY
Oral: - unsuccessful(enzymatic degradation in GIT)
- enclosing insulin in microspheres and
concurrent administration of proteolytic
enzyme inhibitors
» minimal success
Rectal: poor bioavailability
lack of patient acceptance
Transdermal: limited success
further clinical studies are required
Intra-nasal: aerosolized insulin
- disadvantages:
smaller surface area of nasal mucosa
drug removed by back of pharynx(mucociliary
clearance & swallowing)
rapid but short lived hypoglycemic effect

147
large doses required
nasal irritation & congestion
Inhaled insulin(pulmonary):
a) dry powder inhalation
b) aqueous aerosol device
a) Dry powder inhalation:
- uses a holding chamber to capture the insulin
cloud and allow for slow deep inhalations
- faster onset of action
- duration of action in between Lispro & RegularIn
- HbA1c comparable with SC insulin
b) Aqueous aerosol device:
- is breath activated, releases insulin when
inspiratory flow rate and volume are optimal
*Both formulations have poor bioavailability
*Long term safety & efficacy studies required
*High cost of therapy

148
 CORTICOSTEROIDS
• Corticosteroids or Corticoids includes:
– Natural Glucocorticoids
– Natural Mineralocorticoids
– Synthetic analogues of both Gluco- & Mineralo-
corticoids
History
• Nobel prize was awarded to:
– Reichstein & Kendall – for isolation & identification
of adrenal steroids
– Hench – for using cortisone in the treatment of
rheumatoid arthritis• Adrenal cortex secretes two classes of
steroids
– Corticosteroids
• Glucocorticoids
–Hydrocortisone (Cortisol)
• Mineralocorticoids
–Aldosterone
– Androgens
Biosynthesis
– Corticosteroids
• 21 ‘C’ compounds
• Have cyclopentanoperhydro-phenanthrene
(steroid) nucleus
• Synthesized in adrenal cortex from cholesterol
• Synthesis takes place under the influence of
ACTH
• Rate of release is governed by rate of synthesis
Adrenal gland
HPA axis & immune inflammatory network
CORTICOSTEROIDS
I .GLUCOCORTICOIDS
a) Short-acting
- Hydrocortisone (cortisol) - cortisone
b) Intermediate-acting
- Prednisolone
- Methylprednisolone
- Triamcinolone
- Deflazacort
c) Long-acting

149
- Betamethasone
- Dexamethasone
d) Inhalational Glucocorticoids
- Beclomethasone
- Budesonide
- Ciclesonide
- Flunisolide
- Mometasone
- Fluticasone
II. MINERALOCORTICOIDS
- Fludrocortisone
- Desoxycorticosterone acetate (DOCA)
MINERALOCORTICOIDS
• Show effect on Na⁺, K⁺ & fluid balance
• MOA – Acts on DCT in kidney
– Bind to MR (mineralocorticoid Receptors)
• ↑ Na⁺ reabsorption
• ↑K⁺ excretion
• ↑ H⁺ excretion
• Adverse effects (with high dose)
– Sodium & water retention – main
– Hypertension – main
– Hypokalemia & Alkalosis
– Promotes CHF associated myocardial fibrosis
GLUCOCORTICOIDS
Mechanism of action
• Glucocorticoids enter cell & interact with
Glucocorticoid Receptors (GR) in cytoplasm –
conformational change occur in GR –
glucocorticoid receptor complex migrates into
nucleus & bind to glucocorticoid response
element (GRE) on chromatin → promote
transcription of specific m-RNA → regulation
of protein synthesis
Intracellular mechanism of action of Glucocorticoids
Physiological functions/Pharmacological actions
• Carbohydrate & Protein metabolism
– ↑ Blood glucose level by:
• Stimulating gluconeogenesis & glycogen
synthesis

150
 • ↓ Peripheral utilization of glucose by skeletal
muscle & adipose tissue
• ↑ Protein breakdown
• Fat metabolisim
• Promote lipolysis
• Cause redistribution of fat → moon face &
buffalo hump
• Electrolyte & Water balance
– Glucocorticoids play a permissive role in renal
excretion of water – maintain normal g.f.r.
– ↓ Total body Ca²⁺ stores by:
• ↓ Ca²⁺ uptake from gut
• ↑ Ca²⁺ excretion by kidney
• Cardiovascular system
– Positive inotropic action on heart
– Potentiate pressor response of blood vessels to NA
– Chronic admn. → Hypertension
• Skeletal muscle
– Maintain normal muscular activity
– Muscle weakness occur
• In hypocorticism – due to hypodynamic circulation
• In hypercorticism – due to hypokalemia & muscle
wasting
• Central nervous system
– High doses of Glucocorticoids → mood elevation,
euphoria, nervousness, restlessness, insomnia,
psychosis & ↑ motor activity
• Hematological actions
– ↑ Circulating RBCs & platelets
– ↓ Lymphocytes, monocytes, eosinophils & basophils• Anti-
inflammatory & Immunosuppressive actions
– Inhibit phosphlipase A in arachidonic acid
metabolism → ↓PGs & LTs production
– Suppress – all components, stages & cardinal signs
of inflammation by:
• ↓Increased capillary permeability
• ↓ Local exudation
• ↓ Cellular infiltration
• ↓ Phagocytic activity
• ↓ Late responses – capillary proliferation, collagen

151
deposition, fibroblastic activity & scar formation
– Favour spread of infection
– Interfere with healing & scar formation
Pharmacokinetics
• Route of admn.
–Oral – Hydrocortisone & its congeners,
including synthetic analogs
– IM or IV – Esters of hydrocortisone & its
synthetic congeners
– Inhalation – Beclomethasone & budesonide
& etc.
– Topical – Betamethasone, Dexamethasone &
Hydrocortisone• Hydrocortisone – plasma t ½ – 1.5 hrs.
• Biological t ½ – longer than plasma t ½
• Metabolized primarily by hepatic microsomal
enzymes
• Synthetic derivatives – resistant to metabolism
– longer acting
• Metabolites – excreted in urine
INDIVIDUAL DRUGS & THEIR FEATURES
Hydrocortisone
– Onset of action – Rapid
– Duration of action – Short
– Activity – Glucocorticoid (Primary)
– Minerolocorticoid (significant)
– Uses
• Replacement therapy – 20mg morning + 10mg
afternoon orally
• Shock, status asthmaticus & acute adrenal
insufficiency – 100mg IV bolus + 100mg 8th
hourly IV infusion
• Ulcerative colitis – as suspension for enema
Prednisolone
– 4 times more potent than hydrocortisone
– More selective glucocorticoid
– Duration of action – Intermediate
– Fluid retention occur with high dose
– HPA suppression – less with single morning
dose/alternate day treatment
– Uses

152
• Allergic, inflammatory & autoimmune diseases
• Malignancies
• Dose – 5-60mg/day oral
Methylprednisolone
– Slightly more potent & more selective than
prednisolone
– Uses
• Ulcerative colitis – As retention enema
• Rheumatoid arthritis, pemphigus & renal
transplant pts. – 1g IV infusion every 6-8 weeks
Triamcinolone
– More potent than prednisolone
– Highly selective glucocorticoid
– Dose – 4-32mg/day oral
– 5-40mg IM, intra-articular inj.
–Topical
Dexamethasone & Betamethasone
– Very potent & highly selective glucocorticoid
– Long acting
– Causes marked HPA axis suppression
– Do not cause fluid retention & hypertension
– Uses
• Allergic & inflammatory conditions – 0.5-1mg/day
oral
• Shock & cerebral edema – 4-20mg/day IV infusion
or IM inj.
• Topical
Fludrocortisone
– Potent mineralocorticoid
– Glucocorticoid activity – limited
– Uses
• Addison’s disease, congenital adrenal hyperplasia
& idiopathic postural hypotension
Desoxycorticosterone acetate (DOCA)
– Mineralocorticoid activity only
– Use
• Addison’s disease – occasionally as replacement
Therapy
Therapeutic uses
• REPLACEMENT THERAPY

153
– Acute adrenal insufficiency
• Associated with disorders of adrenal glad or
abrupt withdrawal of Glucocorticoids
• An emergency condition characterized by – GI
symptoms, dehydration, hyponatremia,
hyperkalemia, weakness, lethargy and
hypotension
• Hydrocortisone/Dexamethasone
– 100mg IV bolus followed by 100mg 8th hrly.
Infusion (With isotonic saline & glucose
solution) – CVP should be monitored
– Chronic adrenal insufficiency (Addison's disease)
• Present with same manifestations of acute
insufficiency but with less severity
• Hydrocortisone – 20mg morning + 10mg afternoon
orally
• With adequate salt & water allowance
• Fludrocortisone may be added in some pts.
– Congenital adrenal hyperplasia
• Genetic deficiency of steroidogenic enzymes
results in ↓ synthesis of hydrocortisone &
aldosterone → ↑ACTH release
• Hydrocortisone in divide doses + Fludrocortison
• USES IN NONENDOCRINE DISEASES
– Empirical & palliative, but may be life saving
– Following general principles must be observed:
• A single dose – not harmful
• Short courses – not likely to be harmful
• Long-term use (high doses) – potentially
hazardous
• Initial dose – depends on severity of disease
• No abrupt withdrawal of therapy after >2
weeks of treatment
• Use local therapy wherever possible
– Rheumatoid arthritis
• In severe cases – Prednisolone 5-10mg given as
adjuvant to NSAIDS
– Osteoarthritis
• In acute exacerbation – intra-articular inj.
• Repeated inj. → joint destruction

154
– Rheumatic fever
• In severe cases – Glucocorticoids provide faster
relief
-GOUT
• In acute gouty arthritis – intra-articular inj
.– Collagen diseases
• In SLE, polyarteritis nodosa, dermatomyositis,
nephrotic syndrome & glomerulonephritis
• Glucocorticoids – life saving drugs – started with
high dose later tapered to maintenance dose
– Severe allergic reactions
• In anaphylaxis, angeoneurotic edema, urticaria &
serum sickness
–Glucocorticoids given by systemic admn. for
short period as supplement to primary
therapy
• In allergic rhinitis & conjunctivitis
–Given by topical admn
.– Autoimmune diseases
• Autoimmune haemolytic anaemia, idiopthic
thrombocytopenic purpura, active chronic
hepatitis – respond to glucocoticoid therapy
• In myesthenia gravis – given as adjunct to
neostigmine
– Bronchial asthma
• In status asthmaticus – given parenterally &
should be withdrawn after emergency
–Eg. Hydrocortisone
• For chronic prophylaxis – given by inhalation
–Eg. Beclomethasone, mometasone etc
.– Other lung diseases
• In premature labor – given to pregnant pts.
–To accelerate lung maturity in fetus
–To prevent respiratory distress syndrome,
intraventricular hemorrhage at birth
• Aspiration pneumonia
• Pulmonary edema from drowning
-INFECTIVE DISEASES
• Only in serious infective diseases – Glucocorticoids
given under chemotherapeutic cover

155
–Pneumocystis carinii pneumonia with hypoxia
in AIDS pts.
–H. influenza type b meninigitis in children <2 yrs
– Ocular diseases
• Used in inflammatory ocular diseases –
Glucocorticoids preventblindness
–In diseases of ant. Chamber – allergic
conjunctivitis, iritis, iridocyclitis & keratitis –
Topical admn.
–In diseases of post. Chamber – retinitis, optic
neuritis & uveitis – systemic admn.
• Glucocorticoids C/I in – herpes simplex keratitis,
ocular injuries & infective conditions
– Skin diseases
• In eczema – Topical admn.
• In pemphigus, exfoliative dermatitis & other severe
dermatological conditions – systemic admn.
– Gastrointestinal diseases
• In inflammatory bowel diseases – ulcerative colitis
& crohn’s disease – oral admn. or retention enema
– Cerebral edema
• In Cerebral edema associated with parasites &
neoplasms
– Malignancies
• In ALL & Lymphomas
–Glucocorticoids act by their lympholytic action
– Thrombocytopenia
• Glucocorticoids – decrease bleeding tendency
– Organ transplantation
• Glucocorticoids given with other
immunosuppressants – Prevent rejection
reaction
– Thyroid storm
• Glucocorticoids – inhibit conversion of T₄ to T₃
– To test adrenal-pituitary axis function
• After Dexamethsone admn. – steroid metabolite
excretion measured in urine daily to know
axis function
Adverse effects of Glucocorticoids
• Adverse effects – related to individual susceptibility,

156
dosage & duration of therapy
– Cushing’s habitus
• Moon face, narrow mouth, supraclavicular
hump & obesity of trunk with relatively thin
limbs – due to redistribution of fat
– Skin
• Fragile skin, purple striae, easy bruising &
hirsutism
• Cutaneous atrophy – on topical use
– Metabolic effects
• Hyperglycaemia with glycosuria – Might
precipitate diabetes
– Suppression of inflammatory & immune response
• Risk of reactivation of latent tuberculosis
• Risk of superinfection with bacteria & fungi
– Hypertension
• With high doses
– Proximal myopathy
• Weakness of proximal limb muscles – with large
dose
• In severe cases – withdraw corticosteroids
– Delay healing
• Wounds & surgical incisions
– Peptic ulceration
• Acute gastritis, Bleeding & perforation of peptic
ulcer
– Retardation of linear growth
• In children receiving high doses of
glucocorticoids
– Behavioral changes
• Nervousness, insomnia, changes in mood &
Psychosis
– Osteoporosis
• Fracture of ribs & vertebrae – occur with
chronic therapy
–Can be prevented by Ca²⁺ supplementation,
Vit. D & Bisphosphonates
– Osteonecrosis
• Avascular necrosis of head of femur & humerus
→ joint pain & stiffness

157
– Cataract
• Posterior subcapsular cataract – occur with
long-term systemic glucocorticoid therapy
• Periodic slit-lamp examination should be done
to detect
– Glaucoma
• Occur after prolonged topical therapy
– Foetal abnormalities
• Steroids can lead to subtle abnormalities in
foetal development
– Suppression of Hypothalamo-Pituitary-Adrenal
(HPA) axis
• Prolonged glucocorticoid therapy for >2 wks →
Suppression of Hypothalamo-Pituitary-Adrenal
(HPA) axis & Adrenal cortex atrophy → abrupt
stoppage of therapy → Acute adrenal
Insufficiency
• Withdrawal of therapy → fever, malaise, arthralgia,
myalgia, postural hypotension & reactivation of the
disease etc..... (withdrawal syndrome)
• To minimise HPA axis suppression
–Gradual withdrawal of therapy
–Use short-acting corticosteroids at lowest
possible dose
–Use for shortest period of time
–Give entire daily dose at one time in the
morning
–Switch to alternate day therapy if possible
–If appropriate, local preparations should be
Used
Contraindications
• Relative contraindications of Corticosteroids
are:
– Peptic ulcer
–Diabetes mellitus
–Hypertension
– Viral & Fungal infections
– Tuberculosis & Other infections
–Osteoporosis
–Herpes simplex keratitis– Psychosis

158
– Epilepsy
– CHF
– Renal failure
• Corticosteroids aggravate all above diseases
• Fixed dose combination of any drug with
corticosteroids for internal use – Banned
HYPERCORTISOLISM
• Hypercortisolism (↑secretion of corticosteroid
hormones) caused by:
– Corticotroph adenomas – over produce ACTH
– Adrenocortical tumors or bilateral hyperplasias –
over produce cortisol
– Adrenocortical carcinomas
– Ectopic ACTH- or CRH- producing tumors
- - - -→ ↑ Corticosteroid production
• Treatment of choice – Surgery
• Adjuvant therapy – Drugs
Drugs used in Hypercortisolism
I. Inhibitors of steroidogenesis
–Ketoconazole
– Metyrapone
–Etomidate
– Mitotane
– Inhibit adrenal steroidogenesis
II. Glucocorticoid antagonist
– Mifepristone
– Acts as antagonist on glucocorticoid receptors(GR)
III. Mineralocorticoid antagonists
– Spironolactone
– Eplerenone
– Act as antagonists on mineralocorticoid receptors
(MR)

159
 CONTRACEPTIVE DRUGS
• Contraceptive drugs – used to prevent
conception
• Family planning – The limitation and spacing of
births in the best interests of mother, child and
rest of the family
Physiology of human reproduction
• At the time of puberty human ovary contains
3,00,000 immature follicles – of which only about
400 mature during reproductive life – of these
only a few get fertilized• Under the influence of FSH ovarian follicle
mature
→Sudden midcycle spurt of LH followed by ovulation
(occurs on day 14 ± 2 of 28 day cycle)
→Oocyte within 12 hrs. reaches ampullary region of
fallopian tube (where fertilization takes place)
→By 18th day of cycle fertilized ovum gets converted
to blastocyst & reaches uterine cavity
→By 21-23rd day of cycle blastocyst begins to get
implanted
→Implantation stage gets completed by 35th day of
cycle• Ovulation may be judged by noting:
– Changes in the cervical mucus
– Vaginal cytology
– Serum progesterone level
– Endometrial biopsy
– Rise in basal body temperature• Fertility can be controlled by
using drugs
which can act by:
– Inhibiting ovulation
– Modifying cervical mucus
– Interfering with implantation
– Slowing down rate of egg transport
– Preventing ovum maturation & sperm
capacitation
– Immunological methods
– Inhibiting spermatogenesis
Contraceptive drugs
I. In Females

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1. Oral Contraceptive Pills (OCPs)
a. Combination Pills c. Emergency Pills
b. Minipills
d. Centchroman(saheli)
2. Injectable Contraceptives
3. Contraceptives implants
4. Progestasert (IUCD)
5. Vaccines
II. In Male
Gossypol
Oral Contraceptive Pills (OCPs)
• Drugs administered orally for contraception
• Convenient, affordable & reliable
– For family planning
– For prevention of unwanted pregnancy
COMBINATION ORAL CONTRACEPTIVE (COC) PILLS
• Popular because of their:
– efficacy, safety, ease of admn. & cost effective
• Combination of estrogen & progestin:
Estrogen
(Ethinylestradiol/Mestranol)
+
Progestin
(Levonorgestrel/Norgestrel/Desogestrel or Norethindrone)
• MOA (as contraceptive)
– Estrogen
• Suppresses FSH rise – inhibits follicular growth
– Progestin
• Suppresses LH peak (surge) – inhibits ovulation
• Increases the certainty of contraceptive effect
• Modifies cervical mucus – makes it thick, more
viscous & hostile to penetration of sperm
• Prevents breakthrough bleeding
• Ensures withdrawal bleeding at the end of cycle
• Reduces menstrual blood loss
• Blocks risk of endometrial carcinoma due to
estrogen• Methods of administration:
– Monophasic Pills
– Biphasic Pills

161
– Triphasic Pills
• Monophasic Pills
• Fixed dose combination (Estrogen+Progestin) pills
• Oral admn. – 1 pill at bedtime – 5th day 25th day (21
days) of 28 day cycle
• Next – 7 days after last dose / 5th day of menstrual cycle
• In Abortion & MTP – Pills started on same day
• After delivery – if breast feeding – Avoid COC pills
– if not feeding – Pills started in 3rd post partum week
• Efficacy – 99-100%• Biphasic & Triphasic Pills
• Estrogen & Progestin – combined in varying proportions
– In early cycle – Estrogen + Progestin (both in low dose)
– In later cycle – Estrogen + ↑ dose of Progestin
– Biphasic Pills – 1-10 days (low dose), 11-21 days (↑ dose
of Progestin)
– Triphasic Pills – 1-7 days (low dose), 8-14 days (↑ dose of
Progestin), 15-21 days (↑↑ dose of Progestin)
• Complex to use & expensive
• Recommended – in women – > 35 years
– women with breakthrough bleeding or
no withdrawal bleeding with monophasic
– with other risk factors• Monophasic pills
– Ethinylestradiol 50µg + Levonorgestrel 0.25mg
– Ethinylestradiol 30µg + Levonorgestrel 0.15mg
– Ethinylestradiol 20µg + Levonorgestrel 0.1mg
– Ethinylestradiol 30µg + Desogestrel 0.15mg
– Ethinylestradiol 20µg + Desogestrel 0.15mg
• Biphasic pills
– Ethinylestradiol 35µg + Norethindrone 0.5, 1.0mg
• Triphasic pills
– Ethinylestradiol 35µg + Norethindrone 0.5, 0.75,
1.0mg
• Practical considerations of combination pills
– Discontinuation of COC pills results in full return of
fertility within 1-2 months
– If a woman on COC Pills misses to take a tablet, she
should take two tablets on the next day & continue as
usual

162
 – If ≥ 2 pills are missed – course should be continued –
along with the use of barrier method for 7-10 days–
next course started on 5th day of menstrual bleeding
– If pregnancy occurs during use of OCPs
• Pregnancy should be terminated (risk of
malformation, genital carcinoma in female offspring
& undescended testes in male offspring)• Pharmacological actions
( COC pills)
• UTERUS
– Prolonged use
• Endometrium – thin and hypoplastic
– Less bleeding
• Cervix – Hypertrophy & polyp formation
– Mucus – thicker & less copious
• OVARY
– Chronic use – depresses ovarian function
– ovaries become small
• BREAST
– Suppress lactation• OTHER EFFECTS
1. CNS – Change in mood & behavior (low incidence)
2. Endocrine function
– Inhibits pituitary gonadotropin secretion
– ↑ plasma T4 & Cortisol
3. Blood
– Thromboembolic phenomenon occurs – due
to ↑ clotting factors (VII, VIII, IX, X & ↓ AT III)
– ↑Platelet aggregation & adhesion
– ↓Activity of fibrinolytic system
4. liver
– Abnormal LFT
– Increases cholelithiasis5. Carbohydrate metabolism
– Hyperglycemia & ↓ glucose tolerance
6. Lipid metabolism
– ↑LDL & ↓HDL
7. CVS
– ↑ HR, CO & BP
8. Skin
– ↑ pigmentation of skin

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 • Adverse effects
– GENERAL
• Nausea, vomiting & anorexia
• Breast engorgement & suppression of
lactation
• Weight gain – due to edema
• Blurring of vision
• Mental depression
• Vaginal infection (vaginal candidiasis)
• Decrease serum levels of Pyridoxine, Folic
acid, Vitamin C, Calcium & Zinc– BLEEDING IRREGULARITIES
• Breakthrough bleeding
• Spotting
• Failure of withdrawal bleeding
• Temporary amenorrhea for 1-2 cycles – rare
• Conception may be delayed for 3-12 months
– THROMBOEMBOLIC PHENOMENA
• Venous thromboembolism, pulmonary embolism,
coronary & cerebral thrombosis (MI & Stroke)
–Related to concentration of estrogen
component
–Risk is more in women > 35 years
–Headache is the warning symptom– WORSENING OF MIGRAINE –
discontinue OCPs
– HYPERTENSION
• Due to increase in plasma angiotensinogen level &
renin activity and also salt and water retention
– LIVER
• Abnormal LFT, Gall stones & benign hepatomas
• Acute hepatitis – OCPs should be stopped
– UTERINE FIBROIDS
• Size of fibroids can undergo enlargement
– CARCINOGENICITY
• Risk of breast cancers
– SKIN PIGMENTATION – 5-40% - reversible
– ACNE & HIRSUTISM – due to androgen like progestins
• Absolute Contraindications
– Pregnancy; Carcinoma of breast & endometrium

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– Thromboembolic & Cerebrovascular disease
– Cardiovascular diseases – CHF, IHD, cardiomyopathy,
valvular heart disease, severe hypertension,
pulmonary hypertension & arterial thrombosis
– Active liver disease & hepatoma
– Hyperlipidaemia
• Relative contraindications
– Diabetes & Obesity – Mentally ill
– Migraine
– Uterine fibroids
– Smoking
– Gallbladder disease
– Age > 35 years
– Undiagnosed vaginal bleeding
• Drug interactions
– Antimicrobial drugs – interfere with enterohepatic
cycling of estrogen – ↓ efficacy of OCPs
– Rifampin, phenytoin, phenobarbitone, and
carbamazepine – inducers of CYP450 – ↓ efficacy
of OCPs
• Therapeutic uses
1. AS ORAL CONTRACEPTIVES
– Monophasic pills (low dose)
• In women with normal menstrual cycle
• Pt. with acne, hirsuitism, leg cramps & scanty
vaginal secretions
– Monophasic pills (high dose)
• In women with premenstrual tension,
edema, wt. gain, irregular & heavy bleeding
• In obese women– Biphasic/Triphasic pills
• Women >35 years who smoke & with
cardiovascular risk factors
2. EMERGENCY CONTRACEPTION
– Monophasic pills (high dose)
• 2 pills within 72 hrs. of coitus & 2 pills 12
hrs. later
3. POLYCYSTIC OVARY SYNDROME
– OCPs have depressant effect on ovaries
4. DYSFUNCTIONAL UTERINE BLEEDING

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5. PREMATURE MENOPAUSE
6. TURNER SYNDROME (XO karyotype)
– Initial Rx with estrogen → followed by OCPs
• Non contraceptive benefits of combination
OCPs
• Less menstrual blood loss – less iron
deficiency
• Lower incidence of endometrial & ovarian
cancer
• Protection against pelvic inflammatory
disease (PID)
• Reduces risk of ectopic pregnancy
Minipills
• Low dose progestin only pill
• Levonorgestrel 30 μg / Norethindrone 0.35 mg
/Norgestrel 75 μg/Norethisterone 350 μg
• Given orally – daily – continuously
• MOA
– reduces sperm penetrability of the cervical mucus
– impairs luteal function
– interferes with implantation
• Less reliable than that of COCs• Use – Suitable as contraceptive
• in pts. whom estrogen is contraindicated – Pts. with
hepatic disease, hypertension, psychosis &
thromboembolism
• For Breast feeding mothers (Ideal option) – should
be started 6 weeks after child birth
• Efficacy – 96-98%
• There is no delay in conception following
cessation of Mini pills
• If one pill is forgotten or delayed by 3 hrs. – does
not protect conception
• ADVERSE EFFECTS
– Causes irregular, short bleeding intervals &
spotting (most frequent adv. effects)
– Headache & dizziness
– Reversible reduction of glucose tolerance
• Non contraceptive benefits of Minipills
– Quality & quantity of breast milk remains

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unaffected by minipills.
– No estrogen side effects.
– May help prevent endometrial & ovarian cancer
and pelvic inflammatory disease.
Emergency contraceptive pills
• Also called as postcoital contrceptives/Morning after
pills
• Should be admn. within 72 hrs. of coitus
• Emergency contraceptive pills – are used along with
antiemetics
– Levonorgestrel 0.75 mg one tablet within 72 hrs.
repeated 12 hrs. later or 2 tab. once
– Ethinylestradiol 50 μg + levonorgestrel 0.25 mg 2 tab.
within 72 hrs. repeated 12 hrs. later
– Mifepristone 600 mg single dose within 72 hrs.
– Ulipristal 30 mg single dose orally within 5 days
– Copper containing IUCD within 5 days• MOA
– Interferes with tubal transport, implantation or causes
regression of carpus luteum (except mifepristone)
– Mifepristone (antiprogestin) – has luteolytic effect –
Interrupts pregnancy after implantation
• Adverse effects
– Nausea & vomiting – 40%
– Headache & dizziness
– Breast tenderness, abdominal & leg cramps
– Failure rate is high – If failure of contraception –
pregnancy should be terminated
– Next period may be delayed or disrupted
• Should be used only in unprotected sex and Rape
Centchroman (saheli)
• Ormeloxifene - Nonsteroidal SERM developed at CDRI,
India
• MOA – It induces utero-embryonic asynchrony – by
accelerating tubal transport and suppressing
proliferative changes of endometrium – prevents
implantaion
• Metabolised in liver, Long plasma t ½ - ~1 week
• Uses – Contraception - 30 mg twice weekly for 12 wks. –
followed by once a week as long as fertility to

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be suppressed
– DUB – 60 mg twice a week → once a week
• Adverse effects – prolongation of menstrual cycle &
enlargement of ovaries
Injectable Contraceptives
I. Long acting Progestin alone preparations
1. Depot-medroxyprogesterone acetate (DMPA)
• 150 mg IM once every 3 months
2. Norethisterone enanthate (NET-EN)
• 200 mg IM every 2 months
• Highly effective, long acting & produce reversible effects
• Therapy may be initiated
– During first 7 days of menstrual cycle
– Immediately after abortion or child birth (non
breast feeding mothers)
– In breast feeding mothers – after 6 weeks• Adverse effects
– Disruption of normal menstrual cycle (1/3 Pts), bleeding
irregularities & spotting (in first year of use)
– Weight gain & Amenorrhea (common with DMPA)
– Ovulation suppression can persist for long after last
injection (> 1 yr.)
– Not suitable for adolescent girls
II. Long acting progestin + long acting estrogen
preparation
1. DMPA + Estradiol cypionate
• Single IM inj. every month
• Advantage – reasonable menstrual bleeding pattern
• Disadvantages – adverse effects related to estrogen
Contraceptive implants
Levonorgestrel implant (Norplant)
• Each capsule contains 36 mg of levonorgestrel in
crystalline form
• Both biodegradable & non-biodegradable prepn. are
available
• 6 cap. admn. by subcutaneous implantation – effective
upto 5 yrs.
• Disadvantage – need for surgical insertion & removal
• Adverse effects
– Local infection

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– Irregular bleeding or amenorrhea (70% - in first year)
– Headache or visual disturbances
Progestasert (IUCD)
• Norgestrel releasing IUCD
• Effective for five years
• Acts locally on endometrium
• Uses
• As Contraceptive in women >35 years of age
• Menorrhagia
• Adverse effects
– ↑ incidence of ectopic pregnancy & infertility,
perforation of the uterus & ↑menstrual blood loss
Vaccine
hCG vaccine - Antifertility vaccine - Not much in use
Transdermal contraceptives
• Transdermal patch contains:
– Ethinylestradiol + Norelgestromin (metabolite of
norgestimate)
• Applied once a week for 3 successive weeks in
a month
• Delivers contained hormones continuously &
allows withdrawal bleeding
• As effective as combination OCPs
• Less effective in very obese women
• Adverse effects are similar to COCs
Male contraceptives
Gossypol
– Nonsteroidal compound obtained from cotton seed
– Dose 20 mg/day for 2-3 months followed by
40-60 mg /week orally
– Causes damage to seminiferous epithelium
• Suppresses spermatogenesis & ↓ sperm motility
– Takes 2-3 months to develop desired effect
– Adverse effects
• GI disturbances
• Hypokalemia, edema, breathlessness & neuritis.
• Permanent azoospermia – on prolonged Rx

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CHEMOTHERAPY OF TUBERCULOSIS
Dr. Sam Pavan Kumar
• Caused by Mycobacterium tuberculosis / bovis
• Discovered by Robert Koch in 1882
• Spreads by droplet infection
• Small size of bacillus, remains airborne for many
hours » source of spread to many
Tb. is difficult to treat: reasons –
Slow growing/multiplying
Caseous lesions:- “persisters”
- decreased blood supply, drug
does not reach the organisms
Remain viable and multiply inside macrophages
Deficient CMI » spread of disease in body
Development of drug resistance
CLASSIFICATION OF DRUGS USED IN TB.
a) Standard / First line drugs:
Bactericidal: Isonicotinic acid hydrazide(INAH)
Rifampicin
Streptomycin
Pyrazinamide
Bacteriostatic: Ethambutol
Thiacetazone
b) Reserve / Second line drugs:
Bactericidal: Capreomycin
Kanamycin
Amikacin
Flouro-Quinolones
Bacteriostatic: Ethionamide
Cycloserine
Clofazamine
A SINGLE DRUG SHOULD NEVER BE USED IN
TREATMENT OF TUBERCULOSIS
INAH:
- Is active against actively growing bacilli
- Penetrate into phagocytic cells » thus active
against intra and extracellular organisms
MOA:
• Converted to active metabolite by mycobacterial
catalase-peroxidase enzyme » inhibits synthesis of

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mycolic acids
( mycolic acids – unique to mycobacteria and
are important constituent of mycobacterial cell
wall )
Kinetics:
o Well absorbed after oral administration
o Food interferes with absorption, hence
administered on empty stomach
o Plasma concentration similar for oral and
parenteral route of administration
o Well distributed to all body fluids and tissues
Metabolism:
- Undergoes acetylation reaction in the liver
Rapid acetylation / acetylators
Slow acetylation / acetylators
Rapid acetylation » faster metabolism »
accumulation of intermediate toxic metabolite -
acetyl hydrazine » hepatotoxicity
Slow acetylation » slower metabolism »
accumulation of INAH » inhibits Pyridoxal kinase
which takes part in formation of Vit B6
(Pyridoxine) » deficiency of B6 » Peripheral
neuropathy
Excretion: mainly by kidney
but is safe even in renal failure
Adverse effects:
Hepatitis
Peripheral neuropathy
Rash
Fever
Shoulder- Hand syndrome
Agranulocytosis
Thrombocytopenia
Precipitate convulsions in patients with
epilepsy
Optic neuritis
Uses:
- Treatment of tuberculosis
- Prophylaxis of tuberculosis
RIFAMPICIN

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• Is a semisynthetic derivative of Rifamycin B
• Rifamycins are groups of structurally similar
complex macrocyclic antibiotics produced by
Streptomyces mediterranei
• Rifamycins include: Rifampin/Rifampicin
Rifabutin
Rifapentine
Spectrum of activity:
- gm+ve : Staph
- gm-ve : E.coli, Pseudomonas, Proteus,
Klebsiella, H.influenza
-others: Chlamydia, Legionella, Mycobacteria
Mech.of action:
- Rifampin binds to the β subunit of bacterial
DNA-dependant RNA-polymerase, forming a complex,
leading to suppression of initiation of chain formation
(not elongation) in RNA synthesis
- it does not bind to human RNA polymerase enzyme
Kinetics:
- Well absorbed after oral administration
- Food interferes with absorption
- Penetrates well into all body fluids and tissues
- Is the only Anti-TB drug that is active against
“persisters”
- Metabolized in liver
- Both the unaltered drug and the metabolites are
secreted into the bile
- Unaltered drug is reabsorbed from the intestine
and undergoes entero-hepatic circulation
- Dosage need not be adjusted in renal failure
Uses:
o Chemoprophylaxis :
Meningococcal meningitis
H.influenza meningitis
o R. + Beta-lactum / Vancomycin:
Staph.encarditis
Staph.osteomyelitis
o R. + Ceftrioxone / Vancomycin:
Penicillin resistant Pneumococcal meningitis
o Eradication of Staph.nasal carriers

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 o In infected pts. with leucopenia
o In treatment of Tuberculosis
o In treatment of Leprosy
Adverse effects:
• Hepatitis
• Flu-like-syndrome (fever, chills, myalgias,
eosinophilia, interstitial nephritis, acute tubular
necrosis, thrombocytopenia, anemia)
• Light chain proteinuria
• Is a potent inducer of hepatic cytochrome P-450
enzymes: CYP 1A2, 2C9, 2C19, 2D6, 3A4 »
accelerates metabolism of Methadone, Warfarin,
Gluco-corticoids, Estrogens, Propranolol,
Quinidine, Digoxin, Sulfonylureas
• Gives reddish-orange color to urine, saliva, sweat,
tears etc.
STREPTOMYCIN:
- Is an Aminoglycoside antibiotic
- First effective anti – TB drug
- Is bactericidal against extracellular organisms, has no activity
against intracellular organisms or
persisters
Mech.of action:
- Enter through the aqueous porin channels of the
bacteria and inhibit protein synthesis by
interfering with translation of mRNA
- Both primary(2-3%) and secondary resistance
seen to streptomycin
Kinetics:
- Given by IM route, painful
- Penetrates only inflamed meninges
Adverse effects:
- Ototoxic: vertigo, ataxia, hearing loss
- Nephrotoxic: less
Uses: Mycobacterial inf., Bacterial endocarditis,
Tularemia, Plague etc.
PYRAZINAMIDE:
• is a semisynthetic derivative of nicotinamide
• Exhibits bactericidal activity at slightly acidic pH
Mech.of action:

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- Is converted to pyrazinoic acid by mycobacterial
enzyme pyrazinamidase which inhibits
mycobacterial fatty acid synthase gene1, involved
in mycolic acid biosynthesis
» inhibition of mycolic acids and cell wall synthesis
- Is a “sterilizing agent” – penetrates macrophages
and monocytes, & exhibit cidal action
Kinetics:
- Well absorbed when given orally
- Widely distributed and penetrates all tissues,
including CSF
- Primarily excreted by renal glomerular filtration
Adverse effects:
• Hepatotoxicity
• Inhibits uric acid excretion » hyperurecemia »
precipitation of gout
• Others: arthralgias, anorexia, N, V, dysuria, fever
ETHAMBUTOL
- Is bacteriostatic
- Is active against mycobacteria only
Mech.of action:
- Inhibits mycobacterial arabinosyl transferase
which is involved in the polymerization reaction of
arabinoglycan, which is an essential component of
mycobacterial cell wall
Kinetics:
- Well absorbed orally
- Excreted unchanged in urine
Adverse effects:
o Optic neuritis: - ↓visual acuity
- loss of ability to differentiate red
from green color
- is dose related
- is reversible
- contraindicated in children due to
inability to check visual acuity
in them
o ↓uric acid excretion » hyperuricemia » gout
o Others: rash, drug fever, joint pains, N, V,
headache, mental confusion

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THIACETAZONE
Is bacteriostatic
Used along with INAH
Causes Steven Johnson syndrome, fever, rashes,
anemia, granulocytopenia, liver and kidney
damage
Not used now-a-days
DOSES OF ANTI-TB DRUGS:
5 mg/kg body wt - INAH
10 mg/kg body wt - Rifampicin
15 mg/kg body wt - Streptomycin
20 mg/kg body wt - Ethambutol (15 – 25 )
25 mg/kg body wt - Pyrazinamide (15 – 30 )
RESERVE DRUGS
ETHIONAMIDE:
• Is structurally and chemically related to INAH
• Blocks mycolic acid synthesis
• Given orally; dose 250-500 mg/day
Adverse effects:
- GI irritation – most common
- Severe postural hypotension
- Depression
Peripheral neuropathy
- Drowsiness
Olfactory disturbances
- Convulsions
Dizziness
• Blurred vision
Diplopia
• Skin rashes
Acne
• Gynaecomastia
Impotence
• Alopecia
Hepatitis
- Pyridoxine needs to be given concomitantly
PARA-AMINO SALICYLIC ACID (PAS)
- Is a structural analogue of PABA
- Action similar to Sulfonamides
- Given orally; dose 10-12 gms/day

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- Excreted by kidney
- Probenicid decreases renal excretion
- Is gastric irritant
Adverse effects:
• Mainly GI, hypersensitivity, skin eruptions, fever,
joint pains, sore throat, hematological
CYCLOSERINE
• Is an antibiotic with broad spectrum action
• Active against: Mycobacteria, E.coli, Staph,
Nocardia, Chlamydia
• Given orally and parenterally
• Crosses BBB
• Not metabolized
• Excreted by kidney
Adverse effects:
- Mainly CNS
- Pyridoxine should be given with it
CAPREOMYCIN
- Is a polypeptide antibiotic
- Inhibits protein synthesis (similar to Streptomycin)
- Is nephrotoxic and ototoxic
- Dose: 15mg/kg/day
FLOUROQUINILONES:
Ofloxacin, Levofloxacin, Ciprofloxacin
RIFAMYCINS:
include Rifampin, Rifapentin, Rifabutin
Rifabutin:
• Derivative of Rifamycin – S
• Activity similar to Rifampin, but better against
MAC
• Cross resistant with Rifampin present
• Is an enzyme inducer, but less potent than
Rifampin
• High tissue concentration
• Eliminated in urine and bile
Adverse effects:
- rash, GI intolerance, neutropenia, uveitis,
arthralgias, thrombocytopenia, flu-like syndrome,
hemolysis, hepatitis
Uses:

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- Prevention of atypical mycobacterial infections in
AIDS
- In treatment of atypical mycobacterial infections
in AIDS, along with Protease inhibitors & NNRTIs
- Prophylaxis of TB
RIFAPENTIN
• active against M.tb and MAC
• Similar to Rifampin
DRUGS FOR MAC
Rifabutin
Macrolides: Azithromycin, Clarithromycin
Fluoroquinilones: Cipro, Levo, Oflox
Clofazamine
Amikacin
PROPHYLAXIS OF TB:
Primary
Secondary
a) Primary: those exposed to TB
no infection
Tuberculin –ve (infants; < 3yrs age)
- INAH: 5mg/kg/day, for 3 months
b) Secondary: infected
*conversion from –ve to +ve skin test in
last 2 years
*those with h/o TB but the disease is
inactive at present
- give INAH x 12 months
BCG VACCINE
• Prepared from bovine TB bacillus(Bacille Calmette Guerin)
• Live, attenuated
• Aim: to increase patient’s resistance by producing
artificial primary TB locally
• Dose: 0.1ml, intradermal, upper half of left deltoid
• Rare complications: cold abscess(give antibiotics)
• Useful: in tuberculin –ve school children
in contacts of cases with active TB
in persons living in areas with high incidence
of TB
• Efficacy: 0 – 80 % (upto 70% against TB meningitis
and miliary TB)

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• Contraindicated: in symptomatic HIV infections
• Current concept: immunostimulant (used
intravesical for prevention of bladder cancer)
DIRECTLY OBSERVED TREATMENT SHORT
COURSE / STRATEGY (DOTS)

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 CHELATING AGENTS
Dr Ch Anil
HEAVY METALS
• Heavy Metal acts as general protoplasmic poison, thus impairing
cell function
• Heavy metals exert toxic effects by combining with and
inactivating functional groups(ligands) of enzymes or other critical
biomolecules
• Exert toxic effects by combining with several
reactive groups like SH groups, essential for
normal physiological functions
CHELATING AGENTS
Chelation : The process by which the organic
compounds combine with the metals to form
relatively stable, non-toxic, water - soluble &
easily excreted ring complexes (chele - claw),
compounds being designated as chelating agents
Chelating agents: Compounds having two or more reactive
groups(ligands) which can form a ring by holding the metal at least from
two sides
• When ring is 5-7 membered, it is most stable
• They prevent or reverse the binding of metallic ion to ligands of
body & enhance excretion of Metals
• Chelating agents compete with body ligands for the heavy metal
• They differ in their affinity for different metals
• These are drugs which complex metallic ions,
forming ring structures within their molecule
• Greek Chele = Crab; compound holds the metal like a crab’s claw
• They are primarily used in heavy metal poisonings
Clinically useful chelating agents
• Should have higher affinity for toxic metal than for calcium (Ca2+
is readily available in plasma and ECF)
• Should also have higher affinity than body ligands for toxic metal
• Their distribution in the body should correspond to that of the
metal to be chelated, and they
should be water soluble
• Efficacy of all chelating agents declines rapidly as interval between
entry of metal in the body & administration of chelator increases
CHELATING AGENTS
• Dimercaprol (British antilewisite; BAL)

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 • Dimercaptosuccinic acid (Succimer)
• Disodium edetate (Na2EDTA)
• Calcium disodium edetate (Ca Na2 EDTA)
• Penicillamine
• Desferrioxamine
• Deferiprone
• Deferasirox
DIMERCAPROL (British antilewisite ; BAL)
• Developed during World War-II
• as antidote to arsenical war gas “Lewisite”
• Oily , pungent smelling, viscous liquid
• The two SH groups of BAL bind those metals
which produce toxicity by binding with SH groups containing
enzymes in the body
• Complex of 2 molecules of dimercaprol with one metal ion is more
stable than 1:1 complex
• Desirable to maintain excess BAL in plasma to allow formation of
2:1 complex
• BAL - metal complex dissociates spontaneously
releasing metal at slow rate;
• BAL is partly oxidized in the body: further
emphasizing necessity to have excess BAL
available
• Urine is alkalinized during dimercaprol therapy –
because dimercaprol - metal complex dissociates faster in acidic
urine & released metal can damage kidney
• Due to dose dependent toxicity – large amounts should not be
given at a time
Uses:
• Poisoning by As, Hg, Au, Bi, Ni and Sb
Given i.m., 5 mg/kg stat, followed by 2–3 mg/kg every 4–8 hours for
2 days, then once or twice a day for 10 days
It is partly oxidized & glucuronide conjugated,but mainly excreted
as such in 4-6 hrs
• Lead poisoning: As adjuvant to Cal. disod. edetate
• As adjuvant to Penicillamine in Cu poisoning & wilson’s disease
A/E:
• Rise in BP, tachycardia, vomiting, tingling and
burning sensations, inflammation of mucous
membranes, sweating, cramps, headache

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 • Antihistamines given 30 min before dimercaprol inj., reduce
intensity of A/E
Contraindications:
• Fe & Cadmium poisoning because BAL – Fe & BAL – cadmium
complex is itself toxic
DIMERCAPTOSUCCINIC ACID (SUCCIMER)
• Structural analogue of dimercaprol
• Water soluble, less toxic and orally effective
• Effective in As, Hg and Pb poisoning
• Also chelate Cu and Zn
S/E :
• Nausea, anorexia and loose motions
DISODIUM EDETATE (NA2 EDTA)
• It is a disodium salt of ethylene diamine
tetraacetic acid
• Potent chelator of calcium
• Causes tetany on i.v. injection (but not on slow infusion)
• Can be used for emergency control of hypercalcaemia - 50mg/kg
i.v. over 2-4hours,but bisphosphonates are preferred
CALCIUM DISODIUM EDETATE (CaNa2EDTA)
• Calcium chelate of Na2EDTA
• High affinity for Pb, Zn, Cd, Mn, Cu and some
radioactive metals
• Removes the metals by exchanging with Ca held by it
• Highly ionized – distributed only extracellularly –
rapidly excreted in urine by glomerularfiltration
• Not metabolized
• Ionic nature - not absorbed from g.i.t
• Given IV – IM is painful
• Does not enter brain or CSF
USES:
• Lead Poisoning – 1 gm is diluted to 200-300 ml in saline and
infused i.v over 1 hr twice daily for 3-5 days
A second course is repeated after 1 week,
allowing time for Pb to redistribute to
extracellular sites
• Fe, Zn, Cu and Mn poisoning & radioactive metal
– but not in Hg poisoning as Hg is more firmly
bound to body constituents & is localized in areas not accessible to
CaNa2EDTA

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 ADRs:
• Kidney damage(Proximal tubular necrosis) –
dose related – toxic metal partly dissociate in
tubule – minimized by maintaining high urine
flow;
• febrile reactions – chills, body ache, malaise,
tiredness
• Anaphylactoid reactions with fall in BP
d-PENICILLAMINE
• Dimethylcysteine
• Degradation product of penicillin
• D –isomer is used therapeutically
• l –isomer – toxic (optic neuritis)
• Absorbed orally
• Little metabolized, excreted in urine and faeces
• It has strong copper chelating property and used for Wilson’s
disease
• It selectively chelates Cu, Hg, Pb and Zn
Uses:
Wilson’s disease (hepatolenticular degeneration) -
Penicillamine(0.5-1gm/day in divided doses)
Potassium sulfide 20mg with each meal -↓dietary Cu
absorption
Copper poisoning: Drug of choice
Mercury: alternate to BAL/succimer in Hg poisoning
Chronic lead poisoning: Adjuvant to CaNa2EDTA , but
Succimer is preferred
Cystinuria and cystine stones
Scleroderma – by increasing the soluble collagen
No more recommended in rheumatoid arthritis
PENICILLAMINE
A/E:
Short term administration –does not cause much problem
- Cutaneous reactions,itching, febrile episodes
may occur
Long term use – pronounced toxicity
–Dermatological, renal, hematological and
collagen tissue toxicities
TRIENTINE (TRIETHYLENE TETRAMINE)
• As effective as penicillamine in reversing

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 neurological lesions of wilson’s disease
• Less toxic than pencillamine
• 400-800 mg thrice daily on empty stomach
DESFERRIOXAMINE
• Ferrioxamine, long chain iron containing complex
- obtained from actinomycete
• Chemical removal of iron from it yields
desferrioxamine – has very high affinity for iron
• 1gm is capable of chelating 85mg of elemental iron
• Straight chain desferrioxamine winds round ferric iron and forms a
stable nontoxic complex which is excreted in urine
• Removes loosely bound iron as well as that from haemosiderin
and ferritin, but not from Hb or Cytochrome
• Low affinity for calcium
• Little of orally administered desferrioxamine is absorbed
• Parenterally – partly metabolized, rapidly
excreted in urine
Uses:
Acute iron poisoning: mostly in children,
important indication , which may be life saving
Transfusion siderosis – 0.5-1 gm/day i.m;
May also be infused iv concurrently with blood transfusion
A/E:
Fall in BP,flushing,itching,urticaria,rashes due to histamine
release
Allergic reactions
Changes in lens & retina – on repeated use
Abdominal pain,loose motions,muscle cramps, fever and dysuria
DEFERIPRONE
• Orally active
• Used in transfusion siderosis(Thalassemis pts)
• Used to clear resulting iron overload due to
repeated blood transfusions in thalassemia
• Less effective, alternative to injected desferrioxamine
• Side effects and cost of treatment are reduced
• Also used for acute iron poisoning (less effective than
desferrioxamine)
• Facilitate removal of iron load in liver cirrhosis
DEFERIPRONE
S/E:

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 • Anorexia, vomiting, altered taste, joint pain,
reversible neutropenia, rarely agranulocytosis
DEFERASIROX
• Oral,selective iron chelator given once daily
• Used in pts with chronic iron overload due to repeated blood
transfusion in thalassemia
• Has high affinity for iron
A/E:
• Nausea,epigastricpain,headache,pruritus,
rash
• GI ulceration & hemorrhages

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CEPHALOSPORINS
Dr. Sam Pavan Kumar
Professor• Are originally derived from the fungus –
Cephalosporium acremonium
• Now semi-synthetic preparations are available
Cephamycins:
are similar to Cephalosporins
But derived from Actinomycetes
Ex: Cefoxitin, Cefotetan
2S O H R₁ C N C C C B A C N C CH₂ R₂ O CCOOH
3• Consists of a β lactam ring and dihydro-thiazine
ring
• The nucleus of cephalosporins:
7-amino cephalosporanic acid
• Substitutions at R₁ alter the antimicrobial activity
• Substitutions at R₂ alter the pharmacokinetics and
metabolic parameters
4Classification of Cephalosporins:
- Classified into 4 generations: 1st,2nd,3rd and 4th
- It also depends on the spectrum of activity
1st generation:
Oral
Parenteral
Cephalexin
Cefazolin
Cephadroxil
Cephalothin
Cephradine
2nd generation:
Oral
Parenteral
Cefuroxime axetil
Cefuroxime
Cefaclor
Cefamandole
Cefprozil
Cefonicid
Loracarbef
Cefoxitin
Cefotetan

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Ceforanide
3rd generation:
Oral
Parenteral
Cefixime
Cefotaxime
Cefpodoxime proxetil
Ceftizoxime
Ceftibuten
Ceftriaxone
Cefdinir
Ceftazidime
Cefaperazone
Moxalactam
4th generation:
Parenteral
Cefipime
Cefpirome
Spectrum of activity:
- 1st gen. exhibits better activity against gm+ve org.
- 3rd and 4th gen. exhibits better activity against
gm-ve org.
Mech. of action:
- Similar to that of Penicillins
General features:
• Older gen. more susceptible to hydrolysis of
β lactam ring, while the newer gen. drugs are
relatively more resistant to β lactamases
• Are soluble in water
• Relatively stable to pH and temperature changes
• Among the parenterally given drugs:
Cephalothin – causes severe pain on IM inj.
hence given by IV route
Others – given either by IM or IV.
10General features (cont)
• Excreted primarily by the kidney
• Probenecid prolongs the duration of action
• Cross placenta
• Penetrate well into CSF: Cefuroxime, Cefoxitin,
Ceftriaxone, Cefepime, Ceftizoxime

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• Attain high concentration in synovial and
pericardial fluids
• High concentration in bile: Cefaperazone
1st Generation:
o Spectrum: mostly gm+ve – Strep., Staph.
some gm-ve – E.coli, Klebiella, Proteus
o Cephalexin & Cephradine: given 4 times a day
o Cefadroxil: given twice daily
Uses: URIs, minor Staph.inf., cellulitis, soft tissue
abscess, UTIs
o Cefazolin: given IM/IV, eighth hourly
narrow spectrum
less cost
effective in surgical prophylaxis
2nd generation:
• Spectrum: both gm+ve and gm-ve & anaerobic inf.
- Staph, strep, N.gonorrhoea,
N.menigitidis, Branhamella
- H.influenza, E.coli, Klebsiella,
Proteus, Enterobacter
- anaerobes likes B.fragilis
Uses: Sinusitis, Otitis, LRTIs, mixed anaerobic inf. like
peritonitis, diverticulitis
132nd generation (cont)
Cefuroxime:
- the only 2nd gen. Ceph. to penetrate into the CSF
- used in meningitis in children
- in community acquired pneumonia
3rd Generation:
Moxalactam:
- not a true cephalosporin
- it has Oxygen atom in place of Sulfur in
6-membered ring
3rd.gen.Ceph. differ from each other in
– pharmacokinetic properties
– antimicrobial activity
Spectrum: mostly active against gm-ve org.
less effective against gm+ve org.
- active against Neisseria, Branhamella,
H.influenza, E.coli, Klebsiella, Proteus, Morganella,

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Serratia marcescens, Citrobacter, Enterobacter
3rd generation (cont)
• Ceftriaxone: most active against N.gonorrhoea
• Ceftazidime & Cefoperazone: Pseudomonas
• Ceftizoxime & Moxalactam: B.fragilis
Pharmacokinetics:
- resistant to β lactamases
- good penetration into body fluids and tissues
3rd generation (cont)
• Cefotaxime: t½ 1 hr, dosing every 4 – 8 hours
• Ceftizoxime: t½ 1.8 hrs, dosing every 8 – 12 hours
• Ceftriaxone: t½ 8 hrs, dosing once a day
(given twice a day in severe infections)
• Ceftazidime: t½ 1.5 hrs, dosing 8th hourly
• Cefixime (oral): t½ 3 hrs, dosing once a day
- Mainly excreted by the kidney
- Cefoperazone (70%) and Ceftriaxone (50%)
excreted in bile {no dosage adjustment in renal insufficiency}
3rd generation (cont)
Uses:
- Meningitis due to Pneumococci, Meningococci,
H.influenza, Pseudomonas
- Sepsis
- Ceftriaxone & Cefixime: N.gonorrhoea
- Ceftazidime: in febrile neutropenic patients
4th Generation:
Ex: Cefipime, Cefpirome
• Highly resistant to β lactamases
• Very good activity against Pseudomonas,
Enterobacteriaceae, Staph.aureus,
Strep.pneumoniae, H.influenza, Neisseria,
Penicillin resistant streptococci
• 100% excreted by kidney
• Excellent penetration into CSF
• t½ 2hrs, dosing every 12th hourly
Adverse effects of Cephalosporins:
1) Allergy and hypersensitivity:
fever, skin rashes, nephritis, granulocytopenia,
hemolytic anemia, anaphylaxis
2) Superinfections

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3) Toxicity:
o local: pain at IM site
thrombophlebitis at IV site
o Cephaloridine: nephrotoxic - interstitial nephritis,
renal tubular necrosis
o Cefamandole, Cefotetan and Cefoperazone cause
hypoprothrombinemia and bleeding disorders.
o Cefoperazone: diarrhea
o Cefamandole, Cefotetan, Cefoperazone and
Moxalactam: disulfiram like reactions
o Pseudomembranous enterocolitis

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BROAD SPECTRUM ANTIBIOTICS
Dr. Sam Pavan Kumar
• Include : Tetracyclines
Chloramphenicol
TETRACYCLINES
Isolated from soil micro organisms
Chlortetracycline – Streptomyces aureafaciens
Oxytetracycline – Streptomyces rimosus
Formulas:
Tetracycline
Chlortetracycline Short acting
Oxytetracycline
Demeclocycline Intermediate acting
Methacycline
Doxycline Long acting
Minocycline
Semi synthetic derivatives

Spectrum:

190
- Aerobic : gm + ve & gm - ve bacteria
- Anaerobic : Actinomyces, Bacteroides
- Rickettsiae
- Coxiella - Vibrio
- Mycoplasma - H. ducreyi
- Chlamydia - H. pylori
- Legionella - Campylobacter
- Ureaplasma - Brucella
- Plasmodium - Yersinia
- Atypical mycobacterium
etc.,
“are bacteriostatic”
Minocycline most active – due to lipophilicity
Doxycyline
Effects on intestinal flora:
- Incompletely absorbed » ↑conc. in bowel » alter
enteric flora » overgrowth of resistant organisms
like Candida, Enterococci, Proteus, Pseudomonas
- Clostridium difficile » pseudomembranous enterocolitis
MOA:
- Tetracyclines enter microorganisms in part by
passive diffusion, and in part by an energy-
dependent process of active transport.
- Susceptible cells concentrate the drug
intracellularly.
- Once inside the cell, they inhibit bacterial protein
synthesis, by binding to the 30s bacterial
ribosome and preventing binding of t-RNA with
AA.
- This prevents addition of amino acids to the growing peptide

191
192
Resistance to Tetracyclines

193
- usually plasmid mediated
Kinetics: Absorption
- GI tract - For most T., incomplete absorption.
- High absorb. for Doxy, Mino
- Absorb impaired with food, milk & dairy
products, Al (OH)₃ gel, Ca++, Mg++, Iron,
Zinc salts, Bismuth subsalicylate
- Oxy T t½ 6-12 hrs, given 2-4 times/day
- Tetra
- Doxy t ½ 16-18 hrs, given 1-2 times / day
- Mino food does not interfere with absorption.
Distribution
- Widely distributed
- Accumulate in liver, spleen, bone-marrow, bone,
dentine, enamel of un-erupted teeth
- Penetrates CSF, placenta
- High conc. in synovial & maxillary sinus mucosa
- Excreted in milk.
Excretion:
- Most T. – kidney
- Mino – liver
- Doxy – feces (safe in renal failure pts.)
Routes of admn.
- Oral
- Parenteral – doxy, tetra, mino
- Topical – Eye: Chlor T; Tetra; Oxy T.
Uses:
1. Rickettsial inf. - Rocky mountain spotted fever
- Epidemic typhus
- Scrub typhus
- Murine typhus
- Rickettsial pox
- Q - fever
2. Mycoplasma - pneumonia
3. Chlamydia
- LGV
- Trachoma
- Pneumonia
- Nonspecific urethritis
4. STDs

194
- Gonorrhoea
- PID
- Acute epididymitis
- penicillin allergic, non-pregnant
syphilitic pts
5. Bacterial - Cholera
- Brucellosis
- Tularemia
- Plague
6. Protozoal - Malaria
7. Acne - Propionobacteria
8. Demeclocycline – in SIADH – (inhibits the action
of ADH in renal tubule)
Toxic effects:
- GI: irritation, ulcers, diarrhea,
pseudo-membranous enterocolitis,
- Photosensitivity: Demeclo. & Doxy.
- Hepatotoxic
Renal: nephrogenic diabetes insipidus – Demeclo.
: Fanconi’s syndrome – N; V; polydipsia,
polyuria, proteinuria, glycosuria, amino-aciduria,
acidosis
- due to ingestion of out dated T.
- due to toxic effect on proximal renal tubules.
Teeth: brownish discoloration of teeth – due to
chelation, T. - Ca+ orthophos. complex
Bones: deposited in bone – ↓ growth
Thrombophlebitis
Benign intracranial tension.
Hypersensitivity reactions:
- Rashes, urticaria, fixed drug eruptions, exfoliative
dermatitis, angioedemo, anaphylaxis
Superinfections
- Vaginal, oral, systemic
CHLORAMPHENICOL
- Broad spectrum antibiotic - Is bacteriostatic
- Isolated from Streptomyces venezulae

195
MOA:
- Inhibit bacterial protein synthesis
- Binds to 50s ribosomal submit at the peptidyl
transferase site and inhibits trans-peptidation
reaction.

Chloramphenicol: also inhibits mammalian

mitochondrial protein synthesis – esp
erythropoietic cells.
Spectrum:
- Similar to Tetracyclines
- Bactericidial against H.influenza, N.meningitidis,
S.pneumoniae

196
 - Active against enterobacteriacea – E.coli,
Klebsiella, Proteus, Vibrio cholerae, Shigella,
Salmonella.
Resistance:
- Plasmid mediated (acetyl transferase – that
inactivates the drug)
Kinetics
- Oral – rapidly absorbed (C. palmitate) = higher. BA than parenteral
- Parenteral – given as prodrug (C. succinate)
- Well distributed
- Elimination: liver – glucoronide conjugation
Uses:
- Not to be routinely used
- Only in infections where benefits of drug
outweighs the risks of potential toxicities
- Typhoid fever
- Bacterial meningitis - H. influenza
- N. meningitidis,
- Anaerobic – Bacteroides
- Rickettsiae
- Brucellosis
- Ocular infections.
Untoward effects:
# Hypersensitivity : rashes, angioedema,
Jarish - Herxheimer reaction
# Hematological
- Dose related: anemia, leucopenia, thrombocytopenia
- Idiosyncratic - aplastic anemia (not dose related)
# Toxic effects: N; V; D; unpleasant taste,
- Perineal irritation
- Blurring of vision, optic neuritis
- Digital paresthesias
- Grey baby syndrome ( ↓ glucoronyl transferase in liver and also ↓
excretion by immature kidney)
Drug Interactions:
1. Inhibit CYP 450 – prolongs t½ of warfarin,
dicoumarol, phenytoin, chlorpropamide,
tolbutamide, rifabutin, antiretrovival protease
inhibitors
2. Rifampicin – enzyme inducer, causes

197
subtherapeutic conc. of Chloramphenicol.

198
ANTIVIRAL DRUGS
Dr. Pushpalatha C.
Antiviral drugs
• Drugs that are effective against viral infections
• General principles of Virus
– Viruses are ultramicroscopic infectious intracellular
parasites of the living
– They cannot make anything on their own – they
utilize
• Host metabolic enzymes
• Host ribosome for protein synthesis– Structure of Viruses
• Nucleic acid core – DNA or RNA
• Often contain crucial virus-specific enzymes
• Surrounded by protein shell “Capsid” and
sometimes an outer lipoprotein membrane
“envelope”
• Capsid/envelop may contain antigenic
glycoprotein
• Complete viral particle - Virion
Classification
Antiherpesvirus agents
- Acyclovir - Ganciclovir
-Valacyclovir - Valganciclovir
- Famciclovir - Cidofovir
- Penciclovir - Foscarnet
- Trifluridine - Fomivirsen
- Idoxuridine
Anti-influenza virus agents
- Amantadine - Zanamivir
- Rimantadine - Oseltamivir
Antihepatitis agents
- Adefovir - Interferons
- Entecavir - Lamivudine
Other antiviral agents
- Ribavirin - Palivizumab
- Imiquimod - Tenofovir
- Telbivudine
Antiretroviral agents
• NRTIs
• NNRTIs

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• PIs
• Fusion/Entry inhibitors
• Integrase inhibitors
Replicative cycle of virus & sites of antiviral drug action

200
ANTIHERPESVIRUS AGENTS
• HSV-1 infection – mouth, face, skin, esophagus & brain
• HSV-2 infection – genital, rectum, skin, hands &
meninges
ACYCLOVIR
• Acyclovir – Acyclic guanosine derivative
• Antiviral spectrum
– HSV-1 (most active)
– HSV-2
– VZV & EBV
– CMV (least active)
Mechanism of action

→→Prevent viral replicationPharmacokinetics

• Routes of admn. – IV, oral, topical & ophthalmic
• Oral BA – 10-30%
• Widely distributed in body fluids & concentrated in milk,
amniotic fluid & placenta
• Excretion – Renal
Therapeutic uses
1. Genital HSV infection
• In primary infection

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– 400 mg orally TID for 7-10 days
• In recurrent infection
– 400 mg orally BD / 200 mg orally TID (chronic Rx)
• Suppresses genital herpes & reduces transmission
2. Mucocutaneous HSV infection
• Orolabial infection
– 2 g orally BD for 1 day
• In immunocompromised pts.
– 800 mg orally five times per day for 5-10 days
• Reduces healing time, duration of pain & period of virus shedding
3. HSV encephalitis
– Higher doses (15-20 mg/kg every 8 hrs) & prolonged
treatment (upto 21 days) are recommended
4. HSV keratocojunctivitis
– Ophthalmic formulations can be used
5. VZV infection
• Vericella (chicken pox)
– In children – 20 mg/kg orally 4 times daily for 5 days
– In adults – 800 mg orally 5 times daily for 7 days
• Treatment should be started within 24 hrs of rash
• Decreases time to crusting, its eruption & duration
of fever
• In vericella pneumonia & encephalitis – IV acyclovir
6. Locaolized herpes zoster
– 800 mg orally five times daily for 7 days
• Treatment should be started within 72 hrs. of rash
• Decreases pain & healing time
7. As prophylactic Rx
– Given to immunocompramised pts. undergoing bone
marrow transplantation or chemotherapy
Adverse effects
• Topical – tingling & burning sensation
• Oral – well tolerated
• IV – renal insufficiency – crystalline nephropathy
- CNS toxicity – altered sensorium, tremours,
myoclonus, delirium, seizures &
extrapyramidal signs
- Phlebitis, rash, nausea & hypotension
VALACYCLOVIR
• Prodrug of acyclovir

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• Oral BA – more than acyclovir
• Other properties similar to acyclovir
FAMCICLOVIR & PENCICLOVIR
• Famcyclovir – prodrug of pencyclovir
• BA – famciclovir > penciclovir
• Intracellular t ½ - prolonged
• Less potent than acyclovir
• Routes of admn. – oral (famciclovir), topical & IV
(penciclovir)
• Therapeutic uses – similar to acyclovir
• Adverse effects – diarrhea, nausea, rash & hallucinations
TRIFLURIDINE & IDOXURIDINE
• First generation antivirals
• Non-specificity MOA (inhibit host as well as viral DNA)
• Systemic admn. – highly toxic
• Topical – in HSV keratitis
GANCICLOVIR
• Acyclic guanine nucleoside analog
• MOA – similar to acyclovir
• Active against – CMV (more active)
– all herpes viruses & EBV
• Route of admn. – oral, IV & intraocular implants
• Uses – in immunocompromised pts. (AIDS & transplant
recipients) with CMV infection of retina & colon
• Adverse effects – Myelosuppression
- Behavioral changes, convulsions & coma,
- GI disturbance, rash, fever & LFT abnormalities
VALGANCICLOVIR
• Prodrug of Ganciclovir
• Oral BA – 60%
• Indication – CMV retinitis with AIDS
• Side effects – Same as Ganciclovir
CIDOFOVIR
• Cytosine nucleotide analog
• Cidofovir Phosphorylation - Independent of viral enzymes
→ inhibits DNA synthesis & gets incorporated into viral
DNA chain
• Resistance to Cidofovir – Occur due to mutation in DNA
polymerase
• Active against – CMV, EBV, Adenovirus, HSV, VZV, HPV

203
 • Active metabolite - Cidofovir phosphate – Has prolonged
intracellular t ½
• Cidofovir phosphocholine – t ½ 87 Hrs – Intracellular reservoir of
active drug
• Use - CMV retinitis – IV Cidofovir – Effective
Adverse reactions (IV)
• Nephrotoxicity (Dose dependent)
– Cidofovir + Probenecid (Blocks active tubular secretion of
cidofovir) – ↓ Nephrotoxicity
• Uveitis & ocular hypotony
• Probenecid related hypersensitivity reactions
FOSCARNET
• Inorganic pyrophosphate
• Direct acting without requiring activation by
phosphorylation – it inhibits – viral DNA ploymerase
– viral RNA ploymerase
– HIV reverse transcriptase
• Active against – HSV (including strains resistant to
Acyclovir)
– CMV (including Ganciclovir resistant
ones)
– HIV
• Development of resistance – Minimum
• Oral admn. – Poor BA (due to GI intolerance)• IV admn. only
• Bone deposition - Up to 30%
- Half life – Several months
• Clinical use – CMV retinitis
- CMV in AIDS
- Acyclovir resistant mucocutaneous H. simplex
- VZV infection in AIDS
Adverse effects
• Potential – Renal insufficiency
- Hypo- or hypercalcemia
- Hypo- or hyperphosphataemia
• Highly toxic to Kidney & CNS
FOMIVIRSEN
• MOA – Binds to mRNA → inhibits early protein synthesis
→ inhibits Viral replication of CMV
• Cross resistance – Not expected
• Used in CMV retinitis with AIDS – IV admn.

204
 Side effects
• Iritis
• Vitreitis
• ↑ intra ocular pressure
ANTI-INFLUENZA VIRUS AGENTS
• Drugs effective against influenza viral infection
AMANTADINE & RIMANTADINE
• Rimantadine – α methyl derivative of Amantadine
• MOA – inhibit uncoating of viral RNA of influenza A →
prevent viral replication
• Uses – for Prophylaxis & treatment of influenza A
– Prophylaxis – ↓ risk of acquisition by 50-90%
– Treatment – if started within 48 hrs. of onset
– ↓ duration of symptoms
• Development of resistance – rapid – upto 50%
• Adverse effects – GI intolerance & CNS effects – Common
– CNS – Nervousness
– Difficulty in concentrating
– Light headedness
– CNS adv. effects – Less frequent with rimantadine
– Dose should be reduced in
• Renal insufficiency
• Pts. > 65 yrs
ZANAMIVIR & OSELTAMEVIR
• MOA – Inhibit neuroaminidase (essential viral
glycoprotein) → inhibit viral release
• Use – Acute uncomplicated influenza A & B infection– Treatment
– If started within 48 hrs & given for 5 days
• ↓ severity
• ↓ duration of illness
• ↓respiratory complications
– Zanamivir – route of admn. – inhalation
• Adverse effects
–Nasal discomfort
–Throat discomfort
–Bronchospasm
– Oseltamivir – Oral prodrug
• Gets activated in gut & liver
• Use – In influenza - for prophylaxis
• Adverse effects – nausea & vomiting

205
ANTIHEPATITIS AGENTS
• Drugs effective against hepatitis virus infection
ADEFOVIR
• Analog of adenosine monophosphate
• Uses – in HBV infection
– In lamivudine resistant strains of HBV
• Adverse effects
– Nephrotoxicity – dose dependent
– ↑ risk – in renal dysfunction
– in prolonged treatment
– Lactic acidosis
– Severe hepatomegaly with steatosis
INTERFERONS
• Endogenous proteins
• Actions – Antiviral
– Immunomodulatory
– Antiproliferative
• Human interferons – 3 types – alfa, beta & gamma
drugs
- Interferon alfa-N1
- Peginterferon alfa 2A
- Interferon alfa-N3
- Peginterferon alfa 2B
- Interferon alfa-2B
- Interferon alfacon-1
- Interferon alfa-2A
• Produced by recombinant DNA technology
• MOA – Bind to specific membrane receptors – initiate
intracellular events
»Enzyme induction
»Suppression of cell proliferation
»Immunomodulatory activities
– Inhibition of virus replication (DNA & RNA viruses)
• Routes of admn. – SC/IM/intralesional inj.
• Therapeutic uses
– HBV infection
– Acute & chronic HCV infection
– Other uses
• AIDS related kaposis sarcoma
• Hairy cell leukemia

206
• H. simplex & H. zoster infection
• CMV infection (in normal &immunocompromised)
• Multiple myeloma
• Condyloma acuminata
• Adverse effects
– Flu-like syndrome
– Thrombocytopenia
– Granulocytopenia
– ↑ serum transaminases
– Induction of autoantibodies
– Alopecia & rash
– Hypotension
– Neuropsychiatric effects
• Contraindications (absolute)
– Psychosis
– Severe depresson
– Neutropenia
– Thrombocytopenia
– Symptomatic heart disease
– Cirrhosis
– Seizures
– H/o organ transplantation
LAMIVUDINE
• Cytosine analog
• Intracellular t ½ in HBV infected cells – 17-19 hrs –
single daily dose
• MOA – Inhibits DNA polymerase in HBV infection
– Inhibits reverse transcriptase in HIV infection
• Uses – In chronic HBV infection
– Admn. before & after liver transplantation –
suppress recurrent HBV infection
– In HIV infection – in combination with other
antiretroviral drugs
OTHER ANTIVIRAL AGENTS
RIBAVIRIN
• Uses
– HCV infection (ribavirin + interferon alfa)
– RSV bronchiolitis/pneumonia in children & infants
(ribavirin inhalation) – ↓ severity & duration
– Lassa fever & viral hemorrhagic fever – early IV

207
therapy – ↓ mortality
• Adverse effects – well tolerated
– Conjunctival irritation
– Bronchial irritation
PALIVIZUMAB
• Humanized monoclonal antibody
• Acts against F. glycoprotein on surface of RSV
• Use – Prevention of RSV infection – In high risk infants &
children
-----

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Immunopharmacology
Dr. K. Govardhan Reddy
Immunomodulators:
I. Immunosuppressants
- Inhibit cell mediated or humoral immunity
or both
II. Immunostimulants
- enhance the immune response
I. Immunosuppressants
Classification
1. Calcineurin inhibitors
(Specific T- cell inhibitors)
- Cyclosporine
- Tacrolimus
2. m-TOR inhibitors
- Sirolimus
- Everolimus
3. Antiproliferative (Cytotoxic) drugs:
- Azathioprine
- Cyclophosphamide
- Methotrexate
- Mycophenolate mofetil (MMF)
4. Glucocorticoids:
- Prednisolone
- Methylprednisolone
5. Biological agents
a. TNFα Inhibitors
- Etanercept
- Infliximab
- Adalimumab
b. IL-1 receptor antagonist
- Anakinra
c. Monoclonal antibodies
IL-2 receptor antagonists
- Daclizumab
- Basiliximab
d. Anti CD-3 antibody
- Muromonab CD3
e. Polyclonal antibodies:
- Rho(D) Immune Globulin

209
 - Antithymocyte Globulin (ATG)
Generation of humoral and CMI & site of action of
immunosuppressant drugs

1. Glucocorticoids 3.
Calcineurin & m-TOR inhibitors
2. Cytotoxic drugs 4. Muromonab & ATG
1. Calcineurin Inhibitors
Cyclosporine:
• It is a cyclic polypeptide
• Obtained from the fungus
• Selectively inhibits CMI
- T- lymphocyte proliferation
- IL-2 & other Cytokine production
• Enhances expression of TGFβ
- an inhibitor of IL-2
Mechanism of action

210
 • Normally when a TH-cell is activated →
Ca2+- calmodulin complex stimulates calcineurin
→ Dephosphorylation of NFAT (Nuclear Factor
for Activated T cells) → Active NFAT enters into nucleus → enhance
IL-2 gene transcription & synthesis
• Cyclosporin – cyclophilin complex binds &
inhibits calcineurin activity → Blocks the
synthesis of IL-2
- IL-2 is the major cytokine for T-cell
multiplication & differentiation
PK:
• Oral, I.V
• Metabolized by CYP3A4
• Excreted mainly in bile
• t1/2 - 24hrs
Uses:
• For prevention & treatment of graft rejection
- in renal, hepatic, cardiac, BM transplantations
• Second line drug in autoimmune disorders
- RA, Bronchial asthma, IBD, Atopic dermatitis,
Psoriasis
- used along with corticosteriods or methotrexate

211
A/E:
• Nephrotoxic, hepatotoxic & neurotoxic
• HTN, hyperuricemia, Hyperglycemia
• Opportunistic infections, seizures, alopecia
• Tremors, hirsutism, gingival hyperplasia
D/I:
• Cyclosporine + aminoglycosides or NSAIDs –
↑ nephrotoxicity
• C + enzyme inducers – graft rejection
• C + CYP3A4 inhibitors – toxicity
Tacrolimus (FK-506):
• More potent than Cyclosporine
• MOA – binds to FK-Binding Protein & inhibits
calcineurin activity
• Oral, I.V
• Metabolized by CYP3A4
• t1/2 - 8hrs
• It is particularly useful in liver transplantation
• Uses, A/E are similar to Cyclosporin except –
hirsutism, hyperuricaemia, hyperlipidemia are
less, but DM is more
2. m-TOR Inhibitors
Sirolimus (rapamycin):
• It is potent immunosuppressant
• Macrolide antibiotic
MOA:
• Sirolimus binds to FKBP-12 → inhibits the
activation of mammalian Target Of Rapamycin
(mTOR) → blocks the progression of cell cycle
from G1 S phase → inhibits proliferation &
differentiation of T- cells
PK:
• Oral BA -15%
• Metabolized by CYP3A4
• Excreted in bile
• t1/2 – 60 hrs
Uses:
• For prophylaxis & therapy of graft rejection
• Coronary angioplasty (sirolimus coated stents)
• In steroid refractory cases & stem cell transplants

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 A/E:
• Thrombocytopenia, BM suppression,
diarrhoea, hyperlipidemia, hepatotoxic,
pneumonitis
Everolimus:
• Similar to sirolimus
• t1/2 - 40 hrs
• Used in cardiac transplantation
3. Antiproliferative drugs
Azathioprine:
• Purine antimetabolite
• It has more immunosuppressant action than
antitumor action
• Prodrug for 6-mercaptopurine (6-MP)
MOA:
• Its selective uptake into immune cells →
intracellular conversion to 6-MP → further
transformation → inhibit purine synthesis &
damage to DNA
• It selectively affects differentiation & function of T cells (CMI)
Uses:
• Organ transplant rejection, RA, IBD
A/E:
• BMD, thrombocytopenia, hepatotoxicity,
GIT toxicity, alopecia
Methotrexate:
• Folate antagonist
• Potent immunosuppressant, markedly depress cytokine
production
• Reduces the proliferation of lymphocytes &
stimulate apoptosis & death of T-lymphocytes
• It has antiinflammatory property
- It prevents the inflammatory effect of IL-1, 2,6,8 & TNF- α
- it increases adenosine levels
• Used to treat GVHD, RA, myasthenia gravis,
Psoriasis, pemphigus
Cyclophosphamide:
• It has more marked effect on B cells (humoral
immunity)
Uses:

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 • BMT
• SLE, multiple sclerosis, wegner’s granulomatosis
A/E:
Haemorrhagic cystitis, myelosuppression, alopecia
Mycophenolate mofetil (MPM)
• Prodrug of mycophenolic acid
MOA:
• Selectively inhibits inosine monophosphate
dehydrogenase (IMPDH)
- highly expressed on lymphocytes & essential
for purine synthesis in the T & B cells
Uses:
• Add on drug to cyclosporin + glucocorticoid in renal
transplantation
• RA, IBD, myasthenia gravis
• Reduces the replication of HIV & EBV viruses
A/E:
• Vomiting, diarrhoea, leukopenia, CMV infection,
GI bleeding
4. Glucocorticoids
• Most commonly used immunosuppressants
MOA:
• They inhibit
- MHC expression
- activation & proliferation of T- lymphocytes
• Inhibits cytokine (IL-1, 2, 6 & TNF-α) synthesis &
release
• ↓ neutrophils & monocytes Chemotaxis
• ↓ Lysosomal enzyme release
Uses:
• To reverse
- acute transplant rejection
- acute exacerbation of autoimmune diseases
• To control GVHD in BMT
• To block “cytokine release syndrome” with
muromonab & ATG
• To limit allergic reactions, caused by other
Immunosuppressants
5. Biological Agents
• These are biotechnologically produced

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 • Reserve drugs for severe & refractory cases of autoimmune
diseases & GVHD
a. TNFα inhibitors
• Activated TH1 cells, macrophages & mast cells secrete TNFα
• Act on TNFR1 & R2 - located on neutrophils,
fibroblasts, endothelial cells & in serum
• TNF α amplifies immune inflammation
- by releasing cytokines (IL-1,6) & enzymes like
collagenases and metalloproteinases
• Mainly used in autoimmune diseases
Infliximab:
MOA:
• It binds & inactivates TNFα
- prevents the release of proinflammatory
cytokines & enzymes
Uses:
• In refractory RA, CD, UC, psoriasis & ankylosing spondylitis
A/E:
• URTIs, headache, activation of latent TB &
Opportunistic infections
Etanercept:
• It is a fusion protein to the TNF receptor
• It binds to both TNF α and β
• Binding to the
TNF α - inhibition of TNF α mediated inflammation
TNF β - promote IL-2 mediated T-cell proliferation
• Uses similar to infliximab
Adalimumab:
• It does not bind to TNF β
• MOA, Uses & A/E similar to infliximab
b. IL-1 receptor antagonist:
Anakinra:
• Activated macrophages & mononuclear cells
produce IL-1
- which activates helper T-cells & induces
production of other ILs & metalloproteinases
• It prevents IL-1 binding to its receptor
• Used in refractory RA
c. Monoclonal Antibodies (MAbs):
• MAbs are produced by fusion of mouse myeloma

215
 cells with single clone of B- cells
- thus single species of antibody can be developed
- that can recognize & react with a specific Ag
(epitope) only
• Their action is directed against T & B lymphocytes,
TNF & ILs• Name of the monoclonal antibody can be
divided into 4 parts
- prefix + target subsystem + origin subsystem + suffix
Ex: Tras + tu + zu + mab
Target – Vi for virus, Ci for circulation, tu - tumor
Origin – “zu” stands for human, “o” for murine,
“xi” for Chimeric (partly human & part mouse)
Suffix – mab
Uses:
1. Organ transplantation:
- Muromonab, Daclizumab, Basiliximab
2. Autoimmune & other diseases:
RA – Infliximab, Adalizumab
Asthma – Omalizumab
Antiplatelet – Abciximab
3. Cancers:
Colorectal – Cetuximab
Breast cancer – Trastuzumab, Rituximab
CLL & lymphoma – Alemtuzumab, Rituximab
IL-2 receptor antagonits:
• CD-25 is the high affinity IL-2 receptor expressed on activated T –
cells
Daclizumab, Basiliximab:
• Anti CD-25 antibodies can specifically act on
those cells
• Used for the prophylaxis of acute organ
transplant rejection
A/E:
• anaphylactic reactions, influenza like syndrome &
opportunistic infections
d. Anti CD3 antibody
Muromonab-CD3:
• CD3 is expressed near to the T cell receptor on T
helper cells
MOA:

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• It binds to CD3 & obstructs approach of the
MHC II antigen to the T cell receptor
• Antigen recognition is interfered & participation
of T cells in the immune response is prevented
• It depletes circulating T-cells from the blood
Uses:
• Acute transplant rejection reaction in steroid
resistant cases
• Used to deplete T cells from the donor bone
marrow before transplantation
A/E:
• Initial dose is associated with “Cytokine release
syndrome” with flu like symptoms
- due to release of TNF α, ILs & Interferons
• Aseptic meningitis, pulmonary edema, seizures
e. Polyclonal antibodies:
a. Antithymocyte Globulin (ATG):
• It is purified from horse or rabbit immunized with
human thymic lymphocytes
• It binds to T lymphocytes & depletes them
• Used to suppress acute allograft rejection in
steroid resistant cases
A/E:
• serum sickness, anaphylaxis, cytokine release
Syndrome
b. Rho (D) / Anti-D Immune Globulin:
• It binds to Rho+ve antigens & prevent antibody
formation in Rh–ve mothers
• It is used for prevention of postpartum/post
abortion formation of antibodies
- in Rh- ve women who have delivered or aborted
an Rho+ve baby or foetus
• Administered within 72 hrs of delivery or abortion
• It prevents Rh haemolytic disease in future
Offspring
II. Immunostimulants
1. Bacillus Calmette Guerin (BCG):
• Live attenuated culture of M. bovis
• Stimulates T- cells & NK cells
Uses:

217
• Immunization for TB
• Treatment of urinary bladder cancer
2. Levamisole:
• It is an anthelmintic drug
• It stimulates T & B-cells, monocyte, macrophage activity
Uses:
• colorectal cancer & vitiligo
3. Thalidomide - Immunomodulator
• It was used for morning sickness & sedative
MOA:
• Immunosuppressant – inhibits the production of
TNF- α & IFN
• Immunostimulant – effect on IL-2,6, reduces
neutrophils phagocytosis & enhance CMI
• Anti-inflammatory - blocks the induction of
COX2
• Antiangiogenesis - blocks the induction of PGE2
Uses: Now reintroduced for
• ENL
• GVHD
• SLE, RA, CD
• Multiple myeloma, MDS
• Treatment of
- cachexia & weight loss in HIV
- N, V & A in cancer patients
A/E:
• Sedation, dizziness, constipation, tremors, rash
• Phocomalia, peripheral neuropathy,
hypothyroidism, DVT
4. Recombinant cytokines
Aldesleukin:
• Recombinant IL-2, obtained from culture of E. coli
• Enhance cellular immunity
Uses:
• Metastatic renal cell carcinoma
• Melanoma
Oprelvekin:
• Stimulates megakaryocytes & their precursors in bone marrow
Use:
• To prevent thrombocytopenia in the patient

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receiving myelosuppressive chemotherapy
Colony - Stimulating Factors: (hematopoitic growth factors)
• Important cytokines that support survival,
proliferation & differentiation of haematopoitic cells
a. Recombinant GM-CSF: Sargramostim
- multipotent haematopoietic growth factor
b. G- CSF: Filgrastim
- stimulates proliferation & differentiation of
neutrophil progenitor cells & activation of
neutrophils
c. Pegylated G-CSF: Pegfilgrastim - longer acting
Use:
• To reduce the severity & duration of neutropenia
induced by cytotoxic drugs
5. Recombinant interferons
a. IFN- α:
• It activates T- lymphocytes, NK cells &
macrophages
• Used in CLL, malignant leukemia, NHL, AIDS
related kaposis sarcoma, hepatitis B & C infections
b. IFN-β:
• Used in multiple sclerosis
c. IFN-ϒ:
• Restores macrophages cytotoxicity
• Used for chronic granulomatous diseases

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TREATMENT OF DIARRHEA
DIARRHEA - in Greek: ‘dia’ – through
‘rheein’ – to flow or run
- “ too rapid evacuation of too fluid stools”
• Is defined as:
“ a stool weight of > 250 gms / day”
OR “an increase in stool frequency of > 3/day”
OR “Liquidity of faeces”
• Cause 4 – 5 million deaths annually, through out
world
• Major cause of death & malnutrition among
children in developing countries
DYSENTRY:
characterized by the presence of blood, mucous
and/or pus in the stools, associated with
abdominal cramps and fever.
Physiology:
o Approx. 9 – 10 L of fluid enter the duodenum/day
o 7.5 – 8.5 L are absorbed in the small intestinal
o 1.4 L are absorbed in the colon
o 0.1 L (100 ml) only is lost in stools/day, normally.
• Normally, two processes occur in the GIT:
- Absorption
- Secretion
a) Absorption:
- sodium - glucose coupled entry
- sodium ion coupled entry
b) Secretion:
- active transport of chloride into the gut lumen
- followed by sodium & water
- modulated by cAMP and cGMP
Diarrhea results from an imbalance between
secretion and absorption of fluid & electrolytes
Mechanisms of Diarrhea:
• An increased osmotic load within the intestines
• Excessive secretion of water & electrolytes in the
intestinal lumen
• Exudation of proteins and fluid from the mucosa
• Altered intestinal motility
Diarrhea and its effects:

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loss of water » shrinkage of ECF
↓ skin turgor
↓ blood volume » ↓BP, ↓urine output,
thready pulse
hypokalemia » paralytic ileus, abd.distension,
hypotonia of skeletal muscles
Loss of bicarb. » acidaemia with
Kussmaul breathing
Other signs: depressed fontanel, sunken eyes,
dry tongue
If untreated » severe hypotension » death
Causes of diarrhea:
- Acute
- Chronic
- Drugs
- Psychological
- Travellers diarrhea
- Pseudo-membranous enterocolitis
Acute diarrheas:
2 types: Non-inflammatory, Inflammatory
a) Non –inflammatory
- Viral: Norwalk, Rota
- Protozoal: Giardia, Cryptosporidium
- Bacterial:
Preformed enterotoxin: S.aureus, B.fragilis,
Cl.perfringens
Enterotoxin production: ETEC, V.cholera
b) Inflammatory:
- Viral: CMV
- Protozoal: E.histolytica
- Bacterial:
Cyto-toxin production: EHEC,
V.parahemolyticus
Mucosal invasion: Shigella, Salmonella,
Cl.jejuni, EIEC
Chronic Diarrheas:
a) Osmotic: Antacids, Lactose intolerance
b) Secretory: VIPoma, ZES, Carcinoid syn, Crohns
c) Inflammatory: U.colitis, Crohns, Malignancy, RT
d) Motility disorders: Post-surgery, DM, IBS

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e) Chronic infections: Giardia, Protozoa, AIDS
f) Malabsorption
Drugs causing diarrhea:
- Antibiotics: Ampicillin, Erythromycin, Tetracycline
- Antacids: Magnesium preparations
- Anti-arrhythmic: Quinidine
- Prokinetic agents: Cisapride
- Anticholinesterases: Physostigmine, Neostigmine
- PG analogs: Misoprostal
- Mood stabilizers: Lithium
- Anti-amoebic: Emetin
EVALUATION:
- Assess percentage of dehydration
- Diagnostic investigations are unnecessary
- 90% of acute diarrheas are mild & self limiting
TREATMENT:
“ the main stay of treatment is the correction of
dehydration, and NOT the reduction of stool
fluid output.”
Treatment consists of: rehydration
anti-diarrheal agents
antibiotic therapy
diet
Rehydration:
Oral
IV
ORT:
- core management of diarrhea
- WHO recommended ORT formulation (ORS):
NaCl 3.5 gms (Na⁺ : 90 mmol)
KCl 1.5 gms
(K⁺: 20 mmol)
(Cl⁻: 80 mmol)
Na.Citrate 2.9 gms (citrate: 30 mmol)
Glucose 20 gms (G: 111 mmol)
Potable water: 1 litre
Cereal based ORS:
• Rely on starch to produce glucose from rice,
wheat, corn, potato
• Undigested starch is fermented in colon to short

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chain fatty acids, which stimulate colonic
reabsorption of sodium & water
• Controls diarrhea much more effectively
Home made equivalent of ORS:
½ tsp. salt
8 tsp. sugar
1 tsp. baking soda
240 ml orange juice
1 litre water
Dose of ORS: “ad libitum”
* ORS to be continued inspite of continuing
diarrhea, as sodium-glucose coupled
reabsorption in intestines is intact and active.
INTRAVENOUS REHYDRATION
- Given in patients with moderate to severe
dehydration
- Also given in patients with persistent vomiting
- ORT can be continued simultaneously
- Best IV fluid: Ringer Lactate
- Dose: 100 ml/kg/first 6hrs
followed by 100ml/kg/24hrs
- Dextrose containing IV fluids are not suitable in
the initial correction of dehydration
Anti-diarrheal agents:
a) Anti-motility drugs:
Opioids: Codiene, Loperamide, Diphenoxylate
Atropine & its analogues
α agonists: Clonidine
PG inhibitors: Aspirin, Indomethacin
Somatostatin analogue: Octreotide, Lanreotide
Miscellaneous: Lactobacillus, Berberine,
Chlorpromazine
Calcium channel blockers: Verapamil
b) GI protectives and adsorbents:
Bismuth salts, Kaolin, Pectin,
Activated wood charcoal
Opioids:
- Action mediated via μ and δ opioid receptors on
enteric nerves, epithelial cells & muscles
- They: ↓ intestinal motility

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↓ secretions
↑ absorption of water & electrolytes
↑ anal sphincter tone
Loperamide: Pethidine analogue
does not cross blood-brain barrier
Diphenoxylate: Pethidine analogue
crosses blood-brain barrier
Rececadotril:
- is an Encephalinase inhibitor
- ↑ local levels of encephalins
» stimulate opioid receptors
» ↓ secretions
- does not decrease intestinal motility
Atropine analogues:
- Propantheline
- Tincture belladona
• Opioids and atropine analogues are not
recommended in children, as they cause:
- paralytic ileus
- further retention of inf.organisms
- toxic megacolon
- intestinal perforation
- peritonitis
- respiratory depression
- death
Clonidine:
- special role in DM with chronic diarrhea
- given as tablet & patch
Octreotide, Lanreotide:
- analogues of somatostatin
- act by inhibition of hormone secretion
- effective in secretory diarrheas due to hormone
secreting tumors of pancreas and GIT
PG inhibitors: Aspirin, Indomethacin
CCBs: Verapamil, Nifedepine
Calmodulin inhibitors: Chlorpromazine
Berberine: alkaloid from Berberis arista
Lactobacillus:
- contain viable spores of lactobacillus
- colonise the intestines

224
- modify the gut flora and their metabolic activity
(Pro-biotic)
- also enhances local IgA antibody production
Bismuth subsalicylate & subcarbonate:
• React with HCl in stomach to form bismuth
oxychloride and salicylic acid
• Salicylic acid - inhibits local PGs
- increases absorption of fluid &
electrolytes
- inhibits secretion
• Bismuth passes unaltered & unabsorbd into faeces
• Relieves nausea and abdominal cramps
• Causes darkening of tongue and stools
• May cause fecal impaction in infants and
debilitated people
Kaolin:
- Is a hydrated aluminium silicate
- Insoluble in water
- Act as adsorbent of bacteria and its toxins
- Binds water, so decreases stool water content
Pectin:
- Obtained from dilute extract of the inner portion
of citrus fruits or from apple pomade
- Acts by physical coating of intestines
*Kaolin 20% + Pectin 1%
Cholestyramine:
• Is an anion exchange resin
• Binds bile acids and some bacterial toxins
• Useful in patients with resection of distal ileum
Activated wood charcoal:
- Is the residue from destructive distillation of
vegetable matter like saw dust, cellulose residue
& coconut shells
- Treated with zinc chloride to increase its
adsorbent power
ANTIBIOTIC THERAPY:
o Most episodes of diarrhea are viral in origin
o Are self limiting
o Antibiotics are of no use in such cases
o Indicated in infective (bacterial) cases

225
o EX: Norfloxacin 400 mg BID (or)
Ciprofloxacin 500 mg BID (or)
Ofloxacin 200 mg BID
PLUS
Metronidazole 400 mg TID (or)
Tinidazole 500mg BID
o Doxycycline in Cholera: 6 mg/kg, single dose,
stat.
DIET:
- Adequate oral fluids containing electrolytes and
carbohydrates
- Frequent of soft and easily digestible foods like
soups, fruit drinks, tea, carbonated beverages
- Avoid: high fiber foods, fats, caffeine, milk
products, alcohol
TRAVELERS' DIARRHEA:
Diarrhea acquired by the visitors to a particular
area
Popular regional names:
Delhi-Belly
Gyppy Tummy
Hongkong Dog
Tokyo Trots
Rangoon Runs
Montezuma Revenge
Caused by ETEC, Shigella, Salmonella, Giardiasis,
Norwalk virus
Transmission: contaminated food & water
Treatment: Ciprofloxacin, Loperamide, ORT
PSEUDO MEMBRANOUS ENTERO-COLITIS:
• Due to indiscriminate use of broad spectrum
antibiotics like Clindamycin, Chloramphenicol,
3rd generation Cephalosporins
• There is alteration of bowel flora and colonization
of gut with Clostridium difficile
• Treatment: Vancomycin, Metronidazole

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PROKINETIC AGENTS
Dr. PushpalathaC.
PROKINETIC AGENTS
• Drugs that enhance
– ↑Coordinated GI motility
– ↑Transit of food material in GI tract (quickens gastric emptying)
CLASSIFICATION
1. D₂ Dopamine receptor antagonists (Benzamides)
– Metoclopramide
– Domperidone
2. 5-HT₃ Serotonin receptor antagonists
– Ondansetron
– Palonosetron
– Granisetron
– Tropisetron
– Dolasetron
– Ramosetron
3. 5-HT₄ Serotonin receptor agonists
– Cisapride
– Tegaserod
– Mosapride
– Procalopride
4. Cholinomimetic agents
– Bethanechol – Neostigmine
5. Motilides
a) Macrolide antibiotics – Erythromycin
b) Motilin receptor agonists – Mitemcinal
6. Miscellaneous
– Octreotide
– Dexloxiglumide

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D₂ Dopamine receptor antagonists
(Benzamides)
– Metoclopramide
– Domperidone
5-HT₄ Serotonin receptor agonists
Cisapride
• Substituted piperidinyl benzamide
• MOA - (+) 5-HT₄ receptors (5-HT₄ agonism) on
ENS→ Promotes Ach release by
PMN in myenteric plexus
→ ↑ LES tone and facilitates GI motility
including colon
• Pharmacokinetics
• Route of admn. – Oral – BA – 33%
• Metabolism – In liver by CYP3A4
• Therapeutic uses
• Withdrawn in many countries due to adverse
effects
• Used only when there is failure of standard
therapy in:
• GERD
• Gastroparesis
• Pseudo-obstruction
• Refractory severe chronic constipation

228
• Neonatal enteral feeding intolerance
• Adverse effects
-Prolongation of QT interval→Torsades de pointes
(Ventricular tachycardia & VF)
-Abdominal cramps & diarrhoea
• Contraindications
• Ventricular arrhythmias
– IHD
• Renal failure
– CHF
• Resp. failure
– Hypokalemia
• Pts with h/o prolonged QT interval
• Drugs known to prolong QT interval
Mosapride
• Selective 5-HT₄ agonist
• Claimed to have fewer side effcts
Tegaserod
• Selective 5-HT₄ partial agonist
• Use – Constipation predominant IBS
Procalopride
• Specific 5-HT₄ receptor agonist
• Acts throughout the length of the intestine
• Use – Women with chronic idiopathic
constipation (if failure of laxatives)
Cholinomimetic agents
Bethanecol (Direct acting cholinomimetic)
• Historical importance in gastroenterology
• Was used in GERD & gastroparesis
• Side effects
• Bradycardia
– Cramps
• Flushing
– Salivation
• Diarrhoea
– Blurring of vision
Neostigmine (Indirect acting cholinomimetic)
• Use - Colonic pseudo-obstruction
- Paralytic ileus
Motilides

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• Motilin – 22 aa peptide hormone
– found in GIT M cells & EC cells
– Acts on – Motilin receptors on smooth
muscles → Contraction
– Causes amplification of Phase III MMC
in upper GI tract
Erythromycin (Macrolide antibiotic)
• MOA - Directly (+) motilin receptors on GI
smooth muscles – Promote the onset of MMC
• Cholinergic facilitation (at low dose)
• Stimulates gastric & small bowel contractility
without effecting colonic motility
• Pharmacokinetics
• Route of administration – Oral / IV
• Dose for gastric stimulation – 3 mg /kg/IV or
200-250 mg orally every 8 hours
• Dose for small bowel stimulation – 40 mg IV
• Therapeutic Use
• Diabetic gastroparesis
• Small bowel dysmotility seen in scleroderma,
ileus, pseudo-obstruction
• Use as prokinetic agent is limited due to
• Undesirable antibiotic effect
• Rapid development of tolerance to prokinetic action
• Pseudomembranous colitis
Mitemcinal
• A macrolide non antibiotic
• Use - Gastroparesis
Miscellaneous
Octreotide
– Somatostatin analog
– Causes induction of phase III MMC (In stomach & small bowel)
– Use – Intestinal dysmotility
Dexloxiglumide
– CCK₁ receptor antagonist
– Improves gastric emptying
– Use – Gastroparesis
– Constipation dominant IBS
– GERD

230
 PHARMACOTHERAPY OF
PEPTIC ULCERS/ACID PEPTIC
DISEASES
Dr. Pushpalatha C.
Peptic ulcers – occur in parts of GIT exposed to gastric
acid & pepsin
– Stomach & duodenum
• Acid-peptic diseases
– Peptic ulcers – Gastric ulcers (GU)
– Duodenal ulcers (DU)
– Stress ulcers
– NSAID induced ulcers
– Gastroesophageal reflux disease (GERD)
• H. pylori – Plays a key role in acid peptic disease
- Ulcer formation
- Recurrence• Smoking – Major environmental factor of peptic
ulcer
• Use of NSAIDs – cause ulcers especially in elderly
• Zollinger-Ellison syndrome – Pathological
hypersecretory (gastric acid) condition
• There will be imbalance between defensive &
aggressive factors
– DEFENSIVE FACTORS – AGGRESSIVE FACTORS
- Gastric mucus - Gastric acid
- Bicarbonate secretion - Pepsin
- Prostaglandins - NSAIDs
- NO - H. pylori
- Mucosal bld. Flow
CLASSIFICATION

a) Proton pump inhibitors

- Omeprazole - Esomeprazole - Rabeprazole
- Pantoprazole - Lansoprazole
b) H2 antihistamines
- Cimetidine - Famotidine - Roxatidine
- Ranitidine - Nizatidine
c) Anticholinergics
- Pirenzepine - Propantheline

231
- Oxyphenonium
d) Prostaglandin analogue
- Misoprostol

a) Systemic antacids
- Sodium bicarbonate - sodium citrate
b) Nonsystemic antacids
- Magnesium hydroxide - Aluminium hydroxide gel
- Magnesium trisilicate - Calcium carbonate
- Magaldrate

- Sucralfate
- Bismuth salts - Colloidal bismuth subcitrate
- Bismuth subsalicylate

- Amoxicillin - Tinidazole - Clarithromycin

- Tetracycline - Metronidazole
Physiological & Pharmacological regulation of gastric secretion
pH 7 pH 2PROTON PUMP INHIBITORS (PPIs)
• Irreversibly inhibit gastric H⁺- K⁺-ATPase proton pump (final
common pathway for acid secretion in response to all
stimuli)
• All PPIs have equivalent efficacy at comparable doses
• PPIs are prodrugs
• MOA
– Drug – gets absorbed in small intestine – from
circulation diffuses into parietal cells – gets accumulated
and ionised at acidic pH in secretory canaliculi – binds
covalently to H⁺- K⁺-ATPase enzyme & irreversibly
inactivates proton pump → inhibits gastric acid secretion
– Reduce 24 hrs acid secretion (basal & stimulated) by 80-
95%•
Pharmacokinetics
– Prodrugs (weakly basic)
– Acid labile drugs
– Enteric coated prepn.(to prevent degradation by acid
in gastric lumen) - ↑ oral BA
– Oral admn. – ½ hr. before breakfast (morning)

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 - with food - ↓ absorption
– Omeprazole – 20-40mg/OD for 7days – reduce 90%
gastric acid output
– IV admn. – Pantoprazole, esomeprazole &
lansoprazole
– Metabolized extensively by CYP2C19 & CYP3A4
– Pantoprazole – more acid stable, lower affinity for
CYP450 & less drug interactions•
Therapeutic uses
– Peptic ulcer
• With once daily regimen (omeprazole 20 mg/day)
–DU – 90% heal in 2 wks, almost all heal in 4
wks
–GU – require larger doses for 8 wks
–PPIs ≥ effective than H2 blockers
–Relief of pain – rapid
– Bleeding peptic ulcer
• Omeprazole – 40mg 12th hrly
• Pantoprazole – 80mg initial dose IV bolus inj.
followed by 8mg/hr constant IV infusion– Gastroesophageal reflux
disease (GERD)
• Including erosive esophagitis
• Complicated or unresponsive to treatment with H2
antagonist
• PPI – admn. once or twice daily
– NSAID associated gastric ulcers
• PPI used – For prevention & treatment
• Higher doses of PPI for > 8 wks Rx – healing rate –
80-90%
– Zollinger-Ellison syndrome (gastrinoma –
hypersecretion of acid)
• Higher daily doses of PPI (Twice the routine dose
for peptic ulcer) – recommended– Nonulcer dyspepsia
• PPI – used as emperical treatment
– Stress related ulcers
• Ulcers of stomach & duodenum occur in profound
illness or trauma requiring intensive care
• Omeprazole (oral immediate release prep.) – twice

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 daily on the first day, then once daily - may be used
to reduce risk of stress related mucosal bleeding –
approved by FDA
– Heart burn
• Omeprazol – OTC – approved for self treatment
– Prophylaxis of aspiration pneumonia
• Given preoperatively – ↓risk of aspiration of acidic
gastric contents during anaesthesia & surgery– Safe in children with
erosive esophagitis & GERD
• Adverse effects
– Generally well tolerated
– GENERAL
• Common side effects
–Nausea & abdominal pain
–Constipation, flatulence & diarrhoea
• Other effects
–Subacute myopathy & arthralgia
–Headache
–Skin rashes– NUTRITION
• ↓ oral absorption of Vit. B12
(gastric acid releases Vit. B12 from food )
• ↓ absorption of iron, calcium & zinc – no mineral
deficiency reported
(gastric acid promotes absorption of minerals)
(use with caution in osteoporosis)
– RESPIRATORY & ENTERIC INFECTIONS
(Gastric acid acts as barrier to colonization & infection of
stomach & intestine from ingested bacteria)
• There will be increased risk of:
–Enteric infections
–Community-acquired respiratory infections
–Nosocomial pneumonia– POTENTIAL PROBLEMS DUE TO
INCEASED SERUM
GASTRIN
• Long term therapy - ↑ serum gastrin levels – ECL
hyperplasia (? Gastric carcinoid tumours) –
routine monitoring of serum gastrin levels
recommended
• Rebound hypersecretion of gastric acid on

234
discontinuation of therapy
– OTHER POTENTIAL PROBLEMS DUE TO DECREASED
GASTRIC ACIDITY
• Atrophic gastritis or intestinal metaplasia•
Drug interactions
– Decrease absorption & BA of other drugs
• Ketoconazole, itraconazole, ampicillin & digoxin
– PPIs – metabolized by hepatic CYP450 enzymes
• Omeprazole – inhibits metabolism of warfarin,
diazepam & phenytoin
- inhibit conversion of clopidogrel to
active anticoagulant form (both
are substrates of CYP2C19)
• Esomeprazole – decrease metabolism of diazepam
• Pantoprazole & rabeprazole – no significant
Interactions
H2 ANTIHISTAMINES
• Competitively block H2 receptors - ↓ gastric acid
secretion
• Less potent than PPIs
• Suppress 24 hrs gastric secretion by 70%
• MOA
– Antagonize H2 receptors (competitively) on the
basolateral membrane of parietal cells – inhibit
cAMP dependent activation of proton pump –
reduce gastric acid secretion
– All phases of gastric acid secretion are suppressed
– Predominantly inhibit basal acid secretion –
effective in reducing nocturnal acid secretion• Pharmacokinetics
– Oral admn. – absorption – rapid
- not interfered by food
- decreased by antacids
– IV admn. – Duration of action – 4-12 hrs. (famotidine >
ranitidine > cimetidine)
– Potency - famotidine > roxatidine > ranitidine > cimetidine
– Metabolism in liver (Small amount of drug)
– Excreted by kidney – Drugs & their metabolites
• Pts. With decreased creatinine clearance – dose should be
reduced

235
 – Cross placenta (should not be administered to pregnant
females)
– Secreted in milk (should be avoided in nursing mothers)•
Therapeutic uses
– Duodenal (DU) & gastric ulcers (GU)
• More valuable in healing DU than GU – Ranitidine
150mg twice daily orally / 300mg at bed time
– Gastroesophageal reflux disease (GERD)
• Reduce heart burn but less effective than PPIs
– Stress related ulcers
• Prevention & treatment – Ranitidine 50mg IV
every 6-8 hrs.
– NSAID induced ulcers
• Used for treatment but not for prevention– Zollinger-Ellison
syndrome
• Used to treat multiple gastroduodenal ulcers due
to gastric hypersecretion
• Less effective than PPIs
– Prophylaxis of aspiration pneumonia – as
preanaesthetic medication
• Adverse reactions (<3%)
– Well tolerated
– Headache, fatigue & myalgias
– Diarrhoea & constipation
– Tolerance to acid suppression effect (within 3 days of Rx)–
Rebound hypersecretion of gastric acid on
discontinuation of therapy
– Rapid IV infusion → bradycardia & hypotension
• Should always be given by slow IV infusion
– Cause blood dyscrasias including thrombocytopenia
– CNS effects (Common with cimetidine & less with ranitidine)
• Confusion, hallucinations & agitation – Occur with
IV admn. in
–Pts. in ICU
–Elderly pts.
–Pts. with hepatic & renal impairment– Cimetidine
• long term use or administered in high doses
–Inhibits binding of testosterone to androgen
receptors & inhibit metabolism of estradiol

236
»Gynecomastia & impotence in men
(antiandrogenic effect)
»Galactorrhea in females
• Inhibits CYP450 – increase the plasma levels of
–Phenobarbitone , phenytoin, propranolol,
warfarin, theophylline & diazepam
• CNS adverse effects . . . .
.ANTICHOLINERGICS
• MOA
– Antagonize muscarinic receptors
• on basolateral memb. of parietal cells – inhibit Ca²⁺
dependent pathway of proton pump activation –
decrease gastric acid secretion
• On ECL cells – inhibit histamine release – decrease gastric
acid secretion indirectly
• ↓ gastric acid secretion – 40-50%
• Not much in use due to
– Less suppression of gastric acid secretion (poor efficacy)
– Availability of better drugs
– Adverse effect profile (antimuscarinic adverse effects)
PROSTAGLANDIN ANALOGUE
• Misoprostol – Synthetic analogue of PGE1
• MOA
– Act as agonist on EP3 receptors
• on basolateral memb. of perietal cells – ↓ cAMP –
↓ gastric acid secretion
• on superficial epithelial cells
–↑ mucous secretion
–↑bicarbonate secretion
• ↑ mucosal blood flow
– Has both gastric acid inhibitory & mucosal protective
effect• Ulcer pain relief – poor
• Decrease gastric acid secretion – modest & dose
dependent
• Pharmacokinetics
– Oral admn. – absorption – rapid
– Plasma t ½ - 30 min.
– Duration of action – 3-4 hrs.

237
 • Therapeutic use
– To prevent NSAID induced gastric mucosal injury &
bleeding (elderly pts. with arthritis on NSAID)
• 200 µg four times daily – orally– Use restricted due to – adverse
effect profile
– need for multiple daily doses
– poor pt. acceptability
– availability of better drugs
• Adverse effects
– Diarrhea & abdominal cramps – In 30% pts.
– C/I – in pregnancy – it stimulates uterine
Contractions
NEUTRALIZATION OF GASTRIC ACID
(ANTACIDS)
• Antacids are basic substances
• MOA
– Neutralize gastric acid in gastric lumen - ↑ gastric pH
• React with gastric HCl to form salt & water
• Taken after a meal orally – act for 2-3 hrs.
• SODIUM BICARBONATE
– Reacts rapidly with gastric HCl & produce CO2& NaCl
• CO2 – results in gastric distention & belching
• Unreacted alkali – readily absorbed – causes metabolic
alkalosis (given in high doses)
• NaCl absorption – exacerbate fluid retention in heart
failure, hypertension & renal insufficiency• CALCIUM CARBONATRE
– Less soluble & reacts more slowly than soidum bicarbonate
– Causes belching & metabolic alkalosis
– Given with calcium containing dairy products → hypercalcaemia,
renal insufficiency (milk-alkali syndrome)
• MAGNESIUM HYDROXIDE & ALUMINUM HYDROXIDE
– Reacts slowly with HCl – form MgCl2 , AlCl3& H2O
– Belching – does not occur
– Metabolic alkalosis – uncommon
– Unabsorbed MgCl2 – causes osmotic diarrhea
– Unabsorbed AlCl3 – causes constipation
– Combination (gelucil) – minimize impact on bowel function
• All antacids – affect absorption of – tetracyclines,

238
fluoroquinolones, itraconazole & iron – avoid admn. of
antacids within 2 hrs. of admn. of these drugs• Uses
– No longer used for healing peptic ulcer because
• Large & frequent doses are needed
• Inconvenient
• Cause acid rebound
• Bowel upset
• Afford little nocturnal protection
• Poor pt. acceptability
– For intercurrent pain relief & acidity
– Nonulcer dyspepsia
– Minor episodes of heart burn
ULCER PROTECTIVES
SUCRALFATE
• Salt of sucrose complexed to sulfated aluminum
hydroxide
• MOA
– In acidic environment (in stomach) – sucralfate
forms a viscous, tenacious paste – that binds
selectively to ulcers or erosions for up to 6 hours –
acts as barrier & protects ulcer base coming in
contact with acid, pepsin & bile
– Stimulates local production of PGs & epidermal
growth factor – cytoprotective effect• Therapeutic uses
– For prophylaxis of stress ulcers – in ICU pts.
• Admn. through nasogastric tube
• Superior to PPIs or H2 antagonists
• PPIs or H2 antagonists – risk of nosocomial pneumonia
– Oral mucositis (radiation or aphthous ulcers)
• Not responding to acid suppression
– Duodenal ulcer
• 1g four times daily (for active DU), 1g twice daily
(maintenance therapy) – orally
• Adverse effects
– Constipation (2% pts.)
– C/I in renal failure
– Inhibit absorption of – phenytoin, digoxin, ketoconazole &
Fluoroquinolones

239
COLLOIDAL BISMUTH SUBCITRATE (CBS) &
BISMUTH SUBSALICYLATE
• MOA
– Binds to base of ulcer & are not absorbed
– Promotes mucous & bicarbonate production
– Also has significant antimicrobial effect against H. pylori
• Use
– As a component of anti H. pylori regimen for Rx of Peptic ulcer
– Nonspecific Rx of dyspepsia & acute diarrhea
– Prevention of traveler’s diarrhea
• Adverse effects
– Prolonged use (due to bismuth toxicity)
• Blackening of tongue, dentures & stool
• Osteodystrophy and Encephalopathy
ANTI-H.PYLORI DRUGS
• H. pylori – Gram –ve bacilli
- Attaches to surface epithelium beneath the
mucus
- produces ammonia – maintain a neutral
microenvironment around it
- promotes back diffusion of H⁺ ions
- ↓ no. of D cells - ↓ somatostatin
production - ↑gastric acid production
- Contributes to
– Ch. Gastritis – Dyspepsia
– Peptic ulcer – Gastric lymphoma
– Gastric carcinoma- once established – persist for the life
• Test for H. pylori 90% +ve in DU &GU
• Single drug therapy – ineffective
• 3 or 4 drugs for two weeks regimen - effective
• Two week regimen
– Triple therapy (3 drugs)
Omeprazole 20 mg / lansoprazole 30 mg
+
Clarithromycin 500 mg
+
Amoxicillin 1 g / metronidazole 500 mg / tetracycline
500 mg
→ all twice daily for two weeks– Quadruple therapy (4 drugs)

240
Omeprazole 20 mg / lansoprazole 30 mg BD
+
Bismuth subsalicylate 525 mg QID
+
Tetracycline 500 mg QID
+
Metronidazole 250 mg QID
→ all daily for two weeks
– - - - - After completion of any therapy, treatment with
PPIs (once daily) continued for another 4-6 weeks to
promote ulcer healing

241
Digestants
• The digestants are the substances intended to
promote digestion of food in the GIT
• A number of prteolytic, amylolytic and lipolytic
enzymes are marketed in combination
formulations
- these are vigorously promoted for dyspeptic
symptoms, and as appetite stimulants• The commonly used
digestants are:
1. Pepsin
2. Pancreatin
3. Papain
4. Rennin
5. Diastase & Takadiastase
1. Pepsin:
• Proteolytic enzyme
• Obtained from gastric mucosa of pigs, cattle or
sheep
Uses:
• Used along with HCl in gastric achylia
(defective acid & pepsin secretion)
- seen in patients with carcinoma of the
stomach, atrophic gastritis & pernicious
anaemia
• To treat digestive enzyme deficiency
2. Pancreatin:
• Obtained from pig pancreas
• It is a mixture of pancreatic enzymes
• It contains amylase, lipase & trypsin
• Administered orally – enteric coated tablets
Uses:
• Replacement therapy in chronic pancreatitis
• Obstruction caused by the cancer of the head of
pancreas
• Cystic fibrosis• Steatorrhoea

242
• After total gastrectomy & pancreatectomy
Adverse effects:
• Nausea, diarrhoea, hyperuricaemia – rare
• Fibrosing colonopathy (prolonged use)
3. Papain:
• Proteolytic enzyme
• Obtained from raw papaya
4. Rennin:
• Obtained from the glandular layer of calf
stomach
• Partially purified milk curdling enzyme
Use:
• Preparation of cheese
5. Diastase & Takadiastase:
• Amylolytic enzymes
• Obtained from the fungus “Aspergillus oryzae”
• It hydrolyses polysacharides to sugars
Use:
• Pancreatic insufficiency
Antiflatulents & Carminatives
• These are the drugs used to expel gas from the
stomach or the intestines in the treatment of
flatulence and colics
• Flatulent dyspepsia may be associated with
disorders such as
- peptic ulcer, biliary tract disease, IBS, GIT
tumors
• They act by mild stimulation therapy
- increasing the GIT motility & causing relaxation
of sphincters• Indian food contains
enough carminatives
in the form of
- cardamom seeds,
ginger, fennel seeds,
asafotida, cloves,
cinnamon bark, &
Coriander
Drugs:
• NaHCO3

243
• Dimethyl polysiloxane
• Gripe water mixture
• Peppermint oil
• Tincture cardamom
• Tincture ginger
• Dill oil• NaHCO3 evolves CO2 & relaxes sphincters &
expulsion of gas
• Along with sodium bicarbonate, they form
important constituents of various “gripe water”
mixtures commonly used in infants to relieve
griping
• Other compounds contain volatile oil, which by
their mild irritation action - relax sphincters &
increasing the GIT motility
Dimethyl polysiloxane (Simethicone):
• It is a silicone polymer
• Antifoaming agent
• Pharmacologically inert &
not absorbed from GIT
• It is allowing the gas to
escape from the GIT
• Used in symptomatic treatment of
- postprandial & postoperative flatulence
- abdominal distension
• It
- coats ulcer surface
- prevents hiccups & reduces flatulence
- eliminates mucus embeded bubbles that
interfere with visualisation during
gastroscopy
• It is available as 40mg
Tablets
Gallstone dissolving agents
• Cholesterol remains dissolved in bile with
the help of bile salts
• A high conc. Of CH: bile salt ratio
favours crystalisation of CH in bile leading to
gallstone formation
• Laparoscopic cholecystectomy is the treatment

244
of choice for gallstones
- but medical therapy used in patients with small
cholesterol stones who are unwilling or unfit for
surgery
Gallstone dissolving agents are:
1. Chenodeoxycholic acid (Chenodiol)
2. Ursodeoxycholic acid (Ursodiol)
1. Chenodiol:
• It promotes dissolution of gall stones by:
- reducing CH synthesis in liver
- improving solubility of CH in bile
• It partially or completely dissolve CH gallstones in
about 40% patients over 1-2 yrs
• Recurrence are common after stopping
medication
• Not used now, because it is less effective & A/E
Adverse effects :
• Diarrhoea
• Rise in hepatic aminotransferase enzymes
• Favouring peptic ulcer formation
• Raise plasma LDL-CH
2. Ursodiol :
• It is more effective & better
tolerated than chenodiol
• It promotes dissolution of gall
stones by:
- Inhibiting intestinal CH absorption
- reducing CH secretion into bile
- promoting solubilization of biliary
cholesterol• It can achieve complete dissolution of biliary CH
stones in upto 50% cases when given for 6-24
months
• Long plasma t1/2 - 4 days, well absorbed orally
• Recurrence are common after stopping
medication
• Poor patient compliance
Adverse effects :
Free of serious side effects
- Favouring peptic ulcer formation

245
TREATMENT OF
CONSTIPATION
Dr. Sam Pavan Kumar
Professor
Physiology:
o Approx. 9 – 10 L of fluid enter the duodenum/day
o 7.5 – 8.5 L are absorbed in the small intestinal
o 1.4 L are absorbed in the colon
o 0.1 L (100 ml) only is lost in stools/day, normally.
2CONSTIPATION:
‘con’ – together
‘stipare’ – to cram or pack
• Principal functions of colon:
- solidification, storage and proper & timely
evacuation of stools
- determined by :
*nature of luminal contents
*integrity of normal colonic absorptive
and neuromuscular function3“Constipation”:
- decreased frequency
- difficulty in initiation
- passage of firm or small volume faeces
- feeling of incomplete evacuation
• More common in women
• Causes:
a) Primary: no specific cause
b) Secondary: lack of dietary fiber
drugs
hormonal disturbances
neurogenic disorders
systemic illnesses
4• Drugs causing constipation:
aluminium containing antacids
calcium preparations
antimuscarinic drugs
iron
opioids
antihistamines
NSAIDS

246
clonidine
verapamil
tricyclic antidepressants
5Treatment of constipation:
a) Pharmacological methods
b) Non-pharmacological methods:
fiber rich diet
plenty of fluid intake
appropriate bowel habits & training
physical activity
attention to psycho-social and emotional factors
change drugs which are causing constipation
6• Agents used to treat constipation are called:
laxatives, purgatives, cathartics,
aperients, evacuants
• Laxation: evacuation of formed faecal matter
from the rectum
• Purgation: evacuation of unformed, watery faecal
matter from the entire colon
• General mechanisms of laxatives:
- retention of intra-luminal fluid
- decreased net absorption of fluid
- effects on motility
7Classification of drugs used in constipation:
1)Stimulant / Irritant laxatives:
Anthraquinones:
Senna
Cascara
Irritant oils:
Castor oil
Miscellaneous:
Bisacodyl
Phenophthalein
Sodium picosulfate
82) Osmotic laxatives:
Saline lax:
Magnessium sulfate/Oxide/Citrate
Sodium phosphate
Sodium-potassium tartrate
Non digestible sugars & alcohols:

247
Lactulose
Glycerine
Mannitol
Polyethylene glycol
93) Bulk laxatives:
Methyl cellulose Agar
Bran Psyllium husk/Isopgul
Plantago seeds Pectins(fruits & veg.)
Sabsa(Ocimum basilicum)
4) Emollient laxatives:
Liquid paraffin
Dioctyl sodium sulfo-succinate(docusate)
5) Pro-kinetic agents:
5HT4 receptor agonists: Cisapride
Opioid receptor antagonists
10Classification based on time of onset of action:
Slow onset: 1 – 3 days
Intermediate onset: 6 – 12 hrs
Rapid onset: 2 – 6 hrs
Stimulant/Irritant laxatives:
• Have direct effect on enterocytes, enteric
neurons and muscle
• Induce low grade inflammation in gut
11Anthraquinone laxatives:
o Senna: derived from leaves of Cassia acutifolia
o Cascara: derived from bark of Cascara segrada
o Rhubarb
• Present in inactive form
• Requires activation in the colon by colonic bacteria
• Evacuation occurs in 6 – 12 hrs
• Have low griping
• Adverse effects: melanosis coli
12Castor oil:
• Derived from the seeds of Ricinus communis
• Contain: toxin protein – ricin
triglyceride
glycerol ricinoleic acid
acts in small intestine
stimulates secretion of fluid

248
& electrolytes 13Castor oil(cont)
• By itself, castor oil is non-irritant
• After ingestion, it undergoes metabolism in the
intestines and triglyceride is liberated
• Quick onset of action in 2 – 3 hrs
• Colonic emptying is complete
• Causes griping
14Phenophthalein:
o Is a basic dye, stains pinkish red
o Stimulates large intestine
o Action begins after 6 – 8 hrs
o Undergoes entero-hepatic circulation
o Causes allergic skin rash
o Has potential carcinogenecity
15Bisacodyl (Dulcolax):
o Can be given orally and rectally
o Requires activation in large bowel by hydrolysis
o Onset of action: orally – 6 hrs
rectally – 30 to 60 mins
o Excessive use cause damage to mucosa
o Tablet should not be chewed, as it causes GI
irritation
Sodium pico-sulfate (Cremalax):
- Like Bisacodyl
16Osmotic laxatives:
• Poorly absorbed from GIT
» retention of water within
» ↑ the stool bulk
» reduce viscosity of intestinal contents
» promote laxation
17Saline laxatives:
o Laxatives containing magnesium and phosphate
ions are called saline laxatives
o MOA: osmotically mediated water retention

249
produces peristalsis
produce inflammatory mediators
stimulate release of cholecystokinin
o Well tolerated by most patients
o Evacuation occurs in 3 – 6 hrs
o Monitor for:
hypermagnesemia, hyperphosphatemia
hyperkalemia, hypernatremia, hypocalcemia
18Uses of Mag. sulfate by different routes of admn:
1) Orally:
- as osmotic laxative in constipation
2) Hypertonic enema(50%):
- for lowering raised intracranial tension
3) Injection(IV/IM):
- for anti-convulsant effect in Ecclampsia or
severe pregnancy induced hypertension
- tocolytic effect in threatened abortion
4) Compress(10%):
- for relieving pain in cellulitis
19Glycerine:
o Is a tri-hydroxy alcohol
o Given rectally (enema or suppository)
o Acts as hygroscopic and lubricant
Poly-ethylene glycol(PEG):
• Poorly absorbed; high osmotic nature
• Prepared in isotonic mixture of sodium sulfate,
bicarbonate, chloride; and potassium chloride
• Available: in powder
ready to use solution
20Lactulose:
• Is a non-absorbable sugar
• Hydrolysed in intestines to organic acids which
osmotically draw water
• Uses:
laxative, in constipation, dose 15-30 ml at night
In hepatic encephalopathy:
inhibits urease producing bacteria
causes ionic trapping of ammonia

250
 stimulates GI motility
dose: 30-45 ml TID(stools 2-3/day)
21Bulk laxatives:
• Are natural or semi-synthetic polysaccharides and
cellulose derivatives
• Given orally » not absorbed » ↑ indigestible
residue » absorb water » intestinal distension
» ↑ motility » evacuation
• Do not produce irritation or griping
• Onset of action: 12 – 36 hrs
• Uses: IBS, hemorrhoids, chronic diarrhea
• Contraindications:
Intestinal stenosis, atony, obstruction,
or megacolon
22Emollient laxatives/Wetting agents:
a) Liquid paraffin(mineral oil):
- obtained from petroleum
- indigestible and poorly absorbed
- softens the stools
Adv.effects:
- interferes with absorption of fat
soluble substances
- elicits foreign body reaction in gut
- cause lipid pneumonitis(if aspirated)
b) Dioctyl sodium sulfosuccinate(Docusate):
lowers surface tension(detergent activity) 23Prokinetic agents:
Cisapride, Mosapride
Metaclopramide
Opioid antagonists: Naltrexone
24Uses of laxatives:
- In constipation
- In old age and pregnancy (↓ intestinal tone)
- Food and drug poisoning
- Following anti-helminthic therapy
- Preoperatively in abdominal surgeries
- Prior to conduction of vaginal deliveries
- Prior to radiological examination of abdomen
- Drug induced constipation
- Hepatic encephalopathy
- In patients with fissure-in-ano, hemorrhoids

251
 - In patients with h/o myocardial infarction, CCF
25Contraindications for use of laxatives:
- Intestinal stenosis
- Intestinal atony
- Intestinal perforation
- Intestinal obstruction
- Intestinal ulcerations
- Congenital megacolon
26Enema:
• Introduction of fluid substances/drugs per-rectally
• 3 types: evacuant enema
retention enema
diagnostic enema
• Commonly used substances as enemas:
tap water
soap water
isotonic sodium chloride
sodium phosphate
glycerine
mineral/vegetable oil 27Enemas(cont)
Uses of enemas:
- prior to surgery
- prior to vaginal delivery
- prior to radiological examination
- prior to colonoscopy
28

252
Estrogens & Anti-estrogens
DR. Pushpalatha C.
Neuroendocrine control of gonadotropin
secretion in females

Hormonal relationships of the human menstrual cycle

253
ESTROGENS
I. Natural estrogens
- Estradiol
- Estriol
- Estrone
II. Synthetic estrogens
a) Steroidal synthetic estrogens
- Ethinylestradiol
- Tibolone
- Mestranol
- Conjugated estrogens (Premarin, cenestin)
- Esters of estrogens (Estradiol valerate,

254
Estradiol cypionate)
a) Nonsteroidal synthetic estrogens
- Diethylstilbestrol - Methallenestril
- Hexestrol - Chlorotrianisene
- Dienestrol - Quinestrol
- Benzestrol
- Methestrol
Pharmacokinetics
• Natural estrogens – Oral – Not much effective
– Rapidly metabolized in liver (first pass effect)
• Synthetic estrogens – Oral – Active
– Metabolism – Slow
– t ½ – Long
– Tibolone – 3 metabolites – exert estrogenic,
progestational & weak androgenic action – used for HRT
• Undergo enterohepatic circulation
• Routes of admin. – Oral, IM, Vaginal, & Transdermal
patches (less effect on hepatic synthesis of proteins)
• Excretion – Bile, urine & breast milk
Natural estrogens – Synthesized from cholesterol
Mechanism of action
• Estrogen (free form) – enters cell by passive
diffusion through plasma membrane - binds
to estrogen receptors (ERα,ERβ) in nucleus →
leads to change in ER conformation causes
receptor dimerization – ER dimer binds to
EREs of target genes – regulate gene transcription
• ERα – Abundant in uterus, vagina, ovaries,
mammary gland, hypothalamus & bld. vessels
• ERβ – Present in ovaries & prostate gland
Physiological and Pharmacological actions
• Estrogen – essential for the development of:
– Female reproductive tract
– Female secondary sexual characteristics
• Estrogen & menstruation
– Estrogen admn. – Stimulate proliferative phase of
endometrium
– Withdrawal of estrogen – causes menstrual flow
(withdrawal bleeding)
• Gonadotropin inhibition

255
 – Continuous admn. of estrogen – suppresses FSH & also
midcycle LH surge – inhibits ovulation in women
• Antiandrogenic action – (-) spermatogenesis in males• Suppresses
lactation
• Cause sodium & water retention (mild)
• ↑BP (after prolonged use)
• Useful in maintenance of bone mass
– By decreasing bone resorption rate
• Causes promotion of union of epiphysis with metaphysis
• Decrease plasma LDL, increase HDL & TG levels
• Increase blood coagulability
– by inducing synthesis of blood coagulation factors
(oral > transdermal)
• Increase lithogenicity of bile
• Carcinogenecity – cancers of endometrium, breast,
vagina & liver
Therapeutic uses
1. Hormone Replacement Therapy (HRT)
• In postmenopausal women – estrogen
therapy (Conjugated estrogen or Ethinyl
estradiol – low dose or Tibolone) reduces
o vasomotor symptoms
o incidence of bone fractures due to osteoporosis
o vaginal dryness & urogenital atrophy (Senile
vaginitis)
o incidence of cardiovascular disease
• For HRT in hysterectomised patients
o Estrogen alone
• For HRT in patients with uterus
o Estrogen & Progesterone
Cyclic regimen - Estrogen for 25 days
addition of Progestin (MPA) for last10-12 days
of estrogen treatment & 5-6 days no
treatment
Continuous regimen – Estrogen+Progestin
2. As oral contraceptive
o Estrogen in combination with progesterone
(combination OCPs)
3. Delayed puberty in girls (Primary hypogonadism)
• In Turner’s syndrome – Failure of ovarian

256
 development
– Ethinyl estradiol 10 µg/day or conjugated estrogen –
initially till vaginal bleeding occurs→ low dose
combination OCPs for 21 days every month
4. Vulvo-vaginitis in children
• Estrogen – makes vaginal pH acidic & epithelium
cornified – prevents bacterial growth
5. Acute severe DUB (Dysfunctional Uterine
Bleeding)
• As adjuvant to progesterone
6. Dysmenorrhoea (severe cases)
7. Carcinoma prostate
– Estrogen – Acts by suppressing androgen production
8. Acne in women
– Estrogen – Acts by suppressing androgen production
9. Hirsutism
– Estrogen – Acts by suppressing androgen production
Adverse effects
• In postmenopausal women
– ↑ incidence of:
• Irregular uterine bleeding
• Endometrial carcinoma (Estrogen alone)
• Breast cancer
• In first trimester of pregnancy
– Diethylstilbestrol causes
• Vaginal & cervical carcinoma in female offspring
• Congenital abnormalities in both male & female
offspring
• In children (< 11 years)
– Fusion of epiphysis & reduction of adult stature• Nausea &
vomiting
• Hyperpigmentation
• Breast tenderness & edema
• Thromboembolism
• Increase in frequency of – migraine,hypertension,
endometriosis, gallbladder disease & epilepsy
Contraindications
• Endometrial carcinoma
• Carcinoma of breast
• Undiagnosed genital bleeding

257
 • Liver disease
• H/o thromboembolic disorder & in heavy smokers
ANTI-ESTROGENS, SERDs, SERMs & ESTROGEN-
SYNTHESIS INHIBITORS
I. Anti-estrogen
- Clomiphene
II. Selective estrogen receptor down-regulator
- Fulvestrant
III. Selective estrogen receptor modulators (SERMs)
- Tamoxifen
- Raloxifene
- Bazedoxifene
- Toremifene
- Ospemifene
IV. Estrogen-synthesis inhibitors (Aromatase inhibitors)
a) Steroidal - Exemestane, Formestane
b) Nonsteroidal – Anastrozole, Letrozole, Vorozole
ANTI-ESTROGEN
• Pure estrogen antagonist
MOA
– ↑ gonadotropin secretion by blocking estrogen
feedback inhibition of pituitary gland → induces Gn
secretion → ↑ LH/FSH release at each secretory
pulse→ ovaries enlarge → ovulation
Pharmacokinetics
– Oral admn. – well absorbed
– Plasma t ½ - long (5-7 days)
– Plasma protein binding – high– Undergoes enterohepatic
circulation
– Accumulates in fatty tissues
– Excretion – feces & urine
Therapeutic uses
– Infertility in females due to anovulation
• 50 mg OD for 5-7 days starting 5th day of cycle
– Polycystic ovary syndrome
• If metformin is not effective clomiphene may be
added
– Oligospermia (in males with low sperm count)
Adverse effects
– Polycystic ovaries

258
– Multiple pregnancies
– Increased risk of ovarian tumors
– Hot flushes
– Gastric upset
– Blurring of vision & alopecia
SELECTIVE ESTROGEN RECEPTOR DOWN-
REGULATOR (SERDs)
• MOA (Fulvestrant)
– Binds to ERα & ERβ – Causes downregulation of ERα
and protects ERβ from degradation
• Pharmacokinetics
– IM depot injection/month
– Excretion – mainly in feces
• Therapeutic uses
– Used in Breast cancer resistant to tamoxifen
• It inhibits proliferation of breast cancer cells
• Adverse effects - Hot flushes, Pharyngitis & GI
symptoms, Back pain & headache
SELECTIVE ESTROGEN RECEPTOR MODULATORS
(SERMs)
Tamoxifen
• Anti-estrogenic action
– Inhibition of proliferation of breast cancer cells
– Causes hot flushes
• Partial agonistic action
– Improves bone density
– Stimulates endometrial proliferation
– ↑Risk of thromboembolism & ↓LDL levels
• Orally effective
• Long duration of action – due to active metabolites
• Therapeutic uses
1. Breast cancer (ER +ve tumors)
• In both pre- and post-menopausal women –
primary & metastatic cases
• For prophylaxis - in high risk pts.
• In stage I carcinoma after excision – to prevent
contra-lateral breast cancer
• Tamoxifen – Less toxic than other anticancer drugs
2. Male infertility
• Used as alternative to Clomiphene

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 • Adverse effects

– Hotflushes,endometrialcarcinoma, Venous thromboembolism,

menstrual irregularities, hair loss depression, anorexia & reduced visual
acuity.

Raloxifene
• Uses – osteoporosis in postmenopausal women
– Breast cancer
• Does not increase risk of endometrial carcinoma
• Reduces total cholesterol & LDL, does not
increase HDL
• Adverse effects – Hot flushes
– Deep vein thrombosis
– Leg cramps
ESTROGEN SYNTHESIS INHIBITORS
(Aromatase inhibitors)
MOA
• Inhibit aromatase enzyme → inhibit estrogen
biosynthesis
– Steroidal compounds – Irreversible action
– Non-steroidal compounds – Reversible action
Therapeutic uses
• Breast cancer (ER +ve cases)
– Early breast cancer – as first line drug for adjuvant
therapy after mastectomy in postmenopausal women
– Advanced breast cancer – Letrozole as first line Rx• Route of
admn. – Oral
• Adverse effects
– Hot flushes & Vaginal dryness
– Thinning of hair
– Nausea, diarrhoea & dispepsia
– Joint pain and stiffness
• Unlike tamoxifen they do not increase risk of:
– Uterine cancer
– Venous thromboembolism

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 Drugs Affecting Calcium Balance
Calcium
• Most abundant body constituent (about 2% BW)
• 99% stored in bones
• Normal plasma calcium: 9-11 mg/dl
Physiological role:
• Controls excitability of nerves & muscles
• Essential for
excitation - contraction coupling in all types of
muscle
excitation - secretion coupling in exocrine &
endocrine glandsrelease of transmitters from nerve endings
• Intracellular messenger for hormones,
autacoids & transmitters
• Controls impulse generation in heart
• Essential for coagulation of blood
• Serves structural function in bone & teethPlasma Calcium level
mainly regulated by
3 hormones
1. Parathormone (PTH)
2. Calcitonin (CT)
3. Calcitriol
• The three primary target tissues for these
regulators are
- bone, kidney & intestine

Absorption & Excretion:

261
- from small intestine - facilitated diffusion
- duodenum - carrier mediated active transport
under the influence of vit.D
• Tubular reabsorption of Ca2+
↑ by - Vit. D & PTH
↓ by - Calcitonin
Preparations:
• Calcium – gluconate, carbonate, citrate, lactate,
Chloride
Uses:
1. Tetany:
- Cal. gluconate i.v
2. As dietary supplement
- In growing children, pregnant, lactating &
menopausal women
3. Osteoporosis:
- along with alendronate/ HRT/ raloxifene
4. In dermatoses, paresthesia & weakness
5. As antacid
ParaThyroid Hormone (PTH)
Biosynthesis, Storage & Release:
• Four parathyroid glands → secretes PTH
• Hypocalcaemia induces, Hypercalcaemia
inhibits PTH release
• Hyperparathyroidism → excess PTH →
Hypercalcaemia
• Cancer cells → over production of PTHrP →
Hypercalcaemia
PTH Actions:
PTH increases plasma
calcium levels by
1. Bone:
• PTH mainly ↑ resorption of calcium from bone
- most prominent action
Mechanism of action:
• PTH acts on PTH receptors present on
osteoblasts, induces the synthesis of RANK-L
(Receptor Activator of Nuclear factor for KB
Ligand)
• It interacts with RANK receptors present on

262
osteoclast precursors & transforms them into
active
• Active osteoclasts secrete acid & proteolytic
enzymes
- which resorbs the bone matrix

2. kidney:
• PTH - ↑ Ca2+ & ↓ po43- reabsorption
• Increase formation of calcitriol by activating
1- α hydroxylase
3. Intestine:
• Indirectly by calcitriol - ↑ Ca2+ & po43- absorption

263
Uses:
• PTH is not used in hypoparathyroidism, because
↑ plasma Ca2+ levels
Teriparatide:
- Recombinant human PTH - for the treatment of
severe osteoporosis
Cinacalcet :
• It inhibits PTH secretion by activating the Ca2+
sensing receptors (CaSR) in the parathyroids
• It is used in secondary hyperparathyroidism - due
to chronic renal disease or parathyroid tumor
Calcitonin
• It is a hypocalcaemic hormone i.e action is
opposite to PTH
• Produced by parafollicular C - cells of thyroid
• ↑ plasma Ca2+ - ↑ calcitonin
• ↓ plasma Ca2+ -↓ calcitonin release
Actions:
• Inhibits osteoclastic bone resorption
• Inhibits proximal tubular reabsorption of
calcium & phosphate
Uses:
1. For diagnosis of medullary carcinoma of thyroid
2. Hypercalcaemic states
3. Postmenopausal osteoporosis - calcitonin with
calcium & vit. D
4. Paget’s disease of bone
5. Malignancy - reduce bone pain
Vitamin D
• Important for the regulation of calcium
homeostasis, together with PTH
• Cholecalciferol (D3) – synthesized in the skin
under the influence of UV rays
• Calciferol (D2):- present in yeast, fungi, bread,
milk
• D1: mixture of antirachitic substances found in
Food
Activation of vitamin D:

264
Actions:
• Calcitriol enhances
- intestinal absorption
- renal tubular reabsorption of Ca2+ & po43-
• Like PTH, calcitriol enhances resorption of calcium
& phosphate from bone
• Osteoblastic cells express VDR & respond to
calcitriol → bone mineralization
Vitamin D deficiency:
• Inadequate intestinal absorption of calcium →
decrease plasma calcium → induce PTH → bone
resorption → bone fails to mineralize in newly laid area,
becomes soft →
- Rickets in children
- Osteomalacia in adults
Uses:
1. Prophylaxis & treatment of rickets &
osteomalacia

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 2. Metabolic rickets
3. Senile or Postmenopausal osteoporosis:
- Vit. D3 + Calcium
4. Hypoparathyroidism
- Dihydrotachysterol or alfacalcidol/calcitriol are
more effective
5. Fanconi syndrome:
- Vit D can raise the lowered phosphate levels6. Calcipotriol -
analouge of vit. D
Used in
locally - psoriasis
Systemically - skin cancer & immunlological
Disorders
Bisphosphonates (BPNs)
• BPNs are analogues of pyrophosphate
• They are most effective antiresorptive drugs
Classification:
First generation:
Etidronate Tiludronate
Second:
Pamidronate Alendronate
Third (More potent):
Risedronate Zoledronate
Actions:
• The BPNs
- binding to the hydroxyapatite crystals of bone
• When osteoclasts attach to the bone matrix,
during resorption process,
- BPNs are released from the bone & internalised
by endocytosis into the osteoclasts to accelerate
their apoptosis
• In addition BPNs also inhibit the release of IL-6 to
suppress differentiation of osteoclast precursors
• The net effect is
- inhibition of osteoclast mediated resorption
- promotion of bone remodeling by ↑ BMD
• The 2nd & 3rd generation drugs block
mevalonate synthesis that appears to be critical
for osteoclast survival
PK:

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 • Oral BA is poor, food decreases their absorption &
produce gastric irritation, esophagitis
- Hence these drugs should be taken on empty
stomach with full glass of water in sitting posture
Therapeutic uses:
1. Osteoporosis:
• The 2nd & 3rd gen’n BPNs are effective in
preventing & treating post menopausal & steroid
induced osteoporosis in both men and women• Alendronate is
more effective than HRT or
raloxifen in conserving BMD & reduce risk of
vertebral & hip fractures
• BPNs are more effective than calcitonin. They are
the first choice drugs now for osteoporosis
2. Paget’s disease:
• BPNs arrest osteolytic lesions, reduce bone pain
& improve secondary symptoms
3. Hypercalcaemia of malignancy
- I.V pamidronate or zoledronate
4. Osteolytic bone metastasis:
• Pamidronate or zoledronate arrests osteolytic
lesions & reduces bone pain
Pamidronate:
• Only by i.v infusion
A/E:
- flu-like reaction, thrombophlebitis, bone pain,
fever, leukopenia
Alendronate:
• Orally effective
A/E:
- esophagitis, gastric erosion, retrosternal pain,
flatulence, headache, body ache
Zoledronate:
• i.v infusion, faster acting
• Drug of choice for hypercalcaemia than
pamidronate
A/E:
- flu-like symptoms, N, V, body ache, dizziness,
renal toxicity & osteonecrosid of jaw

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DRUGS ACTING ON UTERUS
Dr. Sam Pavan Kumar
UTERUS
primarily affecting
Endometrium Myometrium
Estrogens Stimulants
Progesterones Relaxants
E/P antagonists
UTERINE STIMULANTS
- Also called Oxytocics / Ecbolics / Abortifacients
- These stimulate uterine contraction
- Used: to induce abortion
induce labor
augment labor
post partum hemorrhage
Classification of Uterine stimulants:
a) Post.Pituitary H: Oxytocin
b) Ergot preparations: Ergometrine
Methyl ergometrine
c) Prostaglandins: PGE₂, PGF₂α, 15-methyl PGF₂α,
Misoprostal
d) Miscellaneous: Ethacridine lactate
Hypertonic saline
Urea
50% glucose in water
OXYTOCIN
• Is a cyclic nonapeptide
• Synthesized and secreted by paraventricular and
supraoptic nucleus of hypothalamus
• Also synthesized from: luteal cells of ovary
the uterus
fetal membranes
• Acts via oxytocin receptors & local PG prodn.
(marked increase in oxy.receptors and
increased sensitivity of uterus to oxy. seen in
last trimester of pregnancy)
• Stimuli for Oxytocin secretion:
sensory stimuli from cervix, vagina
sensory stimuli from nipple by suckling at breast
estradiol

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pain
dehydration
hemorrhage
hypovolemia
• Stimuli that inhibit Oxytocin:
relaxin (ovarian polypeptide)
ethanol
Physiological roles of Oxytocin:
• Uterus:
↑ force of contraction
↑ frequency of contraction
- causes contraction of the fundus and upper half
of uterus with relaxation of lower segment
- these effects are estrogen dependant
- progesterone inhibits this effect
• Breast:
- contraction of myoepithelial cells surrounding
mammary glands and causes milk ejection
Pharmacokinetics:
o Orally not active, destroyed by trypsin in gut
o Routes: IV, IM, Nasal, Buccal lozenges
o Continuous slow IV – preferred
o t½: in non pregnant: 10 – 15 mins
in pregnant women: 3 mins
o Inactivated by oxitocinase, present in plasma,
uterine tissue & placenta
Adverse effects: water retention
• Uses of Oxytocin:
induction of labor
augmentation of labor
in uterine inertia
post-partum hemorrhage
induce therapeutic abortion
oxytocin challenge test
milk ejection
ATOSIBAN:
oxytocin receptor antagonist
may be used in treatment of preterm labor
ERGOT ALKALOIDS
- obtained from fungus Claviceps purpura, that

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 grows on rye and other grains
- Called as “St. Anthony’s fire”
Include:
a) Amino-acid alkaloids:
Ergotamine
Ergosine
Ergotoxin
b) Amine alkaloids:
Ergometrine
c) Semi-synthetic dihydrogenated amino acid
alkaloids:
Dihydro ergotamine
Hydergine
Pharmacological actions:
1) Uterus: causes contraction
the response depends on the alkaloid,
dose, degree of uterine maturity,
stage of gestation
- Ergometrine & Methyl ergometrine produce
immediate and powerful response
- Small doses: ↑force of contraction with normal
relaxation in between contractions
- Higher doses: powerful and sustained contractions
- Capable of stimulating the uterus during any phase of estrous
cycle or gestation, but uterus at full term & immediate post-partum is
highly sensitive
2) Vascular actions:
α blocking effect » ↓BP: Dihydroergotamine,
Hydergine
Direct vasoconstrictor effect: Ergotamine,
Ergometrine
(no α blocking effect)
3) GIT: ↑peristaltic effect: Ergotamine
4) Misc.: Partial 5HT agonists: Ergotamine
Ergometrine
5HT antagonist: Methysergide
Pharmacokinetics:
• Ergotamine - erratic oral absorption
DHE - high first pass metabolism
-metabolized in liver

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- excreted in bile
- t½: 20 mins.
• Ergometrine - rapidly absorbed after
Methylergometrine oral administration
- metabolized & excreted
More rapidly
t½: 0.5-2 hours
Therapeutic uses:
o Postpartum hemorrhage: Ergometrine
Methyl ergometrine
o Uterine involution: Methyl ergometrine, orally,
0.2 mg TID, for 7 days after delivery
o In therapeutic abortions
o Acute migraine
PROSTAGLANDINS
• Discovered by von Euler
• Sources/sites:
human seminal fluid, iris, lung,
brain, thymus, pancreas, kidneys,
ovary, myometrium, menstrual fluid
• PGE, PGF₂α and methyl PGF₂α are potent uterine
stimulants
• They increase the tone and amplitude of uterine
contractions
• Cause ripening of cervix
• Sensitize the uterus to oxytocin
• Also cause oxytocin release
Preparations:
1. Dinoprost: PGF₂α
given intra-amniotic
to induce 2nd trimester abortion
2. Dinoprostone: PGE₂ (Primiprost)
given intra vaginal pessary for induction of labour
3. Carboprost: methyl PGF₂α (Prostodine)
given deep IM In abortions and control of PPH
4. PGF₂α gel (Cerviprime): given intracervically
for ripening of cervix
5. Misoprostal: PGE₁
orally/intravaginally for abortions
vaginally for cervical dilatation

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Therapeutic uses:
o Cervical priming
o Therapeutic abortion
o Post partum hemorrhage
o Induction of labor
o Augmentation of labor
ETHACRIDINE LACTATE (Emcredil/ Vecredil)
- is an acridine compound
- Used extra-amniotically for 2nd trimester abortion
- Administered through foleys catheter, introduced
between decidua and amniotic sac
- Dose: 10 ml of 0.1% soln. – for each gestational
week, upto a maximum of 150 ml
- Takes approx. 30 hrs. for abortion
HYPERTONIC SALINE - 20%
• Given intra-amniotically for 2nd trimester
abortion
• Given after trans-abdominal amniocentesis and
initial removal of 100 ml of amniotic fluid
UREA
o 40 – 80 gms. in 35 ml of 5% glucose in water
o Waiting period of 2 – 5 days
UTERINE RELAXANTS (TOCOLYTICS)
- Are drugs which decrease uterine motility
- Used to : delay or postpone labor (preterm)
arrest threatened abortion
in dysmenorrhea
Criteria for tocolytic therapy:
GA > 20 weeks and < 36 weeks
Estimated fetal body weight 2500 gms
Cervical dilatation < 4 cms
Cervical effacement of < 80%
Membranes have not ruptured
Absence of maternal complications
Absence of feto-placental complications
No evidence of fetal pulmonary maturity
Classification of tocolytics:
a) β₂ adrenergic agonists: Ritodrine
Salbutamol, Terbutaline
Isoxsuprine

272
b) Calcium channel blockers: Nifedepine
c) Magnesium sulfate
d) Ethanol
e) PG synthesis inhibitors: Aspirin, Indomethacin
f) Progesterone
g) Aminophylline
β₂ agonists:
- Bind to specific receptors on uterine muscle
» activate guanylyl cyclase
» ↑cAMP
» phosphorylate cell membrane proteins
» sequester intracellular Ca++
» inhibition of contractile elements
RITODRINE
• Selective β₂ agonist
• Dose: 50 μgms/min IV infusion, gradually
increased till uterine contractions cease or
maternal heart rate rises to 120/min
• Followed by IM/oral, 10 mg, Q4H – Q6H
Adverse effects:
o CVS: hypotension, tachycardia,
arrhythmias, pulmonary edema
o Metabolic: hyperglycemia,
hyperinsulinemia, hypokalemia
o Central: anxiety, restlessness, headache
o Neonate: hypoglycemia, ileus
MAGNESIUM SULFATE
• Is an effective alternative tocolytic when β₂
agonists are contraindicated
• MOA: ionic magnesium antagonizes calcium flow
» decreases the frequency of sm.m.cell ac.pot.
» uncouples excitation-contraction of sm.m
» relaxes the contractile elements of sm.m
• Dose: 2-4gms IV over 10-20mins
followed by 1-2 gms/hr iv infusion
regulated by uterine response
• Maternal side effects:
vomiting, flushing, resp.depression,
depressed reflexes,
inhibition of cardiac conduction, cardiac arrest

273
• Contraindications: heart blocks
myocardial damage
kidney damage
ETHANOL
- Given by IV infusion as 10% soln., 0.8gm/kg/hr
MOA: inhibits release of oxytocin
inhibits PGF₂α
direct suppressant action on myometrium
- Adv.effects: intoxication, restlessness,
hypoglycemia, lactic acidosis,
diuresis, tachycardia
PROGESTERONE
- given prophylactically in bad obstetric history
- Weekly injection of 17α-OH progesterone
- Given IM from 14th week to 37th week of GA
- Ineffective after onset of preterm labor
CCB – NIFEDEPINE
• Reduce tone of myometrium and oppose
contractions
• Orally 10mg every 2-3 hrs, followed by 10mg 6th
hourly

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Drug therapy during Pregnancy
Dr. Pushpalatha C.
• Drugs prescribed during pregnancy
– For the benefit of the mother
– Without harming the fetus
• Pharmacokinetic considerations during
pregnancy
1. Maternal pharmacokinetics
2. Placental pharmacokinetics
3. Embryonic & fetal pharmacokinetics
1. Maternal pharmacokinetics
– Pharmacokinetics during pregnancy
– Physiological changes during pregnancy may lead to
alterations in pharmacokinetics of drugs
• Absorption
• Distribution
• Metabolism
• Excretion
– Absorption
• Oral drugs – ↓absorption → low plasma conc.
• Inhaled drugs – ↑absorption
– Distribution
• ↑Total body water & fat – ↑Volume of
distribution – ↑Loading dose
• ↓Plasma albumin conc. – ↑free drug conc.
– Metabolism
• Induction of hepatic metabolizing enzymes –
↑Metabolic degradation of lipid soluble drugs
– Excretion
• ↑Renal blood flow & GFR – ↑Renal drug excretion
2. Placental pharmacokinetics
• Placental absorption
• Placental metabolism
• Placental transfer of drugs
– Placental absorption
• Placenta retains significant amount of drugs
→ Provides fetal protection
– Placental metabolism
• Placental enzymes (CYP450, sulfating,
acetylating & glutathione transferase) –

275
Metabolize drugs that resemble endogenous
Molecules
– Placental transfer of drugs
• Placental transfer of drugs occur by following
ways:
a) Diffusion
» Drug transfer depends on conc. gradient
b) Influence of physicochemical properties
» Low mol. wt., lipid sol. & nonionised
drugs – easily transferred across placenta
c) Influence of pH differences
» Fetal blood pH < Maternal blood pH
» Nonionised weak bases – easily cross into
fetal bloodd) Facilitated transport & Active transport
• Facilitated transport
»Carrier mediated & not energy mediated
Eg. Glucose, Cefalexin
• Active transport
»Energy mediated & against conc. gradient
Eg. Amino acids, Methyldopa
3. Embryonic & Fetal pharmacokinetics
• Fetal drug distribution
• Embryonic & Fetal drug metabolism
– Fetal drug distribution
• Fetus
– ↑ Body water than adults
– ↓ Fat than adults
– Vol. of distribution
- ↑ Hydrophilic agents
- ↓ Lipophilic agents
– Embryonic & fetal drug metabolism
• Fetal liver & adrenals – Capable of metabolizing
substrates by oxidation
• ↓ Glucuronidation in fetal liver
EFFECTS OF DRUGS ON EMBRYONIC & FETAL
DEVELOPMENT
Stages of antinatal development
1. Blastogenesis
2. Embryogenesis
3. Fetogenesis

276
4. A short term labour – Delivery stage
1. Blastogenesis
– Lasts about 16 days from conception
– Congenital malformation – Due to drugs – Not
observed
– Exposure to harmful drugs – Produce All or none effect
• Kills embryo or damaged cells replaced by
undifferentiated cells
2. Embryogenesis
– Upto & including 8th week
– Rapid development of major organs (organogenesis) occur
– Exposure to harmful drugs – Causes congenital
malformations or abortion
3. Fetogenesis
– 2nd & 3rd trimester
– Characterized by – Rapid growth & differentiation
– Exposure to harmful drugs
– Teratogenic or produce other effects
– Physical & mental retardation
– Behavioral teratogenicity
– Premature labor
– Neonatal toxicity
– Cancer (Postnatal)
4. A short labour – Delivery stage
– Danger of toxicity – In neonatal period
TERATOGENICITY
– it is Morphological, Biochemical & Behavioural
birth defect
– Induced by any exogenous agent at any stage of
pregnancy
– Detected at birth or later in life
– Teratogen – Exogenous agent
– Ability to produce congenital
malformations or functional defects
– Teratogenic drugs – 30 (around)
– In clinically effective doses
Teratogenic mechanisms
– Poorly understood
– Multifactorial
– Direct action of drugs – on differentiation process

277
E.g. Vit. A & its analogues – alter normal process
of differentiation
– Deficiencies of critical substances → abnormality
E.g. Folic acid deficiency during pregnancy →
Neural tube defect
– Continued exposure to drug – Produces cumulative
effect → affect development of several organs
E.g. Ethanol – fetal alcohol syndrome (CNS, growth
& facial development affected)
Counseling for a planned pregnancy
– To minimize risk of congenital anomalies
– General advice
– Avoidance of
– All drugs
– Alcohol
– Smoking
– Vit. A products
–Daily supplementation of
– Folic acid 400 μg
– In chronic conditions
– Treatment adjustments – Eg. Epilepsy
Counseling during an unplanned pregnancy
– H/o ongoing or past exposure to
–Drugs
– Chemicals
–Other environmental factors
– Possible future avoidance of drugs
– Informing pt. about possible risk / no risk
DRUGS PRESCRIBED DURING PREGNANCY
Prescription precautions
– Initially avoid drugs & attempt nondrug treatment
– Avoid drugs in first trimester
– In unavoidable situations
• Select known safe drug in pregnancy
• Give lowest effective dose in shortest time possible
DRUGS ACTING ON CNS
• Drugs given at term/during labour → cause CNS
depression in neonates
– Diazepam
– Antidepressants

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 – Phenothiazines
– Opioids
EPILEPSY
– Adequate seizure control is important – Otherwise harmful to
fetus
– Polytherapy should be avoided
– Phenobarbitone/Carbamazepine (low dose)
NSAIDs
– Paracetamol - Safe
– Aspirin – 1st trimester – Not teratogenic
– should not be used 2 weeks before EDD – it
will cause
- Postmaturity & Prolonged labour
- PPH & Neonatal bleeding
- Premature closure of PDA
HYPERTENSION
– α-Methyldopa – Safe & preferred for oral Rx
– CCBs (Nifedipine) – category C – Safe
– Hydrolazine & labetalol – in emergency – Safe
– β – blocker (atenolol, metoprolol & pindolol) –
category C – Safe
– ACE inhibitors – should not be used
• Renal function & Skull developmental
abnormalities
– Furosemide – Crosses placenta & causes oligomnios
HEART DISEASE
– Rx should be similar to non-pregnant women
– Cardiac arrhythmias
• Digoxin – Drug of choice
- No malformations & fetotoxicity
• Quinidine – Oxytocic activity - Mild
ANAESTHESIA
– In early pregnancy
• No evidence of Congenital malformations
– During delivery – N₂O – Continuous exposure
• ↑ Fetal N₂O conc.
–No congenital malformations
–Neonatal depression
ANTIMICROBIAL AGENTS
– Penicillins & Cephalosporins – Safe

279
– Erythromycin base – Safe
– Erythromycin estolate – Hepatotoxic
– Aminoglycosides – Ototoxic – Avoided
– In serious infections – Gentamicin & Tobramycin - Preferred
TUBERCULOSIS
– Isoniazid, Ethambutol & Rifampicin – Crosses
placenta – No congenital malformations
MALARIA
– Chloroquine – Rx of acute attack – Safe
– Quinine/Proguanil – Chloroquine resistant malaria
NAUSEA & VOMITING
– Reassurance
– High carbohydrate diet
– Biscuits (early morning)
– Pyridoxine
– Drugs (If required)
• Antihistaminic anti-emetics
–Cyclizine
–Meclizine
–Diphenhydramine
–Dimenhydrinate
– Metachlopramide – 3rd trimester - Safe
PEPTIC ULCER
– Rx – Dietary modifications
–Non-systemic antacids
–H₂ blockers – Ranitidine / Famotidine
CONSTIPATION
– Generally responds to – High fiber diet
– Plenty of liquids
– Mild laxatives – Lactulose
- Ispaghula
BRONCHIAL ASTHMA
– Bronchodilators – Salbutamol (β₂ agonist) – can be used
DIABETES MELLITUS
– Dietary restrictions
– Insulin – safe
– Oral hypoglycemic agents – contraindicated
– In IDDM
• Insulin requirement
–Decreased - In 1st trimester

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–↑ 2-3 times – By term
–↓ to pre-pregnancy level – After delivery
– Gestational diabetes
• Highly purified insulin/human insulin
preparations should be used
DRUGS OF ABUSE IN PREGNANCY
Alcohol
• Highly teratogenic
• Fetal alcohol syndrome
– CNS dysfunction
– Craniofacial dysmorphology
– Antenatal & Post-natal growth retardation
– Other anamolies
Tobacco
• In last trimester – High risk – Small for gestation age
Caffeine
• High amounts - Growth retardation
• Moderate amounts – Can be used
Cocaine
• Crosses placenta
• At vascular beds – Acts as vasoconstrictor
• During fetal period
– Prematurity & ↓ Birth wt.
– Abruptio placenta
– Spontaneous abortion
– Intra uterine death (IUD)
– Genitourinary malformations
FDA teratogenic risk categories
Category Risk Examples
A No risk Folic acid
B
No confirmatory
evidence of risk
in humans Metronidazole
C No human data most of the
available however, drugs
fetal risk is shown
in controlled
animal studies
(risk cannot be

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 ruled out)
D Positive evidence phenytoin
of fetal risk
exists (Potential benefit
overweigh potential risk)
X Absolutely thalidomide
contraindicated in
pregnancy
Drugs with Significant Adverse Effects on the
Foetus
Drug – Trimester - Effect
• ACE inhibitors – All, especially second and
third trimester
– Renal damage
• Androgens - Second and third trimester
– Masculinization of female fetus
• Antidepressants (TCAs) - Third trimester
– Neonatal withdrawal symptoms have been
reported in a few cases with clomipramine,
desipramine, and imipramine
• Barbiturates - All trimesters
– Chronic use can lead to neonatal dependence &
Cognitive loss has been described.
• Busulfan - All trimesters
– Various congenital malformations; low birth weight
• Carbamazepine - First trimester
– Neural tube defects
• Chlorpropamide - All trimesters
– Prolonged symptomatic neonatal hypoglycemia
• Clomipramine - Third trimester
– Neonatal lethargy, hypotonia, cyanosis, hypothermia
• Cocaine - All trimesters
– Increased risk of spontaneous abortion, abruptio- placentae, and
premature labor; neonatal cerebral infarction, abnormal development,
and decreased
school performance
• Cyclophosphamide - First trimester
– Various congenital malformations
• Diazepam - All trimesters

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 – Chronic use may lead to neonatal dependence and increase risk
for oral cleft
• Diethylstilbestrol - All trimesters
– Vaginal adenosis, clear cell vaginal adenocarcinoma
• Ethanol - All trimesters
– Risk of fetal alcohol syndrome and alcohol-related
neurodevelopmental defects
• Heroin - All trimesters
– Chronic use leads to neonatal dependence
• Iodide - All trimesters
– Congenital goiter, hypothyroidism
• Isotretinoin - All trimesters
– Extremely high risk of CNS, face, ear, and other
malformations
• Lithium - First trimester
– Ebstein's anomaly
• Methadone - All trimesters
– Chronic use leads to neonatal dependence
• Methotrexate - First trimester
– Multiple congenital malformations
• Metronidazole - First trimester
– May be mutagenic (from animal studies; there is no evidence for
mutagenic or teratogenic effects in humans)
• Organic solvents - First trimester
– Multiple malformations and effects on brain
Development
• Penicillamine - First trimester
– Cutis laxa, other congenital malformations
• Phencyclidine - All trimesters
– Abnormal neurologic examination, poor suck reflex and feeding
• Phenytoin - All trimesters
– Fetal hydantoin syndrome
• Streptomycin - All trimesters
– Eighth nerve toxicity described in a few cases
• Smoking (constituents of tobacco smoke) - All
trimesters
– Intrauterine growth retardation; prematurity;
sudden infant death syndrome; perinatal
complications
• Tamoxifen - All trimesters

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– Increased risk of spontaneous abortion or fetal
damage
• Tetracycline - All trimesters
– Discoloration and defects of teeth and altered bone Growth
• Thalidomide - First trimester
– Phocomelia (shortened or absent long bones of
the limbs) and many internal malformations
• Valproic acid (Sodium valproate)
–All trimesters- Neural tube defects
– First trimester - Hypoplastic nasal bridge,
chondrodysplasia
– Second trimester - CNS malformations
• Warfarin - Third trimester
– Risk of bleeding. discontinue use 1 month before
delivery
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