Pharmacology 3

For 4th year Pharmacy Students

Faculty of Pharmacy

Deraya University

PL415

By
Prof./ Ramadan A.M. Hemeida

Associate Prof./ Remon Roshdy Rofaeil

Dr./ Reham Hassan Mohy-Eldein

Dr./ Yasmen Montaser Khalifa

2022/2023

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 Contents
Chapter 1: Chemotherapy
Introduction …………………..…………………………… 1
Sulfonamides …………….………………………………… 10
Cell wall synthesis inhibitors ……………………………… 13
Nucleic acids synthesis Inhibitors…………………………. 24
Protein synthesis inhibitors………………………………… 26
Treatment of tuberculosis …………………………………. 37
Antifungal drugs …………………………………………... 40
Antiviral drugs …………………………………………….. 43
Antiparasitic drugs ………………………………………… 47
Cancer chemotherapy ……………………………………… 49

Chapter 2: Pharmacology of endocrine system

Hypothalamic and pituitary hormones …………………….. 57
Thyroid gland ………………………………...…….……… 65
Calcium homeostasis ……………………...……………….. 69
Treatment of Diabetes Mellitus ……………………………. 73
Corticosteroids …………………………………………….. 83
Male sex hormone …………………………………………. 87
Female sex hormones ……………………………………… 90

Chapter 3: Immunopharmacology ……………………… 95

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 Chemotherapy
Antibacterial Drugs
Classifiactions of antibacterials
1. According to spectrum
A. Narrow-spectrum antibiotics: Chemotherapeutic agents acting
only on a single or a limited group of microorganisms are said to have
a narrow spectrum. For example, isoniazid is active only against
mycobacteria.
B. Extended-spectrum antibiotics:
Extended spectrum is the term applied to antibiotics that are effective
against gram-positive organisms and against a significant number of
gram-negative bacteria. For example, ampicillin is considered to have
an extended spectrum because it acts against gram-positive and some
gram-negative bacteria.
C. Broad-spectrum antibiotics:
Drugs such as tetracycline and chloramphenicol affect a wide variety
of microbial species and are referred to as broad-spectrum antibiotics.
Administration of broad-spectrum antibiotics can drastically alter the
nature of the normal bacterial flora and precipitate a superinfection of
an organism such as Clostridium difficile, the growth of which is
normally kept in check by the presence of other microorganisms.
2. According to type of action
Generally, antibacterials can be classifed on the basis of type of action:
bacteriostatic and bactericidal. Antibacterials, which destroy bacteria
by targeting the cell wall or cell membrane of the bacteria, are termed
bactericidal and those that slow or inhibit the growth of bacteria are
referred to as bacteriostatic. Actually, the inhibition phenomenon of
bacteriostatic agents involves inhibition of protein synthesis or some
bacterial metabolic pathways. As bacteriostatic agents just prevent the
growth of the pathogenic bacteria, sometimes it is difficult to mark a
clear boundary between bacteriostatic and bactericidal, especially
when high concentrations of some bacteriostatic agents are used then
they may work as bactericidal

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3. According to mechanism of action
Mechanism of action Drug
folic acid synthesis Sulfonamides, trimethoprim
inhibitors
cell wall synthesis Penicillins, cephalosporins, vancomycin
inhibitors
Inhibition of bacterial Aminoglycosides, chloramphenicol,
protein synthesis macrolides, tetracyclines,
streptogramins, linezolid
Inhibition of nucleic acid Fluoroquinolones, rifampin
synthesis
Notes:
-Better avoid combination between bacteriostatic and bactericidal.
-Minimum inhibitory concentration (MIC): the lowest concentration of
a chemical which prevents visible growth of a bacterium.
-Time-dependant killing: the longer the duration of blood
concentration of drug is above MIC, the higher rate of killing (e.g.
penicillins,cephalosporins). Thus, frequent daily administration or
continuous i.v. is preferable than once-daily dosag
-Concentration-dependant killing: the more the intial concentration is
above the MIC, the more the bacyerial killing e.g. Aminoglycosides
and Quinolones. Thus, once daily administration is preferable than
multiple dose administration.
-Post-antibiotic effect is persistence of effect after the levels of the
antibiotic have fallen below the MIC.
Antibacterial combinations
It is therapeutically advisable to treat patients with a single agent that is
most specific to the infecting organism. This strategy reduces the
possibility of superinfection, decreases the emergence of resistant
organisms and minimizes toxicity. However, situations in which
combinations of drugs are employed do exist. For example, the
treatment of tuberculosis benefits from drug combinations.

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A. Advantages of drug combinations
Certain combinations of antibiotics, such as β-lactams and
aminoglycosides, show synergism; that is, the combination is more
effective than either of the drugs used separately. Because such
synergism among antimicrobial agents is rare, multiple drugs used in
combination are only indicated in special situations—for example,
when an infection is of unknown origin.

To prevent development of drug resistance (e.g treatment of TB), In

mixed infection (e.g. intrabdominal infection), In life threatening
infection (e.g. meningitis) and decrease the toxicity of drugs (by
reduction of the dose and hence reduce the risk of adverse effects) e.g.
the doses of penicillins when combined with aminoglycoside are
smaller than the doses of penicillin when used as a monotherapy).

B. Disadvantages of drug combinations:

A number of antibiotics act only when organisms are multiplying.
Thus, coadministration of an agent that causes bacteriostasis plus a
second agent that is bactericidal may result in the first drug interfering
with the action of the second. For example, bacteriostatic tetracycline
drugs may interfere with the bactericidal effect of penicillins and
cephalosporins.

Problems with antimicrobial drugs

1- Superinfection
Clostridium difficile infection is strongly associated
with antibiotic treatment, especially antibiotics that kills many different
types of bacteria (for example fluoroquinolones and extended-spectrum
cephalosporins). Also, C. difficile can be resistant
to antibiotics commonly used in health care settings.

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2- Resistance: Mechanisms of resistance
a. Naturally resistant strains
-Many Gram-negative bacteria possess outer cell membranes which
protect their cell walls from the action of some penicillins and
cephalosporins.
-Facultatively anaerobic bacteria (e.g. Escherichia coli) lack the ability
to reduce the nitro group of metronidazole which remains in an
inactive form. (Reduction of nitro group of metronidazole by the
organisms is essential for the activation of this drug)
b. Spontaneous mutation:
In this scenario, a subset of bacterial cells derived from a susceptible
population develop mutations in genes that affect the activity of the
drug, resulting in preserved cell survival in the presence of the
antimicrobial molecule. Once a resistant mutant emerges, the antibiotic
eliminates the susceptible population and the resistant bacteria
predominate.
c. Transmission of genes from other organisms (horizontal)
It is the commonest and most important mechanism. Genetic material
may be transferred through:
-Conjugation: cell to cell contact through a sex pilus or bridge
-Transduction: in bacteriophage (a virus that infect bacteria)
-Transformation: is the uptake and incorporation into the bacterial
genome of free DNA released into the environment by other bacterial
cells.

Biochemical mechanisms of resistance

For an antibiotic to be effective, it must reach its target in an active
form, bind to the target, and interfere with its function. Accordingly,
bacterial resistance may be due to:
1-Chemical alterations of the antibiotic
The production of enzymes capable of introducing chemical changes to
the antimicrobial molecule is a well-known mechanism of acquired
antibiotic resistance in both gram-negative and gram-positive bacteria.
Interestingly, most of the antibiotics affected by these enzymatic
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modifications exert their mechanism of action by inhibiting protein
synthesis at the ribosome level. Many types of modifying enzymes
have been described, and the most frequent biochemical reactions they
catalyze include:
-Acetylation (aminoglycosides, chloramphenicol, streptogramins)
-Phosphorylation (aminoglycosides, chloramphenicol),
-Adenylation (aminoglycosides, lincosamides). Regardless of the
biochemical reaction, the resulting effect is often related to steric
hindrance that decreases the avidity of the drug for its target, which, in
turn, is reflected in higher bacterial MICs.
2. Destruction of the antibiotic molecule:
The main mechanism of β-lactam resistance relies on the destruction of
these compounds by the action of β- lactamases. These enzymes
destroy the amide bond of the β-lactam ring, rendering the
antimicrobial ineffective.
3-Decreased Antibiotic Penetration and Efflux
Decreased permeability
Many of the antibiotics used in clinical practice have intracellular
bacterial targets or, in case of gram-negative bacteria, located in the
cytoplasmic membrane (the inner membrane). Therefore, the
compound must penetrate the outer and/or cytoplasmic membrane in
order to exert its antimicrobial effect. Bacteria have developed
mechanisms to prevent the antibiotic from reaching its intracellular or
periplasmic target by decreasing the uptake of the antimicrobial
molecule. This mechanism is particularly important in gram-negative
bacteria, limiting the influx of substances from the external milieu. In
fact, the outer membrane acts as the first-line of defense against the
penetration of multiple toxic compounds, including several
antimicrobial agents. Hydrophilic molecules such as β-lactams,
tetracyclines and some fluoroquinolones are particularly affected by
changes in permeability of the outer membrane since they often use
water-filled diffusion channels known as porins to cross this barrier.
The prime example of the efficiency of this natural barrier is the fact
that vancomycin, a glycopeptide antibiotic, is not active against gram-
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negative organisms due to the lack of penetration through the outer
membrane

Efflux Pumps
The production of complex bacterial machineries capable to extrude a
toxic compound out of the cell can also result in antimicrobial
resistance. The description of an efflux system able to pump
tetracycline out of the cytoplasm of E. coli dates from the early 1980s
and was among the first to be described.

Changes in Target Sites

A common strategy for bacteria to develop antimicrobial resistance is
to avoid the action of the antibiotic by interfering with their target site.
To achieve this, bacteria have evolved different tactics, including
protection of the target (avoiding the antibiotic to reach its binding site)
and modifications of the target site that result in decreased affinity for
the antibiotic molecule.

3-Resistance Due to Global Cell Adaptations

Through years of evolution, bacteria have developed sophisticated
mechanisms to cope with environmental stressors and pressures in
order to survive the most hostile environments, including the human
body. Bacteria need to compete for nutrients and avoid the attack of
molecules produced by other rival organisms in order to gain the
―upper hand‖. Inside a particular host, bacterial organisms are
constantly attacked by the host’s immune system and in order establish
themselves in particular biological niches, it is crucial that they adapt
and cope with these stressful situations. Development of resistance to
daptomycin (DAP) and vancomycin (low-level in S. aureus) are the
most clinically relevant examples of resistance phenotypes that are the
result of a global cell adaptive response to the antibacterial attack.

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How to minimize the emergence of resistance?
1-Use the Right Drug by the Right Dose in the Right Patient by the
Right Route for the Right Duration (5 Rights).
2-Using antimicrobial combinations in certain cases (e.g. TB)
3-The newest members of antimicrobials are not used as long as older
drugs are effective.

Chemoprophylaxis
It is the use of drugs to prevent disease or infection.
Indications: -In healthy individuals (e.g., use of anti-TB drugs in
healthy contacts of TB-patients)
-In secondary bacterial infection in high risk patients. e.g low
immunity, infants, elderly, diabetics.
-In recurrence or activation of diseases (e.g. use of long acting
penicillin to prevent endocarditis in patients with Rheumatic heart
disease).

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 Sulfonamides
Mechanism of action:
Sulfonamides exert their antibacterial effect by blocking the production
of folates in bacteria. Folates are required for several one-carbon
transfer reactions involved in the production of new purine and
pyrimidine bases, which are required for the production of new DNA.
Thus drugs that block folate metabolism block bacterial cell
replication. Folates are required for the biosynthesis of purines and
pyrimidines in humans as well. However, the selective toxicity of
folates to bacteria is due to a key difference in folate metabolism
between bacteria and humans (see figure below). For humans, folic
acid is a vitamin that is acquired in the diet. Most bacteria, on the other
hand, synthesize their own folic acid.

Classification of Sulfonamide Members:

All members contain sulfanilamide group:
1-Sulfonamides that are absorbed and excreted rapidly, eg:
Sulfamethoxazole.
2- Sulfonamides that is topically used, eg: sulfadiazine (used in burns)
3- Long-acting Sulfonamides, eg: Sulfadoxine
4- Sulfasalazine (Sulfapyridine + 5-aminosalicylic acid combination) is
poorly absorbed from the bowel lumen (used in ulcerative colitis)
Pharmacokinetics
Mostly are absorbed in the intestine. However, Sulphasalazine is
designed for local bowel effect (not absorbed). Sulfonamides pass the

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placenta and reach the fetal circulation, where it may cause
antibacterial and toxic effects.

Metabolism and Elimination

Most of a dose of a sulfonamide is excreted unchanged into the urine,
which is one of the key reasons that sulfonamides are valuable agents
for the treatment of urinary tract infections. For the small portion of the
dose that is not excreted in an unchanged manner, one of the important
metabolic routes is N-acetylation of the free para-amino group in the
liver.

Uses of sulfonamides:
Note: Clinical uses of sulfonamides as a single drug have been reduced
sharply because of the development of more effective antimicrobial
agents, and the gradual increase in the resistance of bacteria.
-Sinusitis and bronchitis, some GIT infections (shigellosis), infection
by Pneumocystis jiroveci in AIDS patients and in nocardiosis.:
Sulfamethoxazole and trimethoprim (cotrimoxazole)
1-Malaria: Sulfadoxin + pyrimethamine.
2-Toxoplasmosis: Sulfadiazin + pyrimethamine
3-Ulcerative colitis: Sulfapyridine + 5-aminosalicylic acid
(Sulfasalazine).

Adverse reactions:
-Crystalluria and nephrotoxicity (with sulfisoxazole because it is
insoluble in urine). These side effects can be prevented via excessive
intake of fluid and alkalanization of urine.
-New-born: (hyperbilirubinemia and kernicterus)
-Blood (hemolytic anemia, aplastic anemia, agranulocytosis,
porphyria), especially in G6PD deficiency people.
-Hypersensitivity

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Drug interaction:
Displaces the following drugs from plasma proteins potentiating their
effects:
-Oral hypoglycemics (sulphonylurea)
-Oral anticoagulants (warfarin).
-Anticonvulsants (hydantoin.
Precautions with the use of sulfonamide:
Pregnancy: may cause jaundice, and kernicterus in newborn.
Children younger than 2 months of age.
Renal or liver function impairment Use drug with caution.
G-6-PD-deficient individuals.
Trimethoprim
Mechanism of action
Trimethoprim, like the sulfonamides, blocks bacterial folate
metabolism and thus synthesis of new nucleic acids. However, it does
it in a completely different manner. Trimethoprim resembles
dihydrofolate, and binds to the folate site on DHFR. However, it
cannot be reduced by the enzyme and thus acts as a potent inhibitor of
the enzyme. All organisms (bacteria and humans included) have
DHFR, but there are subtle differences in the structure between the
human and bacterial enzymes.
Due to this difference, trimethoprim binds ~100,000 times more tightly
to the bacterial form of DHFR, and thus has little effect on human
folate metabolism. Blocking the reduction of dihydrofolate to
tetrahydrofolate has a dramatic effect on nucleic acid production.
Trimethoprim-sulfamethoxazole
(Co-trimoxazole)
(In ratio 5: 1)
Advantages of SMX-TMP combination
-Synergism (1 + 1 > 2).
-Bactericidal instead of bactriostatic.
-Low incidence of resistance.
-Broad antibacterial spectrum.

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 Inhibitors of cell wall synthesis
All inhibitors of cell wall synthesis are bactericidal.

Penicillins
Mode of action of penicillins:
1. Inhibition of cell wall synthesis by blocking transpeptidation:
-Penicillin binds to penicillin binding protein (PBP) receptor on the
surface of bacterial cell wall. PBP is the receptor for substrate
peptidoglycan precursor in bacteria. Antibiotics penicillin acts as
alternative substrate and binds to PBP receptor and then inhibits
transpeptidase which results in inhibition of cell wall synthesis.
2. Activation of autolytic enzymes:
-Penicillin causes activation of autolytic enzymes of bacteria which
creates lesion sin bacteria causing their death.
-Autolysins are present in bacterial cell wall which maintains
appropriate shape and size of cell and also helps in cell division. The

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activity of autolysin is regulated by components such as cell wall and
teichoic acid.
-Use of antibiotics penicillin causes destruction of cell wall and
disintegration of teichoic acid as a result of which autolysin is activated
and cause cell lysis.
Types of penicillin:
1-Natural penicillin
-These are active against Gram positive bacteria, very less against
gram negative rods but act against gram negative cocci (gonococci and
Meningococci)
-Susceptible to hydrolyse by β-lactamases.
-Examples: penicillin G( Benzyl penicillin), penicillin VK
2-Anti-staph penicillin (β-lactamase resistant penicillin)
-These penicillin are relatively stable to Staphylococcal β-lactamase
enzyme.
-They have little activity against Gram positive bacteria
-Inactive against Gram negative bacteria
-Examples: Methicillin, Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin.
3. Broad spectrum penicillin (aminopenicillins, beta-lactamase
sensitive)
-These antibiotics have higher activity against Gram Positive and gram
Negative bacteria but are destroyed by β-lactamases as ampicillin &
amoxicillin
4-Extended Antipsudomonal penicillin as carbincillin & ticarcillin
Mechanisms of resistance:
1- Inactivation of penicillin by β-lactamase (the most common).
2- Modification of target PBPs.
3- Impaired penetration of drug to target PBPs.
4- Increased efflux.

Pharmacokinetics:
-Absorption of oral penicillins is decreased by food (should be given 1-
2 h before or after meals) except amoxicillin.

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-Distributed widely to most areas of body, with poor penetration to
eye, prostate and CNS. However, inflamed meninges permit the
passage of penicillin, thus used in bacterial meningitis.
-Metabolized to limited extent in the liver.
-About 6o% is excreted unchanged by the kidneys mainly by tubular
secretion, consequently, dose adjustment is required in renal
impairment. Penicillin serum level can be increased by inhibition of
renal excretion.

Important features of selected members:

1. Penicillin G (Benzylpenicillin)
-Acid labile (not suitable for oral route)
There are two long acting derivatives of penicillin G, procaine
penicillin (12-24 h) and benzathine penicillin (up to 21 day)
2. Penicillin V (phenoxy methyl penicillin)
Similar to penicillin G but it is acid stable
3. Ampicillin: Similar to Penicillin G but acid stable.
It is excreted primarily in the bile (enterohepatic circulation).
4. Amoxicillin
Similar to ampicillin but better absorbed, not affected by food, gives
higher blood level, and less incidence of GIT side effects.

Penicillinase resistant penicillins (anti-staph. Penicillin) (e.g.

Methicillin, cloxacilin, dicloxacillin, fluocloxacillin, nafcillin).
Present in combination with extended spectrum penicillin to be a broad
spectrum [e.g amoxicillin + flucloxacillin]

Clinical uses of penicillin

1. Penicillin G:
-Penicillin G is the drug of choice in infection caused by Pneumococci,
Streptococci, Meningococci, Gonococci and Staphylococci (Non β-
lactamase producing Staphylococci).

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-They are effective against Spirochaetes, Bacillus anthracis and other
gram positive rods, Clostridium spp and other anaerobes but inactive
against Bacteroides fragillis (gram –ve rod).
-They are also active against Listeria spp and Actinomycetes.

2. Penicillin V:
-Penicillin V is used for the treatment of mild respiratory tract infection
such as Pharyngitis, otitis media, sinusitis etc.
-It is oral drug.

3. Benzathine Penicillin G:
-Benzathine penicillin G is the insoluble salt of penicillin G and it is
used for intramuscular injection. This is slow acting drug for prolong
use.
-A single dose of 1.2 million units of benzathine penicillin G is suitable
for treatment of β-hemolytic Streptococcal pharyngitis.
-4 million units of benzathine penicillin G injected once in 1-3 weeks
in an appropriate proportion measure for primary and latent Syphilis.

4. Ampicillin, Amoxycillin, Carbenicillin, Ticarcillin, azolocillin,

Mezlocillin and Piperacillin:
-Ampicillin is active against coli, Salmonella, Shigella and H.
influenzae but not active against indole +ve Proteus
(P.vulgaris), Pseudomonas, Klebsiella and Enterobacter.
-Amphicillin and Amoxycillin are commonly used for treatment of
common UTI caused by coliforms bacteria and for the treatment of
mixed secondary bacterial infection of respiratory tract.
-Ampicillin was a drug of choice in meningitis caused
by influenzae but nowadays Ceftriazone is used because of emergence
of β-lactamase producing strain of H. influenzae.
-Ampicillin and Amoxyccillin are alternative drug in typhoid fever but
should not be used in non-invasive Salmonella gastroenteritis.
-Carbenicillin is active against Pseudomonas and Proteus but not
against Klebsiella.
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-Ticarcillin also active against Pseudomonas and proteus in lower dose
than Carbenicillin.
-Azolocillin, Mezlocillin and Piperacillin have greater activities
against Pseudomonas than Carbenicillin.
5.Β-lactamase resistant penicillin: Methicillin, Nafcillin, Oxacillin,
Cloxacillin, Dicloxacillin
-These penicillins are used to prevent infection caused by β-lactamase
producing streptococci.
-These drugs are highly protein bound therefore they consumed 1 hour
before and after meals.
-Except Methicillin all β-lactamase resistant penicillin are suitable for
oral administration. However methicillin is nephrotoxic and is not
suitable for theurapeutic use.
Adverse reactions:
1-Hypersensitivity
-Most common drug implicated in drug allergy Rash, itching,
urticarial, fever, wheezing, angioneurotic edema , serum sickness
exfoliative dermatitis and anaphylaxis,Rare but fatal.
-More common with parenteral administration.
-Highest with procaine penicillin
-Partial cross sensitivity b/w different types
-A scratch test or intradermal test
2-Pain at injection site
3-Thrombophlebitis of injected vein
4-Nausea on oral use
5-Diarrhoea – with extended spectrum penicllin, caused by a disruption
of the normal balance of intestinal organisms.
6-CNS :
-Mental confusion, Muscle twitchings
-Convulsions & coma
-Epileptics are at risk particularly.
7- Nephritis – all can cause but seen particularly with methicillin, so
not used.

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 Drug interaction:
1-Potentiation: Probencid competes with penicillin on excretory
pathway leading to increased plasma concentration of penicillins
2-Antagonism: Bacteriostatic (e.g.Tetracyclins) with bactericidal
effect of penicillin.
3- Synergism: Aminoglycoside and penicillins
Warning: both drugs shouldn’t be mixed in the same syringe.
Why synergism occurs???
Because penicillin by inhibiting the cell wall synthesis facilitates the
entry of aminoglycosides to act on protein synthesis. Furthermore,
penicillin is mainly acting against gram -ve while aminoglycosides act
mainly against gram +ve.
-Failure of other drugs actions: penicillins decrease the effect of oral
contraceptive pills.
Beta-Lactamase inhibitors
Beta lactamases enzymes produced by gram positive and gram
negative bacteria that inactivate beta lactam antibiotics by opening beta
lactam ring.
Beta lactamase inhibitors
-Clavulanic acid
-Sulbactam
-Tazobactam
1-Amoxicillin + clavulanate: effective for beta lactamase producing
strains of staph (not MRSA), H. Influ, gonococci, E.coli .
2-Ampicillin + sulbactam: given orally/parenterally. Used effectively
for mixed intra-abdominal and pelvic infections.
3-Pipercillin + tazobactam
Note: Hepatotoxicity has been reported with the use of amoxicillin +
clavulanic acid but not with amoxicillin alone. It may be due to
immunologic reaction to clavulanic acid.

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 Cephalosporins
Antimicrobial activity
The cephalosporins have been grouped into "generations"
corresponding to their development by the pharmaceutical industry in
response to clinical needs. In general, the later generations of
cephalosporins have greater gram-negative activity at the expense of
gram-positive activity.
A. First generation agents
-Cefazolin
-Cephalothin
-Cephalexin (oral)
-All of these drugs inhibit gram-positive cocci (S. pneumoniae, S.
aureus, except enterococci), and some gram-negative rods such as
E. coli, Klebsiella, Proteus mirabilis.
-None of these drugs are active against Enterococci which have
PBPs with low affinity for the cephalosporin molecule.
-These drugs are widely used for common infections, surgical
prophylaxis, skin and soft tissue infections where the likely
organisms are gram-positives (Streptococci or Staphylococci) or
community acquired gram-negatives.

Clinical uses: They are rarely the drug of choice of any infection.
1. May be used for the treatment of non complicated UTI.
2. Cellulitis or soft tissue infection by Staph or Strep.
3. Cefazolin is a drug of choice for surgical prophylaxis. However, it
does not penetrate CNS.

B. Second generation agents

-Cefuroxime
-Cefoxitin
-Cefotetan
-These are parenteral drugs with increased gram-negative activity.
-Cefuroxime is stable to the common plasmid-mediated penicillinases,
increasing its spectrum of activity beyond that of the first generation
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drugs to cover β-lactamase producing organisms of the upper
respiratory tract such as Hemophilus and Branhamella.
-Cefoxitin (and cefotetan) have increased activity against anaerobic
organisms. They are often used to treat infections involving GI tract
flora (gram-negatives such as E. coli, Bacteroides ).

Clinical uses:
1- Upper & lower respiratory tract infection caused by H. influenza,
Moraxella catarrhalis.
2- Peritonitis in mixed infection caused by aerobic and anaerobic
bacteria.

C. Third generation agents

Parenteral:
-Cefotaxime
-Ceftriaxone
-Ceftazidime
-Cefoperazone
Oral:
-Cefixime
1. Cefotaxime
-Cefotaxime was initially developed for gram-negative infections
but is also highly active against S. pneumoniae, particularly strains
of S pneumoniae which are intermediately resistant to penicillin.
-It has good penetration into the CSF in the presence of
inflammation, and thus, is currently the drug of choice for
meningitis due to either Streptococci or gram negative organisms
(N. menigitidis, H. influenzae) until susceptibility testing is
available. It is active against most E. coli, Klebsiella, and many
common gram negative rods, but not P. aeruginosa.
2. Ceftriaxone
-Ceftriaxone has a spectrum of activity very similar to that of
cefotaxime, but has a much longer half-life and is more active.

19
 Thus, a single intramuscular dose can provide bactericidal activity
in the blood against many organisms for 12-24 hours.
-This drug is extremely popular in an outpatient setting to cover
potentially septic patients with pneumococcal infection (S.
pneumoniae), as well as N.gonorrhoea which can be effectively
treated in a single injection in many cases.
-Due to its high levels of activity, it is effective in the CSF and is
often used to treat CNS infections, including CNS-Lyme disease.
3. Ceftazidime
-Ceftazidime has a side chain similar to piperacillin and hence, is
particularly active against P. aeruginosa. It has less activity against
gram positive organisms.
-It achieves adequate CSF levels.
4. Cefoperazone
Undergoes biliary excretion so safe in renal patient.

Clinical uses of third generation:

1-The drugs of choice for serious infections caused by Klebsiella,
Enterobacter, Proteus, Serratia, and Haemophilus spp
2-Cefotaxime, ceftriaxone are approved for treatment of meningitis
cused by pneumococci, meningococci, H. influenza, ...
3-Cefixime can be given orally in respiratory and urinary tract
infections.
4-Ceftriaxone is the therapy of choice for all forms of gonorrhea.
Pharmacokinetics:
A. Oral compounds
-A large number of oral cephalosporins are available. A prototypic
drug is cephalexin. Cefaclor was developed to cover β-lactamase-
producing H. influenzae which produce penicillinase. However,
drugs with increased stability to β-lactamases have also been
marketed.
-In general, these have longer half lives to increase the ease of
administration, and are quite expensive.

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B. Distribution
-As hydrophilic molecules, these drugs do not penetrate into
phagocytic cells. However, in other areas, such as in lung, kidney,
muscle, bone, placenta, interstitial, synovial and peritoneal fluids,
and in urine, excellent drug levels are achieved. The cephalosporins
are also found in the bile.
-Cefotaxime, ceftriaxone, ceftazidime enter CSF in concentrations
adequate to treat meningitis.

C. Metabolism
-Cefotaxime is metabolized to desacetyl derivative, but this
derivative has antibacterial activity and has longer half-life.

D. Elimination
-By kidney: combination of active tubular secretion and glomerular
filtration, varies with agent. Accordingly, probenecid blocks secretion
of some compounds and some of the drugs can accumulate to varying
degrees in presence of renal failure.
Hemodialysis removes these drugs; peritoneal dialysis minimal effect.
E. Adverse effects of Cephalosporins
1. Nephrotoxicity
2. Hypersensitivity
Rash, urticaria, eosinophilia, fever, anaphylaxis (rare).
3. Hypoprothrombinemia (cefoperazone).
3. Hematologic
Leukopenia and rarely hemolytic anemia.
4. Superinfection with fungi, resistant gram-negative organisms.
5. Miscellaneous: Phlebitis, false positive tests, e.g., Coombs.

Monobactam
-Active against only gram-negative rods. Including P. aeruginosa.
-Used as alternative to penicillin in allergic patients.
-Given IV, eliminated by the kidney.
-May cause skin rash and raise liver enzymes.
21
 Carbapenems
-Imipenem
-Meropenem
-Ertapenem
Derived from a compound produced By streptomyces cattleya.
-binds to penicillin binding proteins and disrupts bacterial cell Wall
synthesis.
-very resistant to hydrolysis by most Beta lactamases.

Imipenem
 Not absorbed orally
 Is rapidly hydrolysed by a dehydropeptidase Found in the
brush border of Proximal renal tubules.
 Given with an inhibitor of dehydropeptidase, Cilastatin . A
prepration with equal amounts of both.
 Dosage should be modified for patients With renal
insufficiency.
Adverse effects
 Nausea & vomiting
 Seizures, when high doses given in patients with CNS lesions
and those with renal insufficiency.
 Patients allergic to penicillin may show hypersensitivity.
 Eosinophilia and neutropenia

Meropenem
-Does not require coadministration with cilastatin because it is not
sensitive to renal dipeptidase.
-Its toxicity is similar to that of imipenem except that it may be less
likely to cause seizures
Non Beta-Lactam drugs
1- Vancomycin (vancocin or vancomycin)
Kinetics:
 Poorly absorbed orally.
 Injection must be given IV infusion over 1-hr.
22
Clinical uses:
1- MRSA infections: methicillin-resistant staphylococci (e.g.
osteomyelitis, pneumonia, endocarditis).
2- Pseudomembranous colitis: used orally, although metronidazole is
preferred due to less resistance.

Adverse effects:
1- infusion-related reactions: Rapid intravenous infusion may cause
urticarial reactions, flushing, tachycardia, and hypotension.
2- "Red-man" syndrome is not an allergic reaction but a direct toxic
effect of vancomycin on mast cells, causing them to release histamine.

Nucleic acid inhibitors

Flouroquinolones (Inhibitors of DNA)
• Bactericidal broad spectrum antibiotics
• Increasingly used because of their relative safety, their availability
both orally and parenterally and their favorable pharamacokinetics
• There is increasing concern about the emergence of resistance to
these agents
Mechanism of Action
 Quinolones are bactericidal. They inhibit bacterial DNA synthesis in
several ways causing rapid cell death
 Quinolones bind the DNA-DNA gyrase (topoisomerase II) complex
blocking further DNA replication
 Quinolones block topoisomerase IV interfering with separation of
interlocked (concatenated), replicated DNA molecules
 There appear to be additional sites of quinolone action that are as yet
not well characterized.
Antibacterial Spectrum
• 1st generation (norfloxacin): limited to Gram negative enteric
bacteria (UTIs)
• 2nd generation (levofloxacin, ciprofloxacin): improved Gram
negative coverage with activity against S. aureus (systemic infections)
, pseudomonas and also against B. anthracis
23
• 3rd generation (sparafloxacin, gemifloxacin):
Improved activity against Gram positives e.g. staphylococci and
pneumococci, also has activity against mycoplasma and legionella
(systemic infections).
Pharmacokinetics
• Well absorbed orally - bioavailability of ≥ 50%
• Some fluoroquinolones are available parenterally
• Excellent tissue distribution. Concentrated in kidney, prostate, lung
and bile usually more than serum. Also Concentrated in bone.
• Quinolones also achieve high intracellular concentration.
• Elimination - Most are eliminated by the kidneys, although some are
eliminated by the liver
Side effects:
-Quinolones are among the most well tolerated antimicrobial agents
-Gastrointestinal, CNS symptoms can occur.
-Damage to cartlige so not used in children below 18 years old except
in pseudomonal infection with cystic fibrosis.
-Allergic reactions - rash, urticaria, drug fever
-Photosensitivity.
-Liver function abnormalities - usually mild, rare fatalities recently
reported following treatment with trovafloxacin
-Joint symptoms - arthralgias, joint swelling, tendonitis
Use of Quinolones
-Empiric therapy of community-acquired pneumonia in selected
settings
-Oral therapy of complicated urinary tract or respiratory tract
infections
-Oral therapy of serious infections such as osteomyelitis, pneumonia
or soft tissue infections
-Typhoid fever.
-Treatment of sexually transmitted diseases: gonorrhea, chancroid,
chlamydial urethritis.
-Empiric therapy of travellers diarrhea.
-Therapy for multidrug-resistant tuberculosis.
24
 Inhibitors of protein synthesis
 Tetracyclines
 Aminoglycosides
 Chloramphenicol
 Macrolides
 Clindamycin
 Streptogramins.
 Linezolid
All are bacteriostatic, except aminoglycosides which are bactericidal

1-Tetracyclines
Members:
 Short acting: oxytetracycline.
 Intermediate acting: demeclocycline.
 Long acting: doxycycline & minocycline.
 Very long acting: tigecycline.

Mechanism of action:
Tetracyclines are potent inhibitors of microbial protein synthesis by
binding to the 30S subunit of bacterial ribosome.

Spectrum of antimicrobial activity

 Bateriostatic broad spectrum against.
 Tetracycline act on gram negative more potently than on gram
positive. Antibacterial activity to gram positive is less than β-
lactam anbiotics. Antibacterial activity to gram negative is less
than aminoglycosides and chloramphenicol.
 S.typhi typhi, S.paratyphi paratyphi, P.aeruginosa aeruginosa,
brucellosis, cholera, plague, rickettsial infection.

Pharmacokinetics
Tetracyclines are deposited in growing bones and teeth teeth, causing
staining and , sometimes dental hypoplasia and bone deformities.

25
Drug interactions:
Pharmacokinetic interactions
 Absorption
-H2 -receptor blocker and antacids can decrease tetracyclines
absorption.
-Acidic drug such as Vit C can accelerate tetracycline absorbing.
-Tetracyclines can be Complexes with Metal ion of multivalence e.g.
Mg2+, Ca2+, Al3+ and Fe3+ and absorption decrease.
 Metabolism:
Induced by (carbamazepine, phenytoin, barbiturates, chronic alcohol),
especially with doxycycline and tigecycline.
Pharmacodynamic interactions:
Antagonistic effect with bactericidal-Penicillin

Clinical uses:
-Infection of Rickettsia（ship fever, Q fever ）
-Infection of mycoplasma (mycoplasma pneumonia)
-infection of the genitourinary system system）
-Infection of chlamydia chlamydia（psittacosis, trachoma and
Lymphogranuloma Venereum）and some spirochetes spirochetes
（recurrent fever fever）
-Plague, brucellosis , cholera, Helicobacter pylori)

Adverse effects:
 Bone and teeth: discoloration, abnormal growth (not used in
young children and pregnant or nursing mother).
 Liver: rise in liver enzymes and fatal hepatotoxicity has been
reported in pregnant women who received high doses of
tetracyclins and had impaired renal functions.
 Hypersensitivity.

26
 2-Aminoglycosides
Naturally occurring:
• Streptomycin
• Neomycin
• Kanamycin
• Tobramycin
• Gentamicin
Semisynthetic derivatives:
• Amikacin (from Kanamycin)
• Netilmicin (from Sisomicin)
 The aminoglycoside antibiotics are widely used for the
treatment of severe gram-negative infections such as
pneumonia or bacteremia, often in combination with a β-lactam
antibiotic.
 Aminoglycosides are also used for gram-positive infections
such as infective endocarditis in combination with penicillins
when antibiotic synergy is required for optimal killing.
 Aminoglycosides exhibit
1- concentration-dependent bacterial killing that kill bacteria at a
faster rate when drug concentrations are higher.
2- concentration-dependent postantibiotic effect. The bacterial
killing continues even though serum concentrations have fallen
below the minimum inhibitory concentration (MIC).
3- Because the postantibiotic effect is concentration-dependent for
the aminoglycosides, higher drug concentrations lead to a longer
postantibiotic effect.

Mechanism of action:
 Aminoglycosides passively diffuse through aqueous channels
formed by porin proteins in the outer membrane of gram-negative
bacteria to enter the peri-plasmic space. Then actively transported
(oxygen is required) across the cytoplasmic membrane to reach
cytoplasm. Thus, the antimicrobial activity of aminoglycosides is
reduced markedly in the anaerobic environment of an abscess.
27
 Transport may be enhanced by cell wall active drugs such as
penicillin and vancomycin.
 Once inside the cell, aminoglycosides bind to 30S ribosomal
subunit and interfere with protein synthesis by causing interference
with the initiation of protein synthesis, misreading of the mRNA
template and incorporation of incorrect amino acids in growing
polypeptide chains.

Antimicrobial activity:
Gram-Negative Aerobes
– Enterobacteriaceae;
E. coli, Proteus sp., Enterobacter sp.
– Pseudomonas aeruginosa
– Gram-Positive Aerobes (Usually in combination with ß-
lactams)
– S. aureus and coagulase-negative staphylococci Viridans
streptococci
– Enterococcus sp. (gentamicin)

Pharmacokinetics:
Absorption
 All are are very poorly absorbed orally. However, gentamicin oral
absorption may be increased in case of ulcers or inflammatory
bowel disease.
Distribution
 Not passage across B.B.B.
 High concentrations are found only in the renal cortex and the
endolymph and perilymph of the inner ear; the high concentration
in these sites likely contribute to the nephrotoxicity and ototoxicity
caused by these drugs.
Elimination
Unchanged in urine and should be adjusted in renal impairment.

28
Clinical uses:
 Treatment of infection caused by gram-negative enteric bacteria.
 Used in combination with Beta-lactam antibiotic to extend the
spectrum as in endocarditis. They have synergestic effects.
 Streptomycin used in TB, brucellosis, plague, tularemia.
 Gentamycin and neomycin can be used topically in skin infection.
 Neomycin can be used orally in GIT infection, preoperative,
hepatic coma.
Adverse effects: (dose dependent and time dependent)
• Nephrotoxicity
– Direct proximal tubular damage - reversible if caught
early
– Risk factors: High troughs, prolonged duration of
therapy, underlying renal dysfunction, concomitant
nephrotoxins
• Ototoxicity
– 8th cranial nerve damage – irreversible vestibular and
auditory toxicity
• Vestibular: dizziness, vertigo, ataxia
• Auditory: tinnitus, decreased hearing
– Risk factors: as for nephrotoxicity
• Neuromuscular paralysis
– Can occur after rapid IV infusion especially with;
• Myasthenia gravis
• Concurrent use of succinylcholine during
anaesthesia
Drug interactions
• Vancomycin, amphotericin B, cyclosporin, and furosemide
enhance the nephrotoxicity potential of the aminoglycosides.
• Loop diuretics including furosemide and bumetanide can
increase the incidence of ototoxicity when aminoglycosides
have been coadministered.
• Penicillins synergize with aminoglycosides (see penicillins)

29
 3- Chloramphenicol
 It is a antibiotics generated from venezuela Streptothrix.
 It can be generated a lot by chemosynthesis.
 The first synthetical antibiotics.
 Its L-isomer is used in clinic.
Mechanism of Action:
 A potent inhibitor of microbial protein synthesis.
 It acts primarily by binding reversibly to the 50s subunit of
the bacterial ribosome ribosome, and interferes with peptidyl
transferase in the step of protein synthesis.
 A bacteriostatic antibiotic.
Antimicrobial Actions:
 Strong effect to gram negative.
 It is active against hemophilies influenzae, Diplococcus
intracellularis and Streptococcus pneumoniae.
 The effect to gram positive is not as good as penicillin and
tetracycline.
 It can repress Rickett Rickett’s organism, chlamydia and
mycoplasma mycoplasma.
Pharmacokinetics:
 Liposolubility High concentration in cerebrospinal fluid.
 Most of the drug binding with glucuronic acid in vivo eliminate
by urine.
Therapeutic uses:
 Due to its severe adverse effects, chloramphenicol is seldom
used in clinic.
 It is used only when the benefits of therapy outweigh the risks
of the potential toxicity and there are no other antimicrobial
agents to select.
 Typhoid fever, bacterial meningitis, anaerobic infections,
rickettsial diseases diseases, and brucellosis.

Adverse effects:
30
1. Bone marrow disturbances
a. Reversible anemia is apparently dose dose-related and occurs
concomitantly with period of treatment.
b. Aplastic anemia is idiosyncratic and usually fatal, which is not
related to dose and therapy.
2. Gray baby syndrome
Appears about 4 days after treatment and manifested by vomiting,
flaccidity, cyanosis, respiratory irregularities, hypothermia, loose green
stool, gray color. This occurs especially in neonate or premature baby
because of
- Insufficient metabolizing enzymes
- In adequate renal excretion.

4- Macrolides
Mechanism of Action
• Bacteriostatic.
• Inhibit bacterial protein synthesis by bind reversibly to the
50S ribosomal subunits Block translocation reaction of the
polypeptide chain elongation.
Members: Erythromycin, Azithromycin, Clarithromycin.
Antimicrobial activity:
• Gram-Positive Aerobes:
– Activity: Clarithromycin>Erythromycin>Azithromycin
• S. pneumoniae
• Beta haemolytic streptococci and viridans
streptococci
• Gram-Negative Aerobes:
– Activity: Azithromycin>Clarithromycin>Erythromycin
– H. influenzae, M. catarrhalis, Neisseria sp.
– NO activity against Enterobacteriaceae
• Anaerobes: upper airway anaerobes
• Atypical Bacteria

31
A- Erythromycin
Pharmacokinetics
Absorption used as enteric-coated tablets, because it is inactivated by
gastric acid,
Distribution Distributed widely except to the CNS.
Elimination: biliary ecretion.
Clinical uses
-It is used as an alternative to in penicillin-allergic individual with
infection caused by streptococci, or pneumococci.
Upper respiratory tract infections of mild to moderate degree caused
by Streptococcus pyogenes; Streptococcus pneumoniae; Haemophilus
influenzae (when used concomitantly with adequate doses of
sulfonamides, since many strains of H. influenzae are not susceptible to
the erythromycin concentrations ordinarily achieved).
-Lower respiratory tract infections of mild to moderate severity caused
by Streptococcus pyogenes or Streptococcus pneumoniae.
Listeriosis caused by Listeria monocytogenes.
Respiratory tract infections due to Mycoplasma pneumoniae.
-Skin and skin structure infections of mild to moderate severity caused
by Streptococcus pyogenes or Staphylococcus aureus (resistant
staphylococci may emerge during treatment).
-Pertussis (whooping cough) caused by Bordetella pertussis.
Erythromycin is effective in eliminating the organism from the
nasopharynx of infected individuals, rendering them noninfectious.
-Diphtheria: Infections due to Corynebacterium diphtheriae , as an
adjunct to antitoxin, to prevent establishment of carriers and to
eradicate the organism in carriers.

Adverse Reactions:
The most frequent side effects of oral erythromycin preparations are
gastrointestinal and are dose-related. They include nausea, vomiting,
abdominal pain, diarrhea and anorexia.
Symptoms of hepatitis, hepatic dysfunction and/or abnormal liver
function test results may occur.
32
Drug interactions
1- Enzyme inhibitor: Erythromycin metabolites can inhibit
cytochrome P 450 enzymes
2- Erythromycin increases serum concentration of oral digoxin by
increasing its bioavailability, by inhibiting Eubacterium lentum,
which inactivates digoxin in the gut.

B- Clarithromycin: Same as erythromycin except:

Pharmacokinetics
Acid stability and eliminated by renal and non-renal routes and dose
adjustment is required in renal impairment.
Clinical uses
Used in combination with amoxicillin and lansoprazole or omeprazole
Delayed-Release Capsules, as triple therapy, are indicated for the
treatment of patients with H. pylori infection and duodenal ulcer
disease to eradicate H. pylori.
Adverse effects: Less frequent GIT adverse effects than erythromycin
Drug interactions:Less effect on HME enzymes.

C- Azithromycin
 High lipid solubility leads to extensive tissue distribution and high
concentrations within cells, resulting in much greater
concentrations in tissue. This results in long elimination half-life,
40 to 68 hours. So, it is administered once daily and for short time.
 Clinical uses: similar to erythromycin.
 Drug interactions: no significant drug intercations.

5- Clindamycin
Clinical uses
 For anaerobic infection.
 Intra-abdominal infection: used in combination with
aminoglycosides.
 Toxoplasmosis: Used in combination with pyrimethamine.

33
Adverse reactions
1- Diarrhea
2- Psudomembraneous colitis (0.01- 10%)

6- Streptogramins (Quinupristin-Dalfopristin)
Mechanism of Action
Quinupristin and dalfopristin are protein synthesis inhibitors bind to
50S ribosomal subunit at two different sites and act synergistically as
bactericidal to ↓ protein synthesis.
Antibacterial Activity:
Acts on gram-positive cocci, including S. pneumoniae, streptococci
and Enterococcus faecium.
Pharmacokinetics
 Used as IV infusion.
 Biliary excretion. Dose adjustment is required in hepatic patients.
Therapeutic Uses
1- Treatment of vancomycin-resistant strains of Enterococcus faecium.
2- MRSA infection.
Side Effects
Infusion-related reactions, such as pain and phlebitis at the infusion site
and arthralgias and myalgias.

7- Linezolid
Mechanism of Action
Linezolid inhibits protein synthesis by binding to the P site of the 50S
ribosomal subunit and inhibits formation of the initiation complex.
Does not (at present) exhibit cross-resistance with other protein
synthesis inhibitors.
Antibacterial Activity
Linezolid is active against gram-positive organisms.
Therapeutic Uses:
 Vancomycin-resistant E. faecium infection
 MRSA infection .
 Skin and skin-structure infections
34
Adverse reactions
 Bone marrow depression.
 Gastrointestinal complaints, headache, rash.
N.B., Linezolid it should be reserved for treatment of infection caused
by multidrug-resistant gram positive bacteria.

35
 Treatment of tuberculosis

 Tuberculosis is highly contagious and spreads through the air

from coughing.
 If not treated, a person with TB infects an average of 10 to 15
new people each year.
 Once thought to be under control, tuberculosis still kills well
over 1.5 million people each year, a figure that is now
increasing slightly each year.

Drugs used in treatment of TB include

Rifampicin
Ethambutol
Streptomycin
Pyrazinamide
Isoniazid

Rational Treatment of TB
First 2 months: rifampicin + isoniazid + (ethambutol or streptomycin
or pyrazinamide).
Later 4 months: rifampicin + isoniazid.

Isoniazid
Mechanism of action
 Inhibition of mycolic acid synthesis which is unique to
mycobacteria cell wall.

How do explain the high selectivity of isoniazid in treating TB?.

Pharmacokinetics
 Well absorbed from GIT
 It undergoes in the liver acetylation and hydrolysis.
 The acetylation is may undergoes genetic variation (Slow
acetylators and rapid acetylators)
36
Therapeutic Uses
1. Treatment of tuberculosis (used in combination with other
drugs).
2. Prophylaxis of TB (used alone)

Adverse effects
 Rapid acetylators will cause hepatotoxicity. Why?
 Slow acetylators will cause peripheral neuritis. Why?
 Bone marrow depression (leucopenia, thrombocytopenia,
anemia).

Drug interaction
Strong HME inhibitor.
Rifampin
Mechanism of action
↓ RNA-polymerase → ↓ RNA synthesis.

Pharmacokinetics
 Well absorbed from GIT.
 Distributed to all tissue and body fluids including CSF.

Therapeutic uses
1- Treatment and prophylaxis of TB
2- Prophylaxis in meningococcal meningitis
3- Staphylococci infections.

Adverse effects:
 Orange red urine
 Rifampin generally is well tolerated.
 The most common are rash, fever, and nausea and vomiting.

Drug interaction
Strong HME inducer
37
Ethambutol
 Orally

Side effects
 Contraindicated below 5 years as it may cause optic neuritis
(patient complains of reduced visual acuity).

Pyrazinamide
 Orally

Adverse effects
 Hepatotoxicity
 Hyperuricemia

38
 Antifungal drugs

Drugs for Systemic fungal Infections:

A- - Azoles:
Mechanism of action (all azoles):
Inhibit ergosterol synthesis

Kinetics
They can be formulated in systemic and/or topical forms.
o Systemic azoles (ketoconazole, fluconazole)
o Topical azoles (miconzaole).
Uses
1. Ketoconazole:
 Systemic fungal infection
 Different types of tinea
 Seborrhaeic dermatitis
2. Fluconazole
 fungal meninigitis
Adverse effects:
 GIT upset
 Elevation of liver enzymes

B- Flucytosine(5-FC):
Mechanism of action
It is converted to 5-FU → inhibit DNA and RNA synthesis.
Clinical uses:
 Fungal meningitis.
Adverse effects:
 GIT disturbance
 Bone marrow depression.

39
c. Amphotericin B:
Mechanism of action
Binds to ergosterol in the plasma membranes of sensitive fungal
cells → form pores → allowing electrolytes (particularly potassium)
and small molecules to leak from the cell → resulting in cell death.
Pharmacokinetics:
 Given IV infusion or locally.
Clinical uses:
 Systemic: Life-threatening systemic fungal infection.
 Locally in eye: fungal keratitis.
 Intra-articular: fungal arthritis.
Adverse effects (2 types):
 Infusion-related reactions: hypotension, tachycardia, chills
and fever.
 Nephrotoxicity
 Hepatotoxicity
 Neurotoxicity
 Bone marrow depression

b) Drugs for superficial fungal Infections

a- Nystatin:
Kinetic
Oral Drops
Use
Topically for candida infection.
Side effects
It has unpleasant taste.
b. Terbinafine:
Mechanism
Inhibit ergosterol synthesis
Kinetic
Used topical or orally.

40
c. Griseofulvin
Kinetics
 Used orally.
 Stored in keratin containing tissues (skin, hair, nail).
Therapeutic Uses:
 Fungal infection of the skin, hair, and nails.
Adverse effects:
 Allergy
 Hepatotoxicity
 GIT irritation

41
 Antiviral drugs
HOW VIRUSES INFECT CELLS
The basic process of viral infection and virus replication occurs in 6
main steps.
1. Adsorption - virus binds to the host cell.
2. Penetration - virus injects its genome into host cell.
3. Viral Genome Replication - viral genome replicates using the
host's cellular machinery.
4. Assembly - viral components and enzymes are produced and
begin to assemble.
5. Maturation - viral components assemble and viruses fully
develop.
6. Release - newly produced viruses are expelled from the host
cell.

Drugs used in treatment of influenza virus

 Uncoating inhibitors (Amantadine and rimantadine).
 release inhibitors (Zanamivir and oseltamivir).

Uncoating inhibitors
Mechanism of action
 Interfere with viral uncoating and release of genetic material inside
the host cell
Amantadine Rimanatadine
Kinetic Pass BBB Does not pass BB
Uses 1. Influenza 1. Influenza
2. Parkinsonism
Side CNS: insomnia, Rare CNS side effects
effects nervousness, confusion,
convulsions

42
 Release inhibitors
 Act by inhibiting neuaminidase enzyme which is essential for viral
release.
Oseltamivir Zanamivir
Kinetic Oral Nasally
Side effects GIT disturbances Respiratory irritation

Drugs for herpes virus (simplex and zoster) infection

Acyclovir
Kinetics:
Topical, oral and I.V.
Clinical uses
1- Herpes simplex virus infection.
2- Varicella-Zoster virus infection.
Adverse effect
 I.V: nephrotoxicity; neurotoxicity.
 Topically: local irritation.
 Oral: diarrhoea.

Drugs used for treatment of AIDS

 Infection with HIV causes depletion of CD4 lymphocytes leading
to cellular immunodeficiency (Acquired Immune Deficiency
Syndrome ; AIDS).
 It is a single strand RNA-retrovirus.
 It replicates by converting its single strand RNA into double strand
DNA by enzyme called reverse transcriptase enzyme, which is
unique to retroviruses.
Classification of anti-HIV drugs
1- Fusion inhibitors (Enfuvirtide) 2- maturation inhibitors
(saquinavir)
3- Reverse transcriptase inhibitors: (e.g. zidouvidine, Nevirapine)

43
Nucleoside reverse transcriptase inhibitors (e.g. Zidouvidine)
Mechanism of action
Clinical uses
1- ↓ Progression and prolonging survival of AIDS-patients.
2- Prevention of prenatal transmission of virus in pregnant infected
women.
Adverse effects
1- Bone marrow depression

NON Nucleoside reverse transcriptase inhibitots (e.g. Nevirapine)

This group has the following characters:
 Highly selective of reverse transcriptase.
 They have no effects of the human blood-forming elements.

Treatment of chronic hepatitis C virus infection

Old regimen:
 Interferon- α (S.C or IM once/week) + ribavirin (orally,
daily).
Disadvantages
 Less success rate
 Longer duration (48 weeks)
 More serious side effects

Recent regimen:
 Sofosbuvir + daclatasvir
 Sofosbuvir + simeprevir
 Sofosbuvir + ledipasvir

Advantages
 More success rate (more than 90%)
 Shorter duration (12 weeks)
 Less side effects

44
 Interferon-α
Pharmacokinetics
 Interferon–α is not absorbed orally and given by I.M. or S.C.
routes.
 Interferon- α is given once per week because of slower rate of
elimination.
Adverse effects
 Flu-like symptoms.
 Loss of hair
 Loss of weight
 Loss of hearing
 Psychic depression
 Bone marrow depression
 Arrhythmia

Ribavirin
- Used orally.
- Adverse effects
1- anaemia.
2- Teratogenic effect

Sofosbuvir
Kinetics
 Used orally
 Used for 12 weeks.
Mechanism
 Inhibits RNA polymerase→inhibitor of viral RNA synthesis.
Side effects
 Headache
 Fatigue
 Insomnia
 Anemia.

45
 Most commonly used antiparasitics
1. Metronidazole
Pharmacokinetics
 Well absorbed from GIT.
 May be used as IV infusion.
Uses
1. Antiparasitic uses
 Amebiasis
 Trichomonas vaganalis
 Giardiasis
2. Antibacterial uses
 Anaerobic infection (gingivitis…..)
Adverse effects
 Nausea and metallic taste (most common).
 Seizures (most serious).

2- Tinidazole
Metronidazole Tinidazole
Shorter duration Longer duration
Weaker effect Stronger effect
More side effects Less side effects

3. Benzimidazoles: Albendazole, Mebendazole, Thibendazole

Uses
Worm infections

46
 4. Praziquantel
Pharmacokinetics:
It is rapidly absorbed orally.
Uses
1. Schistozomiasis
2. Cestodes (e.g cysticercosis).
Adverse effect:
 GIT disturbances: anorexia and vomiting
 Dizziness.
Contraindications
It is not recommended for pregnant or nursing mothers.

47
Goal of treatment
 The ultimate goal of chemotherapy is a cure but the true cure
requires the eradication of every neoplastic cell.
 If a cure is not attainable we try to control the disease (stop
the cancer from enlarging and spreading) to extend survival and
maintain the best quality of life.
In either case, the neoplastic cell burden is initially reduced
(debulked), either by surgery and/or by radiation, followed by
chemotherapy, immunotherapy, or a combination of both.
 In advanced stages of cancer, the likelihood of controlling the
cancer is far from reality and the goal is palliation (that is,
alleviation of symptoms and avoidance of life-threatening
toxicity). This means that chemotherapeutic drugs may be used
to relieve symptoms caused by the cancer and improve the
quality of life, even though the drugs may not lengthen life.
Tumor susceptibility and the growth cycle
 The fraction of tumor cells that are in the replicative cycle
growth fraction influences their susceptibility to most cancer
chemotherapeutic agents. Rapidly dividing cells are generally
more sensitive to anticancer drugs, whereas slowly proliferating
cells are less sensitive to chemotherapy.
a. Cell-cycle specific anticancer drugs: they are effective only
against replicating cycling cells
b. Cell-cycle nonspecific anticancer drugs:they ar effective
against both replicating and resting cells.

Anticancer Drug Combinations

The use of combination chemotherapy is important for several reasons
1- It provides maximal cancer cell kill.
2- It may prevent or slow the subsequent development of
cellular drug resistance.

48
Resistance to Cancer chemotherapy
 Primary resistance: there is absence of response to drugs from
the start e.g, malignant melanoma, renal cell cancer and brain
cancer
 Acquired resistance: it develops in response to exposure to a
given anticancer agent. E.g., increased expression P-
glycoprotein which leads to enhanced drug efflux and reduced
intracellular accumulation of a broad range of anticancer agents.

Common adverse effects

Most chemotherapeutic agents have a narrow therapeutic index.
Common side effects like

 Severe vomiting
 Bone marrow suppression
 Alopecia.

Minimizing adverse effects

1- Some toxic reactions may be ameliorated by interventions,

such as the perfusing the tumor locally (for example, a sarcoma
of the arm), removing some of the patient's marrow prior to
intensive treatment and then reimplanting.
2- We may administer a drug to minimize a serious side effect
occurs with anticancer drugs. For example:

 Methotrexate + leucovorin: Leucovorin rescue is used in

conjunction with high-dose MTX therapy to rescue normal cells
from methotrexate toxicity such as bone marrow depression
(discussed later).
 Cyclophosphamide + MESNA: 6-mercaptoethano sulphonate
sodium (MESNA) protects from hemorrhagic cystitis occurs
with cyclophosphamide (discussed later).
 Doxorubicin + dexrazone: dexrazone protects against
cardiotoxicity occurs with doxorubicin.
49
Examples of anticancer drugs

Alkylating agents Anti- Metabolites Anti-Tumour

Antibiotics
Cyclophosphamide Methotrexate Doxorubicin

Mechlorethamine 5- Fluoro Uracil Bleomycin

Carmustine
Microtubule Inhibitors Biological agents Steroid Hormones
and its antagonists
Vincristine BCG Corticosteroids
Fluvestrant
Vinblastine Interferon Tamoxifen
Letrozole
Flutamide
Bicalutamide
Leuprolide

50
 Antimetabolites

Antimetabolites are structurally related to normal compounds that

exist within the cell. They generally interfere with the synthesis of
normal purine or pyrimidine nucleotide.
A. Methotrexate (MTX)
Mechanism of action
 MTX has an unusually strong affinity for Dihydrofolate reductase
(DHFR) and effectively inhibits the enzyme.
 MTX becomes polyglutamated within the cell a process that favors
intracellular retention of the compound. MTX polyglutamates also
potently inhibit DHFR.
 This inhibition deprives the cell of folate coenzymes and leads to
decreased production of purines and pyrimidines. This leads to
decreased DNA, RNA, and protein synthesis and, ultimately, to cell
death.

Therapeutic uses
1- Cancer: leukemia, lymphoma in children, breast cancer, and head
and neck carcinomas.
2- Autoimmune diseases: low-dose MTX is effective in these diseases
such as severe psoriasis and rheumatoid arthritis as well as Crohn's
disease.

Side effects
In addition to common side effects it may cause also Nephrotoxicity
and Hepatotoxicity.

How to minimize MTX side effects?

 Leucovorin converted to methylene-tetrahydrofolate so by pass the

block caused by MTX.
 Leucovorin is taken only by normal cell and not by cancer cells.
 This is termed “leucovorin rescue”.

51
Figure (1): Mechanism of action of methotrexate
FH2; dihydrofolate, FH4; tetrahydrofolate

52
B. 5-flurouracil

Mechanism of action

It inhibits thymidylate synthase enzyme which is needed to form

thymine. Absence of thymine will result in cancer cell death.

Side effects

It is characterized by severe ulceration of the oral and GI

mucosa. allopurinol mouthwash has been shown to reduce oral
toxicity.

Alkylating agents

Common mechanism of alkylating agents

They are transported into the cell, where the drug forms a
reactive intermediate that alkylates the N7 nitrogen of a guanine
residue in one or both strands of a DNA molecule. This alkylation
leads to cross-linkages between guanine residues in the DNA chains
thus facilitating DNA strand breakage.
Examples of alkylating agents

 Mechlorethamine: used in hodjkin lymphoma

 Cyclophosphamide

Mechanism of action
Cyclophosphamide is the most commonly used alkylating agent.
It is first biotransformed to the active compounds, phosphoramide
mustard and acrolein. Reaction of the phosphoramide mustard with
DNA is considered to be the cytotoxic step.

53
 Activation of cyclophosphamide by hepatic cytochrome P450.
Therapeutic uses
1. Neoplastic diseases: Burkitt's lymphoma and breast cancer
2. Non-neoplastic disease entities (in low doses): such as
nephrotic syndrome and rheumatoid arthritis.
Adverse effects
It is characterized by hemorrhagic cystitis, which can lead to
fibrosis of the bladder. Hemorrhagic cystitis has been attributed to
acrolein in the urine.
How to manage hemorrhagic cystitis occurs with cyclophosphamide?
Adequate hydration as well as IV injection of MESNA (sodium
2-mercaptoethane sulfonate), which neutralizes the toxic metabolites,
minimizes this problem.

Antibiotic anticancer

e.g., doxorubicin

Mechanism of action
1. Interactions with DNA, leading to disruption of DNA
function.
2. Inhibit topoisomerases (I and II)
3. Produce of free radicals in cancer cells

54
Side effects
Cardiotoxicity

 Irreversible, it occurs as a result of the generation of free

radicals and lipid peroxidation.
 Irradiation of the thorax increases the risk of cardiotoxicity
 There has been some success with the iron-
chelator dexrazone in protecting against the cardiotoxicity
of doxorubicin.

Steroid hormones and their antagonists

 Corticosteroids: Prednisone is used in acute lymphocytic

leukemia and in the treatment of both Hodgkin's and non-
Hodgkin's lymphomas.
 Fluvestrant : Anti-estrogen used in breast cancer.
 Tamoxifen: selective estrogen receptor modulator used in breast
cancer.
 Letrozole: Aromatase enzyme inhibitor used in breast cancer.
 Flutamide and Bicalutamide: anti-androgens used in prostate
cancer.
 Leuprolide: long acting GnRH analogue used in breast and
prostate cancer.

55
 Endocrinal pharmacology
Hypothalamic and Pituitary hormones
The pituitary gland comprises of the anterior pituitary and the
posterior pituitary which receive independent neuronal input from
the hypothalamus. The hypothalamus regulates the function of
the anterior pituitary by releasing hypothalamic hormones which
are transported to the anterior lobe through the hypothalamo-
hypophyseal portal circulation. The posterior pituitary hormones
are synthesized in the hypothalamus and transported through the
hypothalamo-hypophyseal neurons to posterior pituitary where
they are stored.
Hormones released from pituitary gland
Lobe Hormone Main Functions Main Secretion
control
Anterior GH - Stimulate bone, muscle and cartilage GHRH
Lobe growth
Prolactin - Stimulate milk production Dopamine inhibit
release
ACTH Stimulate adrenal cortex to release CRH
corticosteroids
FSH - Stimulates maturation of follicle. GnRH
- Stimulates spermatogenesis
LH - Stimulate ovulation GnRH
- Stimulate testosterone release
TSH - Stimulate thyroid gland to release T 3 TRH
and T4
Posterior Oxytocin Stimulate uterine contraction Suckling
Lobe ADH Stimulate water reabsorption Extracelleular
fluid volume and
electrolyte status

56
 Somatostatin (Growth hormone-inhibitory hormones
 Actions:
 ↓ Release of growth hormone.
 ↓ Release of thyroid stimylating hormone.
 ↓ Release of most gastrointestinal hormones.
 ↓ Mesenteric blood flow.
 Uses: limited uses due to short half-life (1-3 min)

Synthetic Growth hormone-inhibitory hormones

1. Octreotide: similar to somatostatin with long duration of action

Uses:

 Acromegaly
 Tumours secreting vasoactive intestinal peptide
(VIPoma)
 Carcinoid tumours
 pituitary adenomas
 Bleeding oesophageal varices.
2. Lanreotide: similar to octreotide.
N.B., The most common side effects is diarrhea (dose related)

Synthetic Growth hormone-releasing hormone (GHRH)

Sermorelin used to diagnose GH secretion.

Growth Hormone

 Recombinant growth hormone (rhGH) is most frequently used.

 Somatropin and somatrem are the two preparations of rhGH.
Uses
1. Pituitary dwarfism
2. Adults with GH deficiency
 Chronic kidney failure
 Short stature at birth with no catch-up growth
3. Prevent severe weight loss in people with AIDS

57
Adverse Effects
- Children generally tolerate growth hormone better than adults.
- Side effects include:
 Arthralgia and Myalgia
 Increased serum glucose
What is the Growth Hormone Receptor Antagonists?
Pegvisomant which is used for treating acromegaly.

Prolactin

 Prolactin per se has no therapeutic use

 So that, dopamine agonists like bromocriptine and cabergoline
decrease prolactin levels whereas dopamine antagonists like
typical antipsychotic drugs (e.g., chlorpromazine) and
methyldopa cause hyperprolactinemia which may manifest as
galactorrhea.
Bromocriptine
Mechanism of action Actions Uses
Activates D2 receptors ↓ prolactin release 1. Hyperprolactinemia
2. Stopping of lactation
↓ GH secretion in 3. Acromegaly
acromegaly
Anti-parkinsonian actions 4. Parkinsonism
Activates D1 receptors
Visceral vasodilatation

Side effects Contraindications

GIT: vomiting and peptic ulcer Peptic ulcer
CVS:
 postural hypotension Ischemic heart diseases
 digital vasospasm Peripheral vascular diseases
CNS: dyskinesia History of mental illness
It should not be used to prevent lactation after
delivery ( in women who choose not to breast
feed ) due to the risk of myocardial infarction,
seizures.

58
 Cabergoline

 It is a new, selective, potent and long-lasting dopamine agonist

which appear to be more effective and better tolerated than
bromocriptine.

GONADOTROPHIN-RELEASING HORMONE(Gn-RH)

 The synthetic analogs of Gn-RH called goserelin and leuprolide.

 Uses: Prostate and breast cancer.

GONADOTROPHINS
Actions of gonadotrophins
FSH LH

Male ↑ spermatogenesis ↑ testosterone secretion

Female ↑ Follicle maturation → ↑ ovulation→ progesterone

estrogen secretion secretion

Sources of gonadotropins:
1-Human chorionic gonadotropins (HCG) is produced by placenta and
excreted in urine of pregnant woman.
2-Human menopausal gonadotropins is a mixture of FSH and LH in
equal amounts and is obtained from the urine of women following the
menopause.

Uses of Gonadotrophin
1- Infertility caused by lack of ovulation as a result of
hypopituitarism, or following failure of treatment with
clomiphene.

2- HCG used in boys with delayed puberty and undescended testis.

59
 Role and control of FSH and LH in male

ANTIGONADOTROPHINS

Danazol
Action Use Side effects
↓ FSH and LH release → Endometriosis Deeping of voice
inhibits sex hormones Decrease the breast size
synthesis → atrophy in Fibrocystic diseases of the Amenorrhea
ovarian and endometrial breast Hairsutism
tissue
Increases the activity of Thrombocytopenic
clot factors No. 8 and 9. purpura
Hemophilia

Posterior pituitary hormones

1) Vasopressin (antidiuretic hormone, ADH)

Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, ADH)
is a nonapeptide hormone formed in the hypothalamus and released
from the posterior pituitary. Its primary function in the body is to

60
regulate extracellular fluid volume by affecting renal handling of
water; however, it also is a potent vasoconstrictor.

 Released in response to ↑ osmolarity or ↓ blood pressure.

Actions

Vasopressin acts on G protein-coupled receptors (V1 and V2

rceptors).

V1 receptor actions V2 receptor actions

 VC  Increase water reabsorption

 Increase motility of GIT  Increase formation of

muscles clotting factors

Vasopressin preparations

1- Arginine vasopressin: synthetic human vasopressin

 Used IV, IM, SC, nasal
 Acts on V1 and V2 receptors
 Short duration of action
Uses:
Hemorrhage (V1); e.g. esophageal varices.

61
 2- Desmopressin
 Highly V2 selective (~4000-fold).
 Long duration of action.
 Taken IV, SC, nasally and recently orally.
Uses
1. Diabetes insipidus
2. Treatment of nocturia due to nocturnal polyuria in adults
who awaken at least 2 times per night to void
(intranasal).
3. Nocturnal enuresis
4. Hemophilia
Side effects of vasopressin preparations
It is more common with arginine vasopressine than with
desmopressin.
 V1 receptor-related: increased blood pressure, GI
cramps, headache.
 V2 receptor-related: water intoxication with
hyponatremia.

Vasopressin antagonists
e.g., Conivaptan and Tolvaptan.
Uses
 Heart failure
 Syndrome of inappropriate ADH secretion (SIADH).

2) Oxytocin
Actions

 On the uterus: it contracts the uterus.

 On mammary gland: contracts myoepithelial cells in the
mammary gland, which causes 'milk let-down'.
Use
 Induction of labor.
Side effects

62
  Dose-related hypotension (due to vasodilatation) with reflex
tachycardia.
Contraindications
 Cephalopelvic disproportion to avoid uterine rupture, maternal
or fetal death.
What is oxytocin antagonist and its use?

Atosiban used in preterm labor (like what????????).

63
 Thyroid hormones pharmacology

Figure (2): Synthesis of thyroid hormones

ABNORMALITIES OF THYROID FUNCTION

1. HYPOTHYROIDISM
 Congenital absence or incomplete development of the thyroid
causes cretinism, characterized by gross retardation of growth
and mental deficiency.
 A decreased activity of the thyroid results in hypothyroidism,
and in severe cases myxoedema. Manifestations include low
metabolic rate, slow speech, deep hoarse voice, bradycardia,
sensitivity to cold and mental impairment.
Treatment of hypothyroidism
 Thyroid hormones and Thyroxine (T4) is the standard
replacement therapy.
 Liothyronine (T3) is the treatment of choice for myxoedema
coma.
Unwanted effects may occur with overdose:
 Signs and symptoms of hyperthyroidism Treatment of
thyrotoxicosis.

64
 2. Hyperthyroidism (thyrotoxicosis)
Who gets thyrotoxicosis?
Thyrotoxicosis occurs in approximately 2% of women and 0.2%
of men. Thyrotoxicosis due to Graves' disease most commonly
develops between the second and fourth decades of life, whereas the
prevalence of toxic nodular goitre increases with age. Autoimmune
forms of thyrotoxicosis are more prevalent among smokers.
How do patient present thyrotoxicosis?
Symptoms of overt thyrotoxicosis include heat intolerance,
palpitations, anxiety, fatigue, weight loss, muscle weakness, and, in
women, irregular menses. Clinical findings may include tremor,
tachycardia, lid lag, and warm moist skin. Symptoms and signs of
subclinical hyperthyroidism, if present, are usually vague and
nonspecific.
How is thyrotoxicosis diagnosed?
In all forms of overt thyrotoxicosis, the serum value of TSH is
decreased and the measurements of T4 or T3 are raised.
How is thyrotoxicosis treated?
1- Thioamides
2- Iodides
3- Radioactive iodine
4- Adjuvant drugs
1. THIONAMIDES
 Members
 Carbimazole , Propylthiouracil
Mechanism of action:
1. Prevent the oxidation of iodide to iodine
2. They inhibit the iodination of tyrosine
3. Inhibit coupling of MIT and D1T to form T3 and T4.
4. Propylthiouracil has the additional effect of reducing the
deiodination of T4 to T3.

65
Therapeutic uses:
 Mild to moderate hyperthyroidism.
 severe hyperthyroidism until
 undergoing thyroidectomy
 Appearance of effect of radioactive iodine.
 Propylthiouracil is used in thyroid storm.
Side effects
1-The most important unwanted effect is agranulocytosis and it is
reversible on cessation of treatment.
2-Rashes are more common.
3- On prolonged use of thionamides, hyperplasia and enlargement of
thyroid gland may occur due to increased TSH.
2. IODIDE
Mechanism
 Inhibit iodination of thyroglobulin.
 Inhibit release of thyroid hormones.
What is the effect and its duration?
 Action lasts for 10-14 days
 There is reduction in size and vascularity of the gland.
Uses of iodide:
(1) Preparation of hyperthyroid subjects for surgical resection of
the gland
(2) Treatment of thyroid storm.
Side effects
Allergic reactions can occur; these include rashes, drug fever,
lacrimation, conjunctivitis.
3. Radioactive iodine
Mechanism of action
 Radioiodine (131I isotope) is given orally for treatment of
hyperthyroidism by destruction of thyroid tissues.
 It is taken up and processed by the thyroid follicle in the same
way as the iodide, becoming incorporated into thyroglobulin.

66
  The isotope emits both β radiation and γ rays.
 The γ rays pass through the tissue without causing damage.
 The β particles have a very short range; they are absorbed by the
tissue and exert a powerful cytotoxic action that is restricted to
the cells of the thyroid follicles, resulting in significant
destruction of the tissue.
When the effects of radioactive iodine (131I) appear?
It is given as one single dose, but its cytotoxic effect on the
gland is delayed for 1-2 months.
Side effects
 Hypothyroidism
 Risk of thyroid cancer following the treatment.
Contraindications
 Children
 Pregnancy
What about I123? It emits only γ rays so it is used in diagnosis of
thyroid function.

4. Adjuvant drugs
1. β-blockers
e.g., propranolol
 It is used for decreasing many of the signs and symptoms of
hyperthyroidism as tachycardia, dysrhythmias, tremor and
agitation.
 Used in thyroid storm.
 Diltiazem, can be used to control tachycardia in patients in
whom -blockers are contraindicated, e.g., those with asthma.

2. Glucocorticoids (e.g. prednisolone )

e.g., Dexamethasone
 It inhibits peripheral conversion of thyroxine to triiodothyronine
 Effective in preoperative preparation.
 Also effective in thyroid storm.

67
 CALCIUM HOMEOSTASIS
Calcium homeostasis refers to the regulation of the
concentration of calcium ions in the extracellular fluid [Ca++].
 Three organs participate in supplying calcium to blood:
 The small intestine is the site where dietary calcium is
absorbed.
 Bone serves as a vast reservoir of calcium. Stimulating
bone resorption of releases calcium into blood, and
suppressing this effect allows calcium to be deposited in
bone.
 The kidney is critically important in calcium
homeostasis. Under normal blood calcium
concentrations almost all of calcium that enters
glomerular filtrate is reabsorbed from the tubular
system back into blood which preserves blood calcium
levels. If tubular reabsorption of calcium decreases
calcium is lost by excretion into urine.

Hormonal Control Systems:

Hormones which increase Hormones which decrease
calcium in blood calcium in blood
1. Parathormone 1. Calcitonin
2. Vitamin D 2. Corticosteroid
Parathyroid hormone
- It is a single chain polypeptide hormone secreted by parathyroid
glands. It is secreted in response to hypocalcemia
- Parathyroid hormone preserves blood calcium by several major
effects:
a) It increases the osteoclastic activity in bone →stimulates
bone resorption
b) PTH indirectly stimulates Ca++ absorption in the small.
c) It increases tubular reabsorption of calcium within the
kidney results in minimal loss of calcium in urine.

68
 Release and actions of PTH
Vitamin D
- Vitamin D plays a major role in control of plasma level of Ca++
Actions
 ↑ absorption of calcium and phosphates from the
small intestine.
 ↓ excretion of Ca++ by the kidneys.
Clinical indications of vitamin D
 Treatment of rickets
 Treatment of hypocalcemia.
 Treatment of osteomalacia.
Calcitonin
- It is secreted from thyroid gland.
Actions
1. Enhances excretion of calcium into urine.
2. Inhibition of bone resorption by inhibiting osteoclastic
activity.

69
 Clinical uses
 Treatment of hypercalcemia.
 Treatment postmenausal osteoprosis.
 Prophylaxis of cancer metastases.
Preparations
 Salmon calcitonin administered intranasally.

Treatment of osteoporosis
Pathophysiology of osteoporosis:
Osteoporosis is associated with decreased bone mineralization
and increased bone resorption through increased osteoclast activity.
This results in decreased bone content of calcium and decreased bone
mass. Fragility of bone makes it more susceptible to fractures,
especially hip bones, wrist, vertebrae and humerus.
(A) Non-pharmacologic prevention of osteoporosis
1-Regular exercise decreases risk of hip fractures by about 50%.
2-Stopping smoking before menopause reduces risk of hip fractures by
25%.
(B) Pharmacologic treatment of osteoporosis
Common mechanism of action of drugs treating osteoporosis:
 ↑ Osteoblast activity.
 ↓ Osteoclast activity.
1- Calcitonin.
2- Raloxifene (look at female sex hormones).
3- Teriparatide
 It is a recombinant segment of human parathyroid hormone.
 Used subcutaneously.
 Once daily for 2 years.
 Side effect: Increased risk of osteosarcoma.

70
 4- Bisphosphonates
e.g., Pamidronate, risedronate.
Mechanism of action
They are incorporated into the bone and promote osteoclast
apoptosis.
Precautions
1. Given orally on empty stomach 30-60 min before food
consumption.
2. G i v e n with 250 ml of plain water.
3. Patient must remain upright for at least 30 min (????????).
Side effects:
 Gastrointestinal disturbances as oesophagitis and peptic
ulcers.
 Osteonecrosis of jaw.
Other uses of bisphosphonates:
1. Hypercalcaemia.
2. Prophylaxis of cancer metastases.
5- Denosumab
Mechanism of action
 Denosumab is a monoclonal antibody against Receptor
activator of nuclear factor-kappa ligand (RANKL).
 Osteoblasts secrete RANKL which activates osteoclast → ↑
bone resorption.
 So that, denosumab by blocking RANKL → ↓ osteoclast
activity → ↓ bones resorption.

Mechanism of action of denosumab

71
 Treatment of diabetes mellitus
DIABETES MELLITUS

 It is a chronic metabolic disorder characterized by a high blood

glucose concentration due to insulin deficiency (or relative
insulin deficiency) and/or insulin resistance.

 The most common complications of diabetes are atherosclerosis

and diabetic retinopathy, nephropathy, neuropathy & comas.

Forms of diabetes mellitus

Type 1 diabetes Type 2 diabetes
(insulin-dependent diabetes (non-insulin-dependent diabetes
mellitus, IDDM or juvenile- mellitus, NIDDM or maturity
onset diabetes) onset diabetes)
Age of onset Usually below 35 years Usually over 35 years
Cause Absolute deficiency of insulin Both insulin resistance and
resulting from autoimmune impaired regulation of insulin
destruction of -cells. secretion.
Treatment  Diet control  Diet
 Insulin  Oral anti-diabetics and if
failed shift to insulin.
INSULIN
Synthesis
 It is synthesized in the -cells as a preproinsulin in the rough
endoplasmic reticulum which is transported to the Golgi apparatus
where it undergoes successive proteolytic cleavage to proinsulin
and then to insulin & C-peptide.
INSULIN SECRETION
 Glucose enters -cells via a membrane transporter. Glucose 
 intracellular ATP  closure of the KATP  membrane
depolarization. Voltage-gated Ca2+ channels open in response
to depolarization  Ca2+ influx   intracellular Ca2+  
insulin secretion.

72
 Release of endogenous insulin after meals

PHARAMACODYNAMICS

 Signal transduction is mediated through insulin-regulated

transmembrane receptors whose intracellular enzyme activity is
tyrosine kinase, which is controlled by binding of insulin to the
extracellular portion of the receptor.

ACTIONS
A. Rapid transport effects:
 It  entry of glucose, amino acids, K+, Mg2+, Ca2+, nucleosides
and PO43- into cells.
 It facilitates glucose uptake by all tissues except brain, renal
tubules, intestinal mucosa and RBCs.
 Insulin  glucose uptake in adipose tissue and muscle by 
facilitated transport of glucose via a transporter called Glut-4.
B. Gradual (anabolic effects):
 CHO metabolism: Insulin  glycogen storage and 
glycogenolysis.
 Lipid metabolism: ↓ lipolysis.
 Protein metabolism: Insulin  protein synthesis and 
protein catabolism.

73
INSULIN PREPARATIONS
Insulin preparation Onset Peak Duration

Rapid-Acting

Aspart 5-15 30-90 min <5 h

min

Lispro 5-15 30-90 min <5 h

min

Glulisine 5-15 30-90 min <5 h

min

Short-Acting

Regular 0.5-1 h 2-3 h 5-8 h

Intermediate, Basal

Neutral protamine Hagedorn 2-4 h 4-10 h 10-16 h

(NPH)

Long-Acting, Basal

Insulin glargine 2-4 h No peak 20-24 h

Insulin detemir 3-8 h No peak 17-24 h

Premixed

Insulin lispro protamine/ insulin 5-15 Dual 10-16 h

lispro min

Insulin lispro protamine/insulin 5-15 Dual 10-16 h

aspart min

NPH/regular 0.5-1 h Dual 10-16 h

74
Insulin Delivery Systems
1. Insulin syringes: used s.c. injection.
2. Insulin Pens: Reusable models use a cartridge filled with
insulin.
3. Insulin Pump: This device is about the size of a pager. You
wear it on your belt or in a pocket. It delivers a steady stream of
insulin to your body 24 hours a day through a needle attached to
a flexible plastic tube. Whenever you eat, you press a button on
the pump to give yourself an extra boost of insulin, called a
bolus.
4. Jet Injectors: These don't have a needle. Instead, they use very
high pressure to push a fine spray of insulin through the pores in
your skin.
5. Inhaled Insulin: inhaled insulin is approved by the FDA for
use before meals.
INSULIN PHARMACOKINETICS
 Insulin is not administered by the oral route.
 Used s.c., however, regular insulin used s.c. and I.V.
 Inactivated in liver and kidney (contain insulinase enzyme
which inactivates insulin).
INDICATIONS OF INSULIN
1. IDDM.
2. NIDDM after failure of diet and oral anti-diabetics.
3. NIDDM in cases of:
 Pregnancy and lactation.
 Infection
 Surgery
 Diabetic ketoacidosis, Diabetic retinopathy and
nephropathy.
COMPLICATIONS OF INSULIN THERAPY
1. Hypoglycemia:
 Causes: Missed meal, insulin overdose or due to strenuous
muscular work.

75
  Symptoms: sweating, tachycardia, tremor, blurred vision and
mental confusion; severe cases may present with convulsions
and coma.
 Treatment:
o In conscious patients: give a sweet drink or a snack.
o In comatose patient: give the following
 Glucose (50% solution, i.v.)
 Glucagon (s.c. or i.m.).
 Adrenaline (SLOWLY diluted IV).
2. Insulin allergy:
 Manifestations: The most common manifestation is a
reaction at site of injection, e.g. rash.
 Treatment: antihistaminics, glucocorticoids, desensitization
regimens and the use of pure insulin.
3. Insulin lipodystrophies:
 Insulin lipoatrophy: It is treated by injecting highly concentrated
pure neutral insulin.
 Insulin lipohypertrophy: it is due to repeated injection at the
same site. It is prevented by proper rotation of injection site.
4. Insulin resistance:
A requirement of  200 units/day indicates that the patient is
resistant to insulin therapy (A need for  1.5 units/kg/day may be also
considered resistance).
Causes: Obesity, surgery, infection, hormones (cortisol and GH).
Mechanisms of resistance:
-Prereceptors: immune insulin resistance due to insulin-binding IgG
antibodies.
-Receptors: insulin receptor down-regulation.
-Post-receptors: genetic mutations in components of the insulin-
signaling pathway.
5.Pseudo-insulin resistance (Somogyi phenomenon):
 Somogyi phenomenon (rebound hyperglycemia):

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 -It follows excessive insulin administration. It is hyperglycemia in the
early hours of the morning, before breakfast, following an
unrecognized insulin-induced hypoglycemic attack during sleep.
-It is caused by release of insulin-opposing or counter-regulatory
hormones (adrenal steroids, GH, glucagon & epinephrine) in response
to hypoglycemia.
-It is an indication to decrease insulin dosage.
 Dawn phenomenon:
-It is morning hyperglycemia due to inadequate insulin therapy.
-It is an indication to increase insulin dosage.
 To differentiate between Somogyi and Dawn phenomena, do 4 a.m.
blood glucose sample.
ORAL ANTIDIABETIC DRUGS
1. SULFONYLUREAS (SUs)
MECHANISM OF ACTION
A. Pancreatic action:
● They inhibit K+ efflux by blocking the KATP channels in the -
cells  cellular depolarization  ↑ Ca2+ influx  ↑insulin
release.
B. Extrapancreatic actions:
i.  tissue sensitivity to insulin
ii.  hepatic gluconeogenesis.
iii.  glucagon secretion.

PREPARATIONS
1st Generation : e.g., Chlorpropamide rarely used.
2nd generation : e.g., Glimepride
Gliclazide
Glibenclamide
.PHARMACOKINETICS
- They are well absorbed after oral administration
- All SUs are metabolized in the liver and all metabolites (including
active ones) are excreted in urine.

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INDICATIONS
 Treatment of NIDDM.
ADVERSE EFFCTS
Adverse effects:
 Hypoglycemia, which can be severe leading to coma.
 Skin rash.
 Weight gain.
 Gastrointestinal upset.
DRUG INTERACTIONS
 Hypoglycemic action of SUs  Hypoglycemic action of SUs
4 ANTI HDHD
Inflammatory; aspirin. -Hormones (corticosteoids,…..etc),
ANTI Coagulant; warafarin. -Diuretics (thiazide and loop
- Bacterial;sulphonamides diuretics),
Fungal; ketoconazole. -pHenytoin
-Diazoxide
CONTRAINDICATIONS
1. IDDM.
2. Patient with critical conditions (pregnancy, surgery, stress and
ketoacidosis)
3. Patients with renal, hepatic and cardiac disease.
MEGLITINIDES
 Members: repaglinide, nateglinide.
 Similar to sulphonylureas with less hypoglycemia.

Metformin
 NO HYPOGLYCEMIA OCCURS WITH THIS DRUG
MECHANISM OF ACTION
1.  glucose absorption from the gut.
2. ↑ anaerobic glycolysis to lactate.
3.  tissue sensitivity to insulin.
4.  hepatic gluconeogenesis.
5.  plasma glucagon level.

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INDICATIONS:
1. NIDDM ( alone or with other anti-diabetic drugs).
2. Type 1 diabetes: used with insulin in some cases of insulin
resistance.
ADVERSE EFFECTS & CONTRAINDICATIONS
1. Transient gastrointestinal disturbances: anorexia, metallic taste,
vomiting, diarrhea and malabsorption of vitamin B12.
2. Lactic acidosis in cases of HF, RF, liver diseases and respiratory
diseases.
CONTRAINDICATIONS
1. Patient with HF, RF, liver diseases and respiratory diseases.
2. Pregnancy
THIAZOLIDINEDIONES
Mechanism of action
 Thiazolidinediones bind to a nuclear receptor called the
peroxisome proliferator-activated receptor-γ (PPARγ) resulting
in
 ↑ insulin sensitivity
 ↓ insulin resistance.
 ↓ hepatic gluconeogenesis
Uses
 NIDDM.
Side effects:
 Weight gain
 Oedema.
 e.g, pioglitazone

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 What are Incretins?

Glucagon-like peptide-1 (GLP-1) receptor agonists

 GLP-1 is an incretin
 Incretins are gut-derived peptides secreted in response to meals
 Actions of GLP-1:
 ↑release of insulin.
 ↓ Appetite.
 Delay gastric emptying.
 E.g., exenatide.
 Used SC.

Dipeptidyl peptidase-IV (DPP-4) inhibitors

 The effects of endogenous incretins are short-lived because of
rapid degradation and inactivation by the enzyme DPP-4.
Mechanism of action
Inhibitors of DPP-4 have been developed to prevent the
inactivation of GLP-1 and prolong the activity of the endogenously
released hormone.
Kinetic: oral.
 E.g., sitagliptin, vildagliptin.

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 Pramlintide
 Pramlintide is a synthetic form of amylin
 Uses: It is approved only as an adjunctive therapy with insulin,
but it can be used both T1DM and T2DM.
Sodium Glucose co-transporter-2 inhibitors
 It is the newest group of medications approved for treatment of
diabetes mellitus.
 Main function of sodium-glucose co-transporter in the kidney’s
proximal tubules is reabsorption of the filtered glucose from the
urine back into the circulation. It is responsible for about 90%
of total glucose reabsorption. Inhibition of this protein leads to
the excretion of the glucose in the urine.
 Uses: NIDDM.
 e.g., canagliflozin.

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 Corticosteroids
 The adrenal gland consists of the cortex and the medulla.
 Medulla secretes epinephrine, whereas the cortex synthesizes
and secretes corticosteroids (glucocorticoids and
mineralocorticoids) and the adrenal androgens.

How Corticosteroids act?

It acts by binding to intracellular cytoplasmic receptors in the target
organ

Mineralocorticoids

 Aldosterone is the endogenous mineralocorticoids

 Aldosterone produces following actions

 ↑ Na and water reabsorption

 ↑ K excretion
 In hyperaldosteronism, there
is hypokalemia and retention
of Na and water leads to
oedema and HTN

Synthetic mineralocorticoids
Fludrocortisone which is used in treating Addison disease.
Aldosterone antagonists
1- Spironolactone
2- Eplerenone
What is the main difference between spironolactone and eplerenone?

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 Glucocorticoids
Pharmacologic effects and duration of action of some commonly
used corticosteroids
Duration Examples Effects
Short Cortisone Glucocorticoid +
Hydrocortisone mineralocorticoid

Intermediate Prednisone Glucocorticoid +

Prednisolone mineralocorticoid
Long Betamethasone Pure glucocorticoid
Dexamethasone

Pharmacokinetics:
• They can be given by oral, parenteral (i.m. & i.v.) and local (topical
& inhalation).
• The endogenous glucocorticoids are carried in the plasma
bound to corticosteroid- binding globulin and albumin.
• Cortisone & prednisone are activated in the liver → hydrocortisone
& prednisolone.
• It is excreted by conjugation with sulfate and glucuronic acid
and finally excreted in the urine.

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 Actions Uses Side effects Contraindica
tions
Metabolic:
 Carbohydrates: ↑ glucose Diabetes mellitus DM
 Lipid : ↑ lipolysis & ↑ FFA. Moon face and buffalo
hump
 Protein: -ve nitrogen balance (↑ Growth retardation in
catabolism and ↓ anabolism) children
Electrolytes:
 Salt and water: ↑ Oedema and HTN HTN
 K+: ↓ Hypokalemia HF
 Ca++: ↓ Hypercalcemia Hypocalcemia Osteomalacia
Vitamin D toxicity Osteomalacia osteoporosis
Anti-Inflammatory :
 ↓ phospholipase A2 → ↓ AA →↓ PGs & Inflammatory diseases Masking of active
Lts synthesis  Encephalitis & Cerebral infection
 ↓ capillary permeability edema.
 ↓ migration of neutrophils  Rheumatic carditis.
 ↓ production of inflammatory mediators  Chronic active hepatitis.
 Nephritis & Nephrotic
syndrome.
 Arthritis.
↑ Gastric HCl Peptic ulcer Peptic ulcer
Anti-Allergic and immunosuppressive: Allergy ↑ Risk of infection Uncontrolled
 Mast cell stabilization Autoimmune diseases infection
 ↓ Ag/ Ab reaction Organ transplantation
 ↓ Ab production
Blood:
 ↑ RBCs and platelets.
 ↑ Blood coagulability. History of
 ↓ WBCs and lymphocytes Leukemia thrombo-
Lymphoma embolism
Euphoria Mood change

↓Pituitary ACTH: -ve feedback Sudden stop: Sudden stop

Addisonian crisis.
↓ Wound healing ↓ Wound healing
Lung: Stimulation of lung Absolute
 ↑Surfactant production in fetal lung at maturation in fetus by giving contraindicati
term. betamethasone to the mother on:
at term. Herpetic
Uricosuric: ↑ uric acid excretion keratitis
Anti-Shock Shock

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Other uses
1. Addison’s disease: hydrocortisone plus a
mineralocorticoid (fludrocortisone).
2. Addisonian crisis (acute adrenocortical insufficiency):
Manifestations: it is characterized by hypotension, hypoglycemia,
vomiting and shock.
Treatment:
 Hydrocortisone Na succinate (i.v.), Fluids: 0.9% NaCl & 5%
glucose
 Blood transfusion
 Heparin and Vasopressin
Precautions during prolonged use of corticosteroids
1. Every day
Diet:
 ↑ proteins
 ↑K+, ↑ Ca++
 ↓ Na, ↓ glucose
2. Every week: Measure:
 Blood pressure
 Blood glucose
 Body weight
3. Every 6 months: X ray on spine
4. Never stop suddenly
5. Increase dose with stress

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 Male sex hormone
Testosterone

- Testosterone is the principle male sex hormone and is responsible for

reproductive growth and development in male vertebrates.

Mechanism of action
- Testosterone either activates androgen receptors in its unchanged
form or gets converted to 5α-dihydrotestosterone (DHT) by the
enzyme 5α-reductase and then binds to androgen receptors. Once
bound, the receptor-hormone complex moves into the cell nucleus and
binds to specific genes sequences on the cellular DNA called hormone
response elements. This modifies the DNA transcription and synthesis
of various proteins, thereby giving rise to the androgenergic effects
exerted by testosterone.

Actions of testosterone
Testosterone plays a major role in the growth and development of the
male reproductive organs such as the testes and prostate.

Some specific effects of testosterone include:

 Anabolic effects of testosterone: Testosterone is the primary
anabolic steroid. It promotes an increase is muscle mass and
strength. Testosterone is also responsible for the mass, density
and strength of bone. In males, an age-related decline in
testosterone increases the risk of bone disorders such as
osteoporosis.
 Androgenergic effects: The growth of primary sexual
characteristics such as the penis and testes are mediated by
testosterone both while the baby forms in the womb and during
puberty.
 Secondary sexual characteristics mediated by testosterone
include deepening of the voice and growth of facial, armpit,
chest and pubic hair.

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 Preparations and uses
Mixed androgenic and Selective anabolic actions
anabolic actions (anabolic steroids)
e.g.,  Testesterone: used as SC  Nadrolone
implant or transdermal
patches.
 Methyltesterone: used
orally.
Uses Delayed puberty. 1. Chronic renal failure
2. Anemia
3. Atheletes :
 improve atheletic
performance, stimulate
muscle growth.

Unwanted effects
1. Salt and water retention leading to oedema.
2. Adenocarcinoma of the liver has been reported.
3. Short staturewhen used in children

Contraindications: Prostate cancers and Liver dysfunction.

Anti-androgens

1. Drugs which competitively block testosterone receptors

Flutamide Bicalutamide
Uses Prostate cancer
SE Gynecomastia Gynecomastia
Hepatotoxicity

2. Drugs with partial agonistic activity on testosterone

receptors
Cyproterone acetate: used to treat hirsutism in females.

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 3. Drugs inhibit formation of dihydrotestosterone
α- Reductase inhibitor
Finastride
 Mechanism of action
It inhibits 5α-reductase that converts testosterone to
dihydrotestosterone, which has a great affinity for androgen receptors
in the prostate gland.
- Uses: Benign prostatic hyperplasia.

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 Female sex hormones
1. Estrogen
Physiological actions
 Ovaries: Estrogen helps stimulate the growth of the egg
follicle.
 Vagina: In the vagina, estrogen maintains the thickness of the
vaginal wall and promotes lubrication.
 Uterus: Estrogen enhances and maintains the mucous
membrane that lines the uterus. It also regulates the flow and
thickness of uterine mucus secretions.
 Breasts: The body uses estrogen in the formation of breast
tissue. This hormone also helps stop the flow of milk after
weaning.
 Estrogens reduce bone resorption and increase bone formation.
 They help in protein synthesis, increase hepatic production of
binding proteins, coagulation proteins (factors II, VII, IX, X,
plasminogen). Estrogens increase platelet adhesiveness and
reduce antithrombin III.
 Estrogens increase good cholesterol (HDL) and also increase
triglycerides. They decrease LDL and promote fat deposition.
 On fluids and electrolytes estrogens cause salt (sodium) and
water retention. In the gastrointestinal tract they reduce bowel
motility and increase cholesterol in bile. They also improve
lung functions.
Preparations:
 Natural estrogens are ineffective as they are destructed by first
pass effect.
 Synthetic preparations as; Diethylstilbesterol, Ethinyl estradiol
which are used orally or IM.
2. Progesterone
Physiological actions
1) Maturation of endometrium.
2) It makes the cervical secretions thick and viscid.

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 3) Decrease the uterine movement.
4) Inhibits the LH and ovulation (in high doses).
Preparations
Synthetic preparations include: e.g Norgesteril, medroxy
progesterone acetate.

HORMONAL CONTRACEPTION
1- Implantable Progestin
 Levonorgestrel Subcutaneous capsules and effective for 5 –
6 years.

2- Injectable Contraceptives
e.g., Medroxy progesterone Acetate: it is long acting used IM every 3
month.

3- Oral Contraceptives (OCs)

It includes different types such as:
a) Progestin only pills
- The main advantage is absence of inhibition of prolaction.
Uses: Contraception with lactation.
Side effects: High rate of failure and Irregular bleeding.

b) Combined OCs (estrogen + progesterone)

Mechanisms of action
1. Inhibition of ovulation through inhibition of FSH and LH.
2. Viscid thick cervical secretion.
3. Changes in the endometrium.
4. Increase the fallopian tube activity that alters the passage of the
sperms.
Uses of combined OCs
1. Contraception.
2. Amenorrhea
3. Dysmenorrhea
4. Dysfunctional uterine bleeding
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 5. Endometriosis.
6. Postpone the menstruation.
Important note:
OCs are usually safe but the risk of side effects increase with
 Smokers
 Older than 35 y.
 History of thromboembolism.
Adverse Effects of O.C.P:
GIT:
 Nausea and vomiting
 Gall stones

CVS:
 Salt and water retention.
 HTN.
 Increasing venous thrombosis
CNS: Depression
Skin: Skin pigmentation and hair fall.

Failure of OCs?
 OCs usually highly effective with low failure rate.
 The main cause of failure is drug interactions.
 Failure of contraception due to co-administration of:
 HME inducers as phenytoin or Rifampicin.
 Broad Spectrum Antibiotics by inhibiting
enterohepatic circulation of estrogens.

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 Drugs affecting estrogen action or synthesis
1) Drug block estrogen receptors in hypothalamus
Clomiphene
Mechanism of action
It competes with estrogen in hypothalamus leading to inhibition of
feedback effects that resulted in increasing the level of FSH and LH
→↑FSH and LH promoting the ovulation and formation of corpus
luteum, so pituitary and ovaries have to be functioning.
Uses
1- It is used in induction of ovulation
2- In vitro fertilization.
Side Effects
 Twins.
 Enlarged cystic ovary.
(2) Selective estrogen receptors modulators (SERM)
a) Tamoxifen
Mechanism of action
It is a selective receptor modulator in specific tissue (breast,
endometrium) and has an estrogenic activity in other tissues as bone,
liver and brain.
Uses:
1. Treatment of breast cancer
2. Prophylaxis in high risk breast cancer women.
Side Effects:
 Weight gain
 Hot flashes.
b) Raloxifene
Mechanism of action: it is a SERM with higher efficacy on estrogen
receptors in bone.
Actions : Decrease of bone resorption that inturn increase Bone density
Uses: Osteoporosis in postmenopausal women.
Side effects
 Hot flashes and leg cramps.

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 (3) Drugs inhibit estrogen synthesis (Aromatase Inhibitors)
Mechanism of action
They inhibit the beta-aromatase enzyme of ovaries and
adrenal cortex.
Uses
Advanced estrogen dependent breast cancer after failure of
tamoxifen.
e.g., Letrozole.

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 Drugs affecting immune response
1- Immunosuppressive drugs
Uses of immunosuppressants
1- Autoimmune conditions
Immunosuppressant drugs are used to treat autoimmune diseases.
With an autoimmune disease, the immune system attacks the body’s
own tissue. Because immunosuppressant drugs weaken the immune
system, they suppress this reaction. This helps reduce the impact of the
autoimmune disease on the body.
Autoimmune diseases treated with immunosuppressant drugs include:
 Psoriasis
 Lupus
 Rheumatoid arthritis
 Crohn’s disease
 Multiple sclerosis
 Alopecia areata
2- Organ transplant
Almost everyone who receives an organ transplant must take
immunosuppressant drugs. This is because your immune system sees a
transplanted organ as a foreign object. As a result, your immune
system attacks the organ as it would attack any foreign cell. This can
cause severe damage and lead to needing the organ removed.
Immunosuppressant drugs weaken your immune system to reduce your
body’s reaction to the foreign organ. The drugs allow the transplanted
organ to remain healthy and free from damage.

Commonly used immunosuppressants

Corticosteroids
 Prednisone
 Budesonide
 Prednisolone
Janus kinase inhibitors
 tofacitinib

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Calcineurin inhibitors
 cyclosporine
 tacrolimus
mTOR inhibitors
 sirolimus
 everolimus
Purines and pyrimidines synthesis inhibitors
 azathioprine
 leflunomide
 mycophenolate
Biologics
 abatacept
 adalimumab
 anakinra
 certolizumab
 etanercept
 infliximab
Monoclonal antibodies
 basiliximab
 daclizumab
2- Immunostimulants
Immunostimulants are substances that stimulate the immune system.
Uses of immunostimulants
 Specific immunostimulants such as vaccines stimulate an
immune response to specific antigenic types.
 Non-specific immunostimulants do not have antigenic
specificity and are widely used in chronic infections,
immunodeficiency, autoimmunity and neoplastic diseases.
Examples of Immunostimulants
 vaccines
 colony stimulating factors
 interferons
 interleukins
 levamisole
95
References
 Goodman & Gilman's: The Pharmacological Basis of
Therapeutics, Thirteenth Edition. 2018. McGraw-Hill
Education.
 Basic & Clinical Pharmacology, Fifteenth Edition. 2021.
McGraw Hill.
 Lippincott Illustrated Reviews: Pharmacology (Lippincott
Illustrated Reviews Series) 7th Edition. Wolters Kluwer.
 Rang & Dale's Pharmacology, 9th Edition. 2018. Elsevier

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