Pharmacokinetics:

Metabolism
 The majority of phase I and phase II reactions take place in the liver)
 Usually both phase I and II reactions ↓↓ lipid solubility
 Drug metabolism usually involves two types of biochemical reactions
1. Phase I reactions 
 Oxidation, reduction, hydrolysis
 Products more active and potentially toxic)
 Mainly performed by the P450 enzymes
 Some drugs are metabolised by specific enzymes  Alcohol dehydrogenase and Xanthine Oxidase.

2. Phase II reactions
 Conjugation
 Products are typically inactive & excreted in urine or bile.
 Glucuronyl, Acetyl, methyl, sulphate and other groups are typically involved

First-pass metabolism 'first-order' "Elimination kinetics" 

 "Rate of drug elimination is proportional to drug concentration"
 Helpful to reduce the drug Conc. To therapeutic level.
 As a consequence much larger doses are need orally than if given by other routes. Ex
1. aspirin
2. isosorbide dinitrate
3. glyceryl trinitrate
4. lignocaine
5. propranolol
6. verapamil
7. isoprenaline
8. testosterone
9. hydrocortisone
 Zero-order kinetics = Saturation Pharmacokinetics
 "Rate of excretion is constant despite changes in plasma concentration (due to saturation of the metabolic process)
 ↑↑Risk of toxicity
1. Alcohol  people may fail a breathalyser test in the morning if they have been drinking the night befor
2. heparin
3. Phenytoin (long half life  needs monitoring)
4. Salicylates

Acetylator Status
 50% of the UK population are deficient in hepatic N-acetyltransferase (affect toxcisity of the drug)
 Drugs affected by acetylator status
1. Isoniazid
 Men  less likely to develop isoniazid hepatotoxicity.
 Concurrent use of Rifampicin and Pyrazinamide is also a risk factor isoniazid hepatotoxicity.
2. Sulfasalazine
3. Procainamide
4. Hydralazine
5. Dapsone

P450 enzyme system

Induction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors, where effects are often seen rapidly

(++++) P450 (- - - -) P450 system

1. Anti- Biotic  Rifampicin 1. Antibiotics  Ciprofloxacin, Erythromycin, Isoniazid
2. Anti fungal  Griseofulvin 2. Anti- Fungal  imidazoles (ketoconazole, Fluconazole)
3. Antiepileptic  Phenytoin, Carbamazepine 3. Anti- Viral  ritonavir
4. Anti- Seizure Barbiturates "phenobarbitone" 4. Anti- Epileptic  Na+ valproate
5. St John's Wort 5. Anti- Depressant SSRIs: fluoxetine, sertraline
6. Chronic alcohol intake 6. Anti- Acid  Cimetidine, Omeprazol
 7. Smoking 7. Anti- Arrhythmic  Amiodarone
(affects CYP1A2(↓↓ Amynophylin effect smokers require more 8. Anti- Gout  Allopurinol
aminophylline) 9. Acute alcohol intake
10. Quinupristin

11. Grapefruit juice (interact with Simvastatin)

DRESS syndrome
 Severe reaction to medication W several organs are commonly affected (Skin, Liver, Kidneys, Lungs and Heart). Not all organs at any one time.
 2-8 weeks after commencing the offending drug. Feature
1. Morbilliform skin rash in 80%, often  Mxfoliative dermatitis,
2. Vesicles and bullae may be seen.
3. Erythroderma 10% of cases, Mucosal involvement in 25% and Facial swelling in 30%.
4. ↑↑ Fever and inflammation of ≥ 1 organs.
5. Systematic symptoms
Haematological Eosinophilia (30% > 2.0 * 109 /L) ↑/↓ WBCs / ↓↓(Platelet & Hb / Atypical lymphocytes)
Enlarged LN (75%)
Mild kidney D  10% (interstitial nephritis is common, renal failure is rare)
CVS  Myocarditis, Pericarditis.
liver enlargement  Hepatitis and rarely hepatic necrosis with liver failure (abnormal liver function " 70-90% ↑↑transaminases),
lung disease  pneumonitis, pleuritis, pneumonia
CNS  meningitis and encephalitis,
GIT in"Severe cases" (acute colitis and pancreatitis can occur)
Endocrine  Thyroiditis and D.M.
Diagnosis
 Difficult to determine the exact drug causing the hypersensitivity as first exposure may have started 8 weeks prior.
 Common drugs
1. Allopurinol
 2. Anti-epileptics
3. Antibiotics
4. Immunosuppresants
5. HIV treatment
6. NSAIDS.

 Suspected diagnosis  Triad of [Extensive Skin rash + ↑↑ fever + Organ involvement] supported by eosinophilia and ↑↑liver function
 RegiSCAR has proposed a diagnostic criteria at least 3 of the following:
1. Hospitalisation
2. Reaction suspected to be drug related
3. Acute skin rash
4. Fever about 38ºC
5. Enlarged lymph nodes at two sites
6. Involvement of ≥ 1 internal organ
7. Blood count abnormalities such as low platelets, raised eosinophils or abnormal lymphocyte count.

 Skin biopsy  "confirm the diagnosis" [inflammatory infiltrate (Eosinophils), Extravasated erythrocytes and Oedema].
 Regular blood tests including FBC, clotting, liver and renal function, CK, viral screen, glucose and thyroid function tests should be
 Investigations looking for complications should be undertaken including ECG, CXR, echocardiogram, and urinalysis.

Treatment
1. All possible medications  stopped and supportive care started.
2. Rash
 Antihistamines, topical steroids and emollients.
 Systemic steroids  severe cases [Exfoliative dermatitis / Pneumonitis / hepatitis]
 Regularly checked and secondary infections  treated with antibiotics
3. Careful fluid balance is necessary and clinicians should be aware of the patients nutritional status.
4. Occasionally immunosuppressants, IV immunoglobulin and plasmapheresis may be started.
5. Potential culprit drugs should not be restarted again.
 6. The mortality is around 8%.
DD
Steven Johnson's syndrome (SJS) and toxic epidermal necrolysis (TEN)  skin disorders with drug reactions (limited to the skin and not ↑↑LFTs.
SJS would typically present with mucosal involvement, whilst TEN causes desquamating skin lesions.

Carbon monoxide poisoning

CO  ↑↑affinity for Hb O2.  Total Hb is normal(Not affect plasma O2), but active sites get occupied by CO ↓↓Hb saturation Hypoxia.
CO has a high affinity left-shift of the oxygen dissociation (early plateau).There are approximately 50 per year deaths from accidental carbon monoxide.
A pulse Oximeter  normal oxygen saturation (ABG is required to check for plasma O2)
Questions may hint at badly maintained housing e.g. student houses.

Features of carbon monoxide toxicity

1. Headache  90% of cases
2. Nausea and Vomiting, Vertigo  50%
3. Confusion, subjective weakness : 30%
4. Severe toxicity
 'pink' skin and mucosae,
 Hyperpyrexia
 Arrhythmias
 Extrapyramidal features
 Coma, death

Investigations
1. Pulse oximetry may be falsely high due to similarities between oxyhaemoglobin and carboxyhaemoglobin  venous or arterial blood gas
2. Typical carboxyhaemoglobin levels
 < 3% non-smokers (Normal)
 < 10% smokers  Heavy smokers may have a carboxyhaemoglobin concentration of 10-15%
 10 - 30%  symptomatic (headache, vomiting)
 > 30%  Severe toxicity
 3. ECG is a useful supplementary investgation to look for cardiac ischaemia

Management
 100% high-flow oxygen via a non-rebreather mask
1. ↓↓ the half-life of Carboxyhemoglobin (COHb)
2. Administered as soon as possible, (minimum 6 h )
3. target O2 saturations are 100%
4. Treatment is continued until all symptoms have resolved, rather than monitoring CO levels
 Hyperbaric oxygen
 Some evidence long-term outcomes may be better than standard oxygen therapy for more severe cases (levels > 25%)
 Other indication for hyperbaric oxygen
1. Loss of Consciousness at any point.
2. Neurological signs other than headache.
3. Myocardial ischaemia or arrhythmia
4. Pregnancy
Cyanide poisoning
 Used in (Insecticides, Photograph development and the production of certain metals Fires involving the burning of plastics.
 Cyanide (- -) Mitochondrial cytochrome c oxidase Enz  cessation of electron transfer chain  histotoxic hypoxia (cells unable to create ATP.

Presentation
1. 'classical' features: brick-red skin, smell of bitter almonds
2. Acute
 Hypoxia
 Hypotension
 Headache, confusion
3. Chronic
 Ataxia
 Peripheral neuropathy
 Dermatitis
 4. Presentation with normal O2 saturations  ↑↑ pO2 and flushing (or 'brick red' skin)  DD. From CO poisoning
Management
1. supportive measures: 100% oxygen
2. Definitive IV Hydroxocobalamin also combination of
 Amyl nitrite (inhaled)
 Sodium nitrite (IV),
 Na thiosulfate (IV)

Mercury poisoning
The commonest cause of mercury poisoning is ingestion via foodstuffs- in particular fish and whale. Features
1. Paraesthesia
2. Visual field defects
3. Hearing loss (Sensorineurl)
4. irritability
5. Renal tubular acidosis

Organophosphate insecticide poisoning

Organophosphate poisoning inhibit acetylcholinesterase  upregulation (++) of nicotinic and muscarinic cholinergic neurotransmission.
In warfare, Sarin gas is a highly toxic synthetic organophosphorus compound that has similar effects.

Features (accumulation of acetylcholine  Parasympathetic ) "mnemonic = SLUD"

1. Salivation
2. Lacrimation
3. Urination
4. Defecation/diarrhoea
5. Bronchorrhea
6. CVS  Hypotension, Bradycardia
7. Small pupils, Muscle fasciculation, Muscle weakness
Management
 1. Atropine
2. the role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefit
Antibiotics: gross mechanism of action
(- -) cell wall formation (- -) protein synthesis (- -) DNA Damages DNA (- -) Folic Acid (- -) RNA
1. (- -) Peptidoglycan cross linking by acting on the Ribosome  Quinolones Metronidazole 1. sulphonamides  Rifampicin
 Penicillins 1. 50Ssubunit  Ciprofloxacin 2. trimethoprim
 Cephalosporins  Macrolides
 Carbopenems  Chloramphenicol
2. Peptidoglycan synthesis: Glycopeptides  Clindamycin
 Vancomycin  Linezolid
 Teicoplanin  > duration of  Streptogrammins
action/ OD after loading dose. 2. 30S subunit
 Aminoglycosides
 Tetracycline
Penicillin allergy
 Allergy to penicillin is common (allergy may be intolerance/side-effects (diarrhoea) or coincidental rash (amoxicillin in patients with infectious mononucleosis).
 Urticarial rash or itching make it ↑↑ likely  IgE mediated allergy.
 Around 0.5-6.5% of patients who are allergic to penicillin are also allergy to cephalosporins. (↑↑ 1st generation, ↓↓ 2nd & 3rd generations)
 History of immediate hypersensitivity to penicillin  should not receive a cephalosporin.
 If a cephalosporin is essential (No alternative antibacterial)
Used with caution Should be avoided
 Cefixime  Cefaclor
  Cefotaxime  Cefadroxil
 Cefuroxime  Cefalexin
 Ceftazidime  Cefradine
 Ceftriaxone  Ceftaroline Fosamil
Types of penicillin:
1. Phenoxymethylpenicillin
2. Benzylpenicillin
3. Flucloxacillin
4. Amoxicillin
5. Ampicillin
6. Co-amoxiclav (Augmentin)
7. Co-fluampicil (Magnapen)
8. Piperacillin + Tazobactam (Tazocin)
9. Ticarcillin + Clavulanic acid (Timentin)

Macrolides
 Erythromycin 1st macrolide used clinically  newer examples  Clarithromycin and Azithromycin.
 Act by (- -) bacterial protein synthesis by blocking translocation (Bacteriostatic in nature, but also depends on dose and type of organism).
 Mechanism of resistance  Post-transcriptional Methylation of the 23S bacterial ribosomal RNA
 Erythromycin  used in gastroparesis as it has prokinetic properties (↑↑Gastric emptying)

Adverse effects
1. GIT "Common"  Nausea is less common with clarithromycin than erythromycin
2. Cholestatic jaundice  risk ↓↓ if erythromycin stearate is used
3. (- -) P450
4. Azithromycin is associated with hearing loss and tinnitus

Common interactions
1. Statins  stopped W Macrolides (significantly ↑↑↑risk of myopathy and rhabdomyolysis)
  (- -) cytochrome P450 isoenzyme CYP3A4 (Metabolises statins).
2. potentially interact with amiodarone, warfarin

Quinolones
Works by (- -) DNA synthesis and are bactericidal in nature. Examples include:
1. ciprofloxacin
2. levofloxacin

Mechanism of action
(- -) topoisomerase II (DNA gyrase) and topoisomerase IV

Mechanism of resistance
Mutations to DNA gyrase, (efflux pumps ↓↓ intracellular quinolone concentration)

Adverse effects
1. ↓↓ seizure threshold in patients with epilepsy
2. Tendon damage (including rupture) - ↑↑↑ risk W steroids (treatment being 8 days before problems occur)
3. Cartilage damage (animal models  generally avoided (but not necessarily contraindicated) in children
4. lengthens QT interval

Contraindications
1. Pregnancy or breastfeeding
2. G6PD

Gentamicin
Aminoglycoside antibiotic  poorly lipid-soluble  therefore given parentally (Infective endocarditis) or topically (Otitis externa).

Adverse effects
1. Ototoxicity
  Auditory or Vestibular Nerve damage
 irreversible
2. Nephrotoxicity
 accumulates in renal failure
 the toxicity is 2ry to acute tubular necrosis (direct damage to the renal tubules)
 concomitant use of furosemide ↑↑risk
 ↓↓ doses and ↑↑monitoring is required

Contraindications Myasthenia gravis

Dosing
1. significant ototoxic and nephrotoxic potential  monitor plasma concentrations
2. Measurement  Both peak (1 hour after administration) and trough levels (just before the next dose)
 if the trough (pre-dose) level is high  ↑↑ interval between the doses
 if the peak (post-dose) level is high  ↓↓ dose

Tuberculosis: drug side-effects and mechanism of action

Rifampicin Isoniazid Pyrazinamide Ethambutol
 inhibits RNA synthesis  (- -) mycolic acid synthesis  Converted by pyrazinamidase into  (- -) arabinosyl transferase Enz (polymerizes
 (- -) bacterial DNA dependent RNA pyrazinoic  (- -) fatty acid arabinose into arabinan)
polymerase  prevent transcription of 1. peripheral neuropathys synthase (FAS) I
DNA into mRNA  add pyridoxine (Vitamin B6)  Optic neuritis
1. Hepatotoxicity  check visual acuity before & during treatmen
1. (++) P450 2. (- -)P450 1. Uric acid  gout
2. Hepatotoxicity 3. Hepatotoxicity 2. Arthralgia, myalgia  Dose adjusting in renal impairment
3. Orange secretions 4. Agranulocytosis
4. flu-like symptoms
Alcohol - problem drinking
S/E
1. Excessive alcohol develop Polyurea ↓↓Ca++ -dependent secretion of (ADH) by blocking channels in neurohypophyseal nerve terminal.
2. Nausea associated with hangovers  vagal stimulation Vomiting Centre .
3. severe episode of alcohol may experience tremors  ↑↑ glutamate production by neurones to "compensate for the previous inhibition by ethanol".

Management
Nutritional support
Alcoholic patients should receive oral thiamine if their 'diet may be deficient'

Drugs used
1. Acute withdrawal  Benzodiazepines.
2. Promotes abstinence  Disulfram
 Alcohol intake  Severe reaction due to (- -) acetaldehyde dehydrogenase.
 Even small amounts of alcohol (Perfumes, Foods, Mouthwashes) can produce severe symptoms.
 CI/ IHD and psychosis

3. ↓↓↓ Craving  Acamprosate

 A weak antagonist of NMDA receptors, improves abstinence

Ethylene glycol toxicity

a type of alcohol used as a Coolant OR Antifreeze. Features of toxicity are divided into 3 stages:
1. Stage 1: symptoms similar to alcohol intoxication  Confusion, Slurred speech, Dizziness
2. Stage 2: metabolic acidosis + high anion gap and high osmolar gap + Also tachycardia + hypertension
3. Stage 3: AKI

Management has changed in recent times

1. Fomepizole, (Inhibitor of alcohol dehydrogenase  now used first-line in preference to ethanol
 2. Ethanol (Traditionally used )  Compete with Ethylene Glycol for the enzyme Alcohol dehydrogenase
 ↓↓↓ Toxic metabolites (glyceraldehydes and glycolic acid)  responsible for the haemodynamic/metabolic features of poisoning

3. Haemodialysis  refractory cases (Metaboloic acidosis)

DD. Methanol poisoning  similar fashion, but with visual disturbance and occasionally blindness. Treated with Fomepizole.

Methanol poisoning
 Methanol poisoning effects (Alcohol "Intoxication, Nausea" + Specific visual problems (blindness, Macular edema) 2ry to accumulation of formic acid.
 The actual pathophysiology of visual loss is not understood but thought caused by a form of optic neuropathy (Accumulation of metabolites in the nerv)
 Metabolic Acidosis W ↑↑ anion gap

Management
1. Fomepizole (competitive inhibitor of alcohol dehydrogenase) or Ethanol
2. Haemodialysis

Paracetamol overdose: management

 Potentially toxic dose of Paracetamol (>75mg/kg)
 Complications of overdose
1. Hepatotoxicity (Metabolic pathways)
 The liver normally conjugates paracetamol with glucuronic acid/sulphate.
 Overdose  conjugation system saturated  Oxidation by P450 mixed function Oxidases 
 ↑↑Toxic metabolite (N-acetyl-B-benzoquinone Imine "NAPQI"
 Normally glutathione acts as a defence mechanism by conjugating with the toxin  (Non-toxic Mercapturic Acid).
 If glutathione stores run-out, the toxin forms covalent bonds with cell proteins, denaturing them and leading to cell death.
 This occurs in hepatocytes & Renal tubules
 N-acetyl cysteine  is a precursor of glutathione  ↑↑ Hepatic Glutathione production (Replenish Glutathione)
  Factors ↑↑ risk of hepatotoxicity Treated on lower threshold (↑↑Toxic metabolites)
 liver enzyme-inducing Drugs (rifampicin, phenytoin, carbamazepine, St John's Wort)
 History of chronic alcohol excess
 Malnourished patients (Anorexia nervosa) or not eaten for a few days, due to depletion of glutathione.

 Factors not ↑↑ risk of hepatotoxicity

 Acute alcohol intake and may actually be protective (- -) CYP2E1, preventing oxidising paracetamol to the toxic metabolite

2. Delayed Nephrotoxicity  especially in significant overdose  Follow up ↑↑ KFTs

Treatment
 Within 1 hour "minority"  activated charcoal ↓↓ absorption of the drug.
 Acetylcysteine should be given if:
1. Staggered overdose or Doubt over the time of ingestion, (regardless of the plasma paracetamol concentration)
2. Concentration ≥ single treatment line (100 mg/L at 4 hours) and (15 mg/L at 15 hours), (regardless of risk factors of hepatotoxicity)

 Acetylcysteine  infused over 1 hour  ↓↓adverse effects.

 Commonly causes an anaphylactoid reaction (non-IgE mediated mast cell release).
 Treatment  stopping the infusion, then restarting at a slower rate.

Criteria for liver transplantation (paracetamol liver failure)

1. Arterial pH < 7.3, 24 hours after ingestion
2. OR all of the following:
 PT > 100 seconds
 Creatinine > 300 µmol/l
 Grade III or IV encephalopathy
Acute intermittent porphyria: drugs
AD  defect in Porphobilinogen deaminase, (enzyme involved in the biosynthesis of haem.
It characteristically presents with abdominal and neuropsychiatric symptoms in 20-40 year olds. ↑↑females (5:1)

Drugs which may precipitate attack Drugs considered safe to use

1.Alcohol 1.Aspirin
2.Barbiturates 2.Beta-blockers
3.Benzodiazepines 3.Codeine
4.Halothane 4.Morphine
5.Thiopental Na 5.Chlorpromazine
6.Oral contraceptive pill 6.metformin
7.Sulphonamides 7.paracetamol
8.penicillin

Alpha-1 Alpha 2 Beta 1 Beta 2 Beta-3

VC  Mainly Presynaptic  (- -) Inc  Mainly in the heart  VD Lipolysis
Relaxation GI smooth muscle NA / Ach Autonomic Nerves)  ↑↑ HR + force  Bronchodilation
Salivary secretion  (- -) Insulin  Relaxation of GI Smooth
Hepatic Glycogenolysis  Platelet Aggregation
Receptors  G- PTN Receptors  G- PTN Receptors  G- PTN
Receptors  G- PTN Coupled Receptors  G- PTN Coupled Coupled Coupled Coupled
2ry messenger  (++) (- - ) Adenylate Cyclase (++) Adenylate Cyclase (++) Adenylate Cyclase (++) Adenylate
phospholipase C → IP3 → DAG Cyclase

Adrenoceptor Agonists
Alpha-1 agonists
1. vasoconstriction (Skin, kidney , mucous membrane)
2. relaxation of GI smooth muscle
 3. Salivary secretion
4. Hepatic glycogenolysis
5. Phenylephrine

Alpha-2 agonists
 clonidine

Beta-1 agonists
 dobutamine

Beta-2 agonists
 salbutamol

Beta-3 agonists
 being developed, may have a role in preventing obesity (stimulation causes lipolysis)

Alpha antagonists
 alpha-1  Doxazosin (Treatment of hypertension and benign prostatic hypertrophy
 alpha-1a  Tamsulosin - acts mainly on urogenital tract

 alpha-2  yohimbine
 non-selective  phenoxybenzamine (previously used in peripheral arterial disease)

Beta antagonists
 Beta-1  Atenolol
 Beta-2  Phentolamine.
 Non-selective  Propranolol

Mixed alpha and beta antagonists

  Carvedilol
 Labetalol

Adrenaline
Sympathomimetic amine with both alpha and beta adrenergic stimulating properties. Indications
1. anaphylaxis  0.5ml 1:1,000 IM
2. cardiac arrest  1ml of 1:1000 IV (10ml 1:10,000 IV)

Management of accidental injection

 local infiltration of phentolamine
 short acting alpha blocker,
 It is normally used mainly to control blood pressure during surgical resection of phaeochromocytoma

Background
 responsible for the fight or flight response
 released by the adrenal glands
 acts on α 1 and 2, β 1 and 2 receptors
 acts on β 2 receptors in skeletal muscle vessels-causing vasodilation
 increases cardiac output and total peripheral resistance
 causes vasoconstriction in the skin and kidneys causing a narrow pulse pressure

Actions on α adrenergic receptors:

 (- -) insulin secretion by the pancreas
 stimulates glycogenolysis in the liver and muscle
 stimulates glycolysis in muscle
Actions onβ adrenergic receptors:
 stimulates glucagon secretion in the pancreas
 stimulates ACTH
 stimulates lipolysis by adipose tissue
 Induces Hyperglycemia, Hyperlactatemia and Hypokalaemia.
 insulin secretion is suppressed by alpha adrenergic stimulation  Hyperglycemia by ↑↑ hepatic glycogenolysis and gluconeogenesis.
 In skeletal muscle, epinephrine ↑↑ glycolysis and glycogenolysis  ↑↑ lactate (serves as a substrate for hepatic neoglucogenesis (Cori cycle).
 There is also a marked increase in oxygen consumption.
 Epinephrine also increases lipolysis and decreases muscular proteolysis.

Dopamine receptor agonists

Indications
1. Parkinson's disease
 delay treatment until the onset of disabling symptoms
 elderly, L-dopa is sometimes used as an initial treatment

2. Prolactinoma/Galactorrhoea
3. Acromegaly
4. Cyclical breast disease
Overview
 Ex: Bromocriptine, Ropinirole, Cabergoline, Apomorphine
 Ergot-derived dopamine receptor agonists (Bromocriptine, Cabergoline, Pergolide"valvular dysfunction")  pulmonary, retroperitoneal and cardiac fibrosi
 ESR, Creatinine and chest x-ray (Prior to treatment and closely monitored)

Adverse effects
1. Nausea/Vomiting  (++) brain Vomiting Centre
2. Postural hypotension
3. Hallucinations
4. Daytime somnolence
Drugs which act on serotonin receptors
Drugs act via modulation of the serotonin (5-HT) system.
It should be noted that 5-HT receptor agonists are used in the acute treatment of migraine whilst 5-HT receptor antagonists are used in prophylaxis.

Agonists Antagonists
1. Sumatriptan  acute treatment of migraine Pizotifen
1.  prophylaxis of migraine attacks.
2. Ergotamine  partial agonist of 5-HT1 receptors Methysergide  rarely used due to the risk of retroperitoneal fibrosis
2.
Cyproheptadine  control diarrhoea in patients with carcinoid syndrome
3.
Ondansetron  antiemetic
4.
Serotonin syndrome
Causes
1. Monoamine Oxidase Inhibitors
2. SSRIs
 St John's Wort, often taken over the counter for depression, can interact with SSRIs to cause serotonin syndrome
 The combination of two or more serotonergic medications greatly increases the risk
3. Ecstasy
4. Amphetamines
Features
 Neuromuscular excitation (Hyperreflexia, myoclonus, rigidity Spasticity)
 autonomic nervous system excitation (hyperthermia)
 altered mental state
 Dilated pupil.

Management
 supportive including IV fluids
 Benzodiazepines
 Severe cases  serotonin antagonists (Cyproheptadine and Chlorpromazine)
St John's Wort
 Effective as tricyclic antidepressants in the treatment of mild-moderate depression
 Mechanism  similar SSRIs + noradrenaline uptake inhibition)
 Should not be prescribed because of uncertainty about appropriate doses, variation of preparations, and potential serious interactions with other drugs'

Adverse effects
1. S/Es in trials similar to placebo
2. Serotonin syndrome
3. (++) P450 system,  ↓ levels of drugs (Warfarin, Ciclosporin, COCP)

Octreotide
 Long-acting analogue of somatostatin (from D cells of pancreas  (- -) GH, Glucagon and Insulin). Uses
1. acute treatment of variceal haemorrhage
2. Acromegaly
st
3. Carcinoid syndrome"1 line", Also Cyprohiptadine can be used.
 4. VIPomas
5. refractory diarrhoea
6. Prophylaxis  Prevent complications following Pancreatic Surgery

Adverse effects
 Gallstones & Billiary Colic (2ry to biliary stasis)

Antiarrhythmics
The Vaughan Williams classification
Class Examples Mechanism of action Notes
Ia 1. Quinidine  Block sodium channels  Quinidine toxicity  cinchonism
2. Procainamide  ↑↑AP duration (headache, tinnitus, thrombocytopaenia)
3. Disopyramide  Procainamide  drug-induced lupus
Ib 1. Lidocaine  Block sodium channels
2. Mexiletine  ↓↓ AP duration
3. Tocainide
Ic 1. Flecainide  Block sodium channels
2. Encainide  No effect on AP duration
3. Propafenone
II 1. Propranolol Beta-adrenoceptor antagonists
2. Atenolol
3. Bisoprolol
4. Metoprolol
III 1. Amiodarone Block potassium channels
2. Sotalol
 Class Examples Mechanism of action Notes
3. Ibutilide
4. Bretylium
IV 1. Verapamil Calcium channel blockers
2. Diltiazem

Flecainide
 1c Ant arrhythmic ↓↓conduction of the action potential by acting as a potent Na channel blocker (specifically the Na v1.5 Na channels).
This may be reflected by ↑↑ QRS complex and ↑↑PR interval. Indications
1. AF
\
2. SVT W Accessory pathway (WPW)

Contraindications
1. Post MI  ↑↑Mortality
2. Structural heart disease (Heart Failure)
3. sinus node dysfunction  2nd-degree or greater AV block
4. Atrial Flutter

Adverse effects
1. -Ve Inotropic
2. Bradycardia
3. Proarrhythmic
4. Oral Paraesthesia
5. Visual disturbances

Procainamide works in a similar way to flecainide but instead induces a rapid blocking of the batrachotoxin activated sodium channels rapidly

Beta-blockers
 Indications
1. angina
2. post-myocardial infarction
3. heart failure  certain beta-blockers improve both symptoms and mortality
4. arrhythmias  rate-control drug of choice in atrial fibrillation
5. Hypertension
6. Thyrotoxicosis
7. Migraine prophylaxis
8. Anxiety

Examples
 Atenolol
 Propranolol: one of the first beta-blockers to be developed. Lipid soluble therefore crosses the blood-brain barrier

Side-effects
1. Bronchospasm
2. Cold peripheries
3. fatigue
4. Sleep disturbances, including nightmares
5. erectile dysfunction

Contraindications
1. uncontrolled heart failure
2. asthma
3. sick sinus syndrome
4. concurrent verapamil use: may precipitate severe bradycardia

Beta-blocker overdose
Features
 1. Bradycardia
2. Hypotension
3. Heart failure
4. Syncope

Management
1. Bradycardic  atropine
2. Resistant cases  Glucagon (+ Ve inotropic action on the heart and ↓↓ renal vascular resistance.
3. Cardiac pacing  reserved for patients unresponsive to pharmacological therapy
4. Haemodialysis is not effective in beta-blocker overdose

Amiodarone
Class III antiarrhythmic  block K channels ↓ repolarisation  prolongs the action potential. other actions blocking Na channels ( class I effect)
 (Atrial, nodal and ventricular tachycardias)
 Very long half-life (20-100 days). → loading doses are frequently used
 Given into central veins (causes thrombophlebitis)
 Proarrhythmic  ↑↑QT interval Coexistent hypokalaemia significantly increases this risk.
 interacts with (p450 inhibitors)  Decreases metabolism of warfarin
 TFT, LFT, U&E(K check), CXR prior to treatment  TFT, LFT every 6 months

Adverse effects of amiodarone use

1. Thyroid dysfunction both hypothyroidism and hyper-thyroidism
2. Corneal deposits
3. Pulmonary fibrosis/pneumonitis
4. liver fibrosis/hepatitis
5. peripheral neuropathy, myopathy
6. photosensitivity
7. 'Slate-Grey' appearance
8. Thrombophlebitis and injection site reactions
9. Bradycardia
 10. ↑↑ QT interval

Amiodarone and the thyroid gland

1 in 6 patients taking amiodarone  thyroid dysfunction

1. Amiodarone-induced hypothyroidism
 Due to ↑↑ iodine content of amiodarone  "Wolff-Chaikoff Effect" (↑↑Iodine  ↓↓Thyroxin)
 Tyroxine replacement + Amiodarone may be continued if this is desirable  VT

2. Amiodarone-induced Thyrotoxicosis
AIT type 1 AIT type 2
Pathophysiology ↑↑↑ iodine-induced thyroid hormone synthesis Amiodarone-related destructive Thyroiditis
Goitre Present Absent
Management Carbimazole or K+ Perchlorate Corticosteroids
Unlike in AIH, amiodarone should be stopped if possible in patients who develop AIT

Calcium channel blockers

Management of CVS disease.  Voltage-gated calcium channels are present in (Myocytes, cells of the conduction system and vascular smooth muscle cells).

Examples Indications & notes Side-effects and cautions

Verapamil Angina, hypertension, arrhythmias Heart failure
Highly negatively inotropic hypotension,
Should not be given with beta-blockers as may Bradycardic,
cause heart block dyspepsia (relax lower oesophageal sphincter)
flushing constipation
Diltiazem Angina, hypertension Hypotension,
Less negatively inotropic but bradycardia,
 Examples Indications & notes Side-effects and cautions
caution W C heart failure or are taking beta-blockers heart failure,
ankle swelling
Nifedipine, amlodipine, Hypertension, angina, Raynaud's Flushing,
felodipine Affects the peripheral vascular smooth muscle > headache,
(dihydropyridines) myocardium (Not worsening of heart failure) ankle swelling
Atropine
antagonist of the muscarinic acetylcholine receptor.
treatment of organophosphate poisoning
tachycardia, mydriasis

Adenosine
Terminate SVT. ↑ by Bupivicaine and dipyridamole (antiplatelet agent) and ↓by theophyllines.
Mechanism of action
causes transient heart block in the AVN, agonist of A1 receptor in the AVN, which ↓ adenylyl cyclase ↓ cAMP  hyperpolarization by ↑ outward K flux.
short half-life (8-10 sec)  infused via a large cannula

Adverse effects
chest pain, bronchospasm avoided in asthmatics , transient flushing, enhance conduction down accessory pathways (e.g. WPW syndrome)

Phosphodiesterase type V inhibitors

 PDE5 inhibitors cause V.D through an increase in cGMP  smooth muscle relaxation in blood vessels supplying the corpus cavernosum
 Used in the treatment of erectile dysfunction & pulmonary hypertension. Examples
1. Sildenafil (Viagra) - this was the first phosphodiesterase type V inhibitor
2. Tadalafil (Cialis)
3. Vardenafil (Levitra)
 Contraindications
1. patients taking nitrates and related drugs such as nicorandil
2. Doxazosin  avoiding alpha-blockers for 4 hours after sildenafil
3. Hypotension
4. Recent stroke or MI (waiting 6 months)

Side-effects
 visual disturbances (blue discolouration, non-arteritic anterior ischaemic neuropathy
 Nasal congestion
 Flushing
 GIT S/E
 Headache
Nicorandil
a vasodilatory drug used to treat angina.
It is a potassium-channel activator with vasodilatation is through activation of guanylyl cyclase  ↑↑ cGMP.

Adverse effects
 headache
 flushing
 anal ulceration

Contraindications
 left ventricular failure

Blood Thinners

Adenosine diphosphate (ADP) receptor inhibitors

 Clopidogrel
 Prasugrel
 Ticagrelor
 Ticlopidine

Mechanism
(ADP) is platelet activation factors, +++ by G-coupled receptors P2Y1 and P2Y12 sustained platelet aggregation and stabilization of the plaque. ADP receptor.

inhibitors drugs blocks P2Y12 receptor.

 ACS undergoing PCI Aspirin (75-100mg daily) + prasugrel (10mg daily), ticagrelor (90mg twice daily), or clopidogrel (75mg daily, if prasugrel or
ticagrelor are not suitable) for 12 months, with aspirin alone thereafter
S/E
ticagrelor may cause dyspnoea due to the ↓ clearance of adenosine

Interactions and contraindications

 Clopidogrel and proton pump inhibitors, particularly omeprazole and esomeprazole
 Prasugrel absolute contraindications prior stroke or TIA, high risk of bleeding, and hypersensitivity
 Ticagrelor contraindicated in a high risk of bleeding, history of intracranial haemorrhage, and hepatic dysfunction. caution in those with acute asthma or COPD,
higher rates of dyspnoea. if his clinical condition allows you are able to wait 3–4 days to observe the patient and understand whether the dyspnoea is transient or
more longer lasting

Mechanism block effects of angiotensin II at the AT1 receptor

 ↓ progression of renal disease in patients with diabetic nephropathy
 losartan ↓↓ CVA and IHD mortality in hypertensive patients
Diagnosis 1st line 2nd line
ACS(medically) ASA (lifelong) & ticagrelor (1Y) If aspirin CI→ clopidogrel (lifelong)
 PCI ASA (lifelong) & prasurgrel or ticagrelor (1 y) If aspirin CI →clopidogrel (lifelong)
Aspirin TIA ASA (lifelong) Aspirin (lifelong) & dipyridamole (lifelong)
 Irreversable block
cyclooxygenase-1 and 2 Ischemic stroke Clopidogrel (lifelong) Aspirin (lifelong) & dipyridamole (lifelong)
(responsible for prostaglandin,
prostacyclin and thromboxane PAD Clopidogrel (lifelong) Asprin (lifelong)
synthesis).
 (- -) Thromboxane A2 (V.C &
platlet adhesion) in platelets  ↓↓ ability of platelets to aggregate
 Recently aspirin is not licensed for routine primary prevention.
 first-line for patients with IHD  DD.( clopidogrel first-line  ischaemic stroke and PAD)
 Dental practice  not to stop Aspirin
 Potentiates
1. Oral hypoglycaemics
2. warfarin
3. steroids

CI  children < 16 (risk of Reye's syndrome). An exception is Kawasaki disease (benefits outweigh the risks.
Selective COX 2 inhibitors (NSAID) directly targets Cyclooxygenase-2 ↓↓ inflammatio and pain, (No GIT ulcer, ↑↑Platelet aggregation↑↑ CVS risk)

Salicylate overdose
 A key concept salicylate overdose  mixed respiratory alkalosis and metabolic acidosis.
 Early (++) "Respiratory Centre"  respiratory alkalosis
 Later (Direct acid effects salicylates + acute renal failure)  acidosis.
 In children  metabolic acidosis tends to predominate.
  Features
1. Hyperventilation (centrally stimulates respiration)
2. Tinnitus
3. Lethargy, Sweating
4. Pyrexia
 Salicylate causes uncoupling of oxidative phosphorylation  ↓↓ ATP production, ↑↑(O2 consumption and CO2) and heat production

5. nausea/vomiting
6. Dysregulation of glucose  hyperglycaemia and hypoglycaemia
7. seizures
8. coma

Treatment
1. General
 ABC
 Charcoal  first-line in patients who have ingested the drug within one hour
2. Urinary alkalinization (IV sodium bicarbonate - enhances elimination of aspirin in the urine
3. Haemodialysis "Indications'
 Serum concentration > 700mg/L
 Metabolic acidosis resistant to treatment
 Acute renal failure
 Pulmonary oedema
 Seizures
 Coma
Quinine toxicity (cinchonism)
known "Cinchonism"  Toxic drug (not so readily acknowledged). antimalarial and prophylactic against leg cramps. Features
Short term fatal
1. CVS
Cardiac arrhythmia
  Common finding  blockade of Na channel↑↑ QRS and k channel  QT intervals  VT or VF causing death.
Flash pulmonary oedema  hypoxia and necessitating positive pressure ventilation.

2. Hypoglycaemia "Common Finding"  (++) Pancreatic insulin secretion and this should be corrected rapidly if present.

3. CNS
Tinnitus, Visual blurring
 DD. difficult to distinguish from aspirin poisoning  measurement of serum salicylate levels.
Permanent neural damage, if the patient survives.

4. Flushed and dry skin and Abdominal pain.

5. Metabolic Acidosis

Long-term fatal.
1. Incipient renal failure

Management
2. largely supportive with fluids, inotropes and bicarbonate as needed
3. Positive pressure ventilation for pulmonary oedema.

Heparin
 heparin Generally +++ Antithrombin III, 2 main types :
1. Unfractionated heparin forms a complex (--) Thrombin, factors Xa, IXa, XIa and XIIa.
2. LMWH  only ↑↑↑ action of antithrombin III on factor Xa

 Adverse effects
1. Bleeding
2. Thrombocytopenia - see below
3. Osteoporosis and an increased risk of fractures
 4. ↑↑ K+  caused by (- -) aldosterone secretion

Standard heparin Low molecular weight heparin (LMWH)

Administration IV S.C
Duration Short Long
Side-effects 1. Bleeding 1. Bleeding
2. Heparin-induced thrombocytopaenia (HIT) 2. Lower risk of HIT and osteoporosis with LMWH
3. Osteoporosis
Monitoring (APTT) Anti-Factor Xa (routine monitoring is not required)
Notes  Useful in  ↑↑ risk of bleeding (terminated rapidly  standard management of VTE treatment
 Also useful in renal failure  prophylaxis ACS

Heparin-induced thrombocytopaenia (HIT)

1. After 5-10 days of treatment
2. Immune mediated - antibodies against complexes of platelet factor 4 (PF4) and heparin (++) platelet activation by cross-linking FcγIIA receptors
3. Prothrombotic condition  Thrombosis and skin allergy
4. > 50% ↓↓ platelets
5. Treatment  alternative anticoagulants Lepirudin and Danaparoid

Dipyridamole
 antiplatelet mainly used in combination with aspirin after an ischaemic stroke or TIA.
 Non-↓↓ phosphodiesterase, (normally break down cAMP), but particularly active against PDE5 (like sildenafil) and PDE6  ↑↑ platelet cAMP ↓↓intracellular Ca+
levels
 ↓↓ cellular uptake of adenosine  ↑↑ adenosine effect (Exogenous use of adenosine (ttt SVT) CI in patients on dipyridamole for this reason.
 inhibition of thromboxane synthase

Anti- Lipid
 Drugs Mechanism of action Adverse effects
Statins HMG Co-A reductase (- -) Myositis, ↑↑ LFTs
+
Nicotinic Acid (H ) ↓↓ Hepatic VLDL Secretion Flushing, Myositis
FibRates Agonist of PPAR-alpha  ++ lipoprotein lipase expression Myositis, Pruritus, Cholestasis
Cholectyramine ↓↓ bile acid reabsorption in small intestine GI side-effects
Up regulating the amount of cholesterol that is converted to bile acid
Ezetimibe ↓↓Cholesterol absorption in the small intestine Headache
Nicotinic acid (niacin)
 Treatment of patients with hyperlipidaemia  limited by side-effects.
 ↑↑ HDL levels.
 ↓↓ Cholesterol and triglyceride concentrations

Adverse effects
1. Flushing: mediated by prostaglandins
2. Myositis  Not to be used W Statin
3. ↓↓ glucose tolerance

Allopurinol
Prevention of gout  (- -) Xanthine Oxidase.
1. should not be started until 2 weeks after an acute attack has settled (Symptoms settle)
2. initial dose  100 mg od,  every few weeks to aim for a serum uric acid of < 300 µmol/l
3. NSAID or colchicine cover should be used when starting allopurinol

Indications for allopurinol

1. Recurrent attacks  started if a second attack, or further attacks occur within 1 year'
2. Tophi
3. Renal disease
4. uric acid Renal stones
 5. Prophylaxis
Cytotoxics  prevent tumer lysis syndrome (lymphoma)
Diuretics
6. Patients with Lesch-Nyhan syndrome often take allopurinol for life

Adverse effects
most significant are dermatological stop allopurinol immediately if they develop a rash:
1. Severe cutaneous adverse reaction (SCAR)
2. Drug reaction with eosinophilia and systemic symptoms (DRESS)
Patients at a high risk of severe cutaneous adverse reaction should be screened for the HLA-B 5801 allele.
 Diuretic use
 Ethnicity (Thai Chinese, Korean descent)
 Chronic kidney disease.
3. Stevens-Johnson syndrome

Interactions
1. Azathioprine
 metabolised to active compound 6-mercaptopurine
 Xanthine oxidase  responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid
 Allopurinol  ↑↑6-mercaptopurine
 Much ↓↓ dose (25%) must  if the combination cannot be avoided
2. Cyclophosphamide
 Allopurinol ↓↓ renal clearance  may cause marrow toxicity
3. Theophylline
 allopurinol causes ↑↑plasma concentration of theophylline by inhibiting its breakdown
Botulinum toxin
licensed indications:
1. Cosmetic
2. Blepharospasm
 3. Hemifacial spasm (UMNL Not Bells palsy )
4. Focal spasticity  cerebral palsy patients, hand and wrist disability associated with stroke
5. Spasmodic torticollis
6. Severe hyperhidrosis of the axillae
7. Achalasia  patient is not suitable for surgical intervention (for example in some elderly patients)

Caustic substance ingestion

The majority of cases are accidental exposures to household products: these are usually of little clinical consequence. Conversely, significant
morbidity can occur when the substance is consumed in larger quantities with the intention of deliberate self-harm.
Types of substance (vital to obtain bottle/label if possible)
Strong alkali Strong acid Oxidising agents
+ + +
 Na Hydroxide, K Hydroxide  Hydrochloric Acid, Nitric Acid  Hydrogen peroxide, Na hypochlorite
 (Dishwasher cleaner, industrial cleaners)  car batteries, WC cleaner  Household bleach
 Liquefactive necrosis (↑↑oesophageal injury)  Coagulative necrosis (↑↑ gastric injury)

Acute management
(general principles, local guidance on timing of endoscopy and PPI may vary)
 ABCDE approach (caution to airway swelling and compromise, look for peri-oral oedema)
 Urgent upper GI surgical referral
 if signs of perforation present (surgical emphysema, mediastinal widening on chest x-ray)
 deally within 12 hours (sometimes 24 hours dependent on local guidance).
 IF wait until after the initial insult recovered  avoid endoscopy between days 5 and 15 post ingestion (oesophageal strength is at its lowest)
 Symptomatic ingestion (drooling, vomiting, dysphagia, odynophagia, chest pain)  urgent assessment with upper GI endoscopy to assess the
degree of ulceration (Zargar classification).
 Extensive injury on endoscopy  prompt consideration of urgent surgical exploration.

 ↑↑ dose IV PPI
 Avoid nasogastric tube  potential re-exposure of the upper GI tract to the substance.
 Avoid neutralisation of ingested substance (with milk)  exothermic reaction will release heat and may cause further injury
  Oral fluid and observation then discharge  in asymptomatic patients (No odynophagia)

Complications
1. Acute
 Upper GI ulceration, perforation
 Upper airway injury and compromise
 Aspiration pneumonitis
 Infection
 Electrolyte disturbance (hypocalcaemia in hydrofluoric acid ingestion)
2. Chronic
 Strictures, fistulae, gastric outlet obstruction
 Upper GI carcinoma (1000-3000 fold)

combined oral contraceptive pill

Advantages Disadvantages
1.highly effective (failure rate < 1 per 100 woman years) 1. forget to take it
2.doesn't interfere with sex 2. No protection against STI
3.contraceptive effects reversible upon stopping 3. ↑↑↑ VTE
4.Periods  regular, lighter and less painful 4. ↑↑↑ Breast and cervical cancer
5.↓↓ovarian cysts, benign breast disease, acne vulgaris 5. ↑↑↑stroke and IHD (especially in smokers)
6.↓↓ risk (Ovarian, Endometrial Cancer (last for decades after cessation 6. Temporary (Headache, Nausea, Breast tenderness)
7.↓↓colorectal cancer 7. Weight gain (Controversial)
8.Protect against PID

Contraindications according to a four point scale, as detailed below:

1. UKMEC 1  No restriction for the use of the contraceptive method
2. UKMEC 2  advantages > disadvantages
3. UKMEC 3 disadvantages > advantages
4. UKMEC 4  unacceptable health risk
 UKMEC 3 conditions UKMEC 4 conditions
1. > 35 years + smoking (< 15 /day) 1. > 35 years + smoking (>15 /day)
2. BMI > 35 kg/m^2* 2. migraine with aura
3. "1st degree relatives < 45 years" + thromboembolic disease 3. history of thromboembolic disease OR thrombogenic mutation
4. Controlled HTN 4. History of stroke OR IHD
5. Carrier gene mutations associated with breast cancer 5. uncontrolled hypertension
(BRCA1/BRCA2) 6. Current breast cancer
6. current gallbladder disease 7. Breast feeding < 6 weeks post-partum
7. Immobility (wheel chair use) 8. Cervical cancer is not a contraindication to use.
(COCP small increase in cervical cancer risk after 5 years & ↑↑2-
fold risk after 10 years.
9. Major surgery with prolonged immobilisation

 Diabetes mellitus diagnosed > 20 years ago is classified as UKMEC 3 or 4 depending on severity
 breast feeding 6 weeks - 6 months postpartum was changed from UKMEC 3 → 2
 Weight Gain is not ↑↑ supported
Concurrent antibiotic use
1. Antibiotics may interfere
 Affect enterohepatic circulation of oestrogen make pills ineffective
 antibiotics might ↓↓absorption of the pill
 'extra- precautions'/ barrier methods  for the duration of antibiotic treatment and for 7 days afterwards
2. precautions should still be taken with enzyme inducing antibiotics (Rifampicin and Rifaximin)

Switching combined oral contraceptive pills

 Contradictory advice.
 pill free interval does not need to be omitted
 missing the pill free interval if the progesterone changes. (more recommended)
Progestogen only pill: advantages/disadvantages
Advantages Disadvantages
1. ↑↑↑ effective 1. Irregular periods
(failure rate = 1 per 100 woman years) May not have periods, Irregular OR Light periods.(Most common)
2. doesn't interfere with sex This is the most common S/E
3. Reversible upon stopping 2. Doesn't protect against STI
4. can be used whilst breast-feeding 3. ↑↑ Incidence of functional ovarian cysts.
5. Used when COCP pill is CI 4. Common S/E
Smokers > 35 Ys  Breast tenderness
History of VTE  weight gain
 Acne
 Headaches
These symptoms generally subside after the first few months

Tamoxifen
 Selective oEstrogen Receptor Modulator (SERM)  oestrogen receptor antagonist and partial agonist.
 It is used in the management of oestrogen receptor positive breast cancer. Adverse effects
1. Menstrual disturbance  vaginal bleeding, amenorrhoea
2. Hot flushes - 3% of patients stop taking tamoxifen due to climacteric side-effects
3. VTE
4. Endometrial cancer
5. Osteoporosis

 Tamoxifen  is typically used for 5 years following removal of the tumour.

 Raloxifene  is a pure oestrogen receptor antagonist, and carries a lower risk of endometrial cancer

Teratogens
Craniofacial
1. ACEI
2. Carbamazepine
3. Valproate
4. Warfarine

Drug/condition Effect
ACE inhibitors  Renal dysgenesis
 Craniofacial abnormalities
1. Carbamazepine  Neural tube defects
2. Valproate  Craniofacial abnormalities
Warfarin  Craniofacial abnormalities
1. Cocaine  IUGR
2. Smoking  Preterm labour
Aminoglycosides Ototoxicity
Chloramphenicol 'Grey baby' syndrome
Tetracyclines Discoloured teeth
Diethylstilbesterol Vaginal clear cell adenocarcinoma

Lithium Ebstein's anomaly (atrialized right ventricle)

Thalidomide Limb reduction defects
Maternal diabetes mellitus 1. Macrosomia
2. Neural tube defects
3. Caudal regression syndrome
4. Polyhydramnios
5. Preterm labour
Digoxin
Cardiac glycoside  rate control (AF) + positive inotropic properties improving symptoms (but not mortality) in patients with heart failure.
 ↓↓ conduction AV node slows the ventricular rate in atrial fibrillation and flutter
 ↑↑ cardiac muscle contraction  (- -) Na+/K+ATPase pump on the same site as potassium  Hypokalaemia  ↑↑ inhibitory effects
 Cause short QT interval
 Also (++) vagus nerve
 digoxin has a narrow therapeutic index
Monitoring & Toxicity
1. digoxin level is not monitored routinely, except in suspected toxicity (within 8 to 12 hours of the last dose)
2. Plasma concentration alone does not determine digoxin toxicity (Might occur within the therapeutic range).
3. likelihood of toxicity (↑↑ progressively from 1.5 to 3 mcg/l.)

Features
1. generally unwell, lethargy, nausea & vomiting, anorexia, confusion, yellow-green vision
2. Arrhythmias (AV block, bradycardia)
3. Gynaecomastia

Precipitating factors
1. Classically: Hypokalaemia
 Hypokalaemia → digoxin more easily bind to the ATPase pump → increased inhibitory effects
2. ↑↑ age
3. Renal failure
4. Myocardial ischaemia
5. ↑↑ (Ca, Na, H) Hypercalcaemia, Hypernatraemia, Acidosis
++
6. ↓↓Mg
7. ↓↓ Abumin
8. ↓ ↓Temperature
9. ↓↓ Thyroid
10. Drugs
  Anti-arrhythmic  Amiodarone, Quinidine, Verapamil, Diltiazem
 Spironolactone (competes for secretion in distal convoluted tubule therefore reduce excretion)
 Thiazides and Loop diuretics (Hypokalaemia)
 Ciclosporin.
Management
1. Digibind
2. correct arrhythmias
3. monitor potassium
Dieuritics
ACE inhibitors
first-line treatment in younger patients with hypertension, heart failure, less effective Afro-Caribbean patients, diabetic nephropathy and have a role in the
secondary prevention of ischaemic heart disease.
Mechanism of action:
 inhibit the conversion angiotensin I to angiotensin II
 ACE inhibitors are activated by phase 1 metabolism in the liver
Side-effects:
 Cough around 15% up to a year after starting treatment increased bradykinin levels
 angioedema: may occur up to a year after starting treatment
 hyperkalaemia
 first-dose hypotension: more common in patients taking diuretics (Giddy = Syncope)
Cautions and contraindications
 pregnancy and breastfeeding - avoid
 renovascular - significant renal impairment undiagnosed bilateral renal artery stenosis
 AS - may result in hypotension
 hereditary of idiopathic angioedema
 specialist advice ACE inhibitors in patients with K >= 5.0 mmol/L
Interactions
 Hypotension  high-dose diuretic therapy > 80 mg of furosemide a day)
Monitoring
  U/E initially and after increasing the dose
 a rise in the creatinine and K may be after starting, acceptable ↑ in creatinine, up to 30%, ↓ GFR of up to 25% from baseline and an ↑ in K up to 5.5
mmol/l*.
st
 K> 6mmol/L should prompt cessation of ACE I in a patient with CKD (1 step)

Angiotensin II receptor blockers

situations where patients have not tolerated an ACEI, due to cough. candesartan, losartan, irbesartan
S/E hypotension and hyperkalaemia.
used with caution in patients with renovascular disease.

Hypomagnesaemia
Cause of low magnesium
1. Alcohol
2. Drugs
 Diuretics  Loop or Thiazide
 Proton pump inhibitors"Omeprazole" when with Loop or Thiazide diuretics but are Not independently associated with hypomagnesaemia.
3. Diarrhoea
4. Conditions causing diarrhea  Crohn's, ulcerative colitis
5. Total Parenteral nutrition  Refeeding Syndrome.
+ ++
6. ↓↓ (K , Ca )  Causes resistance for correction
7. Metabolic disorders  Gitleman's and Bartter's

Features
1. may be similar to hypocalcaemia Paraesthesia, Tetany,Seizures, Arrhythmias
2. ↓↓ PTH secretion → hypocalcaemia
3. ECG similar to those of Hypokalaemia (QT prolongation.)
4. ↑↑ Digoxin Toxicity

Treatment
 1. < 0.4 mmol/l
IV 40 mmol of Mg++ sulphate over 24 hours

2. > 0.4 mmol/l

++
 oral Mg Salts (10-20 mmol orally per day)
 Diarrhoea can occur with oral magnesium salts  Magnesium salts can be given as "Laxatives".
 Other uses  (Torsade de Pointes), acute asthma and prevention/treatment of seizures in pre-eclampsia.
Lithium toxicity
Lithium is a mood stabilising  most commonly prophylactically in bipolar disorder but also as an adjunct in refractory depression.
It has a very narrow therapeutic range (0.4-1.0 mmol/L) and a long half-life  excreted primarily by the kidneys.
Lithium Toxicity generally occurs following concentrations > 1.5 mmol/L  Precipitated by:
1. Renal failure
2. Dehydration
3. Drugs:
 Diuretics  (Especially Thiazides" loop diuretics are safer)
 ACE inhibitors/ARBS
(Both should not be commenced in hypertensive patient on Lithium)
 NSAIDs
 Metronidazole.
Features of toxicity
1. Coarse tremor (a fine tremor is seen in therapeutic levels)
2. Coma
3. Acute confusion
4. Hyperreflexia
5. Seizure
Management
1. Mild-moderate toxicity (Apathy and Restlessness)  volume resuscitation with normal saline
2. Haemodialysis  Severe toxicity
 Level > 2 mmol/L
  Neurological symptoms (Seizures, Confusion)
 Renal failure.

3. Na+ bicarbonate is sometimes used  ↑↑ alkalinity of the urine (++) lithium excretion

Tricyclic overdose
Amitryptiline and Dosulepin (dothiepin) are particularly dangerous in overdose. Features
1. Early features relate to anticholinergic properties
 Dry mouth
 Dilated pupils
 Blurred vision.
 Agitation
 Sinus tachycardia

2. Features of severe poisoning include:

 Arrhythmias
 Seizures
 Metabolic acidosis
 Coma

3. ECG changes include:

 widening of QRS
 Widening of QRS > 100ms ↑↑risk of seizures
 QRS > 160ms is  ventricular arrhythmias.

 sinus tachycardia
 prolongation of QT interval
Management
1. 50 gm of charcoal if within one hour of ingestion.
 2. IV bicarbonate
 1st-line therapy (50 ml of 8.4%) if

 pH < 7.1
 QRS > 100 ms
 Arrhythmias
 Hypotension

3. Other drugs for arrhythmias

 class 1a (Quinidine) and class Ic (Flecainide) are CI  ↑↑ depolarisation
 class III drugs (Amiodarone)  avoided (↑↑QT interval)
 Response to lignocaine is variable.

4. IV lipid emulsion  increasingly used to bind free drug and reduce toxicity (Also Verapamil, BB)
5. Dialysis is ineffective in removing tricyclics

Oculogyric crisis
A dystonic reaction form of extrapyramidal disorder to certain drugs or medical conditions. Features
1. Restlessness, Agitation
2. involuntary upward deviation of the eyes
Causes
 Antipsychotics
 Dopaminergic medications (classically Metoclopramide and Haloperidol)
 Post encephalitic Parkinson's disease

Management
 IV Anti-Muscarinic
1. Benztropine
2. Procyclidine
 3. diphenhydramine

Cocaine
 Alkaloid derived from the coca plant (recreational stimulant)  (XX) the uptake (Dopamine, Noradrenaline and Serotonin)
 Cardiovascular effects
1. Myocardial infarction
2. hypertension
3. Aortic dissection
4. both tachycardia and bradycardia may occur
5. QRS widening and QT prolongation.

Neurological effects
1. seizures
2. Mydriasis
3. Hypertonia, hyperreflexia

Psychiatric effects
1. agitation
2. psychosis
3. hallucinations
Others
1. ischaemic colitis following cocaine ingestion. (abdominal pain or rectal bleeding)
2. Hyperthermia
3. Metabolic acidosis
4. Rhabdomyolysis

Management of cocaine toxicity

 Benzodiazepines  generally first-line for most cocaine-related problems
  Chest pain  (Benzodiazepines + Glyceryl trinitrate). (MI  1ry PCI)
 Hypertension  (benzodiazepines + sodium nitroprusside)
 Beta-blockers in cocaine-induced CVS "controversial"  risk of unopposed alpha coronary spasm) If a reasonable alternative in an exam choose it

Ecstasy poisoning
(MDMA, 3,4-Methylenedioxymethamphetamine) Clinical features
1. CNS  agitation, anxiety, confusion, ataxia
2. CVS  tachycardia, hypertension
3. ↓↓↓ Na
4. ↑↑ Temperature
5. Rhabdomyolysis

Management
 supportive
 Dantrolene may be used for hyperthermia if simple measures fail

Novel psychoactive substances

Medical term  Recreational drugs (MDMA and Cannabis). Termed as 'Legal Highs'/ "M-CAT"

Stimulants Cannabinoids Hallucinogenic Depressant Other substances

 Similar to MDMA, Amphetamines "Synthetic Cannabinoid  Dissociatives and  Opioid OR 1. Gamma-hydroxybutyric acid (GHB)
 ↑↑Serotonin, Dopamine Noradrenaline, receptor agonists" Psychedelics Benzodiazepine-based and gamma-butyrolactone (GBL)
'high' and euphoria  Referred to as 'spice' 1. Pill or a powder 'G', 'Geebs' or 'Liquid Ecstasy'
 Sprayed on to 1. Dissociatives similar to 2. Similar to the original drug Respiratory ↓↓
 Common Ex herbal mixtures ketamine (sense of not & S/E are similar  When taken with other respiratory ↓↓(
1. "Mephedrone"  smoked. being connected to the 3. benzodiazepine NPS  alcohol)
 ('bath salts','M-CAT'.'meow meow').  liquid ( inhaled physical body or time. ↑↑ longer half-life  can be potentially life threatening
 Cathinone similar to khat, a plant in using e-cigarettes  Ex: Methoxetamine
East Africa ('mexxy') 2. Nitrous oxide: 'Hippie crack'
 2. Benzylpiperazine  S/E like cannabis
 ('Exodus', 'Legal X', 'Legal E') 2. Psychedelics  Similar
effect to LSD although
 Swallowed as a pill/powder ('bombing') may also be a stimulant
or snorted

 S/E
 similar to MDMA/cocaine.
 risk of serotonin syndrome

immunosuppressant drugs
1. Mycophenolate mofetil
 (- -) Inosine Monophosphate Dehydrogenase (needed for purine synthesis)
 as T and B cells are particularly dependent on this pathway it can reduce proliferation of immune cells
 Used in organ transplantation and autoimmune conditions.

2. Azathioprine
is metabolised to the active compound mercaptopurine, a purine analogue that inhibits (Purine) DNA synthesis. Methotrexate is an
antimetabolite which inhibits dihydrofolate reductase
Cyclosporine + tacrolimus: inhibit calcineurin thus decreasing IL-2

3. Cyclosporine
 ↓↓Calcinurin (Phosphatase ++ T-cell) by binding to Cyclophilin forming a complex & ↓↓ IL-2 release  ↓↓ proliferation of T cells.(Like Tacrolimus)
 'virtually non-myelotoxic'.
 S/E (↑↑↑ fluid, BP, K+, hair, gums, glucose)
1. Nephrotoxicity Fluconazole (- -) metabolism of ciclosporin (↑↑Ciclosporin Nephrotoxicity).
2. Hepatotoxicity
 3. fluid retention HTN
4. hyperlipidaemia
5. ↑↑↑K
6. Hypertrichosis ( ↑↑Hair)
7. gingival hyperplasia
8. Tremor
9. impaired glucose tolerance
10. ↑↑ susceptibility to severe infection
Indications
1. Organ transplantation
2. Rheumatoid arthritis
3. Psoriasis (has a direct effect on keratinocytes as well as modulating T cell function)
4. Ulcerative colitis
5. Pure red cell aplasia
4. Tacrolimus
Tacrolimus is a macrolide used as an immunosuppressant to prevent transplant rejection. It has a very similar action to ciclosporin:
 ↓↓proliferation of T cells by reducing IL-2 release
 binds to FKBP protein forming a complex  (- -) calcineurin (a phosphotase (++) various transcription factors in T cells)
 More potent than ciclosporin  incidence of organ rejection is less.
 Nephrotoxicity and impaired glucose tolerance is more common

4. Methotrexate
Antimetabolite that inhibits Dihydrofolate reductase (Enzyme essential for the synthesis of purines and pyrimidines)  preventing the reduction of
dihydrofolic acid to tetrahydrofolic acid.
It is considered an 'important' drug as whilst it can be very effective  careful prescribing and close monitoring is essential. Indications
1. inflammatory arthritis, especially rheumatoid arthritis
 2. psoriasis
3. some chemotherapy acute lymphoblastic leukaemia
Adverse effects
1. Mucositis
2. Myelosuppression
3. Pneumonitis
4. Pulmonary fibrosis
5. Liver fibrosis
Pregnancy
 Avoided for at least 6 months after treatment has stopped
 Men using methotrexate need to use effective contraception for at least 6 months after treatment
Prescribing methotrexate
 High potential for patient harm  taken weekly, rather than daily
 FBC, U&E and LFTs need to be regularly monitored  before starting treatment and repeated weekly until therapy stabilized  monitored
 folic acid 5mg once weekly  taken > 24 hours after methotrexate dose
 Starting dose  7.5 mg weekly
 only one strength prescribed (usually 2.5 mg)

Interactions
 avoid prescribing trimethoprim OR Co-trimoxazole concurrently - ↑↑↑ risk of marrow Aplasia
 ↑↑ - dose Aspirin  ↑↑ risk of methotrexate toxicity secondary to reduced excretion

Methotrexate toxicity
Treatment of choice is folinic acid
Hydroxychloroquine
is used in the management of rheumatoid arthritis and systemic/discoid lupus erythematosus. It is pharmacologically very similar to chloroquine which is
used to treat certain types of malaria.

Adverse effects
 bull's eye retinopathy - may result in severe and permanent visual loss
o recent data suggest that retinopathy caused by hydroxychloroquine is more common than previously thought and the most recent RCOphth guidelines
(March 2018) suggest colour retinal photography and spectral domain optical coherence tomography scanning of the macula
o baseline ophthalmological examination and annual screening is generally recommened

A contrast to many drugs used in rheumatology, hydroxychloroquine may be used if needed in pregnant women.

Monitoring

 the BNF advises: 'Ask patient about visual symptoms and monitor visual acuity annually using the standard reading chart'

Azathioprine
is metabolised to the active compound mercaptopurine, a purine analogue that inhibits purine synthesis. A thiopurine methyltransferase (TPMT) test may
be needed to look for individuals prone to azathioprine toxicity.

Adverse effects include

 bone marrow depression

 nausea/vomiting
 pancreatitis
 increased risk of non-melanoma skin cancer
 A significant interaction may occur with allopurinol and hence lower doses of azathioprine should be used.

Azathioprine is generally considered safe to use in pregnancy.

Tumour necrosis factor (TNF)

pro-inflammatory cytokine with multiple roles in the immune system
TNF is secreted mainly by macrophages and has a number of effects on the immune system, acting mainly in a paracrine fashion:
1. activates macrophages and neutrophils
2. acts as costimulator for T cell activation
3. key mediator of bodies response to Gram negative septicaemia
4. similar properties to IL-1
5. anti-tumour effect (e.g. phospholipase activation)

TNF-alpha binds to both the p55 and p75 receptor. These receptors can induce apoptosis.
It also cause activation of NFkB
Endothelial effects include increase expression of selectins and increased production of platelet activating factor, IL-1 and prostaglandins
TNF promotes the proliferation of fibroblasts and their production of protease and collagenase. It is thought fragments of receptors act as binding
points in serum

Systemic effects include pyrexia, increased acute phase proteins and disordered metabolism leading to cachexia

TNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe
rheumatoid

TNF blockers
1. infliximab: monoclonal antibody, IV administration
 2. etanercept: fusion protein that mimics the inhibitory effects of naturally occurring soluble TNF receptors, subcutaneous administration
3. adalimumab: monoclonal antibody, subcutaneous administration
4. adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelination

Monoclonal antibodies
Manufactured by "Somatic cell hybridization Technique"  fusion of myeloma cells with spleen cells from a mouse "immunized with the desired antigen".
The fused cells are termed a "Hybridoma"  act as a 'factory' for producing monoclonal Abs.
The main limitation  mouse antibodies are immunogenic  formation of human anti-mouse antibodies (HAMAs)
This is overcomed by combining the Variable region from the mouse body + Constant region from human antibody.

Uses
1. Medical imaging when combined with a radioisotope
2. Identification of cell surface markers in biopsied tissue
3. Diagnosis of viral infections

Example Mechanism of action Uses

(anti-TNF) Infliximab 1. Rheumatoid arthritis
2. Crohn's
TNF alpha antagonist Etanercept T.B and viral hepatitis should be ruled out prior to starting therapy Psoriasis
anti-IL17 Brodalumab completed registration for psoriasis reserved however for patients who fail to
control on other interventions
Anti- IL6 Toclizumab Rheumatoid arthritis
OKT3 (anti-CD3) Muromonab-CD3 1. prevent organ rejection

(anti-CD20)Twenty Rituximab 1. Non-Hodgkin's lymphoma

2. Rheumatoid arthritis
 (anti-CD52) Alemtuzumab Chronic lymphocytic
Leukaemia
"Programmed Cell Death"  PD-1 receptors (on the surface of T cells) cancer cell express the PD-L1 protein
inhibitor (PD-1) Nivolumab antibodies  block this receptor & disable T cells.
 The PD-1 inhibitors  block this receptor, leaving T- cells to remain active and
alert other immune cells (Macrophages to the cancer)
. Cytotoxic T-lymphocyte Ipilimumab  down-regulates T cell responses by cancer
associated protein4 (CTLA-4)  Blocking this with inhibitors  (++) immune system against cancer.

Nivolumab + Ipilimumab  Undergoing trials  Solid malignancies lung,oesophageal& head and neck 3. Stage 4 Metastatic Melanoma
 Prolonged therapy Hypophysitis and Hypothyroidism (Conistipation,.. 4. Lymphoma.

 "Epidermal growth factor 1. Cetuximab Oncogenic (++) Tyrosine kinases autophosphorylates the receptor Cancer cell 1. Metastatic colorectal cancer.
receptor antagonist"(EGFR) 2. Erlotinib growth. 2. SQ. cell cancers.
 (HER1) "Human epidermal (Tarceva) 3. head and neck cancer
growth factor" antagonist
(HER2/neu receptor Trastuzumab  2 main cancers overexpress HER2 Breast 30% & gastric adenocarcinoma 20%1. Metastatic breast cancer
antagonist): (Herceptin)  Acts on tyrosine kinase receptors  anti-tumour effects by binding to HER2 2. Trastuzumab + cisplatin +
receptor stopping the activation of tyrosine kinases capecitabine OR 5-fluorouracil
 for HER2 +Ve metastatic
stomach adenocarcinoma
HER3  Overexpression of HER3  (Breast Ovarian, Colorectal, SQ cell carcinoma)
 (++) tyrosine kinase receptors
"Vascular Endothelial Growth Bevacizumab  Acts on tyrosine kinase receptors Colorectal cancer
factor inhibitors" (VEGF) (B Blood)  Inhibits VEGF receptors (which stimulates angiogenesis)
Platelet-Derived Growth Factor 1. Imatinib Acts on tyrosine kinase receptors Treatment of leukaemias
Receptor (PDGFR) 2. Dasatinib

glycoprotein IIb/IIIa Abciximab Prevention of ischaemic event in patients undergoing PCI

receptor antagonist

ALK-1 inhibitors Crizotinib Acts on anaplastic lymphoma kinase (a tyrosine kinase).

Trastuzumab (Herceptin)
 (- -) HER2/neu receptors  Stop (++) Tyrosine Kinases.
 Two main cancers which overexpress HER2 include breast 30% and gastric adenocarcinoma 20%
 Trastuzumab + cisplatin + capecitabine or 5-fluorouracil  HER2 positive metastatic adenocarcinoma of the stomach.
 It is used mainly in metastatic breast cancer although some patients with early disease are now also given trastuzumab.
 Adverse effects
1. Flu-like symptoms and diarrhoea are common
2. Cardiotoxicity  more common when Anthracyclines also used. (Echo before starting treatment)

Immunoglobulins: therapeutics
 formed from large pool of donors (5,000)  IgG molecules with a subclass distribution similar to that of normal blood
 Half-life of 3 weeks

Uses of IV immunoglobulins
1. 1ry and 2ry Immunodeficiency
2. ↓↓ serum IgG levels following haematopoietic stem cell transplant for malignancy
3. Idiopathic thrombocytopenic purpura
4. Myasthenia gravis
5. Guillain-Barre syndrome
6. chronic inflammatory demyelinating polyradiculopathy
 7. Kawasaki disease
8. Toxic Epidermal Necrolysis
9. Dermatomyositis
10. Pneumonitis induced by CMV following transplantation

Metformin
 A biguanide used  type 2 D.M. it does not cause hypoglycaemia and weight gain USES
1. 1st-line D.M, particularly (overweight).
2. Polycystic ovarian syndrome
3. Non-alcoholic fatty liver disease

Mechanism of action
1. (++) AMP-activated protein kinase (AMPK)
 Major cellular regulator of lipid and glucose metabolism (++) (glucose uptake, fatty acid oxidation, insulin sensitivity)/ (- -)gluconeogenesi
2. ↑↑ insulin sensitivity
3. ↓↓ hepatic gluconeogenesis
4. may ↓↓gastrointestinal absorption of carbohydrates

Adverse effects
1. GIT "5 %Common" (nausea, anorexia, Diarrhoea, Bloating)  intolerable in 20%
2. ↓↓ Vit B12 absorption - rarely a clinical problem
3. Lactic Acidosis* with severe liver disease or renal failure

Contraindications
1. Chronic kidney disease
 Reviewed if Creatinine is > 130 µmol/l (or eGFR < 45 ml/min)
 Stopped if the creatinine is > 150 µmol/l (or eGFR < 30 ml/min)
2. ↑↑ Tissue hypoxia (Recent MI, Sepsis, AKI and severe dehydration)
 May cause Lactic Acidosis
  Metabolic Acidosis W ↑↑Anion gap

3. Iodine-containing x-ray contrast media (Angiography, CA, IV Pyelography (IVP)

 ↑↑ renal impairment due to contrast nephropathy
 Discontinued on the day of the procedure and for 48 hours thereafter

4. Alcohol abuse is a relative contraindication

Starting Metformin
1. Metformin should be titrated up slowly to ↓↓incidence GIT side-effects
 500mg od with food for 14 days (at least 1 week)  then 500mg bd for 14 days then review.

2. Unacceptable side-effects (GIT) Modified-release metformin (evening) should be considered

 started at 500mg once per day ↑↑ 10-15 days on the basis of blood glucose measurements
 Up to 2 g daily of the standard-release  may start with the same daily dose of metformin modified-release.
Motion sickness
Motion sickness  nausea and vomiting occurs when ↑↑discrepancy between visually perceived movement and the vestibular systems sense of movement

Management ( Hyoscine > Cyclizine > Promethazine)

1. Hyoscine (Transdermal patch)  most effective treatment (Use is limited due to S/E)
2. Non-sedating antihistamines (Cyclizine or Cinnarizine)  in preference to sedating preparation (Promethazine).

Finasteride
Finasteride is 5 alpha-reductase inhibitor (enzyme metabolises testosterone into dihydrotestosterone. Indications
1. Benign prostatic hyperplasia
2. male-pattern baldness

Adverse effects
1. Impotence
2. Ejaculation disorders
 3. ↓↓ libido
4. Gynaecomastia and Breast tenderness
5. Finasteride causes decreased levels of serum prostate-specific antigen

Drug causes of Agranulocytosis

1. Antithyroid drugs  Carbimazole, Propylthiouracil
2. Antipsychotics  atypical antipsychotics (CLOZAPINE)
3. Antidepressant  Mirtazapine
4. Antiepileptics  Carbamazepine, Valproate
5. Antibiotics  Penicillin, Chloramphenicol, Co-trimoxazole
6. Cytotoxic drugs  Methotrexate

Drugs cause impaired glucose tolerance:

1. Thiazides, furosemide (less common)
2. Steroids
3. Tacrolimus, Ciclosporin
4. Interferon-alpha
5. Nicotinic acid
6. Antipsychotic
7. Beta-blockers cause a slight impairment of glucose tolerance  used with caution in diabetics as they can interfere with the
metabolic and autonomic responses to hypoglycaemia

Drug-induced thrombocytopenia
(probable immune-mediated)
1. Heparin
2. Antibiotics  Penicillins, Sulphonamides, Rifampicin
3. Anticonvulsants  Carbamazepine, Valproate
4. Quinine
 5. Abciximab
6. NSAIDs (enhance platlet aggregation )
7. Diuretics: Furosemide

G6PD Drugs
Absolute CI High risk Small risk No theoretical risk
Quinolones 1. Primaquine Chloroquine 1. Trimethoprim
 Ciprofloxacin 2. Sulfonamides 2. Ibuprofen
 Norfloxacin 3. Methylene blue 3. sodium valproate
 Moxifloxacin) 4. Dapsone
5. Doxorubicin

Drug causes of urticaria

1. Aspirin (common)
2. NSAIDs
3. Penicillins  Most common antibiotic (Doxycycline might cause but less common)
4. Opiates

Drug-induced urinary retention

1. Tricyclic Antidepressants  Amitryptiline (has also anti- cholinergic effect)
2. Anticholinergics
3. Opioids
4. NSAIDs
5. Disopyramide

Drugs causing lung fibrosis

Patient might presented W chronic cough & dyspnea + fine inspiratory crackles , FEV1/FVC ratio >70%.
1. Amiodarone
 2. Nitrofurantoin
3. Penicillamine
4. Cytotoxic agents  Busulphan, Bleomycin, Cyclophosphamide
5. Anti-rheumatoid drugs  Methotrexate, Sulfasalazine
6. Ergot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide)

Drugs causing ocular problems

Corneal Opacities Cataracts Optic neuritis Retinopathy
1. Amiodarone 1. Steroids 1. Amiodarone 1. Chloroquine (hydroxychloroquine).
2. Indomethacin 2. Ethambutol 2. Quinine
3. Metronidazole 3. Vigabatrin.
Sildenafil can cause both blue discolouration and non-arteritic anterior ischaemic neuropathy

Drugs causing photosensitivity

 A maculopapular erythematous rash on the forearms and face and anterior chest W sun exposure  typical of a photosensitivity rash
1. Anti - Biotics  Tetracyclines, Sulphonamides, Ciprofloxacin
2. Anti –arrhythmic  Amiodarone
3. Anti- glycemic  Sulphonylureas
4. NSAIDs  Piroxicam
5. Psoralen
6. Diuretics  Thiazides

Toxin Treatment
Paracetamol  activated charcoal if < 1 hour ago
 N-acetylcysteine (NAC)
 liver transplantation
 Toxin Treatment
Salicylate  Urinary alkalinization is now rarely used
 CI  Cerebral and pulmonary oedema (most units now proceeding straight to haemodialysis severe poisoning)
 haemodialysis
Opioid/opiates Naloxone
Benzodiazepines  Flumazenil  (Risk of seizures with flumazenil  only used with severe or iatrogenic overdoses).
 The majority  supportive care only
Tricyclic  IV bicarbonate  ↓↓ seizures and arrhythmias in "severe toxicity"
Antidepressants  Arrhythmias
1. Correction of acidosis is the first line
2. Class 1a (Quinidine) and class Ic antiarrhythmics (Flecainide) are contraindicated  prolong depolarisation.
3. Class III drugs (Amiodarone) avoided  prolong the QT interval.
4. Response to lignocaine is variable
 Dialysis is ineffective in removing tricyclics
Lithium  Mild-moderate toxicity  volume resuscitation with normal saline
 Haemodialysis  severe toxicity
+
 Na bicarbonate  sometimes used ↑↑ alkalinity of the urine it promotes lithium excretion
Warfarin Vitamin K, prothrombin complex
Heparin Protamine sulphate
Beta-blockers  if bradycardic then atropine
 in resistant cases glucagon may be used
Ethylene glycol  ethanol has been used for many years
 works by competing with ethylene glycol for the enzyme alcohol dehydrogenase
 this limits the formation of toxic metabolites (e.g. Glycoaldehyde and glycolic acid) which are responsible for the
haemodynamic/metabolic features of poisoning
 fomepizole, an inhibitor of alcohol dehydrogenase, is now used first-line in preference to ethanol
 Haemodialysis also has a role in refractory cases
Methanol poisoning  fomepizole or ethanol
 Toxin Treatment
 haemodialysis
Organophosphate  Atropine
insecticides  the role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefit
Digoxin Digoxin-specific antibody fragments
Iron Desferrioxamine a chelating agent
Lead Dimercaprol, calcium edentate
Carbon monoxide  100% oxygen
 hyperbaric oxygen
Cyanide Hydroxocobalamin; also combination of amyl nitrite, sodium nitrite, and sodium thiosulfate

Therapeutic drug monitoring

Phenytoin Ciclosporin Digoxin Lithium
Not monitored routinely immediately before dose  at least 6 hrs post-dose  range = 0.4 - 1.0 mmol/l
immediately before dose (checked if)  take 12 hrs post-dose
1. adjustment of phenytoin dose
2. suspected toxicity
3. detection of non-adherence to medication

Haemodialysis in overdose
Drugs cleared with haemodialysis " BLAST" Drugs cannot be cleared with haemodialysis "BBDDT"
1. Barbiturate 1. beta-blockers
2. Lithium 2. benzodiazepines
3. Alcohol (inc methanol, ethylene glycol) 3. tricyclics
4. Salicylates 4. digoxin
5. Theophyllines (charcoal haemoperfusion is preferable) 5. dextropropoxyphene (Co-proxamol)
Prescribing in patients with heart failure
The following medications may exacerbate heart failure:
1. Thiazolidinediones
Pioglitazone is contraindicated as it causes fluid retention
2. Verapamil
negative inotropic effect
3. NSAIDs/glucocorticoids
should be used with caution as they cause fluid retention
low-dose aspirin is an exception - many patients will have coexistent CVS disease and the benefits of taking aspirin easily outweigh the risks
4. Class I antiarrhythmics
Flecainide (negative inotropic and proarrhythmic effect)

Prescribing in patients with renal failure

avoid in renal failure Accumulate in CKD "Dose adjustment" Relatively safe "according degree CKD"
1. Antibiotics 1. Most antibiotics 1. Antibiotics
Tetracycline Penicillins Erythromycin
Nitrofurantoin Cephalosporins Rifampicin
Vancomycin
2. NSAIDs Gentamicin 2. Diazepam
3. Lithium Streptomycin 3. Warfarin
4. Metformin Ethambutol

2. Digoxin
3. Atenolol
4. Methotrexate
5. Sulphonylureas
6. Furosemide
7. Opioids
Oxycodone  safer opioid moderate to
 end-stage renal failure metabolised in the liver
Morphine metabolites  accumulate in renal failure
Diabetes drugs:Side effect
Drug Side-effect
Metformin  GIT side-effects
 Lactic acidosis
Sulfonylureas  Hypoglycaemic episodes
 Chlorpropamide  ↑↑ appetite and weight gain
 SIADH
 Liver dysfunction (cholestatic)
Glitazones  Weight gain
 Fluid retention (CI : Heart failure)
 Liver dysfunction
 Fractures
Gliptins Pancreatitis
Prescribing in pregnant patients
Very few drugs are known to be completely safe in pregnancy.
If given history of absence/ Non-effective contraception  treated as pregnant

Antibiotics
1. Tetracyclines
2. Aminoglycosides
3. Sulphonamides
4. Trimethoprim
5. Quinolones (Avoid due to arthropathy in some animal studies)

Other drugs
1. ACE inhibitors, ARBs
 2. Statins
3. Warfarin
4. Sulfonylureas
5. Metformin
 Sometimes used in pregnancy
 many diabetic women are converted to insulin for the duration of the pregnancy to try and maximise control and minimise complications
6. Retinoids (including topical)
7. Cytotoxic agents
The majority of antiepileptics (Valproate, Carbamazepine and Phenytoin) are known to be potentially harmful. The decision to stop such treatments however
is difficult as uncontrolled epilepsy is also a risk

St John's Wort
 shown to be as effective as tricyclic antidepressants in the treatment of mild-moderate depression
 SSRIs + Noradrenaline uptake inhibition has also been demonstrated)
 Should not be prescribed or advised because of uncertainty about appropriate doses, variation in the nature of preparations, and potential serious
interactions with other drugs'
 S/E
1. profile in trials similar to placebo
2. can cause serotonin syndrome
3. (++) P450 system decreased levels of drugs (Warfarin/ Ciclosporin/ ↓↓ effectiveness COCP)

Receptor Agonist Antagonist

Alpha Alpha-1 Decongestants Benign prostatic hyperplasia (tamsulosin)
( phenylephrine/oxymetazoline) Hypertension (doxazosin)
Alpha-2 Glaucoma
 Receptor Agonist Antagonist
(Topical brimonidine)
Beta-1 Inotropes (e.g. dobutamine) Non-selective & selective beta-blockers (e.g. atenolol, bisoprolol)
Beta-2 Bronchodilators (salbutamol) Non-selective beta-blockers (propranolol, labetalol)
Dopamine Parkinson's disease (Ropinirole) Schizophrenia "antipsychotics"
Prolactinoma haloperidol)
Anti-emetics
metoclopramide/domperidone)
GABA Benzodiazepines Flumazenil
Baclofen
Histamine-1 Antihistamines
( loratadine)
Histamine-2 Antacids
(ranitidine)
Muscarinic Glaucoma Atropine
(pilocarpine) Bronchodilator (ipratropium bromide, tiotropium)
Urge incontinence (oxybutynin)
Nicotinic Nicotine Non-depolarising muscle relaxants ( atracurium)
Varenicline (Smoking cessation)
Depolarising muscle relaxant (Suxamethonium)
Oxytocin Inducing labour Tocolysis
(Syntocinon) (atosiban)
Serotonin Triptans Anti-emetics
(for acute migraine, e.g. zolmitriptan) (ondansetron)