Pharmacology

Definitions and Classification

Enteral Routes

Parenteral Routes

Choice of Route

• Determined by the physicochemical properties of the drug (lipid solubility, ionisation, molecular size, irritancy), the site of desired action, the speed required, the condition of the patient, and the accuracy of dosage needed
• Drugs destroyed by gastric acid or enzymes must not be given orally — insulin, heparin, benzylpenicillin, streptomycin
• Drugs with very high first-pass metabolism need a much larger oral than parenteral dose, or a route that bypasses the liver
• In shock, only the intravenous route is reliable, because peripheral vasoconstriction makes subcutaneous and intramuscular absorption erratic

Mechanisms of Drug Transport Across Membranes

Novel and Special Drug Delivery Systems

• The aim of every one of these is the same — to hold the concentration within the therapeutic window for longer, with fewer doses and less toxicity

Applied Aspects

• Sublingual nitroglycerin acts within a minute, precisely because it avoids the liver — swallowed, it is almost entirely destroyed by first-pass metabolism and is useless for acute angina
• Never give an intramuscular injection to a patient on warfarin or with a bleeding disorder
• Adrenaline in anaphylaxis is given intramuscularly, not subcutaneously, because absorption is faster and more reliable, and not intravenously except by experienced hands, because of the risk of arrhythmia
• The intraosseous route is a life-saving alternative in children and in shocked patients where venous access fails
• Depot intramuscular preparations transform adherence in conditions where daily dosing fails — benzathine penicillin for rheumatic fever prophylaxis, and depot antipsychotics
• Correct inhaler technique matters more than the drug; most apparent treatment failure in asthma is a failure of delivery, and should be checked before the dose is escalated
• Never give an oily or particulate preparation intravenously — it causes embolism; oily preparations are given by deep intramuscular injection only
• Adding adrenaline to a local anaesthetic causes vasoconstriction, slowing absorption and so prolonging the block and reducing systemic toxicity — but it must never be used in digits, the nose, ears or penis
• The Z-track technique for intramuscular iron prevents staining of the skin by preventing leakage back along the needle track
• Sharps injury and needle reuse are serious hazards of the parenteral route in resource-limited settings, transmitting hepatitis B, C and HIV; the oral route should be preferred wherever it will serve
• Intrathecal vincristine is invariably fatal and has caused deaths through confusion with intravenous methotrexate; strict labelling and separate handling protocols exist for this reason alone
• Nasogastric administration is not the same as oral — some formulations block the tube, and enteral feed interacts with phenytoin and fluoroquinolones
• Compliance is the commonest reason a drug appears not to work, and is improved by simple regimens, once-daily dosing and clear explanation more than by any change of agent
• Always ask how a patient is taking a drug, not just whether — with food, with milk, crushed, or with an antacid; each can abolish absorption entirely

Definitions

• Bioavailability of an intravenous dose is 100% by definition, because the drug is placed directly into the circulation
• Calculated as the ratio of the area under the concentration–time curve (AUC) after oral administration to that after an intravenous dose, expressed as a percentage
• Bioequivalence — two formulations of the same drug are bioequivalent if their rate and extent of absorption do not differ significantly; this is the basis on which generic drugs are approved

The PH Partition Hypothesis

Most drugs are weak acids or weak bases and exist in ionised and unionised forms → Only the unionised, lipid-soluble form crosses membranes by passive diffusion → The proportion is governed by the henderson–hasselbalch relationship between the drug’s pKa and the pH of the medium → weak acids are unionised in an acid medium → absorbed from the stomach (aspirin, barbiturates) → weak bases are unionised in an alkaline medium → absorbed from the intestine (morphine, quinine, atropine) → In practice most absorption occurs in the small intestine whatever the pKa, because its surface area is enormous

Factors Affecting Absorption

• Food generally delays absorption; it reduces the absorption of ampicillin, tetracycline, rifampicin and levodopa, but increases that of griseofulvin, carbamazepine and lipid-soluble drugs by stimulating bile flow

First-pass Metabolism

• Drugs with high first-pass metabolism — propranolol, morphine, lignocaine, glyceryl trinitrate, verapamil, isoprenaline, testosterone, salbutamol, pethidine, chlorpromazine, imipramine, levodopa
• Consequences — low and variable bioavailability, so the oral dose must be much larger than the parenteral dose (propranolol oral 40 mg against 1 mg intravenously); marked inter-individual variation
• Routes that bypass it — sublingual, transdermal, rectal (partially), inhalational and all parenteral routes
• It is saturable, so bioavailability rises disproportionately at higher doses; and it is reduced in liver disease and in portosystemic shunting, so ordinary doses may become toxic

Factors Modifying Bioavailability

• Everything that affects absorption, plus first-pass metabolism
• Formulation differences between manufacturers — historically important for digoxin, phenytoin and warfarin, where small changes in bioavailability cause clinical failure or toxicity
• Enterohepatic circulation prolongs the presence of a drug and increases the effective exposure
• Efflux transporters — P-glycoprotein in the gut wall pumps drug back into the lumen, reducing bioavailability; it is inhibited by verapamil, quinidine and grapefruit juice

Absorption from Different Sites

Bioavailability Curves

• Two formulations may have the same AUC but different Cmax and Tmax — the same extent of absorption at a different rate. For a sustained-release product this is the intention; for an analgesic needed quickly it may make the product useless

Applied Aspects

• Bioavailability matters most for drugs with a narrow therapeutic index — digoxin, phenytoin, warfarin, lithium, theophylline — where a 20% change in absorption can mean the difference between failure and toxicity
• Do not switch brands casually for narrow-index drugs; where a patient is stable, the same formulation should be continued
• Tetracyclines and fluoroquinolones must be separated from milk, antacids and iron by at least two hours, or they will not be absorbed at all — a common and entirely avoidable cause of treatment failure
• Enteric-coated and sustained-release tablets must never be crushed, as this destroys the release mechanism and may deliver the whole dose at once
• In vomiting or malabsorption, use a parenteral route rather than assuming an oral dose has been absorbed
• Generic substitution is generally safe and greatly reduces cost, which matters enormously in India — provided the products are genuinely bioequivalent and quality-assured
• Take levothyroxine on an empty stomach, well separated from calcium and iron, since both markedly reduce its absorption and cause apparent treatment resistance
• Grapefruit juice raises the bioavailability of many drugs by inhibiting intestinal CYP3A4 and P-glycoprotein — statins, calcium channel blockers, ciclosporin
• Counterfeit and substandard medicines remain a real problem in parts of the world, and are a cause of apparent treatment failure that no amount of dose adjustment will overcome

Definition

Volume of Distribution

• It is called "apparent" because it is a mathematical construct, not a real anatomical space — a value of 13,000 L for chloroquine simply means very little of it remains in plasma
• Clinical uses — it determines the loading dose (loading dose = Vd × target plasma concentration), and it predicts whether a drug can be removed by dialysis

Factors Affecting Distribution

Redistribution

• A highly lipid-soluble drug given intravenously first enters the well-perfused brain, producing rapid action
• It then redistributes to less well-perfused muscle and fat, and the brain concentration falls
• Action is terminated by redistribution, not by metabolism
• The classical example is thiopentone — anaesthesia lasts only about 10 minutes after a single dose, although the drug is eliminated over many hours. Repeated doses saturate the fat and produce prolonged action, which is why it is unsuitable for maintenance

Plasma Protein Binding

• Only the free (unbound) drug is pharmacologically active, and only the free drug can be metabolised, excreted or cross membranes
• Binding is reversible and acts as a reservoir — as free drug is eliminated, bound drug is released, prolonging the duration of action
• Highly bound drugs — over 90%: warfarin (99%), phenytoin, diazepam, furosemide, sulphonylureas, NSAIDs
• Displacement interactions — one drug displaces another from albumin, transiently raising the free concentration; clinically important only for highly bound drugs with a small Vd and a narrow therapeutic index, such as warfarin displaced by aspirin, phenylbutazone or sulphonamides
• Hypoalbuminaemia in nephrotic syndrome, cirrhosis, malnutrition and burns raises the free fraction; a "normal" total phenytoin level may then represent a toxic free level

Barriers to Distribution

Drug Reservoirs and Sequestration

• A reservoir prolongs action but also prolongs toxicity — which is why chloroquine retinopathy appears after cumulative use and why amiodarone toxicity persists for months after the drug is stopped

Applied Aspects

• Calculate the loading dose from Vd when a rapid effect is needed — digoxin, amiodarone, phenytoin — because reaching steady state otherwise takes four to five half-lives
• Measure free phenytoin in hypoalbuminaemia, uraemia and pregnancy, or correct the total level, since the total is misleading
• Dialysis is futile for drugs with a large Vd; for digoxin poisoning, digoxin-specific antibody fragments are used instead
• In obesity, dose lipid-soluble drugs on total body weight and water-soluble drugs (aminoglycosides, digoxin) on ideal or adjusted body weight
• Neonates have less albumin and a higher free fraction, and sulphonamides displace bilirubin from albumin, risking kernicterus — which is why they are avoided in the newborn
• Assume any drug given to a pregnant woman reaches the fetus, and prescribe only where the benefit clearly outweighs the risk

Definition and Purpose

• Without metabolism, lipid-soluble drugs would be reabsorbed from the renal tubule indefinitely and never eliminated — this is the whole point of the process
• The liver is the principal site; also gut wall, kidney, lung, plasma and skin

Phase I Reactions

Phase II Reactions

Enzyme Induction and Inhibition

• Rifampicin causes failure of oral contraceptives, warfarin, corticosteroids, oral hypoglycaemics and antiretrovirals — clinically vital in India, where rifampicin is so widely used for tuberculosis
• Autoinduction — carbamazepine and rifampicin induce their own metabolism, so the dose may need increasing after a few weeks
• With a prodrug the effects reverse — an inducer increases the activation of codeine to morphine and may cause toxicity

Factors Modifying Drug Metabolism

• Age — neonates have immature enzymes, especially glucuronidation (grey baby syndrome, kernicterus); the elderly have reduced hepatic mass and blood flow, so doses must be lower
• Genetic polymorphism (pharmacogenetics) — slow acetylators (about 50% of Indians) develop isoniazid neuropathy and hydralazine-induced lupus more readily; fast acetylators risk isoniazid hepatotoxicity. atypical pseudocholinesterase causes prolonged apnoea after succinylcholine; TPMT deficiency causes azathioprine toxicity; CYP2D6 polymorphism affects codeine and many antidepressants
• Liver disease — reduces metabolism and first-pass extraction; doses must be reduced, particularly for high-extraction drugs
• Nutrition, hormones, disease and concurrent drugs

Applied Aspects

• Paracetamol overdose is the classic example of a toxic metabolite — at normal doses NAPQI is conjugated with glutathione, but in overdose glutathione is depleted and NAPQI causes centrilobular hepatic necrosis. N-acetylcysteine replenishes glutathione and is effective if given early. Chronic alcoholics and the malnourished are at higher risk from lower doses
• Always review co-prescription for interactions when adding rifampicin, an azole antifungal or a macrolide — these three account for a large share of clinically important metabolic interactions
• Pyridoxine is given with isoniazid to prevent peripheral neuropathy in slow acetylators, and is routine in India
• Grapefruit juice inhibits intestinal CYP3A4 and can raise levels of statins, calcium channel blockers and ciclosporin substantially — patients should be told
• Enzyme inhibition acts within hours, induction within weeks; that difference in timing determines how quickly a patient must be monitored after a change
• Test for G6PD deficiency before primaquine and dapsone, both metabolised to oxidant intermediates that precipitate haemolysis — directly relevant to malaria treatment in India
• Reduce doses of hepatically metabolised drugs in cirrhosis, and avoid sedatives entirely where encephalopathy is a risk
• Pharmacogenetic testing is entering routine practice — HLA-B*15:02 before carbamazepine in South-East Asians, TPMT before azathioprine, and HLA-B*57:01 before abacavir
• Neonates cannot glucuronidate, so chloramphenicol accumulates and causes grey baby syndrome, and bilirubin conjugation is limited — both are consequences of one immature enzyme
• Metabolism does not always mean detoxification; for paracetamol, methanol and halothane it is metabolism that creates the danger, which is why the antidotes act on the metabolic pathway rather than on the parent drug
• Ethanol is the classical antidote in methanol poisoning, competing for alcohol dehydrogenase and preventing the formation of formic acid; fomepizole does the same more safely
• Hepatic drug metabolism cannot be measured routinely, unlike renal function; dosing in liver disease therefore relies on clinical judgement and on starting low
• Smoking is a potent enzyme inducer and is easily forgotten; theophylline and clozapine levels rise when a patient is admitted to hospital and stops smoking, sometimes to toxic levels

Routes of Excretion

Renal Excretion

• 1. Glomerular filtration — only the free, unbound drug is filtered
• molecules under about 20,000 daltons pass → 2.
• Active tubular secretion — in the proximal tubule, by separate carriers for acids (penicillin, probenecid, salicylate, methotrexate, frusemide, uric acid) and bases (quinine, morphine, amiloride, dopamine) → These carriers are saturable and drugs compete — probenecid blocks penicillin secretion and prolongs its action → Secretion is not limited by protein binding, because binding is reversible and the carrier strips the drug from albumin → 3.
• Passive tubular reabsorption — lipid-soluble, unionised drug diffuses back as water is reabsorbed → urine pH determines how much is reabsorbed → Net renal excretion = filtration + secretion − reabsorption

Clearance and Half-life

• Steady state is reached after 4 to 5 half-lives of regular dosing, and about 94% of the drug is eliminated in the same time after stopping
• A loading dose achieves the target concentration immediately and is determined by Vd; the maintenance dose replaces what is cleared and is determined by clearance. The two answer different questions

Kinetics of Elimination

• Some drugs change order with dose — aspirin and phenytoin follow first-order kinetics at low doses and zero-order once the enzymes saturate, which is exactly why they are dangerous

Therapeutic Drug Monitoring

• Indicated when the drug has a narrow therapeutic index, shows wide inter-individual variation, has no easily measured clinical endpoint, follows zero-order kinetics, or where toxicity is hard to distinguish from the disease
• Drugs commonly monitored — digoxin, phenytoin, lithium, theophylline, aminoglycosides, vancomycin, ciclosporin, carbamazepine, methotrexate
• Sample at steady state, that is after 4 to 5 half-lives, and at a standardised time — usually a trough level immediately before the next dose. Aminoglycosides need both peak (for efficacy) and trough (for toxicity)
• Digoxin must be sampled at least 6 hours after the dose, otherwise the distribution phase gives a falsely high reading
• Treat the patient, not the number — a level is interpreted together with the clinical state, renal function, albumin and interacting drugs

Enterohepatic Circulation

A drug is conjugated in the liver, usually with glucuronic acid → The conjugate is excreted in bile into the intestine → Intestinal bacterial beta-glucuronidase hydrolyses the conjugate → The free, lipid-soluble drug is reabsorbed from the gut → It returns to the liver by the portal vein — and the cycle repeats → The result is a prolonged half-life and a characteristic second peak in the plasma concentration curve

• Drugs undergoing significant enterohepatic circulation — oral contraceptives (oestrogens), morphine, digoxin, rifampicin, chloramphenicol, phenolphthalein, warfarin
• Broad-spectrum antibiotics can cause oral contraceptive failure by killing the gut flora that deconjugate oestrogen, so it is excreted instead of being reabsorbed
• Interrupting the cycle accelerates elimination — repeated doses of activated charcoal ("gut dialysis") are used in poisoning with phenobarbitone, theophylline, carbamazepine, dapsone and quinine

Applied Aspects

• Renal impairment requires dose adjustment for renally excreted drugs — aminoglycosides, digoxin, lithium, methotrexate, vancomycin; either the dose is reduced or the interval lengthened, guided by creatinine clearance
• Serum creatinine is a poor guide in the elderly and the malnourished, because muscle mass is low; estimated clearance is more reliable
• Enterohepatic circulation prolongs action — interrupting it with activated charcoal accelerates elimination of phenobarbitone, theophylline, carbamazepine and dapsone in overdose
• Urinary alkalinisation for salicylate and phenobarbitone poisoning, and forced diuresis where appropriate; both follow directly from ion trapping
• Probenecid was once used deliberately to prolong penicillin action when the drug was scarce — an interaction turned to advantage
• Phenytoin dose increments must be small once the level approaches the therapeutic range, because of its zero-order kinetics; a routine dose increase can precipitate nystagmus, ataxia and confusion
• Aminoglycosides are now given once daily in most indications — their bactericidal effect is concentration-dependent and they show a post-antibiotic effect, while their toxicity depends on the trough; a high peak with a low trough is therefore ideal
• Loop diuretics need a threshold concentration at the tubule, so in renal impairment the dose must be increased rather than the frequency
• Milk excretion matters to the breastfed infant, and drugs are best taken immediately after a feed to minimise the concentration at the next one
• Warn patients that rifampicin colours urine, sweat, tears and saliva orange-red, and will stain soft contact lenses permanently — a harmless effect, but alarming if unexpected and a cause of stopping treatment
• Renal function must be checked before and during aminoglycoside, vancomycin and amphotericin therapy, since all three are both nephrotoxic and renally cleared — a self-reinforcing hazard
• Metformin is withheld before contrast studies and in acute illness, since renal impairment causes it to accumulate and precipitate lactic acidosis
• Age-related decline in renal function is silent — an elderly patient with a normal creatinine may still have a clearance of 40 mL/min, and digoxin and aminoglycoside doses must be reduced accordingly
• Haemodialysis removes some drugs and not others; for a dialysed patient the dose is usually given after the session, or a supplementary dose is added
• The kidney is both a route of excretion and a target of toxicity, and the two interact — nephrotoxicity reduces clearance, which raises levels, which increases nephrotoxicity further
• Estimate clearance rather than reading creatinine using Cockcroft–Gault or an eGFR, particularly in the elderly, the obese and the malnourished
• A drug level is only interpretable if the timing is known — an unlabelled sample is worse than no sample, because it invites a wrong dose change
• Toxicity and under-treatment can look identical — phenytoin toxicity causes seizures, and digoxin toxicity causes arrhythmia; the level distinguishes them when the clinical picture cannot

Definition

Mechanisms of Drug Action

Receptors — Definition and Terminology

Types of Receptor

• The time scale follows directly from the mechanism — opening a pore is instantaneous, a second messenger cascade takes seconds, phosphorylation takes minutes, and making new protein takes hours. This is why an intravenous corticosteroid does not relieve acute bronchospasm, and why adrenaline does

G Proteins and Second Messengers

• Other messengers — cGMP (nitric oxide and atrial natriuretic peptide; the target of sildenafil, which inhibits its breakdown by phosphodiesterase-5), and calcium–calmodulin
• Toxins acting on G proteins — cholera toxin locks Gs ON (persistent cAMP rise and massive intestinal secretion); pertussis toxin locks Gi off

Non-receptor Targets in Detail

• Selective toxicity is the central principle of chemotherapy — exploiting a target the pathogen has and the host does not, or one that differs enough in structure to allow discrimination

Regulation of Receptors and Applied Aspects

• Down-regulation — prolonged exposure to an agonist reduces receptor number or sensitivity; the basis of tolerance to opioids and of tachyphylaxis to beta-agonists
• UP-regulation — prolonged blockade increases receptor number; this is why abrupt withdrawal of a beta-blocker causes rebound angina, tachycardia and infarction, and why clonidine withdrawal causes a hypertensive crisis. These drugs must be tapered
• Receptor selectivity is relative, not absolute — salbutamol is beta2-selective but causes tremor and tachycardia at higher doses, because selectivity is lost as the dose rises
• Drug design targets receptor subtypes to improve selectivity — beta1-selective blockers for asthmatic patients with heart disease, H2 blockers for acid without the sedation of H1 blockade
• Steroids take hours to act because they work through gene transcription — so in acute asthma or anaphylaxis they are started early but adrenaline or a bronchodilator provides the immediate effect
• Constitutive receptor activity explains inverse agonists, and matters clinically for antihistamines and some beta-blockers, which are inverse agonists rather than pure antagonists
• Selective toxicity has limits — antifungals and antivirals are more toxic than antibacterials because fungi are eukaryotes and viruses use host machinery, leaving fewer targets the host does not share

Types of Dose–response Relationship

• The semilogarithmic plot is used because it straightens the middle of the curve, allowing a wide range of doses on one graph and easy comparison of drugs
• ED50 — the dose producing the specified effect in 50% of the population (quantal), or 50% of the maximal response (graded)

Potency and Efficacy

Agonists and Antagonists on the Curve

Competitive and non-competitive antagonism

Therapeutic Index and Drug Safety

• A high therapeutic index means a safe drug — penicillin has a very high index; a low index means a dangerous one
• Narrow therapeutic index drugs — digoxin, phenytoin, lithium, theophylline, warfarin, aminoglycosides, cytotoxics, insulin; these require therapeutic drug monitoring
• The certain safety factor = TD1/ED99, and is a more stringent measure, because the therapeutic index compares two midpoints and ignores the spread of the curves — two drugs with the same index may differ greatly in how much their curves overlap

Other Concepts

Structure–activity Relationship and Drug Design

• Structure–activity relationship (SAR) — small changes in chemical structure produce predictable changes in affinity, efficacy, selectivity and pharmacokinetics
• Examples — adding a bulky substituent to the catecholamine nitrogen shifts activity from alpha to beta selectivity (adrenaline → isoprenaline); removing a hydroxyl group makes the molecule resistant to catechol-O-methyltransferase and orally active (salbutamol)
• Isosteric substitution replaces an atom or group with one of similar size and electronic properties, retaining activity while altering metabolism
• Enantiomers frequently differ — usually only one is active; S-warfarin is several times more potent than R-warfarin; the tragedy of thalidomide involved a racemic mixture whose enantiomers interconvert in the body
• Rational drug design now begins from the three-dimensional structure of the target — as with the HIV protease inhibitors and the tyrosine kinase inhibitor imatinib

Applied Aspects

• Choose a drug on efficacy and safety, not potency — the commonest error in interpreting drug promotion
• Competitive antagonism can be overcome by raising the agonist dose, which is why very large doses of atropine are used in organophosphorus poisoning, and why naloxone must sometimes be repeated as it is shorter-acting than morphine
• Irreversible antagonism requires new receptor synthesis to recover — aspirin’s effect on platelets lasts their whole 7 to 10 day lifespan because platelets have no nucleus
• Monitor plasma levels for narrow-index drugs, and be alert to interactions, since a small change in concentration matters
• The ceiling effect explains why opioids have no maximum analgesic dose, while paracetamol does — increasing paracetamol beyond the ceiling adds only hepatotoxicity
• Individual variation means the population curve is only a guide; the dose must be titrated to the patient in front of you
• A steep dose–response curve leaves little room for error — with warfarin and insulin a small dose change produces a large effect, which is why both are titrated against a measurement rather than given at a fixed dose
• Combining drugs with different mechanisms allows a lower dose of each and so fewer dose-related effects — the rationale for combination antihypertensive and antitubercular therapy
• The maximum tolerated dose is often below the maximally effective one, and it is toxicity rather than efficacy that sets the ceiling in practice — conspicuously so with cytotoxic drugs

Definitions

• An adverse event is any untoward occurrence during treatment, whether or not it is caused by the drug — the distinction matters in trials and in causality assessment
• Doses "normally used in man" excludes deliberate overdose and poisoning
• Adverse reactions cause about 5% of hospital admissions and are a leading cause of iatrogenic death

Rawlins–thompson Classification

Types of Adverse Reaction BY Mechanism

Drug Allergy

• Severe cutaneous reactions — Stevens–Johnson syndrome and toxic epidermal necrolysis are most often caused by sulphonamides, allopurinol, carbamazepine, phenytoin, lamotrigine, nevirapine and NSAIDs; mortality in toxic epidermal necrolysis exceeds 30%
• HLA-B*15:02 predicts carbamazepine-induced Stevens–Johnson syndrome in South-East Asian populations, and testing is recommended before starting it

Causality Assessment and Reporting

• WHO causality categories — certain, probable, possible, unlikely, conditional, unassessable; the Naranjo scale is a structured scoring system
• The strongest evidence is DE-challenge (improvement on stopping) and RE-challenge (recurrence on restarting) — though deliberate re-challenge is rarely ethical
• Pharmacovigilance is the science of detecting, assessing and preventing adverse effects; India runs the Pharmacovigilance Programme of India (PvPI)
• Spontaneous reporting (the yellow card system) is the main method of detecting rare type B reactions, because clinical trials are far too small to find an event occurring in 1 in 10,000 patients
• Under-reporting is the chief weakness — probably under 10% of reactions are reported; every clinician has a duty to report

Organ-specific Drug Toxicity

Applied Aspects

• Prevention — take a careful drug and allergy history, avoid unnecessary polypharmacy, start low and go slow in the elderly, adjust for renal and hepatic function, and anticipate interactions
• Always ask what happened when a patient reports an "allergy" — most reported penicillin allergy is nausea or a non-specific rash, and wrongly labelling a patient allergic denies them the best treatment for life
• Type B reactions cannot be predicted but can be recognised early — warn patients on carbimazole or clozapine to report a sore throat, and on antiepileptics to report a rash
• Stop the offending drug and record the reaction prominently; the record is what protects the patient at the next admission
• Post-marketing surveillance found the problem in every famous drug withdrawal — thalidomide, practolol, rofecoxib, cerivastatin — because none was detectable in pre-marketing trials
• In India, self-medication and over-the-counter sale of prescription drugs are widespread, and a drug history must ask specifically about them rather than relying on what is volunteered

Introduction

Patient-related Factors

Disease-related Factors

Drug-related Factors

• Tolerance — a diminished response after repeated administration, requiring an increased dose; may be pharmacokinetic (enzyme induction, as with barbiturates) or pharmacodynamic (receptor down-regulation, as with opioids)
• Cross-tolerance between related drugs — alcohol and benzodiazepines; different opioids
• Tachyphylaxis — rapid tolerance developing within minutes to hours, typically from depletion of a mediator or receptor desensitisation; ephedrine and amphetamine (noradrenaline depletion), nitrates
• Drug resistance — a term reserved for micro-organisms and tumour cells, not for the host
• Cumulation — when the dosing interval is shorter than needed for elimination; a risk with long half-life drugs such as digoxin and amiodarone
• Dependence and addiction; drug interactions as discussed separately

Placebo and Psychological Factors

• A placebo is an inert substance given as a medicine; the placebo effect is the benefit produced by expectation rather than by pharmacological action
• It is a real, measurable phenomenon, with objective correlates including endorphin release, and is reversed by naloxone in placebo analgesia
• NOCEBO — adverse effects produced by negative expectation
• Uses — as a control in randomised trials, which is its principal and legitimate role
• Every treatment has a placebo component, contributed by the consultation, the explanation and the doctor’s manner; recognising this is not cynicism but good practice
• Deceptive use of placebo in practice is ethically problematic, since it requires deceiving the patient and undermines trust if discovered

Drug Dosage and Individualisation

• Paediatric doses should never be derived by simply halving an adult dose — children are not small adults, and the ratio of surface area to weight is much higher in the young

Applied Aspects

• Review the whole drug list at every visit, and stop what is no longer needed — deprescribing is as much a skill as prescribing
• Calculate paediatric doses on body weight or surface area, never by scaling down an adult tablet by guesswork
• Assume every drug crosses the placenta and enters milk, and check before prescribing in pregnancy or lactation
• Check renal function before and during treatment with renally cleared drugs, particularly in the elderly where creatinine underestimates impairment
• Anticipate genetic variation where it is common locally — give pyridoxine with isoniazid, and screen for G6PD deficiency before primaquine
• Explain the treatment properly — understanding improves adherence and recruits the placebo component honestly, without deception
• Beware the prescribing cascade — an adverse effect mistaken for a new disease and treated with a further drug; a diuretic causing gout treated with allopurinol, or a calcium channel blocker causing oedema treated with a diuretic
• The commonest cause of an unexpected drug response is a drug the patient is taking that you do not know about — including herbal preparations, another doctor’s prescription, and medicines borrowed from relatives
• Adherence falls as the regimen becomes more complex; once-daily dosing and fewer tablets do more for outcome than most changes of agent
• Titrate against a measurable endpoint wherever one exists — blood pressure, INR, glucose, symptom score — rather than continuing a fixed dose indefinitely
• Malnutrition is common in India and alters drug handling — low albumin raises the free fraction, and reduced enzyme activity slows metabolism; doses derived from Western populations may not transfer directly
• Ask about traditional and ayurvedic preparations specifically, since patients do not regard them as drugs; some contain heavy metals or undeclared corticosteroids

Stages of Drug Development

Drug discovery — target identification, screening of compound libraries, rational design, lead optimisation → preclinical studies — in vitro and animal work on pharmacodynamics, pharmacokinetics and toxicology (acute, subacute, chronic, reproductive, mutagenicity, carcinogenicity) → Regulatory approval to test in humans → phase I → phase II → phase III clinical trials → Marketing approval → phase IV — post-marketing surveillance, continuing indefinitely

• Typically 10 to 15 years and enormous cost, with only a small fraction of candidate molecules reaching the market

Phases of Clinical Trial

Essential Features of a Good Clinical Trial

Ethical Considerations

• The declaration OF helsinki is the governing statement of principle; in India, trials are regulated by the CDSCO under the New Drugs and Clinical Trials Rules, with ICMR ethical guidelines
• Informed consent must be genuine — in a written form the participant understands, in their own language, with the freedom to refuse or withdraw at any time without prejudice to their care
• Vulnerable groups need special protection — children, pregnant women, the mentally ill, prisoners, and the illiterate or economically disadvantaged; audio-visual recording of consent is required in India for vulnerable participants
• Compensation for trial-related injury is a legal requirement in India
• Equipoise — a trial is ethical only while there is genuine uncertainty about which arm is better; once the answer is clear the trial must stop, which is the role of the data safety monitoring board

Pharmacovigilance and Drug Withdrawal

• Pharmacovigilance is the science relating to the detection, assessment, understanding and prevention of adverse effects
• Methods — spontaneous (voluntary) reporting, cohort event monitoring, prescription event monitoring, record linkage, and case-control studies
• The Pharmacovigilance Programme of India (PvPI), coordinated by the Indian Pharmacopoeia Commission, collects reports through adverse drug reaction monitoring centres
• Famous withdrawals — thalidomide (phocomelia, which created modern drug regulation), practolol (oculomucocutaneous syndrome), rofecoxib (myocardial infarction), cerivastatin (rhabdomyolysis), terfenadine (torsades de pointes)
• India has banned many irrational fixed-dose combinations, a significant and continuing public health measure

Types of Clinical Study

Applied Aspects

• Read a trial critically — was it randomised and blinded, was the comparator fair and given at a proper dose, was the endpoint clinically meaningful, was the analysis by intention to treat, and how large was the absolute benefit rather than the relative risk reduction?
• Relative risk reduction exaggerates benefit; the number needed TO treat is far more informative and honest
• A surrogate endpoint can mislead badly — antiarrhythmic drugs suppressed ectopic beats after infarction and increased mortality, which the cast trial demonstrated only because it measured deaths
• Report suspected adverse reactions, particularly for newly marketed drugs; the system depends entirely on clinicians doing so
• Rational prescribing — the right drug, for the right patient, in the right dose, by the right route, for the right duration, at the lowest cost; and the WHO essential medicines list is the practical embodiment of it
• Be sceptical of promotional material — it emphasises potency, relative risk and surrogate endpoints, and is not a substitute for the primary literature
• Check that the control arm was treated properly — a new drug can be made to look good by comparing it with too low a dose of the standard treatment, or with the wrong comparator altogether
• Beware composite endpoints, where a benefit driven entirely by the softest component (such as hospitalisation) is presented as though it applied to the hardest (death)
• Trial populations differ from real patients — the elderly, children, pregnant women and those with comorbidity are commonly excluded, so results may not transfer to the patient in front of you
• India is a major site for global clinical trials, which brings both access to new treatments and a real risk of exploitation; robust ethics review and genuine informed consent are what separate the two
• Absence of evidence is not evidence of absence — a trial that fails to show a difference may simply have been too small, which is why the sample size calculation and the confidence interval matter more than the p value alone
• Subgroup analyses are hypothesis-generating, not conclusive; with enough subgroups, a spurious "significant" finding is almost guaranteed by chance alone
• Declare and consider conflicts of interest — industry-funded trials more often report favourable results, which does not invalidate them but does warrant closer reading
• A trial answers the question it was designed to ask, and no other; extending its conclusion to a different population, dose or duration is an assumption, not a finding
• Report suspected reactions even when uncertain — the value of spontaneous reporting lies in the accumulation of signals, and waiting for certainty defeats the purpose of the system

Organisation of the Autonomic Nervous System

Cholinergic Transmission

Choline is taken into the nerve terminal by a carrier — the rate-limiting step, blocked by hemicholinium → Choline acetyltransferase combines it with acetyl-CoA → acetylcholine → Stored in vesicles by a vesicular transporter, blocked by vesamicol → The action potential opens voltage-gated calcium channels → Calcium-dependent exocytosis; blocked by botulinum toxin (which cleaves snare proteins) and by aminoglycosides; increased by black widow spider venom → Acetylcholine acts on muscarinic or nicotinic receptors → Rapidly hydrolysed by acetylcholinesterase to choline and acetate; choline is recaptured

Adrenergic Transmission

Tyrosine enters the neuron and is converted by tyrosine hydroxylase to dopa — the rate-limiting step, inhibited by metyrosine → dopa → dopamine by dopa decarboxylase (blocked by carbidopa) → Dopamine enters the vesicle by VMAT, blocked by reserpine → Inside the vesicle, dopamine beta-hydroxylase makes noradrenaline → (In the adrenal medulla only, PNMT converts it to adrenaline) → Release by calcium-dependent exocytosis; blocked by guanethidine, and inhibited by presynaptic alpha2 autoreceptors → Action terminated chiefly by reuptake-1 (net) into the neuron — blocked by cocaine, tricyclic antidepressants → Metabolised by MAO (neuronal, mitochondrial) and COMT (extraneuronal) to VMA

• Reuptake, not enzymatic destruction, is what mainly terminates noradrenergic transmission — the opposite of acetylcholine, and the reason cocaine and tricyclics potentiate sympathetic effects so strongly
• Indirectly acting sympathomimetics (tyramine, amphetamine, ephedrine) enter the neuron by the same reuptake carrier and displace stored noradrenaline — so they are blocked by cocaine and by reserpine, and show tachyphylaxis as stores are exhausted

Dual Innervation and Predominant Tone

Classification of Autonomic Drugs

Applied Aspects

• Atropine is the antidote in organophosphorus poisoning, which is common in rural India; it reverses the muscarinic effects (bronchial secretion, bradycardia, miosis) but not the nicotinic ones, so muscle weakness and respiratory failure persist and require pralidoxime and ventilation
• Titrate atropine against drying of bronchial secretions, not against pupil size or heart rate — secretions are what kill
• Beta-blockers are relatively contraindicated in asthma (beta2 blockade) and mask the warning signs of hypoglycaemia in diabetics, except sweating
• Sweat glands are sympathetic but cholinergic, which is why anticholinergics cause dry skin and hyperthermia, and why atropine poisoning gives a patient who is "hot as a hare, dry as a bone, red as a beet, blind as a bat and mad as a hatter"
• Alpha1 blockade relieves prostatic obstruction by relaxing smooth muscle in the prostate and bladder neck — tamsulosin is relatively uroselective
• Never give a beta-blocker before alpha-blockade in phaeochromocytoma, as unopposed alpha stimulation precipitates a hypertensive crisis
• Cocaine and tricyclic antidepressants block reuptake-1, so they potentiate directly acting sympathomimetics and block indirectly acting ones — a distinction that is regularly examined
• Reserpine depletes vesicular stores and so abolishes the effect of tyramine and amphetamine while leaving adrenaline effective
• Denervation supersensitivity — after sympathetic denervation, receptors up-regulate and the tissue becomes far more sensitive to circulating catecholamines; relevant in Horner syndrome testing
• Autonomic neuropathy in diabetes causes postural hypotension, gastroparesis, impotence and silent myocardial infarction, and alters the response to many autonomic drugs

Classification of Cholinergic Drugs

Pharmacological Actions

Therapeutic Uses

Organophosphorus Poisoning

• Common and important in India, from agricultural insecticide, often self-poisoning
• Mechanism — irreversible phosphorylation of acetylcholinesterase; "ageing" makes the bond permanent after some hours, after which oximes no longer work
• Muscarinic features — mnemonic "dumbbells": Diarrhoea, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Lethargy, Salivation
• Nicotinic features — fasciculations, weakness, paralysis, tachycardia and hypertension from ganglionic stimulation
• CNS features — anxiety, confusion, convulsions, coma, central respiratory depression
• Death is from respiratory failure — bronchial secretions, bronchospasm, respiratory muscle paralysis and central depression acting together
• Treatment — decontamination, airway and ventilation; atropine in large repeated doses titrated to dry secretions; pralidoxime to reactivate the enzyme, given early before ageing; diazepam for convulsions
• Intermediate syndrome — proximal muscle weakness 24 to 96 hours later, needing ventilation; and delayed polyneuropathy weeks later

Muscarinic and Nicotinic Effects Compared

• This is why atropine alone is not enough in organophosphorus poisoning — it treats only half the syndrome, and a patient can be pink, dry and still dying of respiratory muscle paralysis

Adverse Effects and Contraindications

• Adverse effects — predictable extensions of the muscarinic actions: salivation, sweating, colic, diarrhoea, bradycardia, hypotension, bronchospasm, blurred vision, urinary urgency
• Contraindicated in bronchial asthma (bronchoconstriction), peptic ulcer (acid secretion), intestinal or urinary obstruction (perforation risk), hyperthyroidism and coronary insufficiency
• Cholinergic crisis in myasthenia — excessive anticholinesterase causes weakness that mimics a myasthenic crisis; the edrophonium test distinguishes them, since it improves myasthenic weakness and worsens cholinergic weakness

Applied Aspects

• Give pralidoxime early — once ageing has occurred it is ineffective, so time matters more than dose
• Atropine dosing in poisoning is far larger than textbook doses, often many milligrams repeated, and is guided by clearing chest secretions rather than by a fixed schedule
• Exclude mechanical obstruction before giving bethanechol or neostigmine for retention or ileus, or perforation may result
• Anticholinesterases used topically in glaucoma cause miosis and dim vision, particularly troublesome at night and in cataract
• Protective equipment and safe storage of pesticides would prevent most Indian cases; this is a public health problem as much as a clinical one
• Physostigmine, not neostigmine, for central antimuscarinic delirium — the tertiary/quaternary distinction determines which drug can act in the brain
• Pilocarpine remains useful in acute angle-closure glaucoma, where pupillary constriction pulls the iris away from the drainage angle
• Anticholinesterases for Alzheimer disease give modest and temporary benefit; they do not alter the underlying disease, and expectations must be set honestly with families
• Bethanechol is resistant to cholinesterase and acts mainly on gut and bladder with little cardiovascular effect, which is why it is preferred for retention and ileus
• Mushroom poisoning of the muscarinic type responds to atropine, while the more dangerous Amanita phalloides type does not and causes hepatic failure — the distinction matters

Classification

Pharmacological Actions

Therapeutic Uses

Atropine Poisoning

• Features — the classical description: "hot as a hare (hyperthermia), dry as a bone (no sweat or saliva), red as a beet (cutaneous vasodilatation), blind as a bat (mydriasis and cycloplegia), and mad as a hatter (delirium)"; with tachycardia and urinary retention
• Commonest in children, from eating belladonna or Datura berries, and from accidental overdose of eye drops; Datura seeds are used criminally in India for stupefaction and robbery
• Treatment — supportive; physostigmine for severe central effects; cooling, catheterisation, and benzodiazepines for agitation. Phenothiazines must be avoided, as they are themselves antimuscarinic

Atropine Substitutes Compared

Adverse Effects and Contraindications

• Adverse effects are simply the actions, unwanted — dry mouth, blurred vision, constipation, urinary hesitancy, tachycardia, confusion in the elderly
• Contraindicated in angle-closure glaucoma and in prostatic enlargement — the two absolute cautions to state
• Use with great care in the elderly, in whom antimuscarinic burden causes confusion, falls, constipation and retention; the cumulative "anticholinergic load" of several drugs is a recognised and avoidable cause of delirium
• Avoid in children with fever, since impaired sweating raises the temperature further

Applied Aspects

• Quaternary compounds do not cross the blood–brain barrier, which is why glycopyrrolate is preferred to atropine in anaesthesia and ipratropium can be inhaled without central effects
• Tropicamide, not atropine, for routine fundus examination — atropine’s cycloplegia lasts a week and is unacceptable to an adult patient
• Always ask about glaucoma and prostatism before prescribing any antimuscarinic, including over-the-counter antihistamines and antispasmodics
• Many drugs have unintended antimuscarinic activity — tricyclic antidepressants, phenothiazines, older antihistamines, oxybutynin — and their effects add up in an elderly patient
• Hyoscine patch for motion sickness must be applied hours in advance, and hands washed afterwards, since transfer to the eye causes unilateral fixed mydriasis that is easily mistaken for a neurological emergency
• Atropine remains a life-saving, cheap and widely available drug in organophosphorus poisoning, and every casualty department in India should hold generous stocks
• Glycopyrrolate causes less tachycardia than atropine and does not cross into the CNS, which makes it the preferred antisialagogue in the elderly
• Tiotropium is once daily and improves outcomes in COPD, whereas ipratropium is short-acting and used four times a day or as needed
• Antimuscarinics for overactive bladder are frequently stopped because of dry mouth and constipation; mirabegron, a beta3 agonist, is an alternative without those effects
• Datura poisoning presents with an anticholinergic syndrome and should be considered in any patient found confused with dilated pupils and dry skin, particularly after travel

Classification of Sympathomimetics

Comparison of the Classical Catecholamines

Selective Agonists and Their Uses

Adrenaline in Detail

• Dose-dependent receptor selectivity — at low dose beta effects predominate (vasodilatation, tachycardia); at high dose alpha effects dominate (vasoconstriction, rise in pressure)
• Anaphylaxis is the first indication — given intramuscularly into the anterolateral thigh, 0.5 mg of 1:1000 in an adult, repeated every 5 minutes as needed. It is the only drug that reverses every feature at once: alpha1 reverses vasodilatation and oedema, beta1 supports the heart, beta2 relieves bronchospasm and stabilises mast cells
• Cardiac arrest — 1 mg of 1:10,000 intravenously
• With local anaesthetics (1:200,000) — vasoconstriction prolongs the block, reduces systemic toxicity and provides a bloodless field; never in digits, nose, ears or penis, where end-arteries risk gangrene
• Other uses — acute severe asthma, control of superficial bleeding, and with croup by nebulisation
• Adverse effects — anxiety, tremor, palpitation, headache, arrhythmia, and cerebral haemorrhage from a hypertensive surge

Dopamine — Dose-dependent Effects

• Dopamine illustrates that receptor selectivity is a matter of dose, not an intrinsic property — the same infusion produces opposite vascular effects at different rates
• Noradrenaline has replaced dopamine as first-line in septic shock, because dopamine caused significantly more arrhythmia in comparative trials

Adverse Effects and Interactions

• General — tachycardia, arrhythmia, hypertension, angina, tremor, anxiety, hyperglycaemia, hypokalaemia (beta2)
• Noradrenaline extravasation causes local necrosis, and must be given through a central line; the antidote is local infiltration of phentolamine
• The cheese reaction — tyramine in fermented foods is normally destroyed by intestinal and hepatic MAO; with an MAO inhibitor it reaches the circulation, displaces noradrenaline and causes a hypertensive crisis
• Beta-blockers plus adrenaline — unopposed alpha action causes severe hypertension and reflex bradycardia
• Halothane sensitises the myocardium to catecholamines, risking ventricular arrhythmia

Applied Aspects

• Learn the anaphylaxis dose exactly — 1:1000 means 1 mg per mL, so 0.5 mg is 0.5 mL intramuscularly; confusion between 1:1000 and 1:10,000 has caused fatal errors
• Adrenaline is given intramuscularly in anaphylaxis, not subcutaneously (too slow) and not intravenously except by experienced hands with monitoring
• Noradrenaline is the first-line vasopressor in septic shock, having displaced dopamine, which causes more arrhythmia
• Salbutamol lowers serum potassium, which is exploited in hyperkalaemia but must be remembered when large doses are given in asthma
• Warn patients on MAO inhibitors about tyramine-rich foods — cheese, wine, pickled and fermented items — and about proprietary cold remedies containing ephedrine
• Check for adrenaline in the local anaesthetic before a ring block; plain lignocaine must be used for digits
• Dobutamine is preferred to dopamine in cardiogenic shock, giving inotropy with less tachycardia and arrhythmia
• Beta2 agonists for tocolysis are now largely replaced by nifedipine and atosiban, which are better tolerated
• Long-acting beta2 agonists must never be used alone in asthma — monotherapy increases mortality; they are always combined with an inhaled corticosteroid
• Phenylephrine nasal drops cause rebound congestion if used beyond a few days, and patients then escalate the very drug causing the problem
• Every patient prescribed an adrenaline auto-injector must be taught to use it, and to carry two — a device left at home or used incorrectly saves nobody

Classification of Adrenergic Blockers

Beta-blockers — Actions and Uses

Adverse Effects and Contraindications

• Bronchospasm — beta2 blockade; asthma is a contraindication, and even cardioselective agents are used only with care
• Bradycardia and heart block; contraindicated in second and third degree block
• Worsening of acute cardiac failure and of peripheral vascular disease (cold extremities, claudication)
• Masking of hypoglycaemia in diabetics — tremor and palpitation are suppressed, though sweating is preserved because it is cholinergic; recovery from hypoglycaemia is also delayed
• Metabolic — raised triglycerides and reduced HDL; impaired glucose tolerance
• CNS — fatigue, nightmares, depression and reduced exercise tolerance, chiefly with lipid-soluble agents such as propranolol
• Abrupt withdrawal causes rebound angina, arrhythmia, hypertension and infarction, from receptor up-regulation; the dose must always be tapered
• Impotence, a frequent unstated reason for non-adherence

Alpha-blockers — Uses and Problems

• Phaeochromocytoma — phenoxybenzamine before surgery, with a beta-blocker added only afterwards; phentolamine for intra-operative crises
• Benign prostatic hyperplasia — tamsulosin, alfuzosin relax prostatic and bladder neck smooth muscle, giving rapid symptomatic relief
• Hypertension — prazosin and doxazosin; now used chiefly as add-on therapy
• First-dose phenomenon — marked postural hypotension and syncope after the first dose of prazosin; the first dose is small and given at bedtime
• Other effects — reflex tachycardia (much less with alpha1-selective agents), nasal stuffiness, failure of ejaculation, and intra-operative floppy iris syndrome with tamsulosin, which the ophthalmic surgeon must be told about before cataract surgery

Comparison of Alpha and Beta Blockade

Applied Aspects

• Never stop a beta-blocker abruptly — taper over one to two weeks; sudden withdrawal has precipitated fatal infarction
• Alpha before beta in phaeochromocytoma, without exception
• Give the first dose of prazosin at bedtime and warn the patient about standing up
• Beta-blocker overdose is treated with atropine, fluids, and glucagon, which raises cardiac cAMP by a route that bypasses the blocked beta receptor
• Ask about asthma before prescribing any beta-blocker, including timolol eye drops — topical ocular beta-blockers are absorbed systemically and have caused fatal bronchospasm
• Tell the ophthalmologist if a patient takes tamsulosin, because floppy iris syndrome complicates cataract surgery and forewarning changes the technique
• Beta-blockers are no longer first-line for uncomplicated hypertension in most guidelines, but remain first-line after infarction, in angina, in arrhythmia and in cardiac failure
• Esmolol has a half-life of minutes, which makes it useful where the effect may need to be withdrawn quickly — in perioperative and intensive care
• Labetalol is the beta-blocker of choice in pregnancy, and atenolol is avoided because of fetal growth restriction
• Timolol eye drops are absorbed systemically and have caused fatal bronchospasm and bradycardia; punctal occlusion after instillation reduces this

Classification of Drugs Used in Cardiac Failure

• The drugs that make patients feel better and the drugs that keep them alive are largely different.
• Diuretics relieve breathlessness within hours and change no survival curve.
• Beta-blockers make the patient feel briefly worse and add years. Treatment must therefore include both, and a patient who feels well on diuretics alone is being undertreated.

Digoxin — Mechanism of Action

Digoxin inhibits the membrane Na+/K+ ATPase → Intracellular sodium rises → The Na+/Ca2+ exchanger, which normally expels calcium using the sodium gradient, works less effectively → Intracellular calcium rises and more is stored in the sarcoplasmic reticulum → Increased force of contraction — positive inotropy → Separately, digoxin increases vagal tone and reduces sympathetic activity → Slowed SA node discharge and AV conduction — negative chronotropy and dromotropy

• The two actions are independent — inotropy is direct and electrolyte-based; the rate-slowing is neural and vagal. That is why digoxin is useful for rate control in atrial fibrillation quite apart from any effect on contractility
• Potassium competes with digoxin for the same site on the ATPase — so HYPOkalaemia increases toxicity and hyperkalaemia reduces its effect

Pharmacokinetics and Uses of Digoxin

• Oral bioavailability about 70%; large volume of distribution (about 440 L), so it is not removed by dialysis
• Mainly excreted unchanged by the kidney — the dose must be reduced in renal impairment and in the elderly
• Half-life about 36 to 48 hours; steady state takes about a week without a loading dose
• Narrow therapeutic index — therapeutic range roughly 0.5 to 2.0 ng/mL, and toxicity may occur within it
• Uses — atrial fibrillation and flutter with fast ventricular rate (particularly with coexisting heart failure), and chronic heart failure with persisting symptoms despite optimal therapy
• Digoxin controls the rate at rest but poorly during exercise, because exercise withdraws the vagal tone it depends on — a beta-blocker is better for ambulant patients

Digoxin Toxicity

Precipitating factors

• Hypokalaemia — the commonest and most important, usually caused by the diuretic given alongside; also hypomagnesaemia and hypercalcaemia
• Renal impairment and old age, reducing clearance
• Hypothyroidism, hypoxia, acidosis, myocardial ischaemia
• Interacting drugs — quinidine, amiodarone, verapamil, macrolides and itraconazole raise digoxin levels (P-glycoprotein inhibition); diuretics act indirectly through potassium

Management of toxicity

• Stop digoxin and any potassium-losing diuretic; correct potassium and magnesium
• Treat bradyarrhythmias with atropine; a temporary pacemaker if needed
• Phenytoin or lignocaine for ventricular arrhythmia; avoid DC cardioversion where possible, as it may precipitate intractable ventricular fibrillation
• Digoxin-specific antibody fragments (Fab) for severe toxicity — life-threatening arrhythmia, hyperkalaemia or massive overdose. Dialysis is useless because of the large volume of distribution

Diuretics in Cardiac Failure

Applied Aspects

• Start beta-blockers at a very low dose and increase slowly, and never during acute decompensation — "start low, go slow, and not when wet"
• Monitor potassium and renal function on any combination of ACE inhibitor, spironolactone and diuretic; the combination causes dangerous hyperkalaemia, and this is a common cause of avoidable admission
• Check the digoxin level at least 6 hours after the dose, and interpret it alongside potassium, renal function and the clinical picture — toxicity occurs at "therapeutic" levels if potassium is low
• Daily weight is the most useful home measure of fluid status, and patients can be taught to adjust their diuretic dose within limits
• Salt and fluid restriction, and avoiding NSAIDs, which cause salt retention and blunt diuretics; a frequent and avoidable cause of decompensation
• In India, rheumatic heart disease remains a major cause of failure in the young, so secondary penicillin prophylaxis matters as much as any pharmacological treatment
• Digoxin is now a fourth-line drug in heart failure, used for persisting symptoms or for rate control, not as an early inotrope
• Ask about visual symptoms and appetite at every review of a patient on digoxin — anorexia and yellow vision often precede arrhythmia
• Sacubitril-valsartan must not be given within 36 hours of an ACE inhibitor, since the combination markedly increases the risk of angio-oedema
• Patient education changes outcome more than most dose adjustments — daily weights, salt restriction, recognising worsening breathlessness early, and never stopping tablets because of feeling well

Classification of Antianginal Drugs

Nitrates — Mechanism

Nitrate is denitrated in vascular smooth muscle, requiring sulphydryl (–SH) groups → nitric oxide is released → Nitric oxide activates guanylyl cyclase → cGMP rises → protein kinase G → dephosphorylation of myosin light chain → smooth muscle relaxation → Predominantly venous at usual doses → reduced venous return → reduced preload, ventricular volume and wall tension → Reduced myocardial oxygen demand — the chief antianginal mechanism

• The main benefit is reduced preload, not coronary dilatation — a point regularly examined. In atheromatous vessels the diseased segment dilates poorly; what helps is unloading the ventricle
• Nitrates also redistribute flow to the subendocardium, which is the most ischaemia-prone layer, and relieve coronary spasm in variant angina

Nitrate Preparations and Tolerance

• Nitrate tolerance develops within 24 hours of continuous exposure, from depletion of sulphydryl groups and neurohumoral counter-regulation
• Prevented by a nitrate-free interval of 8 to 12 hours daily — patches removed overnight, and asymmetric oral dosing (for example 8 am and 2 pm rather than twelve-hourly)

Adverse Effects and Interactions

• Throbbing headache — the commonest; from meningeal vasodilatation; usually settles in a few days and is not a reason to stop
• Postural hypotension, dizziness, flushing, reflex tachycardia
• Methaemoglobinaemia in overdose
• Absolute contraindication with phosphodiesterase-5 inhibitors (sildenafil, tadalafil) — both raise cGMP by different routes, and the combination causes profound, sometimes fatal hypotension. The interval must be at least 24 hours (48 for tadalafil)
• Avoid in hypertrophic obstructive cardiomyopathy, severe aortic stenosis and right ventricular infarction, where the ventricle depends on preload

Calcium Channel Blockers

Management of Acute Coronary Syndrome

• Oxygen is given only if the saturation is low — routine oxygen in a normoxic patient confers no benefit and may cause harm through coronary vasoconstriction

Applied Aspects

• Teach patients how to use sublingual glyceryl trinitrate — sit down first (it causes hypotension), do not swallow the tablet, and seek help if pain persists beyond 15 minutes or two doses
• Tablets lose potency within about 8 weeks of opening the bottle; a burning sensation under the tongue suggests the tablet is still active; spray preparations keep better
• Never give a nitrate to a patient who has taken sildenafil — ask directly, since patients rarely volunteer it, and the interaction has killed
• Verapamil must not be combined with a beta-blocker, and neither should be given in acute failure
• Ankle oedema from amlodipine does not respond to diuretics, because it is caused by precapillary dilatation rather than by fluid overload; reducing the dose or adding an ACE inhibitor helps
• Every patient with angina needs aspirin and a statin unless contraindicated — the symptomatic drugs do not substitute for them
• Increasing frequency or severity of angina, or pain at rest, indicates an acute coronary syndrome and needs urgent assessment, not a higher dose of nitrate
• Variant (Prinzmetal) angina is caused by spasm, and responds to nitrates and calcium channel blockers; beta-blockers may worsen it by leaving alpha-mediated constriction unopposed
• Ivabradine slows the sinus node without negative inotropy, which makes it useful where a beta-blocker is contraindicated or the rate remains high on maximal beta-blockade

Vaughan Williams Classification

Amiodarone

• Class III principally, but has properties of all four classes — sodium and calcium channel block, beta-blockade and potassium channel block; the most broadly effective antiarrhythmic
• Uses — atrial fibrillation (conversion and maintenance), ventricular tachycardia and fibrillation, and in cardiac arrest refractory to defibrillation; effective where structural heart disease makes other agents unsafe
• Remarkable pharmacokinetics — volume of distribution about 5,000 L and a half-life of 25 to 100 days; a loading regimen is essential and effects persist for months after stopping

Proarrhythmia and QT Prolongation

• Antiarrhythmic drugs can cause arrhythmia — the central paradox of the class
• Torsades DE pointes — polymorphic ventricular tachycardia with a twisting axis, occurring on a background of prolonged QT; caused by class IA and III drugs, and by many non-cardiac drugs
• Non-cardiac drugs prolonging QT — erythromycin and clarithromycin, fluoroquinolones, antipsychotics (haloperidol), antidepressants, ondansetron, antifungals, antimalarials
• Precipitated by hypokalaemia, hypomagnesaemia, bradycardia, female sex, congenital long QT syndrome, and combining two QT-prolonging drugs
• Treatment — stop the drug, intravenous magnesium sulphate, correct potassium, and increase the rate by pacing or isoprenaline; ordinary antiarrhythmics make it worse
• The cast trial showed that flecainide and encainide, given after myocardial infarction to suppress ventricular ectopics, increased mortality — the classic warning against treating a surrogate marker rather than an outcome

Drugs for Specific Arrhythmias

Adenosine and Other Agents

Applied Aspects

• Always correct potassium and magnesium first — many arrhythmias resolve with electrolyte correction alone, and no antiarrhythmic works reliably in their presence
• In atrial fibrillation, rate control is as good as rhythm control for most patients, and carries less drug toxicity
• Anticoagulation, not the antiarrhythmic, prevents the stroke in atrial fibrillation; the decision is made on the CHA2DS2-VASc score and is independent of whether rhythm is restored
• Baseline and follow-up tests before amiodarone — thyroid, liver, chest radiograph, and eye examination; and warn about sun protection
• Review every drug list for QT-prolonging combinations, particularly when adding an antibiotic or antiemetic to a patient already on an antiarrhythmic or antipsychotic
• A defibrillator, not a drug, is the treatment for pulseless ventricular tachycardia and fibrillation; drugs are adjuncts and never delay defibrillation
• Adenosine is contraindicated in asthma (bronchospasm) and its effect is blocked by theophylline and potentiated by dipyridamole
• Verapamil must never be given for a broad-complex tachycardia of uncertain origin — if it is ventricular tachycardia, the result may be fatal hypotension
• An implantable defibrillator outperforms every antiarrhythmic drug for prevention of sudden death in high-risk patients, and drugs are increasingly used to reduce shocks rather than as primary treatment

Classification of Diuretics

Loop Diuretics in Detail

• Inhibit the Na-K-2Cl cotransporter in the thick ascending limb, abolishing the medullary concentration gradient so the urine cannot be concentrated
• Also cause loss of calcium and magnesium, since their reabsorption depends on the lumen-positive potential created by potassium recycling — hence their use in hypercalcaemia
• Act from the luminal side, so they must be secreted into the tubule; this is why they still work in renal impairment (given a large enough dose) and why they compete with uric acid secretion, causing hyperuricaemia
• Intravenous frusemide venodilates within minutes, relieving pulmonary oedema before any urine is passed — a mechanism independent of diuresis
• Uses — acute pulmonary oedema, cardiac failure, nephrotic syndrome, cirrhosis with ascites, hypercalcaemia, hyperkalaemia, and acute kidney injury (to convert oliguric to non-oliguric failure, though this does not improve survival)

Adverse Effects BY Class

• Thiazides retain calcium; loop diuretics lose it — so thiazides are used to prevent recurrent calcium stones and may help osteoporosis, while loop diuretics are used to treat hypercalcaemia. The commonest single point of confusion in the topic

Uses of Individual Agents

Diuretics and Potassium

• Combining a loop or thiazide with a potassium-sparing agent balances the effect and is often better than potassium supplements, which are poorly tolerated
• Hypokalaemia is dangerous chiefly through arrhythmia, and its risk is multiplied by digoxin and by any QT-prolonging drug

Applied Aspects

• Monitor electrolytes and renal function after starting or increasing any diuretic; hypokalaemia and hyponatraemia are the commonest causes of admission related to these drugs
• Combine a loop with a thiazide for resistant oedema — "sequential nephron blockade" is markedly synergistic, but causes profound electrolyte loss and needs close monitoring
• Give diuretics in the morning, and the second dose by early afternoon, so that nocturia does not destroy sleep and adherence
• Spironolactone plus an ACE inhibitor plus NSAIDs is a recognised recipe for lethal hyperkalaemia, particularly in the elderly with impaired renal function
• Diuretic resistance may be due to poor adherence, excess salt intake, NSAIDs, gut oedema impairing absorption, or hypoalbuminaemia; look for a cause before escalating the dose
• In cirrhotic ascites, spironolactone comes first, with frusemide added in a ratio of about 100:40 mg; reversing the order causes hypokalaemia and precipitates encephalopathy
• Correct hypokalaemia before it causes harm — it precipitates digoxin toxicity, arrhythmia and, in cirrhosis, hepatic encephalopathy through increased ammonia production
• Ototoxicity of loop diuretics is dose- and rate-related, so intravenous frusemide is given slowly, and the combination with an aminoglycoside is avoided where possible
• Weigh the patient daily rather than relying on charts — a loss of about 0.5 to 1 kg a day is a safe target in oedema, and faster loss risks hypovolaemia and renal impairment
• Thiazides are ineffective once the GFR falls below about 30, and persisting with them wastes time while the patient remains congested
• Metolazone is the exception, retaining activity at low GFR, and is used briefly with a loop diuretic in resistant oedema under close supervision
• Acetazolamide is self-limiting — the metabolic acidosis it induces reduces its own effect within a few days, which is why it is a poor diuretic but a useful drug for other purposes
• Mannitol is contraindicated in established anuria and in cardiac failure, where the initial plasma expansion can precipitate pulmonary oedema
• Ask about NSAID use in any patient whose diuretic seems to have stopped working — they blunt the response by inhibiting renal prostaglandins, and are often bought without prescription

Overview of Haemostasis and Drug Targets

Vessel injury → platelet adhesion (von Willebrand factor, GPIb) and activation → Release of ADP and thromboxane A2 recruits more platelets — the target of aspirin and clopidogrel → GPIIb/IIIa receptors bind fibrinogen and cross-link platelets — the target of abciximab and tirofiban → The coagulation cascade generates thrombin, which converts fibrinogen to fibrin — the target of heparin, warfarin and the direct oral anticoagulants → Fibrin is eventually dissolved by plasmin — the target of thrombolytics and, in the opposite direction, of tranexamic acid

• Arterial thrombi are platelet-rich ("white"), forming under high shear on ruptured plaque — so antiplatelet drugs are used
• Venous thrombi are fibrin-rich ("red"), forming in stasis — so anticoagulants are used. This single distinction dictates the choice of drug throughout

Anticoagulants Compared

Warfarin — Interactions and Management

• Potentiated by — enzyme inhibitors (metronidazole, ciprofloxacin, azoles, amiodarone, cimetidine), displacement from protein binding (aspirin, sulphonamides), reduced vitamin K (broad-spectrum antibiotics), liver disease, and antiplatelet drugs adding to the bleeding risk
• Antagonised by — enzyme inducers (rifampicin, carbamazepine, phenytoin, barbiturates, St John wort) and a high dietary vitamin K intake (green leafy vegetables)
• Patients should keep vitamin K intake consistent rather than avoid it — the dose is titrated to habitual diet
• Management of a high INR — withhold doses; oral vitamin K if the INR is very high or there is minor bleeding; prothrombin complex concentrate with intravenous vitamin K for major bleeding
• Direct oral anticoagulants — dabigatran (direct thrombin inhibitor) and rivaroxaban, apixaban, edoxaban (factor Xa inhibitors); fixed dose, no routine monitoring, fewer interactions, less intracranial bleeding. Reversal — idarucizumab for dabigatran, andexanet alfa for the Xa inhibitors. not used in mechanical heart valves or severe mitral stenosis, where warfarin remains essential

Antiplatelet Drugs

Thrombolytics and Antifibrinolytics

• Thrombolytics convert plasminogen to plasmin, which digests fibrin — streptokinase (antigenic, cannot be repeated within a year), alteplase, tenecteplase, reteplase (fibrin-selective, not antigenic)
• Uses — ST-elevation myocardial infarction where primary angioplasty is unavailable, acute ischaemic stroke within the window, massive pulmonary embolism, and occluded catheters
• "Time is muscle" — benefit falls sharply with delay, and is greatest within the first hour
• Contraindications — active bleeding, recent surgery or trauma, previous intracranial haemorrhage or recent stroke, aortic dissection, severe uncontrolled hypertension, bleeding diathesis
• Antifibrinolytics act in the opposite direction — tranexamic acid and aminocaproic acid block plasminogen binding to fibrin; used in trauma (given early), menorrhagia, dental extraction in haemophilia, and post-partum haemorrhage

Direct Oral Anticoagulants Compared with Warfarin

Applied Aspects

• Match the drug to the clot — antiplatelets for arterial disease (coronary, cerebral, peripheral), anticoagulants for venous thrombosis and for cardioembolic stroke prevention in atrial fibrillation
• Suspect heparin-induced thrombocytopenia if the platelet count falls by more than half after 5 to 10 days; it causes thrombosis, not bleeding, and heparin must be stopped and replaced with a non-heparin anticoagulant
• Warfarin needs patient education above all — a record book, consistent diet, awareness of interactions, and prompt reporting of bleeding; in India, access to reliable INR testing is often the limiting factor and may itself decide between warfarin and a direct oral anticoagulant
• Never assume a herbal preparation is inert — garlic, ginkgo and ginger all affect platelet function and add to bleeding risk
• Stop antiplatelets and anticoagulants appropriately before surgery, balancing bleeding against thrombotic risk; for high-risk patients, bridging with heparin may be needed
• Tranexamic acid given within 3 hours reduces death in trauma and in post-partum haemorrhage — cheap, widely available, and one of the most cost-effective interventions in emergency care
• Low molecular weight heparin accumulates in renal failure, so unfractionated heparin is preferred where clearance is very poor, being cleared by the reticuloendothelial system
• Protamine fully reverses unfractionated heparin but only partly reverses the low molecular weight form, and can itself cause hypotension and anaphylaxis if given rapidly
• Aspirin resistance is more often non-adherence or concurrent NSAID use — ibuprofen competes for the COX-1 site and can block aspirin’s antiplatelet effect if taken first
• Check platelet count before and during heparin therapy, since heparin-induced thrombocytopenia is diagnosed on a falling count and is easily missed without a baseline
• Anticoagulation decisions rest on balancing two risks, and scores exist for both — CHA2DS2-VASc for stroke and has-bled for bleeding; a high bleeding score prompts correction of reversible factors rather than automatic withholding

Definition and Synthesis

• Histamine is formed from histidine by histidine decarboxylase, and destroyed by histaminase (diamine oxidase) and by methylation
• Stored in — mast cell and basophil granules (bound to heparin), enterochromaffin-like (ECL) cells of the gastric mucosa, and histaminergic neurons of the posterior hypothalamus

Histamine Receptors

Actions of Histamine

• Cardiovascular — arteriolar vasodilatation (H1 and H2) with a fall in blood pressure; increased capillary permeability causing oedema; direct cardiac stimulation (H2)
• The triple response OF LEWIS after intradermal injection — (1) a red spot from local capillary dilatation; (2) a bright red flare spreading outward, from arteriolar dilatation mediated by an axon reflex; (3) a wheal from increased permeability and oedema
• Respiratory — bronchoconstriction, marked in asthmatics; increased bronchial secretion
• Gastric — powerful stimulation of acid secretion through H2 receptors; histamine is the final common mediator of acid secretion, which is why H2 blockers work whatever the stimulus
• Nerve endings — itching and pain
• Histamine releasers — morphine, tubocurarine, vancomycin (causing "red man" syndrome if infused rapidly), radiocontrast media, polymyxin B, and the anaphylatoxins C3a and C5a

Antihistamines — Classification

Uses of H1 Antihistamines

• Allergic disorders — allergic rhinitis, urticaria, angio-oedema, atopic dermatitis, drug and insect-bite reactions, conjunctivitis
• They relieve itch, sneezing and rhinorrhoea well, but nasal blockage poorly, since congestion is largely mediated by leukotrienes
• Motion sickness and vertigo — promethazine, cinnarizine, dimenhydrinate; effective through their antimuscarinic and central actions, so only first-generation drugs work
• Nausea and vomiting, including of pregnancy (doxylamine with pyridoxine) and of vestibular origin
• Sedation and insomnia — promethazine, diphenhydramine; a short-term measure only
• Common cold — symptomatic relief comes from the antimuscarinic drying effect, not from any antihistamine action
• As an adjunct in anaphylaxis — but never as the primary treatment, which is adrenaline

Anaphylaxis — the Clinical Consequence of Mass Histamine Release

• Adrenaline is the only drug that reverses every feature, and it must be given intramuscularly into the anterolateral thigh without waiting for intravenous access — 0.5 mg of 1:1000 in an adult, repeated after 5 minutes if needed
• Antihistamines and steroids are adjuncts, never the primary treatment; deaths continue to occur because an antihistamine was given while adrenaline was delayed
• Anaphylactoid reactions — clinically identical but caused by direct mast cell degranulation without IgE, so they can occur on first exposure; caused by radiocontrast, vancomycin, opioids and NSAIDs
• Patients on beta-blockers may respond poorly to adrenaline; glucagon is used, as it raises cardiac cAMP by a route that bypasses the blocked receptor

Adverse Effects and Applied Aspects

• First generation — sedation and impaired psychomotor performance (dangerous when driving or operating machinery, and additive with alcohol), dry mouth, blurred vision, urinary retention, constipation, and confusion in the elderly
• Contraindicated or used with care in glaucoma and prostatic enlargement, because of the antimuscarinic action
• Avoid first-generation drugs in the elderly, in whom they contribute substantially to anticholinergic burden, falls and delirium
• Antihistamines do not prevent anaphylaxis and must never delay adrenaline — a recurring and lethal error
• H2 blockers — ranitidine, famotidine, cimetidine; used for peptic ulcer and reflux. Cimetidine is a potent enzyme inhibitor and has antiandrogen effects (gynaecomastia, impotence); famotidine and ranitidine do not
• Widely sold over the counter in India in cold and cough preparations, often combined irrationally; sedation in a driver or a student is a real and unrecognised harm
• Antihistamines do not work well for nasal blockage, which is leukotriene-mediated; an intranasal corticosteroid is the more effective treatment for allergic rhinitis
• Cetirizine causes more sedation than loratadine or fexofenadine in a minority of patients, so "non-sedating" should not be taken as absolute
• Every patient who has had anaphylaxis needs an adrenaline auto-injector, training in its use, a written plan, and referral for allergy assessment to identify the trigger
• Chlorpheniramine remains widely used and useful in India because it is cheap and available parenterally, but its sedative and antimuscarinic effects must be weighed, particularly in the elderly
• H2 blockers have largely been displaced by proton pump inhibitors for acid suppression, though famotidine retains a place where a proton pump inhibitor is unsuitable
• Ranitidine was withdrawn worldwide after nitrosamine contamination was found, and famotidine is now the usual alternative
• Warn patients about driving and machinery when prescribing any first-generation antihistamine, and about the additive effect of alcohol

Eicosanoid Synthesis

Membrane phospholipids → phospholipase A2 — inhibited by corticosteroids (through lipocortin/annexin-1) → arachidonic acid → Two pathways diverge → cyclo-oxygenase (COX) — inhibited by NSAIDs → prostaglandins, prostacyclin and thromboxane A2 → 5-lipoxygenase — inhibited by zileuton → leukotrienes (LTB4, and the cysteinyl leukotrienes C4, D4, E4 — the old "SRS-A") → Cysteinyl leukotriene receptors are blocked by montelukast and zafirlukast

• Corticosteroids act above the branch point, so they suppress both prostaglandins and leukotrienes; NSAIDs act below it and suppress only the cyclo-oxygenase arm. This single fact explains why steroids are far more powerful anti-inflammatory agents — and why NSAIDs can divert arachidonic acid into the leukotriene pathway and precipitate asthma

Cox-1 and Cox-2

Classification of Nsaids

Pharmacological Actions

Adverse Effects

• Gastrointestinal — the commonest: dyspepsia, erosions, ulceration, bleeding and perforation. Caused both by loss of mucosal prostaglandins (a systemic effect, so it occurs with parenteral and rectal routes too) and by local irritation
• Renal — prostaglandins maintain renal blood flow when it is threatened, so NSAIDs precipitate acute kidney injury in hypovolaemia, cardiac failure, cirrhosis and old age; also sodium and water retention, hyperkalaemia, and analgesic nephropathy with chronic use
• Cardiovascular — increased risk of infarction and stroke (greatest with coxibs and diclofenac, least with naproxen); worsening of hypertension and cardiac failure
• Respiratory — aspirin-sensitive asthma, part of the triad with nasal polyps and rhinitis; caused by diversion of arachidonate to leukotrienes, so it is a class effect, not an allergy
• Hepatic — raised transaminases; nimesulide and diclofenac are the chief offenders
• Haematological — bleeding; rarely agranulocytosis and aplastic anaemia (phenylbutazone, metamizole)
• Skin — rashes; rarely Stevens–Johnson syndrome

Choosing Between Nsaids

• The choice is a balance of two opposing risks, and there is no NSAID that is best on both counts — which is why the patient’s own risk profile, not the drug’s reputation, should decide

Applied Aspects

• Use the lowest effective dose for the shortest time, and reassess rather than continuing indefinitely; most NSAID harm comes from prolonged use for chronic pain
• Co-prescribe a proton pump inhibitor for patients over 65, those with previous ulcer, and those on steroids, anticoagulants or antiplatelets
• Avoid NSAIDs in renal impairment, cardiac failure, cirrhosis and dehydration; the combination of an NSAID, an ACE inhibitor and a diuretic is a well-recognised cause of acute kidney injury
• Paracetamol first for simple pain and fever, particularly in children and the elderly
• Aspirin is avoided in children under 16 because of REYE syndrome
• NSAIDs are sold freely over the counter in India, and patients rarely report them; asking directly is essential in anyone with dyspepsia, renal impairment or unexplained anaemia
• Never combine two NSAIDs — toxicity is additive and efficacy is not; this includes overlooking low-dose aspirin already being taken
• Avoid NSAIDs in the third trimester, where they may close the ductus arteriosus prematurely and cause oligohydramnios
• Reassess the indication at every review — most long-term NSAID use began as a short course that was never stopped

Pharmacokinetics

• Rapidly absorbed from the stomach and upper intestine; hydrolysed to salicylic acid, which is the active moiety for most effects
• Highly bound to plasma albumin (80–90%), and displaces warfarin, sulphonylureas, methotrexate and bilirubin
• Metabolism shows a change of order — first-order at low doses, zero-order at anti-inflammatory and toxic doses, because conjugation with glycine and glucuronic acid saturates. Hence a small dose increase can cause a large rise in level
• Excretion is greatly increased by alkalinising the urine, since the ionised salicylate cannot be reabsorbed — the basis of treatment in poisoning

Dose-dependent Actions

Therapeutic Uses

• Cardiovascular prophylaxis — acute coronary syndrome (300 mg chewed), and lifelong secondary prevention after infarction, stroke or transient ischaemic attack
• Analgesic and antipyretic — now largely replaced by paracetamol and ibuprofen
• Acute rheumatic fever — still a standard treatment for the arthritis, in which the response is dramatic and almost diagnostic
• Kawasaki disease — one of the few paediatric indications, given with intravenous immunoglobulin
• Pre-eclampsia prophylaxis — low-dose aspirin from early pregnancy in women at high risk
• Possible reduction in colorectal cancer with long-term use, though not an accepted indication on its own