Pharmacokinetics & Adverse Drug Reactions
1. What this chapter covers, and how NEET PG actually tests it
Pharmacokinetics is usually learned as a set of formulas, which is why it feels arbitrary.
Each parameter exists to answer exactly one clinical question, and knowing which question makes the formula obvious.
Volume of distribution answers how much drug is needed to fill the body, so it sets the loading dose.
Clearance answers how fast drug is removed, so it sets the maintenance dose.
Half-life answers how long the drug persists, so it sets the dosing interval and the time to reach steady state.
| Parameter | Question it answers | Clinical use |
|---|---|---|
| Bioavailability | How much reaches the circulation | Route and dose conversion |
| Volume of distribution | How much fills the body | Loading dose |
| Clearance | How fast is it removed | Maintenance dose |
| Half-life | How long does it persist | Dosing interval, steady state |
| Order of kinetics | Does rate depend on concentration | Toxicity prediction |
2. Absorption and bioavailability
2.1 What limits absorption
Only unionised, lipid-soluble drug crosses membranes readily, so the pH of the compartment determines how much is available to cross.
Weak acids are unionised in acid and are therefore absorbed in the stomach; weak bases are unionised in alkali and are absorbed in the small intestine.
Despite that rule, most oral absorption occurs in the small intestine regardless of the drug, because its surface area is so much greater that it overwhelms the pH effect.
Ion trapping is the same principle applied to elimination: alkalinising the urine ionises a weak acid such as aspirin and traps it in the tubule, which is why urinary alkalinisation is used in salicylate poisoning.
2.2 Bioavailability and first pass
Bioavailability is the fraction of an administered dose reaching the systemic circulation unchanged, and it is 100 per cent for an intravenous dose by definition.
First-pass metabolism is why some oral doses must be far larger than the intravenous equivalent, and it occurs in gut wall and liver before the drug ever reaches the systemic circulation.
Sublingual, rectal to a partial extent, transdermal and inhalational routes bypass it.
Glyceryl trinitrate is given sublingually for precisely this reason, since oral administration would leave almost nothing active.
3. Distribution, clearance and half-life
3.1 Volume of distribution
Volume of distribution is an apparent volume, not a real one, and it can far exceed total body water.
A very large volume of distribution means the drug has left the plasma and concentrated in tissue, which is why such drugs cannot be removed by dialysis.
Digoxin, with a volume of distribution of several hundred litres, is the standard example, and this is why digoxin toxicity is treated with antibody fragments rather than dialysis.
Drugs confined to plasma by high protein binding, such as warfarin, have small volumes of distribution.
3.2 Clearance and steady state
The loading dose depends only on volume of distribution, so it does not change in renal or hepatic impairment.
The maintenance dose depends on clearance, so it must be reduced when clearance falls.
That single distinction is the most clinically useful thing in this chapter, and it is examined repeatedly.
Steady state is reached after approximately four to five half-lives, regardless of dose or dosing interval.
The same four to five half-lives are needed for a drug to be effectively eliminated after stopping it.
3.3 Orders of kinetics
First-order kinetics means a constant fraction is eliminated per unit time, so the rate rises with concentration and the half-life stays constant. Most drugs behave this way.
Zero-order kinetics means a constant amount is eliminated per unit time, because the eliminating enzyme is saturated, so small dose increases produce large concentration rises.
Phenytoin, ethanol, aspirin at high dose, warfarin and theophylline follow zero-order kinetics, and each is correspondingly dangerous in overdose.
Phenytoin is the clearest example: moving from a therapeutic to a toxic level can follow a modest dose increase, which is why levels are monitored.
3.4 Pharmacodynamics: potency, efficacy and the curve
Pharmacokinetics is what the body does to the drug; pharmacodynamics is what the drug does to the body.
Potency is the dose required to produce an effect, and it shifts the dose-response curve left or right. Efficacy is the maximum effect achievable, and it raises or lowers the ceiling of the curve.
A more potent drug is not a better drug, since a lower dose achieving the same maximum offers no clinical advantage. Greater efficacy does matter, because it means a higher ceiling.
Furosemide has greater efficacy than a thiazide, which is why it works when a thiazide has failed; that is a ceiling difference, not a potency difference.
A full agonist produces the maximal response; a partial agonist cannot, however high the dose.
A partial agonist therefore acts as an antagonist in the presence of a full agonist, because it occupies receptors while producing less effect, which is why buprenorphine can precipitate withdrawal in someone on heroin.
An inverse agonist produces the opposite effect to the agonist, which requires the receptor to have constitutive activity.
3.5 Receptor families and onset speed
Which receptor family a drug acts on predicts how quickly it works, which is a useful first filter in an unfamiliar stem.
Ligand-gated ion channels act in milliseconds, because the effect is the ion flux itself; nicotinic receptors and GABA-A are the examples.
G protein-coupled receptors act in seconds, since a second messenger cascade must be generated; muscarinic, adrenergic and opioid receptors belong here.
Enzyme-linked receptors act over minutes to hours, as with insulin and growth factor receptors.
Nuclear receptors act over hours to days, because the effect requires gene transcription and new protein synthesis.
That last point explains why corticosteroids have no immediate action in acute asthma, and why a bronchodilator is still needed alongside them.
3.6 Antagonism and the therapeutic window
A competitive antagonist is surmountable, shifting the curve rightward with the maximum preserved.
A non-competitive or irreversible antagonist is insurmountable, lowering the maximum.
Phenoxybenzamine is the standard irreversible antagonist, which is why its alpha blockade in phaeochromocytoma cannot be overcome by surging catecholamines during tumour handling.
A narrow therapeutic index is what mandates drug level monitoring, and the drugs requiring it are a short and examinable list: digoxin, lithium, phenytoin, theophylline, warfarin, aminoglycosides, ciclosporin.
Tolerance develops gradually with repeated dosing; tachyphylaxis develops rapidly, over hours, and is typical of drugs acting through neurotransmitter depletion.
4. Metabolism and drug interactions
4.1 The two phases
Phase I reactions are oxidation, reduction and hydrolysis, performed largely by cytochrome P450, and they generally produce a more polar metabolite.
Phase II reactions are conjugation, principally glucuronidation, and they produce a water-soluble product for excretion.
Phase II reactions are preserved in the elderly and in liver disease better than phase I, which is why lorazepam, oxazepam and temazepam are preferred benzodiazepines in those groups.
Those three undergo glucuronidation only, so they have no active metabolites accumulating.
4.2 Enzyme induction and inhibition
| Inducers | Inhibitors |
|---|---|
| Rifampicin | Erythromycin, clarithromycin |
| Carbamazepine, phenytoin, phenobarbitone | Ketoconazole and azoles |
| Chronic alcohol | Acute alcohol |
| Griseofulvin | Ciprofloxacin |
| Smoking | Ritonavir, cimetidine |
| St John's wort | Grapefruit juice, valproate, isoniazid, metronidazole |
Induction requires new protein synthesis and therefore takes days to weeks; inhibition is competitive and happens within hours.
That difference in timing is the practical key: an interaction appearing the day a drug is started is inhibition, while one appearing a fortnight later is induction.
Rifampicin induction of oral contraceptive metabolism causing contraceptive failure is the classic examined consequence.
4.3 Genetic variation
Slow acetylators accumulate isoniazid, hydralazine and procainamide, and are prone to drug-induced lupus and isoniazid neuropathy.
Pseudocholinesterase deficiency prolongs suxamethonium apnoea.
G6PD deficiency causes haemolysis with primaquine, sulphonamides, nitrofurantoin and dapsone.
4.4 Excretion and special populations
Renal excretion is the sum of glomerular filtration, active tubular secretion and passive reabsorption.
Only unbound drug is filtered, so heavily protein-bound drugs are cleared slowly despite normal renal function.
Probenecid competes for the active secretion pathway, which is why it prolongs penicillin levels, and the same competition explains why it was historically used to extend scarce supplies.
Enterohepatic circulation returns drug conjugated in bile to the circulation after intestinal bacteria deconjugate it, prolonging the effective half-life.
That mechanism explains why broad-spectrum antibiotics can reduce oral contraceptive efficacy, and why cholestyramine shortens the action of drugs that undergo it.
Neonates have immature glucuronidation, which is why chloramphenicol accumulates and causes grey baby syndrome.
The elderly have reduced renal clearance, reduced phase I metabolism, a higher fat-to-water ratio increasing the volume of distribution of lipophilic drugs, and greater central nervous system sensitivity.
5. Adverse drug reactions
5.1 Classification
Type A reactions are augmented pharmacology: dose-dependent, predictable, common, and generally not fatal.
Type B reactions are bizarre: not dose-dependent, unpredictable, rare, and more often fatal.
The distinction matters because type A reactions are managed by dose reduction while type B reactions require permanent withdrawal.
Type C reactions are chronic, type D delayed such as carcinogenesis and teratogenesis, and type E are end-of-treatment withdrawal effects.
5.2 The organ toxicities worth knowing
| Toxicity | Drugs |
|---|---|
| Nephrotoxicity | Aminoglycosides, amphotericin B, cisplatin, ciclosporin, NSAIDs |
| Ototoxicity | Aminoglycosides, furosemide, cisplatin |
| Hepatotoxicity | Paracetamol, isoniazid, valproate, methotrexate |
| Pulmonary fibrosis | Bleomycin, amiodarone, busulfan, methotrexate |
| Cardiotoxicity | Doxorubicin, trastuzumab, 5-fluorouracil |
| Haemorrhagic cystitis | Cyclophosphamide, ifosfamide |
| Peripheral neuropathy | Vincristine, isoniazid, metronidazole, cisplatin |
| Gingival hyperplasia | Phenytoin, ciclosporin, nifedipine |
Aminoglycosides and cisplatin appear in both the nephrotoxic and ototoxic lists, so combining them is particularly hazardous.
Doxorubicin cardiotoxicity is cumulative and dose-limiting, and dexrazoxane is used to reduce it.
5.3 Teratogenicity
The first trimester is the period of greatest risk because organogenesis occurs then.
| Drug | Effect |
|---|---|
| Thalidomide | Phocomelia |
| Isotretinoin | Craniofacial and cardiac defects |
| Warfarin | Nasal hypoplasia, stippled epiphyses |
| ACE inhibitors | Renal dysgenesis, oligohydramnios |
| Valproate, carbamazepine | Neural tube defects |
| Tetracycline | Teeth staining, bone effects |
| Aminoglycosides | Ototoxicity |
| Lithium | Ebstein anomaly |
Warfarin is teratogenic in the first trimester and causes fetal haemorrhage later, so heparin is substituted in pregnancy because it does not cross the placenta.
5.4 Specific antidotes
| Poisoning | Antidote |
|---|---|
| Paracetamol | N-acetylcysteine |
| Opioid | Naloxone |
| Benzodiazepine | Flumazenil |
| Warfarin | Vitamin K, prothrombin complex concentrate |
| Heparin | Protamine sulphate |
| Organophosphate | Atropine plus pralidoxime |
| Digoxin | Digoxin-specific antibody fragments |
| Methanol, ethylene glycol | Fomepizole or ethanol |
| Iron | Desferrioxamine |
| Cyanide | Hydroxocobalamin, sodium thiosulphate |
N-acetylcysteine works by replenishing glutathione, which is what normally conjugates the toxic paracetamol metabolite, and it is most effective within eight hours.
Atropine in organophosphate poisoning reverses muscarinic effects only, so pralidoxime is needed to reactivate acetylcholinesterase and address nicotinic effects.
5.5 Drug development and pharmacovigilance
The clinical trial phases are examined directly, and each answers a different question.
| Phase | Participants | Question answered |
|---|---|---|
| Preclinical | Animals, cell systems | Is it plausibly safe and active |
| Phase I | 20 to 100 healthy volunteers | Is it safe, and what does the body do to it |
| Phase II | 100 to 300 patients | Does it work, and at what dose |
| Phase III | 1000 to 3000 patients | Is it better than existing treatment |
| Phase IV | Post-marketing population | What rare or long-term harms appear |
Phase I uses healthy volunteers, with the important exception of cytotoxic agents, which are too toxic to give to anyone without the disease and so enter phase I in patients.
Phase IV matters because rare adverse effects cannot be detected in a few thousand participants; a reaction occurring in one in ten thousand people needs a far larger exposed population to appear.
That is exactly how thalidomide and rofecoxib were identified, and it is the justification for spontaneous reporting systems.
In India, the Pharmacovigilance Programme of India collects such reports, and any clinician may submit one.
Causality assessment asks whether the timing fits, whether the reaction is recognised for that drug, whether it improved on withdrawal, and whether it recurred on rechallenge.
Rechallenge gives the strongest evidence but is rarely justified, since deliberately reproducing a serious reaction is difficult to defend.
6. Worked examples
Example 1
A patient with severe renal impairment requires urgent digoxin loading. How should the loading and maintenance doses be adjusted?
The two doses depend on different parameters, which is the whole point of the question.
Loading dose is volume of distribution multiplied by target concentration, and renal impairment does not change volume of distribution.
The loading dose is therefore unchanged, while the maintenance dose must be reduced because clearance has fallen.
Giving a reduced loading dose would simply delay reaching therapeutic concentration without reducing toxicity risk.
Example 2
A woman on the combined oral contraceptive pill starts rifampicin for tuberculosis and becomes pregnant two months later.
Rifampicin is a potent inducer of cytochrome P450, increasing metabolism of oestrogen and progestogen.
Induction requires synthesis of new enzyme protein, so it develops over days to weeks and persists for weeks after the drug is stopped.
The two-month interval fits induction precisely, and would not fit competitive inhibition, which acts within hours.
Alternative or additional contraception is required during rifampicin therapy and for some weeks afterwards.
Example 3
A patient on phenytoin at 300 mg daily has a level of 15 micrograms per millilitre. The dose is increased to 400 mg and the level rises to 35 with nystagmus and ataxia.
A 33 per cent dose increase producing more than a doubling of concentration is not first-order behaviour.
Phenytoin follows zero-order kinetics at therapeutic concentrations because its metabolising enzyme is already saturated, so a constant amount is cleared per unit time regardless of how much more is given.
Any additional drug therefore accumulates almost entirely, which is why phenytoin dose increases must be small and levels monitored.
7. Traps the exam sets repeatedly
Reducing the loading dose in renal impairment. Loading dose depends on volume of distribution, which is unchanged; only maintenance dose depends on clearance.
Expecting dialysis to remove a drug with a large volume of distribution. The drug is in tissue, not plasma, so dialysis clears very little of the total body burden.
Confusing the timing of induction and inhibition. Inhibition appears within hours, induction over days to weeks.
Giving atropine alone in organophosphate poisoning. It addresses muscarinic effects only, and pralidoxime is needed for the nicotinic component.
Treating all benzodiazepines as equivalent in liver disease. Lorazepam, oxazepam and temazepam undergo glucuronidation only, which is preserved better than phase I metabolism.
Assuming greater potency means a better drug. Potency only sets the dose on the label; efficacy sets the ceiling, and it is the ceiling that determines whether a drug works when another has failed.
Expecting a corticosteroid to act immediately. Nuclear receptors require gene transcription, so the onset is hours, which is why bronchodilators are still needed in acute asthma.
Summary
Every kinetic parameter answers one clinical question, and knowing the question makes the formula obvious.
Volume of distribution sets the loading dose, clearance sets the maintenance dose, and half-life sets the interval and time to steady state.
Loading dose is unchanged in organ impairment; maintenance dose must fall with clearance.
Steady state and effective elimination each take four to five half-lives.
First-order kinetics clears a constant fraction; zero-order clears a constant amount and makes overdose disproportionate, as with phenytoin.
Phase II conjugation is better preserved than phase I in the elderly and in liver disease, which determines benzodiazepine choice.
Enzyme inhibition acts within hours and induction over days to weeks, and the timing in a stem identifies which is occurring.
Type A adverse reactions are dose-dependent and managed by dose reduction; type B are unpredictable and require withdrawal.
Aminoglycosides and cisplatin are both nephrotoxic and ototoxic, and combining them compounds the risk.
Potency shifts the dose-response curve sideways while efficacy sets its ceiling, and only efficacy determines whether a drug works when another has failed.
Receptor family predicts onset speed, from milliseconds for ion channels to days for nuclear receptors.
A narrow therapeutic index is what mandates monitoring, and the drugs needing it form a short list.
Clinical trial phases each answer a different question, and phase IV exists because rare harms cannot appear in a few thousand participants.
Antidotes work by defined mechanisms, and N-acetylcysteine replenishing glutathione is the clearest example.
