Q4 LONG ANSWER 10M ★ High-yield

Describe the factors modifying drug action and dosage. Add a note on tolerance and the placebo effect.

Pharmacology · 2nd Professional — Para-Clinical

Introduction

The response to a standard dose varies widely between individuals, and understanding why is the basis of individualising therapy.

Patient-related Factors

Factor	Effect
Body weight and surface area	Dose per kg in children; body surface area for cytotoxics; obesity increases the volume of distribution of lipid-soluble drugs
Age — neonates and infants	Immature hepatic enzymes (especially glucuronidation), immature renal function, an incomplete blood–brain barrier, less plasma protein and more body water. Hence grey baby syndrome with chloramphenicol, and kernicterus with sulphonamides
Age — the elderly	Reduced hepatic mass and blood flow, reduced renal clearance, less lean body mass and albumin, and increased CNS sensitivity. "start low and GO slow"; avoid long-acting benzodiazepines and anticholinergics
Sex	Women are usually smaller with a higher fat proportion; some drugs are more toxic (digoxin, some antiarrhythmics); pregnancy and lactation impose their own constraints
Genetic factors (pharmacogenetics)	Slow acetylators (about half of Indians) — isoniazid neuropathy, hydralazine lupus; atypical pseudocholinesterase — prolonged apnoea with succinylcholine; G6PD deficiency — haemolysis with primaquine and dapsone; CYP2D6 and CYP2C19 polymorphism; TPMT deficiency — azathioprine toxicity
Route and time of administration	Chronopharmacology — corticosteroids are given in the morning to mimic the natural rhythm and minimise adrenal suppression; statins are traditionally given at night, when cholesterol synthesis peaks
Diet and nutritional state	Protein malnutrition reduces enzymes and albumin; grapefruit juice and cruciferous vegetables alter metabolism; tyramine-rich food with MAO inhibitors

Disease-related Factors

Disease	Consequence
Liver disease	Reduced metabolism and first-pass extraction; reduced albumin; portosystemic shunting; increased CNS sensitivity. Avoid sedatives and hepatotoxic drugs; use prednisoLONE rather than prednisone
Renal disease	Reduced excretion of renally cleared drugs; reduce the dose or lengthen the interval, guided by creatinine clearance. Avoid nephrotoxic drugs
Cardiac failure	Reduced hepatic and renal perfusion; gut oedema slows absorption
Thyroid disease	Hypothyroidism slows metabolism and increases sensitivity to digoxin and opioids; hyperthyroidism does the reverse
Gastrointestinal disease	Altered absorption
The condition being treated	Aspirin lowers a raised temperature but not a normal one; morphine causes less euphoria when given for genuine pain; digoxin has a stronger effect in atrial fibrillation

CLINICAL PEARL

The elderly are the group in whom every factor points the same way. Renal clearance falls, hepatic mass falls, albumin falls, lean mass falls, receptor sensitivity rises, and polypharmacy multiplies interactions — all simultaneously. This is why "start low, go slow" and regular review of every drug are not cautious platitudes but the single most effective way to prevent iatrogenic harm.

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

Approach	Basis	Used for
Standard (fixed) dose	The same dose for all adults; adequate where the therapeutic index is wide	Most antibiotics, analgesics, antihistamines
Dose per body weight	Mg/kg; more accurate at the extremes	Children, and drugs with a narrow index
Dose per body surface area	Mg/m2; correlates better with physiological variables such as cardiac output, blood volume and glomerular filtration than weight does	Cytotoxic drugs; some paediatric prescribing
Titration to effect	The dose is adjusted against a measurable response	Antihypertensives (blood pressure), insulin (glucose), warfarin (INR), levodopa
Titration to plasma level	Therapeutic drug monitoring	Digoxin, phenytoin, lithium, aminoglycosides
Loading then maintenance	Loading dose from Vd, maintenance from clearance	Digoxin, amiodarone, phenytoin

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

All questions in General Pharmacology: Pharmacodynamics

Every Pharmacology chapter →