Pharmacokinetics & ADME

Pharmacokinetics (PK) is "what the body does to the drug" — the quantitative description of Absorption, Distribution, Metabolism and Excretion (ADME). NEET PG loves this chapter because it converts simple equations (Vd, clearance, half-life) into clinical and numerical vignettes. Master the formulas plus a handful of high-yield examples and you can crack most questions cold.

Definitions & core parameters

Pharmacokinetics deals with drug movement and concentration over time, whereas pharmacodynamics (PD) is "what the drug does to the body" (receptor, efficacy, potency). ADME governs the plasma concentration–time curve; PD governs the effect produced at that concentration.

Parameter	Definition	Formula / unit
Bioavailability (F)	Fraction of administered dose reaching systemic circulation unchanged	F = (AUC oral / AUC IV) × 100; IV = 100%
Volume of distribution (Vd)	Apparent volume into which drug distributes to give observed plasma conc.	Vd = Dose / C₀ (L or L/kg)
Clearance (CL)	Volume of plasma cleared of drug per unit time	CL = Rate of elimination / C = 0.693 × Vd / t½
Half-life (t½)	Time for plasma concentration to fall by 50%	t½ = 0.693 × Vd / CL
Elimination rate constant (k)	Fraction of drug removed per unit time	k = 0.693 / t½ = CL / Vd
AUC	Area under conc.–time curve = total drug exposure	mg·h/L

High-yield: Vd and CL are the two independent primary parameters. Half-life is a derived parameter — it depends on both (t½ = 0.693 × Vd / CL). So a drug's half-life can rise either because Vd increases or because clearance falls.

Absorption & bioavailability

Absorption is movement of drug from the site of administration into blood. The dominant mechanism for most drugs is passive diffusion of the unionised, lipid-soluble fraction across membranes.

• pH partition hypothesis: Weak acids (aspirin, phenobarbitone) are unionised and better absorbed in acidic media (stomach); weak bases (morphine, atropine) ionise in acid and are absorbed mainly from the alkaline small intestine. Despite this, the small intestine is the major site of absorption for nearly all oral drugs because of its enormous surface area.
• Ion trapping: A drug accumulates on the side of a membrane where it is more ionised. Classic example — phenobarbitone (weak acid) overdose treated with urinary alkalinisation to trap the ionised drug in tubular fluid and enhance excretion.

First-pass (presystemic) metabolism

Drug absorbed from the gut is carried by the portal vein to the liver before reaching systemic circulation; extensive hepatic (and gut-wall) metabolism here reduces oral bioavailability.

High-yield first-pass drugs (mnemonic "PROPID-MN-LL"): Propranolol, Lidocaine/Lignocaine, Nitroglycerin, Morphine, Verapamil, Imipramine, Isoprenaline, Salbutamol, Testosterone. These need a much larger oral than parenteral dose, or are given by routes bypassing the liver.

Routes that bypass first-pass: sublingual, buccal, rectal (partly), transdermal, inhalation, parenteral. GTN is given sublingually precisely to dodge near-complete first-pass loss.

High-yield: Lower oral bioavailability does not mean a drug is useless — propranolol is effective orally because active metabolites and dose titration compensate. But high inter-individual variation in first-pass makes plasma levels unpredictable.

Distribution & volume of distribution (Vd)

After absorption the drug distributes between plasma, interstitial fluid and intracellular fluid. Vd is an apparent (not real) volume linking dose to plasma concentration.

Vd = Amount of drug in body / Plasma concentration

Reference body-water compartments (70 kg adult): plasma ≈ 3 L, ECF ≈ 14 L, total body water ≈ 42 L.

Vd value	Interpretation	Examples
Small (~5 L)	Confined to plasma; large, highly plasma-protein–bound molecules	Heparin, warfarin
Intermediate (~15 L)	ECF distribution	Aminoglycosides, mannitol
~42 L	Total body water	Ethanol, phenytoin
Very large (>42 L, even >body weight)	Extensive tissue/fat sequestration	Digoxin (~500 L), chloroquine, tricyclics, amiodarone

High-yield: A large Vd → drug is poorly dialysable (most drug is in tissues, not plasma), and gives a long half-life. Digoxin's huge Vd is why digoxin toxicity is not managed by dialysis but with digoxin-specific antibody (Fab) fragments.

Factors increasing Vd: high lipid solubility, low plasma protein binding, high tissue binding. Plasma protein binding: acidic drugs bind albumin; basic drugs bind α₁-acid glycoprotein. Only the free (unbound) fraction is pharmacologically active and eliminated. Displacement interactions (e.g. sulphonamides displacing warfarin/bilirubin) transiently raise free drug.

High-yield: In neonates, sulphonamides/ceftriaxone displace bilirubin from albumin → kernicterus — hence avoid ceftriaxone in neonates with jaundice.

Metabolism (biotransformation)

The liver is the principal site. Metabolism converts lipophilic drugs into more water-soluble, excretable metabolites.

Phase I (non-synthetic — oxidation, reduction, hydrolysis): mainly via cytochrome P450 (CYP); introduces/exposes a functional group. May produce active or toxic metabolites.

Phase II (synthetic — conjugation): glucuronidation, sulphation, acetylation, glutathione conjugation, methylation. Usually yields inactive, highly polar, readily excreted products. Glucuronidation (UGT) is the commonest.

Flow of biotransformation: Lipophilic drug → Phase I (CYP adds –OH/–COOH) → Phase II (conjugation) → water-soluble metabolite → renal/biliary excretion.

High-yield CYP enzyme inducers (mnemonic "CRAP GPS"): Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbitone, Sulphonylureas/Smoking, St John's wort. Inducers ↓ plasma levels of co-administered substrates (e.g. rifampicin lowers OCP efficacy → contraceptive failure).

High-yield CYP inhibitors (mnemonic "SICKFACES.COM"): Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (acute), Chloramphenicol, Erythromycin/clarithromycin, Sulphonamides, Ciprofloxacin, Omeprazole, Metronidazole, Grapefruit juice. Inhibitors ↑ plasma levels → toxicity.

Important active/toxic metabolites: codeine → morphine (via CYP2D6); paracetamol → NAPQI (hepatotoxic, detoxified by glutathione; saturation in overdose causes hepatic necrosis — antidote N-acetylcysteine); primidone → phenobarbitone; enalapril → enalaprilat (prodrug). Pharmacogenetics: slow vs fast acetylators (INH, hydralazine, procainamide, dapsone) — slow acetylators get more INH-induced peripheral neuropathy and SLE-like syndrome.

High-yield: First-order metabolism is the rule. A few drugs show zero-order (saturation/Michaelis–Menten) kinetics at therapeutic doses — mnemonic "PEWZ"/"Pheny-Eth-Warf-Asp": Phenytoin, Ethanol, Warfarin, Aspirin (high dose), Theophylline, Tolbutamide. For these, small dose increments cause disproportionate, sometimes toxic, rises in plasma level.

Excretion

The kidney is the major route. Renal handling = glomerular filtration + active tubular secretion − tubular reabsorption.

• Only free drug is filtered. Highly protein-bound drugs depend on tubular secretion (e.g. penicillins via organic anion transporter — probenecid blocks secretion → prolongs penicillin action).
• Lipid-soluble/unionised drug is reabsorbed; ionised drug is trapped and excreted — basis of forced diuresis with pH manipulation.
• Other routes: biliary (with possible enterohepatic recirculation — prolongs action, e.g. OCP, morphine, digoxin), pulmonary (volatile anaesthetics, alcohol — breath analyser), milk, sweat, saliva.

High-yield — urinary pH for poisoning: Alkalinise urine (sodium bicarbonate) for acidic drugs — phenobarbitone, salicylates, methotrexate. Acidify urine (rarely used) for basic drugs — amphetamine, quinine. Remember: "Acidic drug → Alkaline urine."

Order of kinetics

Feature	First-order	Zero-order
Rate of elimination	Proportional to concentration	Constant (fixed amount/time)
Enzyme/transporter	Not saturated	Saturated
Half-life	Constant	Variable (↑ with dose)
Clearance	Constant	Decreases with dose
Plot (log conc. vs time)	Straight line	Curvilinear
Examples	Most drugs	Ethanol, phenytoin (high dose), aspirin (high dose), theophylline

High-yield: In first-order kinetics a constant fraction is eliminated per unit time; in zero-order a constant amount. Ethanol is metabolised at ~15–20 mg/dL/hour regardless of blood level — a classic zero-order example.

Half-life, steady state & dosing

• After IV bolus, plasma concentration falls; drug is ~97% eliminated in 5 half-lives (50→75→87.5→93.75→96.875%).
• On repeated dosing / infusion, steady state (Css) is reached in ~4–5 half-lives — independent of dose and dosing interval. Dose and interval determine the level, not the time to reach steady state.
• Loading dose = Css × Vd / F — used to attain therapeutic level rapidly (digoxin, heparin, lignocaine). Determined by Vd.
• Maintenance dose rate = Css × CL / F — determined by clearance, replaces what is eliminated.

High-yield: Loading dose ∝ Vd; maintenance dose ∝ clearance. In renal/hepatic impairment, clearance falls → reduce maintenance dose (or lengthen interval); the loading dose usually stays unchanged because Vd is unaltered.

Quick worked examples

• Vd: 500 mg IV gives C₀ of 10 mg/L → Vd = 500/10 = 50 L.
• Clearance: CL = 0.693 × Vd / t½. If Vd = 50 L and t½ = 5 h → CL = 0.693 × 50 / 5 = 6.93 L/h.
• Half-life from k: if k = 0.1 /h, t½ = 0.693/0.1 = 6.93 h.

Dosing in organ impairment

• Renal impairment: for renally-excreted drugs (aminoglycosides, vancomycin, digoxin, lithium, many β-lactams) reduce dose or extend interval; guide with creatinine clearance (Cockcroft–Gault) and therapeutic drug monitoring (TDM).
• Hepatic impairment: caution with high–first-pass and high–hepatic-extraction drugs (propranolol, morphine, lignocaine); reduced metabolism and hypoalbuminaemia raise free drug.

Bioavailability vs bioequivalence

• Bioavailability = rate and extent of drug reaching systemic circulation (compare AUC, Cmax, Tmax).
• Bioequivalence = two formulations of the same drug have comparable bioavailability (90% confidence interval of AUC/Cmax ratio within 80–125%). Crucial for narrow-therapeutic-index drugs (warfarin, digoxin, phenytoin, lithium) where brand switching can cause toxicity or failure.

High-yield: Therapeutic Index = TD₅₀ / ED₅₀ (or LD₅₀/ED₅₀ in animals). Narrow-TI drugs (digoxin, lithium, warfarin, phenytoin, theophylline, aminoglycosides) need TDM.

Therapeutic drug monitoring (TDM) — when

Indicated for drugs with: narrow therapeutic index, poor concentration–dose correlation, zero-order kinetics, significant drug interactions, or where toxicity mimics disease. Classic TDM drugs: digoxin, lithium, phenytoin, theophylline, aminoglycosides, vancomycin, cyclosporine, valproate, carbamazepine. Sample at steady state; trough levels generally guide most drugs (peak + trough for aminoglycosides).

Key differentials / commonly confused concepts

Confused pair	Distinguishing point
Vd vs Clearance	Vd relates dose to concentration (governs loading dose); CL is volume cleared/time (governs maintenance dose)
Bioavailability vs Bioequivalence	F = absolute fraction reaching circulation; bioequivalence = two products comparable (80–125%)
Zero vs first order	Constant amount vs constant fraction eliminated
First-pass vs hepatic clearance	First-pass = presystemic loss before reaching circulation; hepatic clearance also acts on systemic drug
Enzyme induction vs inhibition	Induction is slow (days–weeks, ↓ levels); inhibition is rapid (↑ levels, fast toxicity)
Inducer effect onset vs inhibitor	Inhibition immediate; induction delayed (needs new enzyme synthesis)

Recently asked / exam angle

• Numericals: calculate Vd, clearance, half-life, loading and maintenance dose — memorise the four formulas; questions plug in dose and C₀.
• "Number of half-lives to steady state" = 4–5 (≈ 94–97% Css). Frequently asked as a single-line MCQ.
• Identify the first-pass drug / route that avoids first-pass (GTN sublingual).
• Match drug to order of kinetics — phenytoin/ethanol/aspirin = zero order.
• Urine alkalinisation for salicylate/phenobarbitone poisoning (image of nomogram or scenario).
• Why digoxin toxicity isn't dialysed (large Vd) — recurring concept question.
• CYP inducer causing OCP/warfarin failure (rifampicin) and inhibitor causing toxicity (erythromycin + theophylline, valproate + lamotrigine).
• Loading dose depends on Vd; maintenance on clearance — direct one-liner.
• Bioequivalence 80–125% CI and narrow-TI drug list.
• Probenecid + penicillin (blocks tubular secretion, prolongs action) — classic interaction MCQ.

Rapid revision

1. Vd = Dose / C₀; large Vd → tissue-bound, long t½, not dialysable (digoxin ≈ 500 L).
2. CL = 0.693 × Vd / t½; clearance is the main determinant of maintenance dose.
3. t½ is derived from Vd and CL: t½ = 0.693 × Vd / CL.
4. 5 half-lives ≈ complete elimination (~97%); 4–5 half-lives to reach steady state.
5. Loading dose ∝ Vd; maintenance dose ∝ clearance.
6. First-pass drugs: propranolol, lignocaine, GTN, morphine, verapamil, salbutamol; bypass via sublingual/IV/transdermal.
7. Zero-order kinetics: phenytoin, ethanol, aspirin (high dose), theophylline, warfarin — constant amount eliminated.
8. First order = constant fraction; zero order = constant amount.
9. Inducers (rifampicin, phenytoin, carbamazepine, phenobarbitone, smoking) ↓ drug levels; inhibitors (erythromycin, ketoconazole, cimetidine, valproate, grapefruit) ↑ levels.
10. Alkalinise urine for acidic poison (phenobarbitone, salicylate, methotrexate); ion trapping enhances excretion.
11. Bioequivalence = AUC/Cmax 90% CI within 80–125%; matters most for narrow-TI drugs.
12. TDM drugs: digoxin, lithium, phenytoin, theophylline, aminoglycosides, cyclosporine — sample at steady state, usually trough.