Pharmacology chapters
Pharmacokinetics
What the body does to a drug: routes and absorption, bioavailability and first-pass effect, distribution and volume of distribution, metabolism (phase I and II, cytochrome P450), excretion, clearance, half-life, first- and zero-order kinetics, steady state, and loading and maintenance doses, with worked calculations.
- Pharmacokinetics is what the body does to the drug: absorption, distribution, metabolism and excretion. Bioavailability is the fraction reaching the systemic circulation unchanged: 100% by IV, lower orally because of incomplete absorption and first-pass metabolism in gut wall and liver (avoided by sublingual, rectal (partly), transdermal and parenteral routes).
- Volume of distribution (dose ÷ plasma concentration) shows how widely a drug spreads: small Vd = stays in plasma (heparin, warfarin); large Vd = into tissues (digoxin, chloroquine). Clearance = rate of elimination ÷ plasma concentration; half-life = 0.693 × Vd ÷ CL.
- Most drugs follow first-order kinetics (a constant fraction eliminated per unit time; steady state after 4–5 half-lives); a few saturate and follow zero-order kinetics (a constant amount per unit time: phenytoin, ethanol, high-dose aspirin). Loading dose = Vd × target concentration; maintenance dose rate = CL × target concentration.
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Overview
Pharmacokinetics (PK) describes what the body does to a drug: absorption, distribution, metabolism and excretion (ADME). Pharmacodynamics is what the drug does to the body (see pharmacodynamics).
Absorption
Most drugs cross membranes by passive diffusion of the non-ionised, lipid-soluble form. Others use carrier transport, active transport or endocytosis.
Ionisation and pH:
- Weak acids (aspirin, barbiturates) are non-ionised in acid, so they are absorbed better from an acidic environment.
- Weak bases (morphine, amphetamine) are non-ionised in alkaline conditions.
- Ion trapping in urine: alkalinising the urine traps weak acids (aspirin, phenobarbitone) and speeds their excretion; acidifying it traps weak bases.
Routes of administration
| Route | Features |
|---|---|
| Oral | Convenient, cheap; variable absorption; first-pass metabolism |
| Sublingual / buccal | Rapid; avoids first-pass (glyceryl trinitrate, buprenorphine) |
| Rectal | Partly avoids first-pass; useful in vomiting or unconscious patients (diazepam in children's seizures) |
| Intravenous | 100% bioavailability; immediate effect; precise; irritant drugs can be given; risk of infection and overdose |
| Intramuscular | Faster than oral; depot preparations (benzathine penicillin) |
| Subcutaneous | Slower, steady absorption (insulin, heparin) |
| Inhalation | Rapid, local effect on lungs (salbutamol, steroids); general anaesthetics |
| Transdermal | Steady, prolonged levels; avoids first-pass (fentanyl, nitrate, nicotine patches) |
| Intrathecal | Bypasses blood-brain barrier (spinal anaesthesia, some antibiotics, methotrexate) |
Bioavailability
Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation unchanged. IV = 100% by definition.
Reduced by: poor absorption, first-pass metabolism, destruction in the gut (benzylpenicillin by acid; insulin by enzymes), food and drug interactions (tetracycline with calcium or iron).
First-pass (presystemic) metabolism: drugs absorbed from the gut pass through the portal vein to the liver before reaching the circulation; much may be metabolised. High first-pass drugs: glyceryl trinitrate, lignocaine (so not given orally), propranolol, morphine, verapamil, imipramine.
F = AUC (oral) ÷ AUC (IV) (same dose)
Drug X: AUC after 100 mg IV = 50 mg·h/L
AUC after 100 mg oral = 20 mg·h/L
F = 20 ÷ 50 = 0.4 → 40% bioavailable
To match the IV exposure orally:
oral dose = IV dose ÷ F = 100 ÷ 0.4 = 250 mg
Distribution
- Plasma protein binding: acidic drugs bind mainly to albumin (warfarin, phenytoin, sulphonamides, NSAIDs); basic drugs to α1-acid glycoprotein. Only the free drug is active and can be metabolised or excreted. One highly bound drug can displace another (sulphonamides displace bilirubin in newborns → kernicterus; NSAIDs or sulphonamides displace warfarin).
- Blood-brain barrier: tight junctions; lipid-soluble drugs cross; inflamed meninges let penicillin in.
- Placenta: lipid-soluble drugs cross (most drugs); risk of teratogenicity.
- Redistribution: thiopentone acts briefly because it moves from brain to muscle and fat, not because it is eliminated quickly.
Volume of distribution (Vd)
The apparent volume into which a drug would have to spread to give its plasma concentration:
Vd = amount of drug in the body ÷ plasma concentration
| Vd | Meaning | Examples |
|---|---|---|
| Small (around 3–5 L, plasma volume) | Stays in plasma: large, highly protein-bound or charged | Heparin, warfarin |
| About 15–40 L | Extracellular or total body water | Aminoglycosides (ECF), ethanol (total body water) |
| Very large (hundreds or thousands of litres) | Concentrated in tissues | Digoxin, chloroquine, tricyclic antidepressants, amiodarone |
Drugs with a large Vd are not removed well by dialysis (most of the drug is in the tissues).
Vd = Dose ÷ C₀
A 500 mg IV dose gives an initial plasma level of 10 mg/L
Vd = 500 ÷ 10 = 50 L
Plasma volume ≈ 3 L, so the drug has spread well beyond the blood into tissues.
Metabolism (biotransformation)
Mainly in the liver. It usually turns lipid-soluble drugs into water-soluble metabolites for excretion, and usually inactivates them. Prodrugs are inactive until metabolised (levodopa, enalapril, cyclophosphamide, clopidogrel, codeine to morphine).
| Phase | Reactions | Notes |
|---|---|---|
| Phase I (functionalisation) | Oxidation (mainly cytochrome P450), reduction, hydrolysis | May give active or toxic metabolites; affected by age and liver disease |
| Phase II (conjugation) | Glucuronidation (commonest), acetylation, sulphation, methylation, glutathione conjugation | Usually inactive, water-soluble products; neonates have poor glucuronidation (chloramphenicol → grey baby syndrome) |
Acetylator status: slow acetylators (genetically) get more isoniazid neuropathy, hydralazine and procainamide lupus.
Cytochrome P450 (CYP): CYP3A4 metabolises the most drugs.
| Enzyme inducers (lower levels of other drugs) | Enzyme inhibitors (raise levels of other drugs) |
|---|---|
| Rifampicin | Ketoconazole, fluconazole |
| Phenytoin, carbamazepine, phenobarbitone | Erythromycin, clarithromycin |
| Chronic alcohol | Acute alcohol excess |
| Smoking (CYP1A2) | Cimetidine |
| Griseofulvin, St John's wort | Ciprofloxacin, isoniazid, valproate, grapefruit juice, omeprazole |
Clinical examples: rifampicin reduces the effect of oral contraceptives and warfarin; erythromycin or ketoconazole raise warfarin and statin levels.
Excretion
- Kidney (main route): glomerular filtration (free drug only), active tubular secretion (penicillin, probenecid blocks it), passive reabsorption (lipid-soluble, non-ionised drugs).
- Bile and faeces; enterohepatic circulation prolongs action (oral contraceptives, morphine); antibiotics that kill gut flora can break it.
- Lungs (anaesthetic gases, alcohol), breast milk, saliva, sweat.
In renal failure, reduce doses of renally cleared drugs (aminoglycosides, digoxin, lithium, metformin).
Clearance, half-life and kinetics
Clearance (CL) is the volume of plasma cleared of drug per unit time:
CL = rate of elimination ÷ plasma concentration
Half-life (t½) is the time for the plasma concentration (or amount in the body) to fall by half:
t½ = 0.693 × Vd ÷ CL
So half-life lengthens when Vd rises or clearance falls (renal or liver failure).
t½ = 0.693 × Vd ÷ CL
Vd = 50 L, CL = 5 L/h
t½ = 0.693 × 50 ÷ 5 = 34.65 ÷ 5 = 6.9 h (about 7 hours)
If kidney failure halves clearance (CL = 2.5 L/h):
t½ = 34.65 ÷ 2.5 = 13.9 h → the half-life doubles
First-order vs zero-order kinetics
| Feature | First-order (linear) | Zero-order (saturation) |
|---|---|---|
| What is eliminated per unit time | A constant fraction | A constant amount |
| Half-life | Constant | Not constant (rises with dose) |
| Why | Enzymes far from saturation | Enzymes saturated |
| Drugs | Most drugs | Phenytoin, ethanol, high-dose aspirin (and theophylline at high doses) |
| Danger | Predictable | Small dose rises → large level rises and toxicity |
First-order (t½ = 4 h), start 100 mg/L:
0 h 100 → 4 h 50 → 8 h 25 → 12 h 12.5 → 16 h 6.25 mg/L
(half lost every 4 hours, whatever the level)
After n half-lives, fraction left = (1/2)ⁿ
4 half-lives: 1/16 = 6.25% left → 93.75% eliminated
5 half-lives: 1/32 ≈ 3% left → about 97% eliminated
Zero-order (ethanol about 10 g per hour), body holds 60 g:
60 → 50 → 40 → 30 ... same amount lost each hour
time to clear = 60 ÷ 10 = 6 hours
Steady state
With repeated doses (or a constant infusion), the drug builds up until rate in = rate out: steady state.
- Reached after about 4–5 half-lives (about 94–97% of the final level), whatever the dose.
- Changing the dose changes the level at steady state, not the time to reach it.
- A loading dose reaches the target level quickly for drugs with a long half-life (digoxin, amiodarone, phenytoin, aminophylline).
Dosing calculations
- Loading dose = Vd × target plasma concentration ÷ F
- Maintenance dose rate = CL × target plasma concentration ÷ F
Target plasma level = 2 mg/L, Vd = 50 L, CL = 5 L/h, given IV (F = 1)
Loading dose = Vd × C = 50 × 2 = 100 mg
Maintenance rate = CL × C = 5 × 2 = 10 mg/h
Daily maintenance = 10 × 24 = 240 mg per day
If given orally with F = 0.5:
Loading = 100 ÷ 0.5 = 200 mg
Daily maintenance = 240 ÷ 0.5 = 480 mg per day
Loading dose depends on Vd; maintenance dose depends on clearance. In renal failure, the maintenance dose is cut; the loading dose usually is not.
Therapeutic index and drug monitoring
Therapeutic index = TD50 ÷ ED50 (toxic dose for 50% ÷ effective dose for 50%). A narrow therapeutic index means the toxic level is close to the effective level; these drugs need therapeutic drug monitoring: digoxin, lithium, phenytoin, theophylline, aminoglycosides (gentamicin), vancomycin, warfarin (by INR), ciclosporin, carbamazepine.
Expect: bioavailability and first-pass (sublingual GTN), ionisation and urine alkalinisation, protein binding and displacement (kernicterus), Vd meaning and dialysis, redistribution of thiopentone, phase I vs II, prodrugs, slow acetylators, CYP inducers and inhibitors with clinical interactions, the t½ formula, first- vs zero-order drugs, steady state in 4–5 half-lives, loading vs maintenance dose, and narrow therapeutic index drugs.
Quick revision
- ADME: absorption, distribution, metabolism, excretion.
- F = AUC oral ÷ AUC IV; IV = 100%; sublingual avoids first-pass.
- Vd = dose ÷ C; large Vd → tissues, not dialysable.
- t½ = 0.693 × Vd ÷ CL; steady state after 4–5 half-lives.
- Zero-order: phenytoin, ethanol, high-dose aspirin.
- Inducers: rifampicin, phenytoin, carbamazepine, phenobarbitone, smoking, chronic alcohol.
- Inhibitors: azoles, macrolides, cimetidine, ciprofloxacin, valproate, grapefruit.
- Loading dose = Vd × C; maintenance = CL × C.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
What is bioavailability?
The proportion of a dose that gets into the systemic circulation unchanged; it is 100% for intravenous drugs and lower for oral drugs because of incomplete absorption and first-pass metabolism.
How long does a drug take to reach steady state?
About 4–5 half-lives, whatever the dose.
Which drugs show zero-order kinetics?
Phenytoin, ethanol and aspirin at high doses.
What does the loading dose depend on?
The volume of distribution and the target plasma concentration (loading dose = Vd × target concentration ÷ bioavailability).