Summative Revision Notes
These notes consolidate all seven Pharmacokinetics Morning Rounds. They are written for rapid pre-exam revision — not first-time learning. Each section heading links to its quiz. The formula reference blocks are printed in the format examiners expect. Every trap identified in the round debriefs appears here as a single-line recall badge.
| Feature | Zero-Order | First-Order |
|---|---|---|
| What is constant? | Amount eliminated per unit time | Fraction (%) eliminated per unit time |
| Rate depends on concentration? | No — rate is fixed | Yes — rate falls as concentration falls |
| Half-life concept | Does not apply (changes with dose) | Constant; independent of dose |
| Plasma conc. vs time plot | Straight line (linear) | Exponential decay (log-linear straight) |
| Clinical examples | Alcohol, phenytoin (high dose), aspirin (OD) | Most drugs at therapeutic doses |
Vd is not a real anatomical volume. It is the hypothetical volume needed to contain all the drug in the body at the same concentration as measured in plasma. A drug with Vd = 700 L in a 70 kg person has not disappeared — it has been sequestered in tissues, leaving almost nothing in plasma. This is why haemodialysis, which filters only plasma, is futile for drugs with large Vd. The swimming pool analogy: dissolve a teaspoon of salt in a glass (high plasma concentration, small Vd) versus a swimming pool (undetectable in plasma, but the drug is still there — in tissues).
3 half-lives → 87.5% eliminated (not 75%) Zero-order: constant amount, not fraction Alcohol, phenytoin OD, aspirin OD = zero-order Most therapeutic drugs = first-order
| Half-lives elapsed | % Eliminated | % Remaining |
|---|---|---|
| 1 | 50% | 50% |
| 2 | 75% | 25% |
| 3 | 87.5% | 12.5% |
| 4 | 93.75% | 6.25% |
| 5 | 96.875% | ~3% |
Half-life governs plasma concentration, not always duration of clinical effect. Phenelzine (MAOI) has a plasma t½ of ~2 hours but requires a 14-day washout before starting serotonergic drugs — because it irreversibly destroys MAO enzyme, and new enzyme synthesis takes 14 days. Being at steady state does not mean reaching a new steady state instantly after a dose change — re-equilibration always takes another 4–5 half-lives.
Steady state reached in 4–5 t½ regardless of dose 95% elimination ≈ 5 × t½ MAOI washout = enzyme resynthesis, not PK clearance k = 0.693 ÷ t½ — memorise this
| Vd value | Drug location | Example |
|---|---|---|
| ~3–5 L | Confined to plasma | Heparin, warfarin, monoclonal antibodies |
| ~15 L | Extracellular fluid | Gentamicin, mannitol |
| ~42 L | Total body water | Ethanol, theophylline |
| >100 L | Extensive tissue sequestration | Chloroquine (>200 L/kg), amiodarone (~5000 L), digoxin (~500 L) |
Haemodialysis is futile for drugs with large Vd — dialysis filters plasma only. With Vd = 500 L (digoxin), less than 1% of total body drug is in plasma at any time. Loading doses are necessary when Vd is large AND half-life is long — waiting for steady state with amiodarone (t½ ~50 days, Vd ~5000 L) would take up to 275 days. The loading dose rapidly fills the large distribution volume to achieve therapeutic levels immediately.
Vd = Dose ÷ C₀ Oral LD = (Cp × Vd) ÷ F Large Vd → dialysis futile Large Vd + long t½ → loading dose needed Benchmarks: 3 L plasma, 15 L ECF, 42 L TBW
Infusion rate is given in mg/hour. Clearance is given in mL/min. You cannot divide directly. Convert first:
mL/min × 60 = mL/hour → ÷ 1000 = L/hourExample: clearance 100 mL/min = 6000 mL/hr = 6 L/hr. Infusion rate 200 mg/hr ÷ 6 L/hr = 33.33 mg/L. The distractor 50 mg/L comes from dividing by 4 (using 100 mL/min as if it were L/hr).
| Extraction ratio | Clearance depends on | Effect of cirrhosis | Examples |
|---|---|---|---|
| High (>0.7) | Liver blood flow | Dramatic rise in oral bioavailability; toxicity on normal doses | Propranolol, morphine, lignocaine, labetalol |
| Low (<0.3) | Enzyme capacity | Modest effect on bioavailability | Warfarin, diazepam, theophylline |
Css = Rate ÷ CL — convert units first CL = 0.693 × Vd ÷ t½ High extraction drugs dangerous in cirrhosis New steady state after rate change = another 4–5 t½ mL/min × 60 ÷ 1000 = L/hr
| TI value | Interpretation | Examples |
|---|---|---|
| >100 | Very wide safety margin | Penicillin, paracetamol (therapeutic range) |
| ~10 | Reasonable margin | Most antihypertensives |
| <2 | Narrow therapeutic index (NTI) — requires monitoring | Digoxin, lithium, phenytoin, warfarin, theophylline, aminoglycosides |
Potency = dose required for a given effect. Lower ED50 = more potent. Efficacy = maximum effect a drug can produce. These are independent axes. A more potent drug is not safer and not more efficacious. Botulinum toxin is the most potent substance known — its margin to lethality is correspondingly tiny. Codeine and morphine have the same ceiling effect (efficacy); morphine is simply more potent.
Classic TI uses median values — the middle of the population. CSF asks what happens when you give the dose needed to treat the most resistant 1% of patients (ED99) to the most sensitive 1% (TD1). A CSF of 2 means these two curves nearly overlap. Digoxin's CSF approaches 1 — explaining why routine therapeutic monitoring is mandatory.
TI = LD50 ÷ ED50 (not inverted) NTI drugs: digoxin, lithium, phenytoin, warfarin, theophylline, aminoglycosides Potency ≠ safety ≠ efficacy CSF = TD1 ÷ ED99 Higher TI = wider safety margin
| Drug / Scenario | Key calculation | Clinical lesson |
|---|---|---|
| Digoxin toxicity | Total body burden = Cp × Vd (4 ng/mL × 500 L = 2000 mcg) | <1% in plasma → haemodialysis futile → use Digibind |
| Theophylline maintenance | Dose = Css × CL ÷ F (convert mL/min → L/hr first) | Units trap: 40 mL/min = 2.4 L/hr, not 40 |
| Phenytoin dose increase | 33% dose rise → 200% Cp rise | Michaelis-Menten saturation: enzymes near-saturated at therapeutic levels |
| Thiopentone offset | Wakes in 10 min; t½ = 11 hours | Redistribution from brain to muscle/fat — not elimination |
| Bioavailability from AUC | F = (AUCoral/Doseoral) ÷ (AUCIV/DoseIV) | Dose-normalise before dividing — the most common error |
At low concentrations: first-order behaviour (enzymes not saturated). At high concentrations: zero-order behaviour (enzymes saturated). Phenytoin operates at the inflection point near therapeutic levels — small dose increases produce disproportionately large rises in plasma concentration. Clinical rule: adjust phenytoin in 25–50 mg increments only and recheck levels after 2 weeks. Other MM drugs: aspirin (high dose), alcohol, salicylates.
Thiopentone: highly lipophilic, rapidly enters brain (high blood flow) → unconsciousness. Then redistributes to muscle and fat (large mass) → brain concentration falls below anaesthetic threshold → patient wakes. Total body drug: barely changed. Terminal t½ of 11 hours reflects slow release from fat + hepatic metabolism, not the clinical offset. Same principle applies to diazepam single-dose clinical duration.
Total drug = Cp × Vd Digoxin toxicity → Digibind, not dialysis Phenytoin: MM kinetics, adjust in 25–50 mg steps Thiopentone offset = redistribution, not elimination Bioavailability: dose-normalise AUCs before ratio
Oral route: gut → portal vein → liver → first-pass metabolism → systemic circulation. Sublingual: superior vena cava → systemic circulation directly (bypasses liver). GTN oral bioavailability <1%; sublingual ~80%. If a patient swallows a sublingual GTN tablet — no therapeutic effect. Transdermal and IV routes also bypass first-pass.
Only free (unbound) drug is pharmacologically active, distributes across membranes, and is available for elimination. Bound drug is inert reservoir. Warfarin 99% bound: displacing 1% of binding sites doubles the free fraction from 1% to 2% — doubling pharmacological effect on the same total dose. High-risk displacing drugs: phenylbutazone, aspirin, NSAIDs, sulfonamides.
| Population | Key PK change | Dosing implication |
|---|---|---|
| Neonates | GFR ~30% adult; immature CYP450; glucuronidation deficient; TBW 80% | Extend dosing intervals; higher mg/kg Vd for water-soluble drugs; avoid chloramphenicol (grey baby syndrome) |
| Elderly | Reduced muscle mass → low creatinine production → serum Cr appears normal despite reduced GFR | Always calculate CrCl (Cockcroft-Gault); never trust serum creatinine alone |
| Pregnancy | Plasma volume +40%; albumin −20%; GFR increases; hepatic CYP activity changes | Expanded Vd dilutes drug; reduced albumin raises free fraction; NTI drugs need monitoring throughout |
| Hepatic failure | High-extraction drugs: dramatically increased oral bioavailability (portosystemic shunting) | Propranolol, morphine, lignocaine — reduce dose substantially or avoid |
| Renal failure | Clearance of renally-excreted drugs falls proportionally with GFR | Reduce dose OR extend interval; both strategies are pharmacokinetically valid |
Sarcopenia (reduced muscle mass) → less creatinine produced → serum creatinine appears "normal" despite severely impaired GFR. Cockcroft-Gault must be calculated in all elderly patients before prescribing renally-cleared drugs. A serum creatinine of 90 µmol/L in an 80-year-old woman of 45 kg may correspond to a CrCl of only 22 mL/min — severe renal impairment requiring significant gentamicin dose reduction and interval extension.
Swallowed GTN → <1% bioavailability → no effect Free drug = active drug Warfarin displacement: 1% → 2% free = double effect Elderly: calculate CrCl, never rely on serum Cr alone Neonates: extend intervals; immature CYP + GFR Pregnancy: monitor NTI drugs throughout
| Formula | Expression |
|---|---|
| Vd | Dose ÷ C₀ |
| t½ | 0.693 × Vd ÷ CL |
| CL (total body) | 0.693 × Vd ÷ t½ |
| Css (infusion) | Infusion rate ÷ CL [units must match] |
| Loading dose (IV) | Target Cp × Vd |
| Loading dose (oral) | (Target Cp × Vd) ÷ F |
| Maintenance dose | Css × CL ÷ F |
| Bioavailability (F) | (AUCoral/Doseoral) ÷ (AUCIV/DoseIV) |
| Therapeutic Index | LD50 ÷ ED50 |
| Certain Safety Factor | TD1 ÷ ED99 |
| k (rate constant) | 0.693 ÷ t½ |
mL/min → L/hr: × 60 then ÷ 1000 ng/mL = mcg/L (equivalent units) mL × concentration → ng or mcg (watch the prefix) Always match time units (hr vs min) before dividing
Digoxin: Vd 500 L, t½ 36 hr, NTI — Digibind for toxicity Amiodarone: Vd ~5000 L, t½ 40–55 days — loading dose mandatory Chloroquine: Vd >200 L/kg — dialysis futile in OD Phenytoin: MM kinetics — 25–50 mg increments only GTN: oral bioavailability <1% — sublingual/IV/transdermal only Propranolol/morphine/lignocaine: high extraction — dangerous in cirrhosis Thiopentone: offset by redistribution to fat, not elimination Warfarin 99% bound: displacement doubles free fraction
Convert units → apply formula → interpret clinically Dose-normalise AUCs before calculating bioavailability Calculate CrCl before prescribing in the elderly — serum Cr alone is unreliable Adjust phenytoin in small increments, recheck after 2 weeks In overdose: calculate Vd before deciding on dialysis In loading dose: remember to divide by F for oral route
mL/min ≠ L/hr — convert before dividing for Css 87.5% eliminated at 3 half-lives, not 75% TI = LD50 ÷ ED50 (not inverted, not subtracted) Potency ≠ safety ≠ efficacy — three independent properties Serum Cr "normal" in elderly ≠ normal renal function Doubling infusion rate doubles Css, but new SS still takes 4–5 t½ MAOI washout = enzyme resynthesis (14 days), not PK clearance (2 hrs) Dose-normalise AUC before bioavailability ratio — not raw AUC