GC035 Clinical Pharmacokinetics
Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in individual patients, involving the study of absorption, distribution, metabolism, and excretion to optimize dosing regimens.
Clinical Pharmacokinetics
Lecture Map: The Big Idea
This lecture, delivered by Dr. Tommy Cheung from the Division of Clinical Pharmacology and Therapeutics at HKU, is fundamentally about understanding what the body does to a drug — and how we use that understanding to design rational dosing regimens and monitor therapy. [1]
Pharmacokinetics (PK) is the mathematical and physiological framework that underpins nearly every prescribing decision you will ever make. When you adjust a dose for renal impairment, give a loading dose of digoxin, check a trough level for vancomycin, or switch from IV to oral antibiotics — you are applying pharmacokinetic principles.
1. Understand the basic concepts of pharmacokinetics (ADME) 2. Define important pharmacokinetic parameters 3. Introduce different compartmental models 4. Understand the design of therapeutic dosing and frequency 5. Understand the rationale of therapeutic drug monitoring
- PK parameters (Vd, CL, t½, AUC, F, Cmax, tmax) are tested directly in MCQs and SAQs.
- Loading dose and steady-state calculations are classic exam stems.
- Therapeutic drug monitoring (TDM) lists and rationale appear repeatedly in past papers.
- This lecture connects to: prescribing in the elderly (GC 079), drug interactions (Block A Clinical Pharmacology II), drugs and the kidney (GC 043), pharmacogenomics (Clinical Pharmacology I), and virtually every therapeutic lecture in the curriculum.
Pharmacokinetics describes what our body does on the drug: Absorption, Distribution, Metabolism, Excretion [1]
This is the fundamental distinction: Pharmacokinetics = body → drug (what the body does TO the drug), versus Pharmacodynamics = drug → body (what the drug does TO the body). Every exam question testing this distinction expects you to know this cold.
Think of a drug's journey through the body as a four-act story:
1. Absorption
Factors affecting absorption: Route of administration, Absorption environment, Dosage form (modified release, extended release), Physiological property [1]
A drug must get from its site of administration into the systemic circulation before it can reach its target. The rate and extent of absorption determine how quickly and how much drug is available.
| Factor | Explanation | Clinical Example |
|---|---|---|
| Route of administration | IV bypasses absorption entirely (100% bioavailability). Oral must survive GI tract and first-pass metabolism. | IV morphine acts within minutes; oral morphine has ~30% bioavailability due to first-pass effect |
| Absorption environment | GI pH, motility, blood flow, presence of food, health of mucosa | Antacids raise gastric pH → reduced absorption of ketoconazole (needs acid environment) |
| Dosage form | Modified/extended-release formulations control rate of drug release | Metoprolol tartrate (short-acting, BD) vs. metoprolol succinate (extended-release, OD) [3] |
| Physiological property | Drug's lipophilicity, molecular size, ionization state (pKa), transporters | Lipophilic drugs cross membranes easily; charged molecules like heparin cannot cross GI epithelium |
First-Pass Effect
After oral absorption, blood drains via the portal vein to the liver BEFORE reaching systemic circulation. Drugs with high hepatic extraction (e.g., morphine, propranolol, GTN) are extensively metabolized on this "first pass," dramatically reducing bioavailability. This is why GTN is given sublingually — it bypasses the portal circulation entirely.
2. Distribution
Distribution depends on: Binding to plasma protein, Physiological volume, Membrane permeability, Preferential tissue perfusion [1]
Once a drug reaches the bloodstream, it distributes to various body compartments. Only the free (unbound) drug is pharmacologically active — it's the free fraction that crosses membranes, binds receptors, and gets metabolized/excreted.
The lecture provides a critical table of organ blood flow:
| Organ | Blood Flow (mL/min) | Organ Mass (kg) | Normalized Flow (mL/min/kg) |
|---|---|---|---|
| Liver | 1700 | 2.5 | 680 |
| Kidneys | 1000 | 0.3 | 3333 |
| Brain | 800 | 1.3 | 615 |
| Heart | 250 | 0.3 | 833 |
| Adipose | 250 | 10 | 25 |
| Others | 1400 | 55.6 | 25 |
| Total | 5400 | 70 | — |
Why this matters: The kidneys receive the highest normalized blood flow — this is why they are such efficient excretory organs and also why they are so vulnerable to drug-induced toxicity (high drug exposure per unit mass). Adipose tissue has very low blood flow per kg, meaning lipophilic drugs accumulate slowly but persist for a long time (think diazepam, thiopental).
This table is directly from the lecture and is classic exam material:
| Compartment | Drug Examples | Why |
|---|---|---|
| Total body water | Small water-soluble molecules (ethanol) | Ethanol distributes everywhere — this is why BAC correlates with total body water |
| Extracellular water | Large water-soluble molecules (mannitol) | Mannitol is too large to enter cells; stays extracellular → osmotic diuretic |
| Blood plasma | Highly plasma protein-bound molecules; very large molecules; highly charged molecules (heparin) | Heparin is large and highly charged → cannot cross membranes → stays in plasma |
| Adipose tissue | Highly lipid-soluble molecules (diazepam) | Diazepam is lipophilic → accumulates in fat → long duration, especially in obese/elderly |
| Bone and teeth | Certain ions (fluoride, strontium) | Fluoride incorporates into hydroxyapatite crystal structure |
Most drugs bind to albumin (acidic drugs) or α1-acid glycoprotein (basic drugs). Only the free fraction is active.
Clinical relevance:
- In hypoalbuminemia (liver disease, nephrotic syndrome, malnutrition), the free fraction of highly protein-bound drugs increases → increased effect/toxicity at the same total plasma concentration
- This is why phenytoin levels must be corrected for albumin — a "therapeutic" total level may actually represent toxic free drug levels in a hypoalbuminemic patient
3. Metabolism
Metabolism: Activate pro-drug or de-activate active drug. Mostly occurs in the liver by Phase I/II reactions. Dependent on circulation, organ function, genetic variability and drug-drug interaction. [1]
Phase 1 metabolism (Cytochrome P450): Oxidation, Reduction, Hydrolysis Phase 2 metabolism (Transferase reaction): Glucuronidation, Acetylation, Methylation, Glycine conjugates, Glutathione conjugates, Sulphate conjugates [1]
| Phase | What It Does | Key Enzymes | Result |
|---|---|---|---|
| Phase I | Introduces or unmasks a functional group (-OH, -NH2, -SH) | CYP450 family (CYP3A4, CYP2D6, CYP2C9, CYP2C19) | Often produces active or reactive metabolites; may activate prodrugs |
| Phase II | Conjugates the drug/metabolite with a polar molecule | UGT, NAT, GST, SULT, COMT | Produces highly polar, inactive, easily excretable products |
Why two phases? Phase I makes the molecule chemically "handleable" by adding a reactive group. Phase II then attaches a large, water-soluble moiety to that group, making the molecule polar enough to be excreted by the kidneys or bile. Not all drugs need both phases — some undergo Phase II directly (e.g., morphine undergoes direct glucuronidation).
From the supporting material: CYP3A4 metabolizes approximately 50% of all drugs — it is the most abundant and most clinically significant isoenzyme. [4] The other key isoenzymes are CYP2D6, CYP2C9, and CYP2C19. [5]
Factors affecting drug metabolism: Pharmacogenomics, Race and ethnicity, Age and gender, Diet, Metabolic drug interaction, Disease condition, Drug-drug interaction [1]
| Factor | Mechanism | Example |
|---|---|---|
| Pharmacogenomics | Genetic polymorphisms in CYP enzymes alter metabolizer status | CYP2C19 poor metabolizers → reduced clopidogrel activation → increased CV events [6] |
| Race/ethnicity | Different allele frequencies across populations | CYP2D6 poor metabolizer phenotype more common in Caucasians (~7%) than East Asians (~1%) |
| Age | Neonates have immature enzyme systems; elderly have reduced hepatic mass and blood flow | Elderly: reduced first-pass metabolism → higher bioavailability of propranolol [7] |
| Gender | Hormonal influences on enzyme expression | Women have slightly higher CYP3A4 activity |
| Diet | Certain foods induce or inhibit CYP | Grapefruit juice inhibits intestinal CYP3A4 → increased bioavailability of simvastatin, cyclosporine |
| Disease | Hepatic disease reduces metabolic capacity | Cirrhosis → reduced CYP activity → accumulation of drugs like diazepam |
| Drug-drug interaction | Enzyme induction or inhibition by co-administered drugs | Rifampicin induces CYP3A4 → reduces cyclosporine levels → transplant rejection |
Prodrug Activation
A prodrug is pharmacologically inactive until metabolized. If the activating enzyme is polymorphic or inhibited, the prodrug won't work. Classic example: Clopidogrel requires CYP2C19 to convert it to its active metabolite. CYP2C19 poor metabolizers get subtherapeutic antiplatelet effect → this is why ticagrelor (direct-acting, not a prodrug) is preferred in ACS. [6] [8]
Excretion routes: Urinary, Biliary, Fecal, Others (e.g., breast milk) [1]
Why This Matters
The route of excretion determines which organ impairments require dose adjustment:
| Route | Mechanism | Clinical Implication |
|---|---|---|
| Renal (urinary) | Glomerular filtration, tubular secretion, tubular reabsorption | Dose reduce in CKD; key for aminoglycosides, digoxin, lithium, metformin |
| Biliary | Active secretion into bile → enters GI tract | Enterohepatic recirculation can prolong drug effect (e.g., mycophenolate) |
| Fecal | Unabsorbed drug or biliary excretion | Rifaximin acts locally in gut, >95% fecally excreted [9] |
| Breast milk | Passive diffusion of lipophilic, un-ionized, unbound drug | Important in prescribing for lactating mothers |
Concentration-Time Curve and Compartmental Models
The lecture introduces the concentration-time curve as the fundamental tool for understanding drug kinetics [1]
After a single oral dose, the plasma concentration rises (absorption phase), peaks (Cmax at time tmax), and then falls (distribution + elimination). The shape of this curve encodes all the PK information we need.
First order kinetics vs. Zero order kinetics. Only when saturation occurs would non-linear behavior become evident. [1]
| Property | First-Order Kinetics | Zero-Order Kinetics |
|---|---|---|
| Definition | Rate of elimination is proportional to drug concentration | Rate of elimination is constant, independent of concentration |
| Half-life | Constant (does not change with concentration) | Not constant (apparent t½ increases with concentration) |
| Equation | dC/dt = −kC | dC/dt = −k₀ |
| Clinical behavior | Predictable; doubling dose doubles steady-state concentration | Unpredictable; small dose increases can cause disproportionate rises in concentration |
| When it occurs | Most drugs at therapeutic doses | When metabolic enzymes are saturated |
| Examples | Most drugs (amoxicillin, metoprolol, warfarin at usual doses) | Phenytoin, ethanol at therapeutic/usual doses; heparin clearance [8] |
Why this distinction is critical: With first-order kinetics, you can confidently predict that doubling the dose will double the steady-state level. With zero-order kinetics (like phenytoin), a small dose increase can tip the patient from therapeutic to toxic because the elimination enzymes are already maxed out.
This table from the lecture is a must-memorize for understanding drug elimination:
| Number of t½ | % Drug Eliminated | % Drug Remaining |
|---|---|---|
| 1 | 50 | 50 |
| 2 | 75 | 25 |
| 3 | 87.5 | 12.5 |
| 4 | 93.75 | 6.25 |
| 5 | 96.88 | 3.12 |
| 6 | 98.44 | 1.56 |
| 7 | 99.22 | 0.78 |
The Rule of Five Half-Lives
After 5 half-lives, ~97% of the drug has been eliminated (or ~97% of steady state has been reached). This is the single most important practical rule in clinical pharmacokinetics. It applies in two critical directions:
1. Washout: After stopping a drug, wait ~5 half-lives for near-complete elimination. 2. Accumulation: After starting a drug at a fixed dose, it takes ~5 half-lives to reach steady state.
If a drug has a t½ of 24 hours → steady state in ~5 days. If a drug has a t½ of 5 days (e.g., amiodarone) → steady state in ~25 days — unacceptably long in an emergency → hence the need for a loading dose.
The seven key PK parameters: Cmax, tmax, AUC, F, Vd, CL, t½ [1]
Parameter-by-Parameter Breakdown
Cmax (Maximum Concentration)
- The peak plasma concentration after a dose.
- Determines whether you exceed the toxic threshold (too high) or achieve therapeutic effect (high enough).
- Clinically: aminoglycoside peak levels correlate with bactericidal efficacy.
tmax (Time to Maximum Concentration)
- The time at which Cmax occurs.
- Reflects the rate of absorption.
- Clinically: a faster tmax means quicker onset of action (important for analgesics, antiarrhythmics).
AUC (Area Under the Curve) [1]
AUC reflects the actual body exposure to drug after administration. Dependent on the rate of elimination and dose administered. Directly proportional to dose when the drug follows linear kinetics. [1]
- AUC is the integral of the concentration-time curve from time 0 to infinity.
- It represents total systemic drug exposure.
- Used to calculate bioavailability and clearance.
- In linear PK: AUC ∝ Dose. In nonlinear PK: AUC increases disproportionately with dose.
F (Bioavailability) [1]
Bioavailability: Fraction of the dose available to the systemic circulation F = [AUC_po × Dose_iv] / [AUC_iv × Dose_po] [1]
- F = 1.0 (100%) for IV administration by definition (the reference standard).
- For oral drugs, F < 1 due to incomplete absorption and first-pass metabolism.
Factors influencing bioavailability: Absorption environment (health of the GI tract, pH, food effect), First pass effect (genetic, drug-drug interaction) [1]
| Factor | How It Reduces F | Example |
|---|---|---|
| Poor GI absorption | Drug destroyed by acid, not absorbed | Insulin (peptide → destroyed in stomach) |
| First-pass hepatic metabolism | Liver extracts drug before systemic delivery | GTN oral F ~1%, sublingual F ~40% |
| First-pass gut wall metabolism | CYP3A4 in enterocytes metabolizes drug | Cyclosporine, midazolam |
| P-glycoprotein efflux | Transporter pumps drug back into gut lumen | Digoxin (affected by P-gp inhibitors like amiodarone) |
Vd (Volume of Distribution)
- Vd = Amount of drug in body / Plasma concentration
- This is a theoretical volume — it does not correspond to any real physiological space.
- It tells you how extensively a drug distributes out of the plasma into tissues.
| Vd Range | Interpretation | Examples |
|---|---|---|
| ~3–5 L | Drug stays in plasma | Heparin, warfarin (highly protein-bound) |
| ~14 L | Drug distributes into extracellular fluid | Mannitol |
| ~42 L | Drug distributes into total body water | Ethanol |
| >42 L (e.g., 500 L) | Drug extensively sequesters in tissues | Digoxin (~500 L), chloroquine, amiodarone |
Clinical significance of Vd:
- Loading dose = Cpmax × Vd [1] — drugs with large Vd need large loading doses
- Drugs with very large Vd are not effectively removed by hemodialysis (drug is in tissues, not plasma)
CL (Clearance) [1]
Clearance limits the time course of action of the drug at its molecular, cellular and organ targets CL = [Metabolism + Excretion] / Plasma drug concentration CL = Dose_iv / AUC OR CL = F × Dose_po / AUC [1]
- Clearance is the volume of plasma completely cleared of drug per unit time (mL/min or L/hr).
- It is the single most important parameter for determining maintenance dose at steady state.
- Total clearance = Hepatic CL + Renal CL + Other CL
Why clearance matters clinically: If a patient's renal clearance drops (CKD), total clearance drops → drug accumulates → toxicity. This is why you dose-adjust renally cleared drugs by eGFR.
t½ (Elimination Half-Life) [1]
t½ = (0.693 × Vd) / CL [1]
- The time for plasma concentration to fall by 50%.
- It is a derived parameter — it depends on both Vd and CL.
- Determines: dosing frequency, time to steady state, time to washout.
The Phenytoin Calculation Example from the lecture: [1]
Phenytoin PK parameters: Bioavailability oral 70-100%, Vd = 70L, CL = 10 L/h, Elimination t½ avg 22hrs (7-42hrs) Calculated: t½ = (0.693 × 70) / 10 = 6.74 hrs
Exam Trap: Phenytoin t½ Discrepancy
The lecture calculates t½ = 6.74 hours using linear PK parameters, but states the clinical average is 22 hours (range 7–42 hrs). This discrepancy exists because phenytoin follows nonlinear (saturable) kinetics at therapeutic doses — the apparent half-life increases as concentration rises because CYP2C9/2C19 become saturated. The 6.74 hr value applies only at very low concentrations where elimination is still first-order. This is a classic exam discriminator.
Therapeutic Dosing and Frequency
Dose depends on: Potency, Bioavailability, Volume of distribution Frequency depends on: Elimination rate Goal: Maintain peak plasma concentration below toxic concentration, and trough drug level above minimally effective level [1]
This is the therapeutic window concept:
Toxic concentration
─────────────────── ← Must stay below this
| Peak (Cmax) |
| /\ |
| / \ | ← THERAPEUTIC WINDOW
| / \ |
| Trough |
─────────────────── ← Must stay above this
Minimum effective concentrationIf a second dose is given after the first dose was completely eliminated (approx. 5 t½), this dosage regimen does not result in any drug accumulation [1]
But in practice, we dose before complete elimination — that's the whole point of maintenance dosing. Each subsequent dose adds to the residual drug from previous doses, and the plasma concentration ratchets upward until input rate = output rate. This equilibrium is steady state.
Steady state is defined as the dosing interval in which the AUC for that interval is equal to the single-dose AUC [1]
As a rule of thumb, steady state can be achieved after 5 elimination half-lives [1]
Css = (Bioavailability × Dose) / (Interval × Clearance) [1]
This equation is gold for exams. It tells you:
- ↑ Dose or ↑ F → ↑ Css
- ↑ Interval or ↑ CL → ↓ Css
- The equation does NOT depend on Vd — Vd affects how quickly you reach steady state (via t½), not the level itself
Loading dose = Cpmax × Vd [1]
Rationale: A drug does not show therapeutic activity unless it reaches the desired steady state. It takes about 4-5 half-lives to attain steady state — too long if the drug has a long half-life. A loading dose gives the desired steady state instantaneously before commencement of maintenance dose. [1]
| Drug | t½ | Time to Steady State Without LD | Why LD Needed |
|---|---|---|---|
| Digoxin | ~36 hr | ~7.5 days | Heart failure/AF needs rapid rate control |
| Amiodarone | ~40 days | ~200 days (!) | Life-threatening arrhythmia needs urgent treatment |
| Phenytoin | ~22 hr | ~4.5 days | Status epilepticus needs immediate seizure control |
| Warfarin | ~36 hr | ~7 days | Thrombosis needs timely anticoagulation |
Loading Dose vs. Maintenance Dose
Loading dose gets you TO therapeutic level quickly. It depends on Vd (how much drug you need to fill the compartment).
Maintenance dose KEEPS you at therapeutic level. It depends on Clearance (how much drug you need to replace what's being eliminated).
A patient with renal failure needs the same loading dose (Vd unchanged) but a reduced maintenance dose (CL reduced).
Linear vs. Nonlinear Pharmacokinetics
PK parameters are not expected to change when different doses are administered and/or when the drug is administered via different routes as a single dose or multiple doses. Characterized by FIRST ORDER KINETICS. Plasma concentration at steady state and AUC are proportional to dose. [1]
PK parameters may vary depending on the administered dose. Other kinetics may be involved, e.g., ZERO ORDER KINETICS. Plasma concentration at steady state and AUC will NOT be proportional to dose. [1]
First-order elimination applies only to compounds eliminated exclusively by mechanisms not involving enzymatic or active transport processes. At clinical dosages, the majority of drugs do not reach saturation concentrations. [1]
This slide is extremely high-yield — it gives specific examples at each ADME step:
| ADME Step | Mechanism | Example |
|---|---|---|
| Absorption | Saturable carrier-mediated absorption | Amoxicillin: extent of absorption decreases with increasing dose |
| Distribution | Saturable plasma protein binding | Disopyramide: protein binding is saturable → Vd increases with dose |
| Metabolism | Saturable enzymatic metabolism | Phenytoin and ethanol: saturable metabolism → ↓ hepatic CL, disproportionate ↑ AUC with dose increase |
| Excretion | Saturable active tubular secretion | Dicloxacillin: saturable active secretion → ↓ renal CL as dose increases |
Phenytoin: The Exam Darling of Nonlinear PK
Phenytoin is the #1 drug tested for nonlinear kinetics. Because its metabolizing enzymes (CYP2C9, CYP2C19) become saturated at therapeutic concentrations, a small dose increase can lead to a MASSIVE increase in plasma concentration. This is why:
- Phenytoin levels must be monitored carefully (TDM)
- Dose adjustments should be made in small increments (25-50 mg)
- The therapeutic range is narrow (10-20 mg/L)
- Toxicity presents as nystagmus → ataxia → sedation → coma in a dose-dependent fashion
Therapeutic Drug Monitoring (TDM)
Clinical practice of measuring a specific drug at designated intervals to maintain a constant concentration. Involves not only measuring drug concentrations, but also the clinical interpretation of the result. Aims at optimizing an individual's dosage regimen. [1]
1. Monitor drug compliance 2. Maintain drug efficacy especially for conditions with poorly defined clinical endpoints 3. Suspected toxicity 4. Monitor and detect drug interaction [1]
Let's unpack each:
- Compliance monitoring: A patient on an antiepileptic who keeps having seizures — is the drug failing, or are they not taking it? A subtherapeutic level answers this.
- Poorly defined endpoints: For seizure prophylaxis, you can't titrate to effect like you can with antihypertensives (where BP is the endpoint). You need a target concentration.
- Suspected toxicity: A patient on digoxin presents with nausea and yellow vision — check the level to confirm toxicity.
- Drug interactions: Starting amiodarone in a patient on digoxin → amiodarone inhibits P-glycoprotein → digoxin levels rise → check digoxin level.
Criteria: Narrow therapeutic range, Established target concentration range, Significant intra-/inter-subject variability, Significant dose-response relationship, Nonlinear pharmacokinetic profile, Availability of cost-effective drug assay [1]
Clinical outcome is unrelated to dose or plasma concentration; Dosage need not be individualized; Pharmacological effects can be clinically quantified; Wide therapeutic index [1]
Example of a drug NOT needing TDM: Antihypertensives — you measure BP directly. The clinical endpoint (BP) is easily quantifiable, and you titrate to that endpoint. No need to measure drug levels.
Example of a drug NEEDING TDM: Lithium — narrow therapeutic range (0.6-1.2 mmol/L), toxicity at > 1.5 mmol/L is life-threatening, levels vary significantly between individuals, and you cannot easily assess "mood stability" as a real-time endpoint.
Drugs requiring therapeutic drug monitoring: Digoxin, Lithium, Phenytoin, Cyclosporin, Tacrolimus, Sirolimus [1]
| Drug | Therapeutic Range | Why TDM Needed | Clinical Notes |
|---|---|---|---|
| Digoxin | 0.5–2.0 ng/mL (older); 0.5–1.0 ng/mL (HF target) | Narrow TI, renal excretion, many interactions (amiodarone, verapamil) | Toxicity: N/V, yellow vision, arrhythmias; hypokalemia potentiates toxicity |
| Lithium | 0.6–1.2 mmol/L (acute); 0.4–0.8 (maintenance) | Very narrow TI, entirely renally excreted, dehydration/NSAIDs/ACEi → toxicity | Check 12h post-dose; toxicity: tremor → confusion → seizures → renal failure |
| Phenytoin | 10–20 mg/L (total); 1–2 mg/L (free) | Nonlinear kinetics, saturable metabolism, highly protein-bound | Correct for albumin; toxicity: nystagmus, ataxia, sedation |
| Cyclosporin | Variable by indication | Narrow TI, metabolized by CYP3A4, many drug interactions | Nephrotoxic; trough (C0) or 2-hour post-dose (C2) monitoring |
| Tacrolimus | 5–20 ng/mL (varies by time post-transplant) | Narrow TI, CYP3A4/P-gp substrate, significant inter-individual variability | Nephrotoxic, diabetogenic; trough level monitoring |
| Sirolimus | 4–12 ng/mL (varies) | Narrow TI, CYP3A4 substrate | Myelosuppressive; used with calcineurin inhibitor-sparing protocols |
Commonly Tested TDM Drugs Beyond This List
While the lecture lists six drugs, examiners also commonly test TDM for:
- Aminoglycosides (gentamicin, amikacin): peak for efficacy, trough for toxicity (nephro/ototoxicity)
- Vancomycin: AUC/MIC-guided dosing now preferred; trough levels traditionally used
- Theophylline: narrow TI, nonlinear kinetics at higher doses
- Valproic acid: narrow TI, highly protein-bound
- Carbamazepine: auto-induces its own metabolism (unique!)
- Methotrexate: high-dose protocols require level monitoring for leucovorin rescue timing
Integration with Related Lectures
Physiological changes with aging affect pharmacokinetics:
- Absorption: Reduced gastric acid, slower gastric emptying → minimal clinical effect for most drugs
- Distribution: Reduced lean body mass, increased adipose → ↑ Vd for lipophilic drugs; reduced albumin → ↑ free fraction
- Metabolism: Reduced hepatic blood flow and mass → reduced first-pass effect and Phase I metabolism (Phase II relatively preserved)
- Excretion: Reduced GFR → reduced renal clearance → drug accumulation
Pharmacokinetic drug–drug interactions: The most frequent involve CYP450 isoenzymes and drug transporters such as P-glycoprotein [7]
- Pharmacokinetic interactions alter drug levels (ADME-based)
- Pharmacodynamic interactions alter drug effects without changing levels
- CYP3A4 is the most abundant CYP; key inhibitors (ketoconazole, ritonavir, grapefruit juice) and inducers (rifampicin, carbamazepine, phenytoin, St. John's wort)
Pharmacogenes typically relate to pharmacokinetics (ADME) or pharmacodynamics (target receptor). E.g., 30-35% of warfarin dose variability attributed to CYP2C9, CYP4F2 (PK) and VKORC1 (PD) polymorphisms. [6]
- Renally excreted drugs (aminoglycosides, digoxin, lithium, metformin) require dose adjustment in CKD
- The Cockcroft-Gault equation or eGFR guides dose adjustments
Exam Intelligence
| Format | Typical Stem |
|---|---|
| MCQ | "Which of the following drugs exhibits nonlinear pharmacokinetics?" / "A patient on Drug X develops toxicity after adding Drug Y. The most likely mechanism is..." |
| SAQ | "Define bioavailability. Write the formula. Name 2 factors that reduce oral bioavailability." / "Explain why a loading dose is given for digoxin." |
| Mini-case | "A 70-year-old with CKD is started on Drug X. After 2 weeks, develops toxicity. Explain the pharmacokinetic basis." |
| Trap | Correct Answer |
|---|---|
| Confusing pharmacokinetics with pharmacodynamics | PK = body → drug (ADME); PD = drug → body (effect) |
| Thinking Vd is a real anatomical volume | Vd is a theoretical proportionality constant — can exceed total body volume |
| Assuming loading dose changes with renal failure | Loading dose depends on Vd (usually unchanged in renal failure); MAINTENANCE dose is reduced |
| Forgetting phenytoin is nonlinear | Small dose changes → large concentration changes; always TDM |
| Timing TDM levels incorrectly | Draw trough levels (just before next dose); lithium: 12h post-dose; digoxin: >6h post-dose (distribution phase) |
| Thinking all drugs need TDM | Only drugs with narrow TI + poor clinical endpoint correlation + significant PK variability |
| Confusing t½ with duration of action | t½ is an elimination parameter; duration of action depends on the drug-receptor interaction and therapeutic window |
From reviewing 4th Summative MCQ/SAQ papers [10][11][12], pharmacokinetics questions have appeared testing:
- Definition and clinical application of bioavailability
- Loading dose rationale and calculation
- Steady-state timing (5 × t½ rule)
- Which drugs require TDM and why
- Nonlinear kinetics (phenytoin, ethanol)
- Drug dose adjustment in renal/hepatic impairment
- CYP450 interactions and clinical consequences
Likely Exam Questions
A 65-year-old man with heart failure is started on oral digoxin. Why is a loading dose given?
Markscheme: Digoxin has a long elimination half-life (~36h). Without loading dose, it would take ~5 × 36h = 180h (~7.5 days) to reach steady state. A loading dose achieves therapeutic plasma concentration immediately. Loading dose = target Cp × Vd. (3 marks)
Define bioavailability. Write the formula to calculate oral bioavailability.
Markscheme: Bioavailability (F) is the fraction of administered dose that reaches the systemic circulation in unchanged form. F = (AUC_po × Dose_iv) / (AUC_iv × Dose_po). For IV, F = 1 by definition. (2 marks)
A patient on phenytoin 300mg daily has a therapeutic level. The dose is increased to 350mg daily. The level rises from 15 to 35 mg/L. Explain why.
Markscheme: Phenytoin exhibits nonlinear (saturable/zero-order) pharmacokinetics. At therapeutic concentrations, CYP2C9/2C19 enzymes are near saturation. A small dose increase leads to disproportionate rise in plasma concentration because clearance decreases as metabolic capacity is exceeded. AUC is not proportional to dose. (4 marks)
Name 4 drugs that require therapeutic drug monitoring. For each, give one reason why TDM is needed.
Markscheme: (1) Digoxin — narrow therapeutic index, renal excretion affected by many interactions; (2) Lithium — very narrow TI, renally excreted, affected by hydration and co-medications; (3) Phenytoin — nonlinear kinetics, narrow TI; (4) Cyclosporin/Tacrolimus — narrow TI, significant CYP3A4 interactions, inter-individual variability. (4 marks)
Explain why maintenance dose (but not loading dose) is reduced in a patient with renal failure taking a renally excreted drug.
Markscheme: Loading dose = Cp × Vd; Vd is usually unaffected by renal failure, so loading dose unchanged. Maintenance dose replaces drug cleared per dosing interval; renal failure reduces clearance → rate of elimination decreased → maintenance dose must be reduced to prevent accumulation and toxicity. Css = (F × Dose) / (τ × CL); if CL ↓, must ↓ Dose or ↑ τ. (4 marks)
Active Recall - Clinical Pharmacokinetics
High Yield Summary
Clinical Pharmacokinetics — What you MUST know for the exam:
- PK = what the body does to the drug (ADME); PD = what the drug does to the body
- Seven key parameters: Cmax, tmax, AUC, F, Vd, CL, t½ — know definitions and formulas
- Bioavailability formula: F = (AUC_po × Dose_iv) / (AUC_iv × Dose_po)
- Half-life formula: t½ = 0.693 × Vd / CL
- Rule of 5 half-lives: ~97% steady state reached (or ~97% eliminated)
- Loading dose = Cp × Vd (depends on Vd, NOT CL); Maintenance dose depends on CL
- Renal failure: Loading dose usually unchanged; maintenance dose reduced
- Linear PK (first-order): AUC proportional to dose; most drugs. Nonlinear PK (zero-order): AUC disproportionate to dose; phenytoin, ethanol
- Phenytoin is THE classic nonlinear PK drug — small dose change → big level change
- TDM drugs from lecture: Digoxin, Lithium, Phenytoin, Cyclosporin, Tacrolimus, Sirolimus
- TDM criteria: Narrow TI, established target range, significant variability, nonlinear PK, cost-effective assay available
- Phase I = CYP450 (oxidation, reduction, hydrolysis); Phase II = conjugation (glucuronidation, acetylation, etc.)
- CYP3A4 is the most abundant CYP enzyme — metabolizes ~50% of drugs
- Steady-state concentration equation: Css = (F × Dose) / (τ × CL)
[1] Lecture slides: GC 035. Clinical pharmacokinetics.pdf (all pages) [2] Lecture slides: GC 043. Drugs and the Kidney.pdf [3] Senior notes: Block A - Clinical Pharmacology of anti-HT and anti-HF medications.pdf [4] Senior notes: Block A - Introduction to Clinical pharmacology (II) (Drug Interactions, adverse drug reactions).pdf [5] Senior notes: Learning_Points_All_Lectures.txt (Section 7: Clinical Pharmacology II) [6] Lecture slides: Clinical Pharmacology- Introduction to Clinical pharmacology (I) (Pharmaco-Genomics, Precision Medicine).pdf [7] Lecture slides: GC 079. Prescribing in older people.pdf (p4, p47) [8] Senior notes: Block A - Clinical pharmacology of antiplatelets and anticoagulation.pdf [9] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (rifaximin) [10] Past papers: 2023 Fourth Summative MCQ.pdf [11] Past papers: 2024 Fourth Summative MCQ.pdf [12] Past papers: 2025 Fourth Summative MCQ.pdf
GC034 Chronic Kidney Disease And Its Complications
Chronic kidney disease is a progressive, irreversible decline in kidney function (GFR <60 mL/min/1.73 m² for ≥3 months or evidence of kidney damage) leading to complications such as anemia, mineral-bone disorder, cardiovascular disease, electrolyte imbalances, and ultimately end-stage renal failure.
GC036 Coffee Ground Vomitustarry Stool: Upper GI Bleeding
Upper gastrointestinal bleeding is hemorrhage originating proximal to the ligament of Treitz, classically presenting with coffee-ground emesis (hematemesis of partially digested blood) and melena (black, tarry stools).