OPRA Pharmacokinetics and Pharmacodynamics: Clearance, Half-Life, Monitoring

Weight and time budget

About 12 questions, or about 15 minutes. Four of the APC's 25 sample questions were in this area, and the sample includes a vancomycin dosing item, so applied pharmacokinetics is visible in the official material. In a 12-week plan, this block is first because everything else depends on it. Expect to spend roughly one and a half to two weeks, with calculations repeated through the rest of the plan.

What is tested

• Absorption and bioavailability. First-pass metabolism, routes of administration and how bioavailability changes the dose.
• Distribution. Volume of distribution and protein binding, and the situations where binding changes matter.
• Clearance, half-life and elimination. How clearance and volume determine half-life, and how half-life determines time to steady state, usually four to five half-lives.
• Loading and maintenance doses. Loading dose depends on volume of distribution. Maintenance dose depends on clearance.
• Order of kinetics. First-order for most drugs. Zero-order, or saturable, kinetics for drugs such as phenytoin and ethanol.
• Metabolism. Cytochrome P450 enzymes, inducers and inhibitors, phase II reactions and pharmacogenomic variation.
• Organ impairment. Renal impairment and dose adjustment. Hepatic impairment and extraction ratio.
• Therapeutic drug monitoring. Vancomycin, gentamicin, lithium, digoxin and phenytoin: when to sample and how to act on a result.
• Interpreting data. Plasma concentration-time curves, area under the curve and bioequivalence.
• Pharmacodynamics. Dose-response relationships, potency and efficacy.
• Special groups. Age, pregnancy, obesity and critical illness effects on drug disposition.

Local points

• Units: SI units throughout. Concentrations in mg/L or micromol/L, clearance in L/hour or mL/min, doses in mg and microgram written in full.
• Monitoring drugs: the exact target ranges and sampling times used in Australia are in the AMH and Therapeutic Guidelines. The general rules (sample at steady state, trough before the next dose for many agents) are textbook-level. Check specific targets in an Australian source before you rely on a number.
• Renal function estimates: questions may give creatinine clearance or an estimated glomerular filtration rate. Know the difference and when each is used for dosing, and check the AMH for the approach it recommends.

Three typical traps

1. Mixing which parameter drives which dose. The loading dose follows volume of distribution. The maintenance rate follows clearance. When a stem changes one of them, ask which dose is affected. Candidates who change both lose the marks.
2. Treating half-life as fixed. Half-life changes when clearance or volume changes. In renal impairment, half-life of a renally cleared drug lengthens, so time to steady state lengthens as well, and accumulation is the risk.
3. Applying first-order thinking to saturable drugs. With phenytoin and ethanol, a small dose rise near saturation can raise the concentration far more than proportionally. Do not scale linearly.

Self-check before you move on

You are ready to leave this block when you can do each of the following without notes. If you cannot, return to that point before taking more mixed blocks.

• Write half-life in terms of volume of distribution and clearance, and say what happens when each changes.
• State why a loading dose depends on volume and a maintenance dose on clearance.
• Estimate time to steady state from a half-life, and explain why it lengthens in renal impairment for a renally cleared drug.
• Explain zero-order kinetics in words, and name two drugs that show it.
• Predict whether an enzyme inhibitor or inducer raises or lowers a substrate drug level.
• Say when to sample a level for a monitored drug and what to do with a high result.
• Read peak, trough and half-life from a concentration-time curve.
• Distinguish potency from efficacy on a dose-response curve.

The aim is understanding you can apply to a new drug, not a bank of memorised cases.

How to revise this area

1. Build four relationships from memory. Half-life from volume and clearance, loading dose from volume, maintenance dose from clearance, and time to steady state from half-life. Write them until they are automatic.
2. Do five problems a day by hand. Mix dose adjustments, concentrations at a given time and renal adjustments. Keep a log of unit errors.
3. Study metabolism as a map. Make a table of inducers, inhibitors and substrates for the main enzymes. Then predict the direction of effect for common pairs, such as an inhibitor with warfarin.
4. Read curves. Practise reading a concentration-time curve for peak, trough, half-life and area under the curve.
5. Connect to therapy. For each monitored drug, write when to measure, what rises and falls, and what to do. Use pharmacology and toxicology for toxicity features.

Spaced repetition suits this area. Revisit the four relationships every few days until the exam. For the calculation methods beyond this block, see calculations, screening and safe use, and for the plan that fits it, the study plan.