Pharmacokinetics, Pharmacodynamics and Pharmacovigilance

Pharmacology — Pharmacokinetics, Pharmacodynamics and Pharmacovigilance, NMC MBBS licence examination syllabus (Nepal Medical Council).

Pharmacokinetics, Pharmacodynamics and Pharmacovigilance

Give the oral dose of some drugs intravenously and you will kill the patient. The reason is a single idea.

The other pharmacology chapters cover drug classes: what each one does and when to use it. This chapter covers the principles they all assume — the reasons behind the numbers on a prescription.

Two questions organise the whole subject:

Pharmacokinetics — what the body does to the drug. Absorption, distribution, metabolism, excretion.
Pharmacodynamics — what the drug does to the body. Receptors, agonists, antagonists.

Then a third question that only appears once a drug is in use: how do we find out what it does to people who were never in the trial?

Bioavailability and the first pass

Blood leaving the gut does not go straight to the body. It travels through the portal vein to the liver first, and the liver metabolises some of the drug before it ever reaches the systemic circulation. That is the first-pass effect.

Bioavailability is the fraction of an administered dose that reaches the circulation intact. An intravenous dose is 100% by definition. An oral dose is always less — and for drugs heavily extracted by the liver, dramatically less.

This has a consequence that is genuinely dangerous in practice: the oral and intravenous doses of the same drug are often very different numbers. Giving an oral-sized dose by the intravenous route, for a drug with low oral bioavailability, delivers a large overdose. Whenever you switch route, check the dose for that route rather than carrying the old number across.

Some routes partly bypass the liver by design — sublingual, rectal and transdermal absorption drains into the systemic circulation rather than the portal vein, which is why those routes exist for drugs that would otherwise be destroyed on the first pass.

Half-life: two questions, one number

Half-life is the time for the plasma concentration to fall by half. Its usefulness is that it answers two different clinical questions with the same number.

How long until the drug is working fully? Starting a regular dose, the concentration climbs and plateaus after roughly four to five half-lives. That is the time to steady state.

How long until it has gone? After stopping, the same four to five half-lives are needed to wash out.

💡 Two practical consequences worth carrying into an exam. First, a loading dose exists precisely because waiting five half-lives is sometimes unacceptable — a larger initial dose fills the volume of distribution quickly, then a smaller maintenance dose holds it there. Second, a drug level checked before steady state is measuring a number that is still rising, so it cannot be interpreted as if it were the eventual concentration. Both of these follow from one idea rather than needing separate memorisation.

A long half-life also explains a class of interaction problem: a drug stopped today may still be present in a week, so the interaction it causes does not end when the prescription does.

Therapeutic index and monitoring

The therapeutic index is the margin between the dose that works and the dose that harms. It determines whether a drug needs measuring at all.

A wide index means large room for error — most drugs, and no routine level checking. A narrow index means the effective and toxic concentrations sit close together, so small changes in dose, in renal function, or in an interacting drug can push a patient from treated to poisoned.

Two principles govern therapeutic drug monitoring, and both are commonly got wrong:

Timing decides the number. A concentration taken shortly after a dose and one taken immediately before the next dose are entirely different measurements. A level drawn at the wrong time is not a slightly wrong answer; it is an uninterpretable one.
Treat the patient, not the level. A concentration inside the quoted range does not exclude toxicity in a patient who looks toxic, and a level marginally outside it does not require action in a patient who is well and stable.

No therapeutic ranges are quoted in this chapter. They differ between assays and laboratories, and a remembered range applied to a different assay is exactly how a dose gets adjusted in the wrong direction. Use the range your laboratory reports.

Pharmacodynamics: what happens at the receptor

Two properties describe how a drug behaves at a receptor. Affinity is how well it binds. Efficacy is whether binding produces an effect. The combinations give the three terms that examinations test.

An agonist has both — it binds and activates, mimicking the natural signal.

An antagonist has affinity but no efficacy — it binds and blocks. On its own it does nothing observable; its effect is entirely to prevent something else from acting.

A partial agonist is the one that causes confusion, and it repays understanding rather than memorising. It activates the receptor weakly. So its behaviour depends on what else is present:

Alone, it produces a submaximal effect — it acts as an agonist.
Alongside a full agonist, it occupies receptors that would otherwise be fully activated, so the overall effect falls — it behaves as an antagonist.

One further distinction changes management. A competitive antagonist competes for the same site, so enough additional agonist can overcome it — raising the dose works. A non-competitive antagonist cannot be outcompeted, so raising the dose does not help. When you are asked whether more agonist will overcome a block, this is the question being tested.

Adverse drug reactions

The classification that matters clinically divides reactions into two kinds, and the division decides what you do about them.

Type A — augmented. An extension of the drug's known pharmacological action, appearing when there is too much drug or too much sensitivity. These are dose-related and predictable: bleeding on an anticoagulant, bradycardia on a beta-blocker. They are common, and the usual response is to reduce the dose.

Type B — bizarre. Unrelated to the known pharmacology, not dose-related, and not predictable from what the drug does. Anaphylaxis and idiosyncratic reactions belong here. They are rare, often serious, and the response is to stop the drug and avoid it in future.

Why reporting matters, and why it falls to you

A drug is licensed on the basis of trials involving at most a few thousand people. That is enough to detect common reactions and nowhere near enough to detect rare ones.

A reaction occurring once in fifty thousand exposures will almost certainly not appear in any pre-licensing trial — but if a million people take the drug, it will affect twenty of them. Rare serious reactions are therefore discovered after licensing or not at all, and the mechanism by which they are discovered is clinicians reporting suspicions.

Two points about reporting that change behaviour:

You do not need to be sure the drug caused it. Suspicion is the threshold. Certainty about a rare reaction is impossible for a single clinician — the pattern only emerges when many suspicions are pooled.
New drugs deserve a lower threshold, because their safety record is by definition incomplete.

Reporting scheme names and forms differ by country and are periodically renamed, so none is given here — find the scheme in use where you practise.

A note on generics

A generic contains the same active drug as the original brand and must demonstrate equivalent bioavailability to be licensed. For the great majority of drugs, generic substitution is entirely appropriate and is what makes treatment affordable.

The exception follows directly from this chapter: for a drug with a narrow therapeutic index, a small difference in bioavailability that would be irrelevant for most drugs can matter — which is why switching preparations of such drugs is done deliberately rather than casually, and with monitoring.

Putting it together

First-pass metabolism means oral and intravenous doses differ — check the dose for the route, never carry the number across.
Four to five half-lives to reach steady state, and the same to wash out. A loading dose exists to skip the wait; a level before steady state cannot be interpreted.
A narrow therapeutic index is what makes monitoring necessary — and timing decides the number.
Treat the patient, not the level.
A partial agonist acts as an agonist alone and an antagonist alongside a full one.
Type A is dose-related — reduce it. Type B is not — stop it.
Rare reactions are only ever found after licensing, which is why suspicion is the reporting threshold.

No doses, half-life values, therapeutic ranges or bioavailability percentages appear in this chapter. Ranges differ between assays and laboratories — use the range your laboratory reports.

Syllabus points

First-pass metabolism and bioavailability
Why oral and IV doses differ — the route-switch trap
Half-life: steady state and wash-out; loading doses
Therapeutic index and when monitoring is needed
Timing of levels; treat the patient not the level
Affinity vs efficacy; agonist, antagonist, partial agonist
Competitive vs non-competitive block
Type A vs Type B reactions; why reporting matters

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