A patient on an oral drug is switched to the intravenous route for the same drug. Why is the dose usually different? ANSWER: because of FIRST-PASS METABOLISM and the bioavailability that follows from it. 1. Blood leaving the gut reaches the LIVER before the systemic circulation, via the portal vein. 2. The liver metabolises part of the dose on that first pass. 3. So the fraction reaching the circulation — the BIOAVAILABILITY — is less than 100%, sometimes far less. 4. Intravenous administration bypasses this entirely and is 100% by definition. THE DANGER: giving an oral-sized dose intravenously, for a drug with low oral bioavailability, delivers a large OVERDOSE. RULE: when the route changes, look up the dose for the new route. Never carry the old number across.

A drug is started at a regular maintenance dose. Roughly how long until it reaches steady state? A. One half-life B. Two half-lives C. Four to five half-lives D. It depends on the dose given ANSWER: C — four to five half-lives. AND THE SAME NUMBER ANSWERS THE OPPOSITE QUESTION: after stopping, four to five half-lives are needed to wash out. D is wrong and is worth understanding: the SIZE of the maintenance dose sets the eventual concentration, but not the TIME taken to reach it. That time depends only on the half-life. TWO CONSEQUENCES: - A LOADING DOSE exists because waiting that long is sometimes unacceptable. - A level checked BEFORE steady state is measuring a number that is still rising, and cannot be read as the final concentration.

Which property makes a drug require therapeutic monitoring? A. A long half-life B. A narrow therapeutic index C. Renal excretion D. High protein binding ANSWER: B — a narrow therapeutic index. Why: the therapeutic index is the margin between the dose that WORKS and the dose that HARMS. When those concentrations sit close together, small changes in dose, renal function or an interacting drug can move a patient from treated to poisoned. A wide index means large room for error and no routine monitoring. TWO MONITORING PRINCIPLES: 1. TIMING decides the number — a sample taken at the wrong point in the dosing interval is uninterpretable, not merely inaccurate. 2. TREAT THE PATIENT, NOT THE LEVEL. A level inside the range does not exclude toxicity in a patient who looks toxic.

Explain how a partial agonist can act as an antagonist. ANSWER: because it activates the receptor WEAKLY, so its net effect depends on what else is present. ALONE It binds and produces a SUBMAXIMAL effect — it behaves as an agonist. ALONGSIDE A FULL AGONIST It occupies receptors that would otherwise have been FULLY activated. Replacing a strong signal with a weak one LOWERS the overall effect — so it behaves as an antagonist. UNDERLYING CONCEPTS: AFFINITY how well the drug binds EFFICACY whether binding produces an effect Agonist = affinity + full efficacy Antagonist = affinity + NO efficacy Partial agonist = affinity + partial efficacy

Distinguish Type A from Type B adverse drug reactions, and give the management implication of each. ANSWER: TYPE A — AUGMENTED An extension of the drug's KNOWN pharmacological action. DOSE-RELATED and predictable. Common. Examples: bleeding on an anticoagulant, bradycardia on a beta-blocker. MANAGEMENT: usually REDUCE THE DOSE. TYPE B — BIZARRE Unrelated to the known action. NOT dose-related. Not predictable. Rare, and often serious. Example: anaphylaxis. MANAGEMENT: STOP the drug and avoid it in future. The distinction is not academic — it decides whether the answer is a smaller dose or a different drug.

Why must adverse reactions be reported even when the clinician is not certain the drug was responsible? ANSWER: because rare reactions cannot be detected before licensing, and certainty is impossible for one clinician. 1. A drug is licensed on trials of at most a few thousand people. 2. A reaction occurring once in 50,000 exposures will almost certainly not appear in such a trial. 3. But if a million people take the drug, it affects twenty of them. 4. So rare serious reactions are found AFTER licensing — or not at all. 5. The pattern only emerges when many individual SUSPICIONS are pooled. THEREFORE: suspicion is the reporting threshold, not proof. And a NEW drug deserves a lower threshold still, because its safety record is by definition incomplete.

Generic substitution is appropriate for most drugs. For which drugs is caution needed, and why? ANSWER: drugs with a NARROW THERAPEUTIC INDEX. REASONING: a generic must demonstrate equivalent bioavailability to be licensed, but "equivalent" permits a small difference. For most drugs that difference is clinically irrelevant, because the margin between the effective and toxic concentration is wide. Where that margin is NARROW, the same small difference can move a patient outside it. SO: substitution of narrow-index drugs is done deliberately and with monitoring, rather than casually at the pharmacy counter. This is a direct application of the therapeutic index concept, which is why it is a favourite examination link.