Adverse reactions, interactions and safe-medication principles
Introduced| English | Meaning |
|---|---|
| type A reactions | type A reactions |
| type B reactions | type B reactions |
| enzyme induction | enzyme induction |
| enzyme inhibition | enzyme inhibition |
A safe drug, a new antibiotic, a bleed
- A patient stable on warfarin for years is given a common antibiotic. A week later the INR has doubled and the gums are bleeding.
- Neither drug was wrong alone. Safety comes from knowing reaction types, interactions and the habits that catch errors.
Two types of reaction
- Type A reactions A型反应 are dose-related and predictable from the drug's action: a β-blocker slowing the heart too much, bleeding on an anticoagulant.
- Type B reactions B型反应 are not dose-related and hard to predict: allergy or a rare idiosyncratic toxicity. They are rare but often serious.
Enzyme induction
- Enzyme induction 酶诱导 (rifampicin, phenytoin, carbamazepine) makes the liver build more CYP enzyme, so another drug's level falls.
- Building enzyme takes days, and so does losing it: the effect starts late and lasts after the inducer is stopped.
A patient on a drug starts rifampicin. What happens to the first drug's level?
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Rifampicin induces enzymes, which takes days to build.
Enzyme inhibition
- Enzyme inhibition 酶抑制 (clarithromycin, grapefruit juice at CYP3A4) blocks existing enzyme, so another drug's level rises.
- It starts with the first doses. Narrow-TI drugs such as warfarin, digoxin and lithium are where this matters most.
Match each event to what lies behind it.
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Two reaction types and two interaction mechanisms.
Enzyme inhibition begins with the first doses, but enzyme induction takes days.
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Inhibition blocks existing enzyme; induction must build new enzyme.
Which group of drugs is most affected by interactions?
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A small change in level crosses from effective to toxic.
Finding rare reactions
- Trials of a few thousand people cannot find a 1-in-10,000 reaction. By the rule of three, you need about 3 × 10,000 = 30,000 patients to have a good (95%) chance of seeing one case.
- So rare type B reactions are found after approval, by reporting: the UK MHRA Yellow Card scheme and the US FDA MedWatch.
A reaction occurs in 1 in 5,000 patients. Using the rule of three, about how many patients are needed for a 95% chance of seeing at least one case?
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3 × 5,000 = 15,000.
The five rights
- Right patient, right drug, right dose, right route, right time: the bedside checks that catch most errors before they reach the patient.
- Report near-misses too. They show where the system lets errors through.
Put the five rights in the order they are usually listed.
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Patient, drug, dose, route, time.
Worked example: the warfarin INR
- (Fictional) Warfarin + clarithromycin (an inhibitor): warfarin clearance falls, the INR rises within days, and bleeding risk climbs.
- Warfarin + rifampicin (an inducer): the INR falls over a week or more, and stays low for weeks after rifampicin stops.
A patient stable on warfarin starts clarithromycin. What should you expect?
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Clarithromycin inhibits CYP3A4 and slows warfarin clearance.
Worked example: how big a study?
- (Illustrative) A reaction occurs in 1 in 2,000 patients. Rule of three: 3 × 2,000 = 6,000 patients for a 95% chance of at least one case.
- A 1,500-patient trial would probably miss it, and seeing one case does not tell you the rate.
Three common slips
- Blaming type B reactions on dose. Dose neither predicts nor prevents them.
- Forgetting the inducer's tail. Its effect lasts after it is stopped, so doses must be re-checked then too.
- Thinking a clean trial means a safe drug. Rare reactions appear only in large populations.
Recap
- Type A = dose-related, predictable; type B = idiosyncratic, rare, serious.
- Induction lowers levels (slow on, slow off); inhibition raises levels (fast on); narrow-TI drugs suffer most.
- Rule of three: about 3n patients to see a 1-in-n reaction; report through Yellow Card (UK) or MedWatch (US); check the five rights.