3.2.3 Pharmacokinetically mediated

Pharmacokinetic and pharmacodynamic interactions

• A pharmacokinetic interaction changes how much of a drug reaches its target by altering absorption, distribution, metabolism or excretion.

• A pharmacodynamic interaction changes the response at an unchanged concentration.

• How much an interaction matters depends on how much the affected pathway contributes, the drug's therapeutic index, and the timing: inhibition acts quickly, while induction develops and resolves over weeks.

Absorption

• Chelation happens when a polyvalent cation binds a drug in the gut into a complex that cannot be absorbed; metal ions bind tetracyclines and quinolones this way.

• Separating the doses helps binding interactions but does not prevent effects from altered gut pH, motility or intestinal enzymes, such as grapefruit juice inhibiting intestinal CYP3A4.

Distribution and protein binding

• Displacement from plasma protein binding raises the free fraction of a highly bound drug, as when clozapine displaces warfarin from albumin and potentiates anticoagulation.

• The measured total level can then fall, so raising the dose of valproate or phenytoin to correct a low total level risks toxicity.

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Enzyme inhibition and induction

• Mechanism-based inhibitors, such as clarithromycin and ritonavir at the cytochrome P450 (CYP) enzyme CYP3A4, inactivate the enzyme until it is replaced, so their effect outlasts withdrawal.

• Inducers include carbamazepine, phenytoin, phenobarbital, rifampicin, St John's wort and tobacco smoke; valproate is not an inducer.

Clozapine

Clozapine is cleared mainly by CYP1A2, with CYP3A4 a minor route, so CYP1A2 inducers, inhibitors and competing substrates drive its plasma level.

• Stopping smoking on an unchanged dose, for example on a smoke-free admission, leads to clozapine toxicity unless the dose is reduced; olanzapine levels rise the same way.

• Nicotine is not the inducer, so nicotine replacement and vaping do not maintain the induction.

• Other antidepressants have a mild or negligible effect on clozapine levels.

• Recovery from infection or restarting smoking lowers clozapine levels again.

Other cytochrome P450 interactions

• Norfluoxetine, fluoxetine's active metabolite, has a half-life of 1 to 2 weeks, which is why its CYP2D6 inhibition persists.

• Trazodone at raised exposure causes postural hypotension and fainting through alpha-1 blockade.

• Fluoxetine and paroxetine can also raise risperidone, aripiprazole and atomoxetine levels through CYP2D6.

• CYP2D6 inhibition reduces activation of prodrugs, so codeine gives less morphine and paroxetine is avoided with tamoxifen.

Anticonvulsants

• Valproate inhibits lamotrigine glucuronidation, roughly doubling its level and raising the risk of toxicity and rash, so lamotrigine starts at half the dose and is titrated more slowly.

• Carbamazepine and phenytoin induce lamotrigine metabolism and lower its level.

• Enzyme inducers, carbamazepine among them, speed valproate clearance and lower its level, while enzyme inhibitors raise it.

• Carbamazepine lowers most co-prescribed anticonvulsants but can raise phenytoin, sometimes to toxic levels.

• An antipsychotic dose raised to compensate for carbamazepine can become toxic when carbamazepine stops.

Contraception and warfarin

• CYP3A4 inducers, including St John's wort, carbamazepine and topiramate, speed clearance of ethinylestradiol and progestogen and cause combined oral contraceptive failure.

• Non-inducing drugs, such as renally excreted anticonvulsants and valproate, leave the pill effective.

• Implants are also affected by induction, but intrauterine contraception and depot medroxyprogesterone are not.

• St John's wort induces CYP3A4, CYP2C9, CYP2C19 and P-glycoprotein through hyperforin, lowering warfarin levels, the international normalised ratio and anticoagulant effect, so it is avoided with warfarin.

Renal elimination and lithium

• Two drugs sharing an active tubular transporter compete at the proximal tubule, so secretion and renal clearance of both fall and plasma levels rise; probenecid reduces penicillin secretion this way.

• Lithium is filtered and reabsorbed alongside sodium without metabolism, so tobacco smoke induction of hepatic enzymes leaves its level unchanged, unlike psychotropics that depend partly on CYP1A2.

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• Vomiting, diarrhoea, fever, sweating, dehydration and low salt intake also raise lithium levels.

• Toxicity presents with coarse tremor, vomiting, ataxia, confusion or seizures; withhold lithium and check an urgent level, renal function and electrolytes.