3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.1.7 Pharmacodynamically mediated
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Written by Resident Doctor Committee · Published
The principle
A pharmacodynamic interaction acts at the site of drug effect, combining the drugs' effects at the target with no change in the amount of either drug reaching it.
A pharmacokinetic interaction changes drug concentration, and a pharmaceutical interaction happens outside the body.
Type | Effect | Example |
|---|---|---|
Additive | The effects roughly sum | Two sedatives deepen sedation |
Synergistic | The combined effect exceeds the sum | An opioid with a benzodiazepine depresses breathing |
Antagonistic | One drug blocks the other | Naloxone blocks morphine at mu receptors |
Serotonin syndrome
Serotonin toxicity arises when drugs acting on separate serotonergic mechanisms are combined.
Mechanism | Drugs |
|---|---|
Reuptake inhibition | Selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), clomipramine, tramadol, pethidine, dextromethorphan, sibutramine |
Reduced breakdown | Monoamine oxidase inhibitors or MAOIs (phenelzine, tranylcypromine, isocarboxazid, moclobemide), linezolid, methylene blue |
Increased release | MDMA, amfetamines |
Direct agonism | Triptans, buspirone, LSD |
Dangerous combinations
An irreversible MAOI with a reuptake blocker, such as a serotonergic tricyclic, carries the highest risk of life-threatening serotonin syndrome, because both routes of serotonin clearance are removed for weeks.
Moclobemide, a reversible inhibitor of MAO-A, is less dangerous.
Pethidine, unlike most opioids, inhibits serotonin reuptake, so with an irreversible MAOI it is the classic fatal combination and must be avoided.
Dextromethorphan, found in over-the-counter cough remedies, inhibits serotonin reuptake and can precipitate serotonin syndrome with an SSRI or an irreversible MAOI.
Linezolid is itself a weak, reversible, non-selective monoamine oxidase inhibitor, so it risks serotonin syndrome with any serotonergic drug.
Sibutramine, an appetite suppressant that inhibits serotonin and noradrenaline reuptake, can precipitate serotonin syndrome with an SNRI, and it may turn up in illicit slimming products.
Fluoxetine and washouts
Fluoxetine and its metabolite norfluoxetine persist for weeks, so serotonin reuptake is still blocked if an MAOI such as phenelzine starts too soon.
Prescribers wait at least five weeks after fluoxetine before starting an MAOI, and commonly at least two weeks after stopping an irreversible MAOI before starting another serotonergic drug.
Recognition and treatment
Serotonin toxicity combines mental state change, autonomic disturbance such as hypertension, and neuromuscular excitation.
Inducible clonus and hyperreflexia are its most specific signs, though severe rigidity can hide them.
It usually starts within hours of a new drug or dose increase, whereas neuroleptic malignant syndrome develops more slowly and causes generalised rigidity.
Clinicians stop the causative drugs and give supportive care, benzodiazepines and cooling, since antipyretics do not treat heat generated by muscle.
Hypertensive crisis with MAOIs
Sympathomimetic decongestants must not be combined with an MAOI, because an indirectly acting sympathomimetic releases stored noradrenaline and precipitates a hypertensive crisis.
Stimulants for attention deficit hyperactivity disorder (ADHD), such as methylphenidate, must not be given with an MAOI, because the monoamines they release or keep in the synapse cannot be broken down.
Guanfacine and atomoxetine, by contrast, are genuinely combined with stimulants.
Other additive effects
Combination | Shared action | Characteristic risk |
|---|---|---|
Two antimuscarinics, such as procyclidine with amitriptyline, or one added to clozapine | Antimuscarinic blockade | Acute urinary retention, especially with an enlarged prostate |
Clozapine with carbamazepine | Bone marrow suppression | Neutropenia and agranulocytosis |
Haloperidol with metoclopramide | Nigrostriatal dopamine D2 blockade | Acute dystonia in the first days, most often in young men |
SSRI with a systemic non-steroidal anti-inflammatory drug (NSAID) | Platelet serotonin depletion plus cyclo-oxygenase inhibition and gastric mucosal injury | Gastrointestinal bleeding |
SSRI with a sodium-lowering drug, such as a thiazide or desmopressin | Separate sodium-lowering effects | Hyponatraemia |
Several drugs that block hERG potassium channels | Delayed repolarisation | QT prolongation |
Metronidazole with alcohol | Disulfiram-like action | Flushing reaction |
The antimuscarinic interaction is pharmacodynamic, not kinetic, and extra antimuscarinics also worsen clozapine bowel hypomotility, which can cause fatal ileus.
Valproate is usually preferred to carbamazepine as the anticonvulsant alongside clozapine.
Topical NSAIDs, opioids and paracetamol do not add to an SSRI's bleeding risk, whereas aspirin and anticoagulants do.