02 - 2. Mechanism of adverse effects

2. Mechanism of adverse effects

© SPMM Course 2. Mechanism of adverse effects Side effect Receptor Agitation α  2 blockade, 5HT2A/2C stimulation, DRI Akathisia D2 blockade, 5HT2A stimulation (hence some data on mirtazapine, 5HT2A antagonist, reducing akathisia) Delirium Anticholinergic effect (antimuscarinic) EPSE D2 blockade reduces with 5HT2A antagonism Hyperthermia Antimuscarinic action, in serotonin syndrome, may be mediated via 5HT2A/2C Insomnia α 1 stimulation, 5HT2Astimulation (hence SSRIs cause insomnia) Amnesia (memory defects) Anticholinergic effects, GABAA stimulation Hyperprolactinaemia D2 blockade, 5HT1A stimulation Disrupted slow wave sleep SWS is maintained by 5HT2A inhibition; 5HT2A stimulation disrupts sleep architecture Sweating Cholinergic effect and increases with noradrenaline reuptake inhibition Postural hypotension α  1  antagonism Appetite loss 5HT2A stimulation (antihistaminics can increase appetite) GI discomfort, nausea, vomiting 5HT3 stimulation Weight gain 5HT2C antagonism and antihistaminic effects Anticholinergic effects Blurred vision, exacerbation of narrow-angle glaucoma, delirium, and photophobia due to mydriasis, dry secretions, constipation, tachycardia, decreased sweating, urinary retention and hyperthermia. Anorgasmia α  1  antagonism,  5HT2A/2C  stimulation  (delayed  ejaculation  in   SSRIs).  Retrograde  ejaculation  due  to  α  1  block,  anticholinergic   and antihistaminic effects. Tardive dyskinesia Supersensitivity of dopamine receptors, which develops because of prolonged therapy with dopamine-blocking drugs Impotence α  2  blockade,  5HT2A/2C  stimulation.  5HT2A/2c  stimulation  can   also reduce libido. Priapism α  1  blockade Obsessions 5HT1D stimulation can induce obsessions. 5HT1A and 2A stimulation reduce OCD. Pathological gambling Habituation of dopamine receptors on repeated use of dopamine agonists (e.g. levodopa) leading to dopamine dysregulation syndrome (DDS)

© SPMM Course Weight gain: No single mechanism can explain the complex metabolic phenomenon of weight gain. Antihistaminic effects, 5HT2A/2C antagonism, insulin resistance (valproate and olanzapine) are noted. Genetic factors seem to involve 5-HT2C receptor. Drugs with a strong 5-HT2C affinity will have a greater impact on body weight of patients with a specific variant of polymorphism of the 5-HT2C receptor promoter regions. Low-potency antipsychotics (chlorpromazine and thioridazine) produce more weight gain and sedation than high-potency agents (haloperidol and fluphenazine).