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THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGY

THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGY. “ The Pathogenesis of Adverse Events: Focus on Antidepressants and Antipsychotics” Vicente S. Cabuquit, MD, FPPA, FPCPsych, DPBP, DPM (Lond.)

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THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGY

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  1. THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGY “ The Pathogenesis of Adverse Events: Focus on Antidepressants and Antipsychotics” Vicente S. Cabuquit, MD, FPPA, FPCPsych, DPBP, DPM (Lond.) Professor,Department of Psychiatry, UERMMMC

  2. ADVERSE EVENTS • Usually sudden, apparently inexplicable reactions of patients on medications. • 90% within one week of treatment • 40% of patients • 33% - CNS adverse events • 36% - GIT adverse events

  3. To Know The Receptors Is To Know The Adverse Events • The actions of drugs on receptors determine the adverse events of drugs • Drugs which act on many receptors can lead to numerous adverse events, some potentially fatal • Conversely, drugs which act on just several receptors can cause less adverse events

  4. MECHANISMS OF ANTIDEPRESSANTS • Tricyclics (TCAs)– inhibit reuptake of 5HT, NE and other receptors plus fast Na channels • SSRIs– selectively inhibit reuptake of 5HT • SNRIs– inhibit reuptake of 5HT and NE • NaSSA – blocks 5HT (5HT2a, 5HT2c, 5HT3) and NE (Ά2)

  5. ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS • TCAs– block Ach, NE, 5HT1, H1 presynaptically; stimulate 5HT, 5HT2, 5HT3 postsynaptically (built- in polypharmacy) Result in : • dry mouth, blurred vision • drowsiness, urinary retention • constipation, dizziness and confusion (elderly) • nausea/vomiting, tachycardia • orthostatic hypotension, tremor • sedation, sexual dysfunction, weight gain

  6. ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS SSRIs– stimulate various 5HT subtypes Result in : • 5HT3 – nausea/diarrhea, headache • 5HT2a – nervousness/restlessness • 5HT2c – nervousness/restlessness

  7. ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS SNRIs– stimulate 5HT1, 5HT2, 5HT3 and noradrenergic receptors Result in: • Similar to SSRIs - plus tachycardia, tremor, orthostatic hypotension, sedation

  8. NaSSA – blocks H1 and Ά2 receptors Result in: Sedation, weight gain, tremors ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS

  9. CLINICAL JUDGEMENTS • Avoid using TCAs as first choice (built- in “polypharmacy”); receptor profile prone to adverse events; could be fatal in overdose (fast Na channels) • First choice: either single receptor (SSRIs) or a dual receptor like NaSSA; safe in overdose • Receptor profile favors NaSSA

  10. DOPAMINE PATHWAYS IN THE BRAIN

  11. CLINICAL IMPLICATIONS OF DOPAMINE PATHWAYS • Nigrostriatal– controls movements; site of EPS events; site of typical antipsychotics • Mesolimbic– involved in many behaviours (pleasure, hallucinations, delusions); site of atypicals

  12. CLINICAL IMPLICATIONS OF DOPAMINE PATHWAYS • Mesocortical– mediates + and – symptoms and cognitive side effects; site of typicals • Tuberoinfundibular– controls prolactin; high levels cause galactorrhea, gynecomastia, amenorrhea, sexual dysfunction; site of typicals and some atypicals (risperidone)

  13. DA ACh SOME ADVERSE EVENTS OF ANTIPSYCHOTICS A normal extrapyramidal system requires a balance of dopamine and acetylcholine concentration.

  14. DA DA DA DA ACh ACh ACh ACh PSEUDO-PARKINSONISM Dopamine ↓ due to post-synaptic antagonism of dopamine receptors and degeneration of the NS dopaminergic pathway variations.

  15. TARDIVE DYSKINESIA

  16. ACh DA ACh DA ACh DA DA ACh TARDIVE DYSKINESIA

  17. What Happens in TD? • Chronic dopamine blockade causes reflex overactivity of dopamine in the basal ganglia • Compensatory upregulation overcomes blockade; initially successful • Later, compensation becomes inadequate; the balance between DA and Ach in the basal ganglia is disturbed. TD sets in

  18. D2 / 5HT2 BLOCKADES (PETscans)

  19. CLOZAPINE AND AGRANULOCYTOSIS Clozapine has 9 neurotransmitter receptors: one of them or several in combination may cause agranulocytosis. Exact cause: ? • 5HT2, 5HT2c, 5HT3 • D1, D2, D4 • M1 • H1 • Ά1

  20. ATYPICALS AND DIABETES • Class effect, with olanzapine and clozapine more likely than others • Weight gain a factor (olz and clz cause biggest gain); also hyperprolactinemia which disturbs insulin metabolism ( in risperidone) • Philippine experience negligible, if at all

  21. “In the name of dopamine, serotonin, noradrenaline, and acetylcholine, and all the other neurotransmitters in the brain, may you remain stable in your systems, now and forever, amen.”* * Cabuquit’s prayer against psychotropic adverse events

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