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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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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.)

Professor,Department of Psychiatry, UERMMMC


Adverse events

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


To know the receptors is to know the adverse events

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


Mechanisms of antidepressants

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)


Actions on receptors causing adverse events

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


Actions on receptors causing adverse events1

ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS

SSRIs– stimulate various 5HT subtypes

Result in :

  • 5HT3 – nausea/diarrhea, headache

  • 5HT2a – nervousness/restlessness

  • 5HT2c – nervousness/restlessness


Actions on receptors causing adverse events2

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


Actions on receptors causing adverse events3

NaSSA – blocks H1 and Ά2 receptors

Result in:

Sedation, weight gain, tremors

ACTIONS ON RECEPTORS CAUSING ADVERSE EVENTS


Clinical judgements

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


Dopamine pathways in the brain

DOPAMINE PATHWAYS IN THE BRAIN


Clinical implications of dopamine pathways

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


Clinical implications of dopamine pathways1

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)


Some adverse events of antipsychotics

DA

ACh

SOME ADVERSE EVENTS OF ANTIPSYCHOTICS

A normal extrapyramidal system requires a balance of dopamine and acetylcholine concentration.


Pseudo parkinsonism

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.


Tardive dyskinesia

TARDIVE DYSKINESIA


Tardive dyskinesia1

ACh

DA

ACh

DA

ACh

DA

DA

ACh

TARDIVE DYSKINESIA


What happens in td

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


D 2 5ht 2 blockades petscans

D2 / 5HT2 BLOCKADES (PETscans)


Clozapine and agranulocytosis

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


Atypicals and diabetes

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


Cabuquit s prayer against psychotropic adverse events

“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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