THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGY “ The Pathogenesis of Adverse Events: Focus on...
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Transcript of THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGY “ The Pathogenesis of Adverse Events: Focus on...
THE PHILIPPINE COLLEGE OF THE PHILIPPINE COLLEGE OF PSYCHOPHARMACOLOGYPSYCHOPHARMACOLOGY
“ “ The Pathogenesis of Adverse Events: The Pathogenesis of Adverse Events: Focus on Focus on
Antidepressants and Antidepressants and Antipsychotics”Antipsychotics”
Vicente S. Cabuquit, MD, FPPA, FPCPsych,Vicente S. Cabuquit, MD, FPPA, FPCPsych,
DPBP, DPM (Lond.) DPBP, DPM (Lond.)
Professor,Professor, Department of Psychiatry, Department of Psychiatry, UERMMMC UERMMMC
ADVERSE EVENTSADVERSE EVENTS
• Usually sudden, apparently inexplicable Usually sudden, apparently inexplicable reactions of patients on medications.reactions of patients on medications.
• 90% within one week of treatment90% within one week of treatment• 40% of patients40% of patients• 33% - CNS adverse events 33% - CNS adverse events • 36% - GIT adverse events 36% - GIT adverse events
To Know The Receptors Is To To Know The Receptors Is To Know The Adverse Events Know The Adverse Events
• The actions of drugs on receptors The actions of drugs on receptors determine the adverse events of drugsdetermine the adverse events of drugs
• Drugs which act on many receptors Drugs which act on many receptors
can lead to numerous adverse events, can lead to numerous adverse events, some potentially fatalsome potentially fatal
• Conversely, drugs which act on just Conversely, drugs which act on just several receptors can cause less several receptors can cause less adverse eventsadverse events
MECHANISMS OF MECHANISMS OF ANTIDEPRESSANTSANTIDEPRESSANTS
• Tricyclics (TCAs)Tricyclics (TCAs) – – inhibit reuptake of 5HT, NE inhibit reuptake of 5HT, NE and other receptors plus fast Na channelsand other receptors plus fast Na channels
• SSRIsSSRIs – – selectively inhibit reuptake of 5HTselectively inhibit reuptake of 5HT
• SNRIsSNRIs – – inhibit reuptake of 5HT and NEinhibit reuptake of 5HT and NE
• NaSSA – NaSSA – blocks 5HT (5HTblocks 5HT (5HT2a2a, 5HT, 5HT2c2c, 5HT, 5HT33) and ) and NE (NE (ΆΆ22))
ACTIONS ON RECEPTORS ACTIONS ON RECEPTORS CAUSING CAUSING
ADVERSE EVENTS ADVERSE EVENTS• TCAsTCAs – – block Ach, NE, 5HTblock Ach, NE, 5HT11, H, H11 presynaptically; presynaptically;
stimulate 5HT, 5HTstimulate 5HT, 5HT22, 5HT, 5HT33 postsynaptically (built- postsynaptically (built- in polypharmacy)in polypharmacy)
Result in :Result in :
• dry mouth, blurred visiondry mouth, blurred vision• drowsiness, urinary retentiondrowsiness, urinary retention• constipation, dizziness and confusion (elderly)constipation, dizziness and confusion (elderly)• nausea/vomiting, tachycardianausea/vomiting, tachycardia• orthostatic hypotension, tremororthostatic hypotension, tremor• sedation, sexual dysfunction, weight gainsedation, sexual dysfunction, weight gain
ACTIONS ON RECEPTORS ACTIONS ON RECEPTORS CAUSINGCAUSING
ADVERSE EVENTS ADVERSE EVENTS
SSRIsSSRIs – – stimulate various 5HT subtypesstimulate various 5HT subtypes
Result in : Result in :
• 5HT5HT33 – nausea/diarrhea, headache – nausea/diarrhea, headache• 5HT5HT2a2a – nervousness/restlessness – nervousness/restlessness • 5HT5HT2c2c – nervousness/restlessness – nervousness/restlessness
ACTIONS ON RECEPTORS ACTIONS ON RECEPTORS CAUSINGCAUSING
ADVERSE EVENTS ADVERSE EVENTS
SNRIsSNRIs – – stimulate 5HTstimulate 5HT11, 5HT, 5HT22, 5HT, 5HT33 and and noradrenergic receptors noradrenergic receptors
Result in:Result in:
• Similar to SSRIs - plus tachycardia, Similar to SSRIs - plus tachycardia, tremor, orthostatic hypotension, tremor, orthostatic hypotension, sedationsedation
ACTIONS ON RECEPTORS ACTIONS ON RECEPTORS CAUSINGCAUSING
ADVERSE EVENTS ADVERSE EVENTS
NaSSANaSSA – blocks H – blocks H11 and and ΆΆ22 receptors receptors
Result in:Result in:
• Sedation, weight gain, tremorsSedation, weight gain, tremors
CLINICAL JUDGEMENTSCLINICAL JUDGEMENTS
• Avoid using TCAs as first choice (built- in Avoid using TCAs as first choice (built- in “polypharmacy”); receptor profile prone to adverse “polypharmacy”); receptor profile prone to adverse events; could be fatal in overdose (fast Na channels)events; could be fatal in overdose (fast Na channels)
• First choice: either single receptor (SSRIs) or a dual First choice: either single receptor (SSRIs) or a dual receptor like NaSSA; safe in overdosereceptor like NaSSA; safe in overdose
• Receptor profile favors NaSSA Receptor profile favors NaSSA
DOPAMINE PATHWAYSDOPAMINE PATHWAYS IN THE BRAIN IN THE BRAIN
CLINICAL IMPLICATIONS OF CLINICAL IMPLICATIONS OF DOPAMINE PATHWAYS DOPAMINE PATHWAYS
• NigrostriatalNigrostriatal – – controls movements; site of controls movements; site of EPS events; site of typical antipsychoticsEPS events; site of typical antipsychotics
• MesolimbicMesolimbic – involved in many behaviours – involved in many behaviours (pleasure, hallucinations, delusions); site (pleasure, hallucinations, delusions); site of atypicalsof atypicals
• MesocorticalMesocortical – – mediates + and – mediates + and – symptoms and cognitive side effects; symptoms and cognitive side effects; site of typicalssite of typicals
• TuberoinfundibularTuberoinfundibular – – controls prolactin; controls prolactin; high levels cause galactorrhea, high levels cause galactorrhea, gynecomastia, amenorrhea, sexual gynecomastia, amenorrhea, sexual dysfunction; site of typicals and some dysfunction; site of typicals and some atypicals (risperidone) atypicals (risperidone)
CLINICAL IMPLICATIONS OF CLINICAL IMPLICATIONS OF DOPAMINE PATHWAYS DOPAMINE PATHWAYS
SOME ADVERSE EVENTS OFSOME ADVERSE EVENTS OF ANTIPSYCHOTICS ANTIPSYCHOTICS
A normal extrapyramidal system requires a A normal extrapyramidal system requires a balance of dopamine and acetylcholine balance of dopamine and acetylcholine concentration.concentration.
DA ACh
ACh
DA
ACh
DA
ACh
DA
PSEUDO-PARKINSONISMPSEUDO-PARKINSONISM
Dopamine Dopamine ↓↓ due to post-synaptic antagonism of due to post-synaptic antagonism of dopamine receptors and degeneration of the NS dopamine receptors and degeneration of the NS dopaminergic pathway variations.dopaminergic pathway variations.
DA ACh
TARDIVE DYSKINESIATARDIVE DYSKINESIA
DA
ACh
TARDIVE DYSKINESIATARDIVE DYSKINESIA
DAAChDA
ACh
DA ACh
What Happens in TD?What Happens in TD?
• Chronic dopamine blockade causes reflex Chronic dopamine blockade causes reflex overactivity of dopamine in the basal gangliaoveractivity of dopamine in the basal ganglia
• Compensatory upregulation overcomes Compensatory upregulation overcomes blockade; initially successfulblockade; initially successful
• Later, compensation becomes inadequate; Later, compensation becomes inadequate; the balance between DA and Ach in the basal the balance between DA and Ach in the basal ganglia is disturbed. TD sets in ganglia is disturbed. TD sets in
DD2 2 / 5HT/ 5HT22 BLOCKADES (PETscans) BLOCKADES (PETscans)
DRUGDRUG DD22
blockadeblockade5HT5HT22
blockadeblockade
TypicalsTypicals 70 – 90%70 – 90% 20%20%
AtypicalsAtypicals 40%40% 60%60%
CLZCLZ 30 – 60%30 – 60% 85 – 90%85 – 90%
CLOZAPINE AND CLOZAPINE AND AGRANULOCYTOSISAGRANULOCYTOSIS
Clozapine has 9 neurotransmitter Clozapine has 9 neurotransmitter receptors: one of them or several in receptors: one of them or several in combination may cause combination may cause agranulocytosis. Exact cause: ?agranulocytosis. Exact cause: ?
• 5HT5HT22, 5HT, 5HT2c2c, 5HT, 5HT33
• DD11, D, D22, D, D44
• MM11
• HH11 • ΆΆ11
ATYPICALS AND DIABETESATYPICALS AND DIABETES
• Class effect, with olanzapine and clozapine Class effect, with olanzapine and clozapine more likely than othersmore likely than others
• Weight gain a factor (olz and clz cause Weight gain a factor (olz and clz cause biggest gain); also hyperprolactinemia biggest gain); also hyperprolactinemia which disturbs insulin metabolism ( in which disturbs insulin metabolism ( in risperidone)risperidone)
• Philippine experience negligible, if at allPhilippine experience negligible, if at all
““In the name of dopamine, In the name of dopamine, serotonin, noradrenaline, and serotonin, noradrenaline, and acetylcholine, and all the other acetylcholine, and all the other neurotransmitters in the brain, neurotransmitters in the brain, may you remain stable in your may you remain stable in your
systems, now and forever, systems, now and forever, amen.”amen.” **
* Cabuquit’s prayer against * Cabuquit’s prayer against psychotropic adverse eventspsychotropic adverse events