Pharmacological therapy & ECT - antipsychotics

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Pharmacological therapy & ECT - antipsychotics
2014-06-28 16:56:25
psy pharm
Classifications, MoA, S.E, CI
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  1. Commonly used antipsychotics - 1st generation
    • - Chlorpromazine
    • - Haloperidol *
    • - Sulpiride
    • - Flupentixol (Depixol) *
    • - Zuclopenthixol (Clopixol) *
    • * can be given in long - acting i.m injection (depot) form

    (1st halo, clopixol - chú hề, bị cúm nên dùng viết - flupentixol)

    - serious motor side-effects (extrapyramidal side-effects (EPSE) - so 1st generation or typical antipsychotics

    - distinction is increasingly viewed as artificial– all antipsychotics can induce extrapyramidal motor side-effects if given at high enough doses
  2. Commonly used antipsychotics - 2nd generation/atypical
    • - Clozapine
    • - Olanzapine
    • - Quetiapine
    • - Risperidone *  (can be depot)
    • - Amisulpride

    (2nd - đỡ risk hơn - rispe ri done, dùng clo tới zà clozapine)

    Clozapine was the first antipsychotic with fewer EPSE,and thus was termed ‘atypical’

    Clozapine is the only ‘true’ atypical antipsychotic in that it has a distinct receptor binding profile and can be effective in two-thirds of the patients for whom other antipsychotics have failed
  3. MoA: primary MoA, of clozapine, of 2nd generation
    • - possible exception of clozapine, is antagonism of dopamine D2 receptors in the mesolimbic dopamine pathway.
    • - Clozapine is a comparatively weak D2 antag onist but has a high affinity for serotonin type 2 recep-tors (5-HT2) and D4 receptors, among many otherreceptor targets.
    • - Most second generation antipsychotics also block 5-HT2 receptors
  4. Side effects
    a) due to blockade of which receptors?
    b) useful and troublesome clinical effects (extra to prev. s.e learnt with antidepressants)
    • - blockade of dopamine D2 receptors occurs throughout the brain, resulting in diverse side-effects
    • - also by blocking muscarinic, histaminergic and adrenergic receptors (as do TCAs)
  5. Big:
    Dopamine D2-receptor antagonism
    (location of dopamine D2-R, Function, Clinical effect x5)
    • - Mesolimbic pathway:
    • Involved in delusions/hallucinations/thought disorder, euphoria and drugdependence
    • -> Treatment of psychotic symptoms

    • - Mesocortical pathway
    • Mediates cognitive and negative symptoms of schizophrenia
    • -> Worsening of negative and cognitive symptoms of schizophrenia

    • - Nigrostriatal pathway(basal ganglia/striatum)
    • Controls motor movement
    • => Extrapyramidal side-effects
    • •Parkinsonian symptoms
    • •Acute dystonia
    • •Akathisia
    • •Tardive dyskinesia
    • •Neuroleptic malignant syndrome

    • - Tuberoinfundibular pathway
    • Controls prolactin secretion –dopamine inhibits prolactin release
    • => Hyperprolactinaemia
    • •Galactorrhoea (breast milk production)
    • •Amenorrhoea and infertility
    • •Sexual dysfunction

    • - Chemoreceptor trigger zone
    • Controls nausea and vomiting
    • => Anti-emetic effect: some phenothiazines, e.g.prochlorperazine (Stemetil®) are very effective intreating nausea and vomiting
  6. Other side-effects (x7 R)
    • - Anticholinergic: muscarinic receptor blockade
    • Dry mouth, constipation, urinary retention, blurred vision

    • -Adrenergic receptor blockade
    • Postural hypotension (dizziness, syncope)

    • - Histaminergic receptor blockade
    • Sedation, weight gain

    • - Cardiac effects
    • Prolongation of QT-interval, arrhythmias, myocarditis, sudden death

    • - Metabolic effects
    • Increased risk of metabolic syndrome

    • - Dermatological effects
    • Photosensitivity, skin rashes (especially chlorpromazine: blue–grey discolouration in the sun)

    • - Other
    • Lowering of seizure threshold, hepatotoxicity, cholestatic jaundice, pancytopenia, agranulocytosis
  7. Metabolic syndrome (x4) & risk associated with which drugs
    - obesity, diabetes,hypertension and dyslipidaemia

    - Risk is particularly high with clozapine and other second generation antipsy-chotics.

    - Metabolic syndrome is associated with increased cardiovascular mortality so it is important to monitor and manage the components of this syndrome.
  8. Rare serious side-effects of clozapine
    • - agranulocytosis (so bone marrow suppresion), myocarditis and cardiomyopathy
    • - so reserved for treatment - resistant cases
  9. CI of clozapine
    • severely reduced consciousness level (sedating)
    • phaeochromocytoma
    • Parkinson’s disease (can exacerbate
    • epilepsy (seizure threshold lowered)
    • cardiac disease (can induce arrhythmias – consider baseline ECG) and metabolicsyndrome).

    Clozapine should not be re-prescribed tosomeone with a history of agranulocytosis
  10. EPSE are due to what? so, effective treatment?
    • The extrapyramidal side-effects (EPSE)
    • of parkinsonian motor symptoms and acute dystonia are due to a relative deficiency of dopamine and an excess of acetylcholine induced by dopamine antagonism in the nigrostriatal pathway.

    This is why anticholinergic drugs are effective treatments
  11. Antipsychotic-induced extrapyramidal side-effects and treatment
    • - Parkinsonian motor symptoms
    • + Muscular rigidity, bradykinesia (lack of, orslowing, of movement), resting tremor.
    • + Generally occurs within a month of startingantipsychotic

    • - Acute dystonia
    • + Involuntary sustained muscular contractions or spasms, e.g. neck (spasmodic torticollis),clenched jaw (trismus), protruding tongue, eyesroll upwards (oculogyric crisis)
    • + More common in young men
    • + Usually occurs within 72 hours of treatment

    • => - Anticholinergics, e.g. procyclidine (i.v. or i.m. if unable to swallow, oral otherwise).
    • - Consider reducing dose of antipsychotic or switching to antipsychotic with fewer extrapyramidalside-effects (e.g. atypical)

    • - Akathisia
    • + Subjective feeling of inner restlessness and muscular discomfort
    • + Occurs within 6–60 days

    • =>+ Propranolol or short-term benzodiazepines
    • + Consider reducing dose of antipsychotic or switching to antipsychotic with fewer extrapyramidal side-effects (e.g. atypical)

    • - Tardive dyskinesia
    • + Rhythmic, involuntary movements of head, limbs and trunk, especially chewing, grimacing of mouth and protruding, darting movements oftongue
    • + Develops in up to 20% of patients who receive long-term treatment with conventional antipsychotics

    • => No effective treatment
    • + Withdraw antipsychotic if possible
    • Clozapine might be helpful
    • Consider benzodiazepines
    • Do not give anticholinergics (may worsentardive dyskinesia)

    - Neuroleptic malignant syndrome
  12. Distinguishing (N)neuroleptic malignant syndrome from (S) serotonin syndrome

    (1. defining features, 2. neuromuscular abnormalities, 3. onset, 4. med hx, 5. typical blood results, 6. general treatment for all, 7. specific tx, 8. mortality)
    • 1. both conditions characterized by triad of
    • - neuromuscular abnormalities
    • - altered consciousness level
    • - autonomic dysfunction (hyperthermia, sweating, tachycardia,unstable blood pressure)

    • 2. (N) reduced activity
    • Severe rigidity (‘lead pipe’); stiff pharyngealand thoracic muscles may lead to dysphagiaand dyspnoea; bradyreflexia
    • (S) increased activity
    • Myoclonus or clonus, hyperreflexia,tremor, muscular rigidity (less severe thanneuroleptic malignant syndrome)

    • 3. (N) insidious
    • (S) acute

    • 4. (N) 4-11 days of initiation or dose increase of dopamine antagonist (any antipsychotic, metoclopramide)
    • (S) after 1 or 2 dose of new serotenergic medication. Most common cause is concurrent SSRI and MAOI

    5. Elevated creatinine kinase, white cell count and hepatic transaminases; metabolic acidosis

    • 6. Discontinue offending drugs.
    • Cool the patient.
    • Monitor and manage hydration and haemodynamics (e.g. intravenous fluids).
    • Consider ITU for monitoring and/or ventilation.
    • Monitor for complications (e.g. pneumonia, renal failure).
    • Use benzodiazepines for sedation if agitated

    • 7. (N) Bromocriptine (to reverse dopamine blockade)Dantrolene (to reduce muscle spasm)ECT
    • (S) Cyproheptadine (5HT - 2A antagonist)

    • 8. (N) 20% untreated
    • (S) Low