Anti-Psychotic Agents PDF

ANTI- PSYCHOTIC AGENTS BY DR. HARSHIKA PATEL KEMU NRSG 232: PHARMACOLOGY II  ANTI-PSYCHOTICS Mainstay of pharmacological treatment for schizophrenia and related disorders Diminish positive symptoms such as hallucinations, delusions, thought disord...

ANTI- PSYCHOTIC AGENTS BY DR. HARSHIKA PATEL KEMU NRSG 232: PHARMACOLOGY II  ANTI-PSYCHOTICS Mainstay of pharmacological treatment for schizophrenia and related disorders Diminish positive symptoms such as hallucinations, delusions, thought disorder Some impact on negative symptoms such as lack of motivation, blunted affect, cognitive impairment Treatment is important as a part of relapse prevention  Clinical indications antipsychotics are prescribed for: Acute psychosis Schizophrenia Acute mania Organic psychosis Adjunct in psychotic depression Severe behavioural disorders in children Adjunct in anaesthesia Adjunct in treatment of alcoholic hallucinosis Tourette’s syndrome  Intractable nausea and vomiting (haloperidol, droperidol) Intractable hiccup (chlorpromazine) Delusional disorders Schizoaffective disorders Schizophreniform disorder, brief reactive psychosis or disorder not otherwise specified Bipolar disorder manic or mixed Major depressive episode with psychotic features Organic mental syndrome with psychotic features Aggressive/disruptive behaviour in delirium, dementia or mental retardation (low doses)  SCHIZOPHRENIA - SYMPTOMS Positive Symptoms(↑↑DA) Negative Symptoms(↓↓NMDA Hallucinations Blunted emotions Delusions (bizarre, persecutory) Anhedonia Disorganized Thought Lack of feeling Perception disturbances Inappropriate emotions FUNCTION Mood Symptoms Cognition Loss of motivation New Learning Social withdrawal Memory Insight Demoralization Suicide ANTI-PSYCHOTICS Antagonise dopamine receptors, resulting in anti-psychotic effects Indications-schizophrenia, acute mania, psychotic depression, Conventional and atypical drugs are available Both of equivalent efficacy when taken at recommended dosages Atypicals have lower incidence of EPSE  BLOCKADE OF D2 RECEPTORS? Nigrostriatal pathway D2 extrapyramidal side effects ANTAGONIST (EPS) and tardive dyskinesia Mesocortical pathway enhanced negative and cognitive psychotic symptoms Mesolimbic pathway dramatic therapeutic action on positive psychotic symptoms Tuberoinfundibular pathway hyperprolactinemia (lactation, infertility, sexual dysfunction) The key steps in the synthesis and degradation of dopamine and the sites of action of various psychoactive substances at the dopaminergic synapse  WHY EXTRAPYRAMIDAL SIDE EFFECTS ? Dopamine and acetylcholine have a reciprocal relationship- Blockade of dopamine receptors increases the activity of acetylcholine Over activity of acetylcholine causes EPSE Blockade of dopamine causes movement disorders in the nigrostriatal pathway Long term blockade causes “upregulation” and leads to tardive dyskinesia  CONVENTIONAL OR TYPICAL ANTIPSYCHOTICS Have four actions – blockade of: Dopamine 2 Muscarinic/ cholinergic Alpha adrenergic Histamine  ATYPICAL ANTIPSYCHOTICS Pharmacologic properties 5HT2A and D2 antagonism (as opposed to conventional drugs which are D2 without 5HT2A antagonism) Atypical drugs – block of d2 and 5HT2a  CONTD.. In reality – not simple serotonin- dopamine antagonists Most complex pharmacological properties Act on multiple serotonin and dopamine receptors, histamine, alpha adrenergic & cholinergic  Atypical versus conventional All equal efficacy (except clozapine) Consideration for: Merits of high versus low affinity drugs Cerebral selectivity of the drugs Adverse effect profile Dose necessary to achieve optimal D2 blockade Patient tolerability, preference, response (from history) MOST COMMON DIFFERENCE Typical antipsychotics are associated with a higher rate of extrapyramidal effects Whereas, atypical antipsychotics are associated with a higher rate of metabolic effects, such as diabetes, weight gain, and elevated blood lipids.  ANTI-PSYCHOTICS Atypical – eg Olanzapine, Conventional – Risperidone, eg Quetiapine, Chlorpromazine, Amisulpride, Haloperidol, Clozapine, Risperdal Stelazine, Consta depots such as intramuscular Flupenthixol, injection, Zuclopenthixol, Aripiprazole, Fluphenazine Paliperidone, Ziprasidone Also have effects on acetylcholine, histamine, serotonin receptors – varying  ATYPICAL ANTIPSYCHOTICS The ‘newer” antipsychotics Effectively treat psychotic symptoms Lower incidence of extra pyramidal side effects than conventional agents Have effects on dopamine, serotonin, histamine and muscarinic receptors  ATYPICAL ANTIPSYCHOTICS Indicatio Current atypicals are in use : Amisulpride ns Aripiprazole Schizophreni a and related Quetiapine psychosis Olanzapine Acute mania Risperidone Behavioural Clozapine disturbance Ziprasidone in dementia Paliperidone (EXTENDED RELEASE)  THERAPEUTIC EFFECTS ON SYMPTOMS Agitation, sleep and appetite often respond in the first 1-2 weeks Personal hygiene and basic interpersonal socialization may take 2-3 weeks and psychotic symptoms can gradually decrease over 2-6 weeks An effective trial should be at least 6-8 weeks at doses that are within the prescribed range  HOW LONG SHOULD ANTIPSYCHOTICS BE TAKEN FOR? At least 6 months after an acute episode reduces relapse rates If the person experiences another episode they may need antipsychotic medication for 2-5 years before ceasing use For those with multiple episodes, they may need medication for much of their life  ADVERSE EFFECTS Sedation Postural hypotension Anticholinergic effects – dry mouth, blurred vision, constipation, urinary hesitancy Weight gain-clozapine, olanzapine Metabolic effects-increased serum lipids, impaired glucose tolerance- clozapine, olanzapine, quetiapine  CONTD… Hyperprolactinaemia-leads to galactorrhoea, amenorrhoea, decreased libido Sexual dysfunction QTC prolongation-leads to cardiac arrhythmias EPSE-extrapyramidal side effects Acute dystonias -laryngeal spasm, oculogyric crises Akathisia-severe sense of agitation, inner restlessness in the limbs, especially the legs SYMPTOMS OF EPSE https://www.youtube.com/watch?v=t_NKR S8lLWA  CONTD… Akathisia – a severe sense of psychomotor agitation Parkinsonism -poverty of movement, tremor, rigidity, drooling, hypersalivation Tardive dyskinesia-involuntary hyperkinetic movements, affects the mouth, lips, tongue, jaws with smacking, tongue writhing, sucking, chewing and tic like movements, limbs and trunk can be affected  CONTD.. Irreversible in some patients Neuroleptic malignant syndrome-rare but potentially fatal – high temp, muscle rigidity, altered consciousness, raised creatinine kinase –cease medication Can happen at anytime during treatment 30% patients will develop syndrome again on rechallenge Typically white cell count, creatine kinase (CK) and LFTs are raised  DEPOT ANTI-PSYCHOTICS Used when concerns around compliance Depot formulations are usually given at intervals of 2-4 weeks by deep intramuscular injection and deltoid muscle Conventional-zuclopenthixol(useful for agitated, aggressive, disturbed behaviour) flupenthixol (may have mood elevating effects) fluphenazine -EPSE common Typical- risperdal consta – onset of action 3 weeks, need oral risperidone to supplement until peak plasma reached (pt. become more sensitive to temperature extremes – too hot may leads malignant hyperthermia)  COMPARATIVE INFORMATION FOR ANTI-PSYCHOTICS Chlorpromazine, Most sedating, most potent Pericyazine anticholinergic effects, least likely to cause EPSE, most likely to cause orthostatic hypotension. Low potency antipsychotics Trifluperazine, Moderately sedating, intermediate Fluphenazine propensity to cause EPSE, some potential to cause orthostatic hypotension Haloperidol, Droperidol, Least sedating, almost no anticholinergic Thiothixene, Pimozide effects, most likely to cause EPSE, least likely to cause orthostatic hypotension, sometimes referred to as ‘high potency’ antipsychotics  CONTD.. Amisulpride Less potential for weight gain and sedation Aripiprazole May cause insomnia, less potential for hyperprolactinaemia Clozapine Effective treatment-resistant patients but has serious side-effects (blood dyscrasias, seizures, cardiomyopathy, myocarditis, orthostatic hypotension, sedation, weight gain).  CONTD… Olanzapine Related to Clozapine may cause sedation, weight gain, peripheral oedema; increased risk of stroke and related mortality in elderly dementia patients Quetiapine Sedating and vasoactive, less potential for hyperprolactinaemia Risperidone, Orthostatic hypotension and Paliperidone hyperprolactinaemia, may be a problem; increased risk of stroke and related mortality in elderly dementia patients Ziprasidone Less potential for weight gain  DRUG INTERACTIONS Cytochrome P450 isoenzymes are significant in psychotropic drug interactions Inducers or inhibitors of this pathway may produce clinically important drug interactions May lead to increase or decrease of medications due to interactions  CONTD… Examples Fluvoxamine inhibits olanzapine and clozapine metabolism Smoking induces olanzapine metabolism SSRIs inhibit most antipsychotics and therefore increase serum concentrations Phenytoin reduces serum concentration of quetiapine (inhibitors) Others – grapefruit juice, antibiotics  CLOZAPINE Used when previously unresponsive to other antipsychotics Serious adverse effect profile Strict guidelines relating to commencement and monitoring Significant risk of agranulocytosis Trial at least 2 different standard antipsychotics at an adequate dose and for an adequate duration prior to commencing clozapine (restore for salvage tx)  USE OF ANTIPSYCHOTICS WITH OLDER PERSONS Various disorders treated with antipsychotics in the elderly – psychosis, bipolar affective disorder, delirium & dementia Use extreme caution because of side effect profile ‘Start low & go slow’ (malone et al 2007) & titrate over longer periods of time to reach the required dose Avoid polypharmacy wherever possible  PREGNANCY & LACTATION Avoid antipsychotics if possible Use the lowest effective dose Neonatal adverse effects observed include generalised hypertonicity and dystonic reactions  CONTD… The safety of atypical agents is yet to be established but preliminary reports there to be no deleterious effects to the foetus Isolated cases of congenital abnormalities with the use of clozapine No increased risk has emerged with the use of Olanzapine The conventional agents are generally preferred Supervised dose reduction and cessation 7-10 days prior to delivery should be considered  WHAT OTHER TREATMENTS ARE AVAILABLE? Remember that antidepressant medication is only part of the Treatment for antenatal depression and anxiety. Also consider: Psychological therapies Exclude organic illness(other than psychiatric) as a cause of mental health symptoms Address any alcohol and/or illicit substance abuse Assess the social situation General lifestyle measures: adequate rest/sleep, balanced diet, exercise The decision to treat should be made on an individual case basis  REFERENCES Therapeutic guidelines – psychotropic version 5 Www.Tg.Com.Au 9329 1566 Australian medicines handbook Www.Amh.Net.Au 08 8303 6977 MIMS online Http://www.Ppmis.Org.Au perinatal psychotropic medicine information service THANK YOU ?