Antipsychotics PDF

ANTIPSYCHOTICS Dr Than Than Aye - Antipsychotic drugs are to reduce hallucinations, delusions, agitation, and psychomotor excitement in schizophrenia, mania, or psychosis secondary to a medical condition. - antipsychotic effect is obtained when D2-receptor occupancy lies in the r...

ANTIPSYCHOTICS Dr Than Than Aye - Antipsychotic drugs are to reduce hallucinations, delusions, agitation, and psychomotor excitement in schizophrenia, mania, or psychosis secondary to a medical condition. - antipsychotic effect is obtained when D2-receptor occupancy lies in the range 60-70%.  TYPES 1. Conventional ( typical/First generation )agents - such as chlorpromazine and haloperidol. - effective dopamine -receptor antagonists 2. Atypical (Second generation) antipsychotics - is ability to produce an antipsychotic effect without causing extrapyramidal side effects, except of risperidone can occur extrapyramidal side effects. - they have a lower likelihood of causing extrapyramidal side effects and the risk of tardive dyskinesia. A list of antipsychotic drugs (Neuroleptics/ major tranquillizers) Phenothiazines Chlorpromazine Trifluoperazine Thioxanthenes Flupenthixol Clopenthixol Butyrophenones Haloperidol Dibenzodiazepines Clozapine Olanzapine Dibenzothiazepine Quetiapine Substituted benzamides Sulpiride Amisulpride Benzisoxazole Risperidone Quinolinone Aripiprazole  (A) Atypical antipsychotics Drug EPS* Prolactin Weight Adverse effects elevation gain Amisulpride + +++ + Insomnia, agitation, nausea, constipation, QT prolongation Sulpiride + +++ + Insomnia, agitation, abnormal liver function tests Clozapine 0 0 +++ Agranulocytosis-white cell monitoring mandatory, myocarditis and myopathy (rare), fatigue, drowsiness, dry mouth, sweating, tachycardia, postural hypotension, nausea, constipation, ileus, urinary retention, seizures, diabetes Olanzapine +/0 + +++ Somnolence, dizziness, oedema, hypotension, dry mouth, constipation, diabetes, QT prolongation Quetiapine 0 0 ++ Somnolence, dizziness, postural hypotension, dry mouth, abnormal liver function tests, QT prolongation, diabetes Risperidone ++ +++ ++ Insomnia, agitation, anxiety, headache, impaired concentration, nausea, abdominal pain, diabetes, QT prolongation Aripiprazole + 0 0 Agitation, insomnia, nausea, vomiting  PHARMACOLOGY Pharmacology of atypical antipsychotic drugs - Atypical has 5-HT2-D2-receptor antagonists - Risperidone is a potent antagonist at both 5-HT receptors and dopamine D2 receptors. - Paliperidone is an active metabolite of risperidone and has very similar pharmacological properties when given orally. - Olanzapine is a slightly weaker D₂-receptor antagonist than risperidone, but has anticholinergic and powerful histamine H₁- receptor-blocking activity. - This gives it strong sedating effects - Quetiapine is also a histamine H,-receptor antagonist; it has modest 5-HT-receptor-antagonist effects, and rather weaker D.- receptor-antagonist properties. - It has a low propensity to cause movement disorders and, like olanzapine, is highly sedating. - Lurasidone is a potent 5-HT, and D, receptor antagonist. - It binds only weakly to histamine H, receptors, which makes it less likely to cause weight gain and sedation than olanzapine or quetiapine. - Asenapine binds potently t0 5HT2–receptor, D2 receptor and alpha-2– adrenoreceptor. It can be used sublingual route. - Sertindole is a potent 5-HT-receptor antagonist with weak D₂-receptor- antagonist effects. - It causes clinically significant effects on the QT interval in the electrocardiogram - Ziprasidone is 5HT2 and D2-receptor and antagonist. It produces somnolence and dizziness, but little weight gain. - It increases the QT interval, and has not been licensed in the UK. - Aripiprazole Less metabolic Side effect. - Clozapine, - Can use in patient fail to respond to conventional agents. - clozapine has a low liability to cause movement disorders, - It has a weak dopamine D2-receptor antagonist but has a high affinity for 5-HT2 receptors. - It has significant risk of leucopenia. (B) Typical Antipsychotics -mainly act on D2 receptors -not widely used because of their side effects eg Haloperdol Depot antipsychotic drugs - Slow-release preparations are used - fluphenazine decanoate, flupenthixol decanoate, zuclopenthixol decanoate, haloperidol decanoate, and pipotiazine palmitate. (Typical antipsychotics) ( are given intramuscularly in an oily medium, Zuclopenthixol acetate reaches peak plasma levels within 1-2 days) - In atypical antipsychotic drugs such as risperidone, paliperidone (an active metabolite of risperidone), aripiprazole, and olanzapine are also available - ( Use in Poor compliance case) Pharmacokinetics - well absorbed, mainly from the jejunum. - hepatic metabolism is completed as they pass through the portal system on their way to the systemic circulation (first-pass metabolism ) - Antipsychotic drugs are highly protein-bound. - With the exception of sulpiride and amisulpride, which are excreted unchanged by the kidney, - Antipsychotic drugs are extensively metabolized by the liver. - The half-life of most antipsychotic drugs (around 20 hours) is sufficient to allow once-daily dosing. - However, quetiapine has a half-life of about 3 hours, and twice- daily dosing in the treatment of schizophrenia is recommended, although modified-release preparations are available. - It takes several weeks for steady-state drug levels to be reached in the plasma. Some unwanted effects of antipsychotic drugs Antidopaminergic movement effects Antihistaminic effects Acute dystonia Sedation Akathisia Weight gain Parkinsonism Tardive dyskinesia Other effects Cardiac arrhythmias Antiadrenergic effects Metabolic syndrome and diabetes Sedation Amenorrhoea Postural hypotension Galactorrhoea Inhibition of ejaculation Hypothermia Pulmonary embolus Anticholinergic effects Dry mouth Reduced sweating Urinary hesitancy and retention Constipation Blurred vision Precipitation of glaucoma Some pharmacokinetic properties of depot antipsychotic drugs Depot Time to peak Time to steady Licensed dosing Typical clinical plasma level (days) state (weeks) interval (weeks) dose (mg) Flupenthixol 3-7 8 2-4 60 decanoate Fluphenazin 1-2 8 2-5 50 e decanoate Haloperidol 7 8-12 4 100 decanoate Pipotiazine 7-14 8 4 50 palmitate Zuclopenthi 7 8 2-4 300 xol decanoate Risperidone 28 8 2 37.5 microsphere s Olanzapine 2-4 12 2-4 300 pamoate Paliperidone 13 20 Monthly 100 palmitate - SIDE EFFECTS (typical) - 1.Extrapyramidal effects - (a)Acute dystonia (contraction of muscle –abn posture ed torticollis,occulogyris crisis,tongue protrution) - This occurs soon after treatment begins, especially in young men - controlled by an anticholinergic agent - (b)Akathisia - This is an unpleasant feeling of physical restlessness and a need to move, leading to an inability to keep still. - first 2 weeks of treatment with antipsychotic drugs - Beta-adrenoceptor antagonists - The best strategy is ta reduce the dose of antipsychotic drug, if - (c)Parkinsonian syndrome - expressionless face, and lack of associated movements when walking, together with rigidity, coarse tremor, stooped posture. - This syndrome often does not appear until a few months after the drug has been taken. - It can be controlled with antiparkinsonian drugs - Antiparkisonism drugs - Benztropine(Congentin) - Procyclidine(Kemadrine) - Trihexyl phenedyl (artane) - Diphenhydramine –Antihitamine IM - (d)Tardive dyskinesia - chewing and sucking movements, grimacing. choreoathetoid movements, and possibly akathisia. - The movements usually affect the face, but the limbs and the muscles of respiration may also be involved. - It can be occur in other cause eg. metoclopramide for chronic gastrointestinal problems. - Epidemiology - Tardive dyskinesia is more common among women, the elderly, and patients who have diffuse brain pathology. - mood disorder is also a risk factor (about 50% of cases). - ttardive dyskinesia is lower with atypical antipsychotic agents such as clozapine, olanzapine, and risperidone than with haloperidol. - Pathophysiology --tardive dyskinesia is uncertain (supersensitivity to dopamine). - Clozapine clonazepam may be effective atypical agent in treating tardive dyskinesia - 2.Antiadrenergic effects - reflex tachycardia, nasal congestion, and inhibition of ejaculation.. - 3.Anticholinergic effects - dry mouth, urinary hesitancy and retention, constipation, reduced sweating, blurred vision, and, rarely, the precipitation of glaucoma. - 4.Antihistaminic effects - H₁-histamine receptor antagonism causes sedation and also increased appetite, excessive weight gain, which contributes towards the development of the metabolic syndrome and type 2 diabetes. - 5.Cardiac conduction defects - Cardiac arrhythmias are sreported. ( prolongation of the QT interval and T-wave changes.) - ECG monitoring is recommended. - Depression - Depression of mood is due to excessive dopamine-receptor-blockade. It’s similar to negative symptoms of schizophrenia. - It is associated with anhedonia and loss of drive (involve mesolimbic forebrain) - 6. Diabetes and metabolic syndrome (can occur in atypical) - We have already seen that, probably due to histamine H, receptor antagonism, patients may gain weight - obesity, which increases the risk of type 2 diabetes - increased lipid levels. Especially with olanzapine, clozapine, and quetiapine - increase the risk of cardiovascular disease and may contribute to the increase in overall mortality seen in patients with schizophrenia (such as myocardial infarction and stroke) - have the 'metabolic syndrome (a combination of central obesity with two out of four of: hypertension, raised fasting glucose, low HDL cholesterol, and raised triglycerides). 7.Endocrine changes - Galactorrhoea and amenorhoea due to high prolactin levels. 8.Other side effects - Hypothermia - lower the seizure threshold - Photosensitivity -Sensitivity reactions, particularly chlorpromazine Metabolic monitoring and interventions (for patients taking antipsychotic drugs) Monitoring (if possible, should start before treatment or as soon as possible afterwards) - Body mass index (once every 4 weeks for 12 weeks, then at least biannually) - Blood glucose (fasting or random: 12 weeks, 6 months, and then annually-switch to HbA1c) - Lipid profile (fasting or random: 12 weeks, 6 months, and then annually)’ - Blood pressure (12 weeks, 6 months, and annually) - Enquire about tobacco smoking and alcohol use at each visit Possible interventions - "Lifestyle" interventions: diet and exercise, advice about smoking and alcohol intake - Switch to antipsychotic drug less likely to cause weight gain - Adjunctive metformin for weight gain (requires monitoring of renal function ) - Medical management of diabetes, dyslipidaemia, and hypertension Side effect of clozapine - significant risk of leucopenia (about 2-3%) -Weekly blood count -for first 18 weeks - 2 weekly intervals - from 18 weeks to 1 year - After 1 year -monthly interval of blood sampling. hypersalivation, drowsiness pastural hypotension, weight gain, and hyperthermia. - Seizures may occur at higher doses. - Constipation - Rarely, fatal myocarditis and myopathy have been reported. 8.The neuroleptic malignant syndrome (Typical) - Rare serious disorder (0.2%) in a small minority of patients with antipsychotics, especially high potency compounds or combined lithium and antipsychotic treatment. - The onset is often, but not invariably, during the first 10 days of treatment. - The clinical picture includes the rapid onset (usually over 24-72 hours) of severe motor, mental, and autonomic disorders, together with hyperpyrexia. The prominent motor symptom - generalized muscular hypertonicity,  The mental symptoms - akinetic mutism, stupor, or impaired consciousness. Hyperpyrexia develops, with evidence of autonomic disturbances in the form of unstable blood pressure, tachycardia, excessive sweating, salivation, and urinary incontinence. - Treatment. - is symptomatic - Diazepam for muscle stiffness - Dantrolene to treat the malignant hyperthermia - Bromocriptine – Dopamine agonist  Contraindications - Myasthenia gravis, Addison's disease, glaucoma - Antipsychotic drugs can produce severe movement disorders and changes in consciousness in some patients with dementia, particularly Lewy body dementia. - In the elderly, especially those with associated with an increased risk of stroke. - Chlorpromazine should be avoid in liver disease. - Clozapine has evidence of bone marrow depression. - Higher rates of cardiac arrest and sudden death due to choking and cardiac conduction - Treatment of acute behavioural disturbance (sometime call rapid tranquillization) - Acute behaviour disturbance include very excited, aggressive, psychomotor excitement, hostility. - lorazepam (1-2 mg) or the use of olanzapine (10 mg), quetiapine (100-200 mg), risperidone (1-2 mg), or haloperidol (5 mg) - If parenteral treatment is needed, lorazepam (2 mg), promethazine (50 mg), and olanzapine (10 mg) are available as intramuscular preparations, - Intramuscular olanzapine should not be given with parenteral benzodiazepines. - Pre treatment ECG monitoring is important. Dosage and D2 receptor blockade of some antipsychotic drugs Drug Relative Maximum D2-receptor dose (oral) BNF dose occupancy in (mg) vivo (%) [daily dose (mg)]* Chlorpromaz 100 1000 80 ine Trifluoperazi 5 NA 80 ne Haloperidol 2 20 80 Flupenthixol 1 18 74 Sulpiride 200 2400 74 Clozapine 60 900 47 Risperidone 2 16 75 Olanzapine 8 20 75 Aripiprazole 5 30 80 Reference: Shorter Oxford Text book of Psychiatry Kaplan and Sadock’s synopsis of psychiatry. THANK YOU