Antipsychotics

Antipsychotics at CNS Receptors

Dopamine: Antagonists at D2 or Partial Agonist at D2 Serotonin: Antagonists at 5-HT2A Histamine: Antagonists at H1 Cholinergic: Antagonists at muscarinic M1-4 Noradrenergic: Antagonists at 1

Dopamine Receptor

Agonists Bromocriptine Carbidopa Levodopa Pergolide Pramipexole Ropinirole Antagonists (Typical)
Also called First generation antipsychotics

Phenothiazones -Aliphatic -Piperazine Thioxanthene Butyrophenones:

Typical/First generation antipsychotics

Phenothiazine Compounds:
Three subclasses:
aliphatic derivatives (e.g. chlopromazine (Thorazine)) piperidine derivatives( e.g. thioridazine (Mellaril) am): relatively less potent piperazine derivatives (e.g. fluphenazine (Prolixin)): relatively more potent

Dopamine Receptor Antigonists

Well absorbed on oral administration Peak plasma concentrations usually within 1-4 hrs after oral administration & 30-60 min. after parenteral administration Smoking, coffee, antacids and food interfere with absorption of these drugs Steady state levels reached in approx. 3-5 days Half life of these drugs are approx. 24 hours Most DRAs are highly protein bound Bioavailability is tenfold if given parenteraly Most of DRAs are metabolized by CYP 2D6 and 3A isozymes

Absorption and Distribution Readily but incompletely absorbed Significant first-pass metabolism Highly lipid soluble and protein bound Large volume of distribution Long clinical duration (e.g., 6 weeks or more to full relapse) Metqbolism Cytochrome P450 Enzymes CYP 3A4: Inhibitors are erythromycin, fluvoxamine Inducers are carbamazepine, phenytoin, phenobarbital CYP 2D6: Inhibitors are buproprion, fluoxetine, paroxetine, quinidine CYP 1A2: Inhibitors are fluvoxamine, omeprazole

Dopamine Receptor Antagonists

Long acting DRAs in US are Haldol and Fluphenazine Given every 1-4 weeks, depending on dose and person It can take up to 6 months of Rx with depot formulations to reach steady-state plasma levels, indicating that PO Rx should be continued during the first months or so

Dopamine Receptor Antagonists

Cause inhibition of dopaminergic neurotransmission DRAs are effective when approx. 60% of D2 receptors in the brain At 80%, we see the beginning of EPS signs DRAs block NA, Cholinergic and Histaminergic receptors Low Potency: Chloropromazine, Thioridazine High Potency: Haldol, Fluphenazine

Indications for DRAs Rx

Borderline P.D. Delirium and dementia Pervasive Developemental disorder Tourettes syndrome Huntingtons disease

Factors affecting the pharmacokinetics of Antipsychotics

Age: Elderly have reduced clearance rates Medical conditions: Decreased Hepatic blood flow means reduced clearance Enzyme inducers: Carbamazepine, Phenytoin Ethambutol, Barbiturates Clearance inhibitors: SSRIs, TCAs, Cimetidine, Beta blockers, Isoniazid, Methylphenidate, Erythromycin Changing in binding proteins: Hypoalbuminemias can occur with malnutrition or hepatic failure

Absorption and Distribution Readily but incompletely absorbed Significant first-pass metabolism Highly lipid soluble and protein bound Large volume of distribution Long clinical duration (e.g., 6 weeks or more to full relapse) Metqbolism Cytochrome P450 Enzymes CYP 3A4: Inhibitors are erythromycin, fluvoxamine Inducers are carbamazepine, phenytoin, phenobarbital CYP 2D6: Inhibitors are buproprion, fluoxetine, paroxetine, quinidine CYP 1A2: Inhibitors are fluvoxamine, omeprazole

Neuroleptic Malignant Syndrome

Can occur at anytime during the course Symptoms: Extreme hyperthermia, severe muscular rigidity, dystonia, akinesia, mutism, confusion, agitaiton, increased pulse rate and BP, all leading to cardiovascular collapse Lab findings: High WBCs, CPK (creatinine phosphokinase, LFTs, plasma myoglobin and myoglobinuria occasionally associated with renal failure Symptoms usually evolve over 24-72 hours This syndrome, if untreated, lasts 10-14 days Diagnosis often missed in early stages and the withdrawal or agitation may be mistakenly be due to increased psychosis Men affected more frequently than women Young > elderly Mortality 20-30%, even higher if depot medications involved, even higher if when high doses of high potency agents are used

Neuroleptic Malignant Syndrome: Rx

Stop the DRAs Cool the patient, Monitor vitals, electrolytes, fluid balance, renal output Antiparkinsonian medications may reduce some of the rigidity Dantrolene: a skeletal muscle relanxant, is useful in doses of 0.82.5mg/kg every 6 hourly, up to dosage of 10mg/day Once able to take orally, Dantrolene can be given in doses of 100200mg/day Bromocriptine: 20-30mg/day in four divided doses or Amantadine can also be added to the regimen Rx usually for 5-10 days When restarting antipsychotics, consider Low-potency drug or Serotonin-dopaminergic antagonist, although they can also cause NMS, including Clozapine

Dopamine Projection Pathways

1. Neostriatal Caudate/Putamen Regulates Motor Function 2. Mesolimbic Nucleus Accumbens and Amygdala Regulates Emotions 3. Mesocortical Limbic Cortex Regulates Attention/Cognition 4. Tuberohypophysial Arcuate Nucleus Regulates Prolactin Release

Blockade of Dopamine D2 Receptors

Emotion - Reduces expression of emotion Cognitive functions Decreases cognitive processes in prefrontal cortex Motor functions Produces akinesia and symptoms of Parkinsonism Endocrine function Produces increased release of prolactin

Side-effects of DRAs
1. Lower seizure threshold Chlorpromazine, Thioridazine and other low-potency drugs are more epileptogenic than high-potency drugs 2. Blockade of histamine H1 rec., Most sedating is Chlorpromazine 3. Central Anticholinergic effects Severe agitation, disorientation, hallucinations, seizures, high fever, dilated pupils, stupor and coma may ensue. Treating anticholinergic toxicity: Discontinue the cause, Consider Physostigmine (Antilirium, Eserine) 2mg slow IV infusion, repeat within 1 hr. as necessary. Avoid too much physostigmine, can cause toxicity: hypersalivation, sweating which can further be treated with Atropine 0.5mg as needed

Side-effects of DRAs
4. Cardiac effects DRAs decrease cardiac contractility, disrupt enzyme contractility in cardiac cells, increase circulating levels of catecholamines and prolong atrial and ventricular conduction time and refractory periods Low-potency DRAs are more cardiotoxic than high-potency Chloropromazine causes prolonged QT and PR intervals, blunting of T-waves and depression of ST-segment. Prolonged QT is a risk for torsade de pointes 5. Sudden death Occurs with cardiac arrhythmias usually, can also occur with seizure, asphyxiation, malignant hyperthermia

Side-effects of DRAs
6. Orthostatic Hypotension Most common with low-potency meds, esp. with Chlorpromazine, Thioridazine and Chlorprothixene. If planning to use IM Low-potency DRAs, always check BP (both lying and standing) before and after the first dose and during the first few days of Rx. Mediated by adrenergic blockade, frequently occurs during first few days of Rx Avoid caffeine and alcohol, drink at least 2 Lt. of fluid a day If not under HTN Rx, should add liberal amount of salt in their diets

Side-effects of DRAs
7. Hematological effects Temporary leukopenia with WBC count of 3500 is common but not a serious problem Life threatening agranulocytosis occurs in 1 of 10,000 8. Peripheral Anticholinergic effects Dry mouth and nose, blurred vision, constipation, uninary retention, mydriasis are common esp. with low potency DRAs Can also cause nausea and vomiting Severe consipaiton = Paralytic ileus (Rx with Pilocarpine temporarily) For urinary retention consider Bethanechol 20-40mg/day good Wt. gain, esp. with low potency DRAs Moban and Loxapine less likely to cause wt. gain

Side-effects of DRAs
9. Endocrine effects Dopamine blockade in the Tubero-infundibular tract causes increased Prolactin which causes breast enlargement, galactorrhoea, amenorrhoea and inhibited orgasm in women and impotence in men SDAs with the exception of Risperidone, are not particularly associated with high prolactin levels, so be the DOC in such patients 10. Sexual Adverse effects Anorgasmia and decreased libido in both men and women 50% of men on antipsychotics report ejaculatory and erectile disturbances

Second Generation Antipsychotics (Atypical Antipsychotics)

Serotonin-Dopamine Antagonists Partial Dopamine Agonists Greater effects against negative symtpoms, cognitive defects and depression Fewer EPS