PM 719 Pharmacology II: Antipsychotic Agents and Lithium PDF

1 PM 719 Pharmacology II Chapter 29 Antipsychotic Agents and Lithium Lecture Notes (LN) Antipsychotic Agents (a) Neuuroleptic = type of antipsychotic drug that produces extrapyramidal side effects (EPS) (b) psychosis = a variety of mental disorders, de...

1 PM 719 Pharmacology II Chapter 29 Antipsychotic Agents and Lithium Lecture Notes (LN) Antipsychotic Agents (a) Neuuroleptic = type of antipsychotic drug that produces extrapyramidal side effects (EPS) (b) psychosis = a variety of mental disorders, delusions, various types of hallucinations, grossly disorganized thinking (c) Schizophrenia = clear sensorium but marked thinking disturbance (d) Schizophrenia is a genetic disorder with high heritability History (a) reserpine which depletes biogenic amine levels were the first to be useful for treating psychotic symptoms (b) chlorpromazine is an antipsychotic that produces EPS, drug blocks DA receptors (c) clozapine, atypical antipsychotic that does not produce EPS Serotonin Hypothesis of Schizophrenia (a) LSD and mescaline (from psychedelic mushrooms) are serotonin (5HT) agonists (b) the basis for their hallucinogenic properties is their binding to 5HT2A receptors (c) atypical antipsychotics are inverse agonists at these receptors (clozapine, quetiapine) (d) inverse agonist = blocks the constitutive activity of the receptor (e) 5HT2A receptors modulate the release of dopamine (DA) in the cortex, limbic region, and striatum Dopamine Hypothesis of Schizophrenia (a) excessive dopamine (DA) activity plays a role in psychosis (b) many antipsychotic drugs block D2 receptors (c) drugs that increase dopamine, (DA) activity often induce a psychosis (amphetamines, levodopa, apomorphine) (d) dopamine (DA) receptor density increased in Schizophrenics who have never been treated with drugs (e) some postmortem studies of Schizophrenics have shown increased dopamine (DA) levels and increased density of D2 receptors (f) imaging studies have shown increased amphetamine and dopamine (DA) release (g) some effective antipsychotic drugs have little to no effect on D2  2 receptors Glutamate Hypothesis of Schizophrenia (a) glutamate is the major excitatory neurotransmitter in the brain (b) phencyclidine (PCP, angel dust) and ketamine are inhibitors of NMDA receptors (c) hypofunction of NMDA receptors located on GABA interneurons could lead to diminished inhibitory influences on neuronal function (d) diminished GABA activity causes over activity of glutamate receptors Basic Pharmacology of Antipsychotic Agents Chemical Types (a) Phenothiazine derivatives (1) alphatic derivatives (chlorpromazine) (2) piperidine derivatives (thioridazine, perphenazine) (a) both types produce sedation and weight gain (b) Thioxanthene derivatives (thiothixene) (c) Butyrophenone Derivatives (1) haloperidol is the most widely used among those in this group (d) Misc Structures (1) typical antipsychotics (pimozide and molindone) (e) Atypical Antipsychotics (1s) clozapine is the prototype Pharmacokinetics (a) absorption and distribution (1) many undergo first pass effect (2) bioavailability averages 25-35% except for haloperidol 65% (b) biotransformation (1) by CYP 2D6, 1A2, 3A4 enzymes Pharmacodynamics Dopamine Systems (a) a wide variety of pathways in the brain used dopamine (DA) (b) these pathways are involved in behaviors from voluntary movement, inhibition of prolactin secretion, eating behavior.  3 Dopamine Receptors (a) efficacy correlates with affinity for the D2 receptors (b) receptors decreases cAMP levels, inhibits Ca channels and opens K channels (c) found pre and post synaptically (d) antagonism at D2 receptors required for antipsychotic action but there may be some exceptions Clinical Pharmacology Adverse Reactions (ADRs) (a) extrapyramidal reactions including Parkinson’s Syndrome, akathisia (uncontrolled restlessness) and acute dystonic reaction (spastic retrocollis or torticollis) (b) tardive dyskinesia, late-onset syndrome of abnormal choreoathetoid movements (c) antimuscarinic effects include urinary retention (d) weight gain, loss of libido, impotence, infertility (e) agranulocytosis (1-2% of patients) caused with clozapine mostly patients on clozapine must have CBC every week for first 6 months and every 3 weeks after that (f) neuroleptic malignant syndrome (1) life threatening disorder (2) due to extrapyramidal effects of antipsychotics (3) symptoms (a) muscle rigidity (b) high fever (sweating impaired) (c) high creatinine kinase (CK) levels reflecting muscle damage (4) symptom caused by rapid blocking of dopamine receptors (5) treat with diazepam (muscle relaxant) and antiparkinsonism drugs  4 Lithium, Mood-Stabilizing Drugs and Other Treatment for Bipolar Disorder (a) Bipolar disorder (once called manic-depressive illness) is on a continuum from schizophrenia (b) occurs in 1-3 % of the adult population (c) most diagnosed in third or fourth decade of life (d) key symptoms in manic phase: excitement, hyperactivity, impulsivity, disinhibition, aggression, diminished need for sleep, cognitive impairment (e) key symptoms in depression: depressed mood, sleep disturbance, anxiety, high risk of suicide Lithium (a) small mw element, monovalent cation (b) distributes mostly into body water (Vd = 0.5 L/Kg) (c) no biotransformation (d) cleared by kidney, half life about 20 hours (e) target Cp levels 0.6 – 1.4 mEq/L (f) closely related to sodium in its properties (g) best-defined effect of lithium is on inositol phosphates (1) inositol trisphosphate and diacylglycerol second messengers in alpha adrenergic and muscarinic transmission (2) lithium inhibits the production of these second messengers and down regulates pathways that use these second messengers Clinical Pharmacology Bipolar Affective Disorder (a) Lithium was once the drug of choice but has been replaced by others (b) numerous ADRs including (1) tremor one of the most common ADRs (2) decreased thyroid function (3) nephrogenic diabetes insipidus (4) edema  5 Other Drugs Used in Place of Lithum Valproic Acid, carbamazepine, lamotrigine all covered in previous chapters. Chapter 29 Antipsychotics Drugs Required in Bold Including all those in the previous text. PHENOTHIAZINE DERIVATIVES block of D2 >> 5HT2A receptors chlorpromazine fluphenazine thioridazine trifluoperazine thiothixene ATYPICAL ANTIPSYCHOTICS block of 5HT2A > block of D2 receptors aripiprazole clozapine olanzapine quetiapine risperidone ziprasidone BUTYROPHENONE block of D2 >> 5HT2A receptors haloperidol MOOD STABILIZERS lithium suppress inositol signaling carbamazepine lamotrigine valproic acid  6 Some of the differences among the antipsychotics for comparison: Orthostatic ACh Drug Sedation Hypotension EPS Effects aripiprazole low low +/0 + clozapine high high 0 +++++ haloperidol low low +++++ + risperidone low mild + + EPS = Parkinson dystonias, dystonias, akathisa. Ach Effects = anticholingeric side effects PM 719 Pharmacology Chap 29 Antipsychotic Drugs BRIEF SUMMARY The operative theory for the cause of schizophrenia, bipolar disorder, and psychosis associated with dementia etc. is that certain CNS neurotransmitters (NT) are elevated in the CNS. Reducing the activity of these NTs is a major goal in drug therapy in patients with these psychotic conditions. The NTs which are in excess vary but include NE, 5HT, and DA. The drugs used in these psychotic conditions act by attaching to and blocking a specific receptor for one or more of the NTs just listed in the previous sentence. First Generation Antipsychotics D2 >>5HT (stronger block of dopamine receptors compared to 5HT (serotonin) receptors). chlorpromazine thiothixene fluphenazine haloperidol thioridazine Second Generation Antipsychotics 5HT > D2 (stronger block of 5HT receptors compared to dopamine receptors).  7 aripiprazole lurasidone ziprasidone brexpiprazole olanzapine cariprazine quetiapine clozapine risperidone NOTE: Focus on the drugs in bold.