Dr. Tracy Womble

1. Neuroleptics Dr. Tracy Womble

2. Neuroleptics • Referred to as antischizophrenic, antipsychotic or major tranquilizers • Primarily for schizophrenia, but effective for other psychotic states • Antipsychotic properties due to dopamine receptor antagonism • Newer “atypical” antipsychotic drugs are serotonin receptor antagonists • Not curative, does not eliminate thinking disorder, but allow patient to function in supportive environment • Pathogenesis of schizophrenia is unknown

3. Schizophrenia • Mental disorder caused by some dysfunction of the brain, occurring in @1% of pop. • Characterized by delusions, hallucinations (hearing voices), thinking and speech disturbances • Often affected during adolescence, chronic disabling disorder • Has strong genetic component • etiology of schizophrenia is unknown • Possible overactivity of mesolimbic dopaminergic neurons • Serotonin receptor involvement • Characterized by 2 components; • breakdown of personality • loss of contact with reality • Antianxiety agents not useful for psychotic disorders • Typical or coventional neuroleptics - chlorpromazine (Thorazine), fluphenazine (Prolixin), haloperidol (Haldol), thiothixene (Navane), trifluoperazine (Stelazine), perphenazine (Trilafon), and thioridazine (Mellaril)

4. Neuroleptics (Antipsychotics) • Reserpine and chlorpromazine were first drugs used for schizophrenia / psychosis • Divided into five major classifications based on structure. Side changes have significant effect on potencies • 1. Phenothiazines • 2. Benzisoxazoles • 3. Dibenzodiazepines • 4. Butyrophenones • 5. Thioxanthenes • Management of psychotic disorder can be determined by familiarity of effects drugs in each class • N-10 position controls degree of side effects

5. Phenothiazine(Typical Antipsychotics) • 3 subclasses • 1. Aliphatic – least potent • Chlorpromazine –intermediate extrapyramidal side effects and intermediate anticholinergic action, high incidence of sedative action • 2. Piperazine – most potent, selective and effective, increased incidence of Tardivedyskinesia • Fluphenazine (Prolixin) • Prochlorperazine (Compazine) • Perphenazine (Trilafon) • 3. Piperidine – least potent, lower incidence of extrapyramidal side effects, high incidence of anticholinergic action • Thioridazine (Mellaril) • Mesoridazine (Serentil)

6. Action of Phenothiazine • CNS – reduces spontaneous anxiety and response to external stimuli, intelligence is not diminished, reflexes not suppressed, mild sedation • Limbic system Da receptors involved in mood/feeling • 5 subclasses of DA receptors (D1-D5) • D1/5 activate, D2/3 inhibit adenylcyclase • D2 involved in psychotic disorders • Blockade of D2 receptor is antipsychotic action • Basal Ganglia – blockade of D1 or D2 results in extrapyramidal side effects • Cardiovascular center – depressed by antipsychotics – hypotension • Chemoreceptor trigger zone (CTZ) – provokes emesis when foreign substance interacts with DA receptor. These receptors are blocked by phenothiazines. (anti-emetic action) • Hypothalmus – DA receptors inhibit release of prolactin, phenothiazines block DA receptors - stimulate release of prolactin – hormonal side effects • Misc. – no physical dependence, mild CNS depressant (toxic dose), decrease seizure threshold • Autonomic effects – anticholinergic action (piperidines – strongest, piperizines – weakest) • Alpha-antogonist

7. Side effects of Phenothiazine • Side effects • Orthostatic hypotension – due to alpha blockade, dose/effect response • Extrapyramidal Syndrome – increased cholinergic activity (Piperazine – highest, Piperidines – lowest) • Parkinson-like Syndrome • Akathesia – uncontrollable restlessness, distress, anxiety • TardiveDyskinesia – develops late in antipsychotic therapy, usually at high doses x 6 months, rhythmic motions of head, face and shoulders, may be irreversible • Do not use DA or Levo-Dopa, use diphenhydramine (Benadryl), benztropine (Cogentin) or trihexephenidyl (Artane).

8. Therapeutic use of Phenothiazines • Tx psychotic disorders • Schizophrenia, senile dementia, extreme paranoia, manic phase of manic depressive syndrome, • Anti-emetics – radiation toxicity, anticancer meds, opioids, gastroenteritis (prochloperazine) [compazine] • Phenothiazines control • positive symptoms – Hallucinations, delusions, hostility, hyperactivity • Not negative symptoms – social withdrawal, lack of expression, decrease in speech patterns

9. Atypical Antipsychotics • In the last decade new "atypical" antipsychotics have been introduced, >effective, <s/e • typical antipsychotics appear to be equally effective for helping reduce the positive symptoms like hallucinations and delusions • but may be better than the older medications at relieving the negative symptoms of the illness, such as withdrawal, thinking problems, and lack of energy.

10. Mechanism of Action of Atypical Antipsychotics • Blockade of DA and / or serotinin receptors. Many also block cholinergic, adrenergic, and histamine receptors – variety of side effects • DA receptor antagonism in brain (typical and atypical antipsychotics) • Neuroleptics are antagonized by agents that increase DA concentration (L-dopa and amphetamines) • Serotonin receptor antagonism in brain (atypical)

11. Atypical Antipsychotics • Admin PO QD or BID • Low or no EPS • 5-HTr antagonist • 5-HT2A receptor • No effect on prolactin • Control both positive and neg. symptoms • The atypical antipsychotics include aripiprazole (Abilify), risperidone (Risperdal), clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon).

12. Atypical Antipsychotics(second generation) • Clozapine • Little to no EPS, high incidence of agranulocytosis (regular CBS’s), High incidence of siezures • Olanzapine (Zyprexa) • Sedation, weight gain, no agranulocytosis, low incidence of siezures • Quetiapine (Seroquel) • Sedation, low incidence of all side effects • Misc. • Lithium carbonate (antimanic drug) • Admin. PO, tx of manic phase of manic depressive syndrome • Has onset time of 6 months, MOA unknown

13. Action of Atypical Antipsychotics • Antipsychotic – reduce hallucinations, agitation, require several weeks to occur • EPS – Parkinsonian symptoms, akathisia, tardive dyskinesia.(clozapine, risperidone show low incidence) • Antiemetic – D2 receptor antagonist in CMZ of medulla (except thioridazine) • Antimuscarinic – blurred vision,dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle – constipation, urinary retention. (all esp. thioridazine and chlorpromazine) • α-blockade – orthostatic hypotension, lightheadedness, alter temperature regulating mechanisms, block D2 receptors in pituitary – prolactin release

14. Therapeutic application of antiemetic agents • Vertigo – meclizine, dimenhydrinate • Motion sickness – scoopolamine, promethazine • Cancer chemo – droperidol, haloperidol, metoclopramide, prochloperazine • Radiation therapy – thiethylperazine, domperidone