PSYC650 Psychopharmacology Antipsychotics And Sedative-Hypnotics

How many people with Sz respond well to classical antipsychotics? 10 Do not respond at all 1.A little over 80% 2.Roughly 50% 3.About 35% 4.Around 15% Respond marginally

Psychopathology Refresher Positive Symptoms –Classical Antipsychotics Negative Symptoms –Atypical Antipsychotics The Dopamine Hypothesis

Mechanisms of Action Classicals are usually D2 and D2-like receptor antagonists Atypicals antagonize D2-like receptors plus some 5-HTa action –LSD –The serotonin hypothesis of negative symptoms

Some Pharmacokinetics Long half-lives, so a 1ce daily dose usually suffices –Often at night to capitalize on sedating effects Elders Beware: –Mostly metabolized in liver –Can induce tachycardia –Anticholinergic reactions

Other General ADRs Lowers seizure threshold Can induce parkinsonian symptoms –Especially Haldol –Can be rectified with anticholinergic drugs Beware…exacerbation of cholinergic ADRs Monitor for dry mouth, disorientation, agitation, confusion, etc. If too bad may need to provide a cholinergic agonist (physostigmine) eature=related

Extrapyramidal Side Effects About 30% of people who take classical antipsychotics –Akathisia (fidgety) –Dyskenisia (impaired voluntary movement) –Dystonia (muscle spasms in head and neck) –Oculogyric crisis (fixed eyeballs) –Torticullis (tilted head) –Hypersalivation –Parkisnonian symptoms

Tardive Dyskinesia

Tardis Sometimes irreversible Anticholiergics sometimes given to prevent EPS can exacerbate tardis

Phenothiazines Early 1950’s Aliphilactics –Largactil (chlorpromazine—Thorazine) –Fewer ADR but lower in potency Anticholinergic, TD, EPS, menstrual changes, weight gain Piperazines –EPS, TD, sometimes anticholinergic, weight changes, orthostatic hypotension, abnormal lactation –prochlorperazine (Compazine) Excellent antiemetic –Fluphenazine (Prolixin) Can do shots 1ce-2ce per month

Phenothiazines-- Piperidines Includes thioridazine (Mellaril) –Similar to aliphiliactics but less sedating and has fewer EPS –Anticholinergic, weight changes, menstrual, lactation, orthostatic hypotension –Long term-high dose: Lens opacity & Retinal pigmentation (esp bad with Mellaril)

Butyrophenones Droperidol (Inapsine), haloperidol (Haldol) Similar to phenothiazines, but faster with less ACH Haldol can be injected as a long-term depot bound substance Droperidol is effective as an antiemetic –Often given for nasuea associated with anasthesia EPS, blood disorders, lactation and menstrual difficulties, postural hypotension, sedation, TD

Atypicals Clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal) Treatment-resistant clients Negative symptoms Fewer ADRs –Anticholinergic, antihistaminic –Serotonin-related symptoms (10-40% patients): constipation, drowsiness, headache, hypersaliation, hypotension, tachycardia –Neutropenia (2% patients) decrease in neutrophil count in blood. Increases susceptibility to bacterial and fungal infections Fatal!

Sedative Hypnotics

Uses… Depresses CNS Anxiety Sleep disturbances Not for depression-associated anxiety If on stimulant, wait for stimulant effects to wear off –“Wide awake drunk”

Dreaming of Drugs Some sedative hypnotics suppress REM, others suppress N-REM May be desirable to prescribe a drug that suppresses the stage at which another disorder ‘strikes’ –N-REM: Night terrors –REM: Nocturnal angina Beware REM rebound

Barbiturates Lots of legends around name –St. Barbara’s day 1903 –“Barbara’s Urates” Over 2,500 barb’s synthesized and 50 marketed Now about 10 are “going strong” –Benzo’s knocked them out of the market Better marketed Lower abuse potential Higher TI

Barbituarates: Pharmacokinetics and Pharmacodynamics Vary in potency, depending on lipid solubility –Most lipophilic is thiopental (Pentothal) Metabolized in liver –Enzyme induction Probably GABA-ergic –Barb’s bind to receptor near GABA receptor –Causes retention of GABA –Increases influx of Cl- –Inhibiting transmission

Barbiturates: ADRs CNS depression –Normal and transient –Slow breathing, low BP OD: Respiratory depression, coma, kidney failure, cardiovascular collapse, death Little use other than sedation –Tolerance can occur in as little as 2 weeks Sometimes therapeutic adjunct Paradoxical effect on elderly and young Can cause insomnia –More frequent and intense dreaming –Angina –Exacerbates gastric ulcers

Benzodiazepines About a zillion of them Chlordiazepoxide (Librium): prototypic Lorazepam (Ativan) Clonazepam (Klonopin) Diazepam (valium) Alprazolam (xanax) Estazolam (ProSom) Triazolam (Halcion)

Mechanism of Action Probably GABA Largely in amygdala and thalamus –Probably via Cl- channels

Benzo ADRs Best anxiolytics, buts… REM suppression at high doses Short acting benzo’s may have rebound insomnia Amnestic effects Confusion Motor coordination Disorientation Lethargy Oversedation Some reports of tachycardia

Benzo Dependence Withdrawal comes in 3 phases: 1.Rebound anxiety and insomnia –could last several days, depending on T-1/2 –Starts 1-4 days after drug removal 2.Anxiety, difficulty concentrating, headache, irritability, sleep problems –Lasts about 1-3 weeks 3.Anxiety –May last several months

Benzoverdose May have to administer a BZ antagonist –Flumazenil –T-1/2 of 1 hour Need to be careful to monitor and readminister as needed Watch for withdrawal as well

Miscellaneous: Chloral Hydrate Knock out drops Quite a few interactions Active metabolite trichloroethanol Tolerance OD potential Severe nausea (take with meals to prevent vomiting)

Miscellaneous Others Buspirone –Only mildly sedating –Serotonergic Methqualone –High abuse potential –Once thought to be an aphrodesiac

Benzodiazepines __________ binding at the _____________ receptor 10 1.Facilitate, GABA 2.Facilitate, 5-HT 3.Inhibit, GABA 4.Inhibit, 5-HT

Your patient on Haldol seems agitated, and when he’s not pacing, he’s rocking back and forth. What’s most likely? 1.Dystonia 2.Akathisia 3.Parkinsonism 4.Tardive dyskinesia 10