PSYC650 Psychopharmacology

1. PSYC650 Psychopharmacology Antipsychotics And Sedative-Hypnotics

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

3. Psychopathology Refresher • Positive Symptoms • Classical Antipsychotics • Negative Symptoms • Atypical Antipsychotics • The Dopamine Hypothesis

4. 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

5. 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

6. 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) http://www.youtube.com/watch?v=OVAUDAn7Tco&feature=related http://www.youtube.com/watch?v=0E7x1mPa3iM&NR=1

7. 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

8. Tardive Dyskinesia

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

10. 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

11. 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)

12. 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

13. 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!

14. Sedative Hypnotics

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

16. 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

17. 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

18. 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

19. 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

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

21. Mechanism of Action • Probably GABA • Largely in amygdala and thalamus • Probably via Cl- channels

22. 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

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

24. 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

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

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

27. 10 Benzodiazepines __________ binding at the _____________ receptor • Facilitate, GABA • Facilitate, 5-HT • Inhibit, GABA • Inhibit, 5-HT

28. 10 Your patient on Haldol seems agitated, and when he’s not pacing, he’s rocking back and forth. What’s most likely? • Dystonia • Akathisia • Parkinsonism • Tardive dyskinesia