psyc650 psychopharmacology antipsychotics and sedative-hypnotics

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PSYC650 Psychopharmacology Antipsychotics And Sedative-Hypnotics

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PSYC650 Psychopharmacology

Antipsychotics And Sedative-Hypnotics

How many people with Sz respond well to

classical antipsychotics?

A li

ttle

over

80%

Rough

ly 5

0%

About

35%

Aro

und 15

%

25% 25%25%25%

1010

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)

http://www.youtube.com/watch?v=OVAUDAn7Tco&feature=related

http://www.youtube.com/watch?v=0E7x1mPa3iM&NR=1

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

Fac

ilita

te, G

ABA

Fac

ilita

te, 5

-HT

Inhi

bit, G

ABA

Inhi

bit, 5

-HT

25% 25%25%25%

1010

1. Facilitate, GABA

2. Facilitate, 5-HT3. Inhibit, GABA4. 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?

Dys

tonia

Aka

this

ia

Par

kins

onism

Tar

dive

dysk

ines

ia

25% 25%25%25%1. Dystonia2. Akathisia3. Parkinsonism4. Tardive

dyskinesia

1010