pharmacology of antipsychotics douglas l. geenens, d.o. university of health sciences college of...

Pharmacology of Antipsychotics

Douglas L. Geenens, D.O.

University Of Health Sciences College of Osteopathic Medicine

Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

Dopamine Hypothesis

• Drugs that increase dopamine will enhance or produce positive psychotic symptoms– E.G. Cocaine, amphetamine

Douglas L. Geenens, D.O. 2000

• All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors– Esp..D-2 receptors

Dopamine Hypothesis

Douglas L. Geenens, D.O. 2000

Dopamine Pathways

• Mesolimbic

• Nigrostriatal

• Mesocortical

• Tuberoinfundibular

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysMesolimbic

• Projects from brainstem to limbic areas.

• Overactivity produces delusions and hallucinations.

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysNigrostriatal

• Projects from the substania nigra to the basal ganglia

– A part of the extrapyramidal system

– Thus side effects are called “extrapyramidal”

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysNigrostriatal

• Controls movements

• The term “neuroleptics” refers to:

– Antipsychotics ability to “quiet the neurological system”

– To their neurological side effects

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysNigrostriatal

• Types of movement disorders caused by this pathway include:– Akathisia

– Dystonia

– Tremor, rigidity, bradykinesia • Drug-induced Parkinsonism

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysNigrostriatal

• Chronic blockade can cause

– Potentially irreversible movement disorder • “Tardive Dyskinesia”

• Role is undetermined

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysMesocortical

• May be associated with both positive and negative symptoms

• Blockade may help reduce negative symptoms of schizophrenia

• May be involved in the cognitive side effects of antipsychotics “mind dulling”

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysTuberoinfundibular

• Blockade produces galactorrhea

• Dopamine=PIF

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysSummary

• Four dopamine pathways– Appears that blocking dopamine

receptors in only one of them is useful

• Blocking dopamine receptors in the other three may be harmful

Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

Antipsychotics

• Phenothiazines (piperidines)– Mesoridazine

• Serentil– Thioridazine

• Mellaril

• Phenothiazines (Aliphatic)– Chlorpromazine

• Thorazine

Douglas L. Geenens, D.O. 2000

AntipsychoticsPhenothiazines (piperazines)

• Perphenazine – Trilafon

• Trifluoperazine – Stelazine

• Fluphenazine – Prolixin

Douglas L. Geenens, D.O. 2000

Antipsychotics

• Thioxanthenes– Navane

• Dibenzazepines– Clozapine

• Clozaril– Ioxapine

• Loxitane

Douglas L. Geenens, D.O. 2000

Antipsychotics

• Butyrophenones– Haloperidol

• Haldol

• Diphenylbutylpiperidines– Pimozide

• Orap

Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

Antipsychotics

• Indoles– Molindone

• Moban

• Rauwolfia– Reserpine

• Serpasil

Douglas L. Geenens, D.O. 2000

Antipsychotics

• Benzisoxazole– Risperidone

• Risperdal

• Thienobenzodiazepines– Olanzapine

• Zyprexa

Douglas L. Geenens, D.O. 2000

AntipsychoticsEfficacy

• All antipsychotics are considered equally effective– Rationale for determining which medication

to use is based on side effect profile

• Primary mechanism of action is– Postsynaptic blockade of the D-2 receptor– “D-2, me too”

Douglas L. Geenens, D.O. 2000

AntipsychoticsEfficacy

• Newer agents– e.g. Clozaril

– Have significant activity at the D-1 receptor;

– Risperdal and Zyprexa have significant 5-HT2 activity

Douglas L. Geenens, D.O. 2000

AntipsychoticsPotency

• Potency is an important variable in terms of pharmacodynamic properties of these medicines.

• Potency determines the predictable side effects of the antipsychotics.

Douglas L. Geenens, D.O. 2000

AntipsychoticsPotency

• Low potency medications cause more:– sedation– Anti-ACH– Orthostatic hypotension

• High potency medications cause more:– EPS

Douglas L. Geenens, D.O. 2000

Dopaminergic D2 Blockade

Possible Clinical Consequences• Extrapyramidal movement

disorders

• Endocrine changes

• Sexual dysfunction

Douglas L. Geenens, D.O. 2000

AntipsychoticsRelative potencies (mg

equivalents)

0

20

40

60

80

100 chlorpromazine(Thorazine)

thioridazine(Mellaril)mesoridazine(Serentil)

loxapine(Loxitane)

molindone(Moban)thiothixene(Navane)

trifluoperazine(Stelazine)

haloperidol(Haldol)fluphenazine(Prolixin)

Douglas L. Geenens, D.O. 2000

Histamine H1 BlockadePossible Clinical Consequences

• Sedation, drowsiness

• Weight gain

• Hypotension

Douglas L. Geenens, D.O. 2000

AntipsychoticsPotency for H-1 blockade

0 5 10 15 20 25

chlorpromazine(Thorazine)

thioridazine(Mellaril)

loxapine(Loxitane)

molindone(Moban)

trifluoperazine(Stelazine)

fluphenazine(Prolixin)

haloperidol(Haldol)

haloperid 0.025

Douglas L. Geenens, D.O. 2000

Alpha-1 receptor blockadePossible clinical consequences

• Postural hypotension

• Reflex tachycardia

• Dizziness

Douglas L. Geenens, D.O. 2000

0

5

10

15

20

25

30

35

40chlorpromazine(Thorazine)

thioridazine(Mellaril)

loxapine(Loxitane)

molindone(Moban)

trifluoperazine(Stelazine)

fluphenazine(Prolixin)

haloperidol(Haldol)

AntipsychoticsPotency for alpha-1 blockade

Douglas L. Geenens, D.O. 2000

Muscarinic receptor blockade

Possible clinical consequences• Blurred vision

• Dry mouth

• Sinus tachycardia

• Constipation

• Urinary retention

• Memory dysfunction

Douglas L. Geenens, D.O. 2000

AntipsychoticsPotency for muscarinic blockade

0

1

2

3

4

5

6

Series 1

chlorpromazine(Thorazine)

thioridazine(Mellaril)

loxapine(Loxitane)

molindone(Moban)

trifluoperazine(Stelazine)

fluphenazine(Prolixin)

haloperidol(Haldol)

Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

ClozarilClozapine

• “Atypical” antipsychotic

• More effective in person’s who fail typical antipsychotic therapy

• At least nine different receptor affinities

Douglas L. Geenens, D.O. 2000

ClozarilClozapine

• One of the most complicated medications in psychopharmacology

• Can cause death via agranulocytosis

• Cost is typically $10,000.00 per year

Douglas L. Geenens, D.O. 2000

Extrapyramidal Symptoms

Dopamine Vs Acetylcholine• Dopamine and Acetylcholine have

a reciprocal relationship in the Nigrostriatal pathway.

• A delicate balance allows for normal movement.

Douglas L. Geenens, D.O. 2000

Extrapyramidal Symptoms

Dopamine Vs Acetylcholine

• Dopamine blockade:

• A relative increase in cholinergic activity– causing EPS

– Those antipsychotics that have significant anti-ACH activity are therefore less likely to cause EPS

Douglas L. Geenens, D.O. 2000

Extrapyramidal Symptoms

Dopamine Vs Acetylcholine• When high potency antipsychotics

are chosen, we often prescribe anti-ACH medication like

– Cogentin, diphenhydramine, or Artane

Douglas L. Geenens, D.O. 2000

Tardive Dyskinesia

• Associated with long-term use of antipsychotics– (chronic dopamine blockade)

• Potentially irreversible involuntary movements around the buccal-lingual-oral area

Douglas L. Geenens, D.O. 2000

Tardive Dyskinesia

• Attempt of decrease dose– will initially exacerbate the

movements

• Increasing the dose will initially decrease the movements

Douglas L. Geenens, D.O. 2000

Neurological Side Effects:

• Dystonic Reactions:– Uncoordinated spastic movements of

muscle groups• Trunk, tongue, face

• Akinesia:– Decreased muscular movements

• Rigidity:– Coarse muscular movement– Loss of facial expression

Douglas L. Geenens, D.O. 2000

Neurological Side Effects:

• Tremors:– Fine movement (shaking) of the extremities

• Akathisia:– Restlessness – Pacing

• May result in insomnia

• Tardive Dyskinesia:– Buccolinguo-masticalory syndrome– Choreoathetoid movements

Douglas L. Geenens, D.O. 2000

Neurological Side Effects of Neuroleptics

3 6 9 12 15

A: DystonicReactions

B: Akinesia

C: Rigidity

D: Tremors

E: Akathisia

F: TardiveDykinesia

Neurological Effects

  Neurological Effects

Tardive Dyskinesia

Onset Acute or insidiousWithin 1 – 30 days

After months or years of treatment, especially if drug dose decreased or discontinued

Proposed Mechanism

Due to decreased dopamine

Supersensitivity of postsynaptic dopamine receptors induced by long term neuroleptic blockade

Treatment Respond to antiparkinsonian drugs

Generally worsen Tardive DyskinesiaOther treatments unsatisfactory; some aimed at balancing Dopaminergic and cholinergic systems. Can mask symptoms by further suppressing dopamine with neuroleptics. Pimozide or loxapine may least aggravate Tardive Dyskinesia.

Extrapyramidal Effects

Type Onset Risk Group

Clinical Course

Treatment

Dystonias Acute (within 5 days)

Young male Acute, painful, spasmodic Oculogyria may be recurrent

I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used

Akathisia Insidious to acute (within 10 days)

12-45% on neuroleptics

May continue though out treatment

I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used

Pseudoparkinsonism Insidious to acute (within 30 days)

12-45% on neuroleptics

May continue through treatment

Oral antiparkinsonian drug. Reduce or change neuroleptic

Douglas L. Geenens, D.O. 2000

Neuroleptic Malignant Syndrome

• An idiosyncratic, life-threatening illness associated with antipsychotic therapy

• Clinical manifestations include– hyperpyrexia – autonomic instability, – “board-like” rigidity

Douglas L. Geenens, D.O. 2000

Neuroleptic Malignant Syndrome

• Resembles malignant hyperthermia associated with

anesthesia

• Treatment involves – Immediate discontinuation of

antipsychotic – Hydration– Maintain vital functions – Prescribe bromocriptine and

dantrolene

Douglas L. Geenens, D.O. 2000