Pharmacology of Antipsychotics Dr Andrew P Mallon

Pharmacology of Antipsychotics

Dr Andrew P Mallon

Douglas L. Geenens, D.O. 2000


Dopamine Hypothesis

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


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

Dopamine Hypothesis


Dopamine Pathways

• Mesolimbic

• Nigrostriatal

• Mesocortical

• Tuberoinfundibular


Dopamine PathwaysMesolimbic

• Projects from brainstem to limbic areas.

• Overactivity produces delusions and hallucinations.


Dopamine PathwaysNigrostriatal

• Projects from the substania nigra to the basal ganglia

– A part of the extrapyramidal system

– Thus side effects are called “extrapyramidal”



• Controls movements

• The term “neuroleptics” refers to:

– Antipsychotics ability to “quiet the neurological system”

– To their neurological side effects



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

– Dystonia

– Tremor, rigidity, bradykinesia • Drug-induced Parkinsonism



• Chronic blockade can cause

– Potentially irreversible movement disorder • “Tardive Dyskinesia”

• Role is undetermined


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”


Dopamine PathwaysTuberoinfundibular

• Blockade produces galactorrhea

• Dopamine=PIF


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



Antipsychotics

• Phenothiazines (piperidines)– Mesoridazine

• Serentil

– Thioridazine • Mellaril

• Phenothiazines (Aliphatic)– Chlorpromazine

• Thorazine


AntipsychoticsPhenothiazines (piperazines)

• Perphenazine – Trilafon

• Trifluoperazine – Stelazine

• Fluphenazine – Prolixin


Antipsychotics

• Thioxanthenes– Navane

• Dibenzazepines– Clozapine

• Clozaril

– Ioxapine • Loxitane


Antipsychotics

• Butyrophenones– Haloperidol

• Haldol

• Diphenylbutylpiperidines– Pimozide

• Orap



Antipsychotics

• Indoles– Molindone

• Moban

• Rauwolfia– Reserpine

• Serpasil


Antipsychotics

• Benzisoxazole– Risperidone

• Risperdal

• Thienobenzodiazepines– Olanzapine

• Zyprexa


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”


AntipsychoticsEfficacy

• Newer agents– e.g. Clozaril

– Have significant activity at the D-1 receptor;

– Risperdal and Zyprexa have significant 5-HT2 activity


AntipsychoticsPotency

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

• Potency determines the predictable side effects of the antipsychotics.


AntipsychoticsPotency

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

• High potency medications cause more:– EPS


Dopaminergic D2 Blockade

Possible Clinical Consequences• Extrapyramidal movement

disorders

• Endocrine changes

• Sexual dysfunction


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)


Histamine H1 BlockadePossible Clinical Consequences

• Sedation, drowsiness

• Weight gain

• Hypotension


AntipsychoticsPotency for H-1 blockade

0 5 10 15 20 25

chlorpromazine(Thorazine)

thioridazine(Mellaril)

loxapine(Loxitane)

molindone(Moban)


fluphenazine(Prolixin)

haloperidol(Haldol)

haloperid 0.025


Alpha-1 receptor blockadePossible clinical consequences

• Postural hypotension

• Reflex tachycardia

• Dizziness


0

5

10

15

20

25

30

35

40chlorpromazine(Thorazine)


loxapine(Loxitane)

molindone(Moban)



haloperidol(Haldol)

AntipsychoticsPotency for alpha-1 blockade


Muscarinic receptor blockade

Possible clinical consequences• Blurred vision

• Dry mouth

• Sinus tachycardia

• Constipation

• Urinary retention

• Memory dysfunction


AntipsychoticsPotency for muscarinic

blockade

0

1

2

3

4

5

6

Series 1

chlorpromazine(Thorazine)


loxapine(Loxitane)

molindone(Moban)



haloperidol(Haldol)



ClozarilClozapine

• “Atypical” antipsychotic

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

• At least nine different receptor affinities


ClozarilClozapine

• One of the most complicated medications in psychopharmacology

• Can cause death via agranulocytosis

• Cost is typically $10,000.00 per year


Extrapyramidal Symptoms

Dopamine Vs Acetylcholine• Dopamine and Acetylcholine have

a reciprocal relationship in the Nigrostriatal pathway.

• A delicate balance allows for normal movement.



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



Dopamine Vs Acetylcholine• When high potency antipsychotics

are chosen, we often prescribe anti-ACH medication like

– Cogentin, diphenhydramine, or Artane


Tardive Dyskinesia

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

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


Tardive Dyskinesia

• Attempt of decrease dose– will initially exacerbate the

movements

• Increasing the dose will initially decrease the movements


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


Neurological Side Effects:

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

• Akathisia:– Restlessness – Pacing

• May result in insomnia

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


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


Neuroleptic Malignant Syndrome

• An idiosyncratic, life-threatening illness associated with antipsychotic

therapy

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


Neuroleptic Malignant Syndrome

• Resembles malignant hyperthermia associated with anesthesia

• Treatment involves – Immediate discontinuation of

antipsychotic – Hydration– Maintain vital functions – Prescribe bromocriptine and dantrolene


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Pharmacology of Antipsychotics Dr Andrew P Mallon