Antipsychotics

Rogie Royce Z. Carandang, RPh, MPH

Objectives
1. To know the basis for the dopamine hypothesis of schizophrenia 2. To understand the mechanism of action of antipsychotic agents with respect to their therapeutic and adverse effects

Rogie Royce Z. Carandang, RPh, MPH

Antipsychotics
aka neuroleptics, major tranquilizers
Neuroleptics because of their tendency to cause movement disorders Major tranquilizers vs minor tranquilizers (anxiolytics)

Rogie Royce Z. Carandang, RPh

Psychosis
Symptoms of delusions, hallucinations, and disorders of thought
Due to increase dopamine levels (as in amphetamines, cocaine)

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Psychosis

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Schizophrenia
1% of population, inheritable
Characterized by positive and negative symptoms, a pattern of social and occupational deterioration, and persistence of the illness for at least 6 months

2 or more symptoms

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Positive Symptoms
1. Hallucinations - auditory, visual, tactile, and/or olfactory hallucinations, voices that are commenting
2. Delusions - grandiose, paranoid, thought broadcasting, thought insertion

3. Bizarre behavior - aggressive/agitated, odd clothing or appearance, odd social behavior, repetitive-stereotyped behavior
Rogie Royce Z. Carandang, RPh

Negative Symptoms

Affective flattening, alogia, asociality

POSITIVE symptoms respond more consistently with medications. NEGATIVE symptoms are less responsive.

Rogie Royce Z. Carandang, RPh

Adverse Effects
Receptor Blocked Side Effect

Dopamine D2
Histamine H1

Parkinsonism/ EPS
Sedation

Muscarinic M

Dry mouth, constipation, urinary retention, blurring of vision Orthostatic hypotension

Adrenergic 1

Rogie Royce Z. Carandang, RPh

Chemical Classification of Antipsychotics

1. PHENOTHIAZINES Aliphatic chlorpromazine Piperidine thioridazine Piperazine fluphenazine, perphenazine
Thioridazine

Chlorpromazine

2. Butyrophenones Haloperidol 3. Thioxanthenes Thiothixene Same structure as Phenothiazine but N replaced by C

Rogie Royce Z. Carandang, RPh

Phenothiazine Ring
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Haloperidol

Chemical Classification of Antipsychotics

4. Dihydroindolines Molindone 5. Diphenylbutylpiperidines Primozide 6. Dibenzoxapine Clozapine, quetiapine 7. Benzisoxazole Risperidone
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Clozapine

Typical vs Atypical Drugs

Typical/First Generation Atypical/Second Generation

Thioridazine (Mellaril, Melleril) Chlorpromazine (Thorazine, Laractyl, Psynor) Perphenazine (Trilafon) Thiothixene (Navane) Fluphenazine (Prolixin, Modezine, Sydepress) Haloperidol (Haldol, Serenace)
Blocks D2 receptors only Treats positive symptoms only Causes movement disorders (Parkinsonism)

Clozapine (Clozaril, Leponex) Quetiapine (Seroquel) Ziprasidone (Geodon, Zeldox) Aripiprazole (Abilify) Olanzapine (Zyprexa) Risperidone (Risperdal)

Blocks 5-HT2 > D2 receptors Treats both positive and negative symptoms Causes little or no movement disorders
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Rogie Royce Z. Carandang, RPh

Low potency vs High potency Drugs

Low Potency Phenothiazines chlorpromazine, thioridazine Sedation, hypotension, anticholinergic effects

High Potency Haloperidol decanoate Fluphenazine decanoate EPS

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Movement Disorders
1. Extrapyramidal symptoms (EPS) aka neuroleptic-induced parkinsonism Most common (15%) Coarse tremors, rigidity, bradykinesia Risk: high potency Tx: lower dose, anticholinergics (benztropine [Cogentin], diphenhydramine, biperiden [Akineton], trihexyphenydyl [Artane])

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Low potency vs High potency Drugs

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Movement Disorders
2. Acute Dystonia - Muscular spasm, involuntary movement - Spasmodic torticollis, trismus, tongue potrusion, ophisthotonos, upward movement of eyes (oculogyric crisis) - Risk: high potency - Tx: IM/IV anticholinergics

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Movement Disorders
3. Neuroleptic malignant syndrome (NMS) Idiosyncratic, life-threatening Motor: Muscular rigidity, dystonia, agitation Autonomic: hyperpyrexia, hypertension Risk: high dose, rapid dose escalation Tx: discontinue meds, supportive, dantrolene, bromocriptine

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Movement Disorders
4. Akathisia - Subjective feeling of muscular discomfort - Agitated, pace relentlessly, alternately sit and stand - Tx: Beta-blockers (propranolol), BZD (lorazepam), clonidine

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Movement Disorders
5. Tardive dyskinesia - Choreoathethoid movements - Tongue protrusion/twisting, lip puckering - Tx: lower dose, change meds

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Other Adverse Effects

1. Agranulocytosis clozapine, chlorpromazine 2. Retinal deposits and visual impairment thioridazine
3. Prolonged QT interval, torsades de pointes ziprasidone

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Other Uses of Antipsychotics

1. Antiemetic (blocks dopamine receptors) prochlorperazine 2. Intractable hiccups chlorpromazine
3. Pruritus (anihistamine) promethazine (Zinmet, Thaprozine)

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End of Lecture!

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