Antisychotic Drugs

Front 1

Psychosis

Back 1

Severe disturbance of perception

Front 2

Schizophrenia

Back 2

Occurs in 1% of population.

Unknown etiology but genetic susceptibility.

Front 3

Positive and Negative Symptoms of Schizophrenia

Back 3

Positive: Bizarre delusions, auditory hallucinations, unusual behaviors. -> Respond to Drug Therapy.

Negative: social isolation, poverty of speech, flat affect, lack of motivation -> unresponsive to drug therapy.

Front 4

Psychosis and Schizophrenia Etiology

Back 4

Clues: Cocaine & Amphetamine inhibit dopamine uptake and chronic use can lead to paranoid psychosis.

Hypothesis: Overactivation of Dopamine in specific parts of the brain, but in schizophrenic brain this isn't so.

Front 5

Psychosis and Schizophrenia Treatment

Back 5

1. Decrease Dopamine neurotransmission.

2. Dopamine Receptor Antagonism

Front 6

Two Dopamine Neuron Locations in the Brain

Back 6

1. Substania Nigra (SN): 90% of DA, projects to the Striatum (Striatonigral Pathway). This path is involved in MOTOR activity.

2. Ventral Tegmental Area (VTA): projects to the Nucleus Accumbens and Frontal Cortex. These are involved in the mesolimbic and mesocortical pathways or pleasure centers.

Front 7

Mechanism of Action: Antipsychotic Drugs

Back 7

Goal: Reduce dopamine neurons that project from VTA to accumbens and frontal cortex.

Mechanism:
1. Antagonists of multiple receptors: dopaminergic, muscarinic, alpha-adrenergic, H1 histaminic, and 5HT2a serotonergic.
2. Blockade of Dopamine receptors.

New role for serotonin receptor blockade possible.

Front 8

Behavior Effects of Antipsychotic Drugs

Back 8

Some effects are immediate due to receptor antagonism.

Some take several weaks due to down-regulation or receptors and neurogenesis. (Like anti-depressants)

Front 9

Physiological Effects of Antipsychotic Drugs

Back 9

Sedation, anti-emesis.

No ataxia or effect on IQ/memory.

Front 10

Therapeutic Effects of Antipsychotic Drugs

Back 10

Immediate: calms patient within hours.

Delayed: Reduces positive symptoms. Reduces delusions and hallucinations and some disordered thinking.

Newer drugs may improve negative symptoms.

Front 11

Behavioral Effects of Antipsychotic Drugs

Back 11

Suprress complex behaviors and decreases motivation/initiative.

Decreases spontaneous movements and aggression.

Promotes disinterest in environement and emotional display.

EXTRA-PYRAMIDAL SIDE EFFECTS (EPSEs)

Front 12

Phenothiazines: 3 main Antisychotic Drugs

Back 12

1. Chlorpromazine
2. Thioridazine
3. Fluphenazine

(Remember: Crazy The Fool)

Front 13

2 Typical Non-Phenothiazines

Back 13

(work like phenothiazines, but different structure)
1. Chloprothixine
2. Haloperidol

Front 14

3 Atypical Non-Phenothiazines

Back 14

First line treatment for new patients

1. Clozapine
2. Sertindole
3. Risperidone

(Remember: Clinical Skills Requirement)

Front 15

Second Generation Atypical Antipsychotic Drugs (6)

Back 15

1. Loxapine
2. Olanzapine
3. Quetiapine
4. Molindone
5. Aripiprazole
6. Ziprasidone

(Remember: LOQ MAZ)

Front 16

Dopamine Receptors and Ligand Affinities

Back 16

Phenothiazines/Typical Non-Phenothiazines: prefer D2 then D1.

Atypical Non-Phenothiazine: D3 or D4 preference.
Better to block D3/D4 receptors.

Front 17

Atypical Anti-Phenothiazine 5HT2a Receptor Antagonits: MOA

Back 17

They block 5HT2a receptors on PREsynaptic nigro-striatal terminals which cause MORE Dopamine release (disinhibition). This results in less net blockade of D1/D2 receptors in nigrostriatal and tuberoinfundibular pathways.

Results in fewer EPSEs and little prolactin increase.

Front 18

Clozapine

Back 18

Atypical Non-Phenothiazine

Antagonizes many NT receptors.

Efficacious for: Positive & Negative symptoms, TD, suicidality, aggression.

AE: agranulocytosis, seizures, myocarditis.

Front 19

Risperidone

Back 19

Atypical Non-Phenothiazine (CSR)

No anticholinergic activity.

Antagonist: D2, 5HT2a, alpha-1, alpha-2 receptors.

Dose related prolactin increase.

Some EPSEs.

Little Sedative effect.

Front 20

Olanzapine

Back 20

Second Generation Antipsychotic Drug.

Antagonizes multiple receptors.

Useful: manic, drug induced, agitated and depressive psychoses. Negative effects.

High risk of Weight Gain.

Front 21

Quetiapine

Back 21

Blocks D2, 5HT2a, H1, A1, A2 receptors.

Good for Mood Symptoms.

Low EPSEs, Little prolactin, Low Weight Gain.

Sedation main SE.

Second line drug.

Front 22

Anti-Muscarinic Effects of Antisychotic Drugs

Back 22

Dry eyes, mouth, skin
Blurred Vision.
Tachycardia
Urine retention, constipation.

Thioridizne: Greatest anti-muscarinic potency.
Haloperiodol: least anti-muscarinic potency.

Front 23

Adverse Effects: Acute Treatment

Back 23

Orthostatic Hypotension. Sedation.

Neuroleptic Malignant Syndrom: tranquilizer effect on genetically susceptible patients. Fever, cognitive and autonomic signs, muscular rigidity. Calcium metabolism defect.

Front 24

Adverse Effects: Chronic Treatment

Back 24

Endocrine imbalance. Since DA is inhibited (which inhibits prolactin), prolactin secretion is increased.

EPSEs (like Parkinson's disease)
Akathesia (restlessness/hyperactivity).

Tardive Dyskenesia: involuntary face/head movements. Irreversible in 50% of patients. Due to DA receptor supersensitivity and GABA receptor subsensitivity.

Front 25

Tardive Dyskenesia

Back 25

Due to chronic treatment with Antipsychotic drugs.

Involuntary face/head movements. Irreversible in 50% of patients. Due to DA receptor supersensitivity and GABA receptor subsensitivity.

Front 26

Advantage of Atypical Non-Phenthiazines

Back 26

No EPSEs, no tardive dyskinesia.

Front 27

Ziprasidone

Back 27

Second generation drug.

Prolonged QT.

Little Wt. gain.