PSYCHIATRIC PHARMACOLOGY

Drugs = Flashcard

Chlorpromazine Clozapine Fluphenzine Haloperidol Thioridazine

I. Psychosis is a severe psychiatric disturbance characterized by

A. Impaired behavior

B. Inability to think coherently

C. Inability to comprehend reality

D. Inability to understand disturbance

E. Symptoms may include delusions and hallucinations

II. Examples

. Schizophrenia (disordered thinking, emotional withdrawal, paranoid delusions and auditory hallucinations)

A. Organic psychoses (e.g., delirium and dementia)

B. Agitated psychotic depressions

C. Mania (?)

III. Antipsychotic agents

. Also called major tanquilizers or neuroleptics

1. suppress spontaneous movement and complex behavior while spinal reflexes remain intact
2. decreased initiative and interest in environment
3. slowness in response to external stimuli
4. easily aroused and capable of giving appropriate answers to direct questions

A. Response to antipsychotic drug therapy

1. patients become less agitated and restless
2. withdrawn and autistic patients may become more responsive and communicative
3. aggressive and impulsive behavior diminishes
4. gradually psychotic symptoms of hallucinations and disordered thinking disappear
5. mid 1950's - 560,000 patients institutionalized

IV. Major side effects of antipsychotics (Extrapyramidal motor effects)

. Early onset symptoms (days to weeks)

1. parkinsonian-like symptoms
1. akinesia
2. mild rigidity
3. tremor at rest
2. akathisia - compulsion to remain in motion
3. acute dystonic reaction - facial grimacing
4. dose related and reversible

A. Late onset symptoms (months to years)

1. Tardive dyskinesia - stereotyped involuntary movement of lips, jaws and tongue, sometimes accompanied by choreiform, purposeless movement of extremities
2. may be irreversible and precipitated by discontinuation of drug
3. frequency may be as high as 15-20% of institutionalized patients
4. seen with all antipsychotics except clozapine

V. Proposed mechanism of action

. Antipsychotic effects - antagonism (receptor blockade) of (excessive?) dopaminergic function (DA₂ receptors) in the limbic system and other areas of the brain

1. all antipsychotics block DA₂ receptors
2. in Parkinson's disease (parkinsonism), levodopa, which is converted to dopamine may produce psychotic symptoms
3. amphetamine and cocaine, which elevate dopamine levels in brain, can produce symptoms of paranoid schizophrenia
4. post-mortems of schizophrenic patients have elevated DA receptor densities
5. similar results based on PET scans

Psychosis
In the psychotic patient DA activity in the limbic region of the brain is elevated. There is a normal balance of DA:ACh activity in the striatum. Administration of antipsychotic drugs decreases DA activity (by blocking DA receptors) in both the limbic system (leading to "normal" behavior) and the striatum (leading to extrapyramidal side effects.) Since the Parkinsonian-like symptoms are due to a relative excess of ACh, they may be reduced by coadministering an anticholinergic drug (e.g., cogentin) or by giving an antipsychotic drug that also has anticholiergic properties (e.g., thioridazine.)

Parkinsonism
Parkinsonism is due to a degeneration of DA innervation of the striatum leading to a relative excess of ACh activity. This imbalance may be corrected in one of two ways. (1) Increasing the level of DA activity by giving its precurser levodopa or (2) decreasing ACh activity by giving an anticholinergic drug. When levodopa is given, however, this may result in elevated DA levels in the limbic system and this may result in behavioral side effects

A. Extrapyramidal - Antagonism of (normal) dopaminergic function in the basal ganglia (striatum) an area of the brain involved in posture and fine aspects of movement)

1. extrapyramidal side effects are due to an imbalance between excitatory (+) cholinergic neurons and inhibitory (-) dopaminergic neurons within the basal ganglia.
2. some antipsychotic agents also block cholinergic receptors (also adrenergic and histamine receptors).
3. the capacity of an antipsychotic agent to produce extrapyramidal side effects is inversely related to its ability to block cholinergic receptors
4. examples

a. Thioridazine - high AntiACh - low extrapyramidal

b. Fluphenazine - low AntiACh - high extrapyramidal

The caudate nucleus receives cholinergic excitatory (+) innervation from the cortex and other areas of the brain and dopaminergic inhibitory (-) innervation from the substantia nigra. The output from the caudate regulates fine skeletal motor activity and depends upon a precise balance of cholinergic and dopaminergic activity.

B. Tardive dyskinesia - "disuse supersensitivity" - prolonged absence of neurotransmitter causes receptor to become extremely sensitive to released dopamine, such that when drug is discontinued and the receptor is no longer blocked, it is bombarded normally released transmitter.

VI. Miscellaneous uses

. Nausea and vomiting

A. Intractable hiccough

B. other neuropsychiatric disorders

1. Gilles de la Tourette's syndrome
2. Huntington's chorea

C. Amphetamine "psychosis"

D. Phencyclidine and ketamine overdose

VII. Drug interactions

. potentiation of opiates, barbiturates and ethanol

A. lower doses of barbs needed in anesthesia

B. lowered seizure threshold - use with care in epileptics

VIII. Side effects

. extrapyramidal

A. orthostatic hypotension

B. nasal stuffiness

C. dry mouth

D. palpitations

E. constipation

F. sedation

G. suppression of bone marrow function and agranulocytosis

1. rare but lethal
2. 1 in 10,000 for most
3. 1-3% with clozapine

H. Neuroleptic Malignant syndrome (NMS)

1. most common with phenothiazines
2. symptoms include hyperpyrexia (>38deg.C), muscle rigidity, autonomic dregulation, fluctuating levels of consciousness
3. discontinue drugs
4. administer dantrolene (muscle relaxant)
5. administer dopamine receptor agonist (bromocriptine)

IX. Tolerance and dependence

. tolerance develops to sedative (days) and hypotensive (weeks) effects but not to antipsychotic effects

A. some reports of muscular discomfort, insomnia, nausea, headache, restlessness upon abrupt discontinuation

X. Toxicity - high therapeutic indices (relatively safe- in terms of lethality, see table below)

XI. Comparison of antipsychotic drugs

. chemical classification - phenothiazines, butyrophenones, thioxanthines

A. See table below

			Adverse Effects
Drugs	TI	Antipsychotic Activity	Sedation	Extrapyramidal	Hypotension
Chlorpromazine (Thorazine)	200	+	+++	++	++
Haloperidol (Haldol)	>1000	+++	+	+++	+
Thioridazine (Mellaril)	70	+	+++	+	++
Fluphenazine (Prolixin)		+++	+	+++	+
Trifluoperazine (Stelazine)		+++	+	+++	+
Clozapine (Clozaril)		+	+++	-	+++

XII. Drugs of choice

. compliance - long acting drug - fluphenazine

A. CV disease - little hypotensive effect - fluphenazine, trifluperazine, haloperidol, amolindone

B. older patients or patients with predisposition to extrapyramidal side effects - thioridazine, amolindone

C. if no sedation wanted - fluphenazine, trifluperazine, haloperidol

D. if patient is taking quinidine for arrhythmias, don't use thioridazine (direct myocardial depressant)