Neuroleptics

Neuroleptics Referred to as antischizophrenic, antipsychotic or

major tranquilizers Primarily for schizophrenia, but effective for other

psychotic states Antipsychotic properties due to dopamine

receptor antagonism Newer “atypical” antipsychotic drugs are

serotonin receptor antagonists Not curative, does not eliminate thinking

disorder, but allow patient to function in supportive environment

Pathogenesis of schizophrenia is unknown

Schizophrenia Mental disorder caused by some dysfunction of the brain, occurring in @1%

of pop. Characterized by delusions, hallucinations (hearing voices), thinking and

speech disturbances Often affected during adolescence, chronic disabling disorder Has strong genetic component etiology of schizophrenia is unknown

Possible overactivity of mesolimbic dopaminergic neurons Serotonin receptor involvement

Characterized by 2 components; breakdown of personality loss of contact with reality

Antianxiety agents not useful for psychotic disorders Typical or coventional neuroleptics - chlorpromazine (Thorazine), fluphenazine

(Prolixin), haloperidol (Haldol), thiothixene (Navane), trifluoperazine (Stelazine), perphenazine (Trilafon), and thioridazine (Mellaril)

Neuroleptics (Antipsychotics)

Reserpine and chlorpromazine were first drugs used for schizophrenia / psychosis

Divided into five major classifications based on structure. Side changes have significant effect on potencies 1. Phenothiazines 2. Benzisoxazoles 3. Dibenzodiazepines 4. Butyrophenones 5. Thioxanthenes

Management of psychotic disorder can be determined by familiarity of effects drugs in each class

N-10 position controls degree of side effects

Phenothiazine(Typical Antipsychotics)

3 subclasses

1. Aliphatic – least potent Chlorpromazine –intermediate extrapyramidal side effects and

intermediate anticholinergic action, high incidence of sedative action

2. Piperazine – most potent, selective and effective, increased incidence of Tardive dyskinesia Fluphenazine (Prolixin) Prochlorperazine (Compazine) Perphenazine (Trilafon)

3. Piperidine – least potent, lower incidence of extrapyramidal side effects, high incidence of anticholinergic action Thioridazine (Mellaril) Mesoridazine (Serentil)

Action of Phenothiazine CNS – reduces spontaneous anxiety and response to

external stimuli, intelligence is not diminished, reflexes not suppressed, mild sedation Limbic system Da receptors involved in mood/feeling

○ 5 subclasses of DA receptors (D1-D5) D1/5 activate, D2/3 inhibit adenyl cyclase D2 involved in psychotic disorders

- Blockade of D2 receptor is antipsychotic action

Basal Ganglia – blockade of D1 or D2 results in extrapyramidal side effects Cardiovascular center – depressed by antipsychotics – hypotension Chemoreceptor trigger zone (CTZ) – provokes emesis when foreign

substance interacts with DA receptor. These receptors are blocked by phenothiazines. (anti-emetic action)

Hypothalmus – DA receptors inhibit release of prolactin, phenothiazines block DA receptors - stimulate release of prolactin – hormonal side effects

Misc. – no physical dependence, mild CNS depressant (toxic dose), decrease seizure threshold

Autonomic effects – anticholinergic action (piperidines – strongest, piperizines – weakest)

Alpha-antogonist

Side effects of Phenothiazine

Side effects Orthostatic hypotension – due to alpha blockade, dose/effect

response

Extrapyramidal Syndrome – increased cholinergic activity (Piperazine – highest, Piperidines – lowest) Parkinson-like Syndrome Akathesia – uncontrollable restlessness, distress, anxiety Tardive Dyskinesia – develops late in antipsychotic therapy,

usually at high doses x 6 months, rhythmic motions of head, face and shoulders, may be irreversible

Do not use DA or Levo-Dopa, use diphenhydramine (Benadryl), benztropine (Cogentin) or trihexephenidyl (Artane).

Therapeutic use of Phenothiazines Tx psychotic disorders

Schizophrenia, senile dementia, extreme paranoia, manic phase of manic depressive syndrome,

Anti-emetics – radiation toxicity, anticancer meds, opioids, gastroenteritis (prochloperazine) [compazine]

Phenothiazines control ○ positive symptoms – Hallucinations, delusions,

hostility, hyperactivity○ Not negative symptoms – social withdrawal, lack

of expression, decrease in speech patterns

Atypical Antipsychotics In the last decade new "atypical" antipsychotics

have been introduced, >effective, <s/e typical antipsychotics appear to be equally

effective for helping reduce the positive symptoms like hallucinations and delusions but may be better than the older medications at relieving

the negative symptoms of the illness, such as withdrawal, thinking problems, and lack of energy.

Mechanism of Action of Atypical Antipsychotics

Blockade of DA and / or serotinin receptors. Many also block cholinergic, adrenergic, and histamine receptors – variety of side effects

DA receptor antagonism in brain (typical and atypical antipsychotics) Neuroleptics are antagonized by agents that increase DA

concentration (L-dopa and amphetamines) Serotonin receptor antagonism in brain (atypical)

Atypical Antipsychotics

Admin PO QD or BID Low or no EPS 5-HTr antagonist

5-HT2A receptor

No effect on prolactin Control both positive and neg. symptoms

The atypical antipsychotics include aripiprazole (Abilify), risperidone (Risperdal), clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon).

Atypical Antipsychotics(second generation)

ClozapineLittle to no EPS, high incidence of agranulocytosis (regular

CBS’s), High incidence of siezures

Olanzapine (Zyprexa)Sedation, weight gain, no agranulocytosis, low incidence of

siezures

Quetiapine (Seroquel)Sedation, low incidence of all side effects

Misc. Lithium carbonate (antimanic drug)

○ Admin. PO, tx of manic phase of manic depressive syndrome○ Has onset time of 6 months, MOA unknown

Action of Atypical Antipsychotics

Antipsychotic – reduce hallucinations, agitation, require several weeks to occur

EPS – Parkinsonian symptoms, akathisia, tardive dyskinesia.(clozapine, risperidone show low incidence)

Antiemetic – D2 receptor antagonist in CMZ of medulla (except thioridazine)

Antimuscarinic – blurred vision,dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle – constipation, urinary retention. (all esp. thioridazine and chlorpromazine)

α-blockade – orthostatic hypotension, lightheadedness, alter temperature regulating mechanisms, block D2 receptors in pituitary – prolactin release

Therapeutic application of antiemetic agents

Vertigo – meclizine, dimenhydrinate Motion sickness – scoopolamine,

promethazine Cancer chemo – droperidol, haloperidol,

metoclopramide, prochloperazine Radiation therapy – thiethylperazine,

domperidone