1. Neuroleptics
Dr. Tracy Womble

2. 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

3. Schizophrenia
Mental disorder caused by some dysfunction of the brain, occurring 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)

4. 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

5. 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)

6. 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

7. Side effects of Phenothiazine
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).

8. 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

9. 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.

10. 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)

11. 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).

12. Atypical Antipsychotics (second generation)
Clozapine
Little 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

13. 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

14. Therapeutic application of antiemetic agents
Vertigo – meclizine, dimenhydrinate
Motion sickness – scoopolamine, promethazine
Cancer chemo – droperidol, haloperidol, metoclopramide, prochloperazine
Radiation therapy – thiethylperazine, domperidone