Post on 05-Jan-2016
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