Transcript Slide 1

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)

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
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
