Receptor Profile of Selected Anti-

Psychotic Drugs Sittie Rahani

Lovely Liana
Canacan
Clapis

Kevin Carl Medical Clerks

Chan
 Antipsychotics

Receptor Profile for:

• Olanzapine
• Risperidone
• Quetiapine
• Clozapine
 DOPAMINE

Dopamine hyperfunction Dopaminergic hypofunction

Mesolimbic (Subcortical Mesocortical (Prefrontal
regions) cortex)

Goodman and Gilman 2015

Goodman and Gilman 2015
2 Hypotheses
Reduction of
Extrapyramidal symptoms
(by counteracting motor
effects of dopa antagonists)

Potentiation of
antipsychotic action of dopa
receptor blockade
  Second generation Antipsychotics
 Atypical antipsychotics
 Serotonin-Dopamine Antagonist
Clozapine  Clozapine is a dibenzothiazepine.
 Clozapine has two major metabolites, one of which, N-
dimethyl clozapine
  Patients with severe tardive dyskinesia
 Intolerant of EPS
 Treatment-resistant mania
 Severe psychotic depression
 Idiopathic Parkinson’s disease
Indication
 Huntington’s disease
 Suicidal patients with schizophrenia or
schizoaffective disorder.
 Most effective drug treatment for patients who
have failed to respond to standard therapies
 Antagonist
5-HT2A
Mechanism of
Action D1D3D4
Dopamine
α- adrenergic Antagonism

receptors
 DOPAMINE
Dopamine
Antagonism

Mechanism of
Action
 Antagonist 5-HT2A
 5-HT2A Antagonism
 D1D3D4

DOPAMINE
 α- adrenergic receptors
 Typical Antipsychotics with only D2 Receptor Blockade

Atypical Antipsychotics with D2 and 5HT receptor Blockade

  Initial dosage is usually 25 mg one or two times daily
 conservative initial dosage is 12.5 mg twice daily
 25 mg a day every 2 or 3
 300 mg a day in divided doses
Dosages  Dosages up to 900 mg a day can be used
 Plasma concentrations greater than 350 μg/mL are associated
with a better likelihood of response.
  Sedation
 Dizziness
 Syncope
 Tachycardia

Side effects  Hypotension

 Diabetes mellitus
 Weight gain
 Sialorrhea
  First year of treatment, there is a 0.73 percent risk of clozapine-
induced agranulocytosis
 The risk during the second year is 0.07 percent

Agranulocytosis
  Contraindications to the use of clozapine
1. White blood cell (WBC) count below 3,500 cells
per mm3
2. Previous bone marrow disorder
3. History of agranulocytosis during clozapine
treatment
Agranulocytosis 4. Use of another drug that is known to suppress
the bone marrow

 Clozapine should be discontinued

 if the WBC count is below 3,000 cells per mm3 or
the granulocyte count is below 1,500 per mm3.
  Drug that is associated with the development of agranulocytosis
or bonemarrow suppression.
 Lithium combined with clozapine may increase the risk of
seizures, confusion, and movement disorders
 neuroleptic malignant syndrome.
 Clomipramine (Anafranil) increases clozapine plasma
concentrations.
Interactions  Risperidone, fluoxetine, paroxetine, and fluvoxamine increase
serum concentrations of clozapine.
 The combination of benzodiazepines and clozapine (Clozaril) has
been reported to cause delirium and should be avoided.
 Addition of paroxetine may precipitate clozapine-associated
neutropenia.
  Second generation Antipsychotics
 Atypical antipsychotics
 Serotonin-Dopamine Antagonist
 Risperidone is a benzisoxazole
 Undergoes extensive first-pass hepatic metabolism to 9-hydroxy
risperidone
Risperidone
  Acute and maintenance treatment of schizophrenia in adults
 Schizophrenia in adolescents age 13 to 17 years
 Acute manic or mixed episodes associated with bipolar I disorder
 Adults
 Children and adolescents age 10 to 17 years
Indication  Risperidone with lithium or valproate
 short-term treatment of acute manic or mixed episodes associated
with bipolar I disorder
 Treatment of irritability associated with autistic spectrum disorder
 Antagonist of Dopamine D2 Receptors
• Decreased Positive symptoms

Antagonist of the serotonin 5-HT2A

• Decreases Negative symptoms via 5-HT1
Mechanism of
action
 Antagonist
 Orthostatic hypotension and other side effects
Dopamine D2
 Serotonin 5-HT2A
 α1-adrenergic
 α2-adrenergic
 Histamine H1 receptors Weight Gain and Somnolence
Mechanism of
action
 Antagonist of the
serotonin 5-HT2A
and dopamine D2
  Initial dosage
 1 to 2 mg at night, which can then be
increased to 4 mg per day.
Dosing  1 to 4 mg per day provide the required D2
blockade for a therapeutic effect.
  EPS of risperidone are largely dosage
dependent
 EPS, dizziness, hyperkinesias,
somnolence, and nausea
Side effects
  Increase in dopamine
in the hypothalamus
decreases prolactin
 Blockade of D2
Receptors decreases
dopaminergic activation

 Results into increase

Hyperprolactenemia in prolactin levels
  Inhibition of CYP2D6 by drugs such as paroxetine and fluoxetine
can block the formation of risperidone’s active metabolite.

Interactions
 Combined use of risperidone and selective serotonin reuptake
inhibitors (SSRIs) may result in significant elevation of prolactin,
with associated galactorrhea and breast enlargement.
 Olanzapine

Treatment-resistant
Schizophrenia Bipolar I disorder
depression
 Pharmacology
Property Implication
1. Well absorbed from the gastrointestinal (GI) Not affected by food or other drugs
tract (85 percent )

2. Peak concentrations: 5 hours Expected side effects

3. Half life: averages 31 hours (21-54 hrs) Single dose is recommended
4. Inactivated by first-pass hepatic metabolism Dose adjustment is not necessary in renal
(about 40 percent) patients
5. Inactive metabolites by glucoronization and Less concern in hepatic patients
oxidation
6. Metabolized by 1A2 and 2D6, but not an Minimal drug interactions
inhibitor or inducer to them
Mechanism of Action
• Relatively normal
dopamine
neurotransmission • Reducing motor side
• 1. Enhancement
Reducing Positive of effects
symptoms Transiently binds and
• Improving cognitive
Dopamine release
• Stabilizing affective dissociates quickly
and affective
symptoms
symptoms
Mechanism of Action

• Weight
Sedationgain
and Cause Metabolic
• contribute
Hyperglycemia
to weight
side effects
• Dyslipidemia
gain
 Dosages
• Psychosis: 5 or 10 mg
• Acute Mania: 10 or 15 mg OD
• Acute agitation associated with schizophrenia and bipolar
disorder: 10 mg IM
• Treatment-resistant patients: 30-40 mg/day
• Starting daily dose: 5-10 mg
• > 20 mg/ day: Not studied

Higher dosageswith
Coadministration are associated with increased
BENZODIAZEPINES
EPS and
is not other adverse effects
approved
 Drug Interactions
• Fluvoxamine (Luvox)
and cimetidine
(Tagamet): increase
• Ethanol: increases
olanzapine absorption
by more than 25
percent
• Carbamazepine and
phenytoin: decrease
 Side effects
• Weight gain
• Somnolence
• Dry mouth
• Dizziness
• Constipation
• Dyspepsia
• Increased appetite
• Akathisia
• Tremor
• Dose-related risk of EPS
Quetiapine

• It is rapidly reabsorbed
from the GI tract
• Peak plasma
Dibenzothiazepine,
concentrations:structurally
1-2 hours
related to clozapine
• Steady but life:
state half differs
7 in
biochemical
hours; effects
optimal dosing is
2-3x per day
Mechanism of Action
Relieves negative
symptoms of
schizophrenia
5HT2A

D2 receptors

Relieves positive
symptoms of
schizophrenia
Mechanism of Action
Blocks 5-HT1A,
D1 and H1, and
alpha 1 and alpha
2 receptors
Does not block
muscarinic or
benzodiazepine
receptors

Sedation and weight

Orthostatic gain
Hypotension
Dosages
 Begin at 25 mg twice
daily
25-300 mg at night:
insomnia
When used at higher
doses, serial ECG studies
are required
Drug interactions
Phenytoin:increases clearance
fivefold
Should be avoided in:
• History of cardiac arrhythmia
such as bradycardia
• Hypokalemia or
hypomagnesemia
• Concomitant use of other
drugs that prolong QTc interval
• Presence of congenital
prolongation of the QT interval
Side effects
Somnolence
Postural hypotension
Dizziness