Antipsychotic Drugs

Schizophrenia

The term "psychosis" denotes a variety of mental disorders- the presence of delusions
(false beliefs), various types of hallucinations, usually auditory or visual, but
sometimes tactile or olfactory, and grossly disorganized thinking in a clear sensorium.
Schizophrenia - psychosis characterized by a clear sensorium but a marked thought
disturbance

Pathophysiology of Schizophrenia:
Dopamine hypothesis:
Proposes that the disorder is caused by relative excess of dopamine in the
mesolimbic-mesocortical pathway
New hypothesis suggests that serotonin is also involved in the pathophysiology
(5-HT2)
5 dopamine receptors (D1 D5)
The typical antipsychotic agents block D2 receptors, and their binding affinity is
very strongly correlated with clinical antipsychotic and extrapyramidal potency

Studies indicate that for antipsychotic efficacy of typical anti-psychotic drugs

would be achieved at least 60% occupancy of striatal D 2 receptors. EPS are seen
when occupancy of D2 receptors reaches 80% or higher.
In contrast atypical antipsychotic drugs(clozapine, olanzapine) are effective at
lower occupancy levels of 3050%, because of their concurrent high occupancy
of 5-HT2A R

Positive and negative symptoms of schizophrenia

Positive symptoms of schizophrenia (hallucination, delusions, thought
dysfunction)
Positive symptoms clearly related to increased dopamine levels in the
mesolimbic pathway
The negative symptoms of schizophrenia include symptoms such as
deficiencies in emotional responsiveness, spontaneous speech and volition.
Negative symptoms are shown in flattening of affect, poverty of speech, and
drive, loss of feeling, social withdrawal and decreased spontaneous movement

Antipsychotics
1. Typical antipsychotic Drugs (D2 receptor antagonist)
Phenothiazines:***
chlorpromazine,
fluphenazine,
Thioridazine,
Trifluoperazine,
Butyrophenone:
Haloperidol***
2. Atypical Drugs (5HT2 antagonists & D4 receptor antagonist; weak D2
affinity)
Clozapine**, asenapine, olanzapine**, quetiapine,
risperidone, sertindole, ziprasidone, zotepine, and aripiprazole***
Mechanism of therapeutic effect
1. Conventional Drugs- antagonistic activity at D2 receptors
2. Atypical drugs antagonistic activity at 5 HT2 receptors and D2 or D4
receptors

Aripiprazole- partial agonist at D2

Therapeutic action is a result of the actions of these drugs at mesolimbic
mesocortical areas in CNS

Differential selectivity among antipsychotics

Chlorpromazine:
Haloperidol:
Clozapine: D4 =
Olanzapine:
Aripiprazole:
Quetiapine:

1 = 5-HT2A > D2 > D1

D2 > 1 > D4 > 5-HT2A > D1 > H1
1 > 5-HT2A > D2 = D1
5-HT2A > H1 > D4 > D2 > 1 > D1
D2 =5-HT2A> D4 > 1= H1 >> D1
H1 > 1>M1, 3 > D2 > 5-HT2A

alpha 1 (postural Hypotension), Histamine block (sedation and weight gain), Seratonin block
()

Dopaminergic Pathways:
Mesolimbic System
From the ventral tegmental area to several brain areas involved in cognition and
emotion
Too much activity here may contribute to schizophrenia
Nigrostriatal Pathway
o From the substantia nigra to the striatum, which modulates the extrapyramidal
motor system (posture, voluntary smooth muscle)
o Insufficient activity here causes Parkinsonism
Tuberoinfundibular Pathway
o From the hypothalamus to the pituitary gland, which modulates prolactin release
o Dopaminergic drugs produce some side effects by acting here
Adverse Effects of Antipsychotics
o Extrapyramidal Syndrome (EPS)- due to dopamine receptor blockade of the (D2)
nigro-striatal pathway
o Types of EPS:****
o Acute Dystonia (spastic retrocolis or torticolis) Immediate onset w/in
few hours
o Akathisias (motor restlessness) Onset is few days to few weeks
o Parkinson-like symptoms (tremors, bradykinesia, rigidity)
o Treated by benztropine, biperiden, trihexphenyl, diphenhydramine

More Side Effects:

o Tardive dyskinesias (occurs later months or years)
A late occurring syndrome
Oral/facial dyskinesias, muscle jerks, writhing of lip muscles
Caused by relative cholinergic deficiency secondary to supersensitivity of DA
receptors
Prevelence is 20- 30 %
Early recognition is important, since advanced cases may be difficult to reverse.
Any patient with TD treated with a typical antipsychotic should be switched
to quetiapine or clozapine (atypical agents least likely to cause TD).
Autonomic Side Effects
Endocrine & metabolic Side Effects
Other Adverse Effects
Therapeutic uses of Antipsychotics
Other uses of Antipsychotics
Lithium Carbonate
Mechanism:
Inhibits the recycling of PIP2-depletion of second messenger- DAG &IP3
Lithium uses
1. Acute mania or bipolar disorder(BPD)
Onset of effect takes 2-3 weeks
Carbamazepine and valproate can be used alone or as adjuncts Li
2. Prophylaxis of BPD
Li is given with a TCA
Other drugs for mania or BPD:
carbamazepine, valproic acid
Lithium toxicity
Adverse effects are common at therapeutic range 0.5-1.4 mmol/l
They are- nausea,vomiting, diarrhea, fine tremors, polydipsia
It causes Nephrogenic diabetes insipidus (polyuria as CD become unresponsive
to ADH-Rx Amiloride.
Benign reversible thyroid enlargement, rarely hypothyroidism
Toxicity >2mmol- confusion (imp 1st sign of toxicity) drowsiness, ataxia, severe
tremors