Pharmacy students should:
– be familiar with the symptoms
& health consequences of
– be able to describe the
mechanism(s) of action and
adverse effects of
The Greek translation is
schizein “split” and phren
“mind” which refers to a split
A group of severe disorders
characterized by atypical:
is a particular type of psychosis-that is, a mental disorder
caused by some inherent dysfunction of the brain, possibly
an overactivity of the mesolimbic dopaminergic neurons.
It is characterized by:
Positive symptoms; are those that can be regarded as
an abnormality or exaggeration of normal function.
Negative symptoms; are those that indicate a loss or
decrease in function
Symptoms of Schizophrenia
+ve symptoms: the presence
of inappropriate behaviors
Delusions (false belief)
perception) often in the form
thinking or speech
-ve symptoms: the absence
of appropriate behaviors
Lack of motivation
poverty of speech
(lack of interest in pleasurable
Dopamine Hypothesis of Schizophrenia
This hypothesis is suggests that excessive dopaminergic activity
plays a role in the disorder:
many antipsychotic drugs strongly block D2 receptors in the
CNS, especially in the mesolimbic-frontal system.
Dopamine precursor or agonist, either aggravate
schizophrenia or produce psychosis de novo in some
patients; such as
levodopa (a precursor),
amphetamines (releasers of dopamine),
apomorphine (a direct dopamine receptor agonist),
Increase in brain dopamine receptor density
• Mesolimbic-mesocortical pathway: the one most
closely related to behavior (mental and emotional)
• Nigrostriatal pathway: it is involved in the
coordination of posture and voluntary movement
• Tuberoinfundibular pathway: inhibit prolactin
• Medullary-periventricular: eating behavior
• Incertohypothalamic: It has a role in sexual
• Used primarily to treat
• also effective in other psychotic
disorders, such as manic states with
psychotic symptoms such as
grandiosity or paranoia and
hallucinations, and delirium.
Neuroleptic drugs are not curative and do not
eliminate the fundamental thinking disorder, but
1. Decrease the intensity of hallucinations and
2. Permit the psychotic patient to function in a
Chemical classification of antipsychotic agents:
A. Phenothiazine derivatives (tricyclic+S+side chain)
Divided depending on side chain:
• Aliphatic group: chlorpromazine oldest
• Piperazine group: trifluperazine, fluphenazine, terphenazine,
• Piperidin group: thioridazine, mesoridazine
Chemical classification of antipsychotic agents:
B. Thioxanthene derivatives: (thiothixene, flupenthixole) less potent
than phenothiazine group.
C. Butyrophenone derivatives: (haloperidol) highly potent like
D. Miscellaneous structures: pimozide, molindone
,loxapine,clozapine, quetiapine,Risperidone sertindole, olanzapine,
Dopamine receptor-blocking activity in the brain:
D1 and D5 receptors: activate adenylyl cyclase.
D2, D3, and D4 receptors: inhibit adenylyl cyclase , or mediate
membrane K+ channel opening leading to neuronal hyperpolarization.
the clinical efficacy of the typical neuroleptic drugs correlates closely
with their relative ability to block D2 receptors in the mesolimbic
system of the brain.
On the other hand, the atypical drug clozapine has a high affinity for
the D4 receptor and 5-HT2, very low affinity to D2 which may explain its
minimal ability to cause extrapyramidal side effects.
Serotonin receptor-blocking activity in the brain:
• Clozapine has high affinity for D1, D2, D4, 5-HT2A, muscarinic,
and α-adrenergic receptors.
• Olanzapine, Risperidone and quetiapine, blocks 5-HT2 receptors
to a greater extent than it does D2 receptors.
an antagonist at the D2, 5-HT2A and 5-HT1D
an agonist at 5-HT1A
• is a partial agonist at D2 and 5-HT1A receptors
• but strong antagonist at 5-HT2A receptors.
1. Antipsychotic actions:
Neuroleptic stage-ALL the drugs also have
• a calming effect
• reduce spontaneous physical movements,
• produce emotional indifference to environment.
The antipsychotic effects usually take several weeks to
occur, suggesting that the therapeutic effects related to
secondary changes in the corticostriatal pathways.
2. Antiemetic effects
Except thioridazine, MOST of the neuroleptic drugs D2receptors of the chemoreceptor trigger zone (CTZ) of
3. Antimuscarinic effects:
SOME; particularly thioridazine, chlorpromazine, clozapine, and
4. Blockade of α-adrenergic receptors:
causes orthostatic hypotension and light-headedness.
5. Alter temperature-regulating mechanisms and can produce
poikilothermia (body temperature varies with the environment).
6. Increases in prolactin release (block D2 receptor)
7. Sedation (H1 blockade) all except haloperidol
1. Schizophrenia Rx
2. Mania (bipolar disorder):
initial Rx of Mania. Atypical antipsychotic drugs are
often used with Lithium.
maintenance Rx of bipolar disorder Olanzapine
and aripiprazole are approved.
3. Prevention of severe nausea and vomiting: Most
commonly prochlorperazine are useful in the
treatment of drug-induced nausea, but NO nausea
arising from motion sickness (scopolamine is the
drug of choice).
4. As tranqulizers to manage agitated and disruptive
5. Treatment of chronic pain with severe anxiety in
combination with opiates.
6. Hiccups: chlorpromazine
7. Antipruritus and sedation: promethazine
8. Pimozide is primarily indicated for treatment of the
motor and phonic tics of tourette disorder
1. Extrapyramidal side effects:
1. It is appearance is time dependent,
-Early phase (reversible)
Acute dystonias* occurring within few days,
(*Rx by Trihexphenidyl, orphenadrine, procyclidine, or
followed by **akathisias (the inability to remain seated due to
#Parkinson symptoms occur a bit later on.
(**&# Rx by propranolol, or antimuscarinic),
-Late phase (irreversible)
Tardive Dyskinesia: inappropriate postures of the neck, trunk,
and limbs, which is irreversible, occurs with chronic treatment
after months or years of treatment.
Tardive Dyskinesia, TD
(D2 supersensitivity phenomenon):
• Patients display rhythmical involuntary movements,
including lateral jaw movements, and “fly-catching”
motions of tongue.
• TD is postulated to result from an increased number
of dopamine receptors
• This makes the neuron supersensitive to the actions
of dopamine, and it allows the dopaminergic input to
this structure to overpower the cholinergic input,
causing excess movement in the patient.
• NB: antimuscarinic increase the severity of TD
• Increase the dose of neuroleptic! Attenuate
Avoiding EP Adverse effects
• Using Those drugs that exhibit strong
anticholinergic activity, such as thioridazine,
show few EP disturbances.
• This contrasts with haloperidol and fluphenazine,
which have low anticholinergic activity and produce
• Clozapine and risperidone: these drugs have a
low potential for causing EP symptoms and
lower risk of Tardive Dyskinesia.
Avoiding EP adverse effects
Risperidone should be included among the
first-line antipsychotic drugs,
whereas clozapine should be reserved for
severely schizophrenic patients who are
refractory to traditional therapy. Clozapine
can produce bone marrow suppression and
CV side effects. The risk of severe
agranulocytosis necessitates frequent
monitoring of WBC count.
Neuroleptic malignant syndrome:
this potentially fatal reaction to neuroleptic drugs
is characterized by muscle rigidity, fever, stupor,
unstable BP, and myoglobinemia.
1. discontinuation of the neuroleptic
2. supportive therapy, administration of:
• or bromocriptine may be helpful.
Anticholinergic; dry mouth, urinary retention,
constipation, and loss of accommodation.
Thioridazine, clozapine, haloperidol (high to less)
Antiadrenergic; Lowering BP and orthostatic
hypotension (α-blocker), ex, phaenothiazine
Endocrine alteration: The neuroleptics depress the
hypothalamus, causing amenorrhea, galactorrhea,
infertility, and impotence.
Significant weight gain & hyperglycemia due to a
diabetogenic with atypical clozapine & olanzapine.
Cautions and contraindications:
1. acute agitation accompanying withdrawal
from alcohol or other drugs may be
aggravated by the neuroleptics (Tx;
2. Chlorpromazine and clozapine are
contraindicated in patients with seizure
disorders, because these drugs can lower
seizure threshold. The neuroleptics can also