Hiwa K. Saaed, PhD
Pharmacology & Toxicology
“neuroleptics/ major tranquilizers”
Pharmacy students should:
– be familiar with the symptoms &
health consequences of
– be able to describe the
mechanism(s) of action and
adverse effects of antipsychotics
Schizophrenia: the Greek translation is schizein “split” and
phren “mind” which refers to a split from reality.
Is a type of chronic psychosis characterized by delusions,
hallucinations (often in the form of voices), and thinking or
The onset of illness is often during late adolescence or early
adulthood. It occurs in about 1% of the population and is a
chronic and disabling disorder.
Schizophrenia has a strong genetic component and probably
reflects some fundamental biochemical abnormality, possibly
a dysfunction of the mesolimbic or mesocortical dopaminergic
It is characterized by:
1. Positive symptoms; are those that can be regarded
as an abnormality or exaggeration of normal
2. Negative symptoms; are those that indicate a loss or
decrease in function
+ve symptoms: the presence
of inappropriate behaviors
Delusions (false belief)
perception) often in the
form of voices
thinking or speech
-ve symptoms: the absence
of appropriate behaviors
Lack of motivation
poverty of speech
anhedonia (lack of interest in
Symptoms of Schizophrenia
• Used primarily to treat schizophrenia, 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 they often:
1. Decrease the intensity of hallucinations and
2. Permit the psychotic patient to function in a
MECHANISM OF ACTION
1. Dopamine antagonism:
ALL of the first-generation and MOST of the second-
generation block D2 dopamine receptors in the brain and the
2. Serotonin receptor–blocking activity:
MOST of the second generation agents appear to exert part
of their unique action through inhibition of serotonin
receptors (5-HT), particularly 5-HT2A receptors.
DOPAMINE HYPOTHESIS OF
This hypothesis is suggests that excessive dopaminergic
activity plays a role in the disorder:
1. many antipsychotic drugs strongly block D2 receptors in
the CNS, especially in the mesolimbic-frontal system.
2. 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),
3. Increase in brain dopamine receptor density; postmortem
• 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 behavior.
A. Phenothiazine derivatives (tricyclic + S + side chain)
Divided depending on side chain:
• Aliphatic group: chlorpromazine oldest
• Piperazine group: trifluperazine, fluphenazine,
terphenazine, prochlorperazine, thiethylperazine
• Piperidin group: thioridazine, mesoridazine
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, and
The antipsychotic drugs are divided into:
• First-generation (conventional, typical, or traditional)
• low potency
• high potency
• Second-generation ( “atypical” antipsychotics)
• does not indicate clinical effectiveness of the drugs,
• specifies affinity for the dopamine D2 receptor, which, in
turn, may influence the adverse effect profile of the drug.
• are competitive inhibitors at a variety of receptors,
but their antipsychotic effects reflect competitive
blocking of dopamine D2 receptors.
• are more likely to be associated with movement
disorders known as extrapyramidal symptoms
• More likely with haloperidol.
• Less likely with chlorpromazine.
• No one drug is clinically more effective than
• Effective in controlling +ve symptoms
• have a lower incidence of EPS than the 1ST-generation
• but are associated with a higher risk of metabolic
side effects, such as
• and weight gain.
• The second-generation drugs appear to owe their
unique activity to blockade of both serotonin and
dopamine and, perhaps, other receptors.
• Effective in controlling -ve symptoms,
• Much More costly, less EPS
DOPAMINE RECEPTOR-BLOCKING ACTIVITY IN THE BRAIN:
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.
Dopamine receptor Type:
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.
SEROTONIN RECEPTOR-BLOCKING ACTIVITY IN THE BRAIN:
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.
The clinical effects of antipsychotic drugs appear to reflect a
blockade at dopamine and/or serotonin receptors.
However, many of these agents also block cholinergic, adrenergic,
and histaminergic receptors.
5. Blockade of α-adrenergic receptors:
6. Other effects
1. Antipsychotic actions:
All antipsychotic drugs can reduce hallucinations and delusions
(known as “positive” symptoms) by blocking D2 receptors in the
mesolimbic system of the brain.
The “negative” symptoms, such as blunted affect, apathy, and
impaired attention, as well as cognitive impairment, are not as
responsive to therapy, particularly with the first-generation
Many second-generation agents, such as clozapine, can
ameliorate the negative symptoms to some extent.
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 and aripiprazole, MOST of the neuroleptic drugs
block D2- receptors of the chemoreceptor trigger zone (CTZ) of the
3. Antimuscarinic effects:
SOME; particularly thioridazine, chlorpromazine, clozapine, and
olanzapine produce anticholinergic effects.
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 Lurasidone and quetiapine are approved.
• as adjunctive agents with antidepressants for treatment of
refractory depression: aripiprazole and quetiapine are used
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. However, risperidone
and haloperidol are also commonly prescribed for this tic
9. Also, risperidone and aripiprazole are approved for the
management of disruptive behavior and irritability
secondary to autism.
1.EXTRAPYRAMIDAL SIDE EFFECTS
1. It is appearance is time and dose dependent,
-Early phase (reversible)
*Acute dystonias “sustained contraction of muscles leading to twisting,
distorted postures” occurring within few days,
(*Rx by Trihexphenidyl, orphenadrine, procyclidine, or diazepam),
followed by **akathisias (the inability to remain seated due to motor
#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
• 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
• 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 temporarily
TARDIVE DYSKINESIA, TD
(D2 SUPERSENSITIVITY PHENOMENON):
• thioridazine, show few EP disturbances: strong
anticholinergic activity. This contrasts with haloperidol and
fluphenazine, which have low anticholinergic activity and
produce EP effects.
• Clozapine and risperidone: a low potential for causing EP
symptoms and lower risk of Tardive Dyskinesia.
• Risperidone should be included among the first-line
• 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.
AVOIDING EP ADVERSE EFFECTS
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
1. supportive therapy, administration of…may be helpful:
2. NEUROLEPTIC MALIGNANT SYNDROME:
• 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.
3. Other side effects:
1. acute agitation accompanying withdrawal from
alcohol or other drugs may be aggravated by the
neuroleptics (Tx; benzodiazepine).
2. Chlorpromazine and clozapine are contraindicated in
patients with seizure disorders, because these drugs
can lower seizure threshold. The neuroleptics can
also aggravate epilepsy.
CAUTIONS AND CONTAINDICATIONS