Second generation antipsychotics

Second generation antipsychotics

• Now the drugs of choice
• Effective intreating the positive s/s of psychosis and have greater
effectiveness in relieving the negative s/s
• Less likely to cause EPS
Second generation antipsychotics
• Clozaril (clozapine) Prototype of the atypicals.
• Effective but considered a second line drug because of its association
with agranulocytosis. Weekly WBCs are indicated during the first 6
months of therapy.
Second generation antipsychotics
• Zyprexa (olanazapine)—can cause EPS but not agranulocytosis.
Causes less sedation, less orthostasis, and anticholinergic effects.
• Seroquel (quietapine) blocks dopamine and serotonin. Relieves
positive and negative symptoms. Many drug interactions as is
metabolized by the cytochrome p450 system.
Second generation cont.
• Risperdal (risperidone)—blocks dopamine and serotonin. Affects both
positive and negative symptoms. Often first choice treatment. Is also
metabolized by cytochrome p450 system. Can cause parkinsonism.
2nd generation
• Abilify (aripiprazole)—newest atypical drug. Is called a partial
dopamine agonist. Has ability to block overstimulated receptors and
stimulate understimulate receptors. Can cause orthostatic
hypotension, tardive dyskinesia, weight gain, hyperglycemia and
neuroleptic malignant syndrome.
Mechanisms of Action
• Most bind to D2 dopamine receptors and block the action of
dopamine but positive effects only occur over time
• Theory is that blockade of dopamine recptors leads to changes in
receptors w/effects on cell metabolism and function
• With chronic drug administration, it is postulated that drugs re-
regulate the abnormal neurotransmission systems
GENERAL CHARACTERISTICS OF TYPICAL
NEUROLEPTICS

• The older, typical neuroleptics are effective antipsychotic

agents with neurologic side effects involving the
extrapyramidal motor system.
• Typical neuroleptics block the dopamine-2 receptor.
GENERAL CHARACTERISTICS OF TYPICAL
NEUROLEPTICS

• Typical neuroleptics do not produce a general depression of

the CNS, e.g. respiratory depression

• Abuse, addiction, physical dependence do not develop to

typical neuroleptics.
GENERAL CHARACTERISTICS OF TYPICAL
NEUROLEPTICS

• Typical neuroleptics are generally more effective

against positive (active) symptoms of schizophrenia
than the negative (passive) symptoms.
THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS

• All appear equally effective; choice usually based on

tolerability of side effects
• Most common are haloperidol ,chlorpromazine and
thioridazine
• Latency to beneficial effects; 4-6 week delay until full
response is common
• 70-80% of patients respond, but 30-40% show only partial
response
THERAPEUTIC EFFECTS OF TYPICAL
NEUROLEPTICS (Continued)

• Relapse, recurrence of symptoms is common ( approx.

50% within two years).

• Noncompliance is common.

• Adverse effects are common.

 ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS

• Anticholinergic (antimuscarinic) side effects:

• Dry mouth, blurred vision, tachycardia, constipation, urinary retention,
impotence
• Antiadrenergic (Alpha-1) side effects:
• Orthostatic hypotension , reflex tachycardia
• Sedation
• Antihistamine effect: sedation, weight gain
DOPAMINE-2
RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN
EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).

• DYSTONIA
• NEUROLEPTIC MALIGNANT SYNDROME
• PARKINSONISM
• TARDIVE DYSKINESIA
• AKATHISIA
Extrapyramidal Symptoms (EPS)
• Affects extrapyramidal system and basal ganglia. Is
the system that includes descending fibers that
reach the medulla other than by the corticospinal
tracts. Is important in maintenance of equilibrium
and muscle tone.
• Symptoms include: dystonia, akathisia, tardive
dyskinesia and parkinsonism
Extrapyramidal side effects 

Neuroleptic drugs are replete with side effects.

Many side effects occur early during treatment
and result from neuroleptic blockade of receptors
in the central and peripheral nervous systems;
others appear later in the course of treatment.
1.”Extrapyramidal” reactions include
• Parkinsonism, which can mimic idiopathic
Parkinson’s disease but is usually of mild degree. It
responds to anticholinergic drugs or amantadine;
Cont…….
• Akatisia is a subjective sense of restlessness usually accompanied by
wild to moderate motor hyperactivity. It is among the most common
of side effects and usually responds to α-adrenergic receptor
antagonists, anticholinergics, antihistamines or amantadine. Akathisia
is sometimes misinterpreted as increased agitation, leading to
increased neuroleptic dosing, resulting in greater akathisia.
Cont…

2.Endocrine effects
DA, released in the median eminence by neurons of the
tuberohypophyseal pathway acts physiologically via D2 receptors
as an inhibitor of prolactin secretion. The result of blocking D2
receptors by antipsychotic drugs is therefore to increase the
plasma prolactin concentration, resulting breast swelling, pain
and lactation, which can occur in men as well as women. Other
less pronounced endocrine changes including a decrease of
growth hormone secretion, but these, unlike the prolactin
response, are unimportant clinically.
Cont….

3.Local anaesthetic
Chlorpromazine is as potent a local anaesthetic as procaine. However, it
is not used for this purpose because of its irritant action. Others have
weaker membrane stabilizing action.
4. Sedation, which tends to decrease with continued use, occurs with
many antipsychotic drugs. Antihistamine (H1) activity is a property of
phenothiazines and contributes to their sedative and antiemetic
properties, but not to their antipsychotic action.
 Cont….

5.Skeletal muscle
Neuroleptics have no effects on muscle fibers or neuromuscular transmission.
They reduce certain types of spasticity: the site of action being in the basal
ganglia or medulla oblongata. Spinal reflexes are not affected.

6.Various idiosyncratic and hypersensitivity reaction can occur, the most

important being.
Jaundice, which occurs with older phenothizines, such as chlorpromazine. The
jaundice is usually mild, and of obstructive origin; it disappears quickly when
the drug is stopped of substituded by an antipsychotic of different class.
Neuroleptic Malignant Syndrome(NMS)
• Rare but potentially fatal reaction that may occur hours to months
after initial antipsychotic drug use. Will present with fever, muscle
rigidity, agitation, confusion, delirium, tachycardia, respiratory failure,
acute renal failure.
• Tx—stop drug, supportive care, dantrolene and amandatine.
MECHANISMS OF ACTION
OF TYPICAL NEUROLEPTICS and Some Side Effects

• DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical

systems for antipsychotic effect.
• DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system)
for EPS
• DOPAMINE-2 receptor supersensitivity in nigrostriatal system for
tardive dyskinesia
 LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:

• Dopamine neurons reduce activity.

• Postsynaptic D-2 receptor numbers increase (compensatory response).
• When D2 blockade is reduced, DA neurons resume firing and stimulate
increased # of receptors >> hyper-dopamine state >> tardive dyskinesia
 MANAGEMENT OF EPS

• Dystonia and parkinsonism: anticholinergic antiparkinson drugs

• Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive

• Akathisia: benzodiazepines, propranolol

• Tardive dyskinesia: increase neuroleptic dose; switch to clozapine

 ADDITIONAL CLINICAL USES OF TYPICAL
NEUROLEPTICS

• Adjunctive in acute manic episode

• Tourette’s syndrome (Haloperidole )
• Control of psychosis in depressed patient
• Phenothiazines are effective anti-emetics,
• Esp. prochlorperazine
• Also, anti-migraine effect
 GENERAL CHARACTERISTICS OF ATYPICAL
Antipsychotic

• Effective antipsychotic agents with greatly reduced or absent EPS, esp.

reduced Parkinsonism and tardive dyskinesia
• All atypical neuroleptics block dopamine and serotonin receptors; other
neurochemical effects differ
• Are effective against positive and negative symptoms of schizophrenia;
and in patients refractory to typical neuroleptics
HYPOTHESIZED MECHANISMS OF ACTION OF
ATYPICAL NEUROLEPTICS

• Combination of Dopamine-4 and Serotonin-2 receptor blockade in

cortical and limbic areas for the “pines” like clozapine

• Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp.

risperidone)
 PHARMACOLOGY OF CLOZAPINE

• FDA-approved for patients not responding to other agents or with

severe tardive dyskinesia
• Effective against negative symptoms
• Also effective in bipolar disorder
• Little or no parkinsonism, tardive dyskinesia, PRL elevation, neuro-
malignant syndrome; some akathisia
 PHARMACOLOGY OF CLOZAPINE
(Continued )

• Other adverse effects;

• Weight gain
• Increased salivation
• Increased risk of seizures
• Risk of agranulocytosis requires continual monitoring
 PHARMACOLOGY OF OLANZAPINE

• Olanzapine is clozapine without the agranulocytosis.

• Same therapeutic effectiveness

• Same side effect profile
 PHARMACOLOGY OF QUETIAPINE

• Quetiapine is olanzapine without the anticholinergic

effects.

• Same therapeutic effectiveness

• Same side effect profile
 Resperidone

• Highly effective against positive and negative symptoms

• Adverse effects:
• EPS incidence is dose-related
• Alpha-1 receptor blockade
• Little or no anticholinergic or antihistamine effects
• Weight gain, PRL elevation
 Adverse Pharmacologic Effects of Antipsychotic Drugs

Type Manifestations Mechanism

Autonomic nervous system Loss of accommodation, dry mouth, difficulty urinating, Muscarinic cholinoceptor blockade
constipation

  Orthostatic hypotension, impotence, failure to ejaculate Adrenoceptor blockade

Central nervous system Parkinson's syndrome, akathisia, dystonias Dopamine-receptor blockade

  Tardivedyskinesia Supersensitivity of dopamine receptors

  Toxic-confusional state Muscarinic blockade

Endocrine system Amenorrhea-galactorrhea, infertility, impotence Dopamine-receptor blockade resulting in
hyperprolactinemia
Other Weight gain Possibly combined H1 and 5-HT2 blockade