Download Antipsychotics

ANTIPSYCHOTICS
Sharini Chandra
s140044
Able to reduce psychotic symptoms in a wide variety of conditions, including
schizophrenia, bipolar disorder, psychotic depression and drug induced
psychoses
Also known as neuroleptics
Two major classes:
Dopamine receptor antagonist (Typical antipsychotics or first generation) chlorpromazine, haloperidol
Serotonin-dopamine antagonist (Atypical antipsychotics or second
generation) - risperidone, clozapine, olanzapine
The atypical antipsychotic drug is now the most widely used type of
antipsychotic drug.
PRINCIPLES OF ANTIPSYCHOTICS
•
Five major principles:
1) Clinicians should define the target symptoms to be treated
2) An antipsychotic that has worked well in the past should be used again. In
absence of such information, the choice of an antipsychotic is usually
based on the side effect profile.
3) The minimum length of an antipsychotic trial is 4-6 weeks of adequate
dosages. If the trial is unsuccessful, a different antipsychotic drug, from a
different class can be tried
4) In general, the use of more than one antipsychotic drug at any one time is
rarely indicated.
5) Patients should be maintained on the lowest possible effective dosage of
medication.
DOPAMINE RECEPTOR ANTAGONIST
(TYPICAL ANTIPSYCHOTICS)
• Post-synaptic blockade of dopamine D2 receptors
• High potency- haloperidol, low potency - chlorpromazine
• Effective in the treatment of schizophrenia particularly of the positive
symptoms (eg. Delusions and hallucinations)
• Two major shortcomings:
• Only a small percentage(25%) are helped enough to recover a reasonable
amount of normal mental functioning.
• Dopamine receptor antagonists are associated with adverse effects like
akathisia, parkinsonian-like symptoms of rigidity and tremor, tardive
dyskinesia and neuroleptic malignant syndrome.
SEROTONIN- DOPAMINE ANTAGONIST
(ATYPICAL ANTIPSYCHOTICS)
• First line of antipsychotics
• Block dopamine receptors but with less affinity
• Since it blocks nigrostriatal D2 receptors less- extrapyramidal side effects
occur less frequently
• Effective for a broader range of patients with schizophrenia than dopamine
receptor antagonist.
• Effective as haloperidol for positive symptoms for schizophrenia, also is
effective for negative symptoms since it blocks serotonin receptors and
cause few extrapyramidal symptoms.
DOPAMINE RECEPTOR ANTAGONIST
(TYPICAL ANTIPSYCHOTICS)
• Chlorpromazine
• used in the treatment: schizophrenia, nausea and vomiting and severe behavioural
disorders in children
• Lipid soluble so are well absorbed orally and concentrate in CNS
• Subject to first pass metabolism and bioavailability ranges from 10%-80%
• Peak plasma level: 1-4 hrs after oral administration and 15-30 minutes after IM injection
• Therapeutic effect: 6 weeks- 6 months
• Metabolised in the liver and excreted by kidneys
• Adverse effects: orthostatic hypotension, anticholinergic and extrapyramidal side effects
( akathisia, dystonia, drug induced parkinsonism and tardive dyskinesia)
• Dosage: 50 – 600mg
CONTRAINDICATIONS
• Use with caution in patients with breast cancer, cardiovascular disease,
severe liver impairment, hyperthyroidism, Parkinson’s disease and epilepsy
• Avoid use in alcohol abusers, in pregnant women, during lactation and in
people frequently exposed to sunlight.
• Haloperidol
• Competitively blocks D2 receptors in the mesolimbic system and causes an
increased turnover of brain dopamine to produce its antipsychotic effect
• Associated with significant degree of extrapyramidal effects but has less effect on
noradrenergic receptors
• Useful antipsychotic and antiemetic and is used to treat severe behavioural
problems in children and in acute mania
• Rapidly absorbed from the GI
• Peak plasma level: 2-6 hrs of oral intake, 20 mins if given IM
• Metabolised in the liver and excreted by kidneys
• Dosage: 0.5 – 12mg
SIDE EFFECTS OF TYPICAL
ANTIPSYCHOTICS
• Movement disorders: Dystonia (muscle spasm) Parkinsonism (tremor, slow
movements) Akathisia (restlessness)
• Tardive Dyskinesia: Uncontrollable muscle spasms resulting in twisting of body
or neck. Occurs in 5% of people taking medication.
• Sedation
• Galactorrhea (stimulation of milk secretions)
• Sexual dysfunction in males
• Liver disorder (rare)
SEROTONIN- DOPAMINE ANTAGONIST
(ATYPICAL ANTIPSYCHOTICS)
• Risperidone And Olanzapine
• Block both 5-HT2 and dopamine D2 receptors
• Less sedating, cause fewer anticholinergic effects and do not have the same
potential to cause serious agranulocytosis
Risperidone
• Risperidone is widely used atypical drug
• A growing body of evidence supports its role as a first- line agent for first break, mildly
to moderately ill patients and for severely ill, treatment refractory patients
• dosage: 0.5- 6.0mg
• Adverse effects: Movement disorder, gastric distress, mild sedation
• Olanzapine
• Olanzapine has been approved recently for use in treatment of acute manic
episodes associated with bipolar disorder
• Less likely to produce extrapyramidal symptoms
• It is useful first line agent, in that patients who do not respond to one serotonin –
dopamine antagonist may respond to another
• 85% is adsorbed from GIT
• Peak conc. : 5 hrs
• Half life : 31 hrs
• Adverse effect of olanzapine : sexual dysfunction, weight gain, mild liver
dysfunction, constipation
• Olanzapine ( oral dosage ) : 5 -20 mg
• Clozapine
• Second line drug
• Antagonises D1,D2 and D4 dopamine receptors, with less affinity for D2 receptors, so
it is less likely to induce extrapyramidal effects.
• Also antagonises 5-HT2, a1 adrenoceptors and histamine H1 receptors
• Useful for patients with tardive dyskinesia
• Clozapine requires strict monitoring in light of its potential to cause neutropenia,
agranulocytosis, myocarditis, toxic megacolon and cardiomyopathy
• Peak plasma conc. Reached in 2 hrs
• Half life: 12 hrs
• Adverse effects: drowsiness, seizure, severe constipation and orthostatic hypotension
• Recommended use: Clozapine 12.5 mg orally, twice daily initially, increasing as
tolerated and according to patient response. Usual effective daily dose is 200 to 600
mg. The maximum dose is 900 mg daily, but this is not usually required
METABOLIC SYNDROME
• Weight gain, diabetes, and dyslipidemia are the components of metabolic
syndrome usually associated with second generation antipsychotics, along with the
consequent risks of diabetic ketoacidosis and cardiovascular disease
• The mechanism is not entirely clear, but there is evidence for both increased
appetite and altered metabolic control with these drugs
• Patient- related factors include pre- existing metabolic issues, and those who are
obese, diabetic or pre diabetic, or have high risk lipid profile are more likely to
experience problems with these medications than other patients.
• Clozapine and olanzapine carry significantly higher risk than other antipsychotics
• The potential morbidity of these symptoms has led to the routine recommendations
for routine short and long – term monitoring of weight, waist circumference, blood
pressure, fasting glucose and lipid profile of patients taking any of the
antipsychotics.
• All patients should be provided with dietary advice and lifestyle assessment (i.e.
patterns of eating, smoking and exercise) and a supportive therapeutic program
aimed at better physical health, with special attention to smoking
cessation/reduction, exercise and a balanced diet. Community rehabilitation and
support programs can be of value. It is also important to monitor bowel function.
Constipation is a major and occasionally lethal side-effect of newer antipsychotic
medication
OTHER ATYPICAL
ANTIPSYCHOTICS: SERTINDOLE
• Effective agent with a favourable profile of adverse effects
• Must be slowly titrated upward to avoid orthostatic hypotension
• May cause sinus tachycardia, nasal congestion, and decreased ejaculatory
volume
• Half life- 3 days, makes it ideal for poorly compliant patients
QUETIAPINE
• Effective antipsychotic drug associated with no increased risk of
extrapyramidal symptoms
• Adverse effects: sedation, tachycardia, weight gain and agitation.
• Initial dose must be titrated upward over 4 days to avoid orthostatic
hypotension and syncope
ZIPRASIDONE
• Effective drug for the treatment of schizophrenia
• Additional benefits for patients with affective symptoms, because it blocks
reuptake of serotonin and norepinephrine and for patients with anxiety
because it is an agonist for 5 HT1A receptors
• Adverse effects: sedation, nausea, dizziness and light headedness
• Weight gain
• Loss of libido
• Hormonal side effects
• Sedation
• Galactorrhea (stimulation of milk secretions)
• Sexual dysfunction in males
• Liver disorder (rare)
• Constipation
ADVERSE PHARMACOLOGIC EFFECTS
OF ANTIPSYCHOTIC DRUGS
TYPE
MANIFESTATION
MECHANISM
ANS
Loss of accommodation, dry
mouth, difficulty urinating,
constipation
Muscarinic cholinoceptor
blockade
Postural hypotension,
impotence
Alpha adrenoceptor blockade
CNS
Parkinson’s syndrome,
akathisia, dystonia, Tardive
dyskinesia
Dopamine receptor blockade
ENDOCRINE
Amenorrhea, galactorrhea,
impotence
Dopamine receptor blockade
resulting in
hyperprolactineamia
OTHERS
Weight gain
Combined H1 and 5HT2
blockade
REFERENCE
• Benjamin James Saddock, Virginia Alcott Saddock, 2007, Kaplam and Saddock’s. Synopsis of
Psychiatry. Behavioral Sciences/Clinical Psychiatry. 10th ed.
• Guidelines of drugs commonly used in treating mental illness and related disorders, 1st edition
FijiPharmac, MOH
• Basic & Clinical Pharmacology, Katzung; 13th Edition
• Pharmacology for Health Professionals; Bryant B, Knights K; 2nd edition
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