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Antipsychotic drugs
Phenothiazines
 Aliphatic side chain:
-Chlorpromazine
-Triflupromazine
 Piperidine side chain:
-Thioridazine
 Piperazine side chain:
-Trifluoperazine
-Fluphenazine
 Butyrophenones
-Haloperidol
-Trifluperidol
-Penfluridol
 Thioxanthenes
-Flupenthixol
 Other heterocyclics
-Pimozide, Loxapine
• Atypical antipsychotics
-Clozapine
-Risperidone
-Olanzapine
-Quetiapine
-Aripiprazole
-Ziprasidone
Schizophrenia - symptoms
Positive Symptoms(↑↑DA)
Hallucinations
Delusions (bizarre, persecutory)
Disorganized Thought
Perception disturbances
Inappropriate emotions
FUNCTION
Cognition
New Learning
Memory
Negative Symptoms(↓↓NMDA)
Blunted emotions
Anhedonia
Lack of feeling
Mood Symptoms
Loss of motivation
Social withdrawal
Insight
Demoralization
Suicide
• Positive/active symptoms include thought disturbances,
delusions, hallucinations
• Negative/passive symptoms include social withdrawal, loss of
drive, diminished affect, paucity of speech. impaired
personal hygiene
Prognosis of Schizophrenia
• 10% continuous hospitalization
• < 30% recovery = symptom-free for 5
years
• 60% continued problems in
living/episodic periods
Etiology
• A gene encodes for neuregulin-1 has
been associated with schizophrenia.
• Hereditary Influences may account for
10% of schizophrenia cases
• Prenatal Biological Trauma 5-10% cases
of schizophrenia
• Perinatal biological trauma
Schizophrenia Pathophysiology
Schizophrenia
Pathophysiology
Past
Pharmacologic
Profile of APDs
Excess dopaminergic
activity
Dopamine D2-receptor
antagonists
Present
-Renewed interest in the
role of serotonin (5-HT)
Combined 5-HT2/D2
antagonists
-NMDA
NMDA agonists
Imbalance in cortical
communication and
cortical-midbrain
integration, involving
multiple neurotransmitters
More selective antagonists
Mixed agonist/antagonists
Neuropeptide analogs
Future
Dopaminergic Pathways and Innervation
Schizophrenia - Dopamine Hypothesis
 Repeated administration of stimulants like amphetamines and
cocaine, which enhance central dopaminergic neurotransmission, can
cause a psychosis that resembles the positive symptoms of
schizophrenia.
 Low doses of amphetamine can induce a psychotic reaction in
schizophrenics in remission.
 Some early studies with postmortem tissue revealed increased
numbers of DA receptors (in particular D2-like) in schizophrenic
patients
Serotonin Hypothesis of Schizophrenia
• Hallucinogens such as LSD (lysergic acid
diethylamide) and mescaline are serotonin
(5-HT) agonists
• 5-HT2A-receptor blockade is a key factor in
the mechanism of action of the main class
of atypical antipsychotic drugs such as
clozapine and quetiapine.
• 5-HT2A-receptor modulate the release of
dopamine in the cortex, limbic region, and
striatum.
Schizophrenia - Glutamate Hypothesis
• Preclinical as well as clinical studies provide evidence of
hypofunction of NMDA receptors as a primary, or at least, a
contributory process in the pathophysiology of schizophrenia
• Several clinical trials with agents that act at the glycine
modulatory site on the NMDA receptor have revealed consistent
reductions in negative symptoms and variable effects of cognitive
and positive symptoms
• These studies also provide evidence that suggests the effects of
clozapine on negative symptoms and cognition may be through
activation of the glycine modulatory site on the NMDA
receptor.
ANTIPSYCHOTICS
• Pre-90’s
– “Typical”, conventional, traditional neuroleptics,
major tranquilizors
– Modeled on D2 antagonism
– EPS/TD
• Post-90’s
– “Atypical”, novel, 2nd generation
– Modeled on 5-HT2/D2 antagonism
– Less EPS, prolactin effects
– Weight gain, sedation, diabetes
Adverse Effects
•
•
•
•
•
•
•
•
Sedation - initially considerable; tolerance usually develops
after a few weeks of therapy; dysphoria
Postural hypotension - results primarily from adrenergic
blockade; tolerance can develop
Anticholinergic effects - include blurred vision, dry mouth,
constipation, urinary retention; results from muscarinic
cholinergic blockade
Endocrine effects - increased prolactin secretion can cause
galactorhea; results from antidopamine effect
Hypersensitivity reactions - jaundice, photosensitivity,
rashes, agranulocytosis can occur
Idiosyncratic reactions - malignant neuroleptic syndrome
Weight gain
Neurological side effects -
Neurological Side Effects of antipsychotics
REACTION
FEATURES
TIME OF
MAXIMAL RISK
PROPOSED
MECHANISM
TREATMENT
Acute dystonia
Spasm of muscles of
tongue, face, neck,
back; may mimic
seizures; not hysteria
1 to 5 days
Unknown
Diphenhydramine,
promethazine
Akathisia
Motor restlessness;
not anxiety or
"agitation"
5 to 60 days
Unknown
Reduce dose or
change drug:
antiparkinsonian
agents,
benzodiazepines or
propranololc may
help
Parkinsonism
Bradykinesia,
rigidity, variable
tremor, mask facies,
shuffling gait
5 to 30 days
Antagonism
of dopamine
Antiparkinsonian
agents helpfultrihexyphenidyl,
procyclidine,
benztropines
a. Many
drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine
hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral
medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian
agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor
antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle;
with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).
REACTION
Neuroleptic
malignant
syndrome
FEATURES
TIME OF
MAXIMAL RISK
PROPOSED
MECHANISM
TREATMENT
Catatonia, stupor,
fever, unstable blood
pressure,
myoglobinemia; can
be fatal
Weeks; can
persist for days
after stopping
neuroleptic
Antagonism
of dopamine
may
contribute
Stop neuroleptic
immediately:
dantrolene or
bromocriptine may
help:
antiparkinsonian
agents not effective
Perioral tremor
Perioral tremor (may
("rabbit" syndrome) be a late variant of
parkinsonism)
After months or
years of
treatment
Unknown
Antiparkinsonian
agents often help
Tardive dyskinesia
After months or
years of
treatment (worse
on withdrawal)
Excess
function of
dopamine
hypothesized
Stop neuroleptics,
then Diazepam,
Change to
clozapine/olanzapine,
Oral-facial
dyskinesia;
widespread
choreoathetosis or
dystonia
Adverse Effects - EPS
Details on two main extrapyramidal disturbances (EPS):
• Parkinson-like symptoms
– tremor, rigidity
– direct consequence of block of nigrostriatal DA2 R
– reversible upon cessation of antipsychotics
• Tardive dyskinesia
•
•
•
•
involuntary movement of face and limbs
less likely with atypical antipsychotics (AP)
appears months or years after start of AP
? result of proliferation of DA R in striatum
» presynaptic?
• treatment is generally unsuccessful
Weight gain – 40% - weight gain now attributed to
ratio of binding to D2 and 5-HT2 receptors; possibly
also histamine (for newer antipsychotics anyway)
Sexual dysfunction
• result from NE and SE blockade
• erectile dysfunction in 23-54% of men
• retrograde ejaculation in
• loss of libido and anorgasmia in men and women
Seizures - <1% for generalized grand mal
Neuroleptic malignant syndrome (1-2% early in trt)
• combination of motor rigidity, hyperthermia, and
autonomic dysregulation of blood pressure and heart
rate (both go up)
• can be fatal in 5-20% of cases if untreated
• treatment – discontinue meds; give trts for fever
and cardiac problems
Sensitivity to sun
• some phenothiazines collect in skin
(chlorpromazine)
• sunlight causes pigmentation changes – grayishpurple (look bruised)
•in eye, brown cornea, brownish cloud to vision and
possibly permanent impairment
Agranulocytosis - <1% (with clozapine)
• reduced white blood cell count
• lowered resistance to infection
• can be fatal
Jaundice – elevated bilirubin in liver - < ½%
Limitations Of Conventional Antipsychotics
 Approximately one-third of patients with
schizophrenia fail to respond
 Limited efficacy against
 Negative symptoms
 Affective symptoms
 Cognitive deficits
 High proportion of patients relapse
 Side effects and compliance issues
Antipsychotic Drugs – New Generations “atypical”
About 40-60% do not respond to phenothiazines or
cannot handle side effects
• Questions remain about the efficacy of
phenothiazines and haloperidole for negative
symptoms
• Drugs needed that are low in extrapyramidal side
effects and at least equal in efficacy for positive
symptoms, perhaps better for negative
Antipsychotic Drugs – New Generations
“atypical”
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•
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•
•
clozapine
risperidone
olanzapine
sertindole
Quetiapine
Aripiprazole
Ziprasidone
Clozapine (1989)
• Selectively blocks dopamine D2 receptors,
avoiding nigrostriatal pathway
• α-blockade
• Also blocks H1
• More strongly blocks 5-HT2 receptors in cortex
which then acts to modulate some dopamine
activity
• Among non-responders to first generation meds or
those who cannot tolerate side effects, about 30%
do respond to Clozapine
Clozapine
• Extrapyramidal side effects are minimal
• May help treat tarditive dyskinesia
• S/E- orthostatic hypotension effects, sedation,
weight gain, increased heart rate
• Increased risk for seizures (2-3%)
• Agranulocytosis in 1%
• Agranulocytosis risks increase when coadministered with carbamazepine
Risperidone (1994)
• Fewer side effects than Clozapine
• Marketed as first line approach to treatment
• Blocks selective D2, norepinephrine, and 5-HT2
• effective for positive and negative symptoms
• Extrapyramidal side effects low (but are shown at
high doses)
• Shares sedation, weight gain, rapid heart beat,
orthostatic hypotension, and elevated prolactin
• No agranulocytosis risks
• Increased risk of stroke in elderly
• May cause anxiety/agitation (possible OCD)
Olanzipine – 1996
• Improved negative symptom reduction
• Argued to be better than risperidone in
extrapyramidal issues
• Does not cause prolactin elevation
• reduced agranulocytosis risks
Sertindole – 1995
•
Improved negative symptom reduction
•
Low risk for extrapyramidal side effects – major advantage
•
No sedation and very mild prolactin elevation– major advantages
•
Shares orthostatic hypotension, tachycardia, and weight gain
•
Common side effects are rhinitis and reduced ejaculatory volume (not
associated with disturbed function)
•
concern about sudden cardiac death or episodes due to cardiac arrhythmia led
to its voluntary removal in 1998
Quetiapine - 1997
•
No increased risks for extrapyramidal symptoms
•
Shares sedation (sleepiness), orthostatic hypotension, weight gain
•
Does cause anticholinergic side effects (like older and Clozapine) – dry
mouth, constipation
•
Does not elevate prolactin
Ziprasidone - 2001
•
Similar to advantages of others, but argued not to cause weight gain
•
May induce cardiac arrhythmias
•
Also has anxiolytic and antidepressant activity
Non- psychiatric Indications
• As Antiemetics
-chlorpromazine, prochlorperazine, haloperidol
• Anaesthesia
-droperidol (with fentanyl)
• Intractable Hiccups
-chlorpromazine
-haloperidol
MCQs
Q1. A female suffering from psychosis, taking
fluphenazine now complains of sudden onset
of high grade fever, muscle rigidity and
altered sensorium. The diagnosis is:
A. Malignant hyperthermia
B. Tardive dyskinesia
C. Akathisia
D. Neuroleptic malignant syndrome
• Ans- D - Neuroleptic malignant syndrome
Q2. Antipsychotic drug induced parkinsonism is
treated by:
A. Levodopa
B. Selegiline
C. Amantadine
D. Central anticholinergic drugs
• Ans- D (Trihexyphenidyl
Procyclidine
Biperiden )
Q3. Least extrapyramidal side effects are seen
with:
A. Clozapine
B. Haloperidol
C. Trifluoperazine
D. Chlorpromazine
• Ans- A- Clozapine
Q4. Risperidone is associated with the risk of:
A. Cerebrovascular accidents
B. Agranulocytosis
C. Diabetes Insipidus
D. Gout
• Ans- A - Cerebrovascular accidents
Q5. The antipsychotic drug that can also be used
as antiemetics:
A. chlorpromazine
B. Clozapine
C. Aripiprazole
D. Loxapine
• Ans- A - chlorpromazine
Q6. The antipsychotics that can also be used as
anaesthetic drug:
A. Chlorpromazine
B. Penfluridol
C. Clozapine
D. Droperidol
• Ans- D - Droperidol
Q7. The antipsychotic drug that can also be used
to treat Intractable Hiccups:
A. Clozapine
B. Chlorpromazine
C. Haloperidol
D. Ziprasidone
• Ans- B, C - Chlorpromazine, Haloperidol
Thank you
Bibliography
• Essentials of Medical Pharmacology -7th edition by KD Tripathi
• Goodman & Gilman's the Pharmacological Basis of Therapeutics 12th
edition by Laurence Brunton (Editor)
• Lippincott's Illustrated Reviews: Pharmacology - 6th edition by Richard A.
Harvey
• Basic and Clinical pharmacology 11th edition by Bertram G Katzung
• Rang & Dale's Pharmacology -7th edition
by Humphrey P. Rang
• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
• Review of Pharmacology by Gobind Sparsh