Transcript Antipsychotic drugs - Dr S Gupta

Psychopharmacology
- Antipsychotic drugs
Dr. Subhash Gupta
The objectives of this session
1. To understand the mechanisms of action of antipsychotic drugs
used in psychiatric practice
2. To understand therapeutic indications of antipsychotic drugs
and their effectiveness
3. To understand factors influencing drug tolerability and adverse
effects
Dopaminergic dysregulation is a core
neurotransmitter abnormality in
schizophrenia although other neurotransmitters
are also thought to be involved
Dopamine
Glutamate
Acetylcholine
Serotonin
Norepinephrine
-Aminobutyric acid
(GABA)
Neuropeptides
(eg, cholecystokinin)
Others?
Goff et al. Med Clin North Am. 2001;85:663.
Crismon and Dorson. Pharmcotherapy: a pathophysiologic approach. 1999.
• Neurotransmitters and Neuromodulators
– Monoamines
Dopamine
– Dopamine:
• A neurotransmitter; one of the catecholamine.
• Implicated roles in movement, attention, learning, reinforcing
effects of abused drugs.
• Synthesized from tyrosine that we obtain from our diet.
• Neurotransmitters and Neuromodulators
– Monoamines
Dopamine
– L-Dopa:
• The levorotatory form of DOPA; the precursor of the
catecholamines; often used to treat Parkinson’s disease because
of its as a dopamine agonist.
• Neurotransmitters and Neuromodulators
– Monoamines
Dopamine
– Nigrostriatal system:
• A system of neurons originating in the substantia nigra and
terminating in the neostriatum (caudate nucleus and putamen of
the basal ganglia); appears to play a role in the control of
movement.
• Neurotransmitters and Neuromodulators
– Monoamines
Dopamine
– Mesolimbic system:
• A system of dopaminergic neurons originating in the ventral
tegmental area and terminating in the nucleus accumbens,
amygdala, and hippocampus; appears to play a role in the
reinforcing effects of drugs that are commonly abused.
• Neurotransmitters and Neuromodulators
– Monoamines
Dopamine
– Mesocortical system:
• A system of dopaminergic neurons originating in the ventral
tegmental area and terminating in the prefrontal cortex; appears
to influence formation of short-term memories, planning, and
preparing strategies for problem solving.
Copyright © 2004 Allyn and Bacon
• Neurotransmitters and Neuromodulators
– Monoamines
Dopamine
– Parkinson’s Disease:
• A neurological disease characterized by tremors, rigidity of the
limbs, poor balance, and difficulty in initiating movements;
caused by degeneration of the nigrostriatal system; Parkinson’s
disease has been treated with L-DOPA.
• Neurotransmitters and Neuromodulators
– Monoamines
Dopamine
– Monoamine oxidase (MAO):
• A class of enzymes that destroy the monoamines; dopamine,
norepinephrine, and serotonin.
• Neurotransmitters and Neuromodulators
– Cocaine and Amphetamine
• Dopamine agonists
• Cocaine blocks DA transporters
• Amphetamine increase DA release and reverses
transporter
ANTIPSYCHOTIC DRUGS – PHARMACOKINETIC
 All have oral absorption
 Not all can be administered intramuscularly (short or longerterm)
 All suffer extensive “first pass” metabolism
 Most have hydrophilic and lipophilic properties
 Some have significant active metabolites e.g. clozapine
 Some have very long half-lives e.g. olanzapine and others are
shorter e.g. quetiapine
 Some have interference in metabolism from smoking e.g.
(olanzapine clearance accelerated)
 Potential metabolic interactions via some SSRIs e.g. fluoxetine
inhibits breakdown of aripirazole via cytochrome inhibition.
 Potential metabolic interactions via some anticonvulsants e.g.
enzyme inducers such as carbamazepine might increase
clearance of some drugs
TYPICAL ANTIPSYCHOTICS
Phenothiazines
Chlorpromazine
Sedative, anticholinergic, antiadrenergic, antihistaminic and dopamine
blockade. Liver toxicity, white cell depression, skin pigmentation. Risk
of cardiovascular collapse if high doses given quickly I.V/I.M
Thioxantines
Flupenthixol
Not as sedative similar range of side-effects to phenothiazines.
Butyrophenones
Haloperidol
Not sedative, few side effects, strong potency of dopamine blockade
Depot preparations:Given in oil-based solution. Up to six-weekly. EPS may be a bit
commoner. Weight gain, sedation major drawbacks. Complications skin necrosis, nerve damage, abscesses
Extrapyramidal side effects
Caused by blocking dopamine receptors in the basal ganglia
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Muscle spasms
Tremor
Dystonia
Akathisia
Parkinsonism
Tardive dyskinesia
TYPICAL ANTIPSYCHOTICS
Important side effects
Anticholinergic side-effects:- Dry mouth, blurred vision, constipation
Anti-adrenergic:- Sedation, postural hypotension
Anti-histaminic:- Sedation
Cardiovascular:- Hypotension, conduction (QTc interval, arrhythmias)
Extrapyramidal:- Parkinson's features (striking, symmetrical),
Dystonia, oculogyric crisis, Akathisia
Motor (T.D)
Neuroleptic malignant syndrome / Central serotonin syndrome
TYPICAL ANTIPSYCHOTICS
Other important side effects
Weight gain
Sexual impairment
Effects of prolactin - galacttorhoea, breast development, amenorrhoea
Lower seizure threshold
Effect on temperature control
Agranulocytosis
Antipsychotics - Principles of treatment
Tardive dyskinesia -summary
Maintain on one antipsychotic
Gradual withdrawal or dosage reduction
Atypical antipsychotics may have advantage
Rate on scale
Akathisia - summary
Recognition!
Reduce dosage
Change to lower potency drug
 BZP may be helpful, anti-cholinergics not always helpful
What is atypical?
• Unlike typical antipsychotics (neuroleptics), atypical
antipsychotics decreased amphetamine induced
hyperactivity in rats in doses that did not produce
catalepsy (immobility).
• Classically, an antipsychotic is said to be atypical when
it improves both positive and negative symptoms of
schizophrenia but:
– Produces minimal or no EPS
– Causes minimal or no sustained prolactin elevation
• Many researchers have proposed greater efficacy in
treating negative symptoms, mood changes and
cognitive deficits, giving rise to broader definitions of
atypicality.
Class
Efficacy
EPS
Prolactin
1st generation
(HPL, CPZ)
Limited
positive
symptoms
to High
Elevating
2nd generation
(risperidone)
Both positive and Dose
Elevating
negative
dependent
symptoms
3rd generation
(clozapine,
olanzapine,
quetiapine)
Broad spectrum Low
(both
positive
and
negative
symptoms
+
mood
and
cognition effects)
Sparing
Why they are atypical?
Serotonin – Dopamine Hypothesis
Fast-off D2 hypothesis – Low affinity and fast
dissociation from D2 receptors
Dopamine D4 hypothesis
Serotonin–Dopamine Hypothesis
• Greater affinity and antagonism at serotonin
5HT2 receptors than at D2 receptors
• So, the name Serotonin – Dopamine
Antagonists (SDA) was coined.
Contradictions to Serotonin
Dopamine Hypothesis
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Typical antipsychotics such as loxapine
and chlorpromazine show equally high
5HT2A occupancy.
Amisulpride is an effective atypical
antipsychotic drugs but doesn’t have
5HT2A affinity.
Other Dopamine theories
• ‘Limbic Specific’
• Extent of D2 blockade:
– Antipsychotic action occurs at a D2-receptor occupancy
rate of 60–70%, whereas a D2 occupancy rate greater
than 80% is believed to increase the risk of EPSs
without increasing efficacy.
– Usual doses of typical antipsychotics occupy 70–90%
of D2- receptors.
– Clozapine, the prototypic atypical agent, occupies only
38–63% of D2-receptors at usual dosages.
– Olanzapine and risperidone may lose their “atypicality”
at higher dosages because of increased binding affinity
for D2-receptors
Fast-off D2 hypothesis
• Atypical antipsychotics are loosely and transiently bound to
and rapidly released from D2 receptor. They continually go on
and off D2 receptors, allowing extensive access of endogenous
dopamine to these receptors.
• Clozapine and quetiapine are most loosely bound and rapidly
dissociated. This explains efficacy in controlling psychosis
without worsening of motor symptoms in parkinsonism
Quetiapine (Seroquel): Most atypical?
Relative binding to D2 receptors
Quetiapine
Loose (fastest dissociation)
Clozapine
Olanzapine
Sertindole
Intermediate
Dopamine
Ziprasidone
Chlorpromazine
Haloperidol
Risperidone
Tight (least dissociation)
Dopamine D4 hypothesis
This concept gained popularity based on 2
findings:
• Clozapine's greater D4Vs D2 affinity
• Elevated D4 receptors in brains of
schizophrenic patients.
But, not applicable to other atypical
antipsychotics
Dopamine System stabilisers
Prescribing information available on last slide
Partial agonism at D2 receptors
Molecular profile
Receptor binding
Intrinsic activity
Full agonist (Dopamine)
Full activation
Antagonist (Typicals/ Atypicals)
No activation
Partial agonist (Aripiprazole)
Stabilises
activity
D2 Receptor
Stahl, J Clin Psychiatry 2001; 62(11): 841-842; Stahl, J Clin Psychiatry 2001; 62 (12): 923-024
Side Effects of atypicals
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Weight gain
Dyslipidemia
Increased glucose levels
Metabolic syndrome
Risk of stroke
EPS, prolactin related side effects
ANTIPSYCHOTIC DRUGS
CLINICAL PROBLEMS
1135 - 1205 approx
• Please divide into two groups. The left hand
side of the room (your left) will be Group One
and right hand side of the room will be Group
Two.
• Look at both clinical scenarios. I will invite
each group to feedback in turn
ANTIPSYCHOTIC DRUGS
CLINICAL PROBLEMS
Scenario One
A 16 year old boy has an 18 month history of self neglect, social
withdrawal and has been very suspicious of his friends. He has
complained of depressed mood. Two weeks ago his G.P. sent him
for urgent psychiatric assessment. He was given chlorpromazine
100mg t.d.s by the doctor he saw. He has been re-referred after a
serious episode of self harm (neck laceration) and complains of
feeling more depressed and agitated.
Discuss the appropriateness of his medication.
Would you change this and if so why?
ANTIPSYCHOTIC DRUGS
CLINICAL PROBLEMS
Scenario Two
A 56 year old man has a 6 month history of hearing voices in the
3rd person. He has previously seen one of your colleagues and
has come for review. He complains of excessive drowsiness and
dizziness and impaired short-term memory. He has gained 10kg
and is more thirsty. His symptoms have been hard to control. He
now takes a range of medication (see next slide).
Can his complaints be explained in terms of his current
treatment?
Would you wish to revise his regime and if so how?
ANTIPSYCHOTIC DRUGS
CLINICAL PROBLEMS
Scenario Two
Propranolol
Olanzapine
Risperidone
Procyclidine
Lorazepam
Temazepam
80mg daily*
35mg daily*
12mg daily*
15mg daily*
2mg PRN 6 hourly
20mg nocte
*All the above are in divided doses
Problems for reflection (add to workbook)
1. An 19 year old woman with schizophrenia is concerned about the
effect of antipsychotic treatment on her fertility. What points would you
need to discuss to help her make an informed choice on treatment?
2. A 45 year old man with schizophrenia has recently changed to
clozapine treatment. He has a past history of childhood epilepsy and
there is a family history of diabetes mellitus. What particular advice
will he need to be given?
3. A 32 year old woman with treatment resistant schizophrenia (to two
typicals, risperidone and olanzapine) has had to stop clozapine
treatment due to a red alert. What alternative treatment options are
there available for her?