Download antipsychotics

Charles University in Prague, Third Faculty of Medicine
GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME
Module Neurobehavioral Science I.
Pharmacology of antipsychotics,
antidepressants and mood stabilizers
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine
Ruská 87, Prague 10,
Academic year 2012-2013
http://vyuka.lf3.cuni.cz
ANTIPSYCHOTICS
Psychotic symptoms
Positive (hallucinations, delusions, thought disorder , abnormal behaviour)
Negative (social withdrawal, emotional flattening, anhedonia, reluctance to
perform everyday tasks)
Aetiology and pathogenesis of schizophrenia
The cause of schizophrenia remains unclear but involves a combination of
genetic factors (multiple genes may be responsible) and environmental
factors (particularly maternal virus infections).
The main neurotransmitters involved in the pathogenesis of schizophrenia
are dopamine and glutamate, serotonin.
Drugs with dopaminergic effects (e.g. amphetamine), activating
serotonergic or glutamatergic receptors (e.g. LSD or ketamine,
respectively) can produce psychotic symptoms.
Neurodegeneration, apoptosis and oxidative stress may also play role in
the pathogenesis of schizophrenia
ANTIPSYCHOTICS
CLASSIFICATION
First-generation („typical“, conventional) antipsychotics
phenothiazines - chlorpromazine
butyrophenones - haloperidol
Second-generation („Atypical“) antipsychotics
MARTA* - clozapine, olanzapine
SDA** – risperidone
Other e.g. sulpiride, quetiapine, aripiprazole
*Multi Acting Receptor Targeted Agents
**Serotonin Dopamine Antagonists
ANTIPSYCHOTICS
Main Effects
Therapeutic antipsychotic, sedative/tranqilizant/anxiolytic/hypnotic, antiemetic
Adverse extrapyramidal, hyperprolactinemia, drowsiness,hypotension,
antimuscarinic, weight gain
ANTIPSYCHOTICS
Mechanism of action:
All antipsychotics antagonize D2 receptors
antagonism of receptors:
dopamine (D1, D2), serotonine (5-HT2A),
acetylcholine (M1), alpha1-adrenergic, histamine (H1)
Carlsson 1963, later
Nobel prize
Correlation between the clinical potency and affinity for dopamine
D2 receptors among antipsychotic drugs.
Figure 45.1 Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs. Clinical potency is expressed as the daily dose
used in treating schizophrenia, and binding activity is expressed as the concentration needed to produce 50% inhibition of haloperidol binding. (From Seeman P et al.
1976 Nature 361: 717.)
Downloaded from: StudentConsult (on 15 December 2012 09:54 AM)
© 2005 Elsevier
ANTIPSYCHOTICS
by blocking dopaminergic
receptors in … produce …
MESOLIMBIC, MESOCORTICAL*
DOPAMINERGIC SYSTEM
Antipsychotic effects
NIGROSTRIATAL
DOPAMINERGIC SYSTEM
TUBEROINFUNDIBULAR
DOPAMINERGIC SYSTEM
Extrapyramidal effects
Endocrine effects
Acute (reversible):
Hyperprolactinemia
Parkinsonism (rigidity,
Gynaecomastia
bradykinesia, tremor, Akathisia
(breast swelling,
(a feeling of motor
pain and lactation)
restlessness), Acute dystonia
(involuntary movements e.g.
protruding tongue, fixed upward
gaze, spasm of neck muscles)
Chronic (irreversible):
Tardive dyskinesia (involuntary
movements of the face and
limbs)
D1
D2
alfa1
++
+++
+++
haloperidol
+
+ ++
clozapine
++
olanzapine
mAch
5-HT2A
Notes
++
++
++
EPS, increased prolactin, hypotension,
antimuscarinic effects
++
-
±
+
++
++
++
++
+++
Risk of agranulocytosis! Regular
blood counts required.
Weight
gain.
No EPS
++
++
++
++
++
+++
Weight gain.
Without risk of
agranulocytosis,
No EPS
risperidone
-
++
++
++
++
+++
Weight gain.
sulpiride
-
+++
-
-
-
-
Increased prolactin (gynaecomastia)
quetiapine
-
+
+++
-
+
+
Weight gain. No EPS
aripiprazole
-
+++
PA
+
+
-
++
Fewer side effects [“Third
generation?“- dopamine stabilizers]
Antipsychotics
chlorpromazine
1st
generation
2nd
generation
H1
As chlorpromazine but fewer
antimuscarinic effects
Significant risk of EPS
(atypical)
EPS=extrapyramidal side effects, PA = partial agonist
Mechanism of action of antipsychotic drugs - summary

Antipsychotic drugs are antagonists or partial agonists at
D2 dopamine receptors, but most also block a variety of
other receptors.

Antipsychotic potency generally runs parallel to activity
on D2 receptors, but activities at other receptors (e.g. 5HT2A and muscarinic) may reduce extrapyramidal side
effects.


Activity at muscarininc, H1 and α receptors may determine
unwanted side effect profile.
Imaging studies suggest that therapeutic effect requires
about 80% occupancy of D2 receptors.
ANTIPSYCHOTICS: CURRENT AND FUTURE DEVELOPMENTS
Preclinical and preliminary clinical studies have
provided encouraging evidence that drugs
modifying activity of specific types of
metabotropic glutamate receptors
may improve positive and negative symptoms as
well as cognitive function in schizophrenia
ANTIDEPRESSANTS
Depression - symptoms
Emotional depressive mood, suicide ideas, feelings of guilt, …
Biological sleep disturbance, fatigue, psychosomatization
Mechanism of action
the monoamine theory
stimulation of neurogenesis, trophic effects
Mechanism of action
the monoamine theory
inhibition of reuptake of monoamines (NA, 5-HT)
IMAO
depletion of monoamines (reserpine)
MONOAMINE THEORY:
NERVE ENDING
(presynaptic)
SYNAPTIC
CLEFT
POSTSYNAPTIC
NEURON
↓ REUPTAKE
imipramin
↓ STORAGE
reserpin
Almost all antidepressants
increase supply of
monoamine transmitters at
postsynaptic receptors
↓ ELIMINATION
by MAO
moklobemid
↑RELEASE
amfetamin
Mechanism of action
stimulation of neurogenesis, trophic
effects
antidepressants increase production of BDNF („Brain-derivedneurotrophic-factor“)
preventing neurogenesis (e.g. by irradiation) prevents
antidepressive effects of antidepressants
chronic stress, corticoids > neuronal loss
ANTIDEPRESSANTS
CLASSIFICATION
Re-uptake inhibitors (RUI)
tricyclic (TCA) - amitriptyline, imipramine
SSRI – fluoxetine, sertraline, citalopram, escitalopram,
paroxetine …
Other e.g. SNRI venlafaxin …, St. John‘s wort
IMAO
irreversible
reversible (RIMA) – moclobemide
ANTIDEPRESSANTS
Individual differences [SSRI = „sixty seven responding individuals“]
Main Effects
Therapeutic antidepressive, anxiolytic (GAD, panic attacks …)
Adverse
TCA: antimuscarinic (dry mouth,blurred vision,constipation,urinary retention)
dangerous in acute overdose (cardiac dysrhytmias )
SSRI: sexual disorders, weight gain, inhibition of CYP2D6 (codeine),
serotonin syndrome (tremor, aggitation, diarhoea, tachycardia)
IMAO: food („cheese reaction“) and drug interactions
Antidepressive effects of antidepressants differ from those of
placebo only in medium and severe depressions
Kirsch I. a spol. PLoS Medicine 5 (2): 260-268,2008 www.plosmedicine.org
MOOD STABILIZERS
Prophylaxis and treatment of mania,
bipolar and unipolar disorder
Lithium –dose must be adjusted according to plasma
concentration! (narrow therapeutic window) !!!
Valproate
Carbamazepine