Transcript CATECHOLAMINES - Drexel University College of Medicine

Antipsychotics
John A. Harvey, Ph.D.
Department of Pharmacology and
Physiology
Neurobiology of Schizophrenia
Schizophrenia represents a major mental illness, or possibly a group of
Illnesses, manifested chiefly by disordered thought processes including
disturbances in attention and associations. This leads to difficulties in
communication, interpersonal relationships and reality testing. Studies
Indicate that schizophrenia occurs 4-times more frequently among
biological relatives than in the general population.
Positive Symptoms
Negative Symptoms
Development of Abnormal Functions
Reduction or Loss of Normal Functions
1. Delusions
2. Hallucinations
3. Disorganized Speech
4. Catatonic Behavior
1. Affective Flattening
2. Avolition
3. Attentional Deficits
Psychiatric Uses Of Antipsychotic Drugs
1. Schizophrenia: Acute and Chronic Maintenance
2. Psychotic Depression (With Antidepressants)
3. Acute Mania (With Lithium)
4. Autism (For Control of Aggressive Behaviors)
5. Gilles de la Tourette’s Syndrome – Chronic Tics
6. Severe Agitation In Mentally Retarded and In
Alzheimer’s Patients
Pharmacological Actions of Antipsychotics At
CNS Receptors
• Dopamine: Antagonists at D2 or Partial Agonist at D2
(aripiprazole)
• Serotonin: Antagonists at 5-HT2A
• Histamine: Antagonists at H1
• Cholinergic: Antagonists at muscarinic M1-4
• Noradrenergic: Antagonists at α1
Therapeutic Targets of Antipsychotics
• Dopamine: Antagonists at D2
• Serotonin: Antagonists at 5-HT2A
Signal Transduction via
Dopamine Receptors
D2 D3 D4
D1
D5
Gs/q
E
Gi
Second Messengers
Trophic Actions:
Neuronal Morphology
Synaptic Plasticity
Gene Expression
Physiological
Responses
5-HT2 Receptor Signaling
Ligands
2A
2C
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Phospholipids
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q/11ß
PLC
IP + DG
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Typical Antipsychotics Have Antagonist Actions That Are
Greater for the Dopamine D2 Than the 5-HT2A Receptor
Phenothiazines & Derivatives
Chlorpromazine
Thioridazine
Fluphenazine
Perphenazine
Butyrophenones
Haloperidol
A Newer Antipsychotic Is a Partial Agonist at the
Dopamine D2 Receptor And A Serotonin 5-HT2A
Receptor Antagonist
Aripiprazole
Atypical Antipsychotics Have Antagonist Actions
that are Greater for 5-HT2A than D2
Risperidone
Olanzapine
Quetiapine
Clozapine
Ziprasidone
A Newer Antipsychotic Is a Partial Agonist at the
Dopamine D2 Receptor And A Serotonin 5-HT2A
Receptor Antagonist
Aripiprazole
Dopamine
Agonist
DA
Large Effect
Large Effect
DA
Antagonist
No Effect
DA
Partial
Agonist
Aripiprazole
Small Effect
Dopamine Hypothesis Of Schizophrenia: An
Increase in Dopaminergic Activity in CNS
1. All Antipsychotics are DA Receptor Antagonists
2. Therapeutic effects correlated with D2 affinity
3. Dopamine Agonists (e.g., Amphetamines) Exacerbate
Schizophrenic Symptoms at Low Doses
4. Higher Doses of Amphetamines Induce Paranoid
Psychotic Reactions in Normal Individuals
5. Evidence of Changes in Dopamine Receptors in
Schizophrenia is Still Controversial
Decreasing affinity
The therapeutic dose of antipsychotics is related to
dopamine D2 receptor antagonism
Increasing dose of drug
Cognitive deficits can be due to too little
as well as too much
receptor activation
2D Graph 1
Y Data
Level of Cognitive Functioning
100
Normal
80
Psychosis
60
40
20
0
0
2
4
6
8
X Data Activation
DA Receptor
Col 1 vs Col 2
10
Dopamine Projection Pathways
1. Neostriatal – Caudate/Putamen – Regulates Motor Function
2. Mesolimbic – Nucleus Accumbens and Amygdala – Regulates
Emotions
3. Mesocortical – Limbic Cortex – Regulates Attention/Cognition
4. Tuberohypophysial – Arcuate Nucleus – Regulates Prolactin Release
Blockade of Dopamine D2 Receptors
• Emotion - Reduces expression of emotion
• Cognitive functions – Decreases cognitive
processes in prefrontal cortex
• Motor functions – Produces akinesia and
symptoms of Parkinsonism
• Endocrine function – Produces increased
release of prolactin
The New England Journal of Medicine
Established in 1812
September 22, 2005, Vol. 353 no. 12
Effectiveness of Antipsychotic Drugs in Patients with
Chronic Schizophrenia
Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy,
M.D., Marvin S. Swartz, M.D., Robert A. Rosenheck, M.D., Diana O. Perkins,
M.D., M.P.H., Richard S.E. Keefe, Ph.D., Sonia M. Davis, Dr.P.H., Clarence E.
Davis, Ph.D., Barry D. Lebowitz, Ph.D., Joanne Severe, M.S., and John K.
Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) Investigators*
Conclusions
• The majority of patients in each group discontinued their
assigned treatment owing to inefficacy or intolerable side
effects or for other reasons.
• Olanzapine was the most effective in terms of the rates
of discontinuation, however it was associated with greater
weight gain and increases in measures of glucose and
lipid metabolism.
• The efficacy of the typical antipsychotic agent
perphenazine appeared similar to that of the atypical
antipsychotics, quetiapine, risperidone, and ziprasidone.
• Although atypical antipsychotics tended to have less
extrapyramidal effects they were not free of them.
Typical Antipsychotics Have Antagonist Actions That Are
Greater for the Dopamine D2 Than the 5-HT2A Receptor
Phenothiazines & Derivatives
Chlorpromazine: First drug
Thioridazine:
Fluphenazine
Perphenazine: Equally Effective with Atypicals
Butyrophenones
Haloperidol: Still Widely Used
Atypical Antipsychotics Have Antagonist Actions
that are Equal or Greater for 5-HT2A than D2
Risperidone: Widely Used
Olanzapine: Well tolerated but greater weight gain
Quetiapine
Clozapine: Agranulocytosis in 2% of patients
Drug
Weight
Gain
Risk for Worsening
Diabetes Lipid
Profile
Clozapine
+++
+
+
Olanzapine
+++
+
+
Risperidone
++
±
±
Quetiapine
++
±
±
Aripiprazole
±
-
-
Ziprasidone
±
-
-
Absorption and Distribution
• Readily but incompletely absorbed
• Significant first-pass metabolism
• Highly lipid soluble and protein bound
• Large volume of distribution
• Long clinical duration (e.g., 6 weeks or more to full relapse)
Metqbolism
• Cytochrome P450 Enzymes
CYP 3A4: Inhibitors are erythromycin, fluvoxamine
Inducers are carbamazepine, phenytoin, phenobarbital
CYP 2D6: Inhibitors are buproprion, fluoxetine, paroxetine, quinidine
CYP 1A2: Inhibitors are fluvoxamine, omeprazole
Metabolism
Thioridazine metabolized to more potent compound –
mesoridazine
Aripiprazole metabolized to active compound dehydroaripiprazole with a half-life of 96 hours
Clozapine metabolized to active compound
N-desmethylclozapine
Excretion
Little excreted unchanged
Adverse Effects of Antipsychotics At CNS
Receptors
• Dopamine: Antagonists at D2
• Serotonin: Antagonists at 5-HT2A
• Histamine: Antagonists at H1
• Cholinergic: Antagonists at muscarinic M1
• Noradrenergic: Antagonists at α1
Adverse Pharmacologic Effects of Antipsychotic Drugs
Type
Manifestations
Mechanism
Autonomic
nervous
system
Loss of accommodation, dry mouth,
difficulty urinating, constipation
Orthostatic hypotension, failure to
ejaculate
Hypotension, arrhythmia
Muscarinic blockade
Central
nervous
system
Parkinson’s syndrome, acute
akathisia(motor restlessness),
acute dystonia (spasm of tongue,
face, neck)
Tardive dyskinesia, tardive dystonia
(choreoathetoid movements or
dystonia)
Toxic-confusional state
Sedation
Dopamine receptor
blockade (Early
Onset)
Endocrine
system
Amenorrhea-galactorrhea, infertility,
impotence
Dopamine receptor
blockade resulting in
hyperprolactinemia
Miscellaneo
us
Neuroleptic malignant syndrome
Not known
Alpha1adrenoreceptor
blockade
Antiadrenergic
Supersensitivity of
dopamine receptors
(Late Onset)
Muscarinic blockade
Antihistaminergic
Sites of production of extra
pyramidal signs by
antipsychotic drugs and
1. DA receptor blockade by
antipsychotics and actions
of D2 agonist bromocriptine
and D1/D2 agonist pergolide
2. Antimuscarinic effect of
benztropine
Glu = glutamate
Ach = acetylcholine
GABA = γ-aminobutyric acid
DA = dopamine
+ = excitatory synapse
▬ = inhibitory synapse
Circuitry for Extrapyramidal
Control of Movement
Side
Effects
Drug
Chemical Class
CPZ
Equi
v
DA2
Affinity
Ch-M
Affinity
Adr1
Affinity
Low potency
Chlorpromazine
Thorazine
Aliphatic
phenothiazine
100
+
+++
+++
Thioridazine
Mellaril
Piperidine
phenothiazine
100
+
+++
+++
Midpotency
Perphenazine
Trilafon
Piperazine
Phenothiazine
8
++
++
++
10
++
++
++
2
+++
-
+
Loxapine
Loxitane
Dibenzoxazepine
Extrapyramidal
I
n
c
r
e
a
s
i
n
g
S
e
v
e
r
it
y
Anticholinergic
Sedation
Hypotension
I
n
c
r
e
a
s
i
n
g
S
e
v
e
r
it
y
Different Antipsychotics Ranked by Functional Class
High potency
Haloperidol
Haldol
Butyrophenone
Fluphenazine
Prolixin
Piperazine
phenothiazine
2
+++
-
+
Dibenzodiazepine
80
+
+++
++
Very
Low
High
2
++
-
++
Low
Low
Atypical
Clozapine
Clozaril
Risperidone
Risperdal
Benzisoxazole
THE END