pharmacology of antipsychotics...1
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Pharmacology of Antipsychotics
Douglas L. Geenens, D.O.
University Of Health Sciences College of Osteopathic Medicine
Douglas L. Geenens, D.O. 2000
Douglas L. Geenens, D.O. 2000
Dopamine Hypothesis
• Drugs that increase dopamine will enhance or produce positive psychotic symptoms– E.G. Cocaine, amphetamine
Douglas L. Geenens, D.O. 2000
• All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors– Esp..D-2 receptors
Dopamine Hypothesis
Douglas L. Geenens, D.O. 2000
Dopamine Pathways
• Mesolimbic
• Nigrostriatal
• Mesocortical
• Tuberoinfundibular
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Dopamine PathwaysMesolimbic
• Projects from brainstem to limbic areas.
• Overactivity produces delusions and hallucinations.
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Dopamine PathwaysNigrostriatal
• Projects from the substania nigra to the basal ganglia
– A part of the extrapyramidal system
– Thus side effects are called “extrapyramidal”
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Dopamine PathwaysNigrostriatal
• Controls movements
• The term “neuroleptics” refers to:
– Antipsychotics ability to “quiet the neurological system”
– To their neurological side effects
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Dopamine PathwaysNigrostriatal
• Types of movement disorders caused by this pathway include:– Akathisia
– Dystonia
– Tremor, rigidity, bradykinesia • Drug-induced Parkinsonism
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Dopamine PathwaysNigrostriatal
• Chronic blockade can cause
– Potentially irreversible movement disorder • “Tardive Dyskinesia”
• Role is undetermined
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Dopamine PathwaysMesocortical
• May be associated with both positive and negative symptoms
• Blockade may help reduce negative symptoms of schizophrenia
• May be involved in the cognitive side effects of antipsychotics “mind dulling”
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Dopamine PathwaysTuberoinfundibular
• Blockade produces galactorrhea
• Dopamine=PIF
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Dopamine PathwaysSummary
• Four dopamine pathways– Appears that blocking dopamine
receptors in only one of them is useful
• Blocking dopamine receptors in the other three may be harmful
Douglas L. Geenens, D.O. 2000
Douglas L. Geenens, D.O. 2000
Antipsychotics
• Phenothiazines (piperidines)– Mesoridazine
• Serentil– Thioridazine
• Mellaril
• Phenothiazines (Aliphatic)– Chlorpromazine
• Thorazine
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AntipsychoticsPhenothiazines (piperazines)
• Perphenazine – Trilafon
• Trifluoperazine – Stelazine
• Fluphenazine – Prolixin
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Antipsychotics
• Thioxanthenes– Navane
• Dibenzazepines– Clozapine
• Clozaril– Ioxapine
• Loxitane
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Antipsychotics
• Butyrophenones– Haloperidol
• Haldol
• Diphenylbutylpiperidines– Pimozide
• Orap
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Douglas L. Geenens, D.O. 2000
Antipsychotics
• Indoles– Molindone
• Moban
• Rauwolfia– Reserpine
• Serpasil
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Antipsychotics
• Benzisoxazole– Risperidone
• Risperdal
• Thienobenzodiazepines– Olanzapine
• Zyprexa
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AntipsychoticsEfficacy
• All antipsychotics are considered equally effective– Rationale for determining which medication
to use is based on side effect profile
• Primary mechanism of action is– Postsynaptic blockade of the D-2 receptor– “D-2, me too”
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AntipsychoticsEfficacy
• Newer agents– e.g. Clozaril
– Have significant activity at the D-1 receptor;
– Risperdal and Zyprexa have significant 5-HT2 activity
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AntipsychoticsPotency
• Potency is an important variable in terms of pharmacodynamic properties of these medicines.
• Potency determines the predictable side effects of the antipsychotics.
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AntipsychoticsPotency
• Low potency medications cause more:– sedation– Anti-ACH– Orthostatic hypotension
• High potency medications cause more:– EPS
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Dopaminergic D2 Blockade
Possible Clinical Consequences• Extrapyramidal movement
disorders
• Endocrine changes
• Sexual dysfunction
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AntipsychoticsRelative potencies (mg
equivalents)
0
20
40
60
80
100 chlorpromazine(Thorazine)
thioridazine(Mellaril)mesoridazine(Serentil)
loxapine(Loxitane)
molindone(Moban)thiothixene(Navane)
trifluoperazine(Stelazine)
haloperidol(Haldol)fluphenazine(Prolixin)
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Histamine H1 BlockadePossible Clinical Consequences
• Sedation, drowsiness
• Weight gain
• Hypotension
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AntipsychoticsPotency for H-1 blockade
0 5 10 15 20 25
chlorpromazine(Thorazine)
thioridazine(Mellaril)
loxapine(Loxitane)
molindone(Moban)
trifluoperazine(Stelazine)
fluphenazine(Prolixin)
haloperidol(Haldol)
haloperid 0.025
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Alpha-1 receptor blockadePossible clinical consequences
• Postural hypotension
• Reflex tachycardia
• Dizziness
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0
5
10
15
20
25
30
35
40chlorpromazine(Thorazine)
thioridazine(Mellaril)
loxapine(Loxitane)
molindone(Moban)
trifluoperazine(Stelazine)
fluphenazine(Prolixin)
haloperidol(Haldol)
AntipsychoticsPotency for alpha-1 blockade
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Muscarinic receptor blockade
Possible clinical consequences• Blurred vision
• Dry mouth
• Sinus tachycardia
• Constipation
• Urinary retention
• Memory dysfunction
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AntipsychoticsPotency for muscarinic blockade
0
1
2
3
4
5
6
Series 1
chlorpromazine(Thorazine)
thioridazine(Mellaril)
loxapine(Loxitane)
molindone(Moban)
trifluoperazine(Stelazine)
fluphenazine(Prolixin)
haloperidol(Haldol)
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Douglas L. Geenens, D.O. 2000
ClozarilClozapine
• “Atypical” antipsychotic
• More effective in person’s who fail typical antipsychotic therapy
• At least nine different receptor affinities
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ClozarilClozapine
• One of the most complicated medications in psychopharmacology
• Can cause death via agranulocytosis
• Cost is typically $10,000.00 per year
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Extrapyramidal Symptoms
Dopamine Vs Acetylcholine• Dopamine and Acetylcholine have
a reciprocal relationship in the Nigrostriatal pathway.
• A delicate balance allows for normal movement.
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Extrapyramidal Symptoms
Dopamine Vs Acetylcholine
• Dopamine blockade:
• A relative increase in cholinergic activity– causing EPS
– Those antipsychotics that have significant anti-ACH activity are therefore less likely to cause EPS
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Extrapyramidal Symptoms
Dopamine Vs Acetylcholine• When high potency antipsychotics
are chosen, we often prescribe anti-ACH medication like
– Cogentin, diphenhydramine, or Artane
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Tardive Dyskinesia
• Associated with long-term use of antipsychotics– (chronic dopamine blockade)
• Potentially irreversible involuntary movements around the buccal-lingual-oral area
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Tardive Dyskinesia
• Attempt of decrease dose– will initially exacerbate the
movements
• Increasing the dose will initially decrease the movements
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Neurological Side Effects:
• Dystonic Reactions:– Uncoordinated spastic movements of
muscle groups• Trunk, tongue, face
• Akinesia:– Decreased muscular movements
• Rigidity:– Coarse muscular movement– Loss of facial expression
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Neurological Side Effects:
• Tremors:– Fine movement (shaking) of the extremities
• Akathisia:– Restlessness – Pacing
• May result in insomnia
• Tardive Dyskinesia:– Buccolinguo-masticalory syndrome– Choreoathetoid movements
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Neurological Side Effects of Neuroleptics
3 6 9 12 15
A: DystonicReactions
B: Akinesia
C: Rigidity
D: Tremors
E: Akathisia
F: TardiveDykinesia
Neurological Effects
Neurological Effects
Tardive Dyskinesia
Onset Acute or insidiousWithin 1 – 30 days
After months or years of treatment, especially if drug dose decreased or discontinued
Proposed Mechanism
Due to decreased dopamine
Supersensitivity of postsynaptic dopamine receptors induced by long term neuroleptic blockade
Treatment Respond to antiparkinsonian drugs
Generally worsen Tardive DyskinesiaOther treatments unsatisfactory; some aimed at balancing Dopaminergic and cholinergic systems. Can mask symptoms by further suppressing dopamine with neuroleptics. Pimozide or loxapine may least aggravate Tardive Dyskinesia.
Extrapyramidal Effects
Type Onset Risk Group
Clinical Course
Treatment
Dystonias Acute (within 5 days)
Young male Acute, painful, spasmodic Oculogyria may be recurrent
I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used
Akathisia Insidious to acute (within 10 days)
12-45% on neuroleptics
May continue though out treatment
I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used
Pseudoparkinsonism Insidious to acute (within 30 days)
12-45% on neuroleptics
May continue through treatment
Oral antiparkinsonian drug. Reduce or change neuroleptic
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Neuroleptic Malignant Syndrome
• An idiosyncratic, life-threatening illness associated with antipsychotic therapy
• Clinical manifestations include– hyperpyrexia – autonomic instability, – “board-like” rigidity
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Neuroleptic Malignant Syndrome
• Resembles malignant hyperthermia associated with
anesthesia
• Treatment involves – Immediate discontinuation of
antipsychotic – Hydration– Maintain vital functions – Prescribe bromocriptine and
dantrolene
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