pharmacology of antipsychotics dr andrew p mallon
TRANSCRIPT
![Page 1: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/1.jpg)
Pharmacology of Antipsychotics
Dr Andrew P Mallon
![Page 2: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/2.jpg)
Douglas L. Geenens, D.O. 2000
![Page 3: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/3.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine Hypothesis
• Drugs that increase dopamine will enhance or produce positive psychotic symptoms– E.G. Cocaine, amphetamine
![Page 4: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/4.jpg)
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
![Page 5: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/5.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine Pathways
• Mesolimbic
• Nigrostriatal
• Mesocortical
• Tuberoinfundibular
![Page 6: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/6.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysMesolimbic
• Projects from brainstem to limbic areas.
• Overactivity produces delusions and hallucinations.
![Page 7: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/7.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysNigrostriatal
• Projects from the substania nigra to the basal ganglia
– A part of the extrapyramidal system
– Thus side effects are called “extrapyramidal”
![Page 8: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/8.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysNigrostriatal
• Controls movements
• The term “neuroleptics” refers to:
– Antipsychotics ability to “quiet the neurological system”
– To their neurological side effects
![Page 9: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/9.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysNigrostriatal
• Types of movement disorders caused by this pathway include:– Akathisia
– Dystonia
– Tremor, rigidity, bradykinesia • Drug-induced Parkinsonism
![Page 10: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/10.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysNigrostriatal
• Chronic blockade can cause
– Potentially irreversible movement disorder • “Tardive Dyskinesia”
• Role is undetermined
![Page 11: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/11.jpg)
Douglas L. Geenens, D.O. 2000
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”
![Page 12: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/12.jpg)
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysTuberoinfundibular
• Blockade produces galactorrhea
• Dopamine=PIF
![Page 13: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/13.jpg)
Douglas L. Geenens, D.O. 2000
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
![Page 14: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/14.jpg)
Douglas L. Geenens, D.O. 2000
![Page 15: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/15.jpg)
Douglas L. Geenens, D.O. 2000
Antipsychotics
• Phenothiazines (piperidines)– Mesoridazine
• Serentil
– Thioridazine • Mellaril
• Phenothiazines (Aliphatic)– Chlorpromazine
• Thorazine
![Page 16: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/16.jpg)
Douglas L. Geenens, D.O. 2000
AntipsychoticsPhenothiazines (piperazines)
• Perphenazine – Trilafon
• Trifluoperazine – Stelazine
• Fluphenazine – Prolixin
![Page 17: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/17.jpg)
Douglas L. Geenens, D.O. 2000
Antipsychotics
• Thioxanthenes– Navane
• Dibenzazepines– Clozapine
• Clozaril
– Ioxapine • Loxitane
![Page 18: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/18.jpg)
Douglas L. Geenens, D.O. 2000
Antipsychotics
• Butyrophenones– Haloperidol
• Haldol
• Diphenylbutylpiperidines– Pimozide
• Orap
![Page 19: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/19.jpg)
Douglas L. Geenens, D.O. 2000
![Page 20: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/20.jpg)
Douglas L. Geenens, D.O. 2000
Antipsychotics
• Indoles– Molindone
• Moban
• Rauwolfia– Reserpine
• Serpasil
![Page 21: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/21.jpg)
Douglas L. Geenens, D.O. 2000
Antipsychotics
• Benzisoxazole– Risperidone
• Risperdal
• Thienobenzodiazepines– Olanzapine
• Zyprexa
![Page 22: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/22.jpg)
Douglas L. Geenens, D.O. 2000
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”
![Page 23: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/23.jpg)
Douglas L. Geenens, D.O. 2000
AntipsychoticsEfficacy
• Newer agents– e.g. Clozaril
– Have significant activity at the D-1 receptor;
– Risperdal and Zyprexa have significant 5-HT2 activity
![Page 24: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/24.jpg)
Douglas L. Geenens, D.O. 2000
AntipsychoticsPotency
• Potency is an important variable in terms of pharmacodynamic properties of these medicines.
• Potency determines the predictable side effects of the antipsychotics.
![Page 25: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/25.jpg)
Douglas L. Geenens, D.O. 2000
AntipsychoticsPotency
• Low potency medications cause more:– sedation– Anti-ACH– Orthostatic hypotension
• High potency medications cause more:– EPS
![Page 26: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/26.jpg)
Douglas L. Geenens, D.O. 2000
Dopaminergic D2 Blockade
Possible Clinical Consequences• Extrapyramidal movement
disorders
• Endocrine changes
• Sexual dysfunction
![Page 27: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/27.jpg)
Douglas L. Geenens, D.O. 2000
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)
![Page 28: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/28.jpg)
Douglas L. Geenens, D.O. 2000
Histamine H1 BlockadePossible Clinical Consequences
• Sedation, drowsiness
• Weight gain
• Hypotension
![Page 29: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/29.jpg)
Douglas L. Geenens, D.O. 2000
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
![Page 30: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/30.jpg)
Douglas L. Geenens, D.O. 2000
Alpha-1 receptor blockadePossible clinical consequences
• Postural hypotension
• Reflex tachycardia
• Dizziness
![Page 31: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/31.jpg)
Douglas L. Geenens, D.O. 2000
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
![Page 32: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/32.jpg)
Douglas L. Geenens, D.O. 2000
Muscarinic receptor blockade
Possible clinical consequences• Blurred vision
• Dry mouth
• Sinus tachycardia
• Constipation
• Urinary retention
• Memory dysfunction
![Page 33: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/33.jpg)
Douglas L. Geenens, D.O. 2000
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)
![Page 34: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/34.jpg)
Douglas L. Geenens, D.O. 2000
![Page 35: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/35.jpg)
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
![Page 36: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/36.jpg)
Douglas L. Geenens, D.O. 2000
ClozarilClozapine
• One of the most complicated medications in psychopharmacology
• Can cause death via agranulocytosis
• Cost is typically $10,000.00 per year
![Page 37: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/37.jpg)
Douglas L. Geenens, D.O. 2000
Extrapyramidal Symptoms
Dopamine Vs Acetylcholine• Dopamine and Acetylcholine have
a reciprocal relationship in the Nigrostriatal pathway.
• A delicate balance allows for normal movement.
![Page 38: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/38.jpg)
Douglas L. Geenens, D.O. 2000
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
![Page 39: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/39.jpg)
Douglas L. Geenens, D.O. 2000
Extrapyramidal Symptoms
Dopamine Vs Acetylcholine• When high potency antipsychotics
are chosen, we often prescribe anti-ACH medication like
– Cogentin, diphenhydramine, or Artane
![Page 40: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/40.jpg)
Douglas L. Geenens, D.O. 2000
Tardive Dyskinesia
• Associated with long-term use of antipsychotics– (chronic dopamine blockade)
• Potentially irreversible involuntary movements around the buccal-lingual-oral area
![Page 41: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/41.jpg)
Douglas L. Geenens, D.O. 2000
Tardive Dyskinesia
• Attempt of decrease dose– will initially exacerbate the
movements
• Increasing the dose will initially decrease the movements
![Page 42: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/42.jpg)
Douglas L. Geenens, D.O. 2000
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
![Page 43: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/43.jpg)
Douglas L. Geenens, D.O. 2000
Neurological Side Effects:
• Tremors:– Fine movement (shaking) of the extremities
• Akathisia:– Restlessness – Pacing
• May result in insomnia
• Tardive Dyskinesia:– Buccolinguo-masticalory syndrome– Choreoathetoid movements
![Page 44: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/44.jpg)
Douglas L. Geenens, D.O. 2000
Neurological Side Effects of Neuroleptics
3 6 9 12 15
A: DystonicReactions
B: Akinesia
C: Rigidity
D: Tremors
E: Akathisia
F: TardiveDykinesia
![Page 45: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/45.jpg)
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.
![Page 46: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/46.jpg)
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
![Page 47: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/47.jpg)
Douglas L. Geenens, D.O. 2000
Neuroleptic Malignant Syndrome
• An idiosyncratic, life-threatening illness associated with antipsychotic
therapy
• Clinical manifestations include– hyperpyrexia – autonomic instability, – “board-like” rigidity
![Page 48: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/48.jpg)
Douglas L. Geenens, D.O. 2000
Neuroleptic Malignant Syndrome
• Resembles malignant hyperthermia associated with anesthesia
• Treatment involves – Immediate discontinuation of
antipsychotic – Hydration– Maintain vital functions – Prescribe bromocriptine and dantrolene
![Page 49: Pharmacology of Antipsychotics Dr Andrew P Mallon](https://reader034.vdocuments.us/reader034/viewer/2022051000/56649f2a5503460f94c44a22/html5/thumbnails/49.jpg)
Douglas L. Geenens, D.O. 2000