The Teeter-Totter Effect Dopamine and Acetylcholine http://www.toonvectors.com/clip-art/cartoon-business-teeter-tott
Dec 14, 2015
The Teeter-Totter EffectDopamine and Acetylcholine
http://www.toonvectors.com/clip-art/cartoon-business-teeter-totter/11037
In the treatment of psychiatric conditions like schizophrenia, there is a delicate balance between the neurotransmitters in the central nervous system▫Including: dopamine (DA), acetylcholine
(ACh), and serotonin (5-HT)
When there is ↑DA or ↓ ACh in the brain, patients may show signs of psychosis or delirium
http://www.medscape.org/viewarticle/585155
Increased DA in the mesolimbic dopamine tract = positive symptoms associated with schizophrenia including:
- Delusions - Bizarre behavior- Hallucinations - Disorganized thinking
Normal = Balance between ACh and DA in the central nervous system
Treatment goal with antipsychotics = restore the balance of dopamine
DAACh
Increased DA in the mesolimbic dopamine tract = positive symptoms of schizoprenia
ACh
DA
DAACh
However, an unwanted consequence of potent D2 antagonism in the nigrostriatal dopamine tract = pseudo-parkinsonismAs DA decreases, this causes an increase in ACh
Mild extrapyradimal side effects (EPS) such as pseudo-parkinsonism can actually be treated with anticholinergics such as:benztropine, diphenhydramine, or trihexyphenidyl ACh
DA
DA
ACh
HOWEVER: excess blockade of ACh (ie: using several anticholinergics) can shift the ACh/DA balance. This may lead to confusion, delirium, hallucinations, and agitation otherwise known as “mad as a hatter”
Therefore: anticholinergic medications (especially in combination) May Increase the Risk of Psychosis• Antihistamines
▫Diphenhydramine
• Tricyclic antidepressants
• Antispasmodics▫Oxybutynin
• Benztropine
• Trihexyphendiyl
• Amantadine
• Metoclopramide
• Antiemetics▫Prochlorperzine▫Promethazine▫Scopolamine
Antipsychotics•First generation antipsychotics
▫D2 receptor antagonists Examples: haloperidol, chlorpromazine,
fluphenazine, perphenazine, thiothixene
• Second generation antipsychotic
▫D2 antagonist + 5-HT2 antagonist Examples: ziprasidone,
olanzapine, aripirazole, quetiapine, risperidone
Risk of EPS With Antipsychotics(proportional to D2 blockade)
• High risk – Fluphenazine– Haloperidol– Perphenazine– Thiothixene
• Moderately high– Chlorpromazine– Thioridazine
• Moderate risk– Asenapine– Olanzapine– Paliperidone– Risperidone– Ziprasidone
• Low– Aripiprazole– Clozapine– Quetiapine
**If pseudo-parkinsonism occurs with a second generation antipsychotic (atypical antipsychotic), consider switching to quetiapine, aripiprazole, or clozapine**
Antipsychotics: adverse effects due to multi-receptor antagonism Dopamine EPS, increased prolactin,
sexual dysfunction
Muscarinic Anticholinergic effects
Histamine Sedation, weight gain
Alpha-1 Orthostatic hypotension, dizziness
Each antipsychotic agent differs in its affinity for each of these receptors
The degree of adverse effects are different for each antipsychotic depending on receptor affinity…Here are some examples
Adverse Effects of Typical (1st Generation) Antipsychotics
High Potentcy(ie: haloperidol)
Low potency (ie: chlorpromazine)
Sedation + +++
EPS ++++ ++
Anticholinergic + +++
Weight gain 0 +++
Prolactin increase +++ +++
Orthostasis + +++
QT prolongation ++ ++++(only Thioridazine)
Unique Bonus Voted most likely to cause Parkinson's
Corneal depositsCholestatis
Too many to list!
+4 to 0 = highest risk to lowest risk
Adverse Effects of Atypical (2nd Generation) Antipsychotics
Clozapine Risperidone Olanzapine
Sedation +++ + ++EPS 0 +++
(esp. at higher doses)
+
Anticholinergic +++ 0 + to ++
Weight gain ++++ ++ ++++
Prolactin increase + ++++ ++
Orthostasis +++ +++ ++
QT prolongation +(possibly dose-
dependent)
++ ++
Unique Bonus Agranulocytosis, seizures Got milk? Diabetes anyone?
+4 to 0 = highest risk to lowest risk
Adverse Effects of Atypical (2nd Generation) Antipsychotics
Quetiapine Ziprasidone Aripirazole
Sedation +++ ++ ++
EPS +/- + +/-Insufficient data to compare
Anticholinergic 0 to + + +
Weight gain ++ 0 0
Prolactin increase + ++ 0
Orthostasis ++ + to ++ + to ++
QT prolongation ++ +++ 0
Unique Bonus HTN EPS is probably low risk except - Akathisia
Tardive dyskinesia
1st Gen Typicals> 2nd Gen Atypicals > Clozapine
+4 to 0 = highest risk to lowest risk
What about the other symptoms associated with schizophrenia?
Negative symptoms = decreased DA in the mesocorticol dopamine tract
http://www.medscape.org/viewarticle/585155
Negative symptoms include:- Poverty of speech- Blunted affect- Withdrawal- Apathy
Hey ! If negative symptoms are associated with less dopamine how do antispychotics (DA antagonists) help?? •Atypical Antipsychotics also block 5-HT2A receptors
▫May increase DA in the mesocortical tract ▫Without eliminating the antipsychotic effect in the
mesolimbic tract
▫In the nigrostriatal tract (remember pseudo-parkinsonism?), it is thought to reverse enough D2 antagonism to reduce EPS
And THAT my friends…….
Is the Teeter-Totter Effect of Dopamine and Acetylcholine
http://www.toonvectors.com/clip-art/cartoon-business-teeter-totter/11037
References1. Crismon ML, Argo TR, Buckly PF. “Chapter 76. Schizophrenia” (Chapter). DiPiro JT,
Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 8e. Retrieved January 16, 2013 from: http://0-www.accesspharmacy.com.libcat.ferris.edu/content.aspx?aID=7987911
2. Josephson SA, Miller BL. “Chapter 25. Confusion and Delirium” (Chapter). In Fauci AS, Kasper DL, Jameson JL, Longo DL, Hauser SL, eds. Harrison’s Principles of Internal Medicine, 18e. Retrieved January 16, 2013 from http://0-www.accesspharmacy.com.libcat.ferris.edu/content.aspx?aID=9096335.
3. DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995 – .[cited 2013 Jan 16]. Available from http://www.ebscohost.com/DynaMed/.
4. Kopala LC, Meltzer HY, Meyer JM, Stahl SM. Are all atypical antipsychotics equal for the treatment of cognition and affect in schizophrenia? Medscape, LLC. 1994-2013. Accessed 2012 Jan 16. Available from: http://www.medscape.org/viewarticle/484929
5. Buchanan RW, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010 Jan;36(1):71-93.