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Antipsychotic drugs "lecture 4" (:<3: Dopaminergic System…
Antipsychotic drugs "lecture 4"
Schizophrenia in general
splitting in mental function
Diagnosis --> 2 or more of the following :
Delusions, hallucinations, disorganized speech, totally
disorganized behavior, negative symptoms
patient is unable to distinguish between his or her own thoughts and perceptions and those that he or she obtains by observing the external world
symptoms
1- positive symptoms
1-thought disturbances, 2-delusions, 3-hallucinations
2- negative symptoms
1-social withdrawal, 2-loss of drive, 3-rareness of speech, 4-impaired personal hygiene
3- cognition (mental action or process of acquiring knowledge and understanding through thought, experience, and the senses.)
1- new learning, 2-memory
4- mood symptoms
1-Loss of motivation, 2-Social withdrawal, 3-Insight, 4-Demoralization, 5-Suicide
etiology ( unclear )
:black_flag: Dopamine hypothesis
Increase in DA activity increases psychosis and vice versa
Evidence for the hypothesis
1- Increased density of dopamine receptors in the brains of
untreated schizophrenics --> the number of receptors in patient are more than the normal number
2- DA agonist make schizophrenia worse
DA receptors are GPCRs
Prognosis of Schizophrenia
1-10% continuous hospitalization
2- < 30% recovery = symptom-free for 5 years --> patient can be recovered but it could happen again after a period of time
3- 60% continued problems in living/episodic periods
Schizophrenia Pathophysiology
:<3: Dopaminergic System
Dopaminergic pathways: neural pathways in the brain which transmit the neurotransmitter dopamine from one region of the brain to another --> we have several pathways for DA
1-
Nigrostriatal pathway
__> Parkinson
2-
Mesolimbic pathway
__> MOOD & MOTIVATION --> increased DA transmission cause Schizophrinia
3-
Mesocortical pathway
__> EMOTION & BEHAVIOR --> reduced DA activity cause negative symptoms
4- Tuberoinfundibular pathway __> Prolactin release
5- Chemoreceptor triggor zone __> Emesis
modern treatment
Antipsychotic classification
1-
Typical
--> conventional, traditional neuroleptics, major tranquilizers
Low concentration of certain dopamine agonists can stereospecifically activate D2-type autoreceptors to decrease dopamine synthesis
Modeled on D2 antagonism __> act by blocking D2 receptors in both mesolimbic-mesocortical pathways as well as nigrostriatal pathways
D2 receptors are located postsynaptically as well as presynaptically (negatively modulate neuronal firing)
improves delusions and hallucinations (+ve symptoms), by causing calming, mood stabilization + Develop Parkinson like disease as a severe side effect
:warning: Adverse Effects
1- Reversible parkinsonism and dystonia ---> so decrease the dose
2- Potentially irreversible tardive dyskinesia --> no treatment + antimuscarinics increase severity
3- Autonomic effects
Muscarinic blockade __> dry mouth, constipation, urinary retention, visual problems
Alpha adrenergic receptor blockade __> postural hypotension
EXAMPLES:
:check: Phenothiazines
:check:Thioxanthenes
:check: Butyrophenones
2-
Atypical
--> novel, 2nd generation
Modeled on 5-HT2/D2 antagonism
act by a mechanism different than or in addition to blocking D2 receptors --> Ex. of other receptors: Adenosine (A2), histamine(H1), and serotonin (5-HT1A)
EXAMPLES:
:check: Benzamides & Benzapine Drvs
:check: Benzisoxazole & benzisothiazole Drvs
:check: Miscellaneous
It was proposed that D3-selective drugs might be developed as antipsychotic agents with preferential limbic antidopaminergic action while saving the extrapyramidal basal ganglia to reduce the neurologic movement disorder side effect
Antipsychotic AKA neuroleptics --> Antipsychotics ability to “quiet or hold neurological system”