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Dopamine Hypothesis (of Schizophrenia)
Disorder caused by excess functional activity of DA in brain
- Based on:
- 1) Many antipsychotic drugs block DA receptors (esp. D2)
- 2) DA agonist drugs (amphetamine, levadopa) exacerbate schizophrenia
- 3) Increased density of DA receptors has been detected in certain brain regions of untreated schizos.
*Not fully satisfactory b/c antipsychotic drugs are only partially effective and other effective drugs have a higher affinity for other (including 5-HT) receptors.
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Blockage of D2 receptors causes
Extrapyramidal symptoms (Parkinson-like symptoms)
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Involuntary movement of the tongue, lips, neck, trunk and limbs. Tx?
Tardive dyskinesia
Tx= Increased antipsychotic drug dose (results in DA sensitization)
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D2 receptor type
G-coupled receptor (inhibitory)
*GI receptor: Inhibts due to blockage of ACh, cAMP/PKA pathway
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Name the Typical Antipsychotics
- Phenothiazines- Chloropromazine, Fluphenazine, Tifluperazine
- Thioxanthanes- Thioridazine
- Butyrophenones- Haloperidol
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Muscular rigidity, fever, altered mental status and stupor, impairment of sweating, unstable BP, and myoglobinemia
Neuroleptic Syndrome
*Can be fatal
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Neuroleptic Syndrome tx
- Withdraw drug immediately
- Administer either:
- Dantrolene
- Bromocriptine
- Diazepam
- DA Agonist
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All antipsychotics block A1 and H1 receptor to some extent except
Haloperidol (doesn't block H1, but still blocks A1)
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New Age Antipsychotic drugs act on
5-HT2 receptors
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Name the New Age Antipsychotic drugs
- Clozapine
- Olanzapine
- Quetiapine
- Risperidone
- Zipasidone
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Side effects of New Age Antipsychotics
- Endocrine and metabolic changes
- Obesity
- Diabetes
- Prolactin Release
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Most prominent for elevated prolactin levels
Risperidine
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Most prominent drugs for weight gain and hyperglycemia side effects
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New antipsychotic that can be used in pregnant women
Olanzapine
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Reserved for tx-resistant schizophrenia
Clozapine
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Causes hematotoxicity (agranulocytosis)
Clozapine
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Clozapine side effect
Hematotoxicity
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Side effects of this drug include gynecomastia, amenorrhea-galactorrhea syndrome, infertility
Risperidone (due to elevated prolactin levels)
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Two drugs that have QT prolongation and can produce Torsades de Pointes
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Lithium is affective for what phase of bipolar disorder
Manic
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Disadvantage of lithium
slow-onset
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Lithium: MoA
Inhibits the Phosphoinositol 2nd messenger cascade
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Lithium: Metabolism
- Excreted almost entirely in the urine
- Clearance Reduced by: Diuretics, NSAIDs, ACE inhibitors, Metronidazole (Ribosomal and Mitochondrial DNA)
- Clearance increased by: Acetazolamide, Alkalinizing agents, Urea, Xanthen preparations (including caffeine)
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Lithium: Adverse Effects
- Reversible Nephrogenic Diabetes Insipidus
- Thyroid Enlargment
- Ebstein's Anomaly in babies of nursing mothers
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Effective in lithium non-responders (now becoming 1st choice drug for BPD in the US)
Valproate
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Used in maintenance tx of bipolar disorder and can cause Stevens-Johnson Syndrome
Lamotrigine
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