Exam 2 ( Antipsychotics)
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A9 nigrostriatal DA neurons
originate in substantia nigra pars compacta dendrites extend into pars reticulata. axons innervate corpus striatum DA release in striatum essential for normal extrapyramidal motor function
A10 mesolimbic DA neurons
originate in midbrain ventral tegmental area (VTA) axons innervate limbic portions of striatum (nucleus accumbens) and cortex DA release from these neurons important for normal affect, orderly thinking, “drive” states, pleasure and reward
D1 vs D2 receptor
D1 = short 3rd intracellular loop, long carboxyl tail D2 = long 3rd intracellular loop, short carboxyl tail
Epidemiology of schizophrenia
1st presents between ages 16 - 20 yr old 1-3% pop overall genetic predisposition, genetic component probably affected by multiple genes both neurochemical (nature) and environmental factors (nurture) likely to contribute to development of disease
Organic psychoses
cause is known, due to impaired cerebral tissue function; cognitive and intellectual decline can be secondary to drug abuse, metabolic or toxic insult, trauma, infections, or structural disease of the nervous system
Dopamine theory of schizophrenia
cause is postulated to be excessive DA transmission, especially within the limbic striatum and limbic cortical areas innervated by A10 DA neurons (mesolimbic and mesocortical DA pathways)
Idiopathic psychoses
cause not known, may have a genetic component. schizophrenia denotes a form of idiopathic psychosis
Positive symptoms
hallucinations, usually auditory (voices talking to patient) delusions (false beliefs), grandiosity, paranoia disorganized thinking, speech; tangential thinking, “word salad” bizarre behavior, catatonia
Negative symptoms
affective (emotional) flattening withdrawal, depersonalization, asociality poverty of speech and thought anhedonia, loss of motivation
Cognitive symptoms
impaired attention, deficits in learning and memory
D2 like family
D2, D3, D4
D1 like family
D1 and D5
D1 receptors
lead to stimulation of adenylate cyclase and increase cAMP Affinity for phenothiazines > butyrophenones
D2 receptor
not associated with stimulation of adenylate cyclase and may inhibit it. Affinity for butyrophenones > phenothiazines
Typical
blockade at D2 receptors > 5-HT2A receptors; antipsychotic potency correlates strongly with D2 receptor blockade Phenothiazine derivatives Thioxanthene derivatives Butyrophenone derivatives Miscellaneous “typical” antipsychotic drugs
Atypical
blockade at 5-HT2A receptors > D2 receptors Loxapine Clozapine Risperidone Quetiapine Olanzapine Ziprasidone Aripiprazole
Manifestation: Loss of accommodation, dry mouth, difficulty urinating, constipation
Mechanism: Muscarinic cholinoreceptor blockade ANS
Manifestation: Parkinson’s syndrome, akathisia, dystonias
Mechanism: Dopamine-receptor blockade CNS
Manifestation: Tardive dyskinesia
Mechanism: Supersensitivity of dopamine receptors CNS
Manifestation: Orthostatic hypotension, impotence, failure to ejaculate
Mechanism: α-Adrenoceptor blockade ANS
Manifestation: Toxic-confusional state
Mechanism: Muscarinic blockade CNS
Manifestation: Amenorrhea-galactorrhea, infertility, impotence
Mechanism: Dopamine-receptor blockade resilient in hyperprolactinemia Endocrine System
Manifestation: Weight Gain
Mechanism: Possibly combined H1 and 5-HT2 blockade
Clozapine (dibenzodiazepine)
1st effective antipsychotic without extrapyramidal side-effects may suppress tardive dyskinesia due to other agents reduces positive and negative symptoms blocks many receptors most serious side effect: agranulocytosis other side effects: hypercholesterolemia, weight gain, diabetes