pharmacology of psychosis Flashcards
Explain the dopamine theory of schizophrenia and its limitations.
Abnormality of brain function in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in the mesolimbic pathway.
mesolimbic pathway normal function
integration of sensory input and motor responses with affective or emotional data.
mesocortical pathway normal function
communication and social abilities.
factors supporting and against dopamine theory of schizophrenia
supporting: Virtually all antipsychotic drugs block dopamine D2 receptors. Drugs that increase dopaminergic activity produce or aggravate psychosis. Against: Block of D2 is immediate but onset of psychosis improvement takes 3-6 weeks.
supporting: Virtually all antipsychotic drugs block dopamine D2 receptors. Drugs that increase dopaminergic activity produce or aggravate psychosis. Against: Block of D2 is immediate but onset of psychosis improvement takes 3-6 weeks.
Describe the mechanism of antipsychotic drug action, including a description of brain dopamine systems affected.
Antipsychotics block dopamine D2 receptors. The main dopamine system affected is the mesolimbic pathway (hyperactivity leads to positive symptoms). Antipsychotics block these positive symptoms. Hypoactivity of the mesocortical pathway leads to negative symptoms of schizophrenia, but D2 blockers are less efficent at reducing these symptoms
How do antipsychotics cause extrapyramidal side effects
antipsychotics block of D2 receptors affeccts the nigrostriatal pathway which plays a role in planned, coordinated movement.
Side effects of antipsychotics on hypothalamus
Block of D2 receptors in hypothalamus interferes with the tuberoinfindibular pathway (in which dopamine normally inhibits pituitary release of prolactin). This leads to hyperprolactinemia as well as poikilothermia (altered thermoregulation) and weight gain
acute vs chronic schizophrenia
acute: features positive symptoms (hallucinations and delusions) and thought disorders. Chronic: features negative symptoms (withdrawal, flattened affect, cognitive problems).
Effects of glutamate excess excitation and excitotoxicity
excess excitation causes seizures and insomnia. Excitotoxicity causes damage to neurons, neurodegeneration and cell death
Role of glutamate in mesolimbic pathway and how it is altered in schizophrenia
Normally, neurons from cortex release glutamate at brainstem to activate GABAergic neurons. This produces tonic inhibition of mesolimbic dopamine neurons. Hypofunction of cortical NMDA-glutamate neurons will cause positive symptoms of schizophrenia
Role of glutamate in mesocortical pathway and how it is altered in schizophrenia
Normally, cortical glutamatergic neurons activate brainstem dopaminergic neurons (VTA) to produce tonic excitation of mesocortical dopaminergic neurons. Hypofunction of cortical NMDA-glutamate neurons will cause negative symptoms of schizophrenia
Describe the relationship between receptor blocking potency-selectivity (esp. 5HT vs DA), efficacy in schizophrenia, and side effect profile for typical and atypical antipsychotic agents.
5HT2 receptors on DA neurons in prefrontal cortex decrease dopamine release. Block of these receptors with atypical agents increases DA release and alleviates the negative symtpoms of schizophrenia. Block of D2 receptors will alleviate the positive symptoms of schizophrenia
List the typical/first generation antipsychotics
haloperidol and chlorpromazine
List the atypical/ second generation antipsychotics
Aripiprazole, risperidone, olanzapine, clozapine
compare the D2/5HT blocking ratio for typical vs atypical antipsychotics
Typical: high D2 / 5HT2A blocking ratio. Atypical: low D2/5HT2A blocking ratio
Which symptoms do antipsychotics block
typical: good efficacy against positive symptoms (due to D2 block) Atypical: good efficacy against negative symptoms (due to 5HT block)
Which antipsychotics have extrapyramidal side effects
typical- due to D2 block
Which typical antipsychotics are high potency and which are low? What are the results of this
High: haloperidol- increased D2 side effects (extrapyramidal) but low muscarinic-histamine-alpha 1 adrenergic side effect. Low: chlorpromazine- decreased D2 side effects, but increased adverse reactions from muscarinic- histamine-alpha 1 adrenergic block
Side effects of muscarinic block
sedation, tachycardia, dry mouth, blurred vision.
side effects of alpha1-adrenergic block
orthostatic hypotension
side effects of histamine block
weight gain- risk of type 2 diabetes
extrapyramidal side effects of D2 block
acute dystonia in 1-5 days (torticollis, trismus, opisthotonos), akathisia in 6-60 days (motor restlessness), pseudoparkinsonism in 5-90 days (tremor, bradykinesia, rigidity), tardive dyskinesia in 3months or longer (involuntary movements of orofacial muscles, choreathetoid movements)
treatment of acute dystonia
anticholinergic agents [diphenhydramine-benztropine]
treatment of akathisia
reduce dose – change drug – try anticholinergic, β blocker or benzodiazepine
treatment of pseudoparkinsonism
anticholinergic agents [diphenhydramine-benztropine]
treatment of tardive dyskinesia
rarely effective, prevention is best
Which antipsychotic causes agranulocytosis
clozapine
distribution/ excretion of antipsychotic agents
•Cross the placenta to exert effects in the fetus and can be excreted in breast milk
IV antipsychotics
not generally advisable
