Antipsychotic drugs Flashcards
Dopamine Hypothesis of Schizophrenia
Abnormality in brain function in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in mesolimbic pathway
Most developed hypotheses for schizophrenia
Moderate success in explanation of disease
Not adequate to explain all aspects of the disease, especially the cognitive impairment.
Provided the basis for much of the early rationale for antipsychotic therapy.
Limitations of the dopamine hypothesis of schizophrenia
Postmortem and in vivo imaging studies show diminished DA activity in cortical and hippocampal regions that may underlie negative symptoms and cognitive impairment
Clozapine is weak D2 blocker but still is an effective antipsychotic agent
Evidence exists for role of serotonin (5-HT) and glutamate neurotransmitter systems (via modulation of dopamine neurotransmission [?])
Mesolimbic pathway
Integration of sensory input and motor responses with affective or emotional data.
Hyperactivity contributes to the occurrence of positive symptoms.
Are most conventional antipsychotics (D2 receptor blockers) better at treating positive or negative symptoms?
positive
Mesocortical pathways
involved in communication and social abilities
Hypoactivity due to cell loss in the prefrontal cortex contributes to presence of negative symptoms (poverty of speech, anhedonia, lack of motivation, social isolation).
What class of meds are better for treating negative symptoms?
Atypical antipsychotic agents such as clozapine or olanzapine (via additional block of 5HT2A receptors)
Nigrostriatal pathways
central role in planned, coordinated movement
Loss of dopamine in this region results in dysregulation of movement (Parkinson’s disease, hypoactivity, bradykinesia, and tremor).
Tuberoinfundibular pathway and side effects it causes from antipsychotics
Hypothalamic neurons release DA in pituitary to inhibit prolactin release.
Antipsychotic drug use (via D2 dopamine receptor blockade) can cause side effects of hyperprolactinemia as well as interference with regulation of body temperature (poikilothermia) and alteration of eating behavior (weight gain)
Serotonin Hypothesis
Activation of 5HT2A receptors is the basis for the hallucinatory effects
Hallucinogens (mescaline – LSD) act in CNS as serotonin agonists.
Brain Serotonin Pathways
Projections from brainstem nuclei to prefrontal cortical areas, limbic region, and striatum have important modulatory actions on dopamine and glutamate neurons
Activation of 5HT2A receptors on DA neurons in the PFC
Decrease DA release
Cause negative symptoms
Activation of 5HT2A receptors on glutamate pyramidal cells in the PFC (not shown here)
Result in stimulation of DA neurons in VTA
Increase DA release in the mesolimbic pathway
Can cause positive symptoms
How to treat both positive and negative symptoms in Schizophrenia?
Using an antagonist of both 5HT2A and D2 receptors
Glutamate Hypothesis
Hypofunction of NMDA receptors located on GABAergic interneurons in the PFC leads to diminished inhibitory influences that affect both mesolimbic and mesocortical dopamine pathways
Gives rise to both positive and negative symptoms.
Direct Brain Glutamate Pathway
Cortical - Brainstem VTA
[increased cortical output leads to increased mesolimbic DA release]
Cortical glutamate neurons to VTA directly innervate and stimulate the mesolimbic DA neurons. Activation of the cortical glutamate neurons leads to activation of mesolimbic DA neurons. NMDA receptors on cortical GABA interneurons mediate inhibition of cortical glutamate output.
Hypofunction in these cortical NMDA-Glu neurons can result in loss of cortical GABA inhibition and increased activity of cortical glutamate neurons resulting in hyperactivity in the mesolimbic pathway and positive symptoms of schizophrenia.
Indirect Brain Glutamate Pathway
Cortical - Brainstem VTA
[increased cortical output leads to decreased mesocortical DA release]
Activation of the cortical glutamate neurons leads first to activation of the VTA GABA interneurons, then inhibition of mesocortical DA neurons. Again, NMDA receptors on cortical GABA interneurons mediate inhibition of cortical glutamate output.
Hypofunction in these cortical NMDA-Glu neurons can result in loss of cortical GABA inhibition and increased activity of cortical glutamate neurons resulting in hypoactivity in the mesocortical pathway and negative symptoms of schizophrenia.
Targets for Antipsychotic Agents
Dopaminergic (D2 - D4), alpha-adrenergic (α1), muscarinic cholinergic (M),histaminergic (H1), and serotonin (5HT2) receptor blockers
Typical antipsychotic agents
Chlorpromazine, Haloperidol (Haldol®)
high D2 / 5HT2A ratio
good efficacy against positive symptoms
Side effects:
high clinical potency (haloperidol-effective in lower doses) because of greater D2 blocking activity that then display an even greater risk of extrapyramidal toxicity.
low clinical potency (chlorpromazine-effective in higher doses) do not block D2 receptors as well and have relatively less extrapyramidal toxicity. BUT, the larger doses that are necessary for comparable antipsychotic efficacy produce side effects at other receptors (antimuscarinic [dry mouth, sedation], α1-blockade [hypotension], antihistamine [sedation])
Atypical antipsychotic agents
Aripiprazole, Olanzapine, Clozapine, Quetiapine
low D2 / 5HT2A ratio
Good 5HT2A block is thought to be associated with good efficacy against negative symptoms of schizophrenia as well as efficacy in treatment-resistant individuals.
Can cause weight gain!
Chlorpromazine
Typical antipsychotic
Side effects:
Dry mouth / tachycardia / loss of accommodation / difficulty urinating / constipation (due to muscarinic blockade)
Orthostatic hypotension / impotence (due to α1-adrenergic blockade)
Sedation: Via antimuscarinic and antihistaminic activity
Haloperidol
Typical antipsychotic
Side effects:
Extrapyramidal symptoms (dopaminergic blockade)
Acute dystonia, Akathisia (restlessness, can’t sit still), Pseudoparkinsonism, Tardive dyskinesias (involuntary movement of lips and tongue)
Clozapine
Atypical antipsychotic
effective in majority of schizophrenic patients that are refractory to other drugs
Side effects: Agranulocytosis: low white blood cell count (leads to limited use of Clozapine), weight gain
Absorption of antipsychotics
Most are incompletely absorbed
Significant first pass effect
Routes of administration: oral, IM solutions, IM depot suspensions
Distribution of antipsychotics
Extensively protein bound in plasma
High lipid solubility (concentrated in lipid-rich tissues, including CNS) extends clinical t1/2 beyond plasma t1/2
Brain levels may exceed plasma levels
WILL cross the placenta to exert effects in the fetus
Metabolism / Excretion of antipsychotics
Little excretion of unchanged drug via kidney
Almost completely metabolized to more polar substances (oxidized by P450 system [phase I], then conjugated).
Can be excreted in breast milk.
Orthostatic hypotension as a side effect is due to what?
Alpha 1 blockers, NOT D2 receptor blockers
Dry mouth / tachycardia / loss of accommodation / difficulty urinating / constipation as a side effect is due to what?
Due to muscarinic blockade
Sedation as a side effect is due to what?
antimuscarinic and antihistaminic activity
Extrapyramidal symptoms are side effects of what?
Dopamine blockade
Olanzapine
Atypical
Effective in schizophrenic patients that are refractory to other drugs
Effective against positive and negative symptoms
Side effects: weight gain and development of diabetes, lowering of seizure threshold
Risperidone
Atypical
Side effects: Extrapyramidal symptoms and hypotension with high doses
