Antipsychotics - Typical and Atypical Antipsychotics Flashcards
What is meant by typical and atypical?
The presence of extrapyramidal signs and symptoms (EPS) (resemble those of parkinsons disease symptoms: tremors, slowed motor functions, stiff limbs, and trouble aintaining balance) are typical in the older (prior to 1975) antipsychotics and are atypical of newer antipsychotics.
What causes EPS?
Blockage of DA activity in the nigrostriatal pathway (specifically the D2 receptors).
Typicals have a high affinity and low dissociation constants for which receptors?
D2 receptors.
Where are D2 receptors found?
60-80% of D2 receptors are found in the striatum of the basal ganglia - which produces EPS.
Why don’t atypicals produce EPS?
Weak affinity and higher dissociation constants for the D2 receptors, thus avoiding the problem of blocking DA in the nigrostriatal system, therefore producing fewer EPS. Also treat a wider range of schizophrenic symptoms.
What DA receptors do atypicals have a higher affinity for?
D3 and D4 receptors.
Where are D3 and D4 receptors not found, where are they found?
Not found in high quantities in the basal ganglia
D3 receptor localized largely in the nucleus accumbens, the terminal point of the mesolimbic projection, with many fewer receptors in the basal ganglia.
D4 receptor is localized largely in the cortex, amygdala, and hippocampus - the regions that are important in cognition, emotion, and learning. Very few D4 receptors in human motor systems.
Thus, atypical antipsychotics depress DA activity in the mesolimbic system and treat psychoses without having a great effect on the nigrostriatal system and causing parkinsonian side effects.
How do typicals and atypicals differ in their function on 5-HT?
Difference in the extent to which they bind to 5-HT receptors, especially the 5-HT2A subtype. Both block to some extent, but atypicals block this receptor to a greater extent.
So typicals have greater affinity for and lower dissociation constants for D2 receptors, and the reverse for 5-HT2A receptors.
And the opposite for atypicals.
How do LSD and psilocybin affect 5-HT2A receptors and what is their effect?
They are agonists at this receptor subtype, and cause psychotic symptoms such as hallucinations.
How do hallucinations occur?
Metabotropic glutamate (mGlu) receptors interact with 5-HT2A receptors to create a functional receptor complex that, when activated y hallucinogenic drugs, triggers unique cellular responses in the cortex.
What association between 5-HT2A receptors and mGlu receptors might create a vulnerability to schizophrenia?
In untreated schizophrenia, there is an upregulation of 5-HT2A receptors, and a downregulation of mGlu receptors, suggesting that an imbalance of 5-HT2A receptors may create vulnerability to psychosis.
What other NT systems do atypicals affect? What does this cause?
Acetylcholine, histamine, NE, and peptide transmitters such as GABA.
May contribute to their therapeutic efficacy and side effect profiles.
- Anticholinergic effects can provide additional mechanism for reducing EPS. However, some of these additional actions may cause unpleasant or dangerous side effects on the body.
Describe Clozapine (Clozaril), its effects, and neuropharmacology.
Firt atypical to come onto the market.
Alleviates the positive symptoms of schizophrenia.
High affinity for D4 receptor subtypes, as well as multiple 5-HT receptor subtypes, muscarinic acetylcholine receptors, and alpha 1 adrenergic receptors. Weak affinity for D2 receptors.
Therapeautic effect thought to result from antagonism of D4 and 5-HT receptors.
What is Aripiprazole (Abilify)?
Sometimes referred to as a third-generation antipsychotic because its mechanism of action is unlike its predecessors. It is a “partial agonist” of Dopamine.
How does Aripiprazole work as a partial agonist?
Modulates (rather than blocks) DA activity at D2, D3, and D4 receptor subtypes. High affinity for these receptors, but does not stimulate them as much as their natural ligand (DA) does. Works as an DA agonist and antagonist.
