SZ- Antipsychotics Flashcards
Antipsychotic Medication
1st generation antipsychotics – typical
2nd generation antipsychotics – atypical
3rd generation antipsychotics – partial agonists
Novel targets for cognition
Dopamine receptors
Two main families of dopamine receptor: D1- and D2-like
Regions of the brain usually have opposing densities of each subtype
The D1-like receptor family contains the D1 and D5 receptor subtypes
Dopamine D1-like receptors are coupled to stimulatory G-proteins and they have a stimulatory effect on neurotransmission when bound by an agonist
D2-like family contains the D2, D3 and D4 subtypes
The D2-like receptors are coupled to inhibitory G-proteins, and have an inhibitory effect on NT when bound by an agonist
D2 receptors can be seen as pre-synaptic auto-receptors, reducing release when high DA in synapse
D1 and D2 receptors are much more prevalent than D3/4/5
What are the 4 major dopamine pathways in the brain?
Mesolimbic pathway
Mesocortical pathway
Nigrostriatal pathway
Tubero-infundibular pathway
Typical antipsychotics (neuroleptics)
E.g. Haloperidol, chlorpromazine
High affinity for dopamine D2 receptors (antagonists)
Effective against the positive symptoms
Ineffective against the negative symptoms and cognitive deficits
Typicals (more than atypicals) cause motor control impairments, due to their increased blockade of dopamine D2 receptors
Dopaminergic adverse effects with typicals
The nigrostriatal pathway projects from the substantia nigra to the striatum, contains 80% of the brain’s dopamine, and controls movement
Parkinson’s disease is due to a lack of dopamine in this pathway
Blocking D2 receptors can cause Parkinson-like or extra-pyramidal symptoms (EPS) and tardive dyskinesia (TD)
Other adverse effects of typicals
Worsen negative and cognitive symptoms – due to blocking D2 in mesocortical pathway
Galactorrhoea caused by increased levels of prolactin – due to blocking D2 receptors in tubero-infundibular pathway
Also cause side effects not related to D2 blockade
Receptor action (non-DA) & their side effects
- Blocking H1 receptors- Drowsiness and can cause weight gain
- Blocking alpha-1 receptors- CV side effects e.g. dizziness, hypotension
- Blocking muscarinic receptors- Dry mouth, blurred vision, constipation, cognitive deficits
Atypical antipsychotics (2nd generation)
e.g. Clozapine, risperidone, olanzapine
Higher affinity for serotonin 5-HT2 receptors than dopamine D2 receptors
“Rich” pharmacology
Effective against the positive symptoms
Some efficacy against the negative symptoms and cognitive deficits
Less likely to cause EPS side effects
Adverse effects of atypicals
- Weight gain & metabolic syndrome caused by 5-HT2c blockade- affects compliance
- CV & obesity related conditions e.g. diabetes and hypertension
- Agranulocytosis with clozapine- check blood every 2 weeks
Risk of weight gain:
Hight risk: Clozapine, Olanzapine
Moderate risk: Risperidone, Quetiapine
Minimal risk: Ziprasidone, Ariprazole
Explain the pharmacology of typicals vs atypicals
All antipsychotics have affinity for D2 receptors
Atypicals are usually 5HT2A antagonists but usually have affinity at many other receptors
What is the hit & run hypothesis (with regards to adverse effects)
Older medicine e.g. Haloperidol bind tightly to the Dopamine D2 receptors in cell membrane and thus create their antipsychotic activity but risk adverse EPS. Once done they slowly come off and unbind from the membrane.
New atypical antipsychotic e.g. Quetiopine loosely bind to the cell membrane, then create their antipsychotic activity without adverse EPS. But the main difference being that they come off fast, allowing them to unbind from the membrane quickly.
Nigrostriatal pathway with atypicals
Seratonin (5HT) normally inhibit DA release via action at the 5HT2A receptor
Atypicals block pre-synaptic 5HT2A receptors causing more DA to be released
DA can then compete with the antagonist for the D2 receptor causing less EPS side effects
What are the advantages & disadvantages of Typical (Classical) antipsychotics- that have high-affinity D2 antagonists.
Advantages- Reduces and prevents recurrence of psychotic symptoms.
Disadvantages- Limited efficacy against negative and cognitive symptoms. High rates of extra-pyramidal (EPS) symptoms and tardive dyskinesia (TD).
What are the advantages & disadvantages of Atypical antipsychotics- that have mixed neuroreceptor antagonists; low affinity D2, high affinity 5HT2A.
Advantages- Reduces and prevents psychotic symptoms; broader efficacy against negative and cognitive symptoms(?); may prevent illness progression. Less EPS and TD.
Disadvantages- Various side effects including blood problems, weight gain, increased glucose, and triglycerides; more expensive. Actual benefits??
What are the advantages & disadvantages of Atypical antipsychotics- that have mixed neuroreceptor antagonists; low affinity D2, high affinity 5HT2A.
Advantages- Reduces and prevents psychotic symptoms; broader efficacy against negative and cognitive symptoms(?); may prevent illness progression. Less EPS and TD.
Disadvantages- Various side effects including blood problems, weight gain, increased glucose, and triglycerides; more expensive. Actual benefits??
What are Third generation antipsychotics?
Aripiprazole (2002) - first effective D2 partial agonist
Cariprazine (2015) – D2 and D3 partial agonist
No EPS even at 80% D2 occupancy
Stabilises the dopamine system
No increase in plasma prolactin
