Antipsychotic drugs Flashcards
First-gen antipsychotics examples (3)
chlorpromazine, haloperidol, loxapine
Second-gen antipsychotics examples (3)
Aripiprazole, clozapine, olanzapine
Burden of SZ
- in top 15 leading causes of disability world-wide
- co-occurring medical conditions like heart disease, liver disease, and diabetes
- suicide risk
- co-occurring mental health
positive symptoms of SZ
hallucinations, delusions, illogical disturbances in flow, order, content of thought, disorganized speech, absence of clear goal-directed behaviour
negative symptoms of SZ
decrease in emotional range, poverty of speech, loss of interests and drive (anhedonia), problems with working memory, worsened attention, deteriorating IQ
- symptoms generally worsened by antipsychotics (def not improved)
antipsychotics are often prescribed just on basis of…
positive symptoms
- these are the symptoms that respond well to anti-psychotics
etiology of SZ
unknown
- maybe genetic but all loci found are low effect
- maybe DA transmission is fucked up (more DA in striatum of SZ patients)
methylene blue
antiparasitic used to treat malaria
- helped with psychosis?
chlorpromazine
Was used to try to sedate/ calm patients down
- ended up curing their positive psychotic symptoms
- chemical lobotomy
Mech of action of antipsychotics
D2 receptor antagonists
- both chlorpromazine and haloperidol bind to D2R
- positive correlation between D2 affinity and clinical potency
GSK3
Glycogen kinase
- linked to psychiatric diseases
- inhibition of this could be target for antipsychotics
Typical antipsychotics ( first gen APS, neuroleptics)
- discovered via
identified based on their ability to antagonize dopamine-mediated behaviours in rodents (locomotor activity)
In support of DA hypothesis of SZ (3)
- antipsychotics block D2Rs
- amphetamine (which pumps dopamine into synapse) induces SZ-like state in normal individuals
- PET imaging shows SZ patients release more DA in basal ganglia when given amphetamine
Against excess DA hypothesis of SZ (5)
- typical anti-psychotics only treat the positive symptoms and can worsen the negative and cognitive symptoms
- amphetamine does NOT induce negative or cognitive symptoms, and can even improve in some patients
- evidence for diminished DA in cortex and hippocampus (dysregulated DA rather than too much?)
- NMDAR antagonists like phencyclidine (PCP/angel dust) cause both positive, negative, and cognitive symptoms in healthy people
- genetic links point to multiple NT systems and neuro-developmental processes
EPS
extrapyramidal side Fx
- typical first gen antipsychotics can cause immobility and muscle rigidity similar to PD at their therapeutic dose
- can be overcome with addition of muscarinic antagonists
mnemonic for muscarinic receptor antagonist side effects
red as a beet, dry as a bone, blind as a bat, mad as a hatter
dry mouth, mydriasis (causes blurred vision), tachycardia, hot and flushed skin, agitation, urinary retention, constipation, and delirium
Muscarinic antagonists for PD and AP-induced PD-like symptoms
Benzatropine partially blocks cholinergic activity in the basal ganglia and has also been shown to increase the availability of dopamine by blocking its reuptake and storage in central sites, and as a result, increasing dopaminergic activity. It is used in the treatment of Parkinson’s disease and dystonia.
Tardive dyskinesia
- occasionally occurs after longterm use of APSY
- symptoms persist even after APSY discontinued
- involuntary twitches of facial muscles also hands and legs
Theory behind tardive dyskinesia
thought to reflect dopamine receptor hypersensitivity
- is also seen with L-dopa treatment in PD
- in both these conditions there are fluctuating states of high and low DA tone depending on drug PK
Hyperprolactinemia
- Dopamine from hypothal prevents secretion of prolactin from pituitary
- more prolactin secreted with D2 blockage
- leads to production of milk and suppression of GnRH - causes disruption of menstrualcycle
What theory did clozapine challenge
that a drug had to induce parkinsonism to be an effective antipsychotic
Atypical antipsychotics
- drugs potentially more effective against depressive, negative, or cognitive symptoms
- better tolerated (fewer EPS)
- generally have greater affinity for 5HT2 receptors than D2 receptors and are antagonists at both
examples of atypical anti-psychotics
risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole
5HT2a activation by drugs like LSD and Psylocibin is asociated with
hallucinations
Metabolic syndrome induced by atypical APS
- diabetes
- weight gain
- CV disease
- hypertension
Side effects / adverse drug reactions to APS
- cause anhedonia (D2R antagonism)
- induce serious motor impairments
- cause sedation/somnolence by antagonizing H1 receptor (espesh chlorpromazine)
-have anti-emetic properties (by blocking D2R at CNS-medulla and PNS-stomach - like D2 blocker anti-nauseant, metoclopramide for migraines) - hyperprolactinemia
- metabolic disorders
- CV disorders
- clozapine can cause WBC loss in agranulocytosis
Adverse effects of antipsychotics due to
on-target (D2 and 5HT) and off-target (H1 and M1 effects)
Antagonism of these receptors leads to which side effect:
- 5HT2C
- 5HT1A
- H1
- D2
- M1 (muscarinic)
- M3
- 5HT2C - weight gain, diabetes
- 5HT1A - weight gain
- H1 - weight gain, diabetes, sedation
- D2 - EPS, weight gain, endocrine effects
- M1 (muscarinic) - anticholinergic (red as a beet, dry as a bone, blind as a bat, mad as a hatter)
- M3 - diabetes
How is aripiprazole different from other antipsychotics?
partial agonist at D2 receptor instead of competitive antagonist
- will activate D2R and increase neurotransmission in areas where DAergic signalling is reduced (cortex and hippocampus)
- will decrease DA in areas where it’s excessive (striatum) by competing a more effective agonist out (DA)
