10-25 L1 Antipsychotic drugs Flashcards
What region of the brain is DA found as the neurotransmitter?
- Striatum
- DA/NE=25
What are the 4 major DA systems in the CNS? Which one is important in Parkinson’s disease?
- Nigrostriatal
- Mesolimbic
- Mesocortical
- Hypothalamic
Nigrostriatal is the most important one.
Which DA system in the CNS is a therapeutic target site of anti-psychotic drugs?
-mesolimbic system -mesocortical system
which DA system in the CNS is a site for adverse effects of anti-psychotic drugs?
-Hypothalamic -Nigrostriatal
What are the main therapeutic target of a typical antipsychotics?
DA systesm (in mesocortical & mesolimbic) pathways via D2 receptor antagonism.
Adverse effects of typical anti-psychotics?
- Motor (EPS) DA systems in nigrostriatel pathways
- Endocrine DA system in hypothalamic pathyways in D2
Describe the typical anti-psychotics action on other targets (due to lack of specificity for DA receptors) These are not clean drugs that affect only one or two targets.
-5-HT receptors muscarinic ACh receptors, alpha1-adrenegeric receptors H1-histamine receptors
Which drugs inhibits the synthesis of both DA & NE? (CARD)
-Cocaine (inhibits reuptake) -alpha-methyltyrosine (inhibits TH in both) -Reserpine (inhibits vesicular uptake) -D-Amphetamine (release neurotransmitter)
What is Desipramine’s action on NE and DA receptors?
inhibits reuptake in NE neurons (but not DA receptors)
“Typical” anti-psychotics are derivatives of what two basic chemical structures?
- Phenothiazines
- Chlorpromazine
- Butyrophenones
- Haloperidol
What is a prominent side effect of typical anti-psychotics?
- movement disorders
- EPS (extrapyramidal symptoms)
Name 4 pro-psychotic drugs and their action
- Levodopa: Increases DA content
- Amphetamine: enhances DA release
- DA receptor agonist: activates DA receptors
- Cocaine: Inhibits DA reuptake
Name 3 anti-psychotic drugs and their action
- alpha-Methyltyrosine: inhibits DA synthesis
- Reserpine: Depletes DA storage
- DA receptor antagonists: inhibits DA signaling.
Describe the therapeutic lag of anti-psychotics
- drugs reach their molecular targets w/in hours,
- but therapeutic effects appear only weeks later
Provide examples of typical anti-psychotic drugs (1st generation or traditional antipsychotics)
(3 +5)
- Chlorpromazine (Thorazine)
- Fluphenazine (Prolixin)
- Haloperidol (haldol)
- perphenazine (Trilafon)
- Prochlorperazine (Compazine)
- Thioridazine (Mellaril)
- Trifluoperazine (Stelazine)
- Thiothixene (Navane)
For typical antipsychotics
- Which DA recetpro is their therapeutic target?
- Which DA receptor mediates antidopaminergic side effects
- Do they interact with other (non-dopaminergic) systems
- Which DA recetpro is their therapeutic target? D2
- Which DA receptor mediates antidopaminergic side effects? D2
- Do they interact with other (non-dopaminergic) systems: Yes they definitely do!
What are extrapyramidal dopaminergic side effects of typical antipsychotics
- acute dystonia
- akathisia
- Parkinsonism
- Tardive dyskinesia
acute dystonia
spasm of muscles of face, tongue, neck and back
akathisia
motor restlessness
Parkinsonism
Rigidty, tremor shuffling gait
Tardive dyskinesia
- oral-facial involuntary movements
- choriform movement of extremities
- Tardive= late
NMS (Neuroleptic Malignant syndrome)
‘Haldol Hyperthermia’
- Rare (<0.01%) but life threatening
- Symptoms
- Hyperthermia
- Autonomic instability
- Muscle rigidity
What do you do, to treat NMS (Neuroleptic malignant syndrome)
- Withdraw typical antipsychotic (DA receptor antagonist)
- Cooling, hydration, supportive care
- Dantrolene (muscle relaxant) for cooling
- Bromocriptine (DA receptor agonist) b/c we are trying to block off the drug that drought this on.
Define the endocrine dopaminergic side effects of typical anti-psychotics?
What is the change in level and outcome
PGC
- prolatin (increase): increased lactation gynecomastia
- Gonadotropins (decrease): inhibits ovulation, menses
- Corticotropins (decrease): decreases adrenal corticosteroid secretion
Atypical antipsychotics carry an increased risk for what disease?
type II diabetes
Huntington’s chorea
mirror image of parkinson’s disease
- genetic
- presentation
- cause
- treatment
- genetic: autosomal dominant, triplet repeat disease
- Presentation: progressive chorea, dementia; incurable
- Cause: Degeneration of striatal neurons
- Treatment: halperidol (a DA receptor antagonist; which would exascerabte PD)
Parkinsons Disease (PD)
vs.
Huntington’s disease (HD)
- PD: underactivity in nigrostriatal pathways
- HD: overactivity in nigrostratal dopamine pathways
atypical (newer) anti-psychotic drugs differ from typical antipsychotic drugs by:
5 points
Atypical: full range of targets (and full mechanism) is unclear
- chemcial structure
- less EPS side effects (D2) **movement disorders
- Few other (non-motor) DA side effects (e.g. endocrine)
- Effective in some patietns who fail to respond to typicals. may be better than typicals for neg. symptoms
- Less potent at D2 than many typicals: must be working also at other targets (5-HTreceptors? D4? alpha1? cholinergic?)
Examples of atypical drugs
(5+3)
CORA-Q
- Aripirazole (Abilify)
- Clozapine (Clozaril)
- Olanzapine (Zyprexa)
- Risperidone (Risperdal)
- Quetiapine (Seroquel)
- ziprasidone (geodon)
- asenapine (saphris)
- palperidone (invega)
What is the advantage of atypical vs typical?
-
Atypical have a wider window
- adverse and therapeutic dosage wider apart
- Has a higher Therapeutic index for EPS (than for typicals)
-
typical have a narrower window
- adverse vs therapeutic close together
List some advese affects for the prototype antipsychotics
-
typicals
- EPS (increase)
- Metabolic abnormalities (no change)
-
atypicals
- EPS (some or no change)
- Metabolic abnormalities (change)
What is a major side effect of clozapine?
- causes agranulocytosis (1-2% of patients genetic)
- basophils and esoniphils thus greater risk of infections in these pts
- also think what would happen in the immune compromised
- thus testing is essential
List the clinical problems with typical and atypical drugs
Both drugs: poor pt compliance
-
Typical
- EPS (e.g. tardive dyskinesia)
- Hyperprolactinemia
- Neuroleptic malignant syndrome (NMS)
-
Atypical
- Weight gain
- metabolic problems
- risk of type 2 diabetes
- other adverse effects (vary drug to drug)
- Notably higher risks in elderly and pediatric patients
Cardiometabolic risk of atypical antipsychotics in youth
What two drugs increase in weight change and LDLchol change?
What drug do you see a change in glucose and insulin?
- Olanzapine & Aripiprazole
- Olanzapine
Atypical antipsychotics have much less _ _ and much more _ _ than typical antipsychotics.
Atypical antipsychotics have much less extrapyramidal toxicity risk** and much more **metabolic toxicity risk than typical antipychotics.
Typical and atypical have what similarities?
- all drugs are lipid soluble
- have large Vd
- well-absorbed orally
- cross BBB well
- long t1/2
- once/day dosing
What is a solution to compliance (which is a big issue in this pt population)?
- depot drugs (hydrophobic derivatives, given by IM injection)
- t1/2= 1-6 weeks
What is a significant risk in this pt population (that you perscribe antipsychotic drugs for )
- suicide is a significant risk in this pt population
- (but suicide by acute overdose of antipsychotic drugs is very difficult and very rare).
