Exam 2 Flashcards
What NT is replaced when treating Parkinsons?
Dopamine
Effect of too much DA in mesolimbic area
psychosis
L-DOPA mechanism
- provides more precursor for DA
- only 5% passes BBB
- need to inc dose after 3-4 years
- less effective as more neurons die off
- ineffective in 1/3 of pts
SEs/toxicities of L-DOPA
- Peripheral: nausea, arrhythmias, orthostatic HypoTN
- Central: psychotic sxs, dyskinesias, on-off phenomenon
On-off phenomenon
- variable metabolism
- on phase: PD sxs are controlled (may have some jerky movements)
- off phase: PD sxs not controlled (dystonias, twisting movements, unusual posture)
- reduced by L-AAD and COMT inhibitors
CIs for L-DOPA
- psychosis, melanoma, narrow-angle glaucoma
- vitamin B6 speeds up peripheral metabolism of L-DOPA (tell pts to avoid it)
- MAOIs prevent metabolism of DA–> hypertensive crisis
- D2 blockers antagonize effects of L-DOPA
Carbidopa mechanism
- L-AAD inhibitor
- Inhibit peripheral L-DOPA metabolism by L-AAD –> increase delivery of L-DOPA to CNS
tolcapone/entacapone mechanism
- COMT inhibitor
- Inhibit peripheral L-DOPA metabolism by COMT
Difference between tolcapone and entacapone
- tolcapone passes BBB–> inhibits central and peripheral COMT
- entacapone doesn’t pass BBB–> inhibits peripheral COMT only
cofactor for L-AAD
- pyroxidine aka vit B6
- pts with Parkinson’s should avoid
what is NOT helped by L-AAD and COMT inhibitors?
CNS effects: dyskinesias, psychotomimesis (more DA is available centrally)
SEs of carbidopa, tolcapone, and entacapone
- nausea, orthostatic hypoTN, vivid dreams, confusion, diarrhea
- tolcapone only: liver toxicity
Selegiline/rasagiline mechanism
- MAO-B inhibitor
- blocks MAO-B metabolism of central DA
- MAO-A still intact to handle catecholamines
SEs and CIs for MAO-B inhibitors
- central effects of L-DOPA worsened
- cannot give with nonselective MAO inhibitor (will cause NE build up–> hypertensive crisis)
- selegiline metabolites: amphetamine and methamphetamine (sounds fun)
Ropinirole/pramipexole mechanism
- D2 receptor agonist
- easily titratable
Therapeutic effects of ropinirole/pramipexole
- can lower L-DOPA dose
- less on-off phenom
- 1st line for younger pts
- given to pts who have build L-DOPA tolerance
SEs and toxicities of ropinirole/pramipexole
- peripheral: hypoTN, anorexia, nausea, constipation, dyspepsia, reflux esophagitis, bleeding peptic ulcers
- can be treated with dopamine antagonist that doesn’t cross BBB
- central: dyskinesias, psychosis, fatigue, somnolence
ropinirole/pramipexole CIs
- psychosis
- recent MI, peripheral vascular dz (at risk for orthostatic hypoTN)
- peptic ulcers
Amantidine mechanism
-enhances DA release from remaining terminals and inhibits DA reuptake
Amantidine therapeutic effects
- good for initial therapy
- benefits short-lived
- reduces bradykinesia, rigidity and tremor (early stages)
Amantidine SEs and toxicities
- restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, confusion (all mild)
- OD: acute toxic psychosis
Benztropine mechanism
-Muscarinic antagonist/ anticholinergic
therapeutic use of anticholinergics/benztropine
- good in combo with L-DOPA
- very mild PD (tremor only)
- doesn’t work as well for bradykinesia
SEs of anticholinergics/benztropine
central: drowsiness, confusion, inattention, restlessness
peripheral: dry mouth, blurred vision, mydriasis (dilated pupils), urinary retention, n/v
CIs of anticholinergics/benztropine
- BPH
- obstructive GI dz
- narrow angle glaucoma
Psychosis def
inability to think coherently or comprehend reality (ex- schizophrenia)
Positive schizophrenic sxs
hallucinations, delusions, disorganization, formal thought disorder
Negative schizophrenic sxs
alogia, affective blunting, avolution, asociality, anhedonia, impaired attention
DA hypothesis of schizophrenia
-untreated schizophrenics have increased D2 receptors in brains
-Antipsychotics block D2 receptors
-Amphetamine, L-DOPA OD–> psychosis
(however, evidence that serotonin and glutamate both play a role)
Dopaminergic tracts in the schizophrenic brain
- Mesocorticolimbic projection
- Nigrostriatal projection
- Tuberoinfundibular system
- Medullary-periventricular neurons
- Dopamine receptors in chemotrigger zone (CTZ)
Mesocorticolimbic projection
- Frontal cortex (cortical limb): too little DA–> negative and cognitive sxs
- Nucleus accumbens (limbic limb): too much DA–> positive sxs
- arises in the ventral tegmental area (VTA)
Nigrostriatal projection
- Substantia nigra to striatum
- this is what dies in PD
- foci of extrapyramidal sxs from antipsychotic meds
Tuberoinfundibular system
- arcuate nucleus of hypothalamus, terminals in the pituitary
- D2 block here causes endocrine SEs (elevated prolactin)
Medullary-periventricular neurons
- motor nucleus of the vagus
- controls eating behavior
- D2 block here causes weight gain
Dopamine receptors in chemotrigger zone (CTZ)
D2 block here has antiemetic properties
Chlorpromazine
- a phenothiazine
- 1st gen antipsychotic
- acute txt of psychotic exisode
- many autonomic effects! slight EPS
- sedation, alpha1 block (huge risk in elderly!), seizures, sunburns!
Haloperidol
- a butyrophenone
- 1st gen antipsychotic
- severe EPS
- lower sedation, less alpha block than phenothiazines/chlorpromazine
- hyperprolactinemia
- generic, cheap, IV or injection
Atypical or 2nd gen antipsychotics
- clozapine
- risperidone
- olanzapine
- ziprasidone
- aripiprazole
- lower EPS than typicals
- increased ratio of serotonin:D2 receptor blockade
Clozapine
- atypical antipsychotic
- selectively causes DPI only in the mesolimbic pathway–> no EPS!
- better against negative sxs
- SEs: risk of agranulocytosis! (2% of pts), wt gain, DM, sedation, anticholinergic effects (esp confusion), seizures
- need to check WBC ct weekly
DPI
- depolarization inactivation
- goal when using antipsychotics
EPS
extrapyramidal sxs
Resperidone
- dose-dependent atypical antipsychotic
- low risk of EPS as long as dose is low
- no risk of agranulocytosis
- alpha1 block, weight gain, elevated prl
Olanzapine
- atypical antipsychotic
- no risk of agranulocytosis
- serious weight gain, DM, small increase in serum prolactin, anticholonergic effects (esp confusion), sedation, hypoTN,
- does NOT increase prolactin
- good for depressive sxs
Ziprasidone
- atypical antipsychotic
- temporarily withdrawn from market d/t wide QT intervals, later reintroduced under another name
Aripiprazole
- trade name: abilify
- atypical antipsychotic
- different mechanism: partial agonist at D2 and 5HT1A receptors, mild antagonist at 5-HT2
- no DM risk, less effect on prl levels
- IM available
- good for depressive sxs
SEs of antipsychotics
- CNS early occurring: dystonia, akasthisia (motor restlessness), parkinsonism, neuroleptic malignant syndrome (NMS), sedation, lower seizure threshold
- CNS late occurring: perioral syndrome (aka Rabbit syndrome), tardive dyskinesia!
- seizures
- ANS: orthostatic hypoTN (alpha1 block), reduced sex drive, inability to ejaculate (alpha1 block), anticholinergic effects (dry mouth, blurred vision, constipation, urine retention)
- Endocrine: increased prolactin, galactorrhea, amenorrhea (exception: olanzepine)
- Heme: agranulocytosis (check WBCs weekly)
- Metabolic: wt gain, DM, hyperlipidemia (esp atypicals)
- Phototoxicity: sunburns (esp phenothiazines/chlorpromazine)
- Cardiac: prolonged QT interval (ziprasidone)
neuroleptic malignant syndrome (NMS)
- catatonia, stupor, fever, unstable BP, myoglobinemia
- STOP APS IMMEDIATELY
- may be fatal (10%)
- occurs w/in weeks, can persist even after stopping APS meds
- prob due to D2 block in hypothalamus
tardive dyskinesia
- late occurring abnormal movements: oral-facial dyskinesias, widespread chorioathetosis, dystonia
- can occur after mos-yrs of txt
- 20% of pts
- due to D2 receptor hypersensitivity
- prevention is CRUCIAL
- no txt
cause of EPS
- D2 blockers disrupt cholinergic and dopaminergic input balance at the GABA receptor/receiving neuron –> cholinergic signals intensify –> EPS (Parkinson-like sxs/too much inhibitory GABA signalling)
- treat EPS with anticholinergics
- prolonged D2 blocks can cause D2 receptor supersensitivity–> tardive dyskinesia (abnl mvmts/too little inhibitory GABA signalling)
- DO NOT treat with anticholinergic! will make it even worse
ADME of APS
A: erratic, dec’d by foods, antacids, anticholinergics
D: concentrates in fatty tisses (good for brain), highly protein bound
M: hepatic microsomal system, conjugated by glucuronic acid
APS DDIs
- potentiation with CNS depressants, antihypertensives
- can interfere with dig
- barbituates enhance metabolism
typical vs atypical APS
- atypicals have less EPS
- atypicals better for negative sxs (exceptionL clozapine)
- atypicals make you fat
APS needed, but pt already has high DM risk?
Don’t use clozaine or olanzapine
APS for psychosis + depressive sxs?
aripiprazole, olanzapine
APS with cardiotoxicity risk?
phenothiazines (chlorpromazine)
alpha block
- orthostatic hypoTN
- especially bad in elderly!
