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69 Cards in this Set

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What are drug induced Parkinsonism:
Neuroleptics, metoclopramide, reserpine, carbamazepine, MPTP
Ex. of Nueropletpics, metoclopromide, reserpine, carbamazapine, MPTP
neuroleptics: haloperidol
Metoclopromide: DA antag
Reserpine: Depletes DA, NE
Carbamazepine: Antiepileptic
MPTP: neurotoxin; analog of Meperidine
Cardinal Features of Park
Tremor
Rigidity
Bradykinesia/akinesia
disorders of gait and posture
Top two surgical therapies for parks
Thalamotomy, pallidotomy
(remove gp and VL thalamus)
Fetal nigral transplantation
L Dopa get rapidly absorbed from the gut with what type of transport
Active
The acid Ph effect absorbtion in what way and what AA competes with its binding site
decreases
Leucine
Does L-dopa go through extensive metabolism and which enzyme is responsible for this
dopamine decarboxylase
What are the major metabolites
DOPAC and HVA
L- DOPA MOA
improve parkinsonism
L-Dopa side effects
GI/ CV
GI: Anorexia
CV: postural hyptoension tach
Tollerance gradually
Side effects of L-DOPA are
GI, CV, Abnormal involuntary movements, behavioral distrubances, flunctuations in response
LDopa SE: GI
NV
action of DA on chemoreceptor trigger zone (CTZ). Tolerance gradually increased
Carbidopa decreases incidence
LDopa SE: CV
tachycardia, postural hypotension
L Dopa SE: involuntary movements
Oralfacial tics: head bobbing and jerking

Dose related: decrease dose and the SE will go away. Carbidopa increases incidence
Tolerance does not develop: Dyskinesisas disappear if dosage decrease
L Dopa SE: behavior disturbances
Depression, anxiety, hallucinations

Gets worse with carbidopa
L Dopa SE: Flunctuations in response
Wearing off phenomenon: severe akinesia when you come off

on/off phenomenon: sudden dyskenisia, diet may affect
May result from alteration of DA-R and post-R changes to plasma levodopa level
Fluctuations may be decreased by taking medication more freq. in smaller doses and prolonged release
How can you decrease end of dose wearing off effect
give COMT inhibitors, a combo of entacapone with 3 different doses of L-Dopa/caridopa
Why is L-Dopa reserved for advanced Park
because your best results are obtained in first 3 to 4 years of treatment. After that refractoriness may develop due to disease progression or increase SE due to drug-induced supersensitivity.
Abrupt Withdrawal of L-dopa
severe akinesia
L-dopa + carbidopa=
Sinemet
L Dopa SE: Flunctuations in response
Wearing off phenomenon: severe akinesia when you come off

on/off phenomenon: sudden dyskenisia, diet may affect
May result from alteration of DA-R and post-R changes to plasma levodopa level
Fluctuations may be decreased by taking medication more freq. in smaller doses and prolonged release
How can you decrease end of dose wearing off effect
give COMT inhibitors, a combo of entacapone with 3 different doses of L-Dopa/caridopa
Why is L-Dopa reserved for advanced Park
because your best results are obtained in first 3 to 4 years of treatment. After that refractoriness may develop due to disease progression or increase SE due to drug-induced supersensitivity.
Abrupt Withdrawal of L-dopa
severe akinesia
L-dopa + carbidopa=
Sinemet

Carbidopa  peripheral inhibitor of DOPA decarboxylase

DOC for Parkinsons, or can use the First-line drugs
What are the properties of Sinemet
Slower onset longer duration
What is the most effect combo for Park
Sinemet
Compared to Ldopa, Sinemet is better because
decrease dopa amount by 75%
greater efficacy with smoother control, may result in less flunctuation
Pyridonxine no longer antag effect of L-dopa
Sinemet SE: CV
less tachy than L-Dopa
Sinemet SE: GI
Less NV
Sinemet: SE nuero/Psych
more server psych disturbances and dyskinesias than L-Dopa
Sinement: caution and contraindications
start low doses and increase gradually
Caution-peptic ulcer, cardiac disease, open-angle glaucoma-mydirasis
Contraindications- angle closure glaucoma, psychosis, malignant melanoma-Ldopa a precursor to melanin
Sinemet: Rx interaction
Pyridoxine
antipsychotic drugs
Anticholinergic drugs
Non-selective MAO inhibitors
--Hypertensive crisis; decrease catechol metab
other dopamine agonists
Bromocriptine: MOA
Used to treat prolactenemia: binds to DA2 receptor decreases prolactin release in pituitary
Bromocroptine: prop
Ergoline Dopamine agonist
Bromocroptine: effects
L-dopa but less effective
Good when used with L-dopa
Bromo: combined with L-dopa to reduce what
on-off phenomena or becomign refractory
When is bromo ideally used
When ldopa is contraindicated

Start with low and move up
Bromo SE: GI
NV, anorexia, constipation
Bromo SE: CV
orthostatic hypotension, cardiac arrythmias more than Ldopa
Bromo SE: involuntary movements
dyskenisias less than L dopa
Bromo SE: psych and neuro
mental disturbances: confusion, hallucination, delusions, nightmares
bromo miscellaneous:
headache, nasal congestion, erythromelalgia (red lower extremeties)
Bromo contraindications
hx: mental illness, CV disease, preg

Low to high
nonergot DA agonists
MOA
Selective D2-R agonists

Great FIRST-LINE DRUG over L-dopa$$ Parkinson

Used for mild disease: 1st line
Combo with L- Dopa
RLS
Nonergot SE:
Naus, fatigue, dizziness, confusion, hallucination, postural hypotension, dyskinesia
Main SE for nonergot
Sudden sleep attacks, during daytime activity
Examples of nonergots
Pramipexolen (mirapex)
Ropinirole (requip)
Rotigotine (neupro)-transdermal patch
Pharmacokinetics of nonergs
pramipexole is rapidly absorbed and is excreted unchanged in urine
Ropinirole is metabolized by CYP1A2. Drugs metabolized by the liver may alter its metab
MOA of selegiline
MAO inhibitor type B
Two type of MAO nhibtors
type A- serotonin NE
Type B- dopamine
MOA of Selegiline
Lack undesirable effects of non-selective MAO inhibitors
(hypertension following ingestion of foods rich in tyramine)
Release NE from sympathetic neurons

**LIPID SOLUBLE, GETS INTO CNS***

May have neuroprotective and anti-apoptotic effects
Selegiline: Clinical use
Adjunctive therapy with L-dopa for advanced disease

May prolong the effect of L-dopa and decrease mild on-off or wearing off akinesia
Selegiline SE:
Dyskinesias and mental distrubaces( eg confusion and hallucina greater than l-dopa

Insomina, anxiety, nausea, hyptension
drug interaction
tricyclic antidepressants, SSRI's: increase risk of Serotonin Syndrome- hypertension tremors rigidity, agitation, hyperthermia
Tolcapone MOA
COMT inhibitor

Inhibit catechol-o-methyl-transferase (COMT)  blocks periphperal conversion of levodopa to 3-o-methyl-DOPA  ↑ L-DOPA entering BRAIN
Tol pharmocokinetics
Rapidly absorbed, bound to plasma protein, and metabolized prior to excretion. Half life of both drug is about 2 hrs 4-6x/d

**NOT lipid soluble, CANNOT get into CNS*** (stays in periphery)
Tolcapone clinical uses
adjunct to L-dopa/carbidopa in patients experiencing on-off phenomenon: may produce smooth response
Tolcapone SE:
Nausea, hypotension, orthostatic hypotension, vivid dreams, hallucination, DIARRHEA **HEPATOTOXICITY (mainly tolcapone though)***
Tolcapone where it works compared to selegilline
*so these are great drugs to give WITH L-dopa b/c Entacapone works in PERIPHERY (COMTi) to prevent brk of L-dopa, allowing more L-dopa to enter CNS and converted to DA, then Selegiline works CENTRALLY (MAO-Bi) to allow Dopamine to work in Basal ganglion (end pt effect).
Amantadine MOA
MOA
Old Belief: ↑ DA release & Blocks DA reuptake

**NEW findings point more to BLOCKING NMDA Glutamate Receptor **this is MOA**

**ORIGINALLY used as anti-viral (NO LONGER used for that), UNPREDICABLE benefit for PARKINSONS$$
Amantadine SE: CNS
CNS: Dizziness, confusion, insomnia, anxiety, excitement, hallucinations
Amantadine SE: CV
Edema; orthostatic hypotension
Amantadine SE: main
$$$Livedo reticularis$$  from local release of catecholamines  vasospastic disease (FISHNET appearance in legs & arms, Reddish, bluish Discoloration in legs & arms)
Amantaidien clinical Use
Mild cases alone

Severe cases: Adjunctive therapy with L dopa or anticholinergic drugs

Start low and go up
Trihexphynidly
Benztropine mesylate MOA
Central anticholinergic drug
Blocks Central M1-R 
Decrease excitatory cholinergic activity from striatal neurons
Trihexphynidly
Benztropine mesylate
Indication
Less effective than levodopa

RECOMMENDED over L-dopa only in: **Younger patients w/ mild disease and pts w/ drug-induced parkinsonism$$$


Tremor and rigidity are most improved *bradykinesia less so
Anticolingergic MOA continued
*this works b/c cortex EXCITES CP (striatal neurons) via ACH **so if inhibit this then **REMOVE inhibition on INDIRECT*** path (so GPL is able to inhibit STN, and therefore INCREASE MOTOR b/c no excitation of inhibition on VL thalamus)*** b/c with Parkinsons, then usually the INDRECT path is Hyperexcited **can think of functioning like a D2R agonist (eventhough diff mech)
Trihexphynidly
Benztropine mesylate SE
Metabolism Side Effects
**SIMILAR to ATROPINE effects
CNS: Drowsiness, confusion, delirium, hallucinations









Peripheral: dry mouth, cycloplegia, constipation, urinary retention (anti-SLUD)