Antiparkinson Drugs Flashcards
cardinal features of parkinsons
resting tremor, muscular rigidity, bradykinesia, gait impairment
principal metabolite of dopamine
HVA - homovanillic acid
what do the D1 and D2 receptors do
- D1: activated adenylyl cyclase
- D2: inhibits adenylyl cyclase, opens K+ channels, suppresses Ca2+ currents
classification of drugs used to treat parkinsons
AAIDD
Amantadine
Antimuscarinics
Inhibitors of Dopamine Metabolism: COMT and MAO
Dopamine Precursors
Dopamine Receptor Agonists: Ergot and Non-ergot dopamine agonists
what is the dopamine precursor drug
Levodopa
mechanism of levodopa
transported into the brain by facilitative L transport system –> converted to dopamine in the brain using DOPA decarboxylase
what drug is given with levodopa and why
Carbidopa - Dopa decarboxylase inhibitor
- it does not cross into the brain but works in the periphery by preventing conversion to dopamine in the periphery so that most of the L-DOPA can cause into the brain
- also conversion to dopamine in periphery –> nausea, vomiting, cardiac arrhythmias, hypotension
what is Sinemet
preparation containing carbidopa and L-DOPA in fixed preparation
what is levodopa’s metabolite
homovanillic acid (HVA) dihydroxyphenylacetic acid (DOPAC)
what happens with long term use of levodopa
it is only effective for 3-5 years then responsiveness becomes lost completely
AE of levodopa
GI effects (dopamine agonists cause nausea and vomiting) CNS effects (Visual and auditory hallucinations and dyskinesia) CVS effects (dopamine stimulates heart -- tachycardia)
what is the on-off phenomenon seen with levodopa
-off periods of marked akinesia alternate over on periods of improved mobility but often marked dyskinesia
contraindications of levodopa
HAV PAMP
- Hypertensive crisis with Phenelzine or Tranylcypromine (MAOI)
- Angle closure glaucoma
- Vitamin B6 (co factor for L-dopa decarboxylase)
- Psychotic patients esp if on Antipsychotics
- Arrhythmias in cardiac patients
- Melanoma
- Peptic ulcers
what are the dopamine receptor agonists
Ergot derivatives: Bromocriptine
Non ergot derivatives: PARR Pramipexole Apomorphine Ropinirole Rotigotine
mechanism of bromocriptine and what is it used to treat
D2 agonist
Parkinsons
Hyperprolactinemia
mechanisms of the non ergot derivatives dopamine agonist
Pramipexole: preferential affinity for D3 receptors
Apomorphine: dopamine agonist
Ropinorole: purely D2 receptor agonist
Rotigotine: transdermal formulation that is dopamine agonist
AE of the nonergot dopamine agonists (minus apomorphine)
GI effects (nausea and vomiting) CVS effects Dyskinesia Mental disturbances: hallucination etc Somnolence
harder ones to reason out:
Pulmonary Infiltrates
Pleural and Retroperitoneal Fibrosis
Erythromelalgia
long term complication of ergot derivatives dopamine agonist
painless digital vasospasm
when is apomorphine usually used
in off periods of akinesia in patients on dopaminergic therapy
since apomorphine is highly emetogenic, what pre treatment is usually used
Trimethobenzamide
Domperidone
contraindication of apomorphine
5-HT3 antagonist -> profound hypotension and loss of consciousness
AE of apomorphine
QT prolongation
what are the inhibitors of dopamine metabolism
MAO inhibitors: Selegiline and Rasagiline
COMT inhibitors: Tolcapone and Entacapone
what are the MAOIs used for in treatment of parkinson
- Selegeline: selectively inhibits MAO-B so prevents breakdown of dopamine and enhances effect of levodopa (little chance for hypertensive crisis)
- Rasagiline: prolongs effects of levodopa-carbidopa in parkinson patients
what is Selegiline metabolized to and its importance
Methamphetamine and Amphetamine –> insomnia if taken after midafternoon
what occurs when carbidopa is used together with levodopa (name the COMT inhibitors)
Tolcapone and Entacapone
-firstly inhibition of dopa decarboxylase by carbidopa –> increased in COMT in order to metabolized levodopa –> increases plasma 3-O-methyldopa (3-OMD) –> competes with levodopa for a carrier hence the levodopa that aren’t bound are not useful since they don’t get into the brain
what is mechanism of COMT inhibitors
Tolcapone and Entacapone
decrease metabolism of levodopa
decreased 3-O-methyldopa (3-OMD)
increased uptake of levodopa
higher concentration of dopamine in the brain
where do the COMT inhibitors exert their effect
Tolcapone in the central and periphery
Entacapone only periphery
why is Entacapone preferred over Tolcapone
- not associated with hepatotoxicity (TOLCAPONE LEADS TO HEPATIC NECROSIS)
- available as fixed dose with levodopa/carbidopa
AE of COMT inhibitors
Entacapone and Tolcapone
- increased levodopa: dyskinesias, nausea, vomiting
- fulminating hepatic necrosis with Tolcapone (every 2 week monitoring of liver function)
- Orange discoloration of urine
mechanism of amantadine in parkinsons
increase synthesis, release, or re-uptake of dopamine from surviving neurons
AE of amantadine
Livedo Reticularis (lace like purplish discoloration of skin)
contraindications/caution that should be taken in patient taken amantadine
caution in patients with history of seizures and heart failure
antimuscarinics used in treatment of parkinsons
Benztropine
Trihexyphenidyl
AE of the antimuscarinics
benztropine and trihexyphenidyl
xerostomia, pupillary dilation, dry mouth, other effects associated with anticholinergics
contraindication of antimuscarinics
benztropine and trihexyphenidyl
Glaucoma
Prostatic Hypertrophy
Pyloric Stenosis
most effective symptomatic treatment of Parkinsons
Levodopa with Carbidopa
reduce motor fluctuations in patients with advanced disease
MAOI and COMT-I
used for control of tremor and drooling
antimuscarinics
