Drugs for Parkinsons Flashcards
Parkinsons
Tremor, rigidity, bradykinesia, mask like expression
-Can be idiopathic (elderly) or as a complication of influenza of 1918, meds, MPTP toxicity, neurological disorders
-Loss of nigrostriatal dopamine neurons, loss of dopaminergic innervation of basal ganglia
Strategies Parkinsons Therapy
1) Replace or mimic dopamine
- D2 (D2, D3, D4) like receptors most important therapeutically in PD and associated with indirect nigrostriatal pathway
- D3 receptors are lower in abundance, but mediate some neuroprotective effects
- synergistic interactions between D1-like and D2-like receptors (balance between them are important for greatest efficacy)
2) anticholinergics, amantadine
Replacing dopamine
- dopamine doesn’t cross BBB, so exploit synthesis of dopamine (from tyrosine with L-DOPA as intermediate)
- L-DOPA is transported in the brain by Tyr transporter
- L-DOPA then decarboxylated into dopamine
Rate limiting step of dopamine synthesis
Tyrosine Hydroxylase
L-DOPA
Levodopa
- reversal of rigidity, tremor, bradykinesia, reduced facial expression
- Improved mental function and sense of well-being
- 1/3 of patients respond well, 1/3 not well at all
L-DOPA side effects
- GI: nausea and vomiting because of stimulating of D2 receptors in chemoreceptor trigger zone (CTZ)
- CV: orthostatic hypotension because of stimulation of dopamine receptors in kidney and vasculature but tolerance develops in a few weeks
- Other: dec prolactin secretion (stimulation of D2 receptors in pituitary), mydriasis (can lead to glaucoma because high levels of dopamine act on b receptors), sweating, sleep disturbances), brownish discoloration of body fluids
L-DOPA long term side effects
Motor: fluctuations in efficacy
- on-off effect or bradykinetic episodes
- wearing off- effects don’t last until next dose
Neurological: abnormal involuntary movements (dystonia, dyskinesias, chorea, oral movements) - 80% of patients taking L-DOPA for 3 years
Psychic- hallucinations, paranoia, mania, anxiety, depression due to stimulation of dopamine receptors in targets of mesolimbic and mesocortical pathways
Neuroendocrine effects- renewed sexual interest and behavior, hypersexuality
L-DOPA pharmacokinetics
-oral administration
-absorption depends on GI transit time (longer transit- more degradation in gut- less absorption (unlike other drugs), decreased by anticholinergics)
-peak levels 1/2-2 hrs
-1/2 life 1-3 hrs
more than 95% decarboxylated in periphery so cannot cross the brain and excreted in urine
Carbidopa
- Structurally like L-DOPA
- Inhibitor of aromatic amino acid decarboxylase in periphery to block metabolization leading increased L-DOPA in brain
- decrease dose of L-DOPA and decrease side effects especially GI effects in periphery
-LDOPA only available in US in formulation with carbidopa
Monoamine Oxidase B Inhibitors
Selegiline, Rasagiline
- MAO-B preferentially metabolizes DA
- blocks catabolism of dopamine, and can inhibit MAO-A at higher doses (requires additional precautions)
- Use in adjunct to L-DOPA (inc efficacy, dec L-DOPA dose, dec on-off effect)
MAO-A metabolizes
5-HT and NE
MAO-B metabolizes
DA
-Inhibited by Selegiline and Rasagiline
Catechol-O-methyl transferase (COMT) inhibitors
Tolcapone
Entacapone
blocks catabolism of dopamine and L-DOPA
Use in adjunct to L-DOPA
Tolcapone
COMT inhibitor
more potent and longer acting
central and peripheral actions
hepatotoxic
Entacapone
peripheral COMT inhibitor
Contraindications of L-DOPA
Abrupt discontinuation
-result in symptoms resembling neuroleptic malignant syndrome because of dopamine receptors being stimulated constantly
Closed angle glaucoma because of stimulation of B receptors
Melanoma- L-DOPA precursor of melanin
Breast feeding mother because inhibits prolactin secretion
Use with Caution for L-DOPA
psychosis, cardiac disease (can cause arrythmias), peptic ulcer (cause bleeding), open angle glaucoma (if intraocular pressure is well controlled)
Monotherapy or add on dopamine agonists
Pramipexole
Ropinerole
Rotigotine
All are D2/D3 agonists, rotigotine is also D1 agonist and is transdermal
Dopamine agonists that are Add on with L-DOPA
Bromocriptine-D2 agonist
Apomorphine- non ergot D1/D2 agonist
Dopamine agonists
Agonist at D2 and other dopamine receptors, activity at D3 may confer greater efficacy and may mediate neuroprotective effects
-Use monotherapy or add on with L-DOPA to improve response especially with fluctuations in efficacy
Dopamine agonist side effects
nausea, vomiting, postural hypotension, hallucinations
-lower incidence of dyskinesias than with L-DOPA
Anticholinergics
Trihexyphenidyl
Benztropine
Procyclidine
Block actions of striatal cholinergic interneurons which lowers GABA activity
Generally less effective than L-DOPA
Used alone early in course of disease
Side effects of anticholinergics
constipation, urinary hesitance, retention, mental confusion, hallucinations
Normal activity of dopamine and ach with GABA
Dopamine from substantia nigra and Ach from striatal cholinergic interneurons in corpus striatum activates GABA
-in parkinsonism, dopamine is not present, so Ach is acting unopposed, leading to inc activation of GABA
Amantadine
Antiviral
Unknown mechanism- may release dopamine and/or have anticholinergic properties and some NMDA activity
-less efficacious than L-DOPA
-also used for tx or prophylaxis of influenza A virus
- monotherapy or adjunct to L-DOPA
- Sometimes used early in treatment and often effective only for few weeks
- approved for parkinson’s dyskinesia in 2017
SE of amantadine
similar to dopamine agonists, may produce livedo reticularis, peripheral edema, headache
-use with caution in pts with seizure disorders
Pimavenserin
Indicated for PD psychosis
-inverse agonist and antagonist activity at 5-HT2a and 5-HT2c receptors
