Drug Management of Parkinsonism By Prof. Mohammad Saleh M. Hassan PhD. (Pharma); MSc. (Ped.); MHPE (Ed.)
Drug management of Parkinsonism Levodopa Ergot derivatives noamine Oxidaes Inhibitors Catechol-Omethyl transferase inhibitors Amantadine Acetylcholineblocking drugs
Dopamine receptors: D1 & D5 stimulate adenylyl cyclase increase camp. D 2- D4 inhibit adenylyl cyclase Stimulation of D2 receptors by dopamine agonists is important for antiparkinsonism.
Levodopa: Dopamine does not cross BBB. Levodopa does cross decarboxylated to dopamine in the brain. Given orally largely metabolized by liver by dopa decarboxylase excreted in urine.
If given alone 1-3% only is available to brain. If given with dopa decarboxylase inhibitor carbidopa 10% cross BBB. The best results are obtained in the first 3 4 years of therapy then the response gradually decreases.
Adverse effects of levodopa: 1-On GIT: -Anorexia, nausea, and vomiting (central on emetic center and peripheral due to decarboxylase inhibition). Minimize vomiting by: -Small frequent doses. -After meals. -Antacids 30-60 min. before the drug. -combine levodopa with carbidopa.
2-CV effects: -Arrhythmias (decreased with combination). -Postural hypotension (diminish with time). -Hypertension (if combined with MAO inhibitors, or with sympathomimetics or with massive doses).
3-Dyskinesias: -Occur in 80% of patients. -Many forms, singly or in combination e.g. chorea, ballismus, athetosis, dystonia, myoclonus, tics, and tremors. -Choreoathetosis is common.
4-Behavioral effects: -Depression, anxiety agitation, insomnia, somnolence, confusion, hallucinations, nightmares, euphoria, change in personality.
5-Fluctuation in response: -May occur in initial phase of treatment. -May be in the form of On-Off phenomenon, where Off is associated with periods of akinesia and On is associated with improved mobility and dyskinesia.
To overcome this phenomenon: -Smaller and more frequent doses. -Addition of dopamine agonists bromocriptine -Reduction of dietary intake of protein and the main protein meals are in the evening. -Use controlled-release formulations Sinemet. -Taking sinemet in liquid form.
6- Other adverse effects: -Mydriasis --? acute glucoma. -Rare blood dyscrasias, hemolysis. -Hot flushes, attack of gout. -Abnormality of smell or taste. -Brownish discolouration of body secretions. -Elevated liver enzymes.
Drug Holidays: -Done with great caution and better avoided. Containdications: -Psychotic patients, angle closur glucoma, melanoma. -Used with caution in cardiac and peptic ulcer patients.
Ergot derivatives -Partial agonist at presynaptic D2 receptors. Bromocriptine Pergolide Bromocriptine: -Dopamine agonist derived from ergot alkaloid.
Given orally, variable absorption, excreted in bile. May be combined with levodopacarbidopa to minimize adverse effects. The daily dose is 7.5-30 mg built up slowly (reduce the concurrently used levodopa to half the dose). It is better to give a test dose of 1 mg initially to the patient inbed to avoid or minimize vascular collapse, then gradually increase the dose.
Adverse effects: GIT: up-set, bleeding from peptic ulcer. CVS: postural hypotension, painless digital vaso- spasm, cardiac arrhythmias. Dyskinesias. Mental disturbances. Others: headache, nasal congestion, increased arousal pulmonary infiltrates, and erythromelalgia.
Contraindications: Psychotic patients, and recent myocardial infarction. Better avoided in peripheral vascular disease and in peptic ulcer.
Pergolide: Dopamine agonist ergot derivative. It stimulates D1 & D2 receptors. Well tolerated but with frequent adverse effects at initial therapy. It looses its efficacy with time down regulation of dopamine receptors. Start with 0.05 mg daily and gradually increase to 3 mg daily and reduce levodopa dose if given concurrently.
Monoamine Oxidase Inhibitors Selegiline Monoamine Oxidase Inhibitors: MAO-A: metabolizes norepinephrine and serotonine. MAO-B: metabolizes dopamine.
Selegiline: Selective MAO-B inhibitor prolongs the antiparkinsonian effect of levodopa. Given orally, 5 mg with breakfast and 5 mg with lunch.
Catechol-O-Methyltransferase inhibitors: Inhibition of dopa decarboxylase activates COMT increased plasma level of methyldopa poor therapeutic response to levodopa. Still currently evaluated before use.
Amantadine: It is an antiviral agent. Unknown mechanism of action, but may potentiate dopaminergic function by increase synthesis, release or reuptake of dopamine. The dose is 100 mg twice daily.
Adverse effects include: restlessness, depression, irritability, insomnia, agitation, excitement, hallucination, confusion, peripheral edema, headache, CHF, postural hypotension, urinary retention, and GIT disturbances. Overdose toxic psychosis, convulsions.
Acetylcholine Blocking drugs: Centrally acting antimuscarinic drugs include: Benztropin mesylate daily dose 1-6 mg Biperiden daily dose 2-12 mg Orphenadrine daily dose 150-400 mg Procyclidine daily dose 7.5-30 mg Trihexaphenidyl daily dose 6-20 mg
Start with low doses and increase gradually. They improve tremors and rigidity but not bradykinesia.
Adverse effects include: drowsiness, mental slowness, inattention, restlessness, confusion, agitation, delusions, hallucinations, and mood changes. Dry mouth, blurring of vision, mydriasis, urinary retention, nausea, vomiting, constipation, tachycardia, arrhythmia, tachypnea and glaucoma.