Drug Management of Parkinsonism. By Prof. Mohammad Saleh M. Hassan PhD. (Pharma); MSc. (Ped.); MHPE (Ed.)
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1 Drug Management of Parkinsonism By Prof. Mohammad Saleh M. Hassan PhD. (Pharma); MSc. (Ped.); MHPE (Ed.)
2 Drug management of Parkinsonism Levodopa Ergot derivatives noamine Oxidaes Inhibitors Catechol-Omethyl transferase inhibitors Amantadine Acetylcholineblocking drugs
3 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.
4 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.
5 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.
6 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 min. before the drug. -combine levodopa with carbidopa.
7 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).
8 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.
9 4-Behavioral effects: -Depression, anxiety agitation, insomnia, somnolence, confusion, hallucinations, nightmares, euphoria, change in personality.
10 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.
11 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.
12 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.
13 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.
14 Ergot derivatives -Partial agonist at presynaptic D2 receptors. Bromocriptine Pergolide Bromocriptine: -Dopamine agonist derived from ergot alkaloid.
15 Given orally, variable absorption, excreted in bile. May be combined with levodopacarbidopa to minimize adverse effects. The daily dose is 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.
16 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.
17 Contraindications: Psychotic patients, and recent myocardial infarction. Better avoided in peripheral vascular disease and in peptic ulcer.
18 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.
19 Monoamine Oxidase Inhibitors Selegiline Monoamine Oxidase Inhibitors: MAO-A: metabolizes norepinephrine and serotonine. MAO-B: metabolizes dopamine.
20 Selegiline: Selective MAO-B inhibitor prolongs the antiparkinsonian effect of levodopa. Given orally, 5 mg with breakfast and 5 mg with lunch.
21 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.
22 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.
23 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.
24 Acetylcholine Blocking drugs: Centrally acting antimuscarinic drugs include: Benztropin mesylate daily dose 1-6 mg Biperiden daily dose 2-12 mg Orphenadrine daily dose mg Procyclidine daily dose mg Trihexaphenidyl daily dose 6-20 mg
25 Start with low doses and increase gradually. They improve tremors and rigidity but not bradykinesia.
26 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.
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