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Parkinsonism:Parkinsonism is a movement disorders with Signs of Rigidity of skeletal muscles, Akinesia (or bradykinesia), Flat facies, and Tremor at rest. (RAFT)EtiologyThe cause of Parkinson disease is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions that are involved in motor control. Picture via temography.So in parkison, the reduction in dopamine disturbs the dopamine-ACH balance leading to exacerbating the motor effects of the later Drug Therapy of ParkinsonismSo the Strategies of drug treatment of parkinsonism involve increasing dopamine activity in the brain or decreasing muscarinic cholinergic activity in the brain (or both). A. Levodopa: precursor of dopamine. 1.Mechanisms : because dopamine has low bioavailability and does not readily cross the blood-brain barrier, its precursor, L-dopa (levodopa) is used. This amino acid is converted to dopamine by the enzyme (DOPA decaroxylase), which is present in many body tissues, including the brain. This create problem, since, conversion of Levodopa to dopamine at body tissues provide no benefit (the benefit must be to offer dopamine to the brain), therefore, Levodopa is usually given with carbidopa , a drug that does not cross the blood-brain barrier but inhibits DOPA decarboxylase in the peripheral tissues. With this combination (Levodopa + carbidopa ) {Sinemet) higher brain?s dopamine concerntration is obtained with lower doses of levodopa is achieved. 2. Pharmacologic effects: -Levodopa Ameliorates the signs of parkinsonism, particularly bradykinesia.-But decrease of responsiveness with time occure due to progression of the disease.3. Toxicity : Most adverse effects are dose-dependent. a- Gastrointestinal effects: Anorexia, nausea, and emesis (primary side effects due to dopaminergic mimetic effect). These can be reduced by taking the drug in divided doses. Tolerance to the emetic action of levodopa usually occurs after several months. b- Dyskinesias: On-Off phenomena . c- Behavioral effects : may include anxiety, agitation, confusion, delusions, hallucinations, and depression.B- Bromocriptine and other dopamine agonists: 1- Mechanism of action: Bromocriptine (Parlodel) is an ergot alkaloid that acts as partial agonist at certain dopamine D2 receptors in the brain; the drug increases the functional activity of the dopamine neurotransmitters pathways.Pergolide is anothor ergot derivative that activate dopamine receptors, it may decrease response fluctuations and prolong the effectiveness of levodopa, but the drug loses its activity with time.2- Clinical use: Bromocriptine and pergolide have been used as individual drugs, in combination with levodopa (and with anticholinergic drugs), and in patients who are refractory to or cannot tolerate levodopa. 3- Toxicity: a-Gastrointestinal effects include anorexia, nausea, and vomiting emesis (primary side effects due to dopaminergic mimetic effect) . c-Behavioral effects include confusion, hallucinations, and delusions; those occur more commonly with bromocriptine and pergolide than with levodopa.* Like levodopa, brompcriptine and pergolide are contraindicated in patients with history of psychosis.* Pramipexole:Recently introduced dopamine receptor agonists; they are not ergot derivatives.# They are presently considered to be first-line drugs in the initial management of Parkinson’s disease. Dyskinesias, postural Hypotension and fatigue have been reported.C- Amantadine:1- Mechanism of action:Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that may involve increasing synthesis or release of dopamine. The drug also has muscarinic blocking actions.2- Pharmacologic effect:It may improve bradykinesia, rigidity, and tremor but is usually effective for only a few weeks.Amanatidine also has antiviral effects.3- Toxicity: Behavioral effects include restlessness, insomnia, hallucination, and acute toxic psychosis.Dermatologic reactions. Miscellaneous effects may include gastrointestinal disturbances, urinary retention (antimuscarinic effect). Amantidine also causes peripheral edema that responds to diuretics. D. Selegiline: 1- Mechanism of action:Selegiline is a selective inhibitor of MAO type B, the enzyme isoform that metabolizes dopamine. Selegiline thus increase brain dopamine levels.2- Pharmacologic effects: The drug is used as an Adjunct to levodopa in parkinsonism and has also been used as the sole agent in newly diagnosed Patients. Hepatic metabolism of selegiline results in the Formation of amphetamine.3- Toxicity: Adverse effects include insomnia, mood changes, dyskinesia and gastrointestinal distreess.E-Antimuscarinic drugs:Their use originated when hyoscine was given to parkinsonian patients in an attempt to reduce diarrhea and it then became apparent that they had other beneficial effects in this disease. Synthetic derivatives are now used orally. These include benzhexol (trihexyphenidyl), orphenadrine, benzatropine, procyclidine. There is little to choose between these. Antimuscarinics produce modest improvements in tremor, rigidity, muscular stiffness and leg cramps.Unwanted effects include dry mouth, blurred vision, constipation, urine retention, glaucoma, toxic confusional states and psychoses. hallucinations specially with benzhexol (trihexyphenidyl) {Arten}. ................
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