Parkinsonism

1. Parkinsonism

2. Parkinsonism is a movement disorder that involves dysfunction in the basal ganglia and the related brain structures. Patients develop the following : (RAFT) 1-Rigidity of skeletal muscles 2-Akinesia 3-Flat facies 4-Tremor at rest

3. PATHOPHYSIOLOGy: Degeneration of dopamine neurons in the substentia nigra with a decrease in the levels of straital dopamine that normally responsible for inhibition of GABA activity. The reduction of dopamine leads to dominent actions of cholinergic neuron on GABA. So the balance between Ach and dopamine is disturbed.

4. Etiology of parkinsonism : 1-naturally :increase during aging or 2-induced by drugs which is either A-reversible (antipsychotic) or B-irreversible the butyrophenones &phenothiazines MPTP which is a byproduct of meperidine analog that causes irreversible parkinsonism. Note: MPTP = (1-methyl 4-phenyl 1,2,3,6- tetrahydropyridine)

5. The strategies of drug treatment in parkinsonism To restore the balance between Ach and dopamine WE MUST: A-Increasing dopamine activity in the brain by 1-Increase synthesis of dopamine or 2-Decrease uptake of dopamine or or 3- Giving dopamine agonist 4- Using drugs that inhibit metabolism of dopamine. B- Decreasing muscarinic cholinergic activity in the brain or 3-Both.

6. DRUGS USED IN PARKINSONISM 1. Levodopa : Dopamine has low bioavailability and does notcrossBBB, Thus L-dope is used. L-dope is converted by dopadecarboxylase to dopamine in many tissues including the peripheral tissues and brain. This lead more dopamine in peripheral region with only few amount of dopamine reaches the CNS

8. For this reason Levodopa is usually given in combination with decarboxylaseinhibitor. Decarboxylaseinhibitor including 1-carbidopa 2-Benserazide

9. This combination is used because Carbidopa 1- Does not cross the BBB 2- Inhibits dopa decarboxylase in the periphery and not centerally 3- Less doses of levodopa is needed 4- Fewer side effects

10. pharmacokinetics: this drug 1-Absorbed rapidly from small intestine. 2- Has a shortt1/2 (1-2 hrs). 3- Affected by Ingestion of meals rich in proteins.

11. Adverse effects: They are dose related. a- CVS : tachycardia and arrhythmias postural hypotension (in early stages) b- GIT : anorexia, nausea, and vomiting (due to stimulation of CTZ) that can be decreased by dividing the dose of the drug. Tolerance to the emetic action occurs after months.

13. c .Behavioral : anxiety, agitation, hallucination, confusion, delusion and depression. d- Dyskineseas:choreoathetosis of the face and distal extremities. Some times myoclonics, tics, and tremors.

14. e- Other adverse effects: -Mydriasis (adrenergic action), -Brown discoloration of saliva and urine (bs stimulation of melanin secretion).

15. Interactions : With a- pyridoxine (Vit. B6 increases the peripheral (breakdown of L-dopa b- General MAOIs lead to hypertensive crisis because of increased catecholamines

16. Contraindication: 1- Antipsychotic drugs. 2- Glaucoma (increases intraocular Pressure). 3- Active peptic ulcer in patients with melanoma. 4- Cardiac problems

18. 2. Dopamine agonists: 2 types: 1- Ergot alkaloids including: A- Bromocriptine B- Pergolide 2-non ‑ ergot alkaloids

19. Bromocriptine: (an ergot alkaloid) acts as 1- a partial agonist on D2 receptor in the brain with 2- Little alpha antagonist effect. Pergolide (ergot alkaloid ) act by activation of dopamine receptors.

20. Clinical use: they are used as 1-individual drugs, 2- Combined with levodopa 3- end-of-dose deterioration of l‑dopa. 3- Intoleration to levodopa. .

21. Side effects: CVS: cardiac arrhythmias and postural hypotension Dyskinesiassimilar to L-Dopa. Behavioral : hallucination, confusion, and delusion (occur more than with L-dopa). GIT : anorexia, nausea, and vomiting.

22. Contraindication: psychosis. Ergotrelatessideeffects: 1- pulmonary infiltrates 2- erthromealgia

23. Non-ergot derivatives: Include -Pramipexole (D3 agonist) and -Ropinirole (pureD2agonist). They are considered to be first line drugs in the initial management of Parkinsonism.

24. Sideeffects: Include postural hypotension, dyskinesias, fatigue and sleepiness.

25. Amantadine: Is an antiviral drug. It enhances Dopamine may be by 1-increasing synthesis and release of dopamine or 2-inhibition of reuptake of dopamine. 3- muscarinic blocking actions.

26. Sideeffectsinclude -Behavioral: restlessness, hallucination, agitation, confusion and acute toxic psychosis. -urinary effects: retention, (anti cholinergic effect) -GIT :effect as nausea and vomiting -postural hypotension. -Dermatological reactions include livedo reticularis -peripheral edema that may respond to diuretics.

27. 4. Selegiline and rasagiline: a selective MAO-B inhibitor, (the enzyme that metabolizes dopamine to nor epinephrine and serotonin) It is used in 1- Newly diagnosed parkinson patients. 2- Adjunct to L-dopa .

28. at low to moderate doses does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin). So its selective . in high doses it loses its selectivity

29. Side effects: mood changes insomnia, GIT upset, hypotension and dyskinesia.

30. Contraindication: with 1-patients taking meperidine 2-selective serotonin reuptake inhibitors.

32. 5-Inhibitor of COMT: They include -Intacapone -Tolcapone. These drugs selectively and irreversibly inhibit C0MT. They compete with levo dopa for active transport to the CNS.

34. Clinicaluses.: adjuncts to levo dopa‑carbidopa giving better response Adverse effects -Tolcapone may cause acute hepatic failure.

35. 6 -Antimuscarinic Drugs: centrally acting antimuscarinic preparations are used as Benzotropine, Biperidin, orphenadine, Procyclidine. Trihexyphenidyl,

36. mechanism of action: block actions of cholinergic neurons in the brain by blocking muscarinic receptors. Adverse effect: 1-CNS effect: drowsiness, confusion, delusion, and hallucination. 2-Peripheral effects: like atropine

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