1. Drugs of Anti-Parkinson’s disease
Department of Pharmacology
Mohammed Q. Mal-Allah

2. Pathogenesis of Parkinson’s disease
Parkinson’s disease (PD) is a progressive disorder of movement that occurs mainly in the elderly. The chief symptoms are:
Tremor at rest, usually starting in the hands (‘pill- rolling’ tremor), which tend to diminish during voluntary activity

3. Pathogenesis of Parkinson’s disease
Muscle rigidity, detectable as an increased resistance in passive limb movement
--Bradykinesia
Suppression of voluntary movements (hypokinesis), due partly to an inherent inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate.

4. Substantia nigra 黑质， corpus striatum 纹状体，　thalamus 丘脑　spinal cord脊索
它的主要病症是不受控制的大肢体运动,伴有认知障碍和精神异常。ＨＤ是一种致死性的神经退行性疾病,病程一般在5年左右。舞蹈病的病变是纹状体投射性ＧＡＢＡ神经元和大脑运动皮层锥体细胞过早死亡。

5. Parkinson’s Disease
Degenerative disease of the basal ganglia causing tremor at rest, muscle rigidity hypokinesia, often with dementia.
Often idiopathic, but may follow stroke, virus infection, can be drug-induced (neuroleptic drugs).

6. Parkinson’s Disease
Associated with marked loss of dopamine from basal ganglia.
Subsequent increase in cholinergic activities

8. Drugs Treatment of Parkinson’s Disease
Drugs that replace dopamine (e.g. levodopa, usually used concomitantly with peripherally acting dopa decarboxylase inhibitor, e.g. carbidopa)
Drugs that mimic the action of dopamine (e.g. bromocriptine, pergolide and others in development)
Levodopa左旋多巴，carbidopa 卡比多巴，Bromocriptine溴隐亭，pergolide培高利特，selegiline司来吉兰，amantadine金刚烷胺，

9. Drugs Treatment of Parkinson’s Disease
MAO-B inhibitors (e.g. selegiline)
Drugs that release dopamine (e.g. amantadine)
Acetylcholine antagonists (e.g. artane)
Levodopa左旋多巴，carbidopa 卡比多巴，Bromocriptine溴隐亭，pergolide培高利特，selegiline司来吉兰，amantadine金刚烷胺，

10. Levodopa
Mechanism:
(1) Because dopamine does not cross the blood-brain barrier levodopa, the precursor of dopamine, is given instead.
(2) Levodopa is formed L-tyrosine and is an intermediate in the synthesis of catecholamines.

11. Levodopa
Mechanism:
(3) Levodopa itself has minimal pharmacologic activity, in contrast to its decarboxylated product, dopamine.
(4) Levodopa is rapidly decarboxylated in the gastrointestinal tract. Prior to the advent of decarboxylase inhibitors (carbidopa), large oral doses of levodopa were required; thus, toxicity from dopamine was a limiting factor.

12. Levodopa Pharmacokinetics:
Levodopa is well absorbed from the small bowel; however, 95% is rapidly decarboxylated in periphery.
Peripheral dopamine is metabolized in the liver to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), which are then excreted in urine.
DOPAC3,4－二羟基苯乙酸，HVA　高香草酸

13. Levodopa Pharmacologic effects:
(1) The effects on bradykinesia and rigidity are more rapid and complete than the effects on tremor. Other motor defects in PD improve. The psychological well-being of patient is also improved.

14. Levodopa Pharmacologic effects:
(2) Tolerance to both beneficial and adverse effects occurs with time. Levodopa is most effective in the first 2-5 years of treatment. After 5 years of therapy, patients have dose-related dyskinesia, inadequate response, or toxicity.

15. Levodopa Adverse effect: Principal adverse effects include:
Anorexia, nausea, and vomiting upon initial administration, which often limit the initial dosage.
Cardiovascular effects, including tachycardia, arrhythmias, and orthostatic hypotension.

16. Levodopa Adverse effect:
(3) Mental disturbances, including vivid dreams, delusions, and hallucination.
(4) Hyperkinesia
(5) On-off phenomena: It means off periods of akinesia with on period of improving mobility

17. This may result from:
1. Decrease sensitivity of dopaminergic receptors.
2.Fluctuation of plasma L-dopa concentration(short half- life).
this can be corrected by giving drug holidays (3-21) days

18. Levodopa Adverse effect:
Sudden discontinuation can result in fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 days.

19. Levodopa Drug interactions:
Vit B6 reduces the beneficial effects of Levodopa by enhancing its extracerebral metabolism.
Therapy with MAO inhibitors must be stopped 14 days prior to the initiation of levodopa therapy.
Phenothiazines, reserpine, and butyrophenones antagonize the effects of levodopa because they lead to a junctional blockade of dopamine action.
Phenothiazine:吩噻嗪, reserpine利血平，butyrophenones丁酰苯

20. L-dopa is combined with peripheral dopa- decarboxylase inhibitors (carbidopa+benserazide) which not cross the BBB increase the brain levels of dopamine and decrease peripheral side effects.
(L-dopa + Carbidopa) Sinemet ®
(L-dopa + Benserazide) Madopar®

21. Carbidopa
Carbidopa is an inhibitor of dopa decarboxylase. Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. As a result, when carbidopa and levodopa are given concomitantly.

22. Carbidopa a. It can decrease the dosage of levodopa.
b. It can reduce toxic side effects of levodopa.
c. A shorter latency period precedes the occurrence of beneficial effects.

26. Selegiline
A selective inhibitor of MAO-B, which predominates in DA-containing regions of the CNS and lacks unwanted peripheral effects of non-selective MAO inhibitors.
It enhances and prolongs the antiparkinsonism effect of levodopa.
It may reduce mild on-off or wearing-off phenomena.

27. Selegiline
Long-term trials showed that the combination of selegiline and levodopa was more effective than levodopa alone in relieving symptoms and prolonging life.

28. Amantadine Therapeutic uses and mechanism of action
Amantadine is an antiviral agent used in the prophylaxis of influenza A2 . It was found to improve parkinsonian symptoms by stimulating the release of dopamine from dopaminergic nerve terminals in the nigrostriatum and delaying its reuptake.

29. Amantadine Therapeutic uses and mechanism of action
Amantadine may be more efficacious in Parkinsonism than the anticholinergic atropine derivatives but is less effective than levodopa. It has been used alone to treat early PD and as an adjunct in later stages.

30. Anticholinergic agents: artane
Mechanism:
Since the deficiency of dopamine in the triatum augments the excitatory cholinergic system in the striatum, the blockade of this system by anticholinergic agents, such as artane, helps to alleviate the motor dysfunction.
Improvement in the parkinsonian tremor is more pronounced than improvement in bradykinesia and rigidity.

31. Artane Therapeutic uses:
Although not as effectives as levodopa or bromocriptine, it may have an additive therapeutic effect at any stage of the disease when taken concurrently.
Adverse effects:
Mental confusion and hallucinations.
It can occur as can peripheral atropine-like toxicity (e.g. cycloplegia, urinary retention, constipation)
muscarine【医】毒蕈碱Cycloplegia【医】睫状体麻痹

32. L-dopa (200 - 250 mg) + Carbidopa (25 - 50 mg) = (Sinemet®)

33. L-dopa (50 mg) + Benserazide (25 mg) = (Madopar®)

34. Lisuride (Dopergin®)

35. Pramipexole (Mirapex®)

36. Selegiline (Jumex®)

37. Entacapone (Comtan®)

38. Benztropine (Cogentin®)

39. Trihexiphenidyl (Parkinol®)

40. Amantadine (Symmetrel®)