1. Drugs for Parkinson’s disease

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:
H ypokinesia
R igidity
T remors

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4. Parkinson’s Disease A degenerative and progressive disorder
Associated with neurological consequences of decreased dopamine levels produced by the basal ganglia (substantia nigra)
Dopamine is a neurotransmitter found in the neural synapses in the brain
Normally, neurones from the SN supply dopamine to the corpus striatum (controls unconscious muscle control)
Initiates movement, speech and self-expression

5. Basis to exploit by drugs:
Balance, posture, muscle tone and involuntary movement depends on the roles of dopamine (inhibitory) and acetylcholine (Ach: excitatory)
Basis to exploit by drugs:
Restore dopamine function
Inhibit Ach within corpus striatum

6. Consequences of dopamine reductions
Tremors – hands and head develop involuntary movements when at rest; pin-rolling sign (finger and thumb)
Muscle rigidity – arthritis-like stiffness, difficulty in bending or moving limbs; poker face
Bradykinesia – problems chewing, swallowing or speaking; difficulty in initiating movements and controlling fine movements; walking becomes difficult (shuffle feet)
Postural instability – humped over appearance, prone to falls

7. Clinical Presentation
Altered body image (depression)
Poor balance
Bradykinesia (slow movement)
Bradyphrenia (slowness of thought)
Constipation
Dribbling/drooling
Dyskinesias (involuntary movements)
Dysphagia (difficulty swallowing
Dystonia (pain spasms)
Excessive sweating (impaired thermoregulation)
Festinating gait
Hallucinations (visual)
Postural hypotension
Restless leg syndrome (leg aches, tingle, or burn)
Rigidity
Sleep disturbance
Slurring/slowing of speech
Tremor

8. Causes number of factors: Environmental – toxins
Free Radicals – there is a increase in post-mortem brain sections
Aging – age related decline in dopamine production
Genetic – genes encode for
-α-synuclein
-Carboxy terminal hydroxylase of parkin & ubiquitin

9. 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。

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12. Action of MPTP
1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) causes irreversible destruction of nigrostriatal dopaminergic neurons in various species, and produces a PD-like state in primates.
MPP+ is taken up by the dopaminergic neurons, selective in destroying nigrostriatal neurons. It inhibits mitochondrial oxidation reactions, producing oxidative stress.
MAO-B
MPTP
MPP+
inhibit
Selegiline

13. Medication Rational Replace depleted levels of dopamine
Stimulate the nerve receptors enabling neurotransmission
Increase the effect of dopamine on nerve receptors (agonist)
Counteract the imbalance of Ach and Dopamine

14. The Drugs: Dopaminergic drugs (improving dopamine functioning)
Levodopa
Dopamine receptor agonists
Amantadine
Selective monoamine oxidase B inhibitors
Catechol-O-methyltransferase inhibitors
Antimuscarinic drugs (Ach inhibitors)

15. Drugs Treatment of Parkinson’s Disease
Dopamine precursor –levodopa
Peripherally dopa decarboxylase inhibitor (carbidopa)
COMT inhibitors ( entacapone, tolcapone)
Drugs that mimic the action of dopamine ( bromocriptine, cabergoline, ropinirole, pramipexole)
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，

16. Drugs Treatment of Parkinson’s Disease
MAO-B inhibitors (e.g. selegiline)
Drugs that release dopamine (e.g. amantadine)
Centrally acting antimuscarinic drugs (e.g. trihexyphenidyl, procyclidine, orphenadrine, benztropine)

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

19. 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.

20. 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.

21. Levodopa Pharmacologic effects:
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.

22. Levodopa Pharmacologic effects:
Tolerance to both beneficial and adverse effects occurs with time. Levodopa is most effective in the first 2-5 years of treatment.
wearing off effect
On-off phenomenon

23. 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.

24. Levodopa Adverse effect:
(3) Mental disturbances, including vivid dreams, delusions, and hallucination.
(4) Hyperkinesia
(5) On-off phenomena

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

26. Levodopa Drug interactions:
Vit B6 reduces the beneficial effects of Levodopa by enhancing its extracerebral metabolism.
Phenothiazines, reserpine, and butyrophenones antagonize the effects of levodopa because they lead to a junctional blockade of dopamine action.

27. 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.

28. Carbidopa Virtue: 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.

29. 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.

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

32. COMT- inhibitors (entacapone)
MoA: inhibits the breakdown of levodopa
Pharmacokinetics: variability of absorption, extensive first-pass metabolism, short half-life
Adverse effects: dyskinesias, hallucinations

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

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

35. Therapeutic uses:
Although not as effectives as levodopa, 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)

36. Huntington’s Chorea Inherited autosomal dominant disorder
Error in huntingtin gene
Synthesis of huntingtin protein (repeats of polyglutamine cause excitotoxicity and apoptosis in cortex and striatum)
Degeneration of GABAergic neurons in the striatum

37. Huntington’s Chorea
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。

38. Huntington’s Chorea Dance like movements of limbs
Rhythmic movements of tongue and face
Dementia
Progressive brain degeneration

39. Huntington’s Chorea Tx
Chlorpromazine
Haloperidol
Olanzapine

40. Alzheimer’s disease Progressive memory loss
Disordered cognitive functions
Reduced verbal fluency
Bedridden as disease progresses
Complications of immobility

41. Alzheimer’s disease
Amyloid plaque (extracellular deposits of β-amyloid protein)
Intraneuronal neurofibrillary tangles (aggregates of highly phosphorylated neuronal protein)
Loss of cholinergic neurons in brain (originates from nucleus basalis in forebrain and project to frontal cortex and hippocampus)

42. Alzheimer’s disease Tx
Anticholinesterases
Tacrine (hepatotoxic)
Donepezil
Rivastigmine
Galantamine
NMDA antagonist
Memantine
Nootropics
Piracetam
Anti-oxidants
Vit. A, C,
Zinc, Selenium
Miscellaneous
Statins
Ibuprofen

43. Multiple Sclerosis Demylenation in brain, spinal cord, optic nerves
autoimmune
Weakness, numbness, spastic paraparesis, diplopia, sphincter disturbances Tx
Interferon beta-1b
Natalizumab
Baclofen, Diazepam (for spasticity)

44. Amyotropic Lateral sclerosis
Neurodegenerative dis. of motor neurons
Muscle wasting and atrophy
Defective superoxide dismutase (defective scavenging of superoxide free radicals)
Defective glutamate uptake (excitotoxicity)
Spontaneous twitching of motor units
Difficulty in chewing & swallowing
Respiratory failure & death within 5 yrs
Tx – Riluzole (↓es glutamate release)

45. Psychostimulants Amphetamine & Methylphenidate
(release NA & DA in brain) -ADHD
Modafinil-
inc alertness & keep awake
Caffeine-
Migraine, allay fatigue, apnoea in premature infants

46. MCQs Q1. In parkinsonism, Carbidopa acts as: Dopamine agonist
Dopamine precursor
Peripheral decarboxylase inhibitor
Dopamine reuptake blocker
Ans- C

47. Q2. In parkinsonism, Entacapone acts as:
Dopamine agonist
Dopamine precursor
COMT inhibitor
Dopamine reuptake blocker
Ans- C

48. Q 3.Which one of the following clinical features of parkinsonism is benefited more by central anticholinergic drugs?
Hypokinesia
Rigidity
Tremors
Festinating gait
Ans C

49. Q 4.Which one of the following clinical features of parkinsonism is resolved first by levodopa?
Hypokinesia
Rigidity
Tremors
Festinating gait
Ans A and B

50. Q5. Tolcapone is withdrawn due to
Cadiotoxicity
Nephrotoxicity
Carcinogenecity
Hepatotoxicity
Ans D

51. Thank you

52. Bibliography
Essentials of Medical Pharmacology -7th edition by KD Tripathi
Goodman & Gilman's the Pharmacological Basis of Therapeutics  12th edition by Laurence Brunton (Editor)
Lippincott's Illustrated Reviews: Pharmacology  - 6th edition by Richard A. Harvey
Basic and Clinical pharmacology 11th edition by Bertram G Katzung
Rang & Dale's Pharmacology -7th edition  by Humphrey P. Rang
Clinical Pharmacology 11th edition By Bennett and Brown, Churchill Livingstone
Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
Review of Pharmacology by Gobind Sparsh