1. The document discusses the pharmacology of drugs used to treat Parkinson's disease. It describes the mechanisms and side effects of various dopaminergic medications like levodopa, dopamine receptor agonists, MAO-B inhibitors, and COMT inhibitors. 2. Anticholinergic drugs are also covered, which are used to treat tremor and rigidity but not bradykinesia. Other drugs mentioned include amantadine and apomorphine. 3. The document concludes with a section on review questions related to the pharmacology of Parkinson's disease treatments.

1. PHARMACOLOGY OF DRUGS OF
PARKINISON DISEASE
Amos Mapesa B.Sc. M.Sc.
BScN
Maasai Mara University, Narok
1

2. PARKINSONISM DISEASE
• Diagnostic manifestation= Bradykinesia.
• Progressive disease
• Incurable disease
• Pharmacologic treatment relive motor symptoms
• Dopaminergic neurons affected=↓ Dopamine
• Cholinergic pathway spared=↑ exaggerated cholinergic activity
2

3. PARKINSONISM DISEASE II
• Dopaminergic neurons are in substantia niagra (midbrain)
• D-2 receptors are putative mediator of PD drugs.
• D-2 receptors are located postsynaptically on striatal neurones.
• D-2 receptors are located presynaptically on substantia Niagara.
3

4. Muscarinic Receptors
Muscarinic Receptors (M1) = Located on striatum

5. COMPONENTS OF BASAL GANGLIA D1=Gs=AC
D2=Gi=AC

6. PATHWAYS
DIRECT= INHIBITORY
INDIRECT =STIMULATORY

8. Dopamine is a derivatives of
tyrosine that is broken down to
adrenaline.

9. GOAL OF TREATMENT
• Enhance availability of dopamine in BBB=↓ Breakdown of Dopamine,
↑ D2 agonists.
• Reduce cholinergic activity in BBB= ↑ anticholinergic drugs.

11. 1. DOPAMINE PRECUSSOR: LEVODOPA -PK
• Rapidly absorbed in small intestines.
• Food delays plasma availability
• Compete with dietary amino acid for absorption
• Peak in plasma 1-2 hours after oral dose
• Plasma t1/2 = 1-3 hours
• 2/3rd appear in urine as metabolite within 8 hours of oral dose.
• Two metabolites= 3-methoxy-4-phenylacetic acid & dihydroxyphenylacetic
acid (DOPAC)
• Only 1-3% of oral Levodopa enters BBB (∴ need of decarboxylase inhibitor
!!!)

12. LEVODOPA-PK
Decarboxylase inhibitor (Carbidopa):-
• Reduce peripheral metabolism to dopamine
• Plasma concentration
• Elongate plasma t1/2
• Improve entry of Levodopa in brain
• Dopamine does not penetrate BBB
• Reduces daily need of LEVODOPA by 75%

13. Levodopa With and
Without Decarboxylase
Inhibitor

14. LEVODOPA-PD
• It is precursor of dopamine
• Therapeutic effect ↓ with time
• Loss of nigrostriatal nerves = ↓ response to levodopa
• Benefits diminish after 3 years
• Levodopa does not lower progression of disease
• Given in combination with CARBIDOPA i.e. 25 mg Cabidopa + 100 mg
Levodopa= ↓ peripheral metabolism, ↑striatal distribution
• Dopamin agonist such as bromocriptine reduce response fluctuations
• Levodopa reduces Bradykinesia

15. LEVODOPA- S/E
• GIT=Anorexia, nausea, vomiting (dopamine stimulate chemoreceptor
trigger zone outside BBB in brain stem)= N/V reduces when carbidopa
is added.
• CVS= arrhythmias (HR) due to increased catecholamine. Postural
hypotension, HTN.
• Behavioral Effects= depression, agitation, insomnia, somnolence,
euphoria (common in Levodopa+Cabidopa due to high CNS levels)
• Behavioral effect treated with atypical antipsychotic (clozapine,
olanzapine, risperidone)=Low affinity on D2 receptors

16. LEVODOPA-SE
• Dopamine dysregulation syndrome –compulsive overuse of levodopa
• Punding –repetitive complex and purposeful motor activity i.e. grooming.
Rx=↓dose
• Dyskinesia (chreoatherosis most common) due to uneven distribution of
striatal dopamine = Rx=↓ Levodopa dose, give Amantadine or clozapine
• Mydriasis, Glaucoma
• Gout, BUN, bilirubin
• Drug holidays(stopping levodopa 3-21 days) may be used to S/E and
improve response.
• Drawback of Drug holiday = immobility which increases risk of aspiration
pneumonia

17. LEVODOPA: DRUG INTERACTIONS
• Pyridoxine (vitamin B6) ↓ therapeutic effect= ↑ extracerebral
metabolism.
• Levodopa+ Monoamine oxidase A inhibitor = Hypertensive crisis
(200/100mmHg)- such combo should be avoided, even 2 weeks of
discontinuance.

18. LEVODOPA: CONTRAINDICATIONS
• Psychotic patients = ↑ mental disturbance
• Angle closure glaucoma
• GIT bleeding may worsen
• History of melanoma= dopamine is precursor of melanin

20. 2. DOPAMINE RECEPTOR AGONIST (DRA)
• Bromocriptine = Selective D2 agonist, enhances levodopa effect,
reduce fluctuation, reduce S/E, reduce dose of levodopa.
• Pergolide= D1 and D2 agonist = causes valvuler heart diseases
• Pramipexole = Preferential D3 receptors, effective for mild
parkinsonism, rapid absorption, adjustment to doses in renal
insufficiency.
• Ropinirole- selective D2 agonist, monotherapy in mild PD, CYP1A2
metabolized
• Rotigotine=skin patch delivery, early PD, has continuous dopaminergic
stimulation than oral drugs, may cause reaction at application site

21. DRA: S/E
Gastrointestinal Effects
• Anorexia and nausea and vomiting – Take with meals to ↓.
• Constipation
• Dyspepsia
• reflux esophagitis.
• Bleeding from peptic ulceration.

22. DRA: S/E II
Cardiovascular Effects
• Postural hypotension @ the initiation.
• Painless digital vasospasm- ergot derivatives (bromocriptine or
pergolide).
• Cardiac arrhythmias with discontinuing treatment.
• Peripheral edema.
• Cardiac valvulopathy with pergolide

23. DRA: S/E III
Mental Disturbances
• Confusion, Hallucinations, Delusions.
• DRA MAY CAUSE Disorders of impulse control:
1. Compulsive gambling, shopping, betting, sexual activity.
2. Due to activation of D2 or D3 receptors in Limbic system.
3. It is dose-dependent. Impulse control.

24. DRA: S/E III
Dyskinesia
• Abnormal movements- Rx: ↓total dose of dopaminergic drugs.
Severity of Complications of DRA RX > levodopa.
• Complications with DRA common with geriatric.
• Complication ↑ as disease advance

25. DRA: C/I
• Psychotic patients
• Recent myocardial infarction
• Active peptic ulceration.
• Ergot-derived agonists C/I in peripheral vascular disease.

26. 3. MONOAMINE OXIDASE INHIBITORS
Two Isoforms of monoamine oxidase in CNS:-
1. MAO-A metabolizes: norepinephrine, 5HT, and dopamine.
2. MAO B metabolizes dopamine selectively.
• MAO Prolong t1/2 of levodopa

27. MAO-B INHIBITORS: Selegiline (Deprenyl)
• Selective irreversible inhibitor MAO B at normal doses
• Inhibit MAO A at ↑ doses
• Retards dopamine breakdown↑ antiparkinsonism effect of levodopa.
• Levodopa dose is ↓ when taken with
• Good adjunctive therapy for declining response to levodopa.
• Standard dose = 5 mg with Breakfast, 5 mg with Lunch.
• S/E: insomnia
• No therapeutic effect on parkinsonism when taken alone.

28. MAO-B INHIBITORS: Rasagiline
• Selective irreversible inhibitor of MAO B.
• Rasagiline potency > Selegiline in ↓ MPTP-induced parkinsonism
• It is an adjunctive therapy to ↑se carbidopa-levodopa t1/2 in:-
1. Advanced disease
2. Response fluctuations.
• Read the ADAGIO trial for more!!

29. MAO-B INHIBITORS: Safinamide
• Rx of response fluctuations in patients taking carbidopa levodopa
• Not effective as monotherapy for Parkinson’s disease.
• Starting dose is 50 mg OD then titrated to 100mg After 2 weeks.

30. MAO-INHIBITORS CONSIDERATIONS
• Patients on meperidine, tramadol, methadone, propoxyphene,
cyclobenzaprine.
• Avoid dextromethorphan while on MAO-B inhibitors
• Avoid other MAO inhibitors while on Rasagiline, selegiline &
safinamide.
• Avoid MAO-B inhibitor while TCI or SSRI causes serotonin syndrome
• Increases the S/E of Levodopa + Carbidopa
• Nonselective MAO inhibitor + Levodopa = Hypertensive Crises due to
accumulation of NE

31. CATECHOL-O-METHYLTRANSFERASE INHIBITORS
(COMTI)
• Decarboxylase inhibitor (Carbidopa) causes compensatory ↑COMT in
plasma.
• This causes ↓response to Levodopa & brain bioavailability.
• Selective COMT inhibitors ↑ t1/2 of levodopa thus brain
bioavailability↑.

32. COMTI: Tolcapone and Entacapone
• MOA: inhibit COMT
• ↑ t1/2 of Levodopa by ↓ peripheral metabolism.
• Levodopa clearance is ↓
• Brain bioavailability of levodopa ↑
• Used in Rx of response fluctuation.
• Entacapone is less hepatotoxic.

33. COMTI: Tolcapone and Entacapone-PK
• Both are rapidly absorbed
• Bound to plasma proteins
• Metabolized before excretion.
• Tolcapone has both central and peripheral effect.
• Entacapone has peripheral effect only.
• Half-life of both drugs i= 2 hours,
• Potency: tolcapone > entacapone.

34. COMTI : Tolcapone and Entacapone-S/E
• Dyskinesia
• Nausea, Diarrhea, Abdominal pain
• Confusion.
• Orthostatic hypotension
• Sleep disturbances
• Orange discoloration of the urine.
• Tolcapone is Hepatotoxic=Liver enzyme levels ↓( avoid in Liver
disease)
• Monitor LFT every 2-4 weeks while on Tolcapone.

36. ACETYLCHOLINE-BLOCKING DRUGS
MOA
• Block M1 receptors in
• Improve the tremor and rigidity of parkinsonism.
• No effect on bradykinesia.

37. ANTIMUSCARINIC DRUGS

38. S/E OF ANTIMUSCARINIC AGENTS
• Cognitive impairment.
• Dyskinesia.
• Acute suppurative parotitis due to dryness of the mouth.
• Constipation.
• Increased heart rate
• HTN
• Insomnia

39. Others Drugs Parkinson's: AMANTADINE
• An antiviral agent
• Weak antiparkinsonism properties.
• Potentiate dopaminergic function.
• Influencing the synthesis, release, or reuptake of dopamine.
• Antagonize the effects of adenosine at A2A receptors=Adenosine
inhibit D2 receptor function.
• Amantadine is an antagonist of the NMDA thus antidyskinetic effect.

40. Others Drugs Parkinson's: APOMORPHINE
• A potent nonergoline dopamine agonist.
• Binds onto D2 receptors in the caudate nucleus and putamen
• Given S/C
• Effective for the temporary relief of akinesia due to dopamine RX
• Rapidly taken blood and then the brain within 10 minutes of SC
• T1/2 persists for up to 2 hours.
• Nausea common and antiemetic

41. APOMOPHINE S/E
• Nausea common and antiemetic.
• Dyskinesia
• Drowsiness, insomnia, chest pain,
• Sweating, Hypotension, syncope
• Constipation, diarrhea,
• mental or behavioral disturbances
• Drug interaction with 5-HT3 antagonists= +++ hypotension

42. REVIEW QUESTIONS
Dopamine agonist ergot derivative that stimulates D1 & D2 receptors
A) levodopa
B) Amantadine
C) pergolide
D) selegiline
E) trihexyphenidyl

43. REVIEW QUESTION
Reason that dopamine itself is not used to treat in Parkinson's disease:
A) It is derivative of amino acid
B) the problem is cholinergic in nature
C) dopamine does not cross the blood-brain barrier
D) levodopa has a higher affinity for the D2 receptor

44. REVIEW QUESTION
Antiviral drug found to have anti-Parkinson's properties:
A) procyclidine
B) pergolide
C) amantadine
D) levodopa
E) reserpine

45. REVIEW QUESTION
Percentage of levodopa that enters the brain unaltered
A) 1-3%
B) 5-10%
C) 15-30%
D) > 50%

46. REVIEW QUESTION
Effective in managing essential tremor
A) propranolol
B) metoprolol
C) primidone
D) diazepam
E) chlordiazepoxide

47. REVIEW QUESTION
Which one of the following combinations of antiparkinsonian
drugs is an appropriate treatment plan?
A. Amantadine, carbidopa, and entacapone.
B. Levodopa, carbidopa, and entacapone.
C. Pramipexole, carbidopa, and entacapone.
D. Ropinirole, selegiline, and entacapone.
E. Ropinirole, carbidopa, and selegiline.

48. REVIEW QUESTION
Peripheral adverse effects of levodopa, including
nausea, hypotension, and cardiac arrhythmias, can be
diminished by including which of the following drugs in
the therapy?
A. Amantadine.
B. Ropinirole.
C. Carbidopa.
D. Tolcapone.
E. Pramipexole.

49. REVIEW QUESTION
Which of the following antiparkinsonian drugs may cause
vasospasm?
A. Amantadine.
B. Bromocriptine.
C. Carbidopa.
D. Entacapone.
E. Ropinirole.

50. REVIEW QUESTION
Modest improvement in the memory of patients with
Alzheimer’s disease may occur with drugs that increase
transmission at which of the following receptors?
A. Adrenergic.
B. Cholinergic.
C. Dopaminergic.
D. GABAergic.
E. Serotonergic.

51. REVIEW QUESTION
First-line anti-Parkinson drug; also used to treat hyperprolactinemia at
lower doses
A) amantadine
B) levodopa
C) bromocriptine
D) selegiline
E) benztropine mesylate

52. REVIEW QUESTION
Carbidopa is useful in the management of Parkinson's disease because
it is an:
A) effective D2 agonist
B) effective D2 antagonist
C) effective peripheral decarboxylase inhibitor
D) effective central decarboxylase inhibitor
E) effective competitor at the GABA receptor

53. REVIEW QUESTION
One is a catechol-o-methyltransferase inhibitor available for managing
Parkinson's disease:
A. Tolcapone
B. Mepenem
C. Cabidopa
D. Selegiline

54. REVIEW QUESTION
This dopamine receptor tied is localized in the substantia nigra zona
compacta and presynaptically on striatal axons from dopaminergic
substantia nigral cells.
A. D1
B. D2
C. D3
D. D4
E. D5

55. REVIEW QUESTION
A dopamine receptor type probably most important in mediating
benefits of dopaminergic anti-Parkinsonian drugs.
A. D1
B. D2
C. D3
D. D4

56. REVIEW QUESTION
Pergolide is a:-
A. D 2 full agonist
B. D1&D4 agonist
C. D1&5 agonist
D. D1&D2 agonist