BASIC PHARMACOLOGY REVISION NOTES BASED ON HIGH YEILD TOPIC AND LECTURE NOTES ANTIPARKINSONIAN DRUGS LEVODOPA DRUGS PERIPHERAL DECARBOXYLASE INHIBITOR COMT INHIBITOR ENTACAPONE TOLCAPONE MAO B INHIBITORS

1. Antiparkinsonian drugs

4. Drugs affecting brain Dopaminergic system Drugs affecting brain Cholinergic system
Dopamine
precursor
Levodopa (L-dopa) Central
anticholinegics
• Trihexyphenidyl(Benzhexol)
• Procyclidine,
• Biperiden,
• BenzatropinePeripheral
decarboxylase
inhibitors:
Carbidopa, Benserazide.
Dopaminergic
agonists:
Bromocriptine,Ropinirole,
Pramipexole,apomorphine
COMT
inhibitors:
Entacapone, Tolcapone Antihistaminics Orphenadrine,Promethazine.
Dopamine
facilitator:
Amantadine

6. Levodopa
• Prodrug
• Precursor of DA
• DOC of parkinsonism
• Doesnot stop progression of disease

7. Levodopa

9. Vitamin B6 is C/I lalong with levodopa
• Increased PLP decreases the effect
of L dopa by increasing peripheral
conversion
Levodopa

10. • P/K
• Well absorbed; metabolized in intestinal wall
• Half life=8 hours
• Actively transported
• Metabolized in liver to O-HMD
• Absorption is reduced by protein meals

14. Improvement of symptoms
• Akinesia  rigidity  tremor
• Tremor is less responsive to levo dopa therapy

15. • C/I of L-dopa
• Acute narrow angle glaucoma
• Peptic ulcer
• Malignant melanoma
• In psychosis
• D/I
• L-Dopa MUST NEVER given with D-2 blockers
• Phenothiazine butyrophenone
• Metochopramide
• Not to be given with:
• TCADs
• non specific MAO inhibitor
• B6 (Pyridoxine)

16. Complications of Levo - Dopa
• Wearing off
• Receptor D2 sensitisation
• d/t constant stimulation
• On off phenomenon

17. S/E
Short term Long term
GI • N & V
• Loss of appetite
Involuntary
movements
• Peak dose dyskinesia
• Diphasic dyskinesia
• Dystonia
Cardiovascular • Postural hypotension (D1
stimulation)
Response
fluctuation
• Wearing off
• On off
sleep • Somnolence
• Insomnia
• Vivid dreams
• Inversion of sleep wake cycle
Psychiatric • Confusion
• Visual hallucination
Psychiatric • Confusion
• Visual hallucination
• delusion

18. • Abrupt withdrawal of levodopa  neurolept malignant syndrome
• Drug taken 30-60 min before meal
• Decreased absorption if in presence of aa

19. Peripheral decarboxylase inhibitor
• Carbidopa (and Benserazide)
• Administered along with levodopa, it increase its t1/2 in periphery and make
more of it available to cross blood-brain barrier to reach its site of action.
Also it reduces Levodopa dose to one fourth.

21. Advantage of peripheral decarboxylase inhibitor Disadvantages of peripheral decarboxylase inhibitor
• Increases duration
• Increases bioavailability
• Dose of levodopa is reduced
• Nausea & vomiting is less
• Reduces cardiac effects of levodopa
• On-off effects are minimized
• Pyridoxine reversal do not occur
• Psychiatric side effects are more
• Postural hypotension pronounced
• Involuntary movements increased

22. COMT
Levodopa 3-O -methyldopa (3-OMD)
COMT
Elevated levels of 3-OMD have been associated with a poor
therapeutic response to levodopa, perhaps in part because 3-
OMD competes with levodopa for an active carrier mechanism
that governs its transport across the intestinal mucosa and the
blood-brain barrier

23. COMT inhibitors
• Entacapnone
• Peripheral COMT only
• Tolcapnone
• Both central & peripheral COMT
• But it can cause rhabdomyolysis & fatal hepatitis

24. Entacapone & tolcapone
• Reduce wearing off phenomenon in patients with levodopa &
carbidopa
• Common A/E similar to levodopa
Entacapone Tolcapone
Peripheral action on COMT Central & peripheral action on COMT
Duration of action  short (<2hrs) More potent & long duration of action
No hepatotoxicity Hepatotoxicty

25. MAO B inhibitors
• Decreases wearing off & on effects
• Selegiline
• Used to prevent progression of disease
• Rasagiline
• Rasagiline is more potent than selegiline

26. MPTP (protoxin) MPP+(toxin)
leads to substantia nigral cell
death and thus to striatal
dopamine depletion and
parkinsonism
MAO
Inhibited by rasageline &
seligiline & prevent progression
to parkinsonism

27. • selegiline or rasagiline (MAO- B)may retard the progression of
Parkinson's disease in humans

28. Selegiline
• Combined with levodopa + carbidopa
• Inhibit MAO-B at lower doses but at higher doses it will also inhibit
MAO-A
• Cheese reaction & serotonin syndrome
• Reduce disease progression
• Selegiline metabolised to amphetamine hence avoided in elderly
(CNS stimulant & can cause seizures)

29. Selegiline transdermal patch is used in
depression
• NOT IN PARKINSONISM

30. Rasagiline
• 10-15 more potent than selegiline
• No amphetamine metabolite
• Given as monotherapy

33. Amantidine
• Anti-Influenza A2 drug
• Dopamine transmission enhancer, NMDA glutamate effect is more important.
• Used as adjunct with levodopa-suppress motor fluctuation and involuntary movements
• Short acting (half life 2 hours)
• Eliminated unchanged in urine
• C/I-
• Renal failure
• Psychiatric patients
• Epilepsy
• S/E
• Livedo Reticularis (due to local CA release)
• Ankle edema- diuretic responsive

34. Amanitidine  livedo reticularis

36. Dopamine agonist
Ergot derived Non ergot derived
• Bromocriptine
• Lisuride
• Pergolide
• Cabergoline
• Ropinirole
• Pramipexole (anti –oxidant)
• Rotigotine
• Apomorphine

37. dopamine agonist
• Monotherapy , adjuvant therpay
• Mode of delivery
• Oral
• Patch rotigotine
• Subcutaneous  apomorphine
• A/E
• Dyskinesia
• Delay onset motor fluctuation

38. Dopamine agonist

39. Bromocriptine

40. Bromocriptine  D1 & D2 receptor agonist

41. Bromocriptine
• D2 receptor agonist
• Weak alpha antagonist
• Commonly used with levodopa

42. Uses of bromocriptine
• Prolactin secreting adenoma
• Amenorrhea/galactorrhea to hyperprolactinemia
• To stop lactation
• Acromegaly

43. Used in treatment of acromegaly

44. • Bromocriptine inhibits release of GH & prolactin

45. Uses of bromocriptine
• Infertility due to hyperprolactinemia
• Parkinsonism
• Suppression of lactation
• Hepatic coma increases alertness as it is dopamine agonist
• Acromegaly
• Neuroleptic malignant syndrome

46. s/e of bromocriptine
• Postural hypotension
• Digital vasospasm
• Erythromelalgia
• Prolonged use  fibrosis ,pleural effusion cardiac & retroperitoneal
fibrosis

47. • Pergolide  cardiac valvular fibrosis

48. Non ergot dopamine agonist
• Long acting :no gangrene
• Cause confusion & hallucination
• Excessive day time sleepiness

49. Cabergoline
• Ergot derivative
• Long t1/2
• Alleviates night symptoms d/t lack of levodopa

50. Non ergot dopamine agonist
Ropinirole Pramipexole Rotigotine Apomorphine
• Non ergot direct D2
receptor agonist
• Used in restless leg
syndrome
• Non ergot D2 receptor
agonist
• More effective against
tremors
Used as transdermal
patch
Sc route

51. Rotigotine transdermal patches are used in Rx
of parkinsonism