This document discusses drugs used to treat Parkinson's disease and other movement disorders. It begins by describing different types of movement disorders including tremors, chorea, tics, Huntington's disease, and Parkinsonism. Parkinsonism is characterized by rigidity, bradykinesia, tremors, and postural instability and is caused by loss of dopamine in the brain. The main drugs used to treat Parkinsonism aim to restore dopaminergic activity. Levodopa is converted to dopamine in the brain but has adverse effects with long term use. Dopamine agonists act directly on dopamine receptors and have fewer side effects than levodopa. Other drug classes discussed include MAO inhibitors, COMT inhibitors, anticholinergics

1. Antiparkinsons Drugs
Ms. K.D.S.V. Karunanayaka (B.Pharm)
Department of Pharmacy
Faculty of Health Sciences
The Open University Sri Lanka

2. Out line
•Movement disorders
•Parkinsonism
•Levodopa
•Dopamine agonists
•MAOIs

3. Movement Disorders
• Several types of abnormal movements are recognized.
•Tremor
•Chores
•Tics
•Huntington’s disease
•Parkinsonism

4. Movement Disorders
• Movement disorders have been attributed to
disturbances of the basal ganglia.
• The basic circuitry of the basal ganglia involves three
interacting neuronal loops that include the cortex and
thalamus as well as the basal ganglia.

5. Tremor
• Rhythmic oscillatory movements around a joint
• Tremor at rest is a characteristic of parkinsonism.
• It associates with rigidity and an impairment of voluntary
activity.
• Also may occur during maintenance of sustained posture
(postural tremor) or during movement (interior tremor)
• Intention tremor occurs in patients with a lesion of the
brain stem or cerebellum.
• Also occur as a manifestation of toxicity from alcohol or
certain other drugs.
MovementDisorders

6. Chorea
• Irregular, unpredictable, involuntary muscle jerks that
occurs in different parts of the body.
• Impaired voluntary activity.
• Mostly affected proximal muscles of the limb.
(Abnormal movements at this site is called as the term
ballismus)
• Occur due to hereditary effects and as a complication
of number of medical disorders.
MovementDisorders

7. Tics
• Sudden coordinated abnormal movements.
• Occur repetitively.
• In face and head, specially in children.
• Can be suppressed voluntarily for short periods of time.
• Repetitive sniffing and shoulder shrugging.
• May be transient or chronic.
• Gilles de la Tourette’s syndrome is characterized by chronic
multiple tics.
MovementDisorders

8. Huntingon’s Disease
• Autosomal dominant inherited disorder caused by an
abnormality of the huntingtin gene on chromosome 04.
• Characterized by progressive chorea and dementia.
MovementDisorders

9. Huntingon’s Disease
MovementDisorders
Katzung 12th Edition

10. Parkinsonism
• Characterized by a combination of rigidity, bradykinesia,
tremor and postural instability.
• Cognitive decline occur in many patients when disease
advance.
• Pathophysiological basis is to exposure to some
unrecognized neurotoxin or to oxidation reaction with the
generation of the free radicals.
• Mutations in parkin gene may cause early onset, autosomal
recessive, familial parkinsonism, or spodiac juvenile onset
parkinsonism.
MovementDisorders

11. Parkinsonism
• Generally progressive, leading to increasing disability unless
effective treatment is provided.
• In parkinsonism, high concentration of dopamine in the basal
ganglia of the brain is reduced.
• Pharmacological attempts to restore dopaminergic activity with
levodopa and dopamine agonists alleviate many of the motor
features.
• Antimuscarinic drugs also gives effect in alleviating motor
features.
• Drugs that induce parkinsonism are dopamine receptor
antagonist (Ex:- Antipsychotics) or lead to the destruction of
dopaminergic nigrostriatal neurons.
MovementDisorders

12. Levodopa
• Dopamine itself does not cross the blood brain barrier.
• Therefore Levodopa is the immediate metabolite of
dopamine, which can cross the blood brain barrier.
• In brain it decarboxylated back in to dopamine.
• Levodopa is the levorotary stereoisomer of DOPA.
• DOPA is the amino acid precursor of dopamine and
norepinephrine.

13. Levodopa – Mechanism of Action
Katzung 12th edition

14. Levodopa – Mechanism of Action
• Dopaminergic neurons originating in the substantia nigra
normally inhibit the GABAergic out put from the straitum ,
whereas cholinergic neurons exert an excitatory effect.
• In parkinsonism, there is a selective loss of dopaminergic
neurons.
• Therefore, dopamine/ Levodopa is covering the loss of
dopamine effectiveness.

15. Levodopa - Pharmacokinetic
• Rapidly absorbed from the small intestine, but absorption
is depend on gastric emptying and the pH of the gastric
contents.
• Ingestion of food delays the appearance of levodopa in the
plasma.
• Certain amino acid in foods may compete with levodopa.
• Peak plasma concentration 1-2 hours after oral dose.
• Plasma half life is 1-3 hours.
• About 2/3 of drug appears as urine metabolites within
8hours of an oral dose.

16. Levodopa - Pharmacokinetic
• Actually 1-3% of administered levodopa enters the
brain unaltered, remainder metabolized
extracerebrally, by decarboxylation of dopamine.
• Levodopa should give high dose when given alone.
• Best is combination with a dopa decarboxylase
inhibitor that not penetrates the BBB.
• Combination decrease metabolism and increase
higher percentage of absorption.

17. Levodopa - Pharmacokinetic
Katzung 12th edition

18. Levodopa – Clinical Use
• Best results in first few years of treatment when
use alone.
• Because the daily dose should reduce time to time
to avoid side effects.
• However early initiation lowers the mortality rate.
• But long term therapy lead to problems.
• Generally Levodopa is given with Carbidopa one of
dopa carboxylase inhibitor. (Sinemet)

19. Levodopa – Clinical Use
• Sinemet firstly given 25/100 mg (Carbidopa 25mg
& Levodopa 100 mg) tds.
• It should take 30-60 minutes before meals.
• Ultimately may require Sinemet 25/250.
• At present CR dosage form also available.
• Parcopa is one of best finding which disintegrate in
the mouth and is swallowed with saliva.
• Parcopa should take 1 hour before meals.

20. Levodopa – Adverse Effects
Gastrointestinal effects:
• Anorexia, Nausea & Vomiting (Occur about 80%
patients)
• These can minimized by take drug in divided doses
with or immediately after meals.
• Antacid 30-60 minutes before meals is also
prescribed.
• Tolerance may develop in many patients.

21. Levodopa – Adverse Effects
Cardiovascular effects:
• Cardiac arrhythmias
• Tachycardia
• Ventricular extra systoles
• Arterial fibrillation – rarely
• Postural hypotension
• Hypertension (Due to nonselective MAOIs)

22. Levodopa – Adverse Effects
Other effects:
• Dyskinesia
• Depression
• Anxiety
• Insomnia
• Confusion
• Hallucinations
•Euphoria
• Mydriasis
•Precipitation of gout
• Brownish discolouration of
saliva

23. Levodopa – Drug Interactions
• Pyridoxine (Vit B6) enhances the extracerebral
metabolism of levodopa.
• Levodopa should not given to patients taking MAO A
inhibitors or within 2 weeks of their discontinuance.

24. Levodopa – Contraindications
• Psychotic patients
• Angle closure glaucoma
• Chronic open angle glaucoma
• Cardiac arrhythmias
• Active peptic ulcers

25. Dopamine Receptor Agonists
• Drugs acting directly on dopamine receptors – MoA
• Not require enzymatic conversions.
• No potentially toxic metabolites.
• Not compete food or other substances.
• Limited adverse effects than Levodopa.
• First line therapy drugs for parkinsonism.
• Sinemet firstly add and then introduces DRA.

26. DRA - Bromocriptine
• D2 receptor agonist.
• Now rarely used.
• Peak plasma level 1-2 hours after oral dose.
• Excreted in bile and feces.
• Daily dose between 7.5mg and 30mg.
• To minimize adverse effects the dose is built up slowly over
2-3 months from starting 1.25mg bd pc, then increased by
2.5 mg every 2 weeks depending on response.

27. DRA - Pergolide
• D1 & D2 receptor agonists.
• Widely used for parkinsonism.
• No longer used due to development of valvular heart
disease.

28. DRA - Pramipexole
• D3 receptor agonists.
• Monotherapy for mild parkinsonism.
• Rapidly absorbed after oral administration.
• Peak plasma level 2 hours.
• Excreted largely unchanged in the urine.
• Start at dosage of 0.125mg tds, doubled after 1week and
again after another week.
• Renal insufficiency may occur.

29. DRA - Ropinirole
• Pure D2 receptor agonists.
• Effective in monotherapy.
• Introduced at 0.25mg tds, and the total daily dose is
then increased by 0.75mg at weekly intervals until the
fourth week and by 1.5mg thereafter.

30. DRA - Rotigotine
• Delivered daily through a skin patch.
• More continuous dopaminergic stimulation than oral
medication..
• This product was recalled in 2008 because of crystal
formation on the patches.

31. DRA – Adverse Effects
•Anorexia
•Nausea & Vomiting
•Constipation
•Dyspepsia
•Postural hypotension
•Peripheral edema
•Dyskinesia
•Confusion
•Hallucinations
•Delusions
•Headache

32. DRA - Contraindications
• Psychotic illness
• Recent myocardial infarction
• Active peptic ulceration
• Peripheral vascular diseases

33. Monoamine Oxidase Inhibitors
•Monoamine oxidase A metabolizes norepinephrine,
serotonin and dopamine.
•Monoamine oxidase B metabolizes dopamine
selectively.
•Combination with Levodopa should avoid as it may
cause hypertensive crisis.

34. MOIs - Selegiline
• Selective irreversible inhibitor of MABO at normal
doses. (Higher – MAAOI)
• Enhances and prolong antiparkinsonism effect of
Levodopa.
• Used as an adjunctive therapy.
• 5mg c. breakfast & 5mg c. lunch
• May cause insomnia when taken later during the day.

35. MOIs - Rasagiline
• MAO B inhibitor.
• Used for early symptomatic treatment.
• Start dose 1mg/d.
• Used as an adjunctive therapy.
• Neither selegiline nor rasagiline should be taken by
patients receiving meperidine, TCAs, Serotonin
reuptake inhibitors because the risk of acute toxic
interactions.

36. Catechol-O- Methyl Transferase Inhibitors
(COMT)
• Inhibition of dopa decarboxylase is associated with
compensatory activation of other pathways of
levodopa metabolism, as COMT.
• It increases plasma levels of 3-O- metyldopa (OMD).
• Elevated levels of 3-OMD cause poor therapeutic
response to Levodopa.
• There are selective inhibitors of COMT such as
Tolcapone & Entacapone.

37. Catechol-O- Methyl Transferase Inhibitors
(COMT)
Adverse effects:
• Dyskinesia
• Nausea
• Confusion
• Diahorrea
• Abdominal pain
• Sleep disturbances
• Orange discolouration of the urine

38. Acetylcholine Blocking Drugs
• Antimuscarinic drugs.
• Improve the tremor and rigidity of parkinsonism.
• Little effect of dyskinesia.
• Started with lower doses, then gradually being
increased.
• But may occur dyskinesia.

39. Acetylcholine Blocking Drugs
Katzung 12th Edition

40. Katzung 12th Edition
Summary of Drug Therapy in Parkinsonism

41. Apomorphine
• Subcutaneous injection of apomorphine hydrochloride (Apokyn),
a potent dopamine agonist.
• Effective in temporary relief of off periods of akinesia in patients
on optimized dopaminergic therapy.
• Rapidly taken into blood then brain.
• Clinical benefit begins about 10 minutes of injection and persists
up to 2 hours.
• Most patients need 3-6 mg tds.
• Adverse Effects – Dyskinesia, drowsiness, chest pain, sweating,
hypotension

42. Amantadine
• An antiviral agent.
• Has Antiparkinsonism activity.
• MoA is unclear, but it may potentiate dopaminergic function.
• Peak plasma level 1-4 hours after an oral dose.
• Plasma half life between 2-4 hours.
• Excreted unchanged in the urine.
• Standard dose is 100mg orally bd/tds.

43. Amantadine
• An antiviral agent.
• Has Antiparkinsonism activity.
• MoA is unclear, but it may potentiate dopaminergic function.
• Peak plasma level 1-4 hours after an oral dose.
• Plasma half life between 2-4 hours.
• Excreted unchanged in the urine.
• Standard dose is 100mg orally bd/tds.

44. Neuroprotective Therapy
• Number of compounds are under investigation as
potential neuroprotective agents that may slow disease
progression.
• Ex:- Antioxidants, Glutamate antagonists, Creatine,
Antiinflammatory Drugs

45. Gene Therapy
• Safety trial of gene therapy for Parkinson’s disorder have
now been completed in USA.
• Phase II trials are now planned and in progress.

46. Drugs which induces Parkinsonism
• Reserpine
• Haloperidol
• Metoclopramide
• Phenothiazine

47. References
• Bennet p.n., Brown M.J & Sharma P., Clinical Pharmacology; 11th
edition; Chapter 21; Page 359 - 370.
• Katzung B.G., Masters S.B & Trevor A.J., Basic & Clinical
Pharmacology; 12th edition; Chapter 28; Page 469 - 483.

48. THANK YOU!