Treatment of Parkinson’s diseases

• Levadopa

• Dopamine agonists (bromocriptine, pergolide, pramipexole).

• MAOI (Selegiline, rasagiline).

• COMT inhibitors( tolcapone, entacapone)

• Amantadine (antiviral)

• Acetylcholine blocking drugs

(benztropine)

Levadopa

3,4 dihydroxyphenyl-L-alanine metabolic precursor of dopamine does enter the brai( L. amino acid

transpoter, LAT)Where it is decarboxylated to dopamine.D2 receptorGiven in combination of Carbidopa

(peripheral dopa decarboxylase inhibitor).

• Metabolism of levodopa (L-DOPA). ALDH, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; D H, dopamine  -hydroxylase; AADC, aromatic L-amino acid decarboxylase; MAO, monoamine oxidase.

• PK

• Main metabolites

• 3- Methoxy-4-hydroxyphenyl acetic acid

• Homovanillic acid, HVA

• Dihydroxyhenylacetic acid ( DOPAC)

Side effects

• GI effects- vomiting• Cardiovascular effects- Postural hypotension,

tachycardia, ventricular extrasystole, atrial fibrillation (rare).

• Dyskinesia (prolong therapy)• Behavioral effects- Depression, anxiety,

agitation, insomnia, confusion, changes in mood.• Drug holidays- discontinue drug 3-21 days

( improve response)• On-off phenomenon-fluctuation in response

• Contraindications

• Angle-closure glaucoma

• Cardiac diseases

• Acid peptic diseases.

• Melanoma

• Interaction- Pyridoxine Vit B6 enhance peripheral metabolism

Levadopa + Carbidopa

• Sinemet- 25/100 ( carbidopa 25 mg, levadopa 100mg).

• Advantage

• Daily dose req of levadopa dec(75%)

• Less frequent GI effects.

• Less metabolism by pyridoxine.

Dopamine agonists.

• Bromocriptine (D2 agonist)

• Pramipexole ( not ergot, )

• Ropinirole

• Rotigine ( skin patches)

• Side effects(Dopamine agonist)• Anorexia, nausea, vomiting (with meals)• Cardiovascular effects- postural

hypotension.• Dyskinesias- • Mental disturbance • Misc- Headache, nasal congestion.• Contraindication• Psychotic illness, MI, peptic ulcers

MAOB-Inhibitor

• Selegiline

• Rasagiline

• Selegiline • Inhibitor MAOB- inhibitor.• Dec. breakdown of dopamine.• Selegiline + levadopa

COMT inhibitors

• Entacapone ( less hepatotoxic)

• Tolcapone

• Adverse effects:

• Dyskinesia, nausea,confusion.

• Diarrhea, abdominal pain, confusion.

Amantadine (antiviral)

• Antiviral agent

• MOA

• Inhibits dopamine degradation

• Inhibits adenosine that inhibits D2 receptors.

• Less effective than levadopa( iatrogenic dyskinesias)

• S/E- restlessness depression, confusion.

Antimuscarinic drugs

• Benztropine

• Biperiden

• Orphenadrine

Antimuscarinic drugs

• MOA• Antagonists at M receptors in basal ganglia.• Reduce tremor, rigidity.

• Toxicity:• Antimuscarinic effects, sedation, mydriasis, urinary

retention, dry mouth.