Parkinsonism is due to an imbalance between the levels of acetylcholine and dopamine in the basal ganglia.

In parkinsonism, the dopamine content is low so that the cholinergic system is dominant.

Parkinsonism
(-)
Substantia nigra

Basal Ganglia

Parkinsons disease

(+)

PARKINSONISM

1. Bradykinesia 2. Rigidity of skeletal muscles 3. Tremors at rest 4. Postural instability 5. Sleep disorders 6. Mood changes 7. Salivation 8. Masked face

Parkinsonism is due to an imbalance between the levels of Ach & dopamine in the basal ganglia. In parkinsonism, the dopamine content is low so that the cholinergic system is dominant.

PARKINSONISM Treatment of parkinsonism 1. Anticholinergic drugs to reduce cholinergic activity or / & 2. Dopaminergic drugs to enhance dopaminergic activity: A. Directs : levodopa (L-dopa), dopaminergic
agonists B. Indirects : MAOI, Amantadine

3. Neuroprotective therapy: Coenzyme Q10, Ubiquinone 30 mg ,1x1

Dopamine receptors

L-Dopa
 It is the precursor of dopamine. L-Dopa
Dopa decarboxylase enzyme p

Dopamine

L-dopa
Pharmacokinetic:
Rapid absorption from small intestine Food interferes with absorption should be taken
30-60 min. before meals or (low protein diet)

So is short (1-3 the T1/2 only 5% of hrs) given dose of L-Dopa

Dopamine is not used because it cannot cross the ganglia & barrier. blood brain improves parkinsonism. dopamine content of basal ganglia

will be converted to dopamine in the basal

L-Dopa can cross the BBB and increase the 95% of given L-Dopa is transformed to dopamine in
the peripheral tissues by decarboxylation

Blood

Brain

L-dopa dose

GIT

Metabolism in GIT

Peripheral tissue (toxicity)

Levodopa with carbidopa

L-dopa dose Blood

Brain

Metabolism in GIT

Peripheral tissue
(toxicity)

Sinemet 275 (Levocar, Lecardopa)

Carbidopa is given with L-dopa.
Carbidopa is a Dopa decarboxylase inhibitor only in the periphery because it can not cross BBB so higher % of the given L-Dopa will reach the basal ganglia. So, give Carbidopa + L-Dopa (Sinemet) 25 : 250

To:
1. Decrease the dose of L-Dopa. 2. Decrease the side effects of L-Dopa. 3. Increase the efficiency in treatment of parkinsonism.

L-dopa
Side effects: ( with carbidopa)

1. GIT : 80 % ; anorexia, N, V 2. Dyskinesias: 80 % (long use) choreoathetosis of

the face & distal extremeties.

3. Fluctuation in response: - End of dose akinesia (wearing off reactions) - On-off phenomena 4. CVS: tachycardia, extrasystoles, postural hypotension

L-dopa
Drug interactions with L-dopa:
1. L-Dopa + Vit. B6 reduces its anti-parkinsonian effect because it elevates dopa decarboxylase activity (if used alone without carbidopa). 2. Antiemetics such as phenothiazines (Dopamine antagonists) 3. L-DOPA + MAOA inhibitors causes hypertensive crisis (due to elevated level of catecholamines). 4. Anti-cholinergic synergism drugs + L-Dopa cause

Dopamine receptor agonists

They act directly on dopamine receptors without need to enzymatic conversion to active metabolites They have no potentially toxic metabolites They dont compete with other substances for active transport into the blood & across the BBB

 Important role in first-line therapy for Parkinsons disease  In patients, who develop fluctuation in response to Ldopa or who become resistant to L-dopa

2- Selegiline
Selectively inhibits monoamine oxidase B (MAOB) which metabolizes dopamine, but doesn't inhibit MAOA (which metabolizes norepinephrine & serotonin). Thus, by decreasing the metabolism of dopamine, selegiline has been found to increase dopamine levels in the brain. It helps to decrease the dose of L-dopa & to decrease the fluctuation in response.

3.

Bromocriptine (Parlodel)

It is an ergot derivative. It is a dopamine receptor agonist. Stimulates dopaminergic receptors in the basal ganglia.

4. Amantadine
An anti-viral drug.
Decreases tremors & rigidity of parkinsonism.

It acts by:

 

Stimulating ganglia.

the

release

of

dopamine in the

from basal

dopaminergic

nerve

terminals

Inhibiting dopamine re-uptake.

Synthetic atropine substitutes 1. Benztropine (Cogentin) (2 mg; 1x2/day) 2. Trihexphenidyl (Artane)

Reduce tremors, excessive salivation

Gradual upgrade of the dose

rigidity,

&

Less side effects than atropine