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Mohammad Shariful Alam (Shohan)

ANTI-PARKINSONISM DRUGS

Parkinsonism: Parkinsonism is a progressive degenerative disease of basal ganglia associated with marked loss of dopamine from the basal ganglia leading to increasing disability unless effective treatment is provided. Clinical features: Parkinsonism is characterized by a combination of1. 2. 3. 4. Rigidity Bradykinesia / hypokinesia (weakness of muscle) Tremor & Postural instabilityo Inability to rapid turn o Short shuffling gait.

Etiology (cause):
I. Idiopathic. Bio-chemical: dopaminergic activity. cholinergic

II. activity III. nigrostriatal pathway.


IV. a) Anti psychotic drug - Haloperidol - Chlorpromazine b) Anti emetic drug - Metachlorproamide c) Anti hypertensive drug dopa. d) Cholinergic drug excess use. V. -

Pathologic:

Damage

to

the

Drug induced:

Reserpine -Methyl

Neurotoxin: MPTP.

Mohammad Shariful Alam (Shohan)

Balance system and parkinsonism:


Two balance systems are important in the extrapyramydal control of motor activity at the level of corpus striatum and substantia nigra. Balance: Normal cholinergic and dopaminergic activity-

Ach

Dopamine

Imbalance: Dopamine Ach

Dopamine conc. Ach conc. Parkinsonism - Hypokinesia - Tremor - Rigidity

Therapeutic target:
Try to increase dopamine conc. by Dopamine agonist. Try to decrease Ach conc. by Anti muscuranic drug.

Ach

Dopamine


Anti muscuranic cholinergic activity antiparkinsonism. Dopamine agonist Dopamine conc. antiparkinsonism.

Drugs for parkinsonism:


I. Drugs that central dopaminergic activity: 1. Dopamine precursor 2. Dopamine agonist Levodopa Bromocriptine Pergolide Lysuride Ropinirole Amantadine

3. synthesis, release & reuptake of Dopamine

4. Dopamine metabolism

a) MAO inhibitors Selegeline Rasageline b) COMT inhibitor Tolcapone Entacapone

Mohammad Shariful Alam (Shohan)

II. Drugs that cholinergic activity: Benztropine Benzhexol Procyclidine Orphenadine

Drug therapy:
1. Initial treatment: 2. Long term treatment: a) carbidopa 25mg) b) benserazide 25mg) Antimuscuranic Alleviate tremor, rigidity but not hypokinesia. Amantidine Selegiline Levodopa + Carbidopa (sinemet = levodopa 250mg + Levodopa + Benserazide (madopar = levodopa 250mg +

Q. Why Dopamine is not given directly? Ans. Dopamine does not cross the blood-brain barrier & if given into the peripheral circulation has no therapeutic effect in Parkinsonism. However, the immediate metabolic precursor of dopamine i.e. L-dopa can cross blood brain barrier and enters the brain, where it is decarboxylated in Dopamine.

L-DOPA
Levodopa can cross blood brain barrier.

Pharmacokinetics: Routes : oral Distribution : 70% metabolized in GIT 27-29% goes to peripheral tissue 1-3% enters into the brain as L-dopa T1/2 : 1-3 hrs.

Action of levodopa in Parkinsonism:


Levodopa Dopa decarboxylase Dopamine (both in CNS and peripheral tissue) Dopamine concentration on basal ganglia Dopaminergic activity Antiparkinsonism action

Mohammad Shariful Alam (Shohan)

Pharmacological properties of L-dopa:


1. CNS effects: Bradykinesia Tremor Rigidity Improvement of: Speech Hand writing Swallowing 2. Psychic effects: General altering response Mental function Interest in self, surroundings and family 3. CVS effects: Initially asymptomatic orthostatic hypotension Transient tachycardia and other arrhythmias 4. Metabolic and endocrine effects: Inhibition of prolactin secretion.

Optimization: It means to dopamine conc. in CNS & peripheral side effects by Carbidopa Benserazide Selegiline Domperidone. Q. Justify the use of combined formulation of Levodopa and Carbidopa.
Ans. L-dopa + Carbidopa

(-) peripheral dopa decarboxylase metabolism of L-dopa in GIT & peripheral tissue availability of L-dopa in brain (10%) Converted into dopamine Dopamine conc.

Mohammad Shariful Alam (Shohan)

Or,
Levodopa is converted into dopamine by dopa decarboxylase. Dopa decarboxylase presents in both brain and peripheral tissue; but peripheral dopamine (from levodopa) cannot cross the blood brain barrier. When levodopa is given in combination with a dopa decarboxylase inhibitor (carbidopa) that does not penetrate blood brain barrier, the peripheral metabolism of levodopa is reduced. So more levodopa is available for enter into the brain and thus increase dopamine concentration in brain.

Result:
Dopamine conc. in CNS by 10% Requirement of the dose of L-dopa by 4 to 5 folds Severity of peripheral side effect.

Adverse effect:
A) Gastro-intestinal: When levodopa is given without peripheral decarboxylase inhibitorAnorexia Nausea Vomiting B) Cardio-vascular effect: a) Tachycardia b) Ventricular extra systole c) Postural hypotension (often asymptomatic) d) Atrial fibrillation (very rarely) e) Hypertension (with MAO inhibitors) C) Dyskinesia D) Behavioral effects: # Depression # Anxiety # Confusion # Delusion

# Agitation # Insomnia # Somnolence

# Hallucination # Nightmare # Euphoria


Mohammad Shariful Alam (Shohan)

E) Fluctuation in response: Due to continued use and On-off phenomenon F) Miscellaneous adverse effects: May causes mydriasis & hence causes precipitation of Glaucoma Blood dyscariasis

Or, Adverse effects: Nausea Vomiting Mental change Agitation & confusion Postural hypotension Cardiac arrhythmia.

Contraindication: Schizophrenia Pregnancy Glaucoma Patient taking MAO inhibitors. Q. What are the complications with long treatment? Ans. I. Early morning akinesia II. Peak dose dyskinesia III. On-off phenomenon - Sudden loss of mobility that the patient stops while walking and feels rooted to the spot or is unable to rise from chair in which he had sat down normally a few moments earlier.

Anti-muscuranic drugs
Some anti-muscuranic drugs: Benztropine Benzhexol Procyclidine Orphenadine 6

M/A:
Antimuscuranic drug competitively block the action of ach. in CNS cholinergic activity Antiparkinsonian effect.

Mohammad Shariful Alam (Shohan)

Adverse effect: Dry mouth Blurred vision Constipation Glaucoma Urinary retention. Q. Justify Selegeline + levodopa. Ans.
Selegiline + Levodopa (-) MAO enzyme Rate of metabolism & release of dopamine in central synapse Dopamine conc. in brain Antiparkinsonian effect

Q. How will you clinically treat Parkinsons disease? Ans. ii. Early stage: o Amantidine + Selegiline antimuscuranic drugs (On the basis of age) iii. Moderate to severe stage: o L-dopa combination Levodopa (250mg) + Carbidopa (25mg) Levodopa (250mg) + Benserazide (25mg) o Selegiline o Bromocriptine iv. Young patient: o L-dopa + Bromocriptine

v.

Other therapy: o o

Physiotherapy Speech therapy.