PHARMACOTHERAPY OF PARKINSONISM

PARKINSONISM

• Parkinsonism is a chronic, progressive, degenerative disorder characterized by rigidity, tremors and bradykinesia.

• In idiopathic parkinsonism there is degeneration of dopamine containing neurons in substantia niagra, resulting dopamine deficiency.

• Hence balance between inhibitory dopaminergic neurons and exitatory cholinergic neurons is disturbed resulting in cholinergic overactivity.

CLASSIFICATION

1. Drugs effecting brain dopaminergic systema) Dopamine precursors: levodopab) Peripheral decarboxylase inhibitors: carbidopa and

benserazide.c) Dopaminergic agonists: Bromocriptine, ropinirole,

pramipexoled) MAO-B inhibitor: Selegiline, Rasagilinee) COMT inhibitors: Entacapone, Tolcaponef) Glutamate(NMDA receptor) antagonist (dopamine

facilitator): Amantadine

2. Drugs affecting brain cholinergic system.a) Central anticholinergics: trihexyphenidyl,

procyclidine, biperidenb) Antihistaminics: Orphenadrine,

promethazine

Dopamine precursor: levodopa• Inactive by itself but is the immediate precursor of

the transmitter dopamine• Major portion of levodopa is converted by

peripheral decarboxylase to dopamine. Only 1 to 2% of administered levodopa crosses BBB and is taken up by dopaminergic neurons, converted to dopamine which is stored and released as a transmitter

• Dopamine produced from levodopa in the brain acts D2 receptors and produce antiparkinsonian effect.

• Why levodopa is always used in combination with carbidopa or benserazide?

Carbidopa and benserazide are peripheral decarboxylase inhibiters so they limits the peripheral decarboxylation to dopamine and increases the bioavailability of levodopa in substantia niagra.

Thus the combination reduces the dose of levodopa.

• Pharmacokinetics 1. Rapid absorption orally 2. Aminoacids in food interfere with absorption so it is given

after 30-60 minutes.3. Metabolic products of levodopa are homovanilic acid and

3,4-dihydroxyphenylacetic acid which are excreted in urine• ADR1. At intiation of therapya) Nausea and vomitingb) Postural hypotensionc) Cardiac arrythmias d) Exacerbation of anginae) Alteration of taste sensation

2. After prolonged usea) Abnormal movements(dyskinesias)b) Behavioural effects: contraindicated in

patients with psychotic disorders.c) Fluctuation in motor performance• Note : special care to be taken in elderly;

patients with ischemic heart disease cerebrovascular, psychiatric, hepatic and renal disease, peptic ulcer, glaucoma and gout.

• Interactions 1. Pyridoxine by enhancing peripheral decarboxylation

abolishes therapeutic effect2. Phenothiazines, butyrophenones, metoclopramide reverse

therapeutic effect of levodopa by blocking DA receptors. Domperidone abolishes levodopa induced vomiting and nausea without affecting its antiparkinsonian effect since it does not cross BBB but reaches CTZ

3. Nonselective MOA inhibitors prevent degradation of DA peripherally and cause hypertensive crisis

4. Antihypertensive drugs accentuates postural hypertension induced by levodopa

5. Atropine and antiparkinsonian anticholinergic drugs reduce efficacy of levodopa

Peripheral decarboxylase inhibitors

Carbidopa and Benserazide• These drugs do not cross BBB• They are always given as combination drugs with levodopa• Advantages 1. Increased bioavailability of DA in basal ganglia2. Prolongation of plasma t1/2 of levodopa3. Reduction incidence GI side effects like nausea and vomiting;

CVS side effects like tachycardia, hypotension and cardiac arrythmias

4. Better patient complaince5. Sustained release preparation of levodopa-carbidopa

combination helps to reduce on/off phenomenon

Dopamine receptor agonists• These drugs have direct action on dopamine receptors • Commonly administered orally• Longer acting than levodopa• Used particularly in patients with frequent fluctuation

of symptoms (on/off phenomenon) BromocryptineErgot derivative with partial agonistic action at D1 and

agonistic action at D2ADR: anorexia, nausea, vomiting, constipation, postural

hypotension, cardiac arrythmias, digital vasospasm, dyskinesia, hallucinations and nasal congestion.

Ropinirole and pramipexole• Non-ergoline derivatives• Used in intial treatment of parkinsonism• Used in monotherapy or in combination with

levodopa-carbidopa• Other indication is in ‘restless leg syndrome’• Ropinirole is a D2 agonist while pramipexole is a

more selective D3 agonist• ADR: nausea, vomiting, confusion, fatigue,

somnolence, hallucination, postural hypotension & dyskinesia

COMT inhibitorsTolcapone and entacapone

• irreversible COMT inhibitors• By inhibiting metabolism of dopamine to 3-O-

methyldopa, they increase the half-life of levodopa and also enhance its bioavailability in CNS

• Tolcapone has both central and peripheral actions with relatively longer duration of action, whereas entacapone inhibits COMT only in the periphery

• Used as adjuvant to levodopa• ADR: dyskinesia, nausea, diarrhoea, confusion,

hypotension, hallucinations. Tolcapone is hepatotoxic while entacapone is not so.

MAO-B inhibitors

Selegiline and Rasagiline• They selectively and reversibly inhibits MAO-B enzyme in

brain.• Orally administered and do not inhibit MAO in the periphery• They retard the metabolism of DA in brain and prevent

formation of toxic metabolites in brain• Enhance as well as prolongs the effect of levodopa• They also reduce ‘on-off’ phenomena• Rasagiline is more potent and longer acting than selegiline so

single daily dose is adequate.• Selegiline metabolites amphetamines and methamphetamine

cause insomnia, anxiety, nausea and vomiting.

NMDA receptor antagonist

Amantadine • An antiviral drug used for treatment and prophylaxis of

influenza A• It is also used in parkinsonism. It facilitates synthesis and

release of dopamine from dopaminergic neurons of brain.• It also has NMDA receptor antagonist action- decreases

glutamate neurotransmission in basal ganglia.• Intial treatment of mild parkinsonism. Can be used with

levodopa• ADR : headache, HF, livedo reticularis, hypotension,

hallucination, nausea, vomiting, constipation, dry mouth and insomia

CENTRAL ANTICHOLINERGICS• Centrally acting anticholinergics like trihexyphenidyl

and benztropine are the drug of choice in drug induced parkinsonism.

• Mainly central action with little peripheral action• They act by reducing the increased cholinergic activity

in the striatum.• They are less effective than levodopa but are cheap

and better tolerated• Effective in reducing tremor and rigidity of

parkinsonism with little effect on hypokinesia• ADR : commonly seen adverse effects of

anticholinergics

• Antihistaminics with anticholinergic properties like promethazine, diphenhydramine, orphenadrine decrease cholinergic overactivity in basal ganglia.

• Levodopa is not the drug of choice in drug induced parkinsonism because:

1. Dopamine receptors are blocked2. There is no defeciency of dopamine