ANTIPARKINSON’S DRUGS

Classification

1. Drugs affecting brain dopaminergic system

Dopamine precursor, Levodopa (l- dopa)

Dopaminergic agonists

- Bromocriptine, Lisuride, Pergolide, Piribedil

Peripheral decarboxylase inhibitors

- Carbidopa, Benserazide

Facilitate dopaminergic transmission

- Amantadine, Selegiline (Deprenyl)

2. Drugs affecting brain cholinergic system

Central anticholinergics

- Trihexyphenidyl (Benzhexol), Procyclidine, Biperidine

Antihistaminics

- Orphenadrine, Promethazine

LEVODOPA

Inactive by itself. 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver) and converted into DA. DA acts on heart, blood vessels, other peripheral organs and on CTZ ­(though located in the brain, i.e. floor of IV ventricle, it is not bound by blood brain barrier). Only about 1-2% of administered levodopa crosses to the brain

ACTIONS OF LEVODOPA

1. CNS: No effect in normal. Marked symptomatic improvement occurs in Parkinsonian patients. Hypokinesia and rigidity resolve first, later tremor as well. Symptoms of posture, gait, handwriting, speech, facial expression, mood, self care and interest in life are gradually normalized. Effect on behaviour: 'general alerting response'.In some patient excitement - frank psychosis may occur; embarrassingly disproportionate increase in sexual activity has also been noted. Dementia does not improve; rather predisposes to emergence of psychiatric symptoms

2. CVS: The peripherally formed DA can cause tachycardia acting on β adrenergic receptors. Though DA can stimulate vascular adrenergic receptors as well, rise in BP is not seen. Instead, POSTURAL HYPOTENSION is quite common; may be a central action - DA and NA formed in brain decrease sympathetic outflow; also DA formed in autonomic ganglia can impede ganglionic transmission. Gradual tolerance develops to both cardiac stimulant and hypotensive actions

3. CTZ: Dopaminergic receptors are present in this area and DA acts as an excitatory transmitter. Peripherally formed DA gains access to the CTZ without hindrance- elicits nausea and vomiting. Tolerance occurs to this action

4. Endocrine: DA acts on pituitary mammotropes to inhibit prolactin release and on somatotropes to increase GH release. Though prolactin levels in blood fall during levodopa therapy, increased GH levels are not noted in parkinsonian patients. Probably the mechanisms regulating GH secretion are altered in these patients

Pharmacokinetics of Levodopa

Rapidly absorbed from the small intestines by active transport process meant for aromatic amino acids. Bioavailability affected by: (i) Gastric emptying(ii) Amino acids present in food compete for the same carrier for absorption.

Levodopa undergoes high first pass metabolism in G.I. mucosa and liver. 1-2% of administered dose that enters brain. The plasma t 1/2 of levodopa is 1 - 2 hours. Pyridoxal; cofactor for enzyme dopa-decarboxylase. Metabolites excreted in urine mostly after conjugation

Adverse Effects of Levodopa

Troublesome, dose related, reversible: Nausea and vomiting, Tolerance develops Postural hypotension; mostly asymptomatic; some experience dizziness, few have fainting attacks; common in patients receiving antihypertensives, Tolerance develops

Cardiac arrhythmias; Due to adrenergic action of peripherally formed DA

Exacerbation of angina, Alteration in taste sensation

After prolonged therapy with Levodopa

Abnormal movements Facial tics, grimacing, choreoathetoid movements of limbs etc.

No tolerance develops to this adverse effect, but dose reduction decreases their severity

Behavioral: anxiety, nightmares etc. to severe depression, mania, hallucinations, mental confusion or frank psychosis. Excessive DA action in limbic system is probably responsible (antidopaminergic drugs are antipsychotic). Fluctuation in motor performance. After 2-5 years of therapy, the level of control of parkinsonian symptomatology starts showing fluctuation. 'End of dose' deterioration (wearing off) which is initially gradual, develops into rapid 'switches' or 'on-off' effect. With time 'all or none' response develops i.e. the patient is alternately well and disabled

Dose of levodopa

Start with 0.25 g BD after meals, gradually increase till adequate response is obtained. Usual dose is 2-3 g/day. LARODOPA®, LEVOPA® 0.5 g tab

Drug Interactions with Levodopa

Pyridoxine: Abolishes therapeutic effect by enhancing peripheral decarboxylation of levodopa. Phenothiazines, butyrophenones, metoclopramide reverse therapeutic effect by blocking DA receptors. Reserpine abolishes levodopa action by preventing entry of DA into synaptic vesicles. Nonselective MAO inhibitors: prevent degradation of synthesis of DA and NA; hypertensive crisis. Antihypertensives: postural hypotension is accentuated; Atropine and other anticholinergic drugs have additive antiparkinsonian action with low doses of levodopa, but retard its absorption; efficacy may be reduced

Peripheral decarboxylase inhibitors

Carbidopa and Benserazide

Extracerebral dopa-decarboxylase inhibitors. they do not penetrate blood brain barrier and do not inhibit conversion of levodopa to DA in brain. Administered along with levodopa, they increase its t1/2

Benefits obtained by Levodopa + Carbidopa

The plasma t1/2 of levodopa is prolonged and its dose is reduced to approximately 1/4^th. Systemic concentration of DA reduced; nausea and vomiting are not prominent­Therapeutic doses of levodopa attained quickly. Cardiac complications are minimized

Pyridoxine reversal of levodopa effect not occur. On-off' effect is minimized since cerebral DA levels are more sustained. Degree of improvement may be higher; some patients, not responding adequately to levodopa alone, also improve

Problems not resolved (or accentuated) by Levodopa + Carbidopa:

1. Involuntary movements. 2. Behavioral abnormalitIes . 3. Postural hypotension.

Currently levodopa always used with a decarboxylase inhibitor, except in patients who develop marked involuntary movements with the combination. Combination of levodopa with carbidopa has been given the name 'Co-careldopa'.

Tidomet -LS®, Syndopa-110®,

Sinemet® 10 mg (Carbidopa) +100mg (Levodopa)

Tidomet PLUS® 25 mg+ 100mg

Tidomet FORTE®, Syndopa-275® 25 mg + 100mg

Benspar® Benserazide 25 mg + 100 mg Cap

Category: Pharmacology Notes