Antiparkinsonian Drugs Classification KDT / Antiparkinsonian Drugs / KDT classification / Classification of Antiparkinsonian drugs

 Antiparkinsonian drugs classification

These are drugs that have a therapeutic effect in parkinsonism. Parkinsonism It is an extrapyramidal motor disorder characterized by rigidity, tremor and hypokinesia with secondary manifestations like defective posture and gait, mask-like face and sialorrhoea; dementia may accompany. If untreated the symptoms progress over several years to end-stage disease in which the patient is rigid, unable to move, unable to breathe properly; succumbs mostly to chest infections/embolism. 

Parkinson’s disease (PD) is a progressive degenerative disorder, mostly affecting older people, first described by James Parkinson in 1817. Majority of the cases are idiopathic, some are arteriosclerotic while postencephalitic are now rare. Wilson’s disease (hepatolenticular degeneration) due to chronic copper poisoning, is a rare cause. The most consistent lesion in PD is degeneration of neurones in the substantia nigra pars compacta (SN-PC) and the nigrostriatal (dopaminergic) tract. This results in deficiency of dopamine (DA) in the striatum which controls muscle tone and coordinates movements. An imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) system in the striatum occurs giving rise to the motor defect. Though the cholinergic system is not primarily affected, its suppression (by anticholinergics) tends to restore balance. The cause of selective degeneration of nigrostriatal neurones is not precisely known, but appears to be multifactorial. Ageing, genetic predisposition, oxidative generation of free radicals, N-methyl-4-phenyl tetrahydropyridine (MPTP)-like environmental toxins and excitotoxic neuronal death due to NMDA-receptor (excitatory glutamate receptor) mediated Ca2+ overload have all been held responsible. Drug-induced reversible parkinsonism due to neuroleptics, metoclopramide (dopaminergic blockers) is now fairly common, while that due to reserpine (DA depleter) is historical

Belladonna alkaloids had been empirically used in Parkinson’s disease (PD). A breakthrough was made in 1967 when levodopa was found to produce dramatic improvement. Its use was based on sound scientific investigations made in the preceding 10 years that: 

• DA is present in the brain; 

 • it (along with other monoamines) is depleted by reserpine; 

 • reserpine induced motor defect is reversed by DOPA (the precursor of DA); 

 • striatum of patients dying of PD was deficient in DA. 

 Thus, parkinsonism was characterized as a DA deficiency state and levodopa was used to make good this deficiency, because DA itself does not cross the blood-brain barrier. In the subsequent years, a number of levodopa potentiators and DA agonists have been developed as adjuvants/alternatives. None of the drugs alter course of the disease in PD, but improve quality of life for a few years.

LEVODOPA 

Levodopa has a specific salutary effect in PD: efficacy exceeding that of any other drug used alone. It is inactive by itself, but is the immediate precursor of the transmitter DA. More than 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver). DA thus formed is further metabolized, and

 the remaining 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). About 1–2% of administered levodopa crosses to the brain, is taken up by the surviving dopaminergic neurones, converted to DA which is stored and released as a transmitter. This is supported by the finding that brains of parkinsonian patients treated with levodopa till death had higher DA levels than those not so treated. Further, those patients who had responded well had higher DA levels than those who had responded poorly.

ACTIONS 

1. CNS

 Levodopa hardly produces any effect in normal individuals or in patients with other neurological diseases. Marked symptomatic improvement occurs in parkinsonian patients. Hypokinesia and rigidity resolve first, later tremor as well. Secondary symptoms of posture, gait, handwriting, speech, facial expression, mood, self care and interest in life are gradually normalized. Therapeutic benefit is nearly complete in early disease, but declines as the disease advances. The effect of levodopa on behaviour has been described as a ‘general alerting response’. In some patients this progresses to excitement frank psychosis may occur. Embarrassingly disproportionate increase in sexual activity has also been noted. Dementia, if present, does not improve; rather it predisposes to emergence of psychiatric symptoms. Levodopa has been used to produce a nonspecific ‘awakening’ effect in hepatic coma

2. CVS 

The peripherally formed DA can cause tachycardia by 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. This may be a central action. Excess DA and NA formed in the 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. The DA formed peripherally gains access to the CTZ without hindrance—elicits nausea and vomiting. Tolerance develops gradually 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

 Levodopa is rapidly absorbed from the small intestines by utilizing the active transport process meant for aromatic amino acids. Bioavailability of levodopa is affected by: 

(i) Gastric emptying: if slow, levodopa is exposed to degrading enzymes present in gut wall and liver for a longer time—less is available to penetrate blood-brain barrier. 

(ii) Amino acids present in food compete for the same carrier for absorption: blood levels         are lower when taken with meals.

 Levodopa undergoes high first pass metabolism in g.i. mucosa and liver. The peripheral and central pathway of metabolism of levodopa is depicted in Fig. 31.2.

     About 1% of administered levodopa that enters brain, aided by amino acid carrier mediated active transport across brain capillaries, also undergoes the same transformation. The plasma t½ of levodopa is 1–2 hours. Pyridoxal is a cofactor for the enzyme dopa-decarboxylase. The metabolites are excreted in urine mostly after conjugation. 

ADVERSE EFFECTS

 Side effects of levodopa therapy are frequent and often troublesome. Most are dose-related and limit the dose that can be administered, but are usually reversible. Some are prominent in the beginning of therapy while others appear late. At the initiation of therapy These side effects can be minimized by starting with a low dose. 

1. Nausea and vomiting It occurs in almost every patient. Tolerance gradually develops and then the dose can be progressively increased. 

2. Postural hypotension It occurs in about 1/3 of patients, but is mostly asymptomatic; some patients experience dizziness, few have fainting attacks. It is more common in patients receiving antihypertensives. Tolerance develops with continued treatment and BP normalizes. 

After prolonged therapy 

1. Abnormal movements (dyskinesias) Facial tics, grimacing, tongue thrusting, choreoathetoid movements of limbs start appearing after a few months of use of levodopa at optimum therapeutic dose. These dyskinesias worsen with time and practically all patients get involved after few years. Their intensity corresponds with levodopa levels. No tolerance develops to this adverse effect, but dose reduction decreases severity. Abnormal movements may become as disabling as the original disease itself, and are the most important dose-limiting side effects. 

2. Behavioural effects They range from mild anxiety, nightmares, etc. to severe depression, mania, hallu cinations, mental confusion or frank psychosis. Excessive DA action in the limbic system is probably responsible (antidopaminergic drugs are antipsychotic). Levodopa is contraindicated in patients with psychotic illness. 

3. 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. Abnormal movements may jeopardise even the ‘on’ phase. This is probably a reflection of progression of the disorder. With progressive degeneration of DA neurones the ability to regulate storage and release of DA may be largely lost: DA is then synthesized in the striatum on a moment-tomoment basis resulting in rapid and unpredictable fluctuations in motor control. Dose fractionation and more frequent administration tends to diminish these fluctuations for a time. Cautious use of levodopa is needed in the elderly; patients with ischaemic heart disease; 

Interactions 

1. Pyridoxine: Abolishes the therapeutic effect of levodopa (if it is not combined with carbidopa) by enhancing its peripheral decarboxylation so that less of it remains available to cross to the brain. 

2. Phenothiazines, butyrophenones, metoclopra - mide reverse the therapeutic effect of levodopa by blocking DA receptors. The antidopaminergic domperidone blocks levodopa induced nausea and vomiting without abolishing its antiparkinsonian effect, because domperidone does not cross blood-brain barrier, but reaches CTZ. Domperidone can be used to allay vomiting due to levodopa. Reserpine abolishes levodopa action by preventing entry of DA into synaptic vesicles.

 3. Nonselective MAO inhibitors: prevent degradation of DA and NA that is synthesized in excess from the administered levodopa at peripheral sites. This may cause hypertensive crisis. 

 4. Antihypertensive drugs: postural hypotension caused by levodopa is accentuated in patients receiving antihypertensive drugs; reduce their dose if levodopa is started.

 5. Atropine, and antiparkinsonian anticholinergic drugs have additive therapeutic action with low doses of levodopa, but retard its absorption—more time is available for peripheral degradation— efficacy of levodopa may be reduced (not when combined with carbidopa).