Parkinsonism

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Chapter: Essential pharmacology : Antiparkinsonian Drugs

It is an extrapyramidal motor disorder characterized by rigidity, tremor and hypokinesia with secondary manifestations like defective posture and gait, masklike face and sialorrhoea; dementia may accompany.


PARKINSONISM

 

It is an extrapyramidal motor disorder characterized by rigidity, tremor and hypokinesia with secondary manifestations like defective posture and gait, masklike face and sialorrhoea; dementia may accompany. If untreated the symptoms progress over several years to endstage 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 (SNPC) 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. Oxidation of DA by MAOB and aldehyde dehydrogenase generates hydroxyl free radicals (•OH) in the presence of ferrous iron (basal ganglia are rich in iron).

 

Normally these free radicals are quenched by glutathione and other protective mechanisms. Agerelated and/or otherwise acquired defect in protective mechanism allows the free radicals to damage lipid membranes and DNA resulting in neuronal degeneration. Genetic predisposition may contribute to the high vulnerability of substantia nigra neurones.

 

Ageing induces defects in mitochondrial electron transport chain. Environmental toxins and/or genetic factors may accentuate these defects in specific areas. A synthetic toxin Nmethyl4phenyl tetrahydropyridine (MPTP), which occurred as a contaminant of some illicit drugs, produces nigrostriatal degeneration and manifestations similar to PD by imparing energy metabolism in dopaminergic neurones. It has been proposed that MPTP-like chemicals may be present in the environment, small quantities of which accelerate age related or otherwise predisposed neuronal degeneration of parkinsonism, but there is no proof.

 

Excess of the excitatory transmitter glutamate can cause ‘excitotoxic’ neuronal death by inducing Ca2+ overload through NMDA receptors.

 

Drug induced temporary 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 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 bloodbrain barrier. In the subsequent years, a number of levodopa potentiators and DA agonists have been developed as adjuvants/ alternatives.

 

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