Parkinson's Disease

Antiparkinsonism Agent

Parkinson’s Disease (PD) is slowly progressive neurological disorder of muscle movements. It is characterised by muscular rigidity, expressionless face, tremor, posture and gait abnormality, bent posture, bradykinesia (Slow to initiate and carry out voluntary movement), akinesia (Loss of the power of voluntary movement.) and depression.Exact reason of PD is unknown. It is linked with destruction of dopaminergic neurons of substantia nigra and corpus striatum. Dopaminergic neurons originate from substantia nigra and terminate in corpus striatum. Substantia nigra is part of extrapyramidal system (part of motor system to control involuntary action). Dopaminergic neurons of substantia nigra influence motor activity.

Striatum is connected with substantia nigra by neurons that secrete GABA. These neurons terminate in substantia nigra. GABA inhibits secretion of Dopamine. GABA and dopamine mutually maintain degree of inhibition.

Secretion of acetylcholine in neostratium has stimulating effect for normal body movement. Secretion of Dopamine from substantia nigra inhibits action of acetylcholine in neostriatum. This maintains balance body movement.

In PD substantia nigra cells degenerate and do not produce sufficient Dopamine. Thus, Dopamine inhibitory effect in neostratium acetylcholine decreases. This produces uncontrolled movement of muscles

Treatment of PD

Antiprkinson’s agents do not inhibit neuronal degeneration or reverse neuronal degeneration. They only provide temporary relief from symptoms of PD. Antiparkinson’s Agent can be divided into two groups:

A.    Dopaminergic mimetic

B.     Cholinergic lytic.

A.    Dopaminergic mimetic: These drugs increase dopaminergic activity.

Ex.

1.      Dopamine Precursor: Livodopa (L-Dopa)

2.      Increase L-Dopa availability in Brain: Carbidopa, Benserazide, Pergolide

3.      Increase release or inhibit Dopamine reuptake: Amantadine

4.      Dopamine receptor Agonist: Bromocriptine

5.      Prolong Dopamine Action: Lisuride, Pergolide, Selegiline

B.     Cholinergic lytic: These drugs decrease activity of Acetlcholine

1.      Anticholinergics: Biperidine, Benztropine, Procyclidine, Trihydroxy Phenidyl

2.      Antihistaminic with anticholinergic activity: Orphenadrine, Promethazine, Chlorphenoxamine.

Levodopa (L-Dopa): L-Dopa is immediate metabolic precursor of Dopamine and Noradrenaline. Dopaminergic neurones in extrapyramidal centre (Substantia nigra) converts L-Dopa into Dopamine.

 Pharmacokinetics: L-Dopa is rapidly absorbed from GIT by active transport. Increase in GIT pH decreases Dopamine absorption. Protein rich food (amino acids) in GIT decreases L-Dopa absorption because both are absorbed by active transport; an saturable process of drug absorption. Thus L-Dopa should be administered in empty stomach 45 minutes prior to food. Delay emptying time increases contact time of L-dopa with gastric enzymes. This degrades dopamine and decreases bioavailability of L-Dopa.

1-2% L-Dopa enters into brain. 90% to 98% L-Dopa undergoes decarboxylation in periphery.

Pharmacodynamics: 1% to 2% L-Dopa enters into brain. Dopaminergic  neurons in extrapyramidal centre (Substantia nigra) converts L-Dopa into Dopamine. Deficiency of dopamine in brain causes PD. L-Dopa is used to treat PD because Dopamine cannot cross BBB.

L-Dopa is effective in initial stage of PD. In advance stage of PD, L-Dopa is not effective because in advance stage number of dopaminergic neurons is very less. These less numbers of neurons cannot convert sufficient amount of L-Dopa into dopamine.

Adverse Effects:

1.      Peripheral Adverse Effects: Maximum amount of L-Dopa is decarboxylised in periphery. Metabolites produce adverse effects in periphery. Ex. Nausea, vomiting, hypotension, cardiac arrhythmias,. Increase in production of melanin turn colour of urine and saliva brown.

2.      CNS Adverse Effects: L-Dopa in CNS causes dyskinesia (abnormal, uncontrolled, involuntary movement) and behaviour abnormalities. It produces “on off phenomena” i.e. sudden immobility, sudden tremor and sudden cramps.

Carbidopa and Benserazide

Both potentiate action of L-Dopa. They prevent decarboxylation of L-Dopa in periphery. They are also known as peripheral Dopamine decarboxylase inhibitor. They do not cross blood brain barrier. They also diminish L-Dopa degradation in GIT. All these increase availability of L-Dopa in brain.

Co administration of carbidopa or Benserazide with L-Dopa has following advantages:

1.      Reduction in dose of L-Dopa

2.      Decrease in nausea and vomiting

3.      Decrease in cardiac arrhythmias

4.      Quick entry of L-Dopa in brain

5.      Effective concentration of L-Dopa in brain

6.      Improvement in PD

7.      Protection of L-Dopa from antagonists like Vitamin 6 (Pyridoxin)

Disadvantage:

Side effects of L-Dopa like behaviour abnormalities and dyskinesia exaggerated. These side effects appear much earlier.

Contra Indications:

1.      Pyridoxine; increases peripheral metabolism of L-Dopa

2.      MAO inhibitors like Pheneizine with L-Dopa causes hypertension. These drugs decrease Dopamine peripheral metabolism that cause hypertension.

3.      L-Dopa increases intraocular pressure in glaucoma patient.

4.      L-Dopa increases cardiac arrhythmia in cardiac patient

5.      Antipsychotic drugs block Dopamine. Thus it can potentiate PD symptoms

Bromocryptine:

It is synthetic alkaloid ergot derivative (ergotamine). It is dopamine agonist. It produces antiperkinsonism action in L-Dopa resistant patient. In PD treatment, it is not used alonedue to serious side effects and high cost. Thus it is not used alone. It is used with L-Dopa. It decreases dose of L-Dopa.

Side effects

1.      CNS: Hallucination, Confusion, Delirium, Deteriorate mental condition.

2.      CVS: Myocardial infarction, Vasospasm in cardiac patient.

3.      GIT: Worsening of peptic ulcer, Anorexia, Vometing, Constipation

Amantadine:

It is antiviral drug to treat influenza. It has also anti-parkinsonism effect. It potentiate dopaminergic activity i.e. increase in dopamine synthesis and its release, block Dopamine reuptake.

Side Effects: It shows little side effects than L-Dopa . Mild reversible hallucination, confusion, restlessness, nightmare.,Headache, dizziness, insomnia, hypotension, lethargy, urinary retention, GIT disturbance, dry mouth and edema. It is less effective than L-Dopa and develops tolerance rapidly

Selegiline/ Deprenyl

Selegiline is also known as deprenyl. Selegiline inhibits MAO B (Mono Amine Oxidase B). MAO B metabolise Dopamine. Thus it inhibits Dopamine metabolism and increases concentration of Dopamine in brain. Due to this property it is administered with L-Dopa to reduce required dose of L-Dopa. It causes postural hypotension, involuntary movements, nausea, vomiting confusion and psychosis.

Anti muscarinic Agents:

They are less effective than L-Dopa. They are used to manage mild symptoms of PD. They are used to manage mild symptoms of PD. Usually they are effective to manage PD symptoms due to side effect of any other drug. In this condition L-Dopa is not much effective. They may be used with L-Dopa to manage symptoms of PD.

Side Effects: Mouth Dryness (xerostomia), visual disturbance, papillary dilation, naisea, vomiting, constipation, increase in intra ocular pressure, drowsiness, confusion, delirium, delusion, hallucination, hypepyrexia and agitation. Sudden withdrawal of drug may exacerbate PD symptoms. They should be withdrawn gradually.

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