Antiparkinsonian Drug

 

Antiparkinsonian Drug

Pathophysiology:

·    Parkinsonism is a common movement disorder that involves dysfunction in the basal ganglia and associated brain structures.

·    Sign include:

a)                 Rigidity of skeletal muscles

b)                 Akinesia /Bradykinesia

c)                  Tremor

d)                 Mask like facies

e)                 Unstable gait.

·    In basal ganglia, the output neurons are controlled by dopamine and acetylcholine.

·    Due to their opposite action, a balance is required.

·    Major Pathology in Parkinsonism is decrane in nigrostriatal dopaminergic neurons, consequently cholinergic Activity becomes dominant.

·    Can be :

   (a) Natural Occurring (Idiopathic)

   (b) Drug induced Parkinsonism.

·    Two major Strategies for Treatment:

   (i) Incrane brain Dopaminergic Activity.

  (ii) Decreane Central Cholinergic Activity.

Dopamine Receptors:

D1  Like: Gs Coupled

D₂ like Gi Coupled

[A] Dopamine Precursors: Levodopa

·    As dopamine does not readily cross the blood-brain barrier, its precursor L-dopa (Levodopa) is used.

·    This Amino acid enters the brain via L-amino acid transporter (LAT) and is converted to dopamine by enzyme aromatic L-amino acid decarboxylase (dopa decarboxylase).

·    Levodopa is usually given with Carbidopa.

·    L-DOPA is broken down by DOPA decarboxylase in the peripheral tissues, which cames side effects.

·    Carbidopa inhibits tissue DOPA decarboxylase:

a)         Prolonged activity levodopa.

b)        Reduced systemic side effects.

Adverse effects

·    Nausea , Vomiting

·    Postural hypotension

·    Arrhythmias

·    Hypertension

·    Mydriasis

·    Dyskinesia

·    Psychotic symptoms

Dopamine Hypothesis:

Reduce dopamine level in Parkinson’s diseases 

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Dopamine agonists are given to patients with parkimorin

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Long term exposure to anti-Parkinson drugs increases risk or severity of schizophrenia

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Treatment of schizophrenia involve reducing dopamine level.

[B] Drugs Inhibiting Metabolism of Dopamine:

(i) COMT Inhibitors: Talcapone and Entacapone

·    COMT (Catechol-o-methyl transferone)

This enzyme metabolizes dopamine as well as L-Dopa to form 30-methyldopa.

·    Tolcapone & Entacapone act by inhibiting this enzyme.

·    Metabolism of L-dopa is inhibited, so more is able to cross BBB. These can be given in combination with L-dopa + carbidopa (inhibition of dopa decarboxylase diverts the metabolism of L-dopa to methylation by COMT)

·    3-O-methyl dopa formed by metabolism of L-dopa competes with it for entry in the brain. Tolcapone and entacapone decrease this interaction.

·    By inhibiting dopamine metabolism in brain (tolcapone only), its duration of action is increased.

·    Tolcapone inhibits COMT in Entacapone inhibits Periphery as well as Brain COMT in Periphery only.

·    Tolcapone & Hepatotoxic (Toxic to liver)

(ii) MAO-B Inhibitors:

·    Selegiline and Rasagiline. inhibitors of MAD-B. are reversible and Selective

·    Initial treatment and adjunct to levodopa.

·   Side effects

Dyskinesis

Psychosis

Insomnia

[C] Dopamine - Receptor Agonists:

·    Pramipexole and Ropinirole

·    These drugs directly activate D₂ Receptors and can be used in Parkinsonism.

 

·    Side effects –

a)        Dyskinesias & Psychosis

b)      Postural Hypotension

 

·   Contraindicated in:

(a) Peptic Ulcer

(b) Psychotic illness

(c) Myocardial Infarction

 

[D] Drugs Decreasing Ach Function:

·    Benztropine & Trihexyphenidyl

·    Both an Muscarinic Blockers

• decrease Tremor and decrease Rigidity but little effect on bradykines

·    Side effect:

Atropine-like

(Urinary Retention, Blurred Vision, dry mouth and constipation)

 

·    Amantadine:

a)        Antiviral, which block Muscarinic Receptor.

b)        Increase Dopamine Release

·    Side effects - Atropine-like