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Levo Dopa -Mechanism of Action, Pharmacological Effects, Uses and Adverse Effects

Parkinson’s disease is chronic progressive disease, only symptoms can be treated. As time passes, since it is progressive, ultimately complete degeneration of dopaminergic fibers occurs. Drugs then become less effective.

Main drug used is levo dopa. It is chemically precursor of dopamine and is a derivative of amino acid L-tyrosine. Chemically it is dihydroxy phenyl alanine.

Mechanism of Action

Since it acts mainly by increasing the stores of dopamine in the brain, as the drug is converted into dopamine by dopa decarboxylase, which is responsible for the effects.

There are five types of dopamine receptors: D1, D2, D3, D4, and D5.

Mainly D2 receptors are involved. To some extent D1 act as well.

D1 are linked with adenyl cyclase and act by increasing cAMP levels.

D2 rather inhibit adenylate enzyme. They decrease the cAMP and inhibit the activation of indirect pathways, which may cause decrease in dopaminergic activity.

Increased cAMP leads to activation of direct pathways. When direct pathways are stimulated, increase in dopaminergic activity occurs.

Both are beneficial.

Pharmacological  Actions of Levodopa
  1. CNS

Main effect. When converted into dopamine, increase in dopaminergic activity occurs, leading to improvement of symptoms of Parkinsonism. It:

  1. Decreases tremors
  2. Decreases rigidity
  3. Improves hypokinesia/akinesia
  4. Improves posture
  5. Improve facial expression (mask like in parkinsonism)
  6. Dopamine receptors are also present in CTZ, when they are stimulated vomiting occurs. This is the main adverse effect. To avoid this, anti-emetic is used. After prolonged use, tolerance to this effect develops.

Domperidone or Cyclizine as antiemetic can be given 30 minutes before L-dopa if required

  1. CVS

Most DOPA is decarboxylated in periphery before entry into brain. When dopamine levels are increased in periphery, alpha and beta receptors are stimulated leading to:

  1. Increase in heart rate
  2. Tachycardia
  3. Increased blood pressure
  4. Sometimes postural hypotension occurs as well.
  5. Dopamine also causes vasodilatation in splanchnic blood vessels
  6. Also cause a decrease in central sympathetic outflow due to alpha 2 receptors negative feedback, decreasing norepinephrine.
  1. Endocrine

Dopamine causes decrease in release of prolactin, also used in hyperprolactemia.

Also decrease secretion of GH in acromegaly

GH increases in normal persons.

Pharmacokinetics

a. Absorption

Well absorbed after oral administration from proximal part of small intestine by active transport mechanism. Absorption decreases

  1.  In hyperacidity
  2. Protein rich food, because of amino acids competes with L-dopa for absorption
  3. Drugs which decrease gastric emptying (domperidone)

Drug is metabolized in liver. Homovalenic acid is the ultimate metabolite of enzymes COMT and MAO.

b. Peripheral metabolism

Since most of drug is decarboxylated peripherally, only 1-5% levo dopa enters brain.

To avoid this effect, dopa decarboxylase inhibitors are used to prevent peripheral conversion into DOPA.

Excretion occurs mainly in bile

c. Half life

Half life is only 1-3 hours, it is shorter after oral absorption

Peak plasma concentration occurs after about 1 hour.

d. Interaction with pyridoxine

Therapeutic uses
  1. Parkinsonism

Drug of choice. start with low dose, gradually increased after 2-4 days. Dose is limited when:

  1. Symptom alleviate, increase in activity is observed
  2. Adverse effects are seen

Once improvement occurs, patient is maintained on drug for 4-5 years. After this decline in response occurs due to:

  1. Development of tolerance
  2. Disease is progressive –degeneration of dopaminergic fibers occurs

Then other agonists are used, or drug is combined with them.

  1. Hyperprolactinaemia

Hyperprolactinemia leads to glactorrhoea and infertility due to decrease in gonadotrophic hormones. Can be used in such patients, drug of choice is bromocryptine.

  1. Hepatic encephalopathy

In coma due to hepatic encephalopathy, as increased stimulation of CNS arouses. Thus it is useful in patient of hepatic failure and encephalopathy.

Adverse effects of levodopa

These are the exaggeration of pharmacological actions.

1. GIT

  • Due to effect on CTZ severe vomiting occurs, anti-emetic drug is given 30 minutes before.

Peripheral D2 antagonist is used. Central D2 antagonists (Metoclopramide) is never used as will further aggravate the situation.

  • Anorexia
  • May also cause increase in symptoms of peptic ulcer.

2. CVS

Due to peripheral conversion into dopamine:

  1. Heart-beta 1 effect, increased heart rate, tachycardia, palpitations, cardiac arrhythmias
  2. Postural hypotension

3. Dyskinesias

Very important adverse effect, related to dose. As drug has to be given for prolonged period, an increase in dose leads to development of dyskinesia or involuntary movements. These include:

  1. Chorea
  2. Ballismus
  3. Athetosis
  4. Dystonia
  5. Myoclonus
  6. Faciolingual tics
  7. Grimacing
  8. Head bobbing
  9. Oscillatory and rocking movements of arms, legs or trunk

Treatment

  1. lowering dose of levodopa
  2. using levodopa alone not in combination
  3. drug holiday, 3-21 days until symptoms disappear
  4. D2 receptor antagonists (oxiperomide and tiapride)

4. Behavioral effects

Due to effects on CNS. These are opposite to Parkinson’s disease and include:

  1. Hallucinations
  2. Psychosis
  3. Mania
  4. Anxiety

To control these effects, dopamine antagonists are not given, as relapse of disease might occur.

2nd generation antipsychotics are used including Clozapine and Olanzapine, which have less extrapyramidal effects.

5. Ocular effects

Because of conversion into dopamine, sympathomimetic effects-mydriasis

6. Blood

  1. Dyscrasias
  2. Positive Coomb’s test

7. Fluctuation in response

Important, as improvement in symptoms occur with a dose on which the patient is stabilized, after 4-5 years, conditions begin to decline again, which are manifested in various forms:

a. Early morning akinesia

Before intake of drug in morning symptoms of Parkinson’s disease appear.

b. Peak dose dyskinesia

When drug levels reach maximum value, dyskinesias and involuntary movements might occur.

c. End of dose deterioration

d. On-off phenomenon

Most important and troublesome for the patient, as fluctuation in the response occurs. During on period, no symptoms are present, while during off period, they reappear.

Reasons

  1. After prolonged administration, decrease in absorption of DOPA occurs.
  2. Decreased entry of levo dopa in brain occurs
  3. Less conversion of levo dopa to dopamine due to decreased activity of dopa decarboxylase in brain

This can be treated by various means:

  1. As decreased absorption occurs, levo dopa is not given with food. Timing of giving drug is adjusted esp. with protein rich food.
  2. Decrease interval between doses, hourly or two hourly basis.
  3. Add other dopamine agonists drugs with DOPA like bromocryptine, apomorphine.

8. Endocrine System

  1. Decreased prolactin secretion
  2. Increased growth hormone secretion in normal
  3. Decreased growth hormone secretion in acromegaly.

This is due to over activity of tuberoinfundibular pathway, leading to increased dopamine.

9. Reproductive System

  1. Priapism (painful erection and tenderness). It is one of the most common symptom of sickle cell anemia. Treatment is intra-cavernous injection of beta blockers.
  2. Brown discoloration of vaginal discharge.

10. Metabolic

  1. Increased blood urea and nitrogen
  2. Increased ALT and AST
  3. Increased ALP
  4. Increased bilirubin

11. Miscellaneous

  1. Darkening of urine with secretions
  2. Darkening of skin due to increase in melanin and increased oxidation of catecholamines to melanin
  3. May be abnormality of taste and smell
  4. Increase in incidence/precipitation of gout in certain patients
  5. In those prone to psychiatric illness, increased incidence of schizophrenia

12. Fenton’s Reaction

When L-dopa is given, it is converted into dopamine, which reacts with oxygen in presence of:

    • MAO b
    • Aldehyde dehydrogenase

The product of this reaction is DOPAC and hydrogen peroxide. Hydrogen peroxide reacts with iron (abundant is substantia nigra) producing oxidative stress, leading to rapid degeneration of dopaminergic neurons producing ‘end of dose phenomenon’.

Central adverse effects include dyskinesias and behavioral effects.

Contraindications
  1. Given carefully to patients suffering from psychosis or psychiatric illnesses
  2. Glaucoma
  3. Cardiovascular diseases
  4. Renal impairment
Dose

Start at low dose 250 mg/day in divided doses. It may be increased to 2-8 grams.

Drug Interactions of levodopa

1. Pyridoxine (vit b6)

Decrease in activity of levo dopa in these patients (patients suffering from T.B, taking isoniazid and bit B6)

Those taking vitamin B complex

As dopa decarboxylase is pyridoxine dependent, increased conversion to dopamine in periphery leads to decrease in response.

2. Antipsychotics

Levo dopa antagonizes the effect of antipsychotics

3. Nonspecific MAO inhibitors

Acts on both MAO  A and B.

Decreases metabolism of catecholamines and dopamine, leading to hypertension, cardiac arrhythmias

4. Anticholinergics

Although given but in high doses or for prolonged periods, can decrease gastric emptying, decreasing motility and absorption of levo dopa.

5. Sympathomimetics

Effect is potentiated. Sometimes patient does not know, because over the counter preparations like nasal decongestants (ephedrine, adrenaline) can aggravate the effects.

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