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Dopamine Receptor Antagonists

Ergot Derivatives

Bromocriptine

Most important and commonly used derivative of ergot alkaloid.

Mechanism of Action

Same as that of levo dopa. Acts as an agonist on D2 receptors.

Pharmacological Actions

CNS

Same as those of levo dopa. As D2 agonist, improvement in symptoms, increased motility and improved posture.

Endocrines

  1. Decrease release of prolactin, so used in hyperprolactenemia
  2. Decrease in GH in acromegaly, increase in normal

Reticular formation

arousal of CNS, so used in hepatic encephalopathy.

Uses

1. Parkinsonism

Second line drug. Given to patients who cannot tolerate levo dopa or those suffering from response fluctuation (on off phenomenon). In such cases used with levo dopa, otherwise has no advantage over levo dopa.


2. Prevention/suppression of lactation

Especially after abortion, delivery. Since drug also has cardiovascular effects, it is given carefully in those suffering from cardiovascular diseases. Other drugs are preferred like Lisuride.
3. Hyperprolactinaemia
4. Acromegaly

As causes a decrease in release of GH.
5. Benign breast disease

Patients suffering from pain in breasts (myastalgia).
6. Hepatic encephalopathy

Reticular arousal, so given.

Adverse effects

Similar to levo dopa.

  1. Vomiting due to effects on CTZ
  2. Due to dopamine agonist effect on CNS –tachycardia, arrhythmias and hypertension
  3. CNS effects –esp. when given in combination with levo dopa.
  4. Can cause severe Postural hypotension. In some even on very first dose. Patient may faint. So first test dose is given, about 1 mg, to see whether hypotensive effects appear or not, given especially after food or when lying down to avoid 1st dose hypotensive effects.
Drug interactions

Metoclopramide & Domperidone (anti-emetic) decrease gastric emptying, cause a decrease in hypoprolactemiac effect.
Dose:
start at low dose of 1-1.25mg, which may be increased to 2-2.5mg ultimately upto 20-80mg, depending upon response of patient.

Lisuride

Although dopamine agonist, used in patients suffering from cardiovascular diseases, otherwise has no other advantage.

Pergolide

Persons who cannot tolerate bromocryptine or have excessive vomiting can be given. It acts both on D1 and D2 receptors.

The advantage is that adverse effects are less than levo dopa and bromocryptine. Half life is 2 hours. Also given orally.

Non-Ergot Derivatives

Pramipexole

Mainly act on D3 in addition to D1 and D2. Drug is given orally. Most is excreted unchanged in urine.

Half life is 8 hours. Bioavailability is 90%.

Important aspect is that it also has anti-oxidant effects. It increases the removal of hydrogen peroxide from brain, so has neuroprotective/neurotrophic effect.

Adverse effects

Same as those of levo dopa including vomiting, hypotension, insomnia, but less than bromocryptine and levo dopa.

Dose is started at 0.125 mg up to 0.5-1.5 mg.

Ropinirole

Mainly act at D1 and D2 receptors. Biavavailability is less than prmipexole when given orally (55%). Metabolized in liver. Half life is 6 hours.

Uses are similar to pramipexole. Given in combination with levo dopa or instead of bromocryptine.

Apomorphine

Oder drug, used as emetic drug. It is chemically a derivative of morphine. In actions resembles dopamine and has both D1 and D2 agonist effects.

Advantages

Given subcutaneously in patients suffering from on off phenomenon.

If drug is given orally, it takes 45-60 minutes, here subcutaneously used, so early recovery.

It is administered for at least 30 days.

Nausea is very troublesome, remedy is pre-treatment with Trimethobenzamide (300 mg T.D)

Selective COMT inhibitors

Catechol-o-methyl transferrase performs little methylation of levo dopa, when metabolized by it, 3-o-methyl dopa is formed.

When drug is given with dopa decarboxylase, more levo dopa is methylated into 3-o-methyl dopa, which can interfere with entry of levo dopa in brain, as competes.

Patients taking dopa decarboxylase inhibitors, decreased response is observed. It can be given to decrease levels of 3-o-methyl dopa. Half life is 2 hours. Usually given in combination with levo dopa when decreased response occurs, so person is taking dopa decarboxylase inhibitors.

Tolcapone Entacapone
More potent Less potent
Hepatotoxic Not so
Both central and peripheral actions Only peripheral action
Less dose required More dose required
Less preferred More preferred

MAO-B Inhibitors

Deprenil acts on MAO-B, causing decrease in metabolism of dopamine, increasing the levels of levo dopa. Always given in combination with levo dopa.

Given especially to patients suffering from fluctuations in response, esp. end of dose akinesia, treatment is facilitated when drug is combined. Dose is 5-10 mg.

L-dopa when given with non selective MAO inhibitors, may cause hypertension crisis (due to peripheral action of norepinephrine) so are not used together.

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