Central Sympathoplegics and Alpha Methyl Dopa

Central sympathoplegics are also known as Alpha 2 Selective Adrenergic Agonists

These are NOT ANTAGONISTS, but are alpha 2 agonists. They still block the effects but are different from other blockers. These include:

1. Alpha methyldopa (Aldomet)
2.  Clonidine
3. Apraclonidine
4. Brimonidine (given topically in eye)
5. Guanfacine
6. Guanabenz

Their main site of action is CNS and are not peripherally acting.

Alpha Methyl Dopa

Alpha methyl dopa is a structural analog of levo dopa, but actions are totally different. It is a prodrug, and is centrally acting (although lipid insoluble) because of aromatic amino acids, so competes levo dopa, producing extra-pyramidal symptoms.

Mechanism of Action

Alpha Methyl Dopa is converted into alpha methyl dopamine in the presence of decarboxylase, which forms alpha methyl noradrenaline by virtue of beta hydroxylase.

Alpha methyl dopa is produced as a prodrug, and needs to be activated. It is actively transported to brain adrenergic neuron terminals, which use same enzymes as those of NE.

Alpha methyl dopa displaces noradrenaline and sits in its place. Guanethidine also does the same. Alpha methyl noradrenaline does not act as a false neurotransmitter. It shows response called pressor effect.

1. It is present in the storage vesicles. Auto receptors are present presynaptically, once stimulated (presynaptic alpha 2 receptors); further release of NE is inhibited by negative feedback, decreasing sympathetic outflow.
2. Alpha methyl dopa stimulates post synaptic alpha 2 receptors (brain stem, nucleus solitaries) to block sympathetic activity.

Tractus solitarius pathways stimulate sympathetic response. They act at alpha 2 receptors post synaptically. In appropriate neurons blocks sympathetic outflow.

Mechanism has been found indirectly. As:

1. Site of action is CNS
2. Are alpha 2 agonists
3. Need to be converted to active forms
4. Presynaptically block
5. Postsynaptically block sympathetic outflow in appropriate neurons

Evidence

Evidence has been found in animal studies:

• Lower doses of alpha methyl dopa are required when used directly in the ventricles of brain, showing site of action is CNS
•  Alpha 2 selective blockers block anti hypertensive effect. Thus they are not antagonists.
•  DOPA decarboxylase inhibitors if given, anti hypertensive effect are blocked, pointing out that conversion of drug is required before it can act.

Pharmacological actions

CVS

1. Cause decrease in blood pressure and decrease in TPR.

2. Have minimum effects on the cardiac output, especially in young adults having normal muscular tone. In older people, cardiac output is reduced because of poor muscle tone.

3. After 12 weeks of therapy if left ventricular hypertrophy occurs (long standing hypertension), drugs relieve this ventricular hypertrophy. There is no valid reason. Evidence is based on studies.

4. No postural hypotension occurs because of only central action, baroreceptors are spared.

5. Actions are more pronounced in the regions where there is increased sympathetic activity.

Kidneys

The renal blood flow is maintained by alpha methyl dopa. Renin secretion is decreased but there is no relevance to hypertension.

When used for prolonged durations, long term pressure control by kidneys lead to salt and water retention, causing blunting of blood pressure. These drugs are usually combined with diuretics.

Pharmacokinetics

The bioavailability is 25% orally.

Onset of action is a little delayed. It takes 6-8 hours before effects become visible. Once the actions start, they persist for 12-24 hours after stoppage of drug intake.

The drug has to be actively transported to brain adrenergic neurons and has to replace noradrenaline.

Thus, it is not used in emergency conditions.

Adverse effects

CNS

1. Ascending reticular activating center sedation
2. dry mouth (central nuclei of medulla blocked)
3. extra pyramidal signs,
4. increased prolactin (dopamine blocks nigrostriatal pathways, producing Parkinsonism like picture; central hypothalamus action if blocked by alpha methyl dopa, increased production of prolactin takes place.

Rare

Positive Coomb’s test

This test is used to detect auto antibodies destroying RBCs producing immune mediated hemolytic anemias. Auto antibodies are also produced against the drug, which cross react with RBCs. This occurs in 10% of the patient.

Hepatotoxicity
Drug fever

These two effects disappear once the drug is withdrawn.

Endocrine

1. Due to decreased dopamine, increased prolactin

2. Gynaecomastia

3. Galactorrhea

Reproductive System

Decreased libido

Nose

Nasal stuffiness

Fever also occurs, disappearing when drug discontinued.

Therapeutic Uses

1. Alpha methyl dopa is still the favourite drug of gynecologists for pregnancy hypertension, because:

a. No teratogenicity is associated
b. No harmful effects in fetus are observed

For other types of hypertensions, it is only used as an add-on drug.

2. Pre-eclampsia or eclampsia

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Clonidine

Apraclonidine

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