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:
- Alpha methyldopa (Aldomet)
- Clonidine
- Apraclonidine
- Brimonidine (given topically in eye)
- Guanfacine
- 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.
- 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.
- 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:
- Site of action is CNS
- Are alpha 2 agonists
- Need to be converted to active forms
- Presynaptically block
- 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
- Ascending reticular activating center sedation
- dry mouth (central nuclei of medulla blocked)
- extra pyramidal signs,
- 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
Clonidine:
Clonidine is imadazoline derivative. It is centrally acting, and is not a prodrug. It is lipid soluble.
Mechanism of action
Mechanism of action of clonidine is different from that of alpha methyl dopa. It does not need to be converted to active metabolite and is active as such. It easily crosses the blood brain barrier and acts as agonist on alpha 2 receptors located in brainstem tractus solitaries.
- It presynaptically inhibits noradrenaline release.
- Postsynaptically, it decreases sympathetic conduction.
- Imidazoline receptors are present in rostroventrolateral medulla which also act and have different action and increase the parasympathetic activity.
Pharmacological actions
CVS
Decreases blood pressure, total peripheral resistance and cardiac output. Because of interaction with receptors, apart from blocking sympathetic system, it also increases parasympathetic outflow (I receptors), leading to decreased heart rate, decreased force of contraction and decreased cardiac output.
Kidneys
Renal blood flow is maintained. Acting as alpha 2 agonist, renin might be decreased. There are chances of tolerance. Kidney functions are maintained.
Adverse effects
CNS
- Sedation
- Dryness of mouth
- Sleep disturbances
- Does not cause extra pyramidal signs
- Does not cause increase in prolactin
- Suicidal tendency
Nasal stuffiness
Contact dermatitis
Some patients are hypersensitive to skin patches of clonidine which are effective for 7 days. This might lead to contact dermatitis.
Rebound hypertension
If Clonidine is withdrawn suddenly, hypertension crisis may occur, even with one to two missed doses. This is because alpha 2 receptors are down regulated due to agonist effect (block sympathetic outflow) while alpha 1 are not (circulating catecholamines produce increased response).
Clonidine has decreased usage now because of rebound hypertension.
Therapeutic uses of Clonidine:
1. Hypertension
2. Withdrawal from narcotics, alcohol and tobacco- to counter increased sympathetic activity during drug withdrawal, craving for drug is reduced by clonidine
3. Menopausal hot flushes –due to increased sympathetic activity
4. Diagnosis of pheochromocytoma
Patients have essential hypertension because of increased noradrenaline due to tumor of adrenal gland. Clonidine is given to control blood pressure, at the same time noradrenaline and adrenaline are decreased.
If patient has pheochromocytoma, blood pressure is controlled but there is persistence of levels of adrenaline and noradrenaline, which leads to diagnosis of pheochromocytoma.
5. To prevent diarrhea by diabetic neuropathy –clonidine producing alpha 2 effect, causes decreased salt and water release in lumen along with decreased cAMP, leading to decreased Cl- out flux and increased Na+ influx, This decreases water outflow, reducing diarrhea.
| Alpha Methyl Dopa | Clonidine |
| Prodrug –conversion required | No conversion required |
| Decrease in sympathetic activity | Decreased sympathetic and increased parasympathetic outflow |
| Decrease TPR, no effect C.OC.O in elderly only | Decrease TPR and C.O |
| Slow onset | Rapid onset |
| Slow termination of effects | Rapid termination |
| Lipid insoluble, but crosses BBB | Lipid soluble |
| Reverses left ventricular hypertrophy | Cannot reverse |
| No rebound HTN | Rebound HTN |
Apraclonidine:
It is topically used in the eye as eye drops, it does not cross blood brain barrier, and is given in low doses so there are less chances of hypertension.
It decreases intraocular pressure by:
- Decreasing production of aqueous humor
- Increasing outflow of aqueous humor
It is protective to neural tissue, thus possibly has some role in treatment of glaucoma.