Sympatholytic agents

Introduction

1.       Sympatholytic agents act by various mechanism other than direct beta-receptor blockade to diminish sympathetic outflow or noradrenaline levels in the body.

2.       Their potential to cause adverse side effects depends on their level of interference of the sympathetic reflex arc – agents that act centrally or at the presynaptic level have been largely replaced by those acting at postsynaptic level.

3.    They are now used as second-line agents in the management of hypertension and in special clinical circumstances where brief and fast lowering of blood pressure is essential.

4.    The general disadvantages of sympatholytics are postural hypotesnion, sexual dysfunction in the male patient and CNS depression with central acting agents.

Clonidine

1.       Mode of action:

a.    An imidazoline.

b.    An agonist to alpha2-receptors in the brain, suppressing sympathetic outflow and reducing blood pressure.

c.    At high doses it also activates peripheral alpha2-receptors.

2.       Reduces blood pressure with little postural or exercise drop.

3.       Abrupt or even gradual withdrawal causes a rebound hypertension.

4.       Pharmacokinetics:

a.    Half-life: 6h.

b.       Onset may be rapid (a few hours) or delayed for a few days.

c.       Subsides over 2 – 3 days.

5.       Adverse effects:

a.       Sedation.

b.    Dry mouth.

6.       Rebound hypertension with:

a.       Beta-blockers.

b.       Tricyclic antidepressants which also antagonize antihypertensive effects.

Other sympatholytics

1.       Methyldopa

a.    Half-life: 1.5h.

b.       Taken up into central and peripheral adrenergic nerve terminals and converted to a false transmitter alpha-methylnoradrenaline.

c.       Alpha-methylnoradrenaline stimulates alpha2-receptors in the hindbrain nuclei to suppress sympathetic discharge resulting in a fall in blood pressure.

d.       Adverse effects: drowsiness, sedation, headache, nightmares, depression, involuntary movements, nausea, flatulence, constipation, positive Coombs test, haemolytic anaemia, leukopenia, thrombocytopenia and hepatitis.

e.       Gynaecomastia and lactation occur due to interference with dopaminergic suppression of prolactin secretion.

f.       Because of its adverse effects methyldopa is no longer used in the routine management of hypertension but remains popular with obstetricians.

2.       Reserpine:

a.    An alkaloid from plants of the genus Rauwolfia.

b.       Depletes adrenergic nerves of noradrenaline by blocking or destroying the storage mechanism within the nerve ending, so that there is less transmitter available for release with resultant fall in blood pressure and sedation.

c.    At higher doses mental depression and parkinsonism develops.

d.       Adverse effects: stuffy nose, diarrhoea, increased gsatric secretion.

3.       Guanethidine:

a.       Cause depletion of noradrenaline at sympathetic nerve terminals.

b.       Being highly polar, it does not enter the CNS.

c.       Adverse effects: postural hypotension, impotence, hypersensitivity to sympathomimetic amines.

d.    Used to reduce intraocular pressure in open angle glaucoma and to reduce thyrotoxic eyelid retraction.

4.       Trimetaphan:

a.    An autonomic ganglion blocking agent.

b.    Very rapid and short duration of action.

c.       Administered i.v. for treating hypertensive crisis and for controlled hypotension in neurosurgery.