Non-Catechol Sympathomimetics

Introduction

1.    The non-catechol sympathomimetic amines are clinically important because some of their actions are more prominent than the others, thus enabling them to be used as CNS stimulants and anorexiants, vasoconstrictors and bronchodilators.

2.    They are not acted on by COMT and many of them are poor substrates of MAO; hence most of them are active orally and have long duration of action.

3.       Some of these drugs, e.g. ephedrine, metaraminol, amphetamine, are capable of acting indirectly through the release of endogenous noradrenaline.

4.       Others like tyramine and phenylethylamine act solely by displacing noradrenaline.

Amphetamine

1.       Mode of action:

a.    Acts by releasing noradrenaline stored in nerve endings in both the CNS and the periphery.

b.       Power CNS stimulant actions in addition to peripheral alpha and beta actions.

c.       Effective in stimulating medullary respiratory center and lessening the CNS depressing effect of other drugs.

2.       Pharmacokinetics:

a.    Half-life: 12h.

b.       Readily absorbed by any usual route.

c.       Largely eliminated unchanged in the urine.

d.       Urinary excretion is pH dependent; being a basic substance, elimination will be greater in an acid urine.

3.       Clinical effects:

a.    10 – 30mg produce wakefulness, alertness and decreased sense of fatigue.

b.       Athletic and simple mental performance are improved.

c.       However, prolonged use or large doses usually give rise to mental depression and fatigue.

d.       Raises both systolic and diastolic blood pressure; heart rate often slowed down but with large doses cardiac arrhythmias may occur.

e.       Contractile effect on bladder sphincter marked enough to enable its use in enuresis and incontinence.

4.       Adverse effects:

a.       CNS: tremor, insomnia, dizziness, weakness, fever and headache.

b.    CVS: anginal pain, flushing, cardiac arrhythmias, hypertension and circulatory collapse.

c.    GI: dry mouth, nausea, diarrhoea, vomiting, abdominal cramps.

5.       Clinical uses:

a.       Narcolepsy: patients pass directly into REM sleep; amphetamine delays onset of REM sleep.

b.    In some hyperactive children with attention deficit disorder; also methylphenidate (Ritalin).

c.       Appetite suppression: alternatives such as dexfenfluramine are preferable.

6.       Dependence and withdrawal:

a.       Chiefly psychological, but there is a withdrawal symptom.

b.       Severe dependence induces behavioral disorders, hallucinations and psychosis.

c.       Withdrawal: lethargy, sleep, desire for food and severe depression.

7.       Acute poisoning:

a.       Excitement and peripheral sympathomimetic effects, convulsions.

b.       Hyperthermia with cardiac arrhythmias, vascular collapse and death.

c.       Treatment is chlorpromazine with added antihypertensive, e.g. labetalol.

8.    Drug interactions:

a.       Antagonism of antihypertensives.

b.       Severe hypertension with MAOIs and beta-blockers.

Ephedrine

1.       Mode of action:

a.       Similar to adrenaline.

b.    Has a greater stimulant effect on the CNS in adults, producing alertness, anxiety, insomnia, tremor and nausea.

c.       Effects come on more slowly and last longer.

d.       Tachyphylaxis occurs.

2.       Pharmacokinetics:

a.    Half-life: 4h.

b.    Well absorbed orally.

c.    Not metabolized by liver.

d.       Excreted largely unchanged by the kidney.

3.       Clinical uses:

a.       Bronchodilator.

b.       Heart block.

c.       Mydriatic.

d.       Mucosal vasoconstrictor.

e.       Relieve pain of dysmenorrhoea.

f.       Nasal decongestant.

Other non-catechol sympathomimetics

1.       Phenylephrine:

a.       Chemically resembles noradrenaline, but has a longer duration of action.

b.    Acts directly on alpha receptors and has little effect on the heart on CNS.

c.    Its pressor action is sustained.

d.    Used during spinal anaesthesia and for orthostatic hypotension.

e.    Used as a nasal decongestant, but sometimes irritates.

2.       Metaprenaline and related bronchodilators:

a.       Metaprenaline, salbutamol, terbutaline and isoetharine are specific beta2-agonists.

b.    They relax smooth muscle of the bronchi, uterus and vascular supply to skeletal muscle but has little effect on the heart and blood pressure.

c.       Metaprenaline, terbutaline and salbutamol are given by continuous infusion to delay premature labor.

3.       Xamoterol:

a.    A partial agonist at beta1-receptors.

b.    At low levels of sympathetic activity it increases heart rate and contractility by its agonist effect, and at high rates it reduces them by its antagonist action.

4.    Use as mucosal decongestants:

a.    Non-catechol sympathomimetics are widely used as nasal and bronchial decongestants in allergic rhinitis, colds, coughs and sinusitis, and to prevent otitic baro-trauma, as nasal drops or as sprays to be sniffed.

b.    They interact with anti-hypertensives and can be a cause of unexplained failure of therapy.