Adrenergic blockers

Alpha receptor blockers

1.    Two subtypes:

a.       Alpha1: mediate vasoconstriction.

b.       Alpha2: presynaptic receptors mediate a reduction of release of noradrenaline.

2.       Cause of reflex tachycardia:

a.    Non-selective alpha blockers activates sympathetic nervous system.

b.       Increase in noradrenaline is not reduced by negative feedback via alpha2 receptors as they are blocked too.

c.    The beta receptors are not blocked and the excess noradrenaline is free to act on them, causing a tachycardia.

3.    An alpha1 blocker that spares the alpha1 receptor so that negative feedback inhibition of noradrenaline release is maintained, is more useful in hypertension.

4.       Adverse effects of alpha-receptor block:

a.       Postural hypotension.

b.       Nasal stuffiness.

c.    Red sclerae.

d.       Failure of ejaculation in males.

Prazosin

1.       Mode of action:

a.       Blocks alpha1 receptors but not presynaptic alpha2-autoreceptors.

b.       Reduces peripheral vascular resistance and blood pressure.

c.       Dilates both arterioles and veins.

2.       Pharmacokinetics:

a.    Half-life: 3h.

b.    Well absorbed orally.

c.    Oral bioavailability of 60%.

d.       Widely distributed in body tissues.

e.       Extensively metabolized in the liver by demethylation and conjugation.

f.       Excreted as unchanged drug and metabolites.

3.       Clinical uses:

a.       Essential hypertension.

b.       Prostatic hypertrophy: acts on bladder alpha1-receptors stimulating contraction.

4.       Adverse effects:

a.       ‘First-dose effect’: brisk hypotension sufficient to cause loss of consciousness within 2h of the first dose.

b.       Nausea, palpitation and dizziness.

c.       Urinary frequency and incontinence.

d.       Impotence.

e.       Blurred vision.

f.       Tinnitus.

Other alpha blockers

1.       Phenoxybenzamine:

a.       Powerful non-selective alpha blocker.

b.    Slow onset, but provide lasting action which lasts 2 days or longer.

c.       Forms irreversible complexes with adrenergic receptors.

d.    Used for Raynaud’s disease and phaeochromocytoma.

e.       Adverse effects: orthostatic and postural hypotension, tachycardia, nasal congestion and miosis.

2.       Phentolamine and tolazoline (transient competitive blockers):

a.    Non-selective alpha blockers.

b.    Have direct stimulatory action on the heart, vasodilatory property and histamine-like actions on the GIT.

c.       Phentolamine is given i.v. for brief effect in adrenal hypertensive crises, diagnosis of phaeochromocytoma and to terminate dental anaesthesia.

d.       Tolazoline is used for the relief of vasospasm in various periphreal vascular diseases.

3.       Ergot alkaloids:

a.    They are partial agonists.

b.    Have effective alpha blocking actions and powerful alpha agonistic actions.

4.       Chlorpromazine:

a.    Has alpha-blocking actions.

b.       Useful clinically in amphetamine overdose.

Beta receptor blockers

1.       Pharmacodynamics:

a.       Selectively block beta-receptor effects of noradrenaline and adrenaline.

b.    They may be pure antagonists or may have some agonist activity in addition (partial agonist).

c.       Partial agonists cause less fall in resting heart rate than do the pure antagonists and may be less effective in angina pectoris.

d.       Abrupt withdrawal may be less likely to lead to a rebound effect if there is some partial agonist action.

2.       Antihypertensive effects:

a.       Blocks cardiac beta1-receptors to slow the heart rate and reduce the force of contraction, thus lowering the cardiac output.

b.       Suppresses the renal secretion of renin causing inhibition of the renin-angiotensin-aldosterone system.

c.       Reduces central sympathomimetic discharge to decrease peripheral vascular resistance.

3.       Clinical response:

a.       Depends on on-going physiological or pathological state of the individual.

b.       Beta-receptor blockade has little effect on the normal heart at rest, but may have profound effect when the sympathetic control of the heart is highest as in exercise.

c.       Similarly its action on respiratory smooth muscle of asthmatics could be hazardous.

d.       Physiological stresses such as exercise, upright posture are not accompanied by hypotension as the alpha-receptors are not blocked.

4.       Pharmacokinetics:

a.       Bioavailability after an oral dose is limited to varying degree and except for pindolol is usually less than 50%.

b.       Rapidly distributed and have large volumes of distribution.

c.       Elimination is rapid with half-lives in the range of 2 – 5h.

d.       Propranolol and metoprolol are extensively metabolized in the liver, pindolol and atenolol less completely so.

e.    Thus liver disease diminished hepatic blood flow and hepatic enzyme inhibition will affect the elimination of propranolol and metoprolol.

5.       Cardiovascular uses:

a.       Angina pectoris: beta-blockade reduces cardiac work and oxygen consumption.

b.       Hypertension.

c.       Cardiac arrhythmias: beta-blockade reduces drive to cardiac pacemakers.

d.       Myocardial infarction: early use within 6h of onset reduces size of infarct; late use for secondary prevention of another myocardial infarction.

e.       Aortic dissection and after subarachnoid haemorrhage: by reducing the force and speed of systolic ejection and blood pressure.

f.       Hepatic portal hypertension and esophageal variceal bleeding: reduction in portal pressure.

g.       Cardiac failure: use in some cases of dilated cardiomyopathy and hypertrophic obstructive cardiomyopathy.

6.       Endocrine effects:

a.       Hyperthyroidism: beta-blockade reduces unpleasant symptoms of sympathetic overactivity.

b.       Phaeochromocytoma.

7.       Other uses:

a.       Anxiety with somatic symptoms.

b.       Migraine prophylaxis.

c.       Alcohol and opioid acute withdrawal symptoms.

d.       Glaucoma: timolol.

8.       Adverse effects:

a.    CVS: bradycardia, hypotension, syncope, shock or angina pectoris.

b.       CNS: ataxia, dizziness, hearing loss, insomnia, mental depression, visual disturbances, fatigue.

c.    GI: nausea & vomiting, diarrhea, epigastric distress, abdominal cramping, constipation and flatulence.

d.       Hypoglycaemia.

e.       Bronchoconstriction, especially in asthmatics.

9.       Contraindications:

a.       Pregnancy.

b.       Diabetes.

c.       Heart failure.

d.       Asthma and chronic obstructive lung disease.

e.       Abrupt withdrawal of therapy can be dangerous in angina pectoris and after myocardial infarction and withdrawal should be gradual.

10.  Drug interactions:

a.       NSAIDs: attenuate antihypertensive effect due to inhibition of formation of renal vasodilator prostaglandins.

b.    Anti-diabetic agents: potentiate hypoglycaemia of insulin and sulphonylurea.

c.       Calcium channel blockers: bradycardia, heart block and cardiac failure.

d.       Rifampicin: increase metabolism.

e.       Warfarin: propranolol inhibits metabolism of warfarin.

f.       Reduce hepatic blood flow and the metabolism of other beta-blockers, lignocaine and chlorpromazine.

g.       Clonidine: withdrawal hypertension.

11.       Overdose:

a.       Causes bradycardia, heart block, hypotension and low output cardiac failure that can proceed to cardiogenic shock.

b.       Atropine: eliminate unopposed vagal activity.

c.       Glucagon: has cardiac inotropic and chronotropic actions independent of beta-receptor.

d.    i.v. injection of a beta-receptor agonist, e.g. isoprenaline.