B-adrenoreceptor antagonists (beta-blockers)

Question 1

What is a catecholamine?

Answer 1

An organic compound that has benzene with two hydroxyl side groups at carbons 1 and 2 and a side chain amine, includes a number of neurotransmitters such as adrenaline and dopamine

Question 2

Oxygen supply and demand balance

Answer 2

Oxygen supply comes from coronary blood flow (including collaterals) and tissue O2 extraction (75-95%)
Supply ischaemia: supply < demand
Demand ischaemia: demand > supply

Question 3

Types of angina

Answer 3

Most angina is chronic stable associated with a fixed coronary stenosis
Prinzmetal’s (variant) angina occurs at rest and is due to coronary spasm/ constriction, rare
Cardiac syndrome X (microvascular angina) is without epicardial coronary disease and likely to be a microvascular disease, more common in women
Unstable (crescendo) angina: sudden onset at rest or exercise, an acute coronary syndrome, thrombosis leads to occlusion at site of plaque rupture

Question 4

What class of drug is propranolol? What is its relative affinity and action?

Answer 4

Propranolol was found to be a specific B receptor antagonist, but it is not selective. Therefore, its affinity for B1 receptors is similar to B2 receptors, so it also has effect on uterine and bronchial smooth muscle.

Question 5

B-adrenoreceptors location

Answer 5

B1: myocardium, SAN, macula densa cells of the kidney
B2: myocardium, skeletal muscle arterioles, uterus, bronchi, enteric smooth muscle and sphincters

Question 6

B antagonist selectivity

Answer 6

So far, no B antagonist has been invented that is absolutely selective for either B1 or B2 receptors. At best, the B-blocker drugs in clinical use are relatively selective for B1 receptors which are present in the heart and kidneys.

Question 7

Give examples of relatively selective B1 antagonists

Answer 7

Atenolol and metoprolol are derivatives of propranolol, widely used for cardiovascular indications. They are relatively more cardioselective than propranolol i.e. they have lower affinity for B2 receptors. However, there is still a risk of non-selective B2 receptor blockade with all these drugs.

Question 8

Give examples of mixed alpha and beta antagonists. What is the action of the A and B receptor blockade?

Answer 8

These include labetalol and carvedilolol. In the case of these drugs, the A receptor blockade causes arteriolar vasodilatation, in addition to the B blockade effects in the heart and other tissues.

Question 9

What is the mechanism of action of beta blockers in hypertension?
What is the resultant effect?

Answer 9

Complex mechanism of action includes: reduction in cardiac output (transient), reduction in renin release (probably most important) and central sympatholytic action
Hypotensive effect takes some time to develop and usually low doses are effective
Widely used but no longer recommended for first line treatment in current guidelines (ACD rule)

Question 10

How do beta blockers work in angina?

Answer 10

By negative chronotropic and inotropic effects, beta blockers reduce cardiac work and hence reduce myocardial oxygen demand. Prophylactic use of beta blockers reduces the number and severity of episodes of angina.

Question 11

Uses of beta blockers in myocardial infarction

Answer 11

After acute MI, there is evidence that some beta blockers reduce early (30 day) mortality. They may also reduce the rate of re-infarction, hence their use in secondary prevention of major cardiovascular events.

Question 12

Use of beta blockers in arrhythmias

Answer 12

Sotalol is a B1/B2 antagonist with additional class III anti-arrhythmic activity. It is used to treat supraventricular tachyarrhythmias. Esmolol is short acting and used intravenously.

Question 13

Use of beta blockers in heart failure

Answer 13

Although negative inotropic action can potentially worsen CHF, low doses produce mortality benefit. Likely to be related to HR slowing and better diastolic filling.

Question 14

Other uses of beta bloakers

Answer 14

Hyperthyroidism- to control clinical symptoms e.g. tachycardia, tremor
Anxiety states- to control clinical symptoms e.g. tachycardia, tremor
Prophylaxis of migraine- unknown mechanism
Glaucoma- timolol, betaxolol, carteolol, metipranolol and levobunol are used topically to reduce rate of production of aqueous humour, reduces intraocular pressure

Question 15

Side effects of beta blockers

Answer 15

Often related to non-selective B2 blockade: bronchospasm, reduced exercise tolerance/ fatigue, cold extremities
May be due to CNS actions: sleep disturbance with nightmares