β-BLOCKERS

Mechanism of action

Here's a video (9m 10s) detailing the mechanism of action of β-blockers.

What are adrenergic receptors?

Adrenergic receptors (or adrenoceptors)

Adrenergic receptors are G-protein coupled receptors found in many different cell types throughout the body.

There are 2 main types of adrenergic receptors: alpha (α) and beta (β).

α receptors have a stronger affinity for noradrenaline, and β receptors have a stronger affinity for adrenaline.

Adrenergic receptors are activated by catecholamines and can be blocked by drugs called alpha-blockers and beta-blockers.

Noradrenaline binds to the β1 adrenoceptor causing intracellular upregulation of cyclic AMP

Catecholamines

Catecholamines are the chemicals that bind to adrenergic receptors causing receptor activation which leads to a sympathetic response (see diagram).

Catecholamines include adrenaline and noradrenaline.

They are secreted as hormones into the blood by the adrenal medulla in response to stress, and they are produced in neurons where they act as neurotransmitters.

Activation of the sympathetic nervous system has multiple effects

An overview of β receptors and their effects

There are 3 subtypes of β receptors:

β1

β1 receptors are found in the heart and their activation increases cardiac output (by increasing heart rate and contractility).

They are also found in the juxtaglomerular apparatus in the kidneys and their activation leads to increased blood pressure by way of increased renin secretion.

β2

β2 receptors are found in smooth muscle and their activation typically causes relaxation. E.g. in the bronchi, β2 activation causes bronchodilatation, which increases tidal volume.They are present in the smooth muscle of arteries that supply vital organs, where they cause vasodilation to shunt blood from the peripheries more centrally (don't confuse these with α1 receptors which instead cause systemic vasoconstriction).

β2 receptors in skeletal muscle promote uptake of potassium into cells and β2 activation in the liver increases blood glucose levels by increasing glycogenolysis.

β3

β3 receptors are found in adipocytes and their activation promotes lipolysis. Their role in human disease in unclear. No β-blockers have clinically relevant effect on β3 receptors.

Table summarising the actions of the 3 subtypes of β adrenergic receptor

The main effects of β1 receptor blockade

Negative inotropy

Cardiac muscle cells determine the strength of contractility of the heart. β1 receptors are expressed in the cardiac muscles cells and their activation usually enhances the opening of L-type calcium channels, leading to increased intracellular Ca2+ and increased contractility.

β-blockers inhibit β1 receptors which reduces influx of Ca2+ into the cardiac muscle cells.
This reduces intracellular Ca2+, which reduces Ca2+ binding to troponin - this normally initiates cardiac muscle cell contraction.
This reduces cardiac muscle cell contraction, causing overall reduced heart contractility (AKA negative inotropy).

The mechanism by which β1 receptor antagonists cause reduced contractility of cardiac myocytes.

Negative chronotropy

Cardiac pacemaker cells at the sino-atrial node determine the heart rate.
The SA node spontaneously generates action potentials that are conducted down the membranes of cardiac myocytes leading to contraction.

This action potential is typically divided into 3 phases:

1st phase: Slow Na+ inflow (via 'funny' channels) and slow Ca2+ inflow (through T-type channels) begin DEPOLARISATION.
2nd phase: Slow Ca2+ inflow (via L-type channels) cause complete DEPOLARISATION and HYPERPOLARISATION.
3rd phase: Fast K+ outflow causes REPOLARISATION.

β1 receptors are expressed in the cardiac pacemaker cells and their activation usually enhances the opening of L-type Ca2+ channels and more rapid intracellular Ca2+ influx. This reduces the length of the 2nd phase and the reduces overall time it takes to generate each action potential, and so more action potentials can be generated in each minute leading to more contractions per minute (or, more simply, a faster heart rate!).

β-blockers inhibit β1 receptors which slows the influx of Ca2+ through L-type channels in the 2nd phase.
This increase the time it takes for the SA node to generate each action potential, thus reducing heart rate (AKA negative chronotropy).

Negative dromotropy

By the the same mechanism as described above, β-blockers reduce the rate of conduction through the AV node (AKA negative dromotropy). This slowed conduction at the AV node increases the delay between atrial and ventricular contraction.

The mechanism by which β1 receptor antagonists cause slowed action potentials in cardiac pacemaker cells.

Reduced blood pressure

Acutely, β-blockers cause a rise in blood pressure due to blockade of β2 receptors that normally cause vasodilatation.

Chronically, β-blockers will lower blood pressure in patients through β1 receptor blockade.

Blocking β1 in the heart reduces contractility and ultimately this reduces systolic arterial pressure.
Blocking β1 in the kidneys reduces renin secretion and subsequent release of aldosterone (via the renin-angiotensin-aldosterone system). This chronically reduces intravascular fluid volume, and ultimately this reduces diastolic blood pressure.

β-blockers do not usually cause hypotension in healthy individuals with normal blood pressure.

Some β-blockers (e.g. carvedilol and nebivolol) are direct vasodilators.

3 factors which increase the secretion of renin from the juxtaglomerular apparatus

The main effects of β2 receptor blockade

Bronchoconstriction

β2 receptors are expressed mainly in the smooth muscle of the bronchi and bronchioles in the lungs.

β2 activation causes relaxation of the smooth muscle and bronchodilatation (this is in order to increase ventilation and O2 delivery, in preparation for increased metabolic demand in 'fight or flight mode').

β-blockers inhibit β2 receptors, leading to bronchoconstriction.

Vasoconstriction

β2 receptors are expressed in visceral arteries (i.e. those which supply vital organs) and their activation causes vasodilatation. α1 adrenoceptors are also found on systemic arteries but their activation causes vasoconstriction.

β-blockers (especially non-selective) can therefore cause vasoconstriction through inhibition of β2 receptors.

Vasoconstriction

Selectivity of β-blockers

Beta-receptor-blocking drugs differ in their relative affinities for β1 and β2 receptors.

The cardioselective β-blockers (β1)

β1 receptors are found in the heart, so drugs which bind preferentially to β1 receptors are called cardioselective β-blockers (you may also see them referred to as 2nd generation β-blockers). These include:

Atenolol
Bisoprolol
Metoprolol
Esmolol

None of the clinically available β-blockers are 100% specific for β1 receptors. As you increase the dose of β-blocker, it becomes less selective - so even the most cardioselective β-blockers will block β2 receptors when given at high doses.

Examples of cardioselective β-blockers

The non-selective β-blockers (β1 and β2)

Drugs which have a high affinity for β1 and β2 receptors are termed non-selective (or 1st generation). These include:

Sotalol
Propanolol
Timolol
Nadolol

Examples of non-selective β-blockers

The vasodilating β-blockers

β-blockade should not normally cause direct vasodilatation (after all, β2 blockade actually causes vasoconstriction!), however some β-blockers are designed to cause some vasodilatation through other mechanisms:

Nebivolol is a highly cardioselective β-blocker and it also causes vasodilatation by increasing nitric oxide production.
Carvedilol and labetalol are non-selective β-blockers that also inhibit α1 adrenergic receptors.

Examples of β-blockers with additional vasodilating effects

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