Antagonists for Adrenergic receptors

What are adrenergic receptors?

Adrenergic receptors or adrenoreceptors are a group of receptors that are widely expressed throughout many of the tissues in the body. They play a very wide role in the sympathetic nervous system. The sympathetic nervous system is what controls the so-called “fight-or-flight” response – a response to stress that primes us to react to danger. Part of the fight-or-fight response involves the regulation of blood pressure – this involves changes to the heart and vasculature that raise blood pressure. As such there are a lot of antihypertensive drugs that target adrenergic receptors.

There are many types of adrenergic receptors, each with different properties. All adrenergic receptors are G-Protein Coupled Receptors (or metabotrophic receptors).

• Alpha adrenergic receptors which mainly increase vasoconstriction and smooth muscle contraction.
• These are a target for alpha-receptor antagonists or “alpha blockers” including Indoramin, Prazosin, Doxazosin, Terazosin
• Beta adrenoreceptors which mainly increase cardiac output and increase renin output from the kidneys.
• These are a target for beta-adrenergic receptor antagonists (or “beta-blockers”) including Atenolol, Propanolol, Metoprolol and Acebutolol

• Beta-blockers used to be quite a commonly prescribed drug, but because they have range of contraindications and side effects – they have largely been surpassed by other drug classes. Alpha blockers tend to be much less effective for treating hypertension so they are rarely used on their own.

How do Adrenergic receptors work?

• Normally in the body, adrenergic receptors respond to circulatory catecholamines – these are a type of circulatory hormone released by the sympathetic nervous system.  Important catecholamines include adrenaline, noradrenaline (and dopamine*)
• At its most basic level, the expression of different types of adrenergic receptors within cells and tissues is responsible for governing the response to sympathetic stimulation of that particular cell or tissue.
• This is because not all of the organs and tissues in your body need to respond in the same way during a “fight-or-flight” situation – the heart needs to beat faster, but the gut needs to stop digesting food so that blood can be used for more important purposes until the danger is passed.
• In this way, the body is able to regulate the activity of a large range of homeostatic mechanisms by just by changing the levels of circulatory factors such as the catecholamines. This is a common theme in homeostasis!

Mechanism of Action

Changes in the activity of circulatory catecholamines such as noradrenaline and adrenaline work directly to effect sympathetic changes to key organs that regulate blood pressure including:

• The central and peripheral nervous system
• The heart and cardiovascular system
• The kidneys

Blocking these receptors using an antagonist is a useful way to lower blood pressure – but a general blockade of these receptors would have profoundly dangerous effects, so drugs that target more specific receptors have been developed.

Beta-blockers cause a reduction blood pressure in several key ways:

Beta blockers used to treat hypertension tend to be specific to beta-1 type receptors.

Blocking beta-1 acts to prevent the effects of the sympathetic nervous system at a few key sites:

• In the heart, they block beta-1 type receptors in the sinoatrial node. The SA node is the “pacemaker” of the heart, responsible for generating impulses that cause contraction. Adrenergic signalling in the SA node increases the heart rate, so antagonists for beta-1 receptors exert a negative chronotrophic effect – they lower the heart rate. This in turn lowers cardiac output, lowering the blood pressure.
• In the kidneys they also work on beta-1 receptors, here in cells of the juxtaglomerular apparatus. Blocking beta-1 receptors lowers the release of the hormone renin. Renin works as part of the renin-angiotensin system. Renin release, normally stimulated by the sympathetic nervous system, causes the release of angiotensin I, which then gets converted into angiotensin II. Angiotensin II causes changes that lead to an increase in fluid retention to raise the blood volume, and vasoconstriction of blood vessels, so raising the blood pressure. When you decrease renin release, you decrease this effect.
• In the central and peripheral nervous system they act in to reduce sympathetic signaling in a general manner – especially where they antagonise beta-receptors in the brainstem. The autonomic nervous system also has so called “prejunctional” beta receptors on nerve terminals – those which are present on the presynaptic membrane. Where these are blocked, they will also act to generally reduce sympathetic transmission.

Out of these three mechanisms, research as to which is the most important factor in their mechanism of action is inconclusive. Some research has suggested that its role in the kidneys may be important, for a variety of reasons:

• In patients who use beta blockers for a long time, those patients who see the greatest reduction are often those with hypertension associated with high renin levels.  Renin is important for regulating blood pressure via the kidneys, so high renin is a strong sign that the kidneys are involved with that form of hypertension.
• Conversely, in patients with hypertension and low renin, such as is often seen in persons of Afro-Caribbean descent, beta-blockers have been found to be less effective.

There is strong evidence, however, that the cardiac effects are important too – so it appears that the effects of both are important.

Alpha Blockers target Alpha-1 type receptors

Most alpha blockers target post-junctional alpha-1 receptors in the peripheral nervous system – in the blood vessels, quite simply this causes a generalised vasodilatation** which lowers venous return, lowering cardiac output.  

Adverse Effects of Beta Blockers

One of the major problems with beta and alpha blockers is the fact that they are commonly associated with adverse effects, and there are a variety of contraindications for their use. For this reason they are generally considered an inferior choice when treating hypertension. There are a variety of cases where it may make sense to use beta blockers – for example where other drugs are not well tolerated by the patient. Similarly it often makes sense to continue use where a patient has been using the beta blockers for a long time and is tolerating them well – especially where that patient has angina or a history of myocardial infarction as it could be dangerous for them.  They also have a variety of “ancillary” effects – that is they have other benefits to patients such as in treating cardiac arrhythmias, pain from angina and are useful after myocardial infarctions for protecting the heart (in fact, beta blockers tend to be used for these effects more often that to treat hypertension).

The reason they cause adverse effects stems from their mechanism of action – adrenergic receptors are widely expressed throughout the body, and even though most beta blockers used for hypertension are quite selective for beta-1 antagonists, they are not exclusively selective for them, and this can result in adverse effects.

Adverse effects include:

• Bradycardia – a slowing of the heart rate.
• Reduced contractility of the myocardium (heart muscle).
• Effects on the central nervous system that include hallucinations and vivid nightmares.
• Vasoconstriction in the periphery causes a slowing of blood supply to the capillaries in the hands and feed – this can lead to coldness, and what is known as “Raynaud’s Phenomenon” – a sudden discoloration and loss of sensation in the fingers and toes. Interestingly, since alpha blockers are vasodilators, they are used to treat Raynaud’s syndrome!
• An increased risk of the onset of diabetes due to changes in glucose metabolism.

One very strong contraindication against use of beta blockers is in asthmatic patients. This is because they rely on sympathetic transmission in the lung parenchyma in order to maintain lung function – sympathetic activity is increased in patients with asthma as a compensatory mechanism by their body to keep their airways open. If a beta-blocker antagonises this function, it can have profound effects and cause bronchospasm and asthma attacks. This is also true to a lesser extent for other chronic obstructive diseases, and doctors use caution where they prescribe beta blockers to these patients.

Adverse Effects of Alpha blockers

One major issue with alpha blockers is that because they cause a generalised vasodilatation, they open up capillary beds and vasculature throughout the body. This can lead to postural or orthostatic hypotension – this is a sudden drop in blood pressure on standing up after lying or sitting, which result in dizziness and in extreme cases syncope. This is because suddenly standing up causes blood to drain down into the lower limbs and, and venous return is not great enough to maintain adequate blood supply to the brain – this is what causes the dizziness and fainting.

This can be a particular problem in the elderly or those with compromised mobility because it greatly increases their risk of falls, and many elderly patients are at much greater risk of falls anyway, especially when in hospital. As such alpha blockers are only used as a last resort, and where they are used it is usually in a low dose in combination with other drugs.

*Dopamine in the peripheral nervous system has been shown to be a natriuretic and a vasodilator, as such it is actually thought to be antihypertensive. Although it is a catecholamine, it does not work through adrenergic receptors, and has its own set of receptors. It does seem to have an important role to play though, because a reduction of dopamine type 2 receptors in the brain has been associated with obesity, a key factor in hypertension, and there are some genetic mutations in dopamine receptors associated with familial hypertension.

 **Vasodilatation is the same as dilation – a dilation of the blood vessels, but dilatation refers to dilation that is an active process – as opposed to just a simple “stretching open” of the vessels due to a lack of vasoconstriction

References

• NICE Guidelines 2004 "Hypertension (CG34): Management of hypertension in adults in primary care"
• KuchelGA Kuchel OG (1991). "Peripheral dopamine in pathophysiology of hypertension. Interaction with aging and lifestyle" Hypertension, Vol 18, 709-721 
• Jose PA, Eisner GM, Felder RA (2003):Regulation of Blood Pressure by Dopamine Receptors.  Nephron Physiol 2003;95:p19-p27
  
• F Contreras (2002): Dopamine, hypertension and obesity. Journal of Human Hypertension, Supplement 1:S13-7
• "Alpha Adrenergic Receptor Antagonists", "Beta Adrenergic Receptor Antagonists", British Hypertension Society web page

 

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