19. Adrenergic receptor antagonists

Last updated on May 7, 2020 at 13:30

α-receptor antagonists

Non-selective

α1-selective

α2-selective

Phenoxybenzamine

Non-subtype selective

α1A-selective

α1B-selective

Yohimbine

Phentolamine

Urapidil

Alfuzosin

Doxazosin

Tamsulosin

Prazosin

Terazosin

β-receptor antagonists

Non-selective

β1-selective

α + β antagonists

Alprenolol

Atenolol Carvedilol

Oxprenolol

Betaxolol

Labetalol

Propranolol

Bisoprolol

Timolol

Esmolol

Sotalol

Metoprolol

Nebivolol
Adrenergic receptors

Three types of alpha adrenergic receptors exist, α1A, α1B and α1D (a C type was discovered but it turned out to be the same as the A type). Each of these subtypes are found in different tissues and have slightly different effects. However, the subtypes are highly homologous, so there is significant overlap.

α1A is mostly found in the bladder. α1B is mostly found in vasculature.

Phaeochromocytoma

Phaeochromocytoma is a cancer of the adrenal medulla which synthesizes large amounts of catecholamines. They bind to α1 receptors, causing vasoconstriction and severe hypertension.

It’s treated surgically but medical treatment is necessary to prevent catecholamine release during surgery. α1 receptor blockers and beta blockers are used.

Non-selective α-receptor antagonists
  • Phenoxybenzamine
  • Phentolamine

Indications:

Phenoxybenzamine (with a beta blocker) is used to prevent catecholamine release from phaeochromocytomas before and during surgery, or as the only treatment in inoperable phaeochromocytomas.

Phentolamine is used to briefly counteract the effects of excessive circulating catecholamines, like with methamphetamine or cocaine overdose, pheochromocytoma or clonidine withdrawal.

Mechanism of action:

Phenoxybenzamine is an irreversible, non-selective alpha blocker.

Phentolamine is a reversible, short-acting non-selective alpha blocker.

Side effects:

Phenoxybenzamine is a “dirty” drug, meaning that it blocks other receptors too, like histamine, acetylcholine and serotonine receptors. It also causes more reflex tachycardia than other types of alpha blockers.

Side effects of all alpha blockers include postural hypotension, tachycardia and gastrointestinal symptoms. These apply also to the alpha blockers below.

Non-subtype-selective α1-receptor antagonists

The only important non-subtype-selective α1-receptor antagonist is urapidil. It’s a rarely used drug that may be used to treat hypertensive crisis.

α1A-receptor antagonists
  • Alfuzosin
  • Tamsulosin

As the α1A receptor subtype is found in higher number in the bladder these drugs are preferred over other alpha blockers to relax the urethral sphincter in case of prostate hyperplasia, easing urination.

α1B-receptor antagonists

Prazosin, doxazosin and terazosin are α1B-selective antagonists. The latter two have longer half-lives and are therefore now preferred instead of prazosin, which was the first drug in this class.

These drugs may also be used to ease urination in prostate hyperplasia. They can also be used to treat hypertension (but never as a first or even second-line option).

α2-selective antagonists

Yohombine is an α2-selective antagonist. It has no clinical use.

β-receptor antagonists

Beta blockers can, like alpha blockers, be classified according to their specificity:

  • Non-selective
    • Propranolol
    • Timolol
    • Sotalol
  • Non-selective with intrinsic sympathomimetic activity (partial agonists)
    • Alprenolol
    • Oxprenolol
  • β1-blockers
    • Atenolol
    • Betaxolol
    • Bisoprolol
    • Esmolol
    • Metoprolol
    • Nebivolol
  • Combined α and β-blockers
    • Carvedilol
    • Labetalol

Also called beta blockers, these drugs are more used than alpha blockers.

Because the β1 subtype is the one responsible for the cardiac effects, β1-selective beta blockers are often called “cardioselective” or “second generation” beta blockers.

Carvedilol, labetalol and nebivolol have vasodilating effects in addition to their beta-blocking effect and are therefore especially useful in cardiology. They’re sometimes called “third generation” beta blockers.

Indications:

Beta blockers have many indications. Only the cardioselective ones are used for the cardiological indications:

  • Hypertension
  • Coronary artery disease
    • Angina pectoris
  • Acute myocardial infarction
    • To prevent cardiac death after AMI
  • (Compensated) heart failure
  • Arrhythmias

Propranolol has some specific indications:

  • Tremors
  • Migraine prophylaxis
  • Portal hypertension
  • Thyroid storm

Labetalol and carvedilol are used in hypertensive emergencies. Labetalol is one of the most commonly used drugs in hypertensive emergiences.

Topical beta blockers like timolol and betaxolol are used to treat glaucoma.

Mechanism of action:

Beta-blockers treat hypertension not by causing vasodilation, but by causing decreased chronotropic and inotropic effects on the heart, reducing renin release and decreasing sympathetic activity centrally. All these effects indirectly decreases blood pressure. This effect comes from blocking β1-receptors.

This also decreases strain on the heart, which is why they’re used in heart failure.

By decreasing the strain on the heart they also improve the symptoms in angina pectoris.

By blocking β2 adrenergic receptors β2-blockers decrease the production of aqueous humour, decreasing the intraocular pressure and relieving glaucoma.

Alprenolol and oxprenolol are partial agonists and not pure antagonists. This gives them a milder beta-blocking effect than the pure antagonists. We used to think that this was beneficial in elderly but nowadays we know that that is not true. You can read more about how partial agonists can be antagonists here.

Nebivolol is special because it induces NO release, causing vasodilation.

Side effects:

  • Bronchoconstriction
    • Is a problem for asthmatics, COPD patients
  • Cardiac depression
    • Can lead to heart failure
  • Bradycardia
  • Hypoglycaemia
    • Because adrenaline releases blood glucose
    • Especially in diabetics
  • Fatigue
    • Due to reduced cardiac output and reduced muscle perfusion
  • Cold extremities
    • Due to loss of β-receptor mediated vasodilation in skin
  • Nightmares
    • Only for propranolol

The cardioselective beta blockers don’t cause vasoconstriction, bronchoconstriction or hypoglycaemia.

Pharmacokinetics:

Betaxolol, bisoprolol, metoprolol, nebivolol, propranolol and timolol are lipophilic, so are carvedilol and labetalol. All have short half-life except betaxolol and bisprolol. However, depot preparations exist for metoprolol and propranolol which circumvents the short half-life.

Atenolol, sotalol and esmolol are hydrophilic.

Most beta blockers are orally absorbed and undergo first-pass metabolism, and there is often significant interpersonal variance in the degree of first-pass metabolism. This makes the oral bioavailabilty highly variable.

Esmolol is special because it’s inactivated by enzymatic hydrolysis, giving it a very short half-life.

Contraindications:

  • Bradycardia
  • Heart block
  • Cardiogenic shock
  • Hypotension
  • Phaeochromocytoma (when given without alpha blockers)
    • Giving beta-blockers alone to a person with phaeochromocytoma would block noradrenaline and adrenaline’s blood pressure-lowering effect on the beta-receptors, which would cause a net increase in blood pressure
  • Asthma
  • Decompensated heart failure

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18. Adrenergic receptor agonists

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20. Pharmacology of protein and peptide mediators, the purinergic system and nitric oxide

14 thoughts on “19. Adrenergic receptor antagonists”

    1. I didn’t think people were interested in that, so I wasn’t going to write a post about it, but since you’re asking will I do it.

  1. hi nick ,
    in topic 14 , you mentioned that drugs based on the their effect, may overlap . can you explain more about overlaping ?

    for example , we can use phenoxybenzamin to ease urination , (but we dont since it,s not it,s primary function)
    you mean this by overlapping ?

    ps, thanks for the topics.

    1. Hey!

      Yes, that’s what I mean. Overlapping can occur in many drug classes but mostly those affecting the autonomic nervous system.

  2. Hi! I was just wondering where you found the different contraindications for beta antagonists. Because when it comes to pheochromocytoma, the book it says that the best way to treat it is by giving both alpha and beta antagonists together. So how is it then contraindicated when giving beta antagonists?

    1. It’s contraindicated to give them alone, because then you block the blood-pressure reducing effects of catecholamines (mediated by beta receptors), so that catecholamines only act on alpha receptors, which cause vasoconstriction and increase blood pressure. But you’re right, in combination they’re essential for the treatment of phaeochromocytoma.

    1. From what I can find, it has very little medical use, although there is some evidence it could be slightly effective for erectile dysfunction. It’s more of an over-the-counter thing.

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