Editorial

Non-Cardiac Effects of Atenolol

HK Chopra, Krishna CK, Ravinder S Sambi, Komal KK

Department of Medicine & Cardiology, Moolchand Medcity, New Delhi

Abstract

The advent of β-blockers especially atenolol, which is a selective β1 blocker, is of paramount clinical importance in treating the cardiovascular disorders like hypertension, angina pectoris, and cardiac arrhythmias. In addition to its cardioprotective benefits, it also has some non-cardiac effects like antimigraine effect, antiglaucoma effect, antianxiety effect, reduces portal pressure, reduces vascularity of thyroid gland, inhibits platelet aggregation, aggravates peripheral vascular disease, decreases insulin sensitivity, alters lipid metabolism, causes sexual dysfunction, induces bronchospasm, etc. This article highlights the potentials and pitfalls of non-cardiac effects of atenolol.

Atenolol have been in use for nearly 25-30 years. It is a β1 receptor selective antagonist, a drug belonging to the group of β-blockers. It was approved by the FDA in August 1981. In addition to its traditional role in treating hypertension and other cardiovascular disorders, atenolol, due to its extra-cardiac effects, are also used for additional purposes such as migraine headaches, hyperthyroidism, glaucoma, anxiety and various other disorders.

Atenolol is a hydrophilic drug. Atenolol does not have intrinsic sympathomimetic properties. Atenolol also does not possess membrane-stabilizing activity. After oral administration of atenolol, about 50- 60% of the dose is rapidly absorbed. tcmax (time elapsed before maximal concentration in the blood plasma is reached) is 2 to 4 hours after oral dosing. However, the action of the usual oral dose lasts over a period of 24 hours. After parenteral administration, the peak effect is seen in 5 minutes and lasts less than 12 hours. Atenolol is minimally bound to plasma proteins, averaging only 10%, which, along with it low lipophilicity, may explain some of its distribution characteristics. Atenolol distribution into the central nervous system (CNS) by crossing the blood-brain barrier is minimal. The concentration found in brain tissue is approximately 15% of the plasma concentration only. The drug crosses the placenta barrier freely. In the milk of breastfeeding mothers, approximately 3 times the plasma concentrations are measured. Atenolol is almost exclusively eliminated renally and is well removable by dialysis. 40-50% of an oral dose is excreted renally as unchanged drug and the rest of the dose is excreted via the fecal route as unchanged drug.

Atenolol selectively blocks sympathetic stimulation mediated by β-1 adrenergic receptors in the heart and vascular smooth muscle. The pharmacodynamic consequences of this activity include: a negative chronotropic effect that decreases heart rate at rest and after exercise; a negative inotropic effect that decreases cardiac output; reduction of sympathetic outflow from the CNS; and suppression of renin release from the kidneys.

Noncardiac Effects of Atenolol

1. Reduces vascularity of thyroid gland
2. Antimigraine effect
3. Antiglaucoma effect
4. Reduces portal pressure
5. Reduces peripheral manifestations of tremors
6. Inhibits platelet aggregation
7. Impairs insulin sensitivity
8. Alters lipid metabolism
9. Enhances weight gain
10. Reduces exercise tolerance and causes fatigue, muscle weakness
11. Worsens sexual activity (erectile dysfunction, impotence and decreases libido)
12. Induces bronchospasm
13. Induces severe depression, nightmares, insomnia, hallucinations
14. Activates peripheral vascular disease (PVD) and exacerbates Raynaud’s syndrome
15. Causes growth retardation in the fetus

Reduces vascularity of thyroid gland: Atenolol reduces vascularity of thyroid gland and controls palpitations, nervousness and tremors, therefore is commonly used as a sole agent or together with antithyroid drugs or radioiodine in perioperative management of thyroid surgery, until euthyroid state is achieved1.

Antimigraine effect: Bengt Forssman et al.2 showed the preventive effect of atenolol on migraine attacks by comparing to placebo in a double-blind cross-over study. The effect of atenolol was significantly better than that of placebo in reduction of the number of headache attacks. Atenolol possesses numerous mechanisms that may contribute to its efficacy in preventing migraine headaches. Possible mechanisms of action are beneficial vasoconstriction, peripheral vascular effects, a central action, 5-HT antagonism, an anxiolytic effect and a multifactorial action. The antimigraine effect is only prophylactic and not for attacks once they have occurred.

Antiglaucoma effect: Atenolol has been shown to have an action both orally and topically on the eye, causing a large and rapid fall of intraocular pressure. In contrast to miotics, it does not affect pupil size or tone of ciliary muscle and does not cause any diminution of vision, No definite hypothesis has been arrived at the mechanism of action of this drug in lowering the intraoccular pressure. More extensive experimental and clincal work is necssary to postulate a definite hypothesis regarding the mechanism of action of this drug. Whether it is through adrenergic receptor which equlates the blood flow in the ciliary process and intra-secleral venous plexus thereby changing the flow rate of aqueous humour or by an unknown mechanism that decreases the rate of aqueous humour formation, is still inconclusive.3 A clinical study by Chauhan JK et al.4 showed that atenolol produces significant and sustained fall in IOP in both normal and raised IOP patients besides lowering of systematic vascular disease, the development of Raynaud’s phenomenon. Severe peripheral vascular disease and even peripheral gangrene may be precipitated.
Antianxiety effect: It also suppresses anxiety in short term stressful conditions, hence used in anxiety states. No overt central effects are produced by atenolol, however subtle behavioural changes, forgetfulness, increased dreaming and nightmares have been reported with long term use of relatively high doses.

Fetal injury: Atenolol crosses the placental barrier, so in pregnancy-induced hypertension, atenolol produces foetal bradycardia28 and lower birth weights or placental weights are slightly common especially when administered in the second trimester.29 No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. Cases of neonatal hypoglycemia have been also reported following maternal use of atenolol at parturition or during breast-feeding as atenolol is excreted into breast milk.

Summary

Use of atenolol began in the 1980s and has risen dramatically since then. Due to its β-1 selectivity it offers more actions with fewer side effects. Uses for this drug continue to increase as their safety and efficacy become increasingly apparent. Today atenolol has widespread application in cardiovascular disease but in addition, due to its extracardiac effects, it is also being used in the management of endocrine disorders, neurologic situations, psychiatric disorders, gastrointestinal problems and sensory disorders. Many new noncardiac effects are still investigational and some effects show even greater promise for therapeutic applications in the future.

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