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Author: Lisa Ling
Editor: Dr. Suneet Sood
Narrator(s): Lisa Ling

Transcript

Today we are going to talk about the relation between beta blocker and intermittent claudication.

Let’s start with a case.

A 45-year-old chronic smoker had episodes of stable angina and was started on propranolol 80 mg daily. He developed bilateral calf claudication two weeks later. He had painful calf muscles after walking for a distance of 100 metres. The pain usually resolved after resting for 5 minutes. Within a week the claudication distance had shortened to 15 meters, and he came to his physician for review. On examination, the femoral pulses were palpable, but the popliteal, dorsalis pedis, and posterior tibial pulses were absent on both lower limbs. The limbs were warm, and the capillary refill was 3-4 seconds. Buerger’s test was negative, indicating that the limb ischemia was not critical. The ankle brachial index was 0.77, indicating moderate disease. His physician stopped the propranolol, and started nifedipine. His claudication distance rapidly improved to 200 meters. A few months later, he had another episode of angina. He visited a different physician, who restarted the propranolol. The claudication distance once again shortened to 15 meters. When propranolol was once again discontinued, the claudication distance improved to tolerable levels again.

Why do we use beta blockers in angina?

In angina we want to reduce both the preload, which is the left ventricular pressure, and the afterload, which is the peripheral resistance. Beta blockers block the effects of adrenaline at the beta adrenoceptors. They work on beta-1 and beta-2 receptors, depending on their selectivity. (1) Firstly, in the heart, beta blockers block beta-1 receptors, and result in a negative inotropic effect. Secondly, beta-1 blockers also suppress the release of renin in the renin-angiotensin-aldosterone system. Reduced renin leads to vasodilatation and reduced plasma volume, and this decreases the cardiac output. (2) Thus, the beta blockers help in angina by decreasing left ventricular pressure as well as the peripheral resistance.

How do beta blockers cause intermittent claudication?

Activation of beta-2 receptors relaxes smooth muscle. In the muscle, the effect is vasodilatation of the arteries to the muscles. Beta blockers oppose this dilatation. In addition, the sympathetic nervous system increases its activity in response to the lowered blood pressure. The unopposed alpha-receptor-mediated effects result in the narrowing of the peripheral vessels. (1) The obstruction of blood flow in the arteries may cause muscle ischaemia and pain in the calf, or rarely the thigh and the buttock, during exercise. (3) Cases have been reported of claudication symptoms worsening after starting propranolol, and improving after stopping propranolol. (4)

Note that beta blockers may be non-selective or selective. Early beta blockers, like propranolol and nadolol are non-selective, and block both beta-1 and beta-2 receptors.  Atenolol, metoprolol, and nebivolol are selective, and only block beta-1 receptors. Consequently, it is more rational to use selective beta blockers in angina and congestive heart failure.

Then, are non-selective beta blockers contraindicated in patients who have intermittent claudication?

A study showed that beta blockers lowered muscle blood flow by about 30%. (5) On the other hand, recent systematic reviews show no adverse effects. (6,7) Many studies in the systematic reviews were based on selective beta blockers, so one would expect fewer clinical effects. Overall, a reasonable approach would be to use selective beta blockers where indicated for angina or congestive heart disease, but to use them with caution in patients with severe peripheral vascular disease. (3,8)

References

1. Katzung BG, Masters SB, Trevor AJ. Basic and clinical pharmacology. 12^th New York: McGraw-Hill Medical; 2012. p. 151-68.
2. Waller JR, Waller DG. Drugs for systemic hypertension and angina. Medicine [Internet]. 2018 Aug [cited 2020 Mar 19];46(9):566-72. Available from: https://www-sciencedirect-com.ezproxy.lib.monash.edu.au/science/article/pii/S1357303918301609
3. Cassar K. Intermittent claudication. BMJ [Internet]. 2006 Nov [cited 2020 Mar 19];333(7576):1002-5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1635612/
4. Fogoros RN. Exacerbation of Intermittent Claudication by Propranolol. N Engl J Med 1980; 302:1089
5. Smith RS, Warren DJ. Effect of beta-blocking drugs on peripheral blood flow in intermittent claudication. Journal of cardiovascular pharmacology, 1982, Vol.4(1), pp.2-4
6. Radack K, Deck C. ß-Adrenergic Blocker Therapy Does Not Worsen Intermittent Claudication in Subjects With Peripheral Arterial Disease. A Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 1991;151(9):1769-1776
7. Paravastu SCV, Mendonca DA, Da Silva A. Beta blockers for peripheral arterial disease. Cochrane Database Syst Rev. 2013 Sep 11;(9):CD005508
8. Ministry of Health Malaysia. Clinical practice guidelines on management of hypertension. 5^th Malaysia: Ministry of Health Malaysia; 2018 [cited 2020 Mar 10]. 160 p.