Beta-adrenoceptor Blockers (Beta-Blockers) (Systemic and Topical)


 

 

Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carvedilol, Celiprolol, Labetalol, Levobunolol, Metoprolol, Nadolol, Nebivolol, Pindolol, Propranolol, Sotalol, Timolol

 

[NB: Systemic absorption can follow topical application of beta-blockers to the eyes – the advice and cautions as listed for systemic beta-blockers should be considered1]

  Issues for Surgery


For hypertension – loss of blood pressure (BP) control if omitted.

For arrhythmias – risk of cardiac arrhythmias if omitted.

For ischaemia heart disease (IHD) – rebound worsening of myocardial ischaemia if stopped abruptly.

For management of heart failure – potential worsening of heart failure symptoms if omitted.

For management of symptoms of hyperthyroidism – increased risk of clinical symptoms of thyrotoxicosis / thyroid storm if omitted.

For symptoms of anxiety (e.g. palpitations, tremor, tachycardia) – risk of loss of symptom control if omitted.

For prophylaxis of migraine – risk of migraine precipitation if omitted.

For prophylaxis of variceal bleeding in portal hypertension – risk of variceal bleeding if omitted.

For management of the symptoms of phaeochromocytoma – risk of hypertensive emergency if omitted.

For hypertrophic cardiomyopathy – increased risk of ventricular arrhythmias and cardiac arrest if omitted.

For essential tremor – loss of symptom control if omitted.

For primary open-angle glaucoma (topical) – increased risk of deterioration in eyesight if omitted for a prolonged period.

Risk of rebound tachycardia and hypertension if stopped abruptly.

Risk of bradycardia and hypotension if continued.

For labetalol, risk of Intraoperative Floppy Iris Syndrome (IFIS) in patients undergoing cataract surgery when continued (see Further Information).


  Advice in the Perioperative period


Elective Surgery 

Check BP and heart rate pre-operatively.

For patients on sotalol, check potassium and magnesium levels pre-operatively (see under Interaction(s) with other Common Medicines used in the Perioperative Period).

Continue2 (including combination products – see below).

The manufacturers of beta-blockers advise ensuring Anaesthetist is aware of use of beta-blockers, but this does not need to be done in advance of the day of surgery3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15.

Patients taking Labetalol undergoing Cataract Surgery 
Ensure the Ophthalmic Surgeon is aware the patient is taking labetalol, which has alpha-adrenoceptor blocker activity (see Further Information).

Consideration of Pre-operative Omission (see Further Information)
If it is deemed strictly necessary to withdraw beta-blocker therapy before surgery please consult product literature for time to stop pre-operatively. In general, beta-blockers should be withdrawn at least 24 hours prior to anaesthesia, sometimes longer3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 16, 17. However, where possible, sudden withdrawal should be avoided, especially in patients with IHD as it may result in increased angina; gradual withdrawal should take place over 1-2 weeks3, 4, 6, 8, 9, 11, 12, 13, 14, 16, 17. If necessary initiation of replacement therapy to prevent exacerbation of angina pectoris should be considered if the decision is made to stop beta-blocker therapy pre-operatively7, 8, 9, 11, 17, 18.

Under no circumstances should beta-blockers be discontinued prior to surgery in patients with phaeochromocytoma or thyrotoxicosis12.

Oral Combination Products: -

  • Tenif® – contains atenolol + nifedipine (also see Calcium-Channel Blockers (CCBs) monograph)
  • co-tenidone – contains atenolol + chlortalidone (also see Diuretics – Thiazide and Related monograph)
  • timolol + amiloride + hydrochlorothiazide (also see Diuretics – Potassium-Sparing monograph and Diuretics – Thiazide and Related monograph)

If necessary, consideration should be given to prescribing the components of oral combination products as separate medicines perioperatively. However, some components of combination products do not exist as individual medicines (e.g. hydrochlorothiazide). If there is any doubt about the need to continue / withhold component agents of a combination product, advice should be sought from an Anaesthetist.

There are numerous ophthalmic preparations, which contain beta-blockers either as single agents, or in combination products (see British National Formulary for currently available preparations) – all of these ophthalmic combination products can be continued pre-operatively.

Emergency Surgery

Continue2 (including combination products as above).

The manufacturers of beta-blockers advise ensuring Anaesthetist is aware of use of beta-blockers, but this does not need to be done in advance of the day of surgery3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15.

The effects of nadolol can be reversed by administration of a beta-receptor agonist such as isoprenaline or dobutamine12.

Pre-operative Initiation of Beta-Blockers for Patients undergoing Non-Cardiac Surgery

For patients not already on a beta-blocker as part of their regular therapy2: -

  • Pre-operative initiation may be considered in patients who are considered high risk for perioperative complications (e.g. undergoing vascular surgery, known IHD or myocardial ischaemia) – for more details see European Society of Cardiology (ESC) / European Society of Anaesthesiology (ESA) Guidelines on non-cardiac surgery: cardiovascular assessment and management.
  • Atenolol or bisoprolol are the first choice agents in patients undergoing non-cardiac surgery, and the dose should be slowly up titrated, well before the procedure; and tailored to appropriate heart rate and blood pressure targets.

Post-operative Advice

Ophthalmic Preparations
Beta-blocker eye drops should be re-commenced when the next dose is due in the post-operative period unless the patient has undergone ophthalmology surgery and the Ophthalmologist requests for them to be withheld.

Oral Preparations
For patients who were taking beta-blockers as part of their regular therapy prior to surgery, treatment should be recommenced post-operatively.

For patients commenced on pre-operative beta-blockade due to risk factors (see above under Pre-operative Initiation of Beta-Blockers), continue treatment post-operatively. The optimal duration of treatment is not clear. There is potential for delayed cardiac events indicating continuation of therapy may be required for several months. If the patient tested positive for pre-operative stress, beta-blockers should be continued long-term2.

Patients undergoing Thyroidectomy
If prescribed for management of symptoms of hyperthyroidism beta-blockers can be stopped post-operatively. They may need to be continued for a few days and then the dose slowly tapered.


Monitor BP and Heart Rate (see Further Information).

For patients on sotalol – monitor serum potassium and magnesium levels (see under Interaction(s) with other Common Medicines used in the Perioperative Period).


  Interaction(s) with Common Anaesthetic Agents


Anaesthesia in the presence of beta-blockers normally appears to be safer than withdrawal of the beta-blocker before anaesthesia19, 20. See Further Information.

Bradycardia (see also under Sympathomimetics and Local Anaesthetics below)

Beta-blockers can increase the risk of bradycardia when used concomitantly with the following1, 4, 5, 7, 8, 9, 10, 11, 12, 13, 16, 17, 19, 21, 22,: -

  • alfentanil, fentanyl or remifentanil
  • cisatracurium
  • neostigmine

Hypotension

Beta-blockers can increase the risk of hypotension when used concomitantly with inhalational or intravenous anaesthetics1, 3, 5, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19.

If hypotension occurs, bear in mind the response to antimuscarinic drugs (e.g. glycopyrrolate and atropine) may be reduced3, 4, 9, 11, 12, 13, 16, 17, 19.

Sympathomimetics

The interactions between beta-blockers and sympathomimetics (e.g. adrenaline / epinephrine) are complex and depend on the selectivity of both drugs22. Concomitant use may lead to an increase in BP, due to alpha-mediated vasoconstriction, and reflex bradycardia1, 4, 5, 7, 8, 9, 11, 13, 14, 16, 17, 22. They have been reports of marked and serious BP rises and severe bradycardia occurring in some patients19. The same interaction could possibly occur with noradrenaline / norepinephrine (although there does not seem to be any case reports to support this theory)19.

The effect is likely to be less with cardioselective beta-blockers (e.g. metoprolol), since beta2-mediated vasodilatation balances out the vasoconstrictor effect19, 22.

Labetalol is less likely to cause acute hypertensive reactions than other beta-blockers due to its alpha-blocking activity9.

Neuromuscular Blocking Drugs (NMBDs)

Concomitant use of atenolol and NMBDs could increase the relaxant effects of these agents4.

Local Anaesthetics

Bupivacaine
Although no specific interaction studies have been conducted, the cardiac effects of sotalol and bupivacaine may be additive. Monitor concurrent use, especially if other drugs affecting the QT-interval are used and consider ECG monitoring19.

Propranolol reduced the clearance of bupivacaine (by 35%) and there is the theoretical possibility that the toxicity of bupivacaine may be increased19, 23. The clinical significance is unclear, but bear it in mind in case of an unexpected response to treatment19.

Lidocaine
Studies have found that some beta-blockers increase the levels of lidocaine (reduced clearance), but the evidence is conflicting12, 14, 19. Nadolol12, 24 and propranolol14, 24 seem most likely to interact; isolated cases of toxicity attributed to the interaction between propranolol and lidocaine have been reported (with an increase in lidocaine levels of approximately 30%)14, 19. The UK manufacturers of propranolol advise avoiding concurrent use14, 19. However, there is some thought that potentially toxic plasma concentrations occur when lidocaine is given in repeated high doses and that the interaction is not clinically significant after short-term treatment with lidocaine at recommended doses24.

Concurrent use of beta-blockers with lidocaine may increase the risk of myocardial depression (e.g. bradycardia)1, 12, 19.

Dobutamine

Atenolol increases the risk of hypertension and bradycardia when given with dobutamine. Manufacturer advises caution1, 19. If concurrent use is necessary, monitor patient and adjust dobutamine dose as necesary19.


  Interaction(s) with other Common Medicines used in the Perioperative Period

 

Hypotension

Beta-blockers can increase the risk of hypotension when used concomitantly with the following the antiemetics droperidol and prochlorperazine1.

Antimicrobials (for patients taking sotalol also see below under QT-Interval Prolongation)

Propranolol levels may be increased when used concomitantly with ciprofloxacin (via CYP1A2 inhibition)19.

Erythromycin inhibits cytochrome P450 enzymes and potentially carvedilol concentrations may be increased7, 16.

Due to their inhibition of P-glycoprotein, macrolide antimicrobials (e.g. clarithromycin) may increase plasma concentrations of celiprolol8.

Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring. Consult current product literature.

Corticosteroids

Corticosteroids (e.g. dexamethasone, hydrocortisone) may cause hypokalaemia (potentially increasing the risk of torsades de pointes with sotalol1, 18, 19). Monitor potassium levels19.

Corticosteroids can decrease the antihypertensive effect of beta-blockers due to water and sodium retention7, 9, 11.

These interactions are unlikely to be an issue where corticosteroids are used as single doses to reduce post-operative nausea and vomiting or as cover for patients at risk of adrenal insufficiency. However, bear the interaction in mind should continued corticosteroid treatment be necessary.

QT-Interval Prolongation (Sotalol only)

Sotalol (but not other beta-blockers) is known to cause QT-interval prolongation1, 19. Co-administration of sotalol with other medicines known to prolong the QT-interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase.

Medicines that may be used in the perioperative period that are known to prolong the QT-interval include1, 18, 19: -

  • ciprofloxacin*
  • clarithromycin*
  • domperidone – avoid
  • droperidol – avoid 
  • erythromycin (particularly intravenous)*
  • granisetron*
  • haloperidol – avoid 
  • loperamide (increased risk with high doses)*
  • ondansetron – avoid
  • prochlorperazine (theoretical risk)*

*monitor ECG with concurrent use if risk factors for QT-interval prolongation also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia)

Iodinated Contrast Media

Atenolol may impede compensatory cardiovascular reactions associated with hypotension or shock induced by iodinated contrast agents4.


  Further Information


Perioperative Use of Beta-Blockers

Perioperative use of beta-blockers is controversial. There is some evidence that continuing or starting beta-blockers perioperatively may be of benefit in patients at risk of cardiovascular events2, 6, 7. The main rationale for perioperative beta-blocker use is attenuation of the stress response1. In patients undergoing general anaesthesia beta-blockers reduce the risk of myocardial ischaemia and arrhythmias (reduction in heart rate and decreased myocardial contractility) during induction and intubation and the post-operative period; however, there is a risk of attenuation of reflex tachycardia and hypotension (due to the reduced ability of the heart to respond to beta-adrenergically mediated sympathomimetic reflex stimuli)2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 16.

The risk-benefit of stopping beta-blockade should be made for each patient. If treatment is continued, an anaesthetic with little negative inotropic activity should be selected to minimise the risk of myocardial depression4

Current Recommendations and Evidence Base
2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management2

Beta-blockers should be continued when prescribed for IHD or arrhythmias. For treatment of hypertension, the absence of evidence for a perioperative cardioprotective effect with other antihypertensive drugs does not support a change in therapy. Beta-blockers should not be withdrawn in patients with stable heart failure due to left ventricular (LV) systolic dysfunction.

If a patient has unstable cardiac disease, non-cardiac surgery should be deferred if possible, so that patients’ medical therapy can be optimised

Cochrane Review: Perioperative beta-blockers for preventing surgery-related mortality and morbidity25
Cardiac Surgery:

Perioperative beta-blockers play a pivotal role in cardiac surgery, as they substantially reduce the high burden of supraventricular and ventricular arrhythmias post-operatively. Their influence on mortality, stroke, acute MI, congestive heart failure, hypotension and bradycardia remains unclear.

Non-cardiac Surgery:
In non-cardiac surgery, evidence shows an association of beta-blockers with increased all-cause mortality and stroke. As the quality of data is low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and acute MI in this setting seems to be offset by the potential increase in mortality and stroke.

Intraoperative Floppy Iris Syndrome (IFIS) and Labetalol

In addition to being a beta-blocker, labetalol has alpha-adrenoceptor blocker activity. IFIS has ben observed during cataract surgery in some patients on or previously treated with tamsulosin. Isolated reports have also bee received with other alpha-adrenoceptor blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during the cataract operation current or past use of alpha-adrenoceptor blockers should be made known to the Ophthalmic Surgeon in advance of surgery9.


  References


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed 14th September 2019]
  2. The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management. European Heart Journal. 2014; 35:2383-2431
  3. Summary of Product Characteristics – Sectral® (acebutolol) 400mg Tablets. SANOFI. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text August 2019]
  4. Summary of Product Characteristics – Atenolol 100mg Tablets. Accord Healthcare Limited. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text April 2016]
  5. Summary of Product Characteristics – Betaxolol 0.5% Eye Drops. FDC International Ltd. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text March 2017]
  6. Summary of Product Characteristics – Bisoprolol 10mg Film-coated Tablet. Accord Healthcare Limited. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text March 2019]
  7. Summary of Product Characteristics – Carvedilol 25mg film-coated tablets. Aurobindo Pharma – Milpharm Ltd. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text September 2018]
  8. Summary of Product Characteristics – Celiprolol hydrochloride 400 mg Tablets. Mylan. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text July 2017]
  9. Summary of Product Characteristics – Labetalol 400 mg Film-coated Tablets. Mylan. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text May 2017]
  10. Summary of Product Characteristics – Betagan® (levobunolol) Unit Dose. Allergan Ltd. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text October 2018]
  11. Summary of Product Characteristics – Metoprolol Tartrate 50 mg tablets. Accord Healthcare Limited. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text March 2019]
  12. Summary of Product Characteristics – Corgard® (nadolol) 80 mg Tablets. SANOFI. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text August 2019]
  13. Summary of Product Characteristics – Nebivolol 10 mg Tablets. Glenmark Pharmaceuticals Europe Ltd. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text March 2019]
  14. Summary of Product Characteristics – Propranolol 40mg Tablets BP. Accord-UK Ltd. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text May 2019]
  15. Summary of Product Characteristics – Timolol Eye Drops 0.5%. FDC International Ltd. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text January 2016]
  16. Beta-Blockers. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 14th September 2019]
  17. Summary of Product Characteristics – Pindolol Tablets 5mg. Mylan. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text January 2018]
  18. Summary of Product Characteristics – Sotalol Hydrochloride 160mg Tablets. Accord Healthcare Limited. Accessed via www.medicines.org.uk 14/09/2019 [date of revision of the text January 2018]
  19. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 14/09/2019]
  20. Anaesthetics, general + Beta blockers. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 14th September 2019]
  21. Atracurium Besilate. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 14th September 2019]
  22. Sympathomimetics. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 14th September 2019]
  23. Bupivacaine. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 14th September 2019]
  24. Lidocaine. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 14th September 2019]
  25. Blessberger H, Kammler J, Domanovits H, Schlager O, Wildner Brigitte, Azar D, Schillinger M, Wiesbauer F, Steinwender C. Perioperative beta-blockers for preventing surgery-related mortality and morbidity. Cochrane Systematic Review – Intervention. Published 2018. Availablat at www.cochranelibrary.com [Accessed 14th September 2019]