Beta-adrenoceptor antagonists (Beta-blockers)

Drug interaction

Beta-adrenoceptor antagonists:

  • Non-selective b1/b2: Carvedilol, Nadolol, Propranolol, Sotalol, Timolol
  • b1-selective: Atenolol, Bisoprolol, Metoprolol, Nadolol, Nebivolol
DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
α-adrenoceptor antagonists:
- Doxazosin
- Phenoxybenzamine
- Phentolamine
- Prazosin
- Terazosin
β-blockers may increase the vasodilator responseMonitor the patient for acute postural hypotension. It is recommended to take the first dose at bedtime. Doxazosin does not present this interaction.
β-adrenoceptor agonistsβ-blockers antagonize their antiasthmatic effectsAvoid the combination with nonselective β-blockers, even when no β-blocker is safe is asthmatic patients
AmiodaroneProduces a non-competitive β-receptor blockade and increases the risk of hypotension, bradycardia and AV block.
Amiodarone plus sotalol increase risk of TdP
Amiodaron inhibits CYP2D6, the isoform that metabolizes metoprolol, nevibolol, propranolol and timololThe combination can be beneficial, but increases the incidence of bradycardia, hypotension and ventricular tachyarrhythmmias. Monitor the BP and the ECG.
AmpicilinReduces the oral absorption of atenolol and possibly of other β-blockersThe clinical relevance is uncertain
Antacids (aluminium/magnesium hydroxide)They delay gastric emptying and may cause a modest reduction in the absorption of atenolol, propranolol and sotalol, but increase the absorption of metoprololUncertain clinical relevance of this interaction
Anticholinesterases:
- Donezepil
- Galantamine
- Rivastigmine
Increase the risk of bradycardia and hypotension. β-Blockers may oppose the efficacy of anticholinesterases in patients with myasthenia gravis.Monitor heart rate
Antidiabetics:
- Insulin
- Sulfonylureas
Propranolol delays the recovery of hypoglucemia after insulin.
β-blockers inhibit some signs of hypoglucemia (palpitations, tremor), while sweating is increased
Monitor glucose levels
Antihypertensive drugsAdditive effect on BPMonitor the BP
BarbituratesThey can reduce the effects of extensively metabolized β-blockers (e.g. metoprolol, propranolol, timolol)Stimulate the metabolism and decrease the plasma levels of these β-blockers Monitor the response of these β-blockers. β-blockers mainly excreted unchanged in the urine (e.g. atenolol, sotalol, nadolol) do not present this interaction
BenzodiazepinesBeta-blockers may increase the effects of benzodiazepinesLabetalol, metoprolol and propranolol reduce the metabolism of diazepamMonitor for increased CNS effects. Alprazolom, lorazepam and oxazepam do not present this interaction.
Bile-acid sequestrants :
- Cholestyramine
- Colesevelam
- Colestipol
Reduce the absorption and plasma levels of propranolol. Colesevelam does not affect the absorption of metoprololTake propranolol at least 1 h before or 3-4 hours after bile-acid sequestrants or replace propranolol by metoprolol
Calcium channel blockers (Dihydropyridines):
- Nifedipine
- Nisoldipine
Additive effects in patients with hypertension and angina. Concomitant therapy may increase the risk of hypotension and HF may occur in patients with latent cardiac insufficiencyDihydropirydines may increase bioavailability and reduce the clearance of β-blockers. Propranolol may increase bioavailability and reduce the clearance of nifedipine Monitor the BP of the patient. Some dihydropyridines (e.g. amlodipine, lacidipine, nicardipine and nimodipine) do not present this interaction
Calcium channel blockers (Non-dihydropyridines):
- Diltiazem
- Verapamil
The combination increases the risk of hypotension, bradycardia, AV block and LV dysfunction/heart failureDiltiazem inhibits the metabolism and increases the plasma levels of propranolol and metoprolol Risk of bradycardia, AV block, heart failure and hypotension. Close monitoring of the patient (BP, ECG) is recommended. Use β-blockers not metabolized by the liver (atenolol, nadolol, sotalol). The association is contraindicated in patients with LV dysfunction
CatecholaminesNon-selective β-blockers (propranolol) increase BP and produce a reflex bradycardia.
β-blockers attenuate the pressor effects of adrenaline, dopamine, dobutamine and noradrenaline
Anaphylactic shock in patients treated with non-selective β-blockers may be resistant to adrenaline
Monitor the hemodynamic response of the patient
Use very low doses of adrenaline. The interaction with adrenaline is minimal wth cardioselective β-blockers (atenolol, bisoprolol, metoprolol, nevibolol)
CimetidineSome cases of bradycardia and hypotensionReduces the metabolism and increases the plasma levels of some extensively metabolized β-blockers (e.g. metoprolol, propranolol)Uncertain relevance of this combination. Famotidine, nizatidine and ranitidine do not interact with beta-blockers
Class IA and IC AADsAdditive cardiodepressant effects (bradicardia, AV block, decreased cardiac contractility)Monitor the ECG and the BP. β-blockers (Except sotalol) can suppress the torsade de pointes induced by class I and III AADs
ClonidineConcomitant use can enhance the hypotensive effect and cause bradycardia or AV block. Sudden cessation of clonidine treatment can be followed by a rapid rise in BP; this reaction appears to be greater after continuation of concomitant β-blocker treatment The β-blocker should be withdrawn several days before the gradual discontinuation of clonidine. Cardioselective β-blockers would be les likely to increase BP levels.
Cocaineβ-blockers potentiate the coronary vasoconstrictor effect of cocaine via the stimulation of α-adrenergic receptorsPatients with coronary artery disease treated with β-blockers should be advised regarding the use of cocaine. β-blockers suppress cocaine-induced arrhythmias
DextropropoxyfeneInhibits the metabolism and increases the plasma levels of metoprolol (and of propranolol)Use β-blockers largely excreted unchanged in urine or adjust their dose
DipyridamolBradycardia can occur because when coadministered with propranololThis is a rare complication
DronedaroneIncreases the risk of bradycardia and AV blockDronedarone inhibits CYP2D and increases the plasma levels of metoprolol and propranololβ-blockers should be coadministered with caution with dronedarone. β-blockers should be initiated at low doses and up-titrated after ECG assessment. In patients on β-blockers at time of dronedarone initiation, an ECG should be performed and the dose of β-blockers adjusted if needed
DigoxinIncreases the risk of bradycardia and AV block. β-blockers may inhibit the positive inotropic effect of digoxinCarvedilol increases digoxin bioavailabilityThis combination can be useful in patients with atrial fibrillation.
Enzymatic inducers:
- Alcohol
- Barbiturates
- Carbamazepin
- Rifampicin
- Tabacco
Decrease the plasma levels of β-blockers metabolized by the liver (alprenolol, carvedilol, metoprolol, propranolol, timolol) Avoid β-blockers that are mainly renally excreted (atenolol, nadolol) and use those largely excreted unchanged in urine Smokers may need higher doses of β-blockers
Ergot derivativesNon-selective β-blockers can increase the risk of peripheral vasoconstriction and hypertensionMonitor the patients receiving this combination for signs of excessive peripheral vasoconstriction (coldness, numbless of hands and feet)
FingolimodIncreases the risk of bradycardiaMonitor the ECG
Fish oilsThey modestly increase the hypotensive effect of some β-blockers Clinical significance uncertain
General anestheticsIncrease the risk of hypotension, cardiodepression and bronchial constrictionβ-blockers should not be withdrawn before anesthesia and surgery
HIV-protease inhibitors:
- Ritonavir
They can decrease the metabolism of metoprolol and propranololUse β-blockers largely excreted unchanged in urine
HydralazineIncreases the plasma levels of extensively metabolised β-blockers (metoprolol, oxprenolol, propranolol)Uncertain relevance of this combination. Use β-blockers largely excreted unchanged in urine
ImatinibInhibits CYP2D6 and increases the plasma levels of metoprolol (and probably of propranololUncertain clinical relevance
LevodopaAdditive risk of hypotension. Propranolol antagonizes the stimulation of cardiac β-receptors by the dopamine derived from levodopa and the tremor induced by levodopaMonitor the BP and the clinical response of the patient
Lidocaineβ-blockers decrease hepatic blood flow and increase the risk of lidocaine toxicityPropranolol, metoprolol and nadolol decrease the hepatic metabolism of lidocaineMonitor the ECG and reduce the dosage of lidocaine
Monoamine oxidase inhibitors (MAOIs)Bradycardia and hypotension have been described when combined with metoprolol, nadolol and propranolol Monitor BP and ECG. Avoid the combination if possible
MorphineIncreases the plasma levels of esmololReduce the dose of esmolol. Monitor the BP and the ECG
Neuroleptics:
- Chlorpromazine
- Haloperidol
- Thioridazine
Increases the risk of hypotension, cardiodepression and QT prolongation. The combination of sotalol and phenothiazines prolong the QT interval and should be avoidedMetoprolol and propranolol ncrease the plasma levels of the other by decreasing metabolism. Atenolol and nadolol do not share this interactionMonitor the clinical response and the ECG. The doses of these drugs can be reduced if needed Coadministration of thioridazine and propranolol is contraindicated
Nonsteroidal anti-inflammatory drugsNSAIDs inhibit prostaglandin-mediated vasodilation and promote salt and water retention and, thus, they can reduce the antihypertensive effects of the β-blockers.
Isolated cases of hypertension have been described
Monitor the BP response
Oral contraceptivesIncrease the plasma levels of metoprolol. No interaction with acebutolol, oxprenolol and propranololThe clinical relevance is uncertain
Potassium-depleting drugs:
- Amphotericin
- Glucocorticoids
- Laxatives
- Loop diuretics
- Thiazides
Increase the prolongation of teh QT interval and the risk of TdP in patients on sotalol Monitor serum potassium levels and ECG
PropafenoneRisk of hypotension, intracrdiac conduction defects and cardiac arrestIncreases (up to 5-fold) the plasma levels of metoprolol and propranolol Monitor the ECG and the BP response
PropoxypheneIncreases the response to metoprolol and propranololInhibits the metabolism of metoprolol and propranololMonitor the response to metoprolol and propranolol
QuinolonesThey prolong the QT interval. Ciprofloxacin reduces the clearance of metoprolol and increases its plasma levelsMonitor the ECG and adjust the β-blocker dose.
Avoid combination with sotalol
QT-prolonging drugsβ-blockers suppress congenital and drug-induced TdP. However sotalol prolongs the QT interval and this effect is potentiated when combined with QT-prolonging drugs Avoid the combination with sotalol
QuinidineIncreased risk of bradycardia, orthostatic hypotension and left ventricular dysfunction.
Sotalol and quinidine prolong the QT interval and can produce TdP
Quinidine inhibits the activity of CYP 2D6 and increases the plasma levels of metoprolol, propranolol, and timolol Closely monitor BP and the ECG. Avoid the combination with sotalol
RifampicinMay reduce the effects of some β-blockers.Rifampicin is a CYP inducer that increases the metabolism of bisoprolol, carvedilol, celiprolol, metoprolol, and propranololThe dose of these β-blockers should be modified as needed even when the clinical relevance of this interaction is uncertain
SSRIs:
- Citalopram
- Escitalopram
- Fluvoxamine
- Fluoxetine
- Paroxetine
- Sertraline
Isolated cases of bradycardia, AV block and heart failure.Fluoxetine and paroxetine inhibits CYP2D6 and may increase plasma levels of carvedilol, metoprolol and propranolol. Citalopram and escitalopram increase metoprolol plasma levels. Fluvoxamine may increase the plasma levels of propranolol Monitor patients treated with metoprolol or propranolol for toxicity. Use β-blockers largely excreted unchanged in urine
TobaccoReduces the effects of β-blockers on heart rate and BPIncreases the metabolism and descreases the plasma levels of metoprolol and propranololIt may be necessary to increase the dosage of the β-blocker.
Vasodilators:
- Nitrates
- Sodium nitroprusside
Increased risk of hypotensionMonitor BP
X-ray contrast mediaβ-blockade is a risk factor for anaphylactic reactions to X-ray contrast mediaPatients with previous history of anaphylactoid reactions can be at risk
ZileutonDecreases heart rateIncreases the exposure to propranololMonitor the ECG

Abbreviations

AADs: antiarrhythmic drugs
AV: atrio-ventricular
BP: blood pressure
CNS: central nervous system
CYP: Cytochrome P450 family
ECG: electrocardiogram
SSRIs: Selective serotonin reuptake inhibitors
TdP: torsades de pointes
VF: ventricular fibrillation.