Metoprolol

Mechanism

Dual mechanism. Amiodarone non-competitively blocks β-adrenoceptors and depresses atrioventricular (AV) conduction; metoprolol is a competitive β-blocker. Effects add up: lowered heart rate and AV conduction. Amiodarone also inhibits CYP2D6 and metoprolol plasma levels rise.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block, prolonged PR. In heart failure: worsening dyspnoea and oedema.

Management

The combination is appropriate in cardiology (atrial fibrillation, post-infarction care). Halve the metoprolol dose when starting amiodarone. Check pulse and ECG at 1 and 4 weeks. If pulse drops below 50 or second-degree AV block appears, adjust metoprolol further.

Mechanism

Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 (bupropion SmPC), the main enzyme that clears metoprolol (metoprolol labels). The Spanish metoprolol SmPC lists bupropion among potent CYP2D6 inhibitors that raise metoprolol plasma levels. The FDA metoprolol label reports that strong CYP2D6 inhibitors doubled metoprolol concentrations; the documents give no figure for bupropion itself. Higher levels reduce the cardioselectivity of metoprolol (FDA metoprolol label). Bupropion keeps inhibiting the enzyme for at least 7 days after the last dose (bupropion SmPC).

Symptoms

Stronger metoprolol effect: slow pulse, dizziness, weakness, low blood pressure, including on standing, and fainting. Marked metoprolol excess can cause severe bradycardia, atrioventricular block, heart failure and bronchospasm (FDA metoprolol label). Because cardioselectivity is reduced, bronchospasm is a particular concern in asthma and chronic obstructive pulmonary disease.

Management

If metoprolol is started in a patient on bupropion, begin at the lower end of the dose range. If bupropion is added to metoprolol, assess whether the metoprolol dose needs lowering and weigh the expected benefit of bupropion against the risk (Spanish bupropion SmPC). The FDA bupropion label also notes that the metoprolol dose may need to be decreased. The FDA metoprolol labels ask for close monitoring when a CYP2D6 inhibitor cannot be avoided, above all of heart rate and blood pressure. Bupropion keeps inhibiting the enzyme for at least 7 days after it is stopped, which matters when doses are changed (bupropion SmPC).

Mechanism

Abrupt clonidine withdrawal on a beta-blocker triggers a hypertensive crisis: the α2 effect is lost while β-blockade persists – an 'unopposed' α1 effect develops with a sharp blood pressure rise. Additional additive bradycardia.

Symptoms

Abrupt clonidine withdrawal causes hypertensive crisis: sharp blood pressure rise, headache, tachycardia, anxiety, sweating. Symptoms appear 18–24 hours after a missed clonidine dose.

Management

For planned clonidine withdrawal, stop metoprolol 3–7 days beforehand, then taper clonidine over 1–2 weeks. Alternative antihypertensives: an ACE-I (enalapril) plus amlodipine without clonidine.

Mechanism

Additive slowing of atrioventricular (AV) conduction and lowered heart rate. In atrial fibrillation this synergistic ventricular rate control is standard; without atrial fibrillation, bradycardia and AV block risks rise.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block, prolonged PR. Older patients: fatigue, weakness.

Management

The combination is appropriate in atrial fibrillation with preserved or reduced ejection fraction. Check pulse and ECG at 1 and 4 weeks. If pulse drops below 50 or second-degree AV block appears, reduce metoprolol; if symptoms persist, hold digoxin temporarily.

Mechanism

Diltiazem slows AV conduction + inhibits CYP3A4 (metoprolol metabolism). Additive bradycardia and AV block.

Symptoms

Bradycardia, AV block.

Management

Avoid combination. Alternative – amlodipine.

Mechanism

Fluoxetine is a strong inhibitor of the CYP2D6 enzyme (fluoxetine SmPC), and metoprolol is a CYP2D6 substrate (metoprolol SmPC). Strong CYP2D6 inhibitors, including fluoxetine, roughly double metoprolol concentrations, and metoprolol loses its cardioselectivity (US metoprolol label). The risk of marked bradycardia, hypotension and AV block rises.

Symptoms

Bradycardia, dizziness, fainting, a drop in blood pressure on standing. The metoprolol SmPC treats a heart rate below 50–55 beats per minute as significant. In heart failure: worsening breathlessness and oedema.

Management

In heart failure the combination is contraindicated: the Spanish fluoxetine SmPC contraindicates fluoxetine with metoprolol used for this indication because of the risk of excessive bradycardia (fluoxetine SmPC). For other indications, the FDA advises combining metoprolol with a CYP2D6 inhibitor only when this cannot be avoided, and then monitoring the patient closely (US metoprolol label). Drugs metabolised by CYP2D6 are started or titrated at the lowest dose in patients on fluoxetine, and this also applies for 5 weeks after fluoxetine is stopped (fluoxetine SmPC). If the patient already takes metoprolol, its dose may need to be reduced when fluoxetine is started (metoprolol SmPC). If the heart rate falls below 50–55 beats per minute, reduce the metoprolol dose gradually or withdraw it slowly (metoprolol SmPC).

Mechanism

Both drugs slow conduction through the atrioventricular (AV) node and sinus node function, lower the heart rate and reduce cardiac contractility; together these effects add up (metoprolol and verapamil labels). There is also a pharmacokinetic part: in patients with angina, verapamil increased metoprolol AUC by 32.5% and peak concentration by 41% (verapamil label). The FDA verapamil label also describes reduced metoprolol clearance.

Symptoms

Marked bradycardia, high-degree atrioventricular (AV) block up to complete heart block, low blood pressure with dizziness, new or worsening heart failure (verapamil and metoprolol labels).

Management

Do not give intravenous verapamil to patients taking beta-blockers, including metoprolol (metoprolol labels). Intravenous verapamil is contraindicated with intravenous beta-blockers; the two should not be given within a few hours of each other (intravenous verapamil labels in Spain and the US). Avoid oral verapamil with a beta-blocker in any degree of ventricular dysfunction; in hypertension the risks of the combination may outweigh the benefits (FDA verapamil label). If tablets are combined, use caution and monitor pulse and blood pressure closely (metoprolol and verapamil labels). If the pulse falls below 50–55 beats per minute, reduce metoprolol gradually or withdraw it slowly (metoprolol label). Marked first-degree atrioventricular (AV) block or progression to second- or third-degree block requires a lower verapamil dose, and rarely stopping it (FDA verapamil label).

Mechanism

Additive bradycardia and sedation. Fall risk in older patients.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

In older patients, check pulse and blood pressure 1–2 weeks after starting alprazolam. Alternative anxiolytic: hydroxyzine or a short lorazepam course.

Mechanism

Amitriptyline is a CYP2D6 substrate, as is metoprolol. Enzyme competition raises both drug levels. Plus additive anticholinergic effect on the heart (bradycardia, PR prolongation).

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: PR prolongation. Older patients: delirium and fall risk.

Management

In older patients, check pulse and ECG 1–2 weeks after starting amitriptyline. Alternative beta-blocker without CYP2D6 dependence: bisoprolol or carvedilol. For neuropathic pain, alternative: gabapentin or pregabalin.

Mechanism

Target combination in angina and hypertension. Amlodipine dilates vessels; metoprolol slows heart rate. The drugs compensate each other's reflex effects.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

Standard combination in ischaemic heart disease with hypertension. Check pulse and blood pressure 1–2 weeks after start. In patients with ejection fraction below 40%, watch for heart failure decompensation.

Mechanism

Metoprolol is mainly metabolised by CYP2D6; clarithromycin does not clinically significantly inhibit CYP2D6. The effect on metoprolol levels is minimal. Additive bradycardia is possible from clarithromycin's direct effect on the cardiac conduction system.

Symptoms

Bradycardia, dizziness, fatigue. Symptoms appear during clarithromycin courses in older patients and concurrent heart failure.

Management

For short clarithromycin courses (7–14 days) with normal heart rate, no adjustment needed. In older patients and prior first-degree AV block, check ECG at one week. For long-term clarithromycin (e.g. Mycobacterium avium complex), antibiotic alternative: azithromycin (minimal HR effect).

Mechanism

Target combination in heart failure with reduced ejection fraction and in arterial hypertension. Synergistic reduction of blood pressure, preload, and afterload.

Symptoms

On starting, in older or hypovolaemic patients: symptomatic hypotension, dizziness, fatigue. Metoprolol bradycardia is amplified as sympathetic activation drops.

Management

Start both drugs at minimal doses with up-titration every 2 weeks to target. Check standing/sitting BP, heart rate, creatinine and potassium at 2 weeks. In heart failure, the goal is maximum tolerated dose; the RCT evidence base is extensive.

Mechanism

Target combination in heart failure and arterial hypertension. Synergistic blood pressure reduction. The ARB does not mask the adrenergic response to hypoglycaemia.

Symptoms

On starting, in older patients: symptomatic hypotension, dizziness. Metoprolol bradycardia is amplified as sympathetic activation drops.

Management

Start both at minimal doses with up-titration every 2 weeks to target. Check standing/sitting BP, heart rate, creatinine and potassium at 2 weeks. In diabetes, monitor for hypoglycaemia: metoprolol is cardioselective and weakly masks adrenergic symptoms.

Mechanism

Metoprolol is cardioselective but at high doses antagonises theophylline's bronchodilator effect. In bronchial asthma, control may worsen.

Symptoms

Exertional dyspnoea, wheezing, more frequent asthma attacks. In COPD: symptom exacerbation.

Management

In asthma and COPD with atrial fibrillation or hypertension, metoprolol is preferred at cardioselective doses (up to 100 mg/day) under pulmonary function monitoring. In severe asthma, consider alternatives — diltiazem or verapamil for rate control in atrial fibrillation. Theophylline is second-line in COPD; consider switching to long-acting beta-2 agonists (formoterol).

Mechanism

Paracetamol is metabolised by CYP2E1 (5%) and predominantly by glucuronidation; metoprolol by CYP2D6. No direct pharmacokinetic interaction.

Symptoms

The combination usually causes no specific symptoms. Each drug's individual side effects remain.

Management

No dose adjustment needed. Paracetamol remains the analgesic of choice in patients on metoprolol.