Beta blockers

gathered from – https://bpac.org.nz/2024/beta-blockers.aspx

Mechanism of Action

• Beta blockers are competitive antagonists of beta-adrenoceptors (β1, β2, β3).
• Inhibit sympathetic nervous system effects (adrenaline/noradrenaline).
  
• ↓ Heart rate (negative chronotropy)
• ↓ Myocardial contractility (negative inotropy)
• ↓ AV nodal conduction
• ↓ Renin release (renal β1 blockade)

Beta-Adrenoceptor Subtypes

• β1-adrenoceptors: ~75% of total; mainly in the heart.
• β2-adrenoceptors: Bronchial, vascular smooth muscle, uterus, liver, skeletal muscle.
• β3-adrenoceptors: Primarily in adipocytes; experimental role in obesity and cardiomyocytes.

📘 Pharmacological Classification

By Receptor Selectivity

Type	Drugs	Notes
Cardioselective (β1-selective)	Bisoprolol, Metoprolol, Atenolol	↓ Bronchospasm risk preferred in asthma/COPD Selectivity decreases at higher doses (may affect β2)
Non-selective (β1 & β2)	Propranolol, Nadolol, Sotalol	↑ Bronchospasm Contraindicated in asthma/COPD
Non-selective + α1-blockade	Carvedilol, Labetalol	Vasodilatory↓ Peripheral vascular resistance (vasodilation) useful in HF, hypertension, pregnancy (labetalol)

2. By Solubility

Solubility	Examples	Metabolism	Implications
Water-soluble	Atenolol, nadolol, sotalol	Renal	↓ CNS penetration → fewer CNS side effects ↓ Dose in renal impairment
Lipid-soluble	Metoprolol, propranolol, carvedilol	Hepatic	↑ CNS effects (e.g. sleep disturbance) ↓ Dose in liver impairment
Mixed	Bisoprolol	Renal + hepatic	Minimal dose adjustment unless severe renal or hepatic dysfunction

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🚫 Absolute Contraindications

Condition	Rationale
Decompensated Heart Failure (unless stabilized)	β-blockers reduce inotropy and may worsen cardiac output in acute decompensation. Initiate only once volume status is optimized and the patient is haemodynamically stable.
Severe Bradycardia or Advanced AV Block (≥2nd degree unless paced)	β-blockers depress sinus node and AV node function, worsening bradyarrhythmias and possibly leading to complete heart block.
Symptomatic Hypotension (SBP <90 mmHg)	Further reduction in cardiac output and perfusion may precipitate shock or syncope.
Symptomatic Bradycardia	β-blockers exacerbate low HR and can precipitate syncopal episodes or fatigue.
Pre-excited Atrial Fibrillation (e.g. WPW Syndrome)	AV nodal blockade (via β-blockers, CCBs, digoxin) increases conduction via accessory pathways, potentially leading to ventricular fibrillation. See below for expanded discussion.
Severe Bronchospasm (e.g. acute asthma)	Non-selective β-blockers block β2 receptors → bronchoconstriction. Even cardioselective agents (e.g. bisoprolol) should be used with caution.
Critical Limb Ischaemia (e.g. PAD with rest pain/ulcers)	β-blockers may unmask α-adrenergic vasoconstriction, worsening peripheral perfusion.

⚠️ Relative Contraindications

Condition	Caution Because…
Diabetes Mellitus (esp. with frequent hypoglycaemia)	Masks adrenergic warning signs of hypoglycaemia (e.g. tremor, palpitations); may blunt glycogenolysis.
Asthma or COPD (mild/moderate)	Risk of bronchospasm—prefer β1-selective agents (e.g. bisoprolol, metoprolol). Monitor FEV₁ and symptoms.
Depression	Some β-blockers (especially lipophilic agents like propranolol) may worsen mood.
Prinzmetal Angina (Vasospastic Angina)	β-blockers may promote unopposed α-adrenergic coronary vasoconstriction. Use calcium channel blockers instead.

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WPW & Pre-excited AF

Definitions

Term	Definition
Wolff-Parkinson-White (WPW) Syndrome	Congenital accessory pathway (Bundle of Kent) bypasses AV node, leading to pre-excitation.
Pre-excited AF	Atrial fibrillation conducting rapidly through accessory pathway, bypassing AV nodal filtering. Risk of ventricular rates >250 bpm → VF.

Why β-blockers Are Dangerous in WPW + AF

• In normal AF, the AV node filters rapid atrial impulses.
• In pre-excited AF, the AV node is bypassed.
• The accessory pathway does not filter, allowing rapid, chaotic impulses to reach ventricles.
• Result: Very fast, irregular, wide QRS tachycardia → haemodynamic collapse or VF.

ECG Clues for Pre-excited AF

Feature	Appearance
Rhythm	Irregularly irregular
QRS	Wide, variable width
Rate	Often >250 bpm
Delta wave	Often absent during AF; may be present on baseline ECG

• Classic vignette: Young patient with palpitations, wide QRS, irregular tachycardia → suspect pre-excited AF.
• Do NOT use β-blockers, NDHP-CCBs, digoxin, or adenosine.

🚫 AV Node Blocking Agents to Avoid in Pre-excited AF

• β-blockers
• Non-DHP calcium channel blockers (verapamil, diltiazem)
• Digoxin
• Adenosine (in this specific context)

✅ Management of Pre-excited AF

If you’re unsure and the patient is:

• Unstable → DC cardioversion (regardless of rhythm).
• Stable, wide QRS, irregular → treat as pre-excited AF or VT — avoid AV node blockers.
• Stable, wide QRS, regular → treat as VT unless clearly SVT with aberrancy.

Rhythm	Typical HR	ECG Pattern	Use Adenosine	Use β-blocker	Use Verapamil	Use Flecainide	Other Notes
AVNRT (AV nodal reentrant tachycardia)	150–250 bpm	Narrow, regular QRS, no visible P waves or retrograde P after QRS	✅ First-line	✅ If stable	✅ Alternative	❌ Not first-line	Vagal → adenosine → β-blocker/verapamil
AVRT (e.g. WPW in orthodromic)	180–250 bpm	Narrow, regular; retrograde P after QRS	✅ First-line	✅ If stable	✅ Alternative	❌ Not first-line	Same as AVNRT. Avoid AV blockers if pre-excitation visible or if patient in AF.
Pre-excited AF (AF with WPW)	250–300 bpm	Irregularly irregular, wide QRS, variable morphology	❌ CONTRAINDICATED	❌ CONTRAINDICATED	❌ CONTRAINDICATED	✅ If structurally normal heart	DC cardioversion if unstable. IV procainamide is another choice.
WPW (baseline)	Sinus rate (60–100 bpm)	Short PR, delta wave, wide QRS	✅ for AVRT if narrow/regular	✅ AVRT only	✅ AVRT only	❌ Avoid in baseline WPW w/o arrhythmia	Avoid AV node blockers if unsure of rhythm type.
SVT (undifferentiated)	150–250 bpm	Usually narrow, regular; sometimes aberrancy	✅ If narrow + regular	✅ If stable	✅ If stable	❌ Not first-line	If wide QRS, treat as VT unless clear it’s SVT with aberrancy
Sinus Tachycardia	100–160 bpm (can be higher in young/fever)	Normal P before every QRS, regular	❌ NO – physiological	❌ Not appropriate	❌ Not appropriate	❌ Not appropriate	Treat underlying cause (pain, fever, hypovolaemia, etc.)
VT (Monomorphic)	120–250 bpm	Wide QRS, regular; AV dissociation may be present	❌ NO – contraindicated	❌ No – can worsen outcome	❌ No – may cause hypotension	❌ Use only if proven SVT with aberrancy	Treat as VT unless proven otherwise; amiodarone, DC cardioversion
Polymorphic VT (e.g. Torsades)	>200 bpm	Wide, irregular QRS, varying morphology	❌ NO	❌ NO	❌ NO	❌ NO	MgSO₄, isoprenaline, pacing depending on QT interval

Key Differentiation Tips (Clinical + ECG)

Feature	AVNRT / AVRT	Pre-excited AF (WPW + AF)	VT	Sinus Tachycardia
Regular?	Yes	No	Usually yes	Yes
QRS Width	Narrow (AVNRT/AVRT)	Wide	Wide	Narrow
P Waves	Hidden or retrograde	Absent / chaotic	Dissociated / AV dissociation	Normal, before every QRS
Response to Vagal/Adenosine	Often terminates	May worsen (⚠️ avoid)	No response	Slows transiently only
Clinical Context	Young, abrupt onset/offset	Young, prior WPW, collapse	Elderly, structural heart disease	Fever, pain, anxiety, etc.

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DRUG INTERACTIONS

• Verapamil/Diltiazem: Additive bradycardia or AV block risk.
  • Never give β-blockers or verapamil to a patient with AF + WPW.
• Amiodarone: Increases β-blocker levels; more bradyarrhythmia.
• CYP2D6 inhibitors: May elevate plasma concentration (especially for metoprolol).

FOOD INTERACTIONS

• Caffeine (Belayneh & Molla, 2020): May delay metabolism → prolonged effect.
• Fatty meals: Increase propranolol absorption (clinically variable effect).

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Drug Profiles and Pharmacokinetics

Drug	Selectivity	Vasodilation	Solubility	Excretion
Atenolol	β1 selective	No	Low	Renal
Bisoprolol	Strong β1 selective	No	Yes	Renal/hepatic
Carvedilol	Non-selective + α1 blockade	Yes	Yes	Hepatic
Labetalol	Non-selective + α1 blockade	Yes	Yes	Hepatic
Metoprolol	β1 selective	No	Yes	Hepatic
Nadolol	Non-selective	No	Low	Renal
Propranolol	Non-selective	No	Yes	Hepatic
Sotalol	Non-selective	No	Low	Renal

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Indications & Recommendations

1. Stable Angina

First-line options:

• Beta blockers
• Calcium channel blockers (CCBs)

No proven superiority between beta blockers and CCBs.

No beta blocker preferred over another based on current evidence.

Choice depends on:

• Co-morbidities (e.g. avoid CCBs in HFrEF)
• Contraindications
• Dosing preference (e.g. once-daily vs multiple doses)
• Adherence likelihood

Cardioselective beta blockers (e.g. bisoprolol, metoprolol) typically preferred for better tolerance and fewer adverse effects.

2. Arrhythmias

from – https://pmc.ncbi.nlm.nih.gov/articles/PMC9868422/ – Wołowiec Ł, Grześk G, Osiak J, Wijata A, Mędlewska M, Gaborek P, Banach J, Wołowiec A, Głowacka M. Beta-blockers in cardiac arrhythmias-Clinical pharmacologist’s point of view. Front Pharmacol. 2023 Jan 9;13:1043714. doi: 10.3389/fphar.2022.1043714. PMID: 36699057; PMCID: PMC9868422.

A. SUPRAVENTRICULAR ARRHYTHMIAS

1. Atrial Fibrillation (AF)

Rate Control:

Beta blockers and non-dihydropyridine CCBs (verapamil, diltiazem) are first-line options.

• Avoid verapamil/diltiazem in HFrEF.
• Preferred beta blockers:
  • Bisoprolol (off-label)
  • Metoprolol succinate
  • Carvedilol (off-label)
• Bisoprolol often preferred:
  • More cardioselective
  • Slightly stronger HR control
• Sotalol:
  • Not preferred for rate control (40 mg bd dose often insufficient)
  • Used for rhythm control at higher doses (≥80 mg bd)
  • Rarely used due to:
    • QT prolongation (torsades risk)
    • Renal excretion (problematic in elderly)
    • SWORD trial → ↑ mortality post-MI with LV dysfunction
• Alternative rhythm control agents: flecainide, amiodarone

• AFFIRM Trial (NEJM, 2002): Randomized 4060 pts to rate vs rhythm control.
  • No survival advantage of rhythm control.
  • β-blockers most effective in HR control, especially in exercise settings.
• ESC 2020 Guidelines (Hindricks et al.):
  • β-blockers are first-line agents for rate control in all AF subtypes.
  • Preferred in patients with reduced LVEF (over NDHP CCBs or digoxin).
  • IV agents for acute rate control: metoprolol tartrate, esmolol, landiolol.
• J-Land Study (Nagai, 2013): IV landiolol superior to digoxin for acute AF in HFrEF (HR control within 2 h: 48.6% vs. 13.9%).

Postoperative AF:

• Meta-analysis (Gao et al., 2007): β-blockers reduce incidence of post-CABG AF.
• ESC recommends prophylactic β-blockers for patients undergoing cardiac surgery unless contraindicated.

2. AVNRT & AVRT

Acute Termination:

• When vagal maneuvers and adenosine are ineffective:
  • Yeh et al. (1985): Propranolol + diltiazem effective in terminating AVNRT.
  • Can be used acutely if mechanism is confirmed as AV nodal–dependent.
• ESC 2019 SVT Guidelines (Brugada et al.):
  • β-blockers useful in non-preexcited AVRT/AVNRT.
  • Not recommended in preexcited AF due to risk of preferential AV nodal block → increased conduction via accessory pathway → VF risk.

Chronic Suppression:

• Considered when catheter ablation is not desirable or feasible.

3. Inappropriate Sinus Tachycardia & POTS

• Ptaszynski et al. (2013): Ivabradine + β-blocker > monotherapy in IST.
• Raj et al. (2009, JACC): Low-dose propranolol (20 mg) improved HR and symptoms in POTS without BP drop.

4. Multifocal Atrial Tachycardia (MAT)

• Arsura et al., 1988: Metoprolol more effective than verapamil in controlling MAT (HR and symptom relief).
• Preferred in those with bronchospastic disease (over NDHP CCBs).

B. VENTRICULAR ARRHYTHMIAS (VA)

1. Acute VT/VF Post-MI

• VALIANT Trial (Piccini et al., 2008): Early β-blocker use within 24 h reduced arrhythmic mortality in post-MI with VT/VF.
• Huikuri et al. (2001): IV β-blockers reduced recurrence of VF in ACS.
• ESC 2015 Guidelines (Priori et al.):
  • Class I recommendation for β-blockers post-MI for VA suppression and SCD prevention.

2. Sustained VT/ICD Patients

• MADIT-II Trial: β-blockers + ICD therapy reduced total and arrhythmic mortality in post-MI patients with low LVEF.
• OPTIC Trial (Connolly et al., 2006):
  • Amiodarone + β-blocker ↓ ICD shocks by 73%.
  • More effective than β-blocker or sotalol monotherapy.
  • Combination carries more side effects → higher discontinuation.

3. Sotalol

• Dual β-blocker + Class III action.
• Smith et al. (2013): Effective in ischemic VT.
• Avoid in:
  • HFrEF without ICD
  • QT prolongation (requires ECG monitoring)
  • Renal impairment

C. CARDIOMYOPATHIES

Type	β-blocker Role
Dilated (DCM)	↓ Mortality, ↓ VT/VF burden (ESC 2015, Priori et al.)
Hypertrophic (HCM)	Symptom relief; modest effect on SCD reduction; used for LVOT obstruction
ARVC	Recommended for NSVT/PVC suppression and in combination with ICD therapy

D. INHERITED ARRHYTHMIA SYNDROMES

Syndrome	Recommendation	Notes
LQTS	Class I (ESC 2015)	Reduce arrhythmic events; benefit in genotype-positive, QTc-normal carriers
CPVT	Class I	Must use β-blockers without ISA (e.g., nadolol, propranolol); also in asymptomatic carriers
Idiopathic VT	IV β-blockers in stable patients	Consider for acute suppression

Guideline	Summary
ESC 2020 (AF)	β-blockers are first-line for rate control in AF (Class I); preferred in HFrEF.
ESC 2015 (VA/SCD)	β-blockers are the cornerstone of post-MI, VT/VF, SCD prevention.
ESC 2022 (VA)	Reaffirms β-blocker use in LQTS, CPVT, idiopathic VT.
AHA/ACC/HRS 2014 (AF)	Preferred rate control agents in structural heart disease and post-MI.
ETG Australia (latest)	Recommends β-blockers in SVT, AF, post-MI VT/VF; dose tailored to cardioselectivity and comorbidity profile.

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C. CARDIOMYOPATHIES

Type	β-blocker Role
Dilated (DCM)	↓ Mortality, ↓ VT/VF burden (ESC 2015, Priori et al.)
Hypertrophic (HCM)	Symptom relief; modest effect on SCD reduction; used for LVOT obstruction
ARVC	Recommended for NSVT/PVC suppression and in combination with ICD therapy

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D. INHERITED ARRHYTHMIA SYNDROMES

Syndrome	Recommendation	Notes
LQTS	Class I (ESC 2015)	Reduce arrhythmic events; benefit in genotype-positive, QTc-normal carriers
CPVT	Class I	Must use β-blockers without ISA (e.g., nadolol, propranolol); also in asymptomatic carriers
Idiopathic VT	IV β-blockers in stable patients	Consider for acute suppression

3. Heart Failure (HFrEF)

• Part of “four pillars” of HFrEF therapy:
  • ARNI (sacubitril/valsartan)
  • Beta blocker
  • MRA (spironolactone, eplerenone)
  • SGLT-2 inhibitor (empagliflozin)
• Preferred agents: Bisoprolol, metoprolol succinate, carvedilol
  • Reduce mortality, hospitalisations, and symptoms

Initial Management in Primary Care

• Start with:
  • ACEi or ARB
  • Beta blocker (low dose, titrate up)
  • ± Loop diuretic for fluid overload
• Escalate if still symptomatic:
  • Add MRA
  • Switch to ARNI (if eligible)
  • Add SGLT-2 inhibitor (esp. in T2DM with CVD)

Preferred Beta Blockers in HFrEF

• Bisoprolol, metoprolol succinate, carvedilol:
  • All improve mortality, symptoms, hospitalisation
• Carvedilol may be superior to metoprolol in HFrEF with AF
• In practice:
  • Bisoprolol/metoprolol often chosen due to once-daily dosing and better tolerance
  • Bisoprolol preferred if:
    • Hypotension or dizziness with ARNI + carvedilol
    • Pulmonary function compromise (protective vs carvedilol)

Heart Failure with Preserved Ejection Fraction (HFpEF)

• No proven mortality benefit from beta blockers.
• May be used if:
  • Co-morbid AF
  • Other cardiovascular indications

4. Post-Myocardial Infarction

Acute Phase

• Beta blocker initiated in secondary care along with:
  • ACE inhibitor
  • Antiplatelet agents
  • Statin
• Reduces:
  • Infarct size
  • Ventricular arrhythmias
  • Long-term remodelling/heart failure
• Usually a cardioselective beta blocker (e.g. bisoprolol, metoprolol); no specific agent preferred per international guidelines.

Ongoing Use

• Echocardiogram at 3 months post-MI to assess:
  • Ejection fraction (EF)
  • Regional wall motion abnormalities (RWMA)
• Beta blocker may be discontinued after 12 months if:
  • EF ≥ 50%
  • No RWMA or signs of remodelling
  • No other indications (e.g. HF, arrhythmia)
• Required long-term if:
  • EF < 50%
  • Evidence of myocardial damage (RWMA)

Evidence

• Long-term beta blocker use not associated with improved outcomes post-MI in low-risk patients (2024 NZ study; median follow-up 3.5 years).
• Reduced benefit in the modern reperfusion era due to widespread PCI, statins, and antiplatelets.

5. Hypertension

General Use

• No longer first-line monotherapy for primary hypertension.
• Preferred antihypertensives: ACEi, ARB, CCB, thiazide-like diuretics.
• Indications for beta blockers:
  • Atrial fibrillation
  • Coronary artery disease
  • Heart failure
  • Women of reproductive age (avoid ACEi/ARBs)(less teratogenic than RAAS inhibitors)

Drug Choice

• Cardioselective (e.g. bisoprolol, metoprolol) or vasodilating (e.g. carvedilol).
• Carvedilol preferred in diabetes (improves insulin sensitivity), but:
  • Twice daily dosing may limit adherence.

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⚠️ Co-morbidity Considerations

Renal Impairment

• Dose adjustment may be needed for water-soluble beta blockers (e.g. atenolol).
• Lipid-soluble beta blockers (e.g. metoprolol) may be better tolerated.
• Bisoprolol generally does not require dose adjustment unless impairment is severe.

Hepatic Impairment

• Dose adjustment may be needed for lipid-soluble beta blockers (e.g. metoprolol, propranolol).
• Consider switching to a water-soluble beta blocker (e.g. atenolol).
• Carvedilol should be avoided in hepatic impairment.
• Bisoprolol usually does not require dose adjustment, unless impairment is severe.

Asthma

• Beta blockers are generally avoided due to bronchospasm risk.
• If required, use cardioselective beta blockers (e.g. bisoprolol, metoprolol) cautiously.

COPD

• Cardioselective beta blockers are recommended, as they are less likely to cause bronchospasm.

Diabetes

• Carvedilol may be preferred in patients with cardiovascular disease and diabetes:
  • Does not worsen glycaemic control.
  • May improve insulin sensitivity.
• In practice, bisoprolol or metoprolol succinate is usually prescribed due to:
  • Once-daily dosing (better adherence).
  • Cardioselectivity
• Caution in type 1 diabetes or insulin use (mask hypoglycaemia symptoms).
• Avoid non-selective agents (e.g. propranolol) in at-risk patients.

Pregnancy

• Labetalol is first-line due to lower neonatal risk.
• Metoprolol or bisoprolol: second-line if needed.
• Atenolol avoided (risk: growth restriction, preterm birth).

Breastfeeding

• Acceptable: carvedilol, labetalol, metoprolol, propranolol (low milk concentration).
• Avoid: atenolol, sotalol, nadolol (high milk levels, especially in neonates).
• Monitor infants: bradycardia, hypotension, hypoglycaemia.

Other Considerations

• Cardioselective agents (bisoprolol, metoprolol, atenolol):
  • Less likely to cause cold extremities.
• Water-soluble agents (atenolol):
  • Less likely to cause CNS side effects (e.g. insomnia, vivid dreams).
• Bisoprolol:
  • Less likely to cause sexual dysfunction.
• Metoprolol:
  • Succinate salt preferred (once-daily dosing) vs tartrate (multiple doses per day).

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🚨 Adverse Effects

Category	Adverse Effect	Notes
CVS	Bradycardia, hypotension	Dose-dependent
Respiratory	Bronchospasm	Non-selective agents (esp. in asthma)
Metabolic	Insulin resistance, weight gain	Less with carvedilol
CNS	Sleep disturbance, fatigue	Lipid-soluble agents (e.g. metoprolol)
Peripheral	Cold extremities	Less with cardioselective BB
Sexual	Erectile dysfunction	Least with bisoprolol/nebivolol

inimising Adverse Effects

• Gradual up-titration improves tolerance.

Specific Adverse Effect Considerations

• Cold extremities: less with cardioselective beta blockers.
• CNS effects (e.g. vivid dreams): less with water-soluble agents (e.g. atenolol).
• Sexual dysfunction:
  • Less common with bisoprolol, nebivolol.
  • Consider PDE-5 inhibitors (e.g. sildenafil) with caution.

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Withdrawal

Not always lifelong; review ongoing need periodically.

Reasons to withdraw:

• Adverse effects (e.g. vasoconstriction, leg ulcers)
• Lack of indication (e.g. EF preserved post-MI)

Tapering required to prevent rebound symptoms:

• Gradual reduction over weeks to months.
• Monitor HR and BP during weaning.

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💡 Special Considerations

• Bisoprolol: Most cardioselective; good for AF, HF, fewer metabolic/CNS effects
• Carvedilol: Best in diabetic CVD; avoid in hepatic dysfunction
• Metoprolol: Widely used; good for once-daily dosing (succinate)
• Atenolol: Minimal CNS effects; but out of favour due to weaker outcome data