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HFrEF — ACEi/ARB Intolerant Pregnancy: Hydralazine: used in hypertensive emergencies in pre-eclampsia. Nitrate component: avoid in pregnancy — limited data.

Hydralazine + Isosorbide Dinitrate (HFrEF)

Brand names: Apresoline (hydralazine)

Adult dose

Dose: Hydralazine: 25-75 mg three to four times daily. Isosorbide dinitrate: 20-40 mg TDS (with 8-hour nitrate-free interval overnight).
Route: Oral
Frequency: Three to four times daily
Max: Hydralazine 300 mg/day; Isosorbide dinitrate 160 mg/day
Combination vasodilator for HFrEF when ACEi AND ARB not tolerated. A-HeFT trial: specific mortality benefit in Black patients. BiDil (fixed combination) licensed in US specifically for self-identified Black patients.

Paediatric dose

Dose: 0.5-1 mg/kg
Route: Oral
Frequency: Three to four times daily
Max: 7.5 mg/kg/day (hydralazine)
Specialist paediatric cardiology only.

Dose adjustments

Renal

No dose adjustment required for either agent

Hepatic

Hydralazine bioavailability higher in severe hepatic impairment (reduced first-pass); use with caution

Paediatric weight-based calculator

Specialist paediatric cardiology only.

Clinical pearls

  • A-HeFT trial (Taylor et al. NEJM 2004): fixed-dose hydralazine 37.5 mg + isosorbide dinitrate 20 mg TDS in Black patients with HFrEF — 43% reduction in mortality; 33% reduction in hospitalisation. Trial stopped early due to overwhelming benefit.
  • Drug-induced lupus: hydralazine causes lupus-like syndrome in 5-10% of patients — more common in slow acetylators (NAT2 gene) and at doses >200 mg/day. Anti-histone antibodies are diagnostic. Fully reversible on stopping.
  • Nitrate tolerance prevention: give isosorbide dinitrate at 8am, 1pm, and 6pm — the overnight nitrate-free period restores nitrate sensitivity.
  • Third-line in UK HFrEF: recommended by NICE/ESC when ACEi AND ARB both not tolerated (e.g., bilateral renal artery stenosis, severe CKD, bilateral angioedema).
  • Slow acetylator risk: slow acetylators at higher lupus risk. Genetic testing available but not routinely required; use lower doses.

Contraindications

  • Idiopathic SLE (hydralazine-induced lupus risk)
  • Severe hypotension
  • HOCM
  • Aortic stenosis
  • Concomitant PDE-5 inhibitors (absolute — severe hypotension with nitrate component)

Side effects

  • Reflex tachycardia (hydralazine — vasodilation-mediated)
  • Drug-induced lupus (hydralazine — dose-dependent; anti-histone antibodies)
  • Headache (nitrate — vasodilation)
  • Nitrate tolerance (require 8-hour nitrate-free interval)
  • Peripheral oedema
  • Flushing

Interactions

  • PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) — ABSOLUTE CONTRAINDICATION with nitrate component (fatal hypotension)
  • Other antihypertensives — additive hypotension

Monitoring

  • Blood pressure
  • Heart rate (reflex tachycardia)
  • ANA/anti-histone antibodies (if lupus symptoms develop)
  • Renal function

Reference: BNFc; BNF 90; A-HeFT Trial (Taylor et al. NEJM 2004); ESC HF Guidelines 2021; NICE NG106; SPC Apresoline. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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