Phentolamine

Why this drug is interesting

Phentolamine is the drug every emergency department is told to keep for vasopressor extravasation, and the drug that most emergency departments cannot immediately locate. It is also, as of its current UK marketing authorisation, licensed for something else entirely.

The gap between the label and the practice is unusually wide here. The SmPC covers reversal of paroxysmal hypertension in phaeochromocytoma and the diagnostic phentolamine test — the latter being an investigation the label itself describes as largely superseded. Meanwhile the use for which it sits on the trolley, infiltration of an extravasated alpha agonist, is not mentioned at all.

Availability in the UK

Each 1 mL ampoule contains 10 mg of phentolamine mesilate, equivalent to 7.45 mg of phentolamine base, and 0.5 mg of sodium metabisulphite — an excipient that can rarely cause severe hypersensitivity reactions and bronchospasm, and which matters in the sulphite-sensitive asthmatic.

Pharmacology

Mechanism

Phentolamine is a competitive, non-selective antagonist at α₁ and α₂ adrenoceptors, of relatively short duration. Blockade of postsynaptic vascular α₁ and α₂ receptors produces vasodilatation and a fall in blood pressure.

The non-selectivity is the source of both its usefulness and its problems. Blocking presynaptic α₂ receptors removes the negative feedback on noradrenaline release, so neuronal noradrenaline output rises — contributing positive inotropic and chronotropic effects. Combined with baroreceptor activation from the falling blood pressure, the result is a reliable tachycardia, which is why phentolamine was long ago displaced from routine hypertensive emergency use by more selective agents.

Kinetics

Onset (IV)

Maximum effect usually visible within 2 minutes

Duration

Blood pressure usually returns to pre-treatment levels within 15–30 minutes, sometimes sooner

Protein binding

54%

Metabolism

Extensively metabolised; approximately 13% excreted unchanged in urine

Renal impairment

No pharmacokinetic studies performed — use with caution

Licensed indications and dosing

Phaeochromocytoma — hypertensive crisis

• "Reversal of paroxysmal hypertension in pheochromocytoma before and during surgical treatment"¹
• 2–5 mg IV for hypertensive crises occurring before surgery or during induction, intubation or tumour removal
• Repeat as necessary with blood pressure monitoring
• Children over 8 years: minimum effective dose 1 mg, adjusted to clinical condition

The diagnostic phentolamine test

The label retains the diagnostic test — 5 mg IV in adults, 1 mg in children, with blood pressure measured every 30 seconds for three minutes then every 60 seconds for seven — and a positive result defined as a fall of more than 35 mmHg systolic and 25 mmHg diastolic. It also states that this use "has largely been replaced by the commonly available urinalysis of catecholamines or other biochemical tests due to their accuracy and safety" and "is not the first choice."¹ It is included here for completeness; it is not an emergency department investigation.

Vasopressor extravasation — the off-label use

The regimen in common use

• 5–10 mg of phentolamine diluted in 10–15 mL of 0.9% sodium chloride
• Infiltrated subcutaneously into and around the extravasation site through multiple small injections, using a fine needle
• As soon as possible — blanching should reverse visibly, and the window narrows with delay
• May be repeated if blanching recurs

The sequence that matters more than the dose

1. Stop the infusion immediately.
2. Leave the cannula in place initially and aspirate what you can through it.
3. Elevate the limb.
4. Then remove the cannula and infiltrate phentolamine.
5. Mark and document the affected area, and arrange review — plastics involvement if there is any tissue compromise.

Contraindications and adverse effects

Cautions

• Gastritis and peptic ulcer — phentolamine stimulates gastrointestinal activity including gastric acid secretion
• Renal impairment — no pharmacokinetic data
• Pregnancy — not recommended; animal reproductive toxicity, very limited human data
• Breastfeeding should be discontinued during treatment

Adverse effects

• Tachycardia — very common (≥1/10) on the label, and expected
• Orthostatic hypotension; acute or prolonged hypotensive episodes, during which myocardial infarction, cerebrovascular spasm and cerebrovascular occlusion may occur
• Angina and arrhythmias
• Dizziness, asthenia, chest pain
• Nasal congestion
• Nausea, vomiting, diarrhoea
• Flushing

Overdose

Hypotension, reflex tachycardia, arrhythmia and shock, with headache, hyperexcitability, visual disturbance, sweating, vomiting, diarrhoea and hypoglycaemia. There is no specific antidote and treatment is symptomatic — remembering that adrenaline is a poor choice for the hypotension, for the reason described above.

Critical appraisal

1. The extravasation evidence is entirely case-based, and always will be. Nobody has randomised an extravasated noradrenaline. The recommendation rests on a mechanism so direct — a competitive antagonist reversing the exact receptor effect causing the ischaemia — that the absence of trials is not really a criticism. It is worth being clear, though, that the outcome data supporting phentolamine over conservative management, warm compresses, or topical nitrate are not there.
2. The licence and the practice have drifted apart in an unusual direction. Most off-label use in emergency medicine is a new use of a familiar drug. Here the drug was reintroduced with a licence for a rare endocrine indication, while the common emergency use it is stocked for went unlicensed. That is a regulatory artefact of how the marketing authorisation was obtained, not a clinical judgement about the extravasation use.
3. The coronary contraindication deserves more attention than it gets. It is stated absolutely in the SmPC, and the population most likely to have a vasopressor extravasate — critically ill, often elderly, frequently with ischaemic heart disease — is precisely the population it excludes. In practice the local dose is small and the decision is usually easy, but it should be a decision.
4. Its displacement from hypertensive emergency practice was correct. Reflex tachycardia, a 15-minute duration and no titratability make it a poor drug for controlled blood pressure reduction compared with a labetalol or a GTN infusion. Its survival is due entirely to the two niches where non-selective alpha blockade is exactly what is wanted.

References

1. 1
   Phentolamine mesilate 10 mg/ml solution for injection — Summary of Product Characteristics, Roma Pharmaceuticals Limited (PL 49578/0038). electronic Medicines Compendium. Sections 2, 4.1–4.5, 4.8, 4.9, 5.1–5.2. Updated 20 Oct 2025; verified 23 Aug 2026.
2. 2
   Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the literature. Ann Pharmacother 2014;48(7):870–86. PubMed
3. 3
   Plum M, Moukhachen O. Alternative pharmacological management of vasopressor extravasation in the absence of phentolamine. P T 2017;42(9):581–92. PMC Relevant where local stock is unavailable — describes topical nitroglycerin and terbutaline alternatives.
4. 4
   TOXBASE — sympathomimetics; phaeochromocytoma crisis. National Poisons Information Service. toxbase.org (NHS login required.)