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Pharmacology · Drugs Acting on Adrenergic Synapses

Non-selective alpha-blockers

Phentolaminum, Phenoxybenzaminum

A group of pharmacological agents that disrupt the transmission of excitation in adrenergic synapses by directly blocking both $\alpha_1$- and $\alpha_2$-adrenoceptors. Their use prevents the interaction of receptors with endogenous noradrenaline and circulating adrenaline, leading to pronounced vasodilation.

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Prototype of the groupPhentolamine is a short-acting drug that competitively blocks receptors.
Ultra-long actionPhenoxybenzamine binds irreversibly and works for more than 48 hours.
Cardiac effectThey cause pronounced tachycardia due to the blockade of presynaptic receptors.
Main targetManagement of hypertensive crises in pheochromocytoma.
4 min readFor medical studentsUpdated 09/24/2026
Material prepared by WhiteCoat Pro editorial team based on platform study guidesReviewed by medical editor: Aulov A. A., general practitioner · 09/24/2026

Drug classification

Non-selective $\alpha_1, \alpha_2$-adrenoceptor blockers are divided by origin into two main subgroups:

  • Synthetic agents. These include the imidazoline derivative phentolamine and the long-acting drug phenoxybenzamine.
  • Ergot alkaloid derivatives. This subgroup includes dihydroergotamine and nicergoline (Sermion).

Pharmacodynamics of phentolamine

Phentolamine acts as the key drug (prototype) of the group. It competitively blocks postsynaptic $\alpha_1$-adrenoceptors, as well as all types of $\alpha_2$-adrenoceptors, including presynaptic ones.

Hemodynamic and metabolic effects:

  1. Decrease in blood pressure. Blockade of vascular wall receptors causes persistent vasodilation, reducing both arterial and venous pressure.
  2. Tachycardia. It has a dual genesis: a reflex response to hypotension and a direct consequence of presynaptic $\alpha_2$-receptor blockade (negative feedback is impaired, an excess of noradrenaline is released, stimulating cardiac $\beta_1$-receptors).
  3. Increased oxygen demand. Tachycardia increases myocardial oxygen demand.
  4. Enhanced renin secretion.

The action of phentolamine when administered intravenously lasts only 10–15 minutes. This is due to the fact that the excess noradrenaline released as a result of presynaptic blockade rapidly displaces the drug from its binding to receptors.

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Phenoxybenzamine: features of long-term blockade

In situations where long-term blood pressure control is required, phenoxybenzamine is used.

Unlike phentolamine, it forms strong covalent bonds with receptors, causing an irreversible blockade. Additionally, the drug inhibits the neuronal reuptake of the neurotransmitter. Due to this mechanism, the hypotensive effect lasts for 48 hours or more. Its side effect profile is similar to that of phentolamine.

Clinical application

The main indication for prescribing non-selective $\alpha$-blockers is associated with pheochromocytoma, a tumor of the adrenal medulla that releases huge doses of catecholamines into the blood.

  • The drugs are used to manage crises, as well as to prepare the patient for surgical removal of the tumor (and during the surgery itself).
  • In unresectable cases, the drugs are prescribed for long-term use, necessarily combined with $\beta_1$-adrenoceptor blockers to prevent tachycardia.

Other indications include:

  • Management of hypertensive crises in clonidine withdrawal syndrome and "tyramine syndrome" (ingestion of cheese or wine while taking MAO inhibitors).
  • Peripheral circulation disorders: Raynaud's disease, obliterating endarteritis, frostbite, and trophic ulcers. The drugs dilate arterioles and precapillaries, eliminating tissue hypoxia.

Side effects and contraindications

Adrenoceptor blockade causes a number of characteristic adverse reactions:

  • Cardiovascular system: orthostatic hypotension (up to fainting upon sudden standing due to blood pooling in veins) and pronounced tachycardia.
  • Mucous membranes: nasal congestion due to edema and vasodilation of the nasal cavity.
  • Gastrointestinal tract and pelvic organs: parasympathetic hyperstimulation. Blockade of presynaptic $\alpha_2$-receptors leads to excessive acetylcholine release. This causes diarrhea, hypersalivation, increased gastric secretion, frequent urination, and ejaculation disorders.

Due to the cardiac workload, the drugs are contraindicated in angina pectoris, a history of myocardial infarction, and baseline arterial hypotension.

Briefly: answers to topical questions

What is the pharmacokinetics of phentolamine (bioavailability, hepatic metabolism, elimination pathways)?

The provided materials lack data on the bioavailability, hepatic metabolism, and elimination pathways of phentolamine. It is indicated that the drug's action is short-lived: 10–15 minutes upon intravenous administration. The short duration of action is due to the fact that excess noradrenaline released as a result of presynaptic $\alpha_2$-adrenoceptor blockade competitively displaces phentolamine from its binding to postsynaptic $\alpha_1$-adrenoceptors. Tablet formulations require administration 3–4 times a day.

At what doses and how often is phentolamine administered to manage a hypertensive crisis in pheochromocytoma?

The provided materials do not contain precise data on specific doses and the frequency of phentolamine administration for managing a hypertensive crisis in pheochromocytoma. It is only known that phentolamine and phenoxybenzamine are used in pheochromocytoma, and that phentolamine is used before and during surgery for the prevention and management of hypertensive crises.

Class and exam questions

What will happen if adrenaline is administered against the background of phentolamine action?

Blood pressure will drop sharply rather than rise. This happens because vasoconstrictor $\alpha$-receptors are blocked by phentolamine, and adrenaline can only act on $\beta_2$-receptors, which cause vasodilation.

Why do diarrhea and frequent urination occur with the administration of phentolamine?

This is a consequence of the effect on the parasympathetic nervous system. The drug blocks presynaptic $\alpha_2$-receptors, which enhances acetylcholine release by postganglionic nerve endings, stimulating gastrointestinal motility and reducing bladder sphincter tone.

How to prevent the development of orthostatic hypotension after injection?

Since the drug dilates veins and inhibits venoconstriction, blood pools in the lower body when transitioning to an upright position. To prevent fainting, the patient should remain in a horizontal position for 1–2 hours after administration.

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What else to study on this topic

  • Mechanisms of reversible and irreversible receptor blockade
  • Sympatholytics: differences from adrenoceptor blockers
  • Pharmacodynamics of ergot alkaloids
  • Tyramine syndrome and clonidine withdrawal syndrome
  • The role of beta-blockers in the combination therapy of pheochromocytoma

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