A long-acting alpha-adrenergic receptor blocker is phentolamine (OraVerse). It helps in the diagnosis of pheochromocytoma and the treatment of norepinephrine extravasation.

Indications of Phentolamine:

• Pheochromocytoma:

  • It is used to prevent and treat hypertension episodes linked to pheochromocytoma brought on by stress or manipulation during the perioperative period, as well as to diagnose pheochromocytoma using the phentolamine-blocking test (see "Note").

• Extravasation management:

  • It works well to both prevent and treat cutaneous necrosis/sloughing following norepinephrine extravasation.

• Local anesthesia reversal (OraVerse):

  • It can be applied to adults and children under the age of three to reverse soft tissue (lip, tongue) anaesthesia and the accompanying functional deficits brought on by an intraoral submucosal injection of a local anaesthetic including a vasoconstrictor.

• Off Label Use Phentolamine in Adults:

  • Hypertensive crisis
  • Extravasation of sympathomimetic vasopressors

Phentolamine (OraVerse)  dose in adults:

Phentolamine (OraVerse) dose in the treatment of extravasation of norepinephrine:

• Local infiltration:
  • 5 to 10 mg injection into extravasation region, diluted in 10 mL of 0.9% sodium chloride (as soon as possible after extravasation is noted but within 12 hours of extravasation).

Phentolamine (OraVerse) dose in the treatment of extravasation of sympathomimetic vasopressors other than norepinephrine (off-label):

• As soon as feasible after extravasation, administer 5 to 10 mg diluted in 10 to 20 mL of 0.9% sodium chloride to the extravasation site.
• The medication may be administered once more if the patient's symptoms persist.

Phentolamine (OraVerse) Dose in the diagnosis of pheochromocytoma (phentolamine-blocking test):

Note:

• Measuring catecholamine concentrations and catecholamine metabolites (such as metanephrine) in the plasma and urine has largely replaced the phentolamine blocking test for the diagnosis of pheochromocytoma.
• Phentolamine should only be used when extra verification is required to make a diagnosis.:
  • IM, IV: 5 mg.

Phentolamine (OraVerse) Dose in the prevention and management of perioperative hypertensive episodes associated with pheochromocytoma:

Note:

• • Alternate medicines are preferable in the perioperative period because to phentolamine's prolonged duration and gradual onset of effect compared to other agents (such as nitroprusside).

• Preoperative:

  • IM, IV: 5 mg given one to two hours before to surgery, repeat as necessary.

• Intraoperative:

  • IV: 5 mg, as needed to stop or treat paroxysms of hypertension, tachycardia, respiratory depression, seizure, or other epinephrine-related side effects brought on by the manipulation of tumours or other stressors (eg, intubation).
  • Others have utilised intermittent 10 mg boluses or an intraoperative continuous infusion of 1 to 6 mcg/kg/minute to manage blood pressure.

Phentolamine (OraVerse) dose for hypertensive crisis (off-label):

Note: Typically used when there is an excess of catecholamine (eg, pheochromocytoma)

• IV: from a 5 mg bolus.
• 15 mg is the maximum single dose.
• After the initial bolus dose, a continuous infusion up to a maximum infusion rate of 40 mg/hour may be given (for example, 1 mg/hour titrated to blood pressure response).

Phentolamine (OraVerse) dose for reversal of oral soft tissue (lip, tongue) anesthesia (OraVerse):

• Infiltration or block technique: Submucosal oral injection:
• Note: The dosage is determined by how many local anaesthetic cartridges are used. Block injection or infiltration:
  • 1 mg if only a quarter of an anaesthetic cartridge was used.
  • If a half-cartridge of anaesthetic was used, the dosage would be 2 mg.
  • If 1 anaesthetic cartridge was used, the dosage was 4 mg.
  • 8 mg if two anaesthetic cartridges were used

Phentolamine (OraVerse) dose in children:

Phentolamine (OraVerse) dose for the extravasation of sympathomimetic vasopressors:

• Manufacturer's labeling: Norepinephrine extravasation:

  • Children and Adolescents:
    • Local infiltration:
      • As soon as extravasation is noticed but no later than 12 hours later, infiltrate the area of extravasation with a tiny amount of a 0.5 to 1 mg/ml solution.

• Alternate dosing: Extravasation of dopamine, epinephrine, norepinephrine, phenylephrine: Limited data available:

  • Infants, Children, and Adolescents:
    • SubQ: Within 12 hours of extravasation, infiltrate the area with a modest amount (e.g., 1 ml given in 0.2 mL aliquots) of a 0.5 to 1 mg/ml solution.
    • The overall dose needed is determined on the extravasation's size.
    • If necessary, a second dose may be administered. Other concentrations could be employed; as stated, a total dose of
    • 1 to 5 ml of a 1 mg/mL solution was required.

Phentolamine (OraVerse) Dose in the diagnosis of pheochromocytoma (phentolamine blocking test):

Note:

• The catecholamine concentrations and catecholamine metabolites (such as metanephrine) in the plasma and urine have virtually replaced the phentolamine-blocking test for the diagnosis of pheochromocytoma.
• Phentolamine should only be used in situations where a diagnosis requires extra verification:

• Manufacturer's labeling:

  • Children and Adolescents:

    • IM: 3 mg.
    • IV: 1 mg.

• Alternate dosing: Limited data available:

  • Children and Adolescents:
    • IV: 0.05 to 0.1 mg/kg/dose.
    • maximum single dose: 5 mg.

Phentolamine (OraVerse) Dose in the prevention and treatment of hypertensive episodes associated with pheochromocytoma:

Note:

• Alternate medicines are preferable in the perioperative period because to phentolamine's prolonged duration and gradual onset of effect compared to other agents (such as nitroprusside).

• Preoperative:

  • Children and Adolescents:
    • IM, IV: 1 mg given one to two hours prior to surgery, with a possible repeat.

• Intraoperative:

  • Manufacturer's labeling:

    • Children and Adolescents:
      • IV:1 mg as needed to prevent or treat paroxysms of hypertension, tachycardia, respiratory depression, seizure, or other adrenaline intoxication-related side effects brought on by manipulating the tumour.

  • Alternate dosing: Limited data available:

    • Infants, Children, and Adolescents:
      • IV: 0.05 to 0.1 mg/kg/dose.
    • Note: Usual adult dose is 5 mg/dose.

Phentolamine (OraVerse) dose for the reversal of oral soft tissue (lip, tongue) anesthesia (OraVerse):

Note:

• The site and administration method (infiltration or block injection) should be the same as those used for administering local anaesthetics; the dose is based on the quantity of the cartridge(s) of local anaesthetic administered.

• Children ≥3 years weighing ≥15 kg and Adolescents:

  • Submucosal oral injection: Infiltration or block technique:

Amount of Local Anesthetic Administered	Dose of OraVerse
¼ Cartridge	¼ Cartridge (0.1 mg)
½ Cartridge	½ Cartridge (0.2 mg)
1 Cartridge	1 Cartridge (0.4 mg)
2 Cartridges	2 Cartridges (0.8 mg)

• Maximum dose:

  • 15 to <30 kg:
    • 0.2 mg/dose
  • ≥30 kg:
    • 0.8 mg/dose;
• Note:
  • A dose of >0.4 mg has not been studied in children <4 years

Phentolamine (OraVerse) Pregnancy Risk Factor C

• Some oral animal reproduction studies have revealed adverse outcomes.
• It is critical for favorable maternal and fetal outcomes to diagnose and treat pheochromocytoma.

Phentolamine use during breastfeeding:

• Phentolamine secretion in breast milk is not known.
• Due to the potential for serious adverse reactions in the breastfed infant, the decision to discontinue phentolamine or discontinue breastfeeding during treatment depends on the benefits of treatment to the mother.
• The manufacturer recommends that the developmental and health advantages of breastfeeding be balanced against the mother's clinical requirement for phentolamine and any potential negative effects on the breastfed child from phentolamine or from the underlying maternal illness.

Phentolamine (OraVerse) Dose adjustment in kidney disease:

There are no dosage adjustments provided in the manufacturer’s labeling.

Phentolamine (OraVerse) Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer’s labeling.

Side effects of Phentolamine (OraVerse):

• Cardiovascular:

  • Bradycardia
  • Hypertension
  • Cerebrovascular Occlusion
  • Hypotension
  • Myocardial Infarction

• Central Nervous System:

  • Mouth Pain
  • Headache
  • Paresthesia
  • Cerebrovascular Spasm

• Dermatologic:

  • Facial Swelling
  • Pruritus

• Gastrointestinal:

  • Diarrhea
  • Upper Abdominal Pain
  • Vomiting
  • Nausea

• Local:

  • Pain At Injection Site

• Neuromuscular & Skeletal:

  • Jaw Pain

• Miscellaneous:

  • Post-Injection Pain

Contraindications to Phentolamine (OraVerse):

• Hypersensitivity to phentolamine or any other component of the formulation.
• Myocardial Infarction (or History of MI)
• Angina
• Coronary insufficiency 

Canadian labeling: Additional contraindications not in the US labeling

• Hypotension

Warnings and precautions

• Cardiovascular effects

  • The effects of phentolamine on the cerebrovascular system can be severe.
  • It can also cause tachycardia or cardiac arrhythmias.
  • Patients with a history or cardiovascular disease should not use it.
  • Therapy should be stopped if angina symptoms worsen or occur.

Phentolamine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Alpha-/Beta-Agonists	The vasoconstricting effects of Alpha-/BetaAgonists may be lessened by Alpha1-Blockers. The vasodilation caused by Alpha1-Blocker may also be resisted by Alpha-/Beta-Agonists.
Alpha1-Agonists	The vasoconstrictive effects of Alpha1-Agonists may be lessened by Alpha1-Blockers. The vasodilation caused by Alpha1-Blockers may also be resisted by Alpha1-Agonists.
Amphetamines	May lessen the effectiveness of antihypertensive agents.
Antipsychotic Agents (Second Generation [Atypical])	Antipsychotic drugs' hypotensive effects may be enhanced by blood pressure-lowering medications (Second Generation [Atypical]).
Barbiturates	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Benperidol	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Beta-Blockers	Alpha1-Blockers may improve their orthostatic hypotensive effects. Ophthalmic products likely carry a lower level of risk than systemic ones. Levobunolol and metipranolol are exceptions.
Brigatinib	May lessen the effectiveness of antihypertensive agents. Antihypertensive Agents' bradycardic action may be strengthened by brutinib.
Brimonidine (Topical)	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Calcium Channel Blockers	The hypotensive action of calcium channel blockers may be strengthened by alpha1-blockers.
Dapoxetine	Alpha1-Blockers may improve their orthostatic hypotensive effects.
Dexmethylphenidate	Can lessen an antihypertensive drug's therapeutic impact.
Diazoxide	The hypotensive effects of blood pressure-lowering medications may be strengthened.
DULoxetine	The hypotensive impact of DULoxetine may be enhanced by blood pressure lowering medications.
Herbs (Hypertensive Properties)	May lessen the effectiveness of antihypertensive agents.
Herbs (Hypotensive Properties)	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Hypotension-Associated Agents	The hypotensive action of hypotension-associated agents may be strengthened by blood pressure lowering medications.
Levodopa-Containing Products	Levodopa-Containing Products' hypotensive effects may be strengthened by blood pressure-lowering medications.
Lormetazepam	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Methylphenidate	May lessen the effectiveness of antihypertensive agents.
Molsidomine	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Nicorandil	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Nitroprusside	Nitroprusside's hypotensive impact may be strengthened by blood pressure-lowering medications.
Pentoxifylline	The hypotensive effects of blood pressure-lowering medications may be strengthened.
Pholcodine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine.
Prostacyclin Analogues	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Quinagolide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Rilmenidine	Alpha1-Blockers may enhance the hypotensive effect of Rilmenidine.
Yohimbine	May diminish the antihypertensive effect of Antihypertensive Agents.
Risk Factor D (Consider therapy modification)
Amifostine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered.
Obinutuzumab	May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion.
Phosphodiesterase 5 Inhibitors	Could make alpha1-blockers' hypotensive effects stronger (Nonselective). Management: Always start a combination with the lowest dose of the medicine being added until the patient is stable on one agent before starting the other. Alpha 1-blockers shouldn't be used concurrently with tadalafil while treating BPH.
Risk Factor X (Avoid combination)
Alpha1-Blockers	May enhance the antihypertensive effect of other Alpha1-Blockers.
Bromperidol	Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents.

 

Monitoring parameters:

• Heart rate
• Blood pressure
• Monitoring and documentation of extravasation site
• Monitoring of patient for orthostasis
• Patient assistance with ambulation

How to administer Phentolamine (OraVerse)?

Extravasation management (treatment), sympathomimetic gasopressors

• The vesicant injection needs to stop right away. Additionally, the IV line needs to be cut.
• The extravasated solution should be carefully removed from the IV line; flushing is not necessary.
• The extremities must be elevated and the needle or cannula must be taken out.
• As soon as possible, but no later than 12 hours after extravasation, provide tiny doses of phentolamine dissolved in 10–20 ml of saline to the extravasation site.
• Apply warm, dry compression.

Pheochromocytoma diagnosis:

• The patient should be kept recumbent in a quiet, dark environment.
• For a maximum of 30 minutes, check your blood pressure every 10 minutes.
• Phentolamine shouldn't be given until the blood pressure is stable (at an untreated hypertensive level).
  • Positive Response:
    • A systolic blood pressure decline of more than 35 mm Hg or more than 25 mm Hg (diastolic).
    • A positive reaction should be confirmed by other diagnostic tests.
  • Negative Response:
    • If blood pressure is high, it shouldn't rise or fall by more than 25mm Hg (diastolic) or 35mm Hg (systolic) respectively.
    • A pheochromocytoma's negative reaction is insufficient, especially when there is a significant prevalence of false positives, like paroxysmal hypotension.

IM:

• After the IM injection, keep an eye on blood pressure for 35 to 40 minutes.
• It is encouraging if blood pressure reaches these values within 20 minutes.

IV:

• As soon as the vascular reaction has faded, swiftly inject the fluid.
• Blood pressure should be checked right away following injections.
• every minute for seven minutes, followed by every 30 seconds for three minutes.
• Usually, the response time is under two minutes at most.
• The entire effect, though, might not show for up to 30 minutes.

Pheochromocytoma-associated hypertensive episode:

• You should give the injection IM or IV at least 2 hours prior to surgery. If necessary, you can repeat it during surgery (IV).

OraVerse: Reversal of anesthesia for oral soft tissue (lip, or tongue)

• Utilize the same dental procedure and site for the submucosal injection of local anaesthesia.

Hypertensive crisis (off label use)

• It should be administered as an IV bolus and then, if necessary, as a continuous IV injection.

Mechanism of action of Phentolamine (OraVerse):

• Phentolamine causes a nonselective competitive blockage of alpha2-adrenergic receptors, thereby causing a brief antagonism in circulating epinephrine or norepinephrine.
• Due to the catecholamines' alpha effects, this lowers blood pressure.
• Dopamine and phenylephrine are examples of sympathomimetic vasoconstrictors that can extravasate and cause tissue damage.
• Presynaptic alpha-2 receptor blocking is what causes phentolamine to have positive inotropic, chronotropic effects on heart.
• This results in presynaptic norepinephrine being released. OraVerse - Phentolamine causes vasodilation, which increases blood flow to the injection site.
• This accelerates the recovery of soft tissue anesthesia.

The onset of action:

• IM: 15 to 20 minutes; IV: 1 to 2 minutes

Peak effect: OraVerse:

• 10 to 20 minutes

Duration:

• IM: 30 to 45 minutes;
• IV: 10 to 30 minutes

Metabolism:

• Hepatic

Half-life elimination:

• IV: 19 minutes;
• Submucosal injection: ~2 to 3 hours

Excretion:

• Urine (~13% as unchanged drug)

International Brand Names of Phentolamine:

• OraVerse
• Rogitine
• Fentanor
• Phentolmin
• Phentosol
• Regitin
• Regitina
• Regitine
• Rogitamine
• Rogitine

Phentolamine Brand Names in Pakistan:

No Brands Available in Pakistan.