Bretylium

• Bretylium is antiarrhythmic agent belonging to the adrenergic neuron blocker class.

• Bretylium is approved for the treatment and prophylaxis of therapy of ventricular fibrillation. It is also used in the treatment of life-threatening ventricular arrhythmias such as Ventricular Fibrillation or Hemodynamically Unstable Ventricular Tachycardia.

• Bretylium get poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Bretylium is negligibly bound to plasma proteins (1–6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance.
• The common side effects associated with Bretylium include nausea, vomiting, diarrhea, loss of appetite, headache, dizziness, drowsiness; breast tenderness or swelling; itching or rash; stuffy nose, nosebleeds; weight gain; impotence, etc.

• Bretylium is available in the form of dosage forms as injections.
• Bretylium is available in India, China, the USA, Europe.

Bretylium is available in the form of injections.

• For intramuscular injection:

Inject 5 to 10 mg bretylium per kg of body weight. Subsequent doses may be given at 1-2 hour intervals if the arrhythmia persists. Thereafter maintaining the same dosage every 6 to 8 hours.

• For Intravenous use:

Injection, must be diluted as described above before intravenous use. Administer the diluted solution at a dosage of 5 to 10 mg bretylium per kg of body weight by IV infusion over a period greater than 8 minutes. More rapid infusion may cause nausea and vomiting, and an inpatient older than 65 years, may increase risk of developing orthostatic hypotension. Subsequent doses may be given at 1 - 2 hour intervals if the arrhythmia persists.

Bretylium is an antiarrhythmic agent belonging to the adrenergic neuron blocker class.

Bretylium is approved for the treatment or prophylaxis and therapy of ventricular fibrillation. It is also used in the treatment of life-threatening ventricular arrhythmias Such As Ventricular Fibrillation Or Hemodynamically Unstable Ventricular Tachycardia

Bretylium inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium's major effect on cardiac tissues is to prolong the action potential and refractory period of atrial and ventricular myocardium and Purkinje fibers. In doing so, it increases the fibrillation threshold. Bretylium produces a biphasic effect on impulse initiation and conduction and on hemodynamics.

Bretylium is approved for use in the following clinical indications.

• Bretylium Injection, is indicated in the prophylaxis and therapy of ventricular fibrillation.
• Bretylium Injection, is also indicated in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine.
• Use of Bretylium Injection, should be limited to intensive care units, coronary care units or other facilities where equipment and personnel for constant monitoring of cardiac arrhythmias and blood pressure are available.
• Following injection of bretylium, there may be a delay of 20 minutes to 2 hours in the onset of antiarrhythmic action, although it appears to act within minutes in ventricular fibrillation. The delay in effect, appears to be longer after intramuscular than after intravenous injection.

Bretylium is available in the form of injection.

Ventricular Arrhythmia

Indicated for prophylaxis and treatment of ventricular fibrillation (VF); also indicated for the treatment of life-threatening ventricular arrhythmias (eg, ventricular tachycardia [VT] unresponsive to first-line antiarrhythmic agents [e.g., lidocaine]

• Initial dose: 5 mg/kg undiluted IV once.
• If Ventricular fibrillation persists: 10 mg/kg undiluted IV and repeat as necessary.
• Maintenance: 1 to 2 mg/min by continuous IV infusion or
  • 5 to 10 mg/kg diluted IV over 8 minutes every 6 hours.

Immediately life-threatening ventricular arrhythmias (eg, VF, unstable VT)

• Other usual cardiopulmonary resuscitative procedures, including electrical cardioversion, should be used prior to and following the injection in accordance with good medical practice
• Undiluted solution: 5 mg/kg IV by rapid injection; if arrhythmia persists, may increase dose to 10 mg/kg and repeat as required.
• Diluted solution for continuous suppression: 1-2 mg/min IV; alternatively, 5-10 mg/kg IV over at least 8 min every 6 hours.
• Use diluted solution
• 5-10 mg/kg IV over at least 8 min; may repeat dose at 1- to 2-hr intervals if arrhythmia persists
• Maintenance: 5-10 mg/kg IV over at least 8 min every 6 hour; alternatively, 1-2 mg/min IV continuous infusion
• Use undiluted solution
• 5-10 mg/kg IM; may repeat dose at 1- to 2-hr intervals if arrhythmia persists
• Maintenance: 5-10 mg/kg IM at every 6 hours and 8 hour.
• Switch of oral antiarrhythmic agent as soon as possible for continued maintenance therapy

Other ventricular arrhythmias

• IV: 

• Use diluted solution
• 5-10 mg/kg IV over at least 8 min; may repeat dose at 1- to 2-hr intervals if arrhythmia persists
• Maintenance: 5-10 mg/kg IV over at least 8 min every 6 hour; alternatively, 1-2 mg/min IV continuous infusion

• IM:

• Use undiluted solution
• 5-10 mg/kg IM; may repeat dose at 1- to 2-hr intervals if arrhythmia persists
• Maintenance: 5-10 mg/kg IM at every 6 hours and 8 hour.
• Switch of oral antiarrhythmic agent as soon as possible for continued maintenance therapy

Bretylium is available in various dosage strengths 50 mg/mL; 200 mg/100 mL-5%; 400 mg/100 mL-5%

Bretylium is approved for the treatment of prophylaxis and therapy of ventricular fibrillation. It is also used in the treatment of life-threatening ventricular arrhythmias Such as Ventricular Fibrillation Or Hemodynamically Unstable Ventricular Tachycardia

Ventricular fibrillation.

Some foods can negatively affect your heart health and have been shown to increase the risk of heart complications. Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk They can also lead to other negative health outcomes like weight gain, diabetes, cognitive decline, and certain cancers.The dietary restriction should be individualized as per the patients requirement

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Hypotension

Administration of bretylium regularly results in postural hypotension, subjectively recognized by dizziness, lightheadedness, vertigo or faintness. Some degree of hypotension is present in about 50% of patients while they are supine. Hypotension may occur at doses lower than those needed to suppress arrhythmias.

Patients should be kept in the supine position until tolerance to the hypotensive effect of bretylium tosylate develops. Tolerance occurs unpredictably but may be present after several days.

Patients over 65 years may be at increased risk of developing orthostatic hypotension, especially when the recommended rate of intravenous infusion is exceeded.

Hypotension with supine systolic pressure greater than 75 mm Hg need not be treated unless there are associated symptoms. If supine systolic pressure falls below 75 mm Hg, an infusion of dopamine or norepinephrine may be used to raise blood pressure. When catecholamines are administered, a dilute solution should be employed, and blood pressure monitored closely because the pressor effects of the catecholamines are enhanced by bretylium tosylate. Volume expansion with blood or plasma and correction of dehydration should be carried out where appropriate.

• Transient Hypertension And Increased Frequency Of Arrhythmias

Due to the initial release of norepinephrine from adrenergic postganglionic nerve terminals by bretylium, transient hypertension or increased frequency of premature ventricular contractions and other arrhythmias may occur in some patients, especially after too vigorous dosing.

• Caution During Use With Digitalis Glycosides

The initial release of norepinephrine caused by bretylium tosylate may aggravate digitalis toxicity. When a life-threatening cardiac arrhythmia occurs in a digitalized patient, bretylium tosylate should be used only if the etiology of the arrhythmia does not appear to be digitalis toxicity and other antiarrhythmic drugs are not effective. Simultaneous initiation of therapy with digitalis glycosides and bretylium tosylate should be avoided.

• Patients With Fixed Cardiac Output

In patients with fixed cardiac output (i.e., severe aortic stenosis or severe pulmonary hypertension), bretylium tosylate should be avoided since severe hypotension may result from a fall in peripheral resistance without a compensatory increase in cardiac output. If survival is threatened by the arrhythmia, bretylium tosylate may be used but vasoconstrictive catecholamines should be given promptly if severe hypotension occurs.

• Hyperthermia

In a small number of patients, hyperthermia, characterized by temperature excess of 106°F, has been reported in association with bretylium tosylate administration.

Temperature rise can begin within one hour or later after administration of drug, and reach a peak within 1-3 days. If hyperthermia is suspected or diagnosed, bretylium tosylate should be discontinued and appropriate treatment instituted immediately.

PRECAUTIONS:

General:

• Dilution For Intravenous Use:

Bretylium Injection should be diluted (one part bretylium with four parts of Dextrose Injection or Sodium Chloride Injection,) prior to intravenous use. Rapid intravenous administration may cause severe nausea and vomiting and even provoke a hypertensive crisis. Therefore, the diluted solution should be infused over a period greater than 8 minutes. In treating existing ventricular fibrillation, bretylium should be given as rapidly as possible and may be given without dilution.

• Use Various Sites For Intramuscular Injection

When injected intramuscularly, not more than 5 mL should be given in a site, and injection sites should be varied, since repeated intramuscular injection into the same site may cause atrophy and necrosis of muscle tissue, fibrosis, vascular degeneration and inflammatory changes.

• Reduce Dosage In Impaired Renal Function

Since bretylium is excreted principally via the kidney, the dosage intervals should be increased in patients with impaired renal function.

Ginseng: Intake of ginseng while taking bretylium will reduce the effectiveness of bretylium. Ginseng is found to increase the blood pressure and therefore should be avoided with antihypertensive medications.

The adverse reactions related to Bretylium can be categorized as follows:

• Common Adverse effects:

Vertigo, Bradycardia, headache, Dizziness, syncope, Increase in Premature Ventricular Contraction, Angina Pectoris

• Less Common adverse effect:

Nervousness, Elevated liver enzymes, joint pain, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesias, bradycardia, cold extremities, hypotension, palpitations, syncope, Anxiety, lethargy, diarrhea, vomiting, Pruritus, drug-induced Parkinson’s disease

• Rare adverse effects:

Heart failure, optic atrophy, bronchospasm, depression, decreased exercise tolerance, Gynecomastia, etc.

The clinically relevant drug interactions of Bretylium is briefly summarized here

• Monoamine Oxidase Inhibitors:

The effects of the release of catecholamines from nerve endings produced by bretylium will be potentiated by monoamine oxidase inhibitors.

The common side effects of Bretylium include the following

Nausea, vomiting, diarrhea, loss of appetite, headache, dizziness, drowsiness; breast tenderness or swelling; itching or rash, stuffy nose, nosebleeds, weight gain, impotence, etc.

The use of Bretylium should be prudent in the following group of special populations:

Carcinogenesis, Mutagenesis, Impairment Of fertility

Bretylium has not been evaluated for carcinogenic or mutagenic potential. There are no available data on potential for impairment of fertility.

• Pregnancy Category C

Animal reproduction studies have not been conducted with dextrose and bretylium. It is also not known whether dextrose and bretylium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bretylium should be given to a pregnant woman only if clearly needed.

• Pediatric Use

The safety and effectiveness of Bretylium Injection, have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

• Geriatric Use

Clinical studies of bretylium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or drug therapy.

Intravenous infusion, especially if administered at a rate beyond that recommended, may produce an increased risk of the orthostatic hypotension in the elderly.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

• In the presence of life-threatening arrhythmias, underdosing with bretylium probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium serum levels were 8000 ng/mL.
• The exaggerated hemodynamic response was attributed to the rapid injection of a very large dose while some effective circulation was still present. Neither the total dose nor the serum levels observed in this patient are in themselves associated with toxicity. Total doses of 30 mg/kg are not unusual and do not cause toxicity when given incrementally during cardiopulmonary resuscitation procedures. Similarly, patients maintained on chronic Bretylium Injection therapy have had documented serum levels of 12,000 ng/mL. These levels were achieved after sequential dosage increases over time with no apparent ill effects.
• If Bretylium Injection is overdosed and symptoms of toxicity develop, administration of nitroprusside or another short acting intravenous antihypertensive agent should be considered for the treatment of the hypertensive response. Long acting drugs that might potentiate the subsequent hypotensive effects of Bretylium Injection should not be used. Hypotension should be treated with appropriate fluid therapy and pressor agents such as dopamine or norepinephrine. Dialysis is probably not useful in the treatment of Bretylium Injection overdose.

Pharmacodynamics:

• Bretylium is a bromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium also suppresses ventricular fibrillation and ventricular arrhythmias.
• Bretylium induces a chemical sympathectomy-like state which resembles a surgical sympathectomy. Catecholamine stores are not depleted by bretylium but catecholamine effects on the myocardium and on peripheral vascular resistance are often seen shortly after administration because bretylium causes an early release of norepinephrine from the adrenergic postganglionic nerve terminals. Subsequently, bretylium blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade regularly causes orthostatic hypotension but has less effect on supine blood pressure.

Pharmacokinetics:

• Absorption:

Bretylium is poorly absorbed following oral administration, and its oral bioavailability is in region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg.

• Distribution:

Bretylium is negligibly bound to plasma proteins (1–6%). Although drug tissue concentrations have not been reported in the humans, high values for apparent volume of distribution suggest extensive tissue binding

• Excretion:

Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration. About 75% of the dose is recovered in the urine after intravenous dosing.

1. https://go.drugbank.com/drugs/DB01158
2. https://www.webmd.com/drugs/2/drug-13572/bretylium-tosylate-injection/details
3. https://pillintrip.com/medicine/bretylium
4. Rapeport WG. Clinical pharmacokinetics of bretylium. Clinical pharmacokinetics. 1985 Mar;10(3):248-56.Doi: https://doi.org/10.2165/00003088-198510030-00004
5. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/abstract/41
6. Koch-Weser J. Bretylium. New England Journal of Medicine. 1979 Mar 1;300(9):473-7. Doi: 10.1056/NEJM197903013000905