Bretylium Norepinephrine

All antiarrhythmic dra are used cautiously in patients with renal or hepatic disease. When renal or hepatic dysfunction is present, a dosage reduction may be necessary. All patients should be observed for renal and hepatic dysfunction. Quinidine and procainamide are used cautiously in patients with CHF. Disopyramide is used cautiously in patients with CHF, myasthenia gravis, or glaucoma, and in men with prostate enlargement. Bretylium is used cautiously in patients with digitalis toxicity because the initial release of norepinephrine with digitalis toxicity may exacerbate arrhythmias and symptoms of toxicity. Verapamil is used cautiously in patients with a history of serious ventricular arrhythmias or CHF. Electrolyte disturbances such as hypokalemia, hyperkalemia, or hypomagnesemia may alter the effects of the antiarrhythmic dru . Electrolytes are monitored frequently and imbalances corrected as soon as possible... 

Pharmacology Bretylium tosylate inhibits norepinephrine release by depressing adrenergic nerve terminal excitability, inducing a chemical sympathectomy-like state. Bretylium blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade causes orthostatic hypotension but has less effect on supine blood pressure. It has a positive inotropic effect on the myocardium. Pharmacokinetics Peak plasma concentration and peak hypotensive effects are seen within 1 hour of IM administration. However, suppression of premature ventricular beats is not maximal until 6 to 9 hours after dosing, when mean plasma concentration declines to less than 50% of peak level. Antifibrillatory effects occur within minutes of an IV injection. Suppression of ventricular tachycardia and other ventricular arrhythmias develops more slowly, usually 20 minutes to 2 hours after parenteral administration. 

Hypotension Hypotension (postural) occurs regularly in about 50% of patients while they are supine, manifested by dizziness, light-headedness, vertigo, or faintness. Tolerance occurs unpredictably but may be present after several days. Hypotension with supine systolic pressure above 75 mm Hg need not be treated unless symptomatic. If supine systolic pressure falls below 75 mm Hg, infuse dopamine or norepinephrine to increase blood pressure use dilute solution and monitor blood pressure closely because pressor effects are enhanced by bretylium. Perform volume expansion with blood or plasma and correct dehydration where appropriate. Transient hypertension and increased frequency of arrhythmias Transient hypertension and increased frequency of arrhythmias may occur due to initial release of norepinephrine from adrenergic postganglionic nerve terminals. 

A unique property of bretylium as an antiarrhythmic agent is its positive inotropic action. This effect, related to its actions on the sympathetic nervous system, includes an initial release of neuronal stores of norepinephrine followed shortly by a prolonged period of inhibition of direct or reflex-associated neuronal norepinephrine release. The onset of bretylium-induced hypotension is delayed 1 to 2 hours because the initial catecholamine release maintains arterial pressure before this time. 

The following interventions are contraindicated Quinidine should not be used because it displaces digoxin from binding sites, and bretylium should not be used because it releases norepinephrine. Carotid sinus stimulation should be discouraged because it may precipitate ventricular fibrillation. 

Release can be blocked by drugs such as guanethidine and bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal (uptake 1 [1], blocked by cocaine, tricyclic antidepressants) or into the postjunctional cell (uptake 2 [2]). Regulatory receptors are present on the presynaptic terminal. (SNAPs, synaptosome-associated proteins VAMPs, vesicle-associated membrane proteins.)... 

Interest in the antiarrhythmic activity of quaternary ammonium compounds continues. Unlike bretylium (11a). its o-iodobenzyl trimethyl-ammonium analog (UM-360, lib) did not inhibit release of norepinephrine from sympathetic nerve endings and did not cause adrenergic stimulation on its own.UM-36O effectively antagonized ventricular arrhythmias produced by ouabain in dogs, an action bretylium did not possess. Both agents elevated the threshold to electrically induced ventricular fibrillation. The same group of workers also studied the profile of a quaternary propan-2-ol derivative (UM- 2h, 12). ° In contrast to tertiary compounds of... 

Bretylium releases norepinephrine from the sympathetic ganglia and postganglionic adrenergic nerve terminals, and blocks norepinephrine reuptake. 

I. Pharmacology. Bretylium is a quaternary ammonium compound that is an effective type III antifibrillatory dmg and also suppresses ventricular ectopic activity. It increases the threshold for ventricular fibrillation and reduces the disparity in action potential duration between nonnal and ischemic tissue, which is believed to abolish boundary currents responsible for reentrant arrhythmias. Its pharmacologic actions are complex. Initially, norepinephrine is released from sympathetic neurons this is followed by a block of further norepinephrine release. In addition, norepinephrine uptake is inhibited at adrenergic neurons. The result is a transient increase in heart rate, blood pressure, and cardiac output that may last from a few minutes to 1 hour. Subsequent adrenergic blockade produces vasodilation, which may result in hypotension. 

The pressor effects of adrenaline (epinephrine) and noradrenaline (norepinephrine) are increased in the presence of bretylium. Amfetamine and protriptyline antagonise the blood pressure lowering effect of bretylium. 

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