Epinephrine, Lidocaine Liquid injectables

Lidocaine hydrochloride stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action.

Systemic plasma levels of lidocaine following Lidocaine Hydrochloride Injection do not correlate with local efficacy.

Absorption — Information derived from diverse formulations, concentrations and usages reveals that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending, for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration.

Distribution — The plasma binding of lidocaine hydrochloride is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL 60 to 80 percent of lidocaine hydrochloride is protein bound. Binding is also dependent on the plasma concentration of the alpha-1‑acid glycoprotein.

Lidocaine hydrochloride crosses the blood-brain and placental barriers, presumably by passive diffusion.

Elimination — The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2 hours.

Metabolism — Lidocaine hydrochloride is metabolized rapidly by the liver, and biotransformation includes oxidative N‑dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine hydrochloride.

Excretion — Approximately 90% of lidocaine hydrochloride administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged by the kidneys. The primary metabolite in urine is a conjugate of 4‑hydroxy-2,6-dimethylaniline.

Patients with Hepatic Impairment — Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine hydrochloride kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction.

Patients with Renal Impairment — Renal dysfunction does not affect lidocaine hydrochloride kinetics but may increase the accumulation of metabolites.

Epinephrine acts on both alpha (α)- and beta (β)-adrenergic receptors. The mechanism of the rise in blood pressure is 3-fold: a direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action), an increased heart rate (positive chronotropic action), and peripheral vasoconstriction.

When administered parenterally or intraocularly, epinephrine has a rapid onset and short duration of action.

Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective half-life of < 5 min. A pharmacokinetic steady state following continuous intravenous infusion is achieved within 10-15 min. In patients with septic shock, epinephrine displays dose-proportional pharmacokinetics in the infusion dose range of 0.03 to 1.7 mcg/kg/min.

The extent of human systemic exposure at the labeled intraocular dose has not been evaluated, however, significant systemic concentrations or plasma exposure of epinephrine are not expected when administered intraocularly.

Epinephrine is extensively metabolized with only a small amount excreted unchanged.

Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys and other extraneuronal tissues. The tissues with the highest contribution to removal of circulating exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and mesenteric organs (12%).