Products & Portfolio (2)
BUPIVACAINE HYDROCHLORIDE
bupivacaine hydrochloride
Post-LOE
SPINAL · INJECTABLE
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. 12.2 Pharmacodynamics Systemic absorption of bupivacaine produces effects on the cardiovascular system and CNS. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. These cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine [ see ]. Following systemic absorption, bupivacaine can produce CNS stimulation, CNS depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering, progressing to convulsions, followed by CNS depression and coma progressing ultimately to respiratory arrest. However, bupivacaine has a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. The duration of local anesthesia after administration of Bupivacaine Hydrochloride in Dextrose Injection, USP is longer than that observed after administration of other commonly used short-acting local anesthetic. There appears to be a period of analgesia that persists after the resolution of the block and the return of sensation. The onset of sensory blockade following spinal block with Bupivacaine Hydrochloride in Dextrose Injection, USP is rapid (generally within one minute); maximum motor blockade and maximum dermatome level are achieved within 15 minutes in most cases. Duration of sensory blockade (time to return of complete sensation in the operative site or regression of two dermatomes) following Bupivacaine Hydrochloride in Dextrose Injection, USP 12 mg averages 2 hours with or without 0.2 mg epinephrine. The time to return of complete motor ability with Bupivacaine Hydrochloride in Dextrose Injection, USP 12 mg averages 3.5 hours without the addition of epinephrine and 4.5 hours if 0.2 mg epinephrine is added. When compared to equal milligram doses of hyperbaric tetracaine, the duration of sensory blockade was the same, but the time to complete motor recovery was l
2019
30
LIDOCAINE HYDROCHLORIDE
lidocaine hydrochloride
Post-LOE
INJECTION · INJECTABLE
CLINICAL PHARMACOLOGY Mechanism of Action: Lidocaine HCl stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. Hemodynamics: Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. Pharmacokinetics and Metabolism: Information derived from diverse formulations, concentrations and usages reveals that lidocaine HCl 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. The plasma binding of lidocaine HCl 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 HCl is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine HCl crosses the blood-brain and placental barriers, presumably by passive diffusion. Lidocaine HCl is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. 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 HCl. Approximately 90% of lidocaine HCl administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. The elimination half-life of lidocaine HCl following an intravenous bolus injection is typically 1.5 to 2 hours. Because of the rapid rate at which lidocaine HCl is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine HCl kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine HCl required to produce overt systemic effects. Objective adverse manifestatio
2020
30
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Portfolio: 2 approved products, 28 clinical trials
Top TAs: Ophthalmology, Metabolic Diseases, Cardiovascular
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