Cocaine
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Mechanism of action
Cocaine hydrochloride is a local anesthetic of the ester type. Cocaine hydrochloride prevents conduction in nerve fibers by reversibly blocking voltage-gated sodium channels and preventing the transient rise in sodium conductance necessary for generation of an action potential.
Pharmacodynamics
Cardiac Electrophysiology
The effect of cocaine hydrochloride topical solution on the QTc interval was evaluated in a randomized, positive- and placebo-controlled four-period crossover thorough QTc study in 32 healthy subjects. NUMBRINO is associated with concentration-dependent QTc prolongation. Based on the concentration-QTc relationship, the mean placebo corrected change from the baseline QTcF (90% two-sided upper confidence interval) are 4.7 ms (6.2 ms) and 15.4 ms (20.1 ms) at peak concentrations of 143 ng/mL (corresponds to 4% single dose, 160 mg) and 434 ng/mL (corresponds to 10% single dose, 400 mg), respectively. The estimates of the QTcF interval are confounded by increased heart rates. The QTc prolongation observed with NUMBRINO (4% single dose) was found to be below the regulatory threshold for concern.
NUMBRINO is associated with increases in heart rate. The mean placebo corrected change from baseline heart rate (90% two-sided upper confidence interval) are 12 (14) bpm and 20 (22) bpm for the 4% and 10%, respectively.
Effects on Cardiovascular System
Cocaine can potentiate central and peripheral sympathetic effects on the cardiovascular system, resulting in increased inotropic and chronotropic effects, increased cardiac activity, and tachycardia. Intense peripheral vasoconstriction may result in elevated systolic and diastolic blood pressure.
Effects on Vascular System
The relationship between local anesthetic effectiveness and toxicity of cocaine is a function of the patient’s state of health, medical condition, nasal mucosa integrity and extent of systemic absorption of cocaine (from the pledgets). When applied to mucous membranes by pledget administration, topical anesthesia develops rapidly and persists for 30 minutes or longer depending on the concentration of cocaine hydrochloride solution used, the dose, and on the vascularity of the tissue.
Pharmacokinetics
Absorption
NUMBRINO is an aqueous solution of cocaine hydrochloride for topical use only.
Absorption
Application of NUMBRINO for 20 minutes by pledget administration to the nasal mucosa in healthy adults may reduce the systemic absorption of the applied dose of cocaine hydrochloride compared to the systemic absorption after non-pledget administration. The estimated mean systemic absorption of cocaine from a single 160 mg dose (4 mL, 4%) was 23.44% of the topically applied dose. (Table 2).
Table 2. Systemic Absorption of NUMBRINO in Healthy Adult Subjects Minimized by Pledget Administration (single nasal dose of 160 mg Cocaine Hydrochloride Topical Solution over 20 minutes)
NUMBRINO
Dose (4 mL)
Age Range (yr)
Application Time
(min)
Estimated1 Systemic Absorption
Mean Cmax
(ng/mL)
Median
Tmax (min)
Cmax (ng/mL)
160 mg (4%)
20-40
20
23.44%
142.68n=33
30
142.7
1Estimated absorbed dose was calculated by subtracting the residual amount of drug in the pledgets from the administered dose; Tmax includes time 0 (the start of pledget insertion to pledget removal (20 minutes) to the time Cmax was observed, i.e. 10 minutes after removal of the pledgets.
Distribution
Cocaine has been described in literature as approximately 84-92% bound to human plasma proteins. Cocaine is extensively distributed to tissues and crosses the blood brain barrier. Its volume of distribution is approximately 2 L/kg. Cocaine crosses the placenta by simple diffusion and accumulates in the fetus after repeated use.
Elimination
Metabolism
Cocaine is metabolized by two major hydrolytic pathways. Cocaine is metabolized by hydrolysis to benzoylecgonine (major, but inactive metabolite) by hepatic carboxylesterase-1. Cocaine is also metabolized by hydrolysis to ecgonine methyl ester (major, but inactive metabolite) by plasma butyrylcholinesterase and hepatic carboxylesterase-2.
Cocaine is minimally metabolized by hydrolysis to ecgonine (minor, inactive metabolite) by carboxylesterase-2.
Cocaine is N-demethylated by the CYP3A4 enzyme system to produce the active metabolite, norcocaine. Total systemic exposure of norcocaine is less than one percent that observed with cocaine.
Excretion
Cocaine is excreted almost exclusively in the urine, as metabolites. Only a minor fraction of cocaine is eliminated unchanged in the urine (<5%).
The apparent elimination half-life of cocaine following administration of NUMBRINO (by pledgets) was 1.54 hours) for the 4% concentration.
Specific Populations
Geriatric Patients
The pharmacokinetics of NUMBRINO in patients over the age of 65 has not of been studied.
Patients with Hepatic Impairment
The pharmacokinetics of NUMBRINO in patients with hepatic impairment has not been studied.
Patients with Renal Impairment
The pharmacokinetics of NUMBRINO in patients with renal impairment has not been studied.
Drug-drug Interactions:
Disulfiram
It has been reported in the published literature that disulfiram treatment increased plasma cocaine exposure, including both AUC and Cmax, by several folds after acute intranasal cocaine administration. Another published literature reported that co-administration of disulfiram increased AUC of plasma cocaine by several folds after intravenous cocaine administration [see Drug Interactions (7.1)].
External links
Source: DailyMed — Cocaine ↗
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.