Cocaine

Cocaine Topical Solution(Sol 4 %)

Classification:
Anesthetics

• Local Anesthetics
  
  • Ester local anesthetics

Ophthalmic Agents

• Ophthalmic Anesthetics

Psychotropic Agents

• Psychostimulants

NOTE: Cocaine is a schedule C-II controlled substance.

Description: Cocaine is a naturally occurring alkaloid present in the leaves of Erythroxylon coca. Cocaine is commercially available in a variety of forms and is applied to mucous membranes of the oral, laryngeal, and nasal cavities for use as a topical anesthetic. It also has been applied to the eye and may be useful in determining the cause of miosis. Cocaine causes significant euphoria, and abuse can lead to physical dependence. Despite being an excellent local anesthetic, the risk of abuse and the intense local vasoconstriction it produces prevent cocaine from being more widely used clinically. It is a controlled substance (schedule II) and is banned and tested for in athletes by the International Olympic Committee.

Mechanism of Action: Following topical application, cocaine, like other local anesthetics, decreases nerve permeability to sodium. This stabilizes the nerve membrane, increasing the threshold of electrical excitability and inhibiting depolarization, and results in the failure to propagate an action potential and initiate or conduct nerve impulses. Direct nerve membrane penetration is necessary for effective anesthesia, which is achieved by applying cocaine directly to the area to be anesthetized. The drug not only lessens sensitivity to pain and touch but, when applied to the nose or mouth, diminishes the acuity of taste and smell.

Unlike other local anesthetics, cocaine also affects the nervous system by potentiating catecholamines. Centrally, the actions of cocaine are presumed to include stimulation of presynaptic release of norepinephrine combined with inhibition of presynaptic reuptake of norepinephrine, dopamine, and serotonin. Peripherally, cocaine stimulates the presynaptic release of norepinephrine and inhibits neuronal reuptake of both norepinephrine and epinephrine. Because cocaine inhibits the reuptake of catecholamines, it is considered an indirect agonist. Indirect agonists are associated with tachyphylaxis due to the ever-decreasing supply of endogenous neurotransmitter than can be displaced from the nerve ending.

Centrally, cocaine causes an acute dopamine release and inhibits dopamine reuptake in the synapse. This causes some of cocaine’s most striking effects of general CNS stimulation, manifested (in descending order) as euphoria, stimulation, reduced fatigue, loquacity, sexual stimulation, increased mental ability, alertness, and increased sociality. With increased doses, tremors and tonic-clonic convulsions may occur, and vomiting centers may be stimulated. Ventral stimulation is soon followed by depression, with the medullary centers becoming depressed; death results from respiratory failure. With regular use, dopamine concentrations in the brain decrease, eventually leading to dopamine-receptor supersensitivity. This change in receptor sensitivity at postsynaptic receptor sites is believed to be the basis for the sensations of withdrawal. Bromocriptine, a central dopamine-receptor (D2) agonist, has been shown to significantly reduce symptoms of cocaine withdrawal. Further supporting the role of dopamine in cocaine’s ability to produce euphoria and withdrawal is the fact that cocaine reinforcement can be blocked by pimozide (a specific dopamine receptor antagonist) but not by phentolamine or phenoxybenzamine (norepinephrine receptor antagonists). Desipramine may also offset symptoms of craving during cocaine withdrawal. Euphoria and withdrawal serve as positive and negative reinforcement, respectively, for the continual use of cocaine.

As a potent indirect-acting sympathomimetic agent, in the periphery cocaine interferes with the uptake of norepinephrine by adrenergic nerve terminals and increases the concentration of this neurotransmitter at postsynaptic receptor sites. Norepinephrine acts on alpha-adrenergic receptors in blood vessels to produce vasoconstriction, which facilitates examination and surgery by reducing congestion, swelling, and bleeding at the site of application. Systemic vasoconstriction is also evident through increased heart rate, arterial blood pressure and blood glucose concentrations, mydriasis, and a risk of cardiac arrhythmias. Tachycardia and hypertension may increase myocardial work and oxygen demand and in some patients, especially those with predisposing cardiovascular disease, myocardial ischemia may result. Labetalol has been reported to provide blockade of clinical adrenergic symptoms associated with cocaine overdose, however others suggest beta-blockers should not be used for this indication. Although alpha-blocking drugs are effective against cocaine-induced coronary vasoconstriction, the alpha-blocking properties of labetalol may be too weak in comparison to its beta-blocking properties. Cocaine contributes to myocardial ischemia in other ways including inducing coronary vasoconstriction, stimulating platelet aggregation, and, in animal studies, accelerating atherosclerosis.

Cocaine is markedly pyrogenic. It increases muscular activity which augments heat production, and vasoconstriction decreases heat loss. Cocaine may also have a direct action on central heat regulation centers.

Pharmacokinetics: Cocaine, when used medically, is administered topically to mucosal surfaces. When used illicitly, cocaine is delivered intravenously, orally, by nasal insufflation or by smoking. Cocaine is well absorbed from a variety of sites, including mucous membranes and the gastrointestinal tract, especially from damaged or inflamed tissue. Absorption from the mucosa, specifically intranasal mucosa, may be limited by the drugs potent vasoconstrictive properties. Oral bioavailability is 30 - 40%, with the remainder eliminated by first-pass metabolism.

The onset of action of cocaine for topical anesthesia typically occurs within 1 minute of application. Maximum effects are seen within 5 minutes and the duration of action ranges from 20 - 60 minutes. Peak effects usually occur 60 - 90 minutes following oral administration, 30 - 60 minutes after insufflation, and within minutes of IV administration or smoking. When cocaine is administered orally or intranasally, the duration of anesthesia ranges from 30 - 60 minutes.

After intranasal or oral dosing the apparent half-life may be several hours due to continued absorption and the plasma half-life after IV dosing or smoking averages 60 - 90 minutes. Cocaine penetrates the central nervous system, rapidly crossing the blood-brain barrier, and also readily crosses the placenta. Cocaine is also excreted in breast milk, where cocaine and benzoylecgonine, a metabolite, have been detected for up to 36 hours after maternal use.

Cocaine is rapidly and extensively metabolized to 3 principle metabolites, ecgonine methyl ester, norcocaine, and benzoylecgonine, and to numerous minor metabolites. The activity of cocaine’s metabolites are unknown. Ecgonine methyl ester is produced by hydrolysis of cocaine through serum cholinesterases, plasma pseudocholinesterases, and hepatic enzymes; N-demethylation in the liver forms norcocaine; benzoylecgonine is formed by hydrolysis, both nonenzymatic and enzymatic, in the liver, plasma, and other tissues. Minor metabolites are produced by oxidation and combined oxidation-hydrolysis.  In the presence of ethanol, cocaine is biotransformed by transesterification to cocaethylene.
Chemical Structure(s) For: Cocaine

Cocaine is rapidly excreted by the kidneys with 85 - 90% of a dose recovered in the urine, 1 - 5% being unchanged parent compound. The elimination half-life is approximately 1 hour. Urine screening procedures can usually detect unchanged drug for up to 4 - 6 hours after dosing; other assays (e.g., EMIT) can detect cocaine metabolites for up to a few days following last administration.