From GSM's Clinical Pharmacology:
Quote:
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.
<a name="mechanism"></a>
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 andinitiate or conduct
nerve impulses. Direct nerve membrane penetration is necessary for
effective anesthesia, which is achieved by applying cocaine directlyto
the area to be anesthetized.The drugnot 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 cocaineare 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
inhibitsdopamine reuptake in the synapse. This causes some of
cocaine's most strikingeffects ofgeneral CNS stimulation,manifested
(in descending order) as euphoria, stimulation, reduced fatigue,
loquacity, sexual stimulation, increased mental ability, alertness, and
increased sociality. Withincreased doses, tremors and tonic-clonic
convulsions may occur, and vomiting centers may be stimulated. Ventral
stimulation is soon followed by depression, withthe 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 (D<sub>2</sub>) 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
theperipherycocaine 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.
<a name="pharmacokinetics"></a>
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.</span> Minor metabolites are produced by oxidation and combined oxidation-hydrolysis. In the presence of ethanol, cocaine is biotransformed by transesterification to cocaethylene.
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.
•Special populations:
Patients with reduced plasma or liver cholinesterase activity may
exhibit a reduced ability to metabolize cocaine. Such patients may
include the elderly (especially elderly males), patients receiving or
exposed to systemic cholinesterase inhibitors, or patients with hepatic
disease or cancer. Occasionally, pregnant patients have slightly
decreased cholinesterase activity. Neonates also exhibit a reduced
capacity to metabolize cocaine.
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18-07-2005, 23:59
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