Fate of Local Anesthetics The metabolic fate of local anesthetics is of great practical importance because their toxicity depends largely on the balance between their rate of absorption and their rate of destruction. The rate of absorption can be reduced considerably by the incorporation of a vasoconstrictor agent in the anesthetic solution. Some of the common local anesthetics are ester, and their activity and toxicity are usually lost as the result of hydrolysis which occur in both liver and plasma. The amide linked local anesthetics are generally degraded by the hepatic endoplasmic reticulum, the initial reactions involving N-dealkylation and subsequent hydrolysis.

Criteria of an ideal local anesthetics It should be nonirritant to the tissue. It should not cause permanent damage to the tissue. Its systemic toxicity should be low. It should be effective in low concentration. Onset of action should be rapid. Duration of action should be adequately prolonged. It should be soluble in water. It should be cheap and available.

Cocaine Source: Cocaine occurs in the leaves of Erythroxylon coca and other species of Erythroxylon. Chemistry: Cocaine is benzoylmethylecgonine. Cocaine is an ester of benzoic acid and a nitrogen containing base. Cocaine is an inexpensive, widely available, and highly addictive drug that is currently abused daily by over 3 million people in the United States.

Mechanism of action The primary mechanism of action underlying cocaine's central and peripheral effects is blockade of nor-epinephrine, serotonin, and dopamine re-uptake into the presynaptic terminals from which these transmitters are released. This block potentiates and prolongs the CNS and peripheral actions of these catecholamines. In particular, the prolongation of dopaminergic effects in the brain's pleasure system (limbic system), produces the intense euphoria that cocaine initially causes. Chronic intake of cocaine depletes dopamine. This depletion triggers the vicious cycle of craving for cocaine that temporarily relieves severe depression.

Pharmacological action of Cocaine Central nervous system: The behavioral effects of cocaine result from powerful stimulation of the cortex and brainstem. Cocaine acutely increases mental awareness and produces a feeling of well-being and euphoria that is similar to that caused by amphetamine. Like amphetamine, cocaine can produce hallucinations, delusions, and paranoia. Cocaine increases motor activity, and at high doses causes tremors and convulsions, followed by respiratory and vasomotor depression. Sympathetic nervous systems: Peripherally, cocaine potentiates the action of norepinephrine and produces the "fight or flight" syndrome characteristic of adrenergic stimulation. This is associated with tachycardia, hypertension, pupillary dilation, and peripheral vasoconstriction.

Cardiovascular system: Small doses of cocaine given systemically may slow the heart rate as a result of central vagal stimulation, but after moderate doses the heart rate increases. The increased cardiac rate probably results from both increased central and peripheral nervous system. Body temperature: Cocaine is markedly pyrogenic. The increased muscular activity attending stimulation by cocaine augments heat production; vasoconstriction decreases heat loss. Also, cocaine may have a direct action on the heat-regulating centre.

Therapeutic uses Cocaine has a local anesthetic action that represents the only current rationale for the therapeutic use of cocaine; cocaine is applied topically as a local anesthetic during eye, ear, nose, and throat surgery. While the local anesthetic action of cocaine is due to a block of voltage-activated sodium channels, an interaction with potassium channels may contribute to cocaine's ability to cause cardiac arrhythmias.

Adverse effects: Anxiety: The toxic response to acute cocaine ingestion can precipitate an anxiety reaction that includes hypertension tachycardia, sweating, and paranoia. Depression: Like all stimulant drugs, cocaine stimulation of the CNS is followed by a period of mental depression. Addicts with-drawing from cocaine exhibit physical and emotional depression as well as agitation. These symptoms can be treated with benzodiazepines or phenothiazines. Heart disease: Cocaine can induce seizures as well as fatal cardiac arrhythmias. Intravenous diazepam and propranolol may be required to control cocaine-induced seizures and cardiac arrhythmias, respectively. The incidence of myocardial infarction in cocaine users is unrelated to dose, to duration of use, or to route of administration. There is no marker to identify those individuals who may have life-threatenting cardiac effects after taking cocaine.