Pharmacokinetics

Cocaine has a half life of 40-50 minutes, and it’s effects on the body are felt rapidly, peaking after 15-20 minutes when ‘snorted’, and wearing off by 1.5 hours. When injected or ‘freebased’, or when crack is smoked, the effects are almost instantaneous, and last for only 15 minutes or so.

Cocaine is metabolised to nearly a dozen pharmacologically inactive metabolites, the most important being benzoylecgonine and ecgonine methyl ester, primarily in the liver by spontaneous hydrolysis. (Casale et al 1994). Plasma cholinesterase also hydrolyses cocaine to ecgonine, and approximately 20% of the drug is excreted untouched into the urine. Both cocaine and its metabolites may be detected in urine up to 15 days after last administration by a chronic user.

Cocaethylene is the ethylbenzoylecgonine form of cocaine produced in the presence of ethanol, resulting from transesterification by hepatic enzymes. (da Matta Chasin et al 2000 p.2). It is pharmacologically active, and it is formed at significantly lower concentrations than either of its parent substances.

Mechanisms of Action

Cocaine is a central nervous system stimulant, which gives rise to feelings of euphoria, excitement, increased motor activity and a feeling of being energised.

Its principal mode of action is the blockade of the transporter protein that is responsible for the reuptake of monoamines (i.e. noradrenaline, serotonin and most importantly dopamine) into presynaptic terminals of neurons releasing these neurotransmitters. The result is that increased concentrations of these monoamines are found in the synaptic space, and their effects are potentiated.

Blockage of the dopamine-reuptake transporter protein gives rise to the characteristic ‘high’ of cocaine. Knockout mice that do not have the gene encoding for this transporter protein are immune to the effects of cocaine, and studies have attempted to identify the exact dopamine receptor subtype on the post-synaptic neuron that is responsible for modulating the effects of cocaine. It appears that the D2 subtype modulates cravings associated with cocaine dependence and drug seeking behaviour, whilst the D1 subtype may modulate feelings of satiety, opening up possibilities for therapeutic targeting of these receptors to treat cocaine dependence and abuse. (Leshner 1996 pp.128-9).

Dopamine hyperactivity as a result of cocaine administration is particularly important in the nigrostriatal dopaminergic system, which incorporates the limbic system of the brain – the ‘pleasure centre’. The activation of the limbic system by the drug gives rise to the intense euphoria, but in the chronic user, monoamine neurotransmitters are depleted, triggering a reactive lowering of mood or depression (serotonin depletion?), as well as disturbed sleep and eating cycles. Body temperature control is adversely affected, and depletion of dopamine has been linked to the onset of schizophrenia in susceptible individuals.  

In high doses, cocaine can cause tremors and convulsions via its effects on the cortex and brainstem, and can lead to respiratory and vasomotor depression. O’Dell et al (2000 p.677) speculate that cocaine activation of serotonin (2) receptors may be responsible for mediating convulsions. Chronic users can experience hallucinations, delusions and paranoia.

Peripherally, cocaine potentiates noradrenaline action, and produces the typical ‘fight or flight’ sympathetic response of tachycardia, hypertension, pupillary dilatation and peripheral vasoconstriction. Table 1 below lists the effects of cocaine.

Table 1. Physical and Psychological Effects of Cocaine  (Sources: Stark et al 1996, Stark 1999, Wetli (1985))

Therapeutic Uses of Cocaine

Cocaine is used as a surface local anaesthetic (it blocks Na⁺-K⁺ activated ATPase across adrenergic neuron cell membranes), particularly in Ear, Nose and Throat (ENT) surgery. It is also sometimes used in palliative care of terminally ill patients.

Dependence and Tolerance

There is tolerance to the psychological effects of cocaine, but not generally to the cardiac effects. However, acute tolerance appears to occur after administration of the drug. This has been noted when studying the effects of cocaethylene, which is formed at a slow rate, and appears in the user’s blood at a time when the effects of cocaine are declining. Cocaethylene is active in the brain, and has a similar effect to cocaine, but the subjective perception of the cocaine ‘high’, and its heart effects are not increased – instead they decline in intensity.

Niesink et al (1999 p.49) describes the ‘super sensitivity’ phenomenon that follows chronic cocaine use, and represents a form of chronic tolerance. Chronic use depletes the amount of monoamine neurotransmitters in the pre-synaptic neuron, and thus the amount available in the synaptic cleft. This is compensated for by an increase in post-synaptic receptors.

Cocaine causes both physical and psychological dependence, the severity of which depends on the route of drug administration. It is more severe when the drug has been injected or smoked. Withdrawal leads to strong craving and drug seeking behaviour, followed by a withdrawal syndrome.

The cocaine ‘crash’ is characterised by

Sufferers are at an increased risk of harming themselves or committing suicide, and frequently find themselves in police custody. Such individuals can be settled with haloperidol and diazepam, whilst their vital signs need close monitoring in a hospital setting where potential complications may be anticipated.

Cocaethylene

When alcohol and cocaine are ingested together, the liver produces the active metabolite cocaethylene. It is produced as a result of the transesterification of cocaine by the same non-specific carboxylesterases that normally convert cocaine to benzoylecgonine, for example, in the absence of ethanol.

Cocaethylene is a non-polar structure, and can cross the blood brain barrier, where it blocks the dopamine-reuptake transporter protein in the same way that cocaine does.

The clinical importance of this metabolite has not been fully determined, but it has a longer half-life than cocaine (2.5 hours), and it is possible that it may prolong the cocaine ‘high’. (Cone et al 1993). However, Perez-Reyes et al (1992 pp. 561-2 and 1994 pp.541-550) have found that cocaethylene appearance in the blood of a cocaine/ ethanol user does nothing to alter subjective cocaine ‘highs’ or increased heart rate etc. Indeed, it appears that the interaction between cocaine and ethanol is ‘order-of-administration’ dependant. Ethanol only appears to enhance the effects of cocaine if it is ingested prior to cocaine.

The issue of cocaine/ ethanol interaction is controversial. Karch et al (1999 pp.19-23) suggest that cocaine toxicity is not enhanced by ethanol-cocaine interactions, when low concentrations of ethanol are ingested. They concede, however, that further research is required to determine the interactions of higher concentrations of ethanol with cocaine.

The US Drug Abuse Warning System (DAWN) has identified cocaine/ethanol abuse as a major cause of emergency medical admissions, and considers the concurrent use of these drugs to be the cause of increases in cocaine related morbidity and mortality, as well as giving rise to an increased risk of dual dependency and worsening of the ‘crash’ associated with chronic use. (Lee Hearn et al 1991 p.698 and da Matta Chasin et al 2000 p.2).

Epidemiological evidence of the combined abuse of cocaine and ethanol in the US estimates that 5 million people had used this combination within 1 month of the National Household Drug Survey (1985), and that 12 million had done so within the preceding year. Despite a general decline in the prevalence of cocaine use reported by the 1990 Survey, the proportion combining both substances had increased. (Perez-Reyes and Jeffcoat 1992 p.553). Data are unavailable for combined use in the UK, but it is conceivable that the increase in cocaine use in the UK will be mirrored with an increase in the combined abuse of cocaine and ethanol.

Further reading ...

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