Cocaine is a major alkaloidal component from the Andean bush Erythroxylon coca. Leaves of this plant are chewed by Andean Indians to decrease the feeling of hunger and fatigue; there is little evidence that dependence is caused by this means of administration. A major health problem arises, however, when cocaine is used in industrialized countries. Thus in the US over 20 million people are estimated to use the drug, by nasal administration ("snorting"), injection of the salts, or smoking the free alkaloid ("crack").
The subjective effects of all the psychostimulants depend on personality, the environment in which it is administered, the dose of the drug, and the route of administration. For example, moderate doses of D-amphetamine (10-20 mg) in a normal person will produce euphoria, a sense of increased energy and alertness, anorexia, insomnia, and an improvement in the conduct of repetitive tasks. Some people become anxious, irritable and talkative. As the dose of amphetamine is increased, the symptoms become more marked and the influence of the environment less pronounced.
Most psychostimulants produce qualitatively similar effects, and include such drugs as methylamphetamine, phenmetrazine, methylphenidate and diethylpropion. The shrub khat, from Yemen and other Middle Eastern countries, contains the stimulant (— )cathinone, which has properties similar to those of the synthetic psychostimulants.
The main difference between cocaine and the amphetamine-like drugs lies in its shorter duration of action, the half-life for cocaine being about 50 minutes while that of amphetamine is 10 hours.
Because of its widespread abuse, particularly in the US, detailed studies have recently been undertaken on the pattern of abuse of cocaine. Some 20% of those experimenting with the drug go on to become regular users (i.e. psychologically dependent). Once dependent, the individual may administer the drug as frequently as every 15 minutes for up to 12 hours at a time. The initial positive social effects, such as increased energy and motivation, eventually give rise to the individual becoming asocial and preoccupied with the drug-induced euphoria. Severe psychological and social impairment finally intervenes. The consequence of long-term abuse is unclear, but it does seem that people taking cocaine by the intranasal route may recover without progressing to other forms of drug abuse.
The reinforcing (i.e. dependence-producing) effects of cocaine are thought to result from its ability to inhibit the reuptake of dopamine and thereby to increase dopaminergic activity, particularly in the ventral tegmental area and the nucleus accumbens, so enhancing the activity of the dopaminergic system in the mesolimbic area (the reward area) of the brain.
By contrast, the stimulant amphetamines, such as D-amphetamine and methylamphetamine, release dopamine from most brain regions. These drugs also inhibit the reuptake of all biogenic amines, but the effects on the noradrenergic and serotonergic systems do not appear to be directly associated with the dependence potential of the drugs.
Fenfluramine is an amphetamine that selectively stimulates the release of 5-HT and lacks dependence and stimulant properties. This drug is used as an anorexiant, a property which it shares with the stimulant amphetamines.
The structures of some of these stimulants are shown in Figure 15.4.
The most serious toxic effects of cocaine involve changes in the cardiovascular system. These include cardiac arrhythmias, myocardial ischaemia and infarction, and cerebrovascular spasm, all of which can be largely explained by the facilitation of the action of catecholamines on the cardiovascular system. Another explanation of the cardiotoxicity of cocaine lies in the direct vasoconstrictive properties of its major metabolite, norcocaine. It seems likely
that the vasoconstrictor effects of cocaine are due to a reduction in sodium flux across the cardiac cell wall, as all local anaesthetics block sodium channels but only cocaine causes vasoconstriction. It has been estimated that about 20% of those dying of cocaine overdose show myocarditis at autopsy. Nevertheless, it has also been established that cocaine increases the release of adrenal catecholamines (adrenaline and noradrenaline) and sensitizes the cardiac adrenoceptors of their action.
Seizures, possibly due to the local anaesthetic effects of the drug at toxic doses, can occur particularly in those predisposed to epilepsy. Although such toxic and often fatal effects occur more frequently after intravenous and inhalational administration, nasal administration has also been reported to result in such toxicity even in young, apparently healthy people. There is a poor correlation between the euphoriant effects of cocaine and its cardiotoxicity, so that someone who uses the euphoriant effects of the drug to regulate the dose may be unaware of the cardiovascular toxicity. Thus one of the main reasons why the cocaine user may die suddenly is the differential psychological and cardiovascular tolerance. This occurs more rapidly in the brain than the heart, and therefore a slight overdose with the drug can lead to heart failure.
Anxiety and panic attacks may be associated with high doses of cocaine. These effects may be associated with paranoid ideation, visual and tactile hallucinations (called formication) and visual pseudohallucinations (seeing snow lights). Ideas of reference, characteristic of stimulant psychosis, also occur.
Similar effects have been reported after abuse of the amphetamines which, in addition, may be associated with increasing stereotyped behaviour and a full psychotic episode (auditory, visual and tactile hallucinations often unassociated with cardiovascular symptoms) which may be difficult to differentiate from paranoid schizophrenia. This is the basis for using amphetamine as a model for schizophrenia, in both animals and human volunteers. The central effects of high doses of cocaine and the amphetamines may be suppressed by the administration of neuroleptics.
The toxicity following the administration of high doses of amphetamines arises as a consequence of the release of catecholamines from peripheral and central sympathetic neurons, combined with their reduced metabolism owing to the reduction in their reuptake. The cardiotoxicity is similar to that described for cocaine, in which sympathetic drive to the heart is increased. There is now evidence that high, chronic doses of the amphetamines can cause a degeneration of dopaminergic neurons, possibly because of the formation of an endogenous neurotoxin, 6-hydroxydopamine.
The amphetamines are weak MAO-B inhibitors, and this may limit the oxidative deamination of such a metabolite and thereby lead to its accumulation. The pronounced anhedonia seen after chronic amphetamine abuse may be ascribed to a degeneration of dopaminergic neurons in the mesolimbic region of the brain.
Acute intoxication with amphetamine is associated with tremor, confusion, irritability, hallucinations and paranoid behaviour, hypertension, sweating and occasionally cardiac arrhythmias; convulsions and death may occur. The cardiovascular effects of the stimulants may be treated by beta-blockers, or by the combined alpha- and beta-blocker labetalol; calcium channel antagonists such as nifedipine may correct the arrhythmias, while intravenous diazepam is of value in attenuating seizures.
This only develops to some of the effects of cocaine, for example the euphoric ''rush'' following intravenous administration and some of the cardiovascular effects, but the degree of tolerance is limited. However, most long-term users do require increasing amounts of the drug to produce the same subjective effects to those experienced initially when taking the drug.
Amphetamine users also develop a tolerance to some of the central effects, such as the euphoria and anorexia, which may lead to the escalation of the dose; this may be partly ascribed to enhanced excretion of the drug. Cross-tolerance occurs between the psychostimulants.
Reverse tolerance, or sensation, can occur with all the psychostimulants, and may be partly related to enhanced mesolimbic forebrain dopaminergic function. Such increased sensitivity to the effects of these drugs need not depend on the drugs being given daily. The stereotyped behaviour seen in amphetamine abusers may be attributed to the increased activity of the striatal dopaminergic system.
Kindling may account for the lowered seizure threshold following chronic cocaine abuse. This phenomenon has been described elsewhere (e.g. in the use of carbamazepine in the treatment of mania), and occurs when small, subconvulsive doses eventually give rise to spontaneous seizures.
Withdrawal effects following the abrupt termination of the administration of psychostimulants comprise depression, anxiety and craving, followed by a general fatigue and disturbed sleep pattern. Hyperphagia and anhedonia are common. In general, the mood returns to normal after several days. There are no grossly observable signs of physical dependence following prolonged psychostimulant abuse. In the US, desipramine has been found to be beneficial in treating the withdrawal effects from cocaine (so-called ''cocaine crash''). The precise mechanism whereby this tricyclic antidepressant produces such an antagonistic effect is uncertain.
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This guide Don't Panic has tips and additional information on what you should do when you are experiencing an anxiety or panic attack. With so much going on in the world today with taking care of your family, working full time, dealing with office politics and other things, you could experience a serious meltdown. All of these things could at one point cause you to stress out and snap.