Many drugs are taken for non-medical purposes, most commonly to generate a sense of well-being or to give pleasure. Drug dependence arises with centrally acting drugs producing a psychological reward and follows repeated administration. It is reinforced by a need to avoid unpleasant withdrawal effects and by the ritual of drug taking itself. Dependence (addiction) is characterized by:
psychological dependence : craving, compulsive drug-seeking behaviour,
physical dependence : habituation/tolerance associated with a withdrawal (abstinence) syndrome, and
tolerance : the need to increase dose to maintain the desired effect.
Drug abuse is important because of the damage done to the individual’s health and the cost to society – in healthcare costs, criminal behaviour, time out of productive work, etc. Drugs abused for their effects in the central nervous system (CNS) include opioids (see Chapter 13 ), stimulants/psychotomimetics (amphetamines, cocaine, lysergic acid diethylamide (LSD)), anxiolytics (benzodiazepines, see Chapter 12 ) and depressants (barbiturates (see Chapter 12 ), solvents). Here we specifically consider nicotine, ethanol , cannabinoids, amphetamines and cocaine . Apart from alcohol and tobacco, the important drugs of abuse are controlled under the Misuse of Drugs Act categories A to C (in the United Kingdom), reflecting their addictive power. Their unauthorized possession is a criminal offence. Drugs misused to improve performance (e.g. anabolic steroids in sports) are not considered here.
Dependence-producing drugs enhance dopaminergic transmission in the important reward pathway from the midbrain to the limbic system and especially to the nucleus accumbens. Tolerance seems to involve adaptive changes to the effects of the drugs. Thus the inhibitory effect of opioids on adenylate cyclase activity in the brain is countered by a rise in the amount of enzyme synthesized. This increased enzyme activity can at least partially explain a rebound withdrawal effect when the drug is discontinued. Downregulation of receptors and receptor desensitization may also be involved. A genetic predisposition towards addictive behaviour has been identified.
Nicotine is taken mainly by tobacco smoking, or less often by chewing, and is strongly addictive. There has been a significant increase in nicotine addiction over recent years with the wide availability of e-cigarettes whereby the user ‘vapes’ uncontrolled amounts of nicotine.
Mechanism of action
Nicotine produces its effects through activation of nicotinic receptors normally activated by acetylcholine (ACh). Activation of nicotinic receptors by nicotine in the CNS leads to the desirable effects and regular use leads to desensitization of these receptors. The behavioural effects depend on dose and may be excitatory or depressant. Indeed smokers may seek either a calming effect or a stimulant effect. Nicotine is reported to enhance learning in rats. Long-term use is associated with a large increase in the number of nicotinic receptors in the CNS. (Tolerance might have been expected to correlate with a decrease in receptor density; the paradoxical increase is most likely due to a high proportion of receptors being in the desensitized state.) Slow release from nicotine patches is used with counselling to assist in quitting the habit of smoking cigarettes to obtain a ‘fix’ of nicotine and increasingly ex-smokers are using e-cigarettes to obtain their nicotine.
Pharmacokinetics and unwanted effects
Nicotine is rapidly absorbed from the lungs and also is well absorbed from patches applied to the skin. It is mostly metabolized by oxidation in the liver and has a half-life of 2 h. Peripheral side effects of nicotine are those expected of stimulation of nicotinic receptors in the autonomic ganglia and the adrenal medulla, e.g. tachycardia and a rise in blood pressure. Stimulation of the posterior pituitary causes antidiuretic hormone (ADH) release and, consequently, decreases urine flow. Adverse effects of tobacco smoking are mainly due to nicotine, tars and carbon monoxide (CO). (In heavy smokers, up to 15% of haemoglobin may be converted to carboxyhaemoglobin.) Lung, throat and bladder cancer are increased in tobacco smokers probably due to the carcinogens in the tars produced by smoking. Smokers also have an increased risk of bronchitis and chronic obstructive pulmonary disease (COPD) thought to mainly be caused by the tars. The increases in coronary heart disease and stroke in smokers are most likely caused by nicotine and CO. Nicotine and CO from smoking in pregnancy may be responsible for low birth weight.
Alcohol dependence is widespread and heavy drinking is a factor in many hospital admissions.
Ethanol has CNS depressant actions similar to those of gaseous anaesthetics and the molecular mechanism is likely to involve enhancement of γ-aminobutyric acid (GABA) A receptor action, inhibition of N -methyl-D-aspartate (NMDA) receptors and inhibition of the opening of voltage-gated calcium ion (Ca 2+ ) channels. Ethanol has a relatively low potency and large quantities are needed to elicit pharmacological actions. Little effect is seen below a plasma concentration of 10 mmol/L and 100 mmol/L (500 mg/100 mL). Higher doses can lead to death (by respiratory depression). Activation of the reward pathways described above probably occurs by depression of an inhibitory input. Inebriation produces the well-known euphoria and increased self-confidence. Less-desirable effects are motor incoordination and aggressive behaviour. Cutaneous vasodilatation can cause heat loss and hypothermia. Ethanol inhibits ADH secretion from the pituitary gland, causing diuresis. Other hormonal effects are feminization of men due to reduced testosterone levels and a Cushing’s syndrome-like action due to enhanced glucocorticoid action. It is suggested that a modest consumption of ethanol has a beneficial effect on coronary heart disease partly due to increasing plasma high-density lipoproteins. The abstinence syndrome includes tremors, nausea and sweating that in alcoholics may progress to delirium tremens (the DTs) characterized by confusion, hallucinations and aggression. DTs may be alleviated by benzodiazepines. In heavy drinkers, tolerance raises the plasma concentration at which performance deteriorates.
Pharmacokinetics and unwanted actions
Ethanol is well absorbed from the gut and is eliminated mainly (90%) by oxidation to acetaldehyde and acetic acid ( Fig. 36.1 ). Metabolism is saturated at relatively low plasma concentrations due to the limited availability of oxidized nicotinamide adenine dinucleotide (NAD + ), leading to zero-order elimination with a fixed rate of approximately 10 mL/h. A small proportion (higher after enzyme induction in heavy drinkers) is oxidized by the P450 system. Limited amounts of ethanol are eliminated unchanged in the breath and urine and provide the basis for police tests of alcohol consumption. Disulfiram inhibits aldehyde dehydrogenase and thus elevates the plasma concentration of acetaldehyde. This produces a range of unpleasant symptoms and its use in chronic alcoholics is intended to discourage alcohol consumption. Long-term alcohol abuse can lead to brain damage, dementia and severe liver damage. The poor diet of alcoholics also contributes to their poor health. The foetal alcohol syndrome , characterized by facial deformities and slow mental development in the baby, follows heavy ethanol consumption in pregnancy.