Pharmacology - An Illustrated Review

15. Drugs of Abuse

Nonmedical use of drugs includes experimental use, in which a person tries a drug out of curiosity; recreational use, when moderate amounts are used to get “high”; and situational use, when drugs are used in specific circumstances, for example, amphetamines to stay alert. Sometimes these patterns can lead to more frequent use and dependence. Some key terms related to drugs of abuse are defined in Table 15.1.

  Table 15.1 image Definition of Terms

Term

Definition

 

Drug abuse

The use, usually by self-administration, of any drug in a manner that deviates from the approved medical or social patterns within a culture.

 

Drug misuse

Inappropriate use of a drug

 

Compulsive drug use or compulsive drug abuse

Continued self-administration of a drug despite the fact that the user may be suffering adverse social or medical consequences. In compulsive drug use, the user feels the drug is needed for his or her well-being. There is a continuum of compulsive drug use, from a simple desire to have more drug to a craving and preoccupation with procurement of the drug.

 

Drug addiction*

According to the World Health Organization, drug addiction is a behavioral pattern of drug use that is characterized by overwhelming involvement with the use of a drug and overwhelming involvement with securing a supply. Along with this, there is a high tendency to relapse after withdrawal.

There is some overlap in the definitions of compulsive use and addiction, and it is not always clear when compulsive use becomes addiction.

 

Tolerance

Decreased responsiveness to a drug with repeated or continued dosing. Cross-tolerance may occur between drugs or between drug classes.

 

Dependence

Continued use of that drug is required to prevent withdrawal.

 

Withdrawal

Withdrawal may consist of physical and/or psychological signs and symptoms that occur upon abstinence from a drug.

 

* There is a difference between addiction and dependence. It is possible for a person to exhibit signs of dependence following withdrawal of a drug, yet not crave the drug.

 

Detoxification

Detoxification is the same for all drugs that produce physical dependence. It involves substituting a longer-acting, orally effective, pharmacologically equivalent drug for the abused drug. The patient is stabilized on the substitute, and then it is gradually withdrawn. There is a high recidivism rate among drug abusers. Currently, there are many psychotherapeutic programs after detoxification, but these programs have success rates varying from 10% to perhaps a maximum of 50%.

 

15.1 Opioids

The pharmacology of these agents is discussed in Chapter 13.

Morphine, Diamorphine (Heroin), Codeine, Meperidine, and Methadone

Effects. The effects of opioids on performance include mental clouding, faulty judgment, and a reduced ability to concentrate. Physical signs of abuse include miosis (pupillary constriction), depression, and apathy.

Tolerance, dependence, and withdrawal. Tolerance, dependence, and withdrawal are characteristic of opioid use.

– Pain relief may be less effective as tolerance develops, even after a single dose. Tolerance develops more slowly to meperidine than morphine.

Opioid withdrawal symptoms are listed in Table 15.2.

  Table 15.2 image Opioid Withdrawal Symptoms*

Early symptoms (10–12 h after withdrawal)

Rhinorrhea (runny nose), perspiration, lacrimation (secretion of tears), and yawning

 

Intermediate symptoms (18–24 h after withdrawal)

Mydriasism, piloerection, anorexia, and muscular tremors

 

Peak symptoms (36–72 h after withdrawal)

Restlessness, hot flashes alternating with chills, an increase in both blood pressure and heart rate, an increase in the rate and depth of respiration, fever of 1°C or more, nausea, retching, vomiting, and diarrhea

 

* Withdrawal from an opioid is generally not life-threatening, although it is almost unbearable. The intensity of the withdrawal symptoms will be in proportion to the amount of drug being used and the duration of the abuse. Withdrawal will be more intense and of a shorter duration after use or abuse of more potent, shorter-acting agents. Likewise, it will be less intense but more prolonged with less potent, longer-acting agents.

 

15.2 Alcohol

Ethanol Toxicology

Alcohol is rapidly absorbed from the gastrointestinal (GI) tract after oral administration. Its acute effects appear within minutes of ingestion. Ethanol is metabolized in the liver, primarily by alcohol dehydrogenase to acetaldehyde, then by acetaldehyde dehydrogenase to acetate. This metabolism follows zero-order kinetics, which means that a constant amount of ethanol is metabolized per unit of time. The implication of this is that as more ethanol is ingested, the degree of intoxication increases rapidly, as well as the time for the blood level to drop to a nonintoxicating level.

Effects. Effects are listed in Table 15.3. See also Figs. 15.1 and 15.2.

  Table 15.3 image Effects of Acute and Chronic Intoxication with Ethanol

System/Tissue

Effects

 

Acute Intoxication

 

CNS

Progressive CNS depression is correlated in time with blood concentrations of ethanol and may include vision and judgment impairments, decreased inhibitions, and muscular incoordination, progressing to staggering gait, slurred speech, and possible coma and death at higher doses.

 

GI system

Increased salivary and gastric secretions, direct irritation to gastric and buccal mucosa, emesis due to a central effect on the chemoreceptor trigger zone, and irritation of the gastric mucosa. Prolonged use also leads to decreased absorption of folates.

 

Other

Suppression of antidiuretic hormone (ADH, vasopressin) secretion

Increased adrenocorticotropin hormone (ACTH), cortisol, and catecholamine secretion

Diuresis due to decreased antidiuretic hormone release

Increased consumption of fluids

Hypothermia

 

Chronic Intoxication

 

CNS

Wernicke syndrome, Korsakoff psychosis, cerebral atrophy, cerebellar atrophy, and alcoholic polyneuropathy

 

GI system

Peptic ulcers, esophagitis, gastritis, pancreatitis, and malnutrition

 

Liver

Steatosis, hepatitis, and cirrhosis (Figs. 15.1 and 15.2)

 

Muscle

Cardiomyopathy and skeletal muscle myopathy

 

Fetus

Fetal alcohol syndrome

 

Other

Face puffy, cheeks and nose flushed, eyes bloodshot, palmar erythema, rhinophyma, acne rosacea, and spider nevi

 

Abbreviations: CNS, central nervous system; GI, gastrointestinal.

 

Fetal alcohol syndrome

Fetal alcohol syndrome is the term used to describe a spectrum of disorders that can occur in a fetus if a woman drinks alcohol when pregnant. It includes the following: abnormal facial features, growth deficiencies, vision or hearing deficits, and mental disabilities, such as difficulty in learning, memory problems, poor attention span, and poor communication skills.

 

Fig. 15.1 image Alcohol catabolism and effects of excess alcohol on the liver.

In hepatocytes, ethanol is broken down into acetic acid via acetaldehyde. This process utilizes the oxidized form of nicotinamide adenine dinucleotide (NAD+), so the requirement for this increases. If alcohol intake is chronic, hepatocytes initially undergo fatty degeneration that is reversible; however, if it continues, cirrhosis occurs as hepatocytes die and are replaced by connective tissue. NADH, the reduced form of nicotinamide adenine dinucleotide.

image

Tolerance, dependence, and withdrawal. Withdrawal symptoms in chronic users of alcohol include tremor, sweating, anxiety, irritability, nausea, vomiting, and insomnia. These symptoms will be mild to moderate in 80 to 85% of patients and more severe in 15 to 20%. Severe withdrawal, known as delirium tremens, is seen in ~1%.

– Benzodiazepines are cross tolerant with alcohol and will alleviate withdrawal symptoms, but they do not have the same stimulating effects on the central nervous system (CNS) as alcohol.

– For serious complications or delirium tremens, replace fluids and electrolytes and treat symptoms. Treat arrhythmias with lidocaine or procainamide, severe tremor with propranolol, and hallucinations and paranoia with a phenothiazine or haloperidol.

Delirium tremens

Delirium tremens is a disorder that occurs as a result of alcohol withdrawal (onset ~72 h after the last drink). Signs include increased pulse, reduced blood pressure, tremors, fits and visual or tactile hallucinations. Treatment is with diazepam.

 

Fig. 15.2 image Liver cirrhosis.

Liver cirrhosis occurs when hepatocytes die and are replaced by connective tissue. Hepatic blood flow is impaired, causing portal hypertension, which in turn causes ascites and the formation of varices. The normal functioning of the liver is reduced, including the elimination of toxins, which can then build up and affect the functioning of the brain.

image

Drugs to Manage Alcoholism

Acute intoxication rarely requires treatment. Management includes supporting ventilation, maintaining temperature, and correcting dehydration, acidosis, or electrolyte imbalance. G astic lavage (stomach pumping) is rarely necessary.

Chronic intoxication may be treated with the agents listed below.

Naltrexone

Mechanism of action. Naltrexone is an opioid antagonist similar to naloxone but with greater bioavailability and longer duration of action. It apparently blocks the ability of alcohol to activate dopaminergic reward pathways.

Pharmacokinetics

– Orally active, but also available in once-monthly injectable, extended-release form

Side effects

– Nausea and liver damage (in high dosages)

Contraindications

– Liver failure or acute hepatitis

Alcoholism and vitamin deficiencies

Alcoholics frequently develop vitamin deficiencies, especially thiamine and niacin. Thiamine (vitamin B1) is essential for carbohydrate metabolism and is a modulator of neurotransmitter activity. Niacin (vitamin B3) is a component of nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), and the reduced form of NADP (NADPH). It is also the cofactor for numerous dehydrogenases. The reason that alcoholics develop such vitamin deficiencies is multifactorial and includes poor nutrition and the role that alcohol plays in the ability of the body to absorb, metabolize, and store vitamins. Vitamin replacement therefore plays a role in the management of alcoholism.

 

Acamprosate

Mechanism of action

– Unclear

Uses. Acamprosate is also approved for prevention of relapse to alcoholism. Concomitant use of disulfiram appears to increase the effectiveness of acamprosate.

Side effects

– Diarrhea

Disulfiram (Antabuse)

Mechanism of action. Disulfiram is an inhibitor of aldehyde dehydrogenase. If alcohol is taken in the presence of disulfiram, blood acetaldehyde levels increase, producing flushing, dysp nea (shortness of breath), nausea, thirst, chest pain, and palpitations. The effects are intended to be unpleasant so as to discourage alcohol ingestion; however, they can be serious and even life-threatening.

Note: Patients must be informed to avoid alcohol, or their life may be in danger. This i ncludes avoiding sauces, cough syrups, and liquid cold medicines that contain alcohol.

Toxicology of Other Alcohols

Methanol

Metabolism. Methanol is metabolized to formaldehyde by alcohol dehydrogenase. This occurs at about one fifth of the rate of ethanol. It is then further metabolized to formic acid.

Effects

– Metabolic acidosis and organ damage

– Methanol can cause blindness by damaging the optic nerve.

Treatment. This involves suppressing methanol metabolism by administering ethanol and giving bicarbonate to correct the acidosis. Fomepizole, which is a synthetic parenteral alcohol dehydrogenase inhibitor, may also be used. It prevents the initial metabolism of methanol (and ethylene glycol) to toxic metabolites.

Ethylene Glycol

Metabolism. Ethylene glycol is metabolized to oxalic acid, causing systemic acidosis.

Toxic effects

– Metabolic acidosis and organ damage

Treatment. Same as for methanol poisoning.

15.3 Benzodiazepines

Benzodiazepines are also discussed in Chapter 9.

Diazepam, Midazolam, Temazepam, Triazolam, Flurazepam, Clonazepam, Oxazepam, Lorazepam, and Alprazolam

Intoxication. Intoxication with benzodiazepines produces progressive CNS depression with increasing dose. They may be fatal at high doses due to respiratory depression and cerebral hypoxia.

Tolerance, dependence, and withdrawal

– Tolerance develops to the effects of benzodiazepines.

– Physical dependence can occur.

– Withdrawal symptoms are generally opposite the effects of the drugs: anxiety, insomnia, and convulsions (in severe withdrawal). They can be minimized by slowly decreasing the dose to wean the patient from the drug.

15.4 Barbiturates

Barbiturates are also discussed in Chapter 9.

Thiopental, Phenobarbital, Thiomylal, Methohexital, Amobarbital, Pentobarbital, and Secobarbital

Intoxication

– Same as for benzodiazepines

Tolerance, dependence, and withdrawal

– Tolerance develops to their sedative and hypnotic effects. No tolerance develops to the anticonvulsant actions of barbiturates.

– True physical dependence occurs.

– Moderate withdrawal consists of rebound increases in rapid eye movement (REM) sleep, insomnia, and anxiety. Seizures and delirium can occur in patients taking high doses for long periods. These patients should be withdrawn slowly to avoid these serious complications.

15.5 Quaaludes

Methaqualone

Methaqualone is a former prescription medication that is now synthesized and sold illicitly. It is a CNS depressant with pharmacology similar to barbiturates.

Intoxication

– Same as for benzodiazepines

Tolerance, dependence, and withdrawal

The symptoms and treatments are the same as for barbiturates.

15.6 Stimulants

Mechanisms of action. Stimulants inhibit the cyclic nucleotide phosphodiesterases, increase cellular Ca2+, and are antagonists at central adenosine receptors.

Caffeine

Effects. Caffeine decreases fatigue, increases arousal, and improves performance, but it produces insomnia and may have a disruptive effect and worsen performance at very high doses.

Tolerance, dependence, and withdrawal

– No tolerance develops to caffeine.

– A throbbing, diffuse headache is the most common symptom of caffeine dependence.

– Symptoms of withdrawal may include nausea, lethargy, and headache.

Amphetamines and Cocaine

Effects

– CNS actions include euphoria, decreased fatigue, alleviation of sleepiness, and decreased appetite. Amphetamines and cocaine may also increase libido and talkativeness. Restlessness may occur, and the heart rate may increase.

– After prolonged self-administration (a “run”) with amphetamines, prolonged sleep, apathy, and depression are common.

– Sympathetic effects may be absent in chronic users.

– Chronic toxicity produces anxiety and confusion, leading to paranoia and psychosis, which is indistinguishable from schizophrenia.

Uses

– Cocaine is sometimes used as a local anesthetic agent.

– Amphetamines are used for attention deficit/hyperactivity disorder (ADHD) and narcolepsy.

Attention deficit/hyperactivity disorder

ADHD is characterized by inattention and hyperactive-impulsive behavior. It is a chronic disorder that affects children but may persist in adulthood. Symptoms are usually evident before the child is 7 years old, with the relative amount of inattention or hyperactivity symptoms differing in each case. Attention deficit symptoms include difficulty in sustaining attention during activities, trouble organizing activities, making careless mistakes in schoolwork, lack of listening when spoken to directly, forgetfulness, and often losing things. Hyperactivity symptoms include fidgeting, squirming, inability to remain seated, inappropriate running or climbing, trouble playing quietly, excessive talking, and always being “on the go.” ADHD is often accompanied by anxiety and depression, making the diagnosis more complicated. The cause of ADHD is unknown, although it is known to have a strong hereditary element. Maternal smoking, drug use, and exposure to toxins have been shown to increase the likelihood of having a child with ADHD. Treatment involves the use of stimulant medications, such as methylphenidate (Ritalin) and dextromethamphetamine. Nonstimulant medications, such as atomexetine, are also used. Therapy plays an important role in the management of this condition.

 

Narcolepsy

Narcolepsy is a chronic sleep disorder that is characterized by sudden attacks of sleep and overwhelming daytime drowsiness. There may also be cataplexy (sudden loss of muscle tone), sleep paralysis (temporary paralysis that occurs when falling asleep or upon waking), hallucinations, and autonomic behavior while sleeping (e.g., talking or performing tasks). People with narcolepsy often have restless nighttime sleep patterns. This condition tends to occur mainly in adolescents and young adults. Damage to hypocretin cells, which regulate wakefulness and the timing of REM sleep, has been implicated as a cause for narcolepsy. Treatment involves the use of stimulant drugs such as modafenil and methylphenidate to help people stay awake; antidepressants to alleviate cataplexy, hallucinations, and sleep paralysis; or sodium oxybate to combat cataplexy.

 

Intoxication

– Acute intoxication causes hyperpyrexia, convulsions, and shock. It may result in death. Treatment involves chlorpromazine which will block many of the acute effects of amphetamines, and diazepam to control convulsions. Acidification of the urine will enhance excretion. Death can occur following acute cocaine use by convulsions or cardiac arrhythmias. Chlorpromazine can be used.

– Chronic intoxication may cause toxic syndrome. Signs and symptoms of toxic syndrome include visual, auditory hallucinations, and tactile hallucinations; paranoia and changes in affect. Treatment for paranoid delusions and excitement involves dopamine antagonists (haloperidol). Acidification of the urine will facilitate excretion of amphetamines.

Tolerance, dependence, and withdrawal

– Marked tolerance develops to amphetamines but not to cocaine.

– Dependence is common and produces an extremely intense drug craving. Physical dependence is minor.

– Withdrawal may include prolonged sleep, laziness, fatigue, overeating, and, occasionally, depression. Craving may persist for years.

15.7 Hallucinogens

Psychedelic Hallucinogens

d-Lysergic Acid Diethylamide (LSD), Psilocybin, and Mescaline

These agents differ primarily in potency. LSD is extremely potent.

Mechanism of action. Their mechanism is unclear, but they are serotonin agonists (see Fig. 7.3, page 70).

Intoxication. Psychedelic hallucinogens may produce vivid visual hallucinations and profound changes in thought processes, with confusion alternating with seemingly vivid perceptions and foresight, but these depend greatly on the situation and the individual.

Side effects

– Paranoia, panic reaction, and overt psychosis.

– Synesthesias and “flashbacks” are unique features (seen in up to 15% of users).

Note: No deaths due to direct drug effects have been reported.

Treatment

– Involves emotional support and antianxiety agents, phenothiazines, or barbiturates in doses to produce sleep

Tolerance, dependence, and withdrawal

– Tolerance and cross-tolerance will occur.

– No dependence or withdrawal

Deliriant Hallucinogens

Phencyclidine and Ketamine

Phencyclidine (PCP) and ketamine are frequently touted as pure tetrahydrocannabinol (THC, the active ingredient in marijuana), LSD, or mescaline.

Intoxication. At low doses, intoxication resembles an acute confused state. At higher doses, serious neurologic, cardiovascular, and psychotic reactions occur.

Side effects. They are mainly psychological and include changes in body image, apparent loss of contact from reality, disorganized thought, and apathy or catatonia. Individuals on PCP may exhibit bizarre and hostile behavior. Use has declined because of unpleasant experiences.

Treatment. Treatment for overdosing involves maintenance of vital functions until the drug effects subside.

Tolerance, dependence, and withdrawal

– Tolerance may develop.

– There is no clear withdrawal syndrome.

15.8 Cannabis

Marijuana and Hashish

The main psychoactive ingredient is tetrahydrocannabinol (THC). Endogenous cannabinoid receptors have been discovered along with an endogenous ligand, anandamide.

Effects

– CNS effects: relaxation, sense of well-being, euphoria, and spontaneous laughter. Short-term memory and capacity to carry out goal-directed behavior are impaired, and there is also motor impairment. THC has variable effects on mood, emotion, and social feelings.

– Heart: tachycardia (paroxysmal atrial tachycardia) may occur.

– Respiratory system: the lungs are adversely affected by smoke.

– Reproductive system: changes in the menstrual cycle, decreased sperm count and motility, and increased number of abnormal sperm

– Amotivational syndrome: no scientific evidence that such a syndrome occurs.

Uses

– Antiemetic in cancer chemotherapy patients

Tolerance, dependence, and withdrawal

– Tolerance develops to the effects of THC.

– Physical dependence does not occur.

– A withdrawal syndrome has not been defined. Many individuals stop using marijuana at will with no craving.

15.9 Tobacco

Nicotine

Mechanism of action. Nicotine mimics acetylcholine at nicotinic receptors. It also decreases the activity of the enzyme monoamine oxidase (MAO) in the brain, which increases dopamine levels.

Intoxication. Nicotine causes an alert pattern in the electroencephalogram. It decreases skeletal muscle tone, appetite, and irritability and has a mild euphorigenic effect.

Tolerance, dependence, and withdrawal

– Withdrawal is variable, but increased appetite and inability to concentrate may persist for months. Intense psychological craving to smoke persists for months to years after quitting smoking.

Treatment

– Nicotine replacement therapy: a variety of strategies are available for administering nicotine in place of smoking, including oral (gum or lozenge), transdermal (patches), and intranasal (spray).

– Varenicline, a partial agonist at the α2β4 subtype of nicotinic acetylcholine receptors, stimulates the receptor to relieve cravings and withdrawal while simultaneously blocking nicotine binding, thus reducing the rewarding effect of smoking.

– Bupropion, an antidepressant drug that inhibits dopamine and norepinephrine reuptake, has some efficacy in nicotine addiction. A sustained-release formulation of bupropion is available for treatment of tobacco dependence.

15.10 Inhalants

Nitrous Oxide, Gasoline, Volatile Solvents, and Aerosols

See page 77 for a further discussion of nitrous oxide.

Intoxication

– Acute toxicity may lead to respiratory arrest and cardiac arrhythmias.

– Direct administration of aerosol propellants has resulted in laryngospasm, airway freezing, and suffocation due to an occluded airway.

– Chronic toxicity varies depending on the solvent but is characterized by irreversible tissue damage. This irreversible tissue damage means that solvent abusers are the most difficult group to rehabilitate.