Drugs of Abuse Flashcards
MECHANISMS OF ADDICTION
The mesolimbic dopamine system is the prime target of addictive drugs. This system originates in the ventral tegmental area and projects to the nucleus accumbens, the amygdala, and the prefrontal cortex. As a general rule, all addictive drugs activate the mesolimbic dopamine system.
Ethanol
Ethanol is classed as a depressant because it produces sedation and sleep. However, the initial effects of ethanol, particularly at lower doses, often are perceived as stimulation due to a suppression of inhibitory systems.
The symptoms of mild intoxication with alcohol vary among individuals. Some experience motor incoordination and sleepiness. Others initially become stimulated and garrulous. As the blood levels increase the sedating levels increase, with eventual coma and death at high alcohol levels.
MECHANISM OF ACTION
Ethanol influences several cellular functions, eg GABAa receptors, Kir3/GIRK channels, adenosine reuptake, glycine receptor, NMDA receptors and 5-HT3 receptors.
WITHDRAWAL SYNDROME
Heavy consumption of ethanol leads to acquired tolerance and physical dependence. Dependence becomes apparent 6-12 hours after cessation of heavy drinking as a withdrawal syndrome that may include tremor, nausea and vomiting, excessive sweating, agitation and anxiety. In some individuals this can be followed by visual, tactile and auditory hallucinations. Generalized seizures may manifest after 24-48 hours. Finally, 48- 72 hours after cessation, an alcohol withdrawal delirium (delirium tremens) may become apparent. Delirium tremens is associated with 5-15% mortality.
The chronic use of alcohol as well as that of other sedatives is associated with the development of depression; the risk of suicide among alcoholics is high.
Alcohol is toxic to many organ systems; as a result, the medical complications of alcohol abuse and dependence include liver disease, cardiovascular disease, endocrine and gastrointestinal effects, and malnutrition, in addition to cognitive deficits. Ethanol readily crosses the placental barrier, a major cause of mental retardation.
TREATMENT OF ALCOHOL WITHDRAWAL
Pharmacologic treatment of alcohol withdrawal syndrome involves the use of medications that are cross-tolerant with alcohol. Benzodiazepines are the preferred agents for treating the symptoms of alcohol withdrawal syndrome. Diazepam and chlordiazepoxide are long-acting agents that have been shown to be excellent in treating alcohol withdrawal symptoms. Because of the long half-life of these drugs, withdrawal is smoother, and rebound withdrawal symptoms are less likely to occur. Lorazepam and oxazepam are intermediate/short-acting drugs; as they are not as dependent on hepatic metabolism as other benzodiazepines, they may be preferable in the elderly and those with liver failure.
TREATMENT OF ALCOHOL ADDICTION
Three drugs are currently FDA-approved for treatment of alcoholism: disulfiram, naltrexone and acamprosate.
Disulfiram, an inhibitor of aldehyde dehydrogenase, has been used adjunctively to create aversion to drinking. If ethanol is consumed by a patient who has taken disulfiram, acetaldehyde accumulation leads to nausea, headache, flushing, and hypotension. No large trials are available that demonstrate increased alcohol abstinence with disulfiram.
Naltrexone is an orally available opioid receptor antagonist. Clinical trials have shown that naltrexone can reduce craving for alcohol, but the effect is modest.
One of the consequences of long-term alcohol consumption is a hyperactive glutamate system that persists even after alcohol consumption ceases. Acamprosate, an NMDA receptor antagonist, has been shown to be efficacious in preventing relapse to alcohol drinking.
The antiepileptic agent topiramate facilitates GABA function and antagonizes glutamate receptors and may decrease mesocorticolimbic dopamine release after alcohol and reduce cravings. Topiramate is not FDA-approved for this indication.
Benzodiazepines and Barbiturates
BENZODIAZEPINES
Benzodiazepines are among the most commonly prescribed drugs worldwide. They are used mainly for the treatment of anxiety disorders and insomnia. Benzodiazepines and barbiturates can cause both physical dependence and addiction, although addiction is rare.
WITHDRAWAL SYNDROME
Signs and symptoms of benzodiazepine withdrawal can include tremors, anxiety, perceptual disturbances, dysphoria, psychosis, and seizures. Rapid recognition and treatment of benzodiazepine withdrawal is crucial because the syndrome can be life- threatening.
MANAGEMENT OF BENZODIAZEPINE WITHDRAWAL
If the patient is on a short-acting drug, they are switched to a long-acting drug; the rationale is that less severe withdrawal symptoms occur with long-acting drugs. Diazepam is the most used agent. Then the dose is gradually reduced.
BARBITURATES
The use of barbiturates has declined greatly in recent years due to the increased safety and efficacy of newer medications. Abuse problems with barbiturates resemble those seen with benzodiazepines.
Methylxanthines
METHYLXANTHINES
Caffeine and the related methylxanthines theophylline and theobromine are ubiquitous drugs occurring in coffee, tea, cola, and other carbonated drinks, chocolate, and in many prescribed and over-the-counter medications. Caffeine is the most widely consumed stimulant.
MECHANISM OF ACTION
Methylxanthines act by blocking adenosine receptors that are expressed presynaptically on many neurons, including adrenergic neurons. Activation of adenosine receptors inhibits norepinephrine release, therefore competitive antagonism of the receptors by caffeine disinhibits norepinephrine release and, thus, acts as a stimulant. Caffeine may also block adenosine receptors on cortical neurons, and thereby disinhibit these neurons.
Additionally, CNS adenosine is a natural promoter of sleep and drowsiness; by blocking adenosine receptors, caffeine has alerting effects and produces insomnia.
ACTIONS
CNS
The caffeine contained in one to two cups of coffee (100–200 mg) causes a decrease in fatigue and increased mental alertness as a result of stimulating the cortex and other areas of the brain.
Consumption of 1.5 g of caffeine (12 to 15 cups of coffee) produces anxiety and tremors.
The spinal cord is stimulated only by very high doses (2–5 g) of caffeine.
CV
A high dose of caffeine has positive inotropic and chronotropic effects on the heart.
Caffeine has a mild diuretic action that increases urinary output of sodium, chloride, and potassium.
GI
Methylxanthines stimulate secretion of HCl from the gastric mucosa; individuals with peptic ulcers should avoid beverages containing methylxanthines.
PHARMACOKINETICS
Methylxanthines are well absorbed orally. Caffeine distributes throughout the body, including the brain. The drugs cross the placenta to the fetus and is secreted into the mother’s milk. Methylxanthines are metabolized in the liver, generally by CYP1A2, and the metabolites are excreted in the urine.
USES
Theophylline is used in chronic asthma.
A combination of caffeine and ergotamine is used for migraine. Caffeine is added to further enhance the vasoconstrictive effect of ergotamine without increasing ergotamine dose.
ADVERSE EFFECTS
Moderate doses of caffeine cause insomnia, anxiety and agitation.
High dose causes emesis and convulsions.
The lethal dose is about 10 g of caffeine (about 100 cups of coffee), which induces cardiac arrhythmias. Death from caffeine is highly unlikely.
TOLERANCE AND WITHDRAWAL
Tolerance can rapidly develop to the stimulating properties of caffeine.
Caffeine withdrawal consists of feelings of fatigue and sedation. With higher doses headaches and nausea can occur.
Addiction is rare. Caffeine is not listed in the category of addicting stimulants.
Cocaine
COCAINE
Widely available and highly addictive drug that is currently abused daily by more than 3 million people in the US. Because of its abuse potential, cocaine is classified as a Schedule II drug by the U.S. Drug Enforcement Agency.
MECHANISM OF ACTION
Cocaine inhibits dopamine, norepinephrine and serotonin reuptake. This block potentiates and prolongs the CNS and peripheral actions of these monoamines. In particular, the prolongation of dopaminergic effects in the brain’s 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.
ACTIONS
CNS
The behavioral effects of cocaine result from stimulation of the cortex and brainstem. Cocaine acutely increases mental awareness and produces a feeling of well-being and euphoria. Involuntary motor activity, stereotyped behaviour and paranoia may occur after repeated doses. Irritability and increased risk of violence are found among heavy chronic users. At high doses, it causes tremors and convulsions, followed by respiratory and vasomotor depression.
SYMPATHETIC NERVOUS SYSTEM
Peripherally, cocaine potentiates the action of norepinephrine resulting in adrenergic stimulation, thus producing the characteristic physical findings of tachycardia, hypertension, mydriasis, and diaphoresis.
PHARMACOKINETICS
Cocaine is often self-administered by chewing, intranasal snorting, smoking, or IV injection. Because the onset of action is most rapid, the potential for overdosage and dependence is greatest with IV injection and freebase (“crack”) smoking. Cocaine is rapidly de-esterified and demethylated to benzoylecgonine, which is excreted in the urine. Detection of this substance in the urine identifies a user.
WITHDRAWAL SYNDROME
The symptoms of withdrawal include dysphoria, depression, sleepiness, fatigue, cocaine craving and bradycardia. Cocaine withdrawal is generally mild, therefore treatment of withdrawal symptoms is usually not required.
TREATMENT OF COCAINE ADDICTION
A large number of agents, mainly antidepressants and dopamine agonists have been tested as treatments for cocaine abuse, but none have demonstrated clear efficacy.
Amphetamines
AMPHETAMINES
Amphetamine was introduced into medical practice in 1936. Many amphetamine derivatives, such as methamphetamine, and methylphenidate were subsequently introduced. Amphetamines are classified as Schedule II drugs by the U.S. Drug Enforcement Agency.
MECHANISM OF ACTION
Amphetamines increase release of catecholamine neurotransmitters, including dopamine. They are also weak inhibitors of MAO and possible direct catecholaminergic agonists in the brain. Behavioral effects are similar to those of cocaine.
ACTIONS
CNS
Behavioral effects probably due to release of dopamine rather than norepinephrine.
Amphetamine stimulates the entire cerebrospinal axis, cortex, brainstem, and medulla.
This leads to increased alertness, decreased fatigue, depressed appetite, and insomnia.
These CNS stimulant effects of amphetamine and its derivatives have led to their use in therapy for hyperactivity in children, narcolepsy, and for appetite control.
At high doses, psychosis and convulsions can ensue.
SYMPATHETIC NERVOUS SYSTEM
Amphetamine acts also on adrenergic system, indirectly, stimulating receptors through norepinephrine release.
PHARMACOKINETICS
Amphetamine is completely absorbed from the GI tract, metabolized by the liver, and excreted in the urine. Amphetamine abusers often administer the drugs by IV injection and by smoking. The euphoria caused by amphetamine lasts 4 to 6 hours (4 – 8 times longer than the effects of cocaine.)
USES
Attention deficit syndrome: Amphetamine and methylphenidate improve attention and alleviate many behavioral problems associated with this syndrome.
Narcolepsy: Amphetamine and Methylphenidate.
ADVERSE EFFECTS
CNS
Insomnia, irritability, weakness, dizziness, tremor, hyperactive reflexes. Confusion, delirium, panic states, suicide tendencies.
CV
Palpitations, arrhythmias, hypertension, anginal pain, circulatory collapse. Headache, chills, sweating. Should not be given to individuals with CV disease or receiving MAOI.
GI
Anorexia, nausea, vomiting, abdominal cramps, diarrhea.
TOLERANCE AND WITHDRAWAL
Tolerance can be marked, and an abstinence syndrome can occur upon withdrawal. Symptoms include increased appetite, sleepiness, exhaustion, and mental depression. Antidepressants may be indicated.
Nicotine
NICOTINE
Active ingredient of tobacco. It is second only to caffeine as the most widely used CNS stimulant and is second only to alcohol as the most abused drug. In combination with the tars and CO in cigarette smoke, nicotine represents a serious risk factor for lung and CV disease, various cancers and other illnesses.
In terms of numbers affected, addiction to nicotine exceeds all other forms of addiction, affecting more than 50% of adults in some countries.
MECHANISM OF ACTION
Nicotine is a selective full agonist of the nicotine receptor. The rewarding effect of nicotine requires involvement of the ventral tegmental area , where nicotinic receptors are expressed on dopamine neurons. When nicotine excites these neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs.
ACTIONS
In low doses, nicotine causes ganglionic stimulation by depolarization.
At high doses, nicotine causes ganglionic blockade.
CNS
Nicotine is highly lipid soluble and readily crosses the blood-brain barrier. Cigarette smoking or administration of low doses of nicotine produces some degree of euphoria and arousal as well as relaxation. It improves attention, learning, problem solving, and reaction time.
High doses of nicotine result in central respiratory paralysis and severe hypotension caused by medullary paralysis.
Nicotine is an appetite suppressant.
PERIPHERAL EFFECTS
The peripheral effects of nicotine are complex. Stimulation of sympathetic ganglia as well as the adrenal medulla increases blood pressure and heart rate. Thus, use of tobacco is particularly harmful in hypertensive patients. Many patients with peripheral vascular disease experience an exacerbation of symptoms with smoking. For example, nicotine- induced vasoconstriction can decrease coronary blood flow, adversely affecting a patient with angina.
Stimulation of parasympathetic ganglia also increases motor activity of the bowel. At higher doses, blood pressure falls, and activity ceases in both the gastrointestinal tract and bladder musculature as a result of a nicotine-induced block of parasympathetic ganglia.
PHARMACOKINETICS
Nicotine is highly liposoluble, therefore absorption occurs readily via the oral mucosa, lungs, gastrointestinal mucosa, and skin.
Nicotine crosses the placental membrane and is secreted in the milk of lactating women.
By inhaling tobacco smoke, the average smoker takes in 1 to 2 mg of nicotine per cigarette (most cigarettes contain 6 to 8 mg of nicotine).
The acute lethal dose of nicotine is 60 mg.
More than 90 % of the nicotine inhaled in smoke is absorbed.
Clearance of nicotine involves metabolism in the lung and the liver and urinary excretion.
Tolerance to the toxic effects of nicotine develops rapidly, often within days after beginning usage.
WITHDRAWAL SYNDROME
Nicotine withdrawal is mild, and involves irritability and sleeplessness. However, nicotine is among the most addictive drugs and relapse after attempted cessation is very common.
Treatment for Nicotine Addiction
TREATMENT FOR NICOTINE ADDICTION
There are three FDA-approved classes of smoking cessation pharmacotherapies: nicotine replacement therapy, sustained-release bupropion and varenicline.
NICOTINE REPLACEMENT THERAPY
Nicotine can be administered by transdermal patch, gum, nasal spray, vapor inhaler or by lozenge for buccal absorption.
SUSTAINED-RELEASE BUPROPION
The atypical antidepressant bupropion has been approved for nicotine cessation therapy. The exact mechanism of action is unclear but it is likely to involve dopamine and norepinephrine reuptake blockade as well as antagonism of nicotinic receptors.
VARENICLINE
Varenicline is a partial agonist at neuronal nicotinic acetylcholine receptors in the CNS. It is useful as an adjunct in the management of smoking cessation. Additionally, varenicline tends to attenuate the rewarding effects of nicotine if a person relapses and uses tobacco. Patients should be monitored for suicidal thoughts, vivid nightmares and mood changes.
Opioids
OPIOIDS
The most commonly abused drugs in this group are heroin, morphine, codeine and oxycodone, and –among health professionals- meperidine and fentanyl.
TOLERANCE, DEPENDENCE AND WITHDRAWAL
All opioids induce strong tolerance and dependence.
Addiction to heroin or other short-acting opioids produces behavioural disruptions and usually becomes incompatible with a productive life.
The withdrawal syndrome is very unpleasant, but not life-threatening. It includes dysphoria, lacrimation, rhinorrhea, yawning, sweating, weakness, gooseflesh, nausea and vomiting, tremor, muscle jerks and hyperpnea.
TREATMENT OF OPIOID WITHDRAWAL
DETOXIFICATION USING OPIOID AGONISTS
Treatment involves replacement of the illicit agent with a long-acting opioid, followed by slow dose reduction. Long acting opioids produce withdrawal syndromes that are milder thus producing a smoother withdrawal. The time-honoured opioid agonist treatment is methadone maintenance.
Buprenorphine, a long-acting partial μ receptor agonist and κ receptor antagonist was approved by the FDA in 2002 for the management of opioid dependence. Buprenorphine produces minimal withdrawal symptoms, has a low potential for overdose and the ability to block heroin effects.
DETOXIFICATION USING ADRENERGIC AGONISTS
Clonidine and lofexidine are increasingly being used in opioid detoxification. Chronic opioid intake leads to tolerance to the effects mediate by opioid receptors like euphoria, and tolerance to the effects of opioids on the ANS, mediated by noradrenergic pathways. Abrupt withdrawal leads to a rebound rapid firing of the neurons. A noradrenergic storm results and is responsible for many of the withdrawal symptoms. Clonidine and lofexidine act as presynaptic α2 agonists, which inhibit this and are able to attenuate symptoms.
DETOXIFICATION USING OPIOID ANTAGONISTS
Naltrexone is an antagonist with a high affinity for the μ opioid receptor. Naltrexone will not satisfy craving or relieve withdrawal symptoms. Naltrexone treatment does not appeal to the average heroin addict, but it can be used after detoxification for patients with high motivation to remain opioid-free.
Marijuana
MARIJUANA
The smoke from burning cannabis contains many chemicals, including 61 different cannabinoids that have been identified. One of these, ∆9-tetrahydrocannabinol (∆9-THC, THC, dronabinol) produces most of the characteristic pharmacological effects of smoked marihuana.
MECHANISM OF ACTION
Two cannabinoid receptor subtypes have been identified: CB1 and CB2. The CB1 receptor is found primarily in the brain and mediates the psychological effects of THC. CB2 receptors are present mainly on immune cells.
Both cannabinoid receptors are G protein-linked receptors. Activation of cannabinoid receptors leads to inhibition of adenylyl cyclase, opening of potassium channels and closing of calcium channels.
Two endogenous cannabinoid ligands have been found (anandamide and 2- arachidonylglycerol). These ligands are not stored, but are synthesized by neurons in response to depolarization and consequent calcium influx.
ACTIONS
THC can produce euphoria, followed by drowsiness and relaxation. It affects short-term memory and mental activity, decreases muscle strength, and impairs highly skilled motor activity.
Its wide range of effects include appetite stimulation, xerostomia, visual hallucinations, delusions, and enhancement of sensory activity.
Adverse effects include increased heart rate, decreased blood pressure, and reddening of the conjunctiva. At high doses, a toxic psychosis develops.
TOLERANCE AND PHYSICAL DEPENDENCE
Tolerance and mild physical dependence occur with continued, frequent use of the drug.
Few abusers seek treatment, but recent studies have suggested that behavioral treatments can stop abuse and improve cognitive functioning.
USES
Therapeutic THC is called dronabinol. Dronabinol is FDA-approved for anorexia associated with weight loss in patients with AIDS; and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetic treatments.
LSD
LSD
The LSD-like group of drugs include LSD (lysergic acid diethylamide), mescaline, psilocybin and their related compounds. These substances differ chemically, but share some chemical features and even more pharmacologic ones. LSD is a semisynthetic chemical related to the ergot alkaloids.
Mescaline and psilocybin are found in nature. These drugs also have chemical resemblances to three major neurotransmitters: norepinephrine, dopamine and serotonin.
MECHANISM OF ACTION
The hallucinogenic actions of LSD appear to be mediated by agonist effects at subtypes of 5-HT2 receptors in the CNS.
Patients who have taken LSD generally present with a combination of somatic and psychomimetic symptoms. Somatic symptoms, which are usually due to sympathomimetic effects, include: mydriasis, hypertension, tachycardia, increased body temperature, flushing, sweating, tremors and piloerection.
TOLERANCE, PHYSICAL DEPENDENCE AND WITHDRAWAL
Tolerance develops to the behavioural effects of LSD after 3 to 4 daily doses, but it does not cause addiction and no withdrawal syndrome has been observed.
ADVERSE EFFECTS
Users may require medical attention because of “bad trips”. Severe agitation may require medication; diazepam is effective.
Phencyclidine (PCP)
PHENCYCLIDINE (PCP)
Originally introduced in 1957 as an anesthetic. Withdrawn in humans due to adverse effects but retained in veterinary practice. Ketamine, an analog, replaced phencyclidine as an anesthetic for use in humans.
PCP is classified as a dissociative anesthetic. PCP acts mainly in the CNS, producing both stimulation and depression. Its sympathomimetic effects are thought to be due to reuptake inhibition of norepinephrine and dopamine. PCP also exerts some cholinergic and anticholinergic effects and has some other actions at nicotinic and opioid receptors. The dissociative properties of PCP are believed to be due to its actions as a non-competitive antagonist at NMDA receptors. NMDA antagonists have been known to produce behavioral effects similar to those observed in schizophrenia.
Clinical manifestations include violent or bizarre behavior, psychosis, nystagmus, tachycardia, hypertension, diaphoresis, miosis, anesthesia, and analgesia. An important diagnostic clue is nystagmus. Many CNS depressants can produce nystagmus when taken in high doses; however, the patient is generally sedated when nystagmus is observed. In PCP exposure, the patient may have nystagmus when he or she is awake and agitated.
There is no specific antidote for PCP. Extreme violent psychotic behavior requires sedation with parenteral benzodiazepines. Seizures should be treated with benzodiazepines.
MDMA (Ecstasy)
MDMA (“ECSTASY”)
The main effect of methylenedioxyamphetamine (MDMA) seems to be to foster feelings of empathy and intimacy without impairing intellectual capacities.
Similar to the amphetamines, MDMA causes release of biogenic amines by reversing the action of their transporters. It has preferential affinity for the serotonin transporter (SERT) and therefore most strongly increases the concentration of serotonin in the synaptic cleft. The release is so profound that there is a marked intracellular depletion for 24 hours after a single dose.
Acute effects of MDMA are dose-dependent and include tachycardia, muscle aches, agitation, hyperthermia and seizures.
Withdrawal is marked by a mood ‘offset’ characterized by depression, lasting up to several weeks.
MDMA produces degeneration of serotonergic neurons in rats.
Inhalants
NITROUS OXIDE
Nitrous oxide is sometimes used as intoxicant by medical personnel. It produces euphoria and analgesia and then loss of consciousness. Usually taken as 35% N2O mixed with O2. Administration of 100% N2O may cause asphyxia and death.
VOLATILE ORGANIC SOLVENTS
Aliphatic and aromatic hydrocarbons. Include substances such as gasoline, paint thinner, lighter fluid, glue and degreasers. Boys in early teen years from lower socioeconomic classes are the principal users. They produce a sense of exhilaration and light-headedness. Toxicity depends on the properties of individual solvents. They have been implicated in cancer, cardiotoxicity, neuropathies and hepatotoxicity.
ORGANIC NITRITES
Amyl nitrite produces dilation of smooth muscle and has been used for treatment of angina. In recent years amyl nitrite and butyl nitrite have been used to enhance erection. They are not addictive.
Anabolic Steroids
ANABOLIC STEROIDS
Anabolic–androgenic steroids are used to increase muscle size and definition by body- building competitors and are sometimes coabused with other growth enhancers, such as human growth hormone. In sports in which mass, physical size, or even total strength is important, the abuse of anabolic steroids provides a shortcut to attainment of the physical stature that might otherwise require much more extensive training and exercise.
Anabolic steroid abuse is not limited to professional athletes and body builders. They are abused by adult men and women who are not athletes, who are blue-collar and white- collar workers, and by male and female athletes at the college, high school, and junior high school levels.
