Medical And Behavioral Toxicity Overview

Quit Alcohol

How To Control Alcohol by Seb Grant

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Alcohol and other drugs of abuse cause considerable adverse health effects. Both legal and illegal drugs (substances) of abuse are taken to modify mood, feeling, thinking, and perception. As with most drugs (medications), both acute and chronic toxicities occur. In general, the term acute refers to the short period of time when the drug is present in the body, exerting its main effects. The term chronic refers to a longer period, usually years. Acute toxicity results in the impairment of behavior leading to other complications (e.g., trauma), and in the case of some drugs, high doses can decrease breathing (respiratory depression) or change the rhythm of the heart, leading to accidental or intentional death. Chronic use can result in organ damage, which may lead to chronic illness or death (as with alcoholic cirrhosis of the liver). Persistent use of many classes of drugs also leads to tolerance (so that an increased amount of the drug is required to produce the same effects) and physiologic (physical) dependence, so that a withdrawal syndrome is associated with sudden cessation of drug use. Drug users who use hypodermic needles and syringes (injecting drug users [IDUs]) are at risk for blood-borne diseases associated with the use of contaminated equipment, such as Hepatitis B and C and human immunodeficiency virus (HIV 1 and 2, the viruses responsible for acquired immunodeficiency syndrome [AIDS]).

This entry focuses on alcohol as the representative drug, but other drugs of abuse are mentioned when appropriate. In North America, the diagnosis of alcohol and other psychoactive substance abuse/dependence is usually made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association (APA). The fourth edition, text revision, referred to as DSM-IV-TR, defines psy-choactive substance dependence as the presence of at least three of the following (within the same 12-month period):

1. tolerance, as defined by either of the following: (a) need for markedly increased amounts of the substance to achieve intoxication or desired effect; (b) markedly diminished effect with continued use of the same amount of the substance

2. withdrawal, as manifested by either of the following: (a) the characteristic withdrawal syndrome for the substance (b) the same (or closely related) substance taken to relieve or avoid withdrawal symptoms

3. the substance is often taken in larger amounts or over a longer period than was intended

4. a persistent desire for or unsuccessful efforts to cut down or control substance use

5. a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chain smoking), or recover from its effects

6. important social, occupational, or recreational activities are given up or reduced because of substance use

7. continued substance use despite knowledge of having had a persistent or recurrent physical or psychological problem that was likely to have been caused or exacerbated (worsened) by the substance (e.g., recurrent cocaine use despite recognition of cocaine-induced depression; continued drinking despite recognition that an ulcer was made worse by alcohol consumption)

The diagnosis of alcohol and other substance abuse (as opposed to dependence) relies on the following:

A maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by one or more of the following occurring at any time during the same 12-month period:

1. recurrent substance use resulting in a failure to fulfill major obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect ofchildren or household)

2. recurrent use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use)

3. recurrent substance-related legal problems (e.g., multiple arrests for substance-related disorderly conduct)

4. continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with family members about consequences of intoxication; physical fights)

Alternatively, the symptoms have never met criteria for substance dependence for this class of substance.

These criteria continue to evolve, as can be tracked at the Web site maintained by the American Psychiatric Association, and are likely to be changed in the future (progress was under way as of 2008 for the publication of DSM-V, which was expected to be published in 2012). Clearly the lack of one of the above diagnoses does not preclude a given person from being at risk for complications of alcohol or drug use (e.g., trauma as a result of intoxication).

acute effects of alcohol

At the level of the cell, very high doses of alcohol (ethanol) seem to act by disrupting fat (lipid)

structure in the central nervous system (anesthetic effect). Lower doses are thought to interact with various proteins and neurotransmitter receptors, such as glutamate, gamma-amino butyric acid (GABA), glycine, serotonin (e.g., 5HT3), and neuronal nicotinic receptors. Other actions may involve modulation of membrane ion (e.g., calcium) channels. The reinforcing (rewarding) effects of alcohol may be mediated via dopamine (a neurotransmitter) in specific brain regions; dopamine acts as an intermediary compound in the reinforcement process. The reinforcement of responses to other drugs of abuse, such as cocaine, is also thought to be mediated via dopamine.

The acute effects of alcohol are well known. In low doses, it causes blood vessels to dilate, and the skin to become flushed and warm. The individual under the influence of alcohol experiences a feeling of relaxation and mild sedation but may become talkative with loss of inhibitory control of emotions. Small doses (one to two drinks) do not impair complex intellectual ability; however, as the dose increases (two or more drinks or as the blood alcohol concentration approaches and exceeds the legal limit) impairment at multiple levels of the nervous system occurs. All types of motor performance are eventually affected, including maintenance of posture, control of speech, and eye movements. Movement becomes slower and more inaccurate. Mental functioning decreases, such that there is impairment in attention and concentration and a diminishing ability to make mental associations. Concurrently, the ability to attend to incoming sensory information is decreased. Night and color vision are impaired. Judgment and discrimination and the ability to think and reason clearly are adversely affected. Further increased doses result in a stuporous condition associated with sleeping, with vomiting, and little appreciation of surroundings. This level is followed by coma and sometimes death from decreases in the functioning of the brain centers that control respiration.

acute effects of other drugs of abuse

Other drugs of abuse can be classified into stimulants, depressants, opioids, and drugs that alter perception (including hallucinogens). The effect of any drug depends on the dose taken at any one time, the previous drug experience of the user, the circumstances in which the drug is taken, and the manner (route of administration) in which the drug is taken.

Stimulants such as cocaine and amphetamine produce euphoria, increased confidence, increased sensory awareness, increased anxiety and suspi-ciousness, decreased appetite, and a decreased need for sleep. Physiological effects include increases in heart rate, blood pressure, and pupil size, and decreases in skin temperature.

Depressants such as the minor tranquillizers (including the benzodiazepines, barbiturates, and other sedative-hypnotics) produce acute effects of a similar nature to alcohol, which is also a depressant. Actual effects vary according to drug, so that benzodiazepines (such as diazepam [Valium]) produce less drunkenness compared to alcohol or barbiturates. The term opioid refers to both drugs derived from opium (opiates) and other synthetic drugs with similar actions, those acting on the same receptor system. The term narcotic is usually synonymous with opioid, but it can technically also include other drugs listed in the Harrison Narcotics Act (e.g., cocaine). Opioids produce euphoria, sedation (to which rapid tolerance develops), itching, increased talkativeness, increased or decreased activity, a sensation of stomach turning, nausea, and vomiting. There are minor changes in blood pressure, and the pupils become constricted (smaller). Drugs that alter perception include those above as well as marijuana, phencyclidine (PCP), and lysergic acid diethylamide (LSD). In general, most drugs of abuse can cause hallucinations under some circumstances. The drugs that more specifically affect perception (hallucinogens) produce a combination of depersonalization, altered time perception, body-image distortion, perceptual distortions (usually visual), and sometimes feelings of insight. Physiological effects such as changes in heart rate and blood pressure may also occur.

harmful effects

This section reviews the harmful effects of alcohol and drugs. Alcohol and drugs contribute not only to the ill health of the individual, but directly to reckless behaviors that result in injury. For example, the impact of alcohol and drug abuse on the rate of motor vehicle accidents is well-known, but individuals under the influence of alcohol or drugs also engage in other dangerous behaviors at a high rate. They are more likely than others to harm themselves accidentally, as in falls or intentionally, as in suicide. They are also more likely to harm others, as when they engage in violent activities and/or in criminal behaviors.

Accidents. Alcohol is a significant factor in accident-related deaths. The main causes are motor-vehicle accidents, falls, drownings, and fires and burns. Approximately 50 percent of motor vehicle fatalities (driver, pedestrian, or cyclist) in the United States are alcohol-related, with the incidence having decreased slightly in the 1990s and early years of the twenty-first century. These alcohol-related accidents are more common at nights and on weekends. Falls are the most frequent cause of nonfatal accidents and the second most frequent cause of fatal accidents. Various studies indicate that alcohol is a factor in 17 to 53 percent of fatal falls and 21 to 77 percent of nonfatal falls (Hingson & Howland, 1987; Kool et al., 2008). Fatal falls occur at the highest rate among young males (Ramstedt, 2008). The higher the blood alcohol content (BAC), the higher is the risk for falls. The third leading cause of accidental death in the United States is drowning. About half (4765%) of adult deaths by drowning are alcohol-related (U.S. Department of Health and Human Services, 2000). Fires and burns are the fourth leading cause of accidental death in the United States. Studies on burn victims show that alcohol intoxication is common. Cigarette smoking while drinking is a common cause of fires and burn injuries, with estimates of the rate of intoxication ranging from 37 to 64 percent. Users of other drugs of abuse (e.g., cocaine and opioids) also have higher rates of accidents than the non-drug-abusing population. The combination of cocaine and alcohol has been reported to be commonly associated with motor-vehicle deaths. Between 1984 and 1987 in New York City, 18 percent of motor-vehicle deaths showed evidence of cocaine use at autopsy. Cigarette smokers have higher rates of accidents than do nonsmokers. In an Australian study of fatally injured drivers, those drivers who tested positive for any psychoactive substance were significantly more likely than drug-free drivers to have been the individual responsible for the accident (Drummer et al., 2004). Drugs that alter perception, such as PCP, are also associated with accidents mostly related to an impaired sense of judgment.

Crime. Associations between criminal activity and alcohol use have been established; however, a clear causal relationship between alcohol use and crime has not been established as of 2008. The strongest association between crime and alcohol use occurs in young males. Other forms of drug abuse (e.g., heroin and cocaine) have much higher associations with criminality. For example, the majority of persons enrolled in methadone programs have extensive criminal careers. Those involved in drug dealing are at a high risk of being either a perpetrator or a victim of homicide.

Family Violence. Several studies show an association between alcohol use/abuse and spousal abuse; however, the nature of this interaction was not well understood as of 2008. Intoxication is associated with negative behaviors among episodic drinkers, which are less common among steady drinkers, suggesting that drinking may be a short-term solution to problems for regular drinkers. Clearly, alcohol use is associated with physical violence in some families, and there also appears to be a link between alcohol and child abuse. Female caregivers with a diagnosis of alcohol abuse, alcohol dependence, recurrent depression, or antisocial personality are more likely to report physical abuse of their children than those without these diagnoses (Bland & Orn, 1986).

Suicide. Alcohol dependence is a risk factor for suicide; the lifetime risk of an alcohol-dependent individual committing suicide ranges from 2 to 18 percent. From 20 to 36 percent of suicide victims have a history of alcohol abuse or had been drinking prior to death. Alcohol use is linked more often to impulsive than to premeditated suicides and to the use of firearms rather than to other modes of killing. Death from overdose of illicit drugs is common; most of these are thought to be accidental but some are intentional.

Trauma or Severe Injuries. A history of trauma has been found to be a marker for (sign of) alcohol abuse. Emergency room trauma victims have high rates of intoxication. Furthermore, heavy alcohol use both interferes with recovery from serious injuries and increases rates of mortality for a given injury. Users of illicit drugs have a higher age-

adjusted rate of mortality than do non-users. Many of these deaths result from trauma.

Effects in Pregnancy. Alcohol is firmly established as a teratogen (an agent that produces defects in the developing fetus) and is considered the most common known cause of mental retardation. Fetal alcohol syndrome (FAS) defects range from specific structural bodily changes to growth retardation and subtle cognitive-behavioral abnormalities. The diagnostic criteria for fetal alcohol syndrome include: prenatal (before birth) and postnatal (after birth) growth retardation; characteristic craniofacial defects; central nervous system (CNS) dysfunction; and organ system malformations. When only some of these criteria are met, the diagnosis is termed fetal alcohol effects (U.S. Department of Health and Human Services, 2000). The abnormalities in physical appearance seem to decrease with age, whereas the cognitive deficiencies tend to persist. There is no clear dose-response relationship between alcohol use and abnormalities. The safe amount of drinking during pregnancy (if it exists at all) is unknown. The peak level of blood (or brain) alcohol attained and the timing in relation to gestation (and particular organ development) are probably more important than the total amount of alcohol consumed during pregnancy. Genetic and maternal variables also seem to be important. Native American and African American children seem to be at high risk. While the public is generally aware of the relationship between alcohol consumption and fetal abnormality, surveys reveal that there is a need for greater public education in this area.

Use of other substances of abuse can also result in negative pregnancy outcomes. Smoking is associated with low birth weight. Cocaine use in pregnancy has been associated with complications (e.g., placental separation and in utero bleeding), and it appears to be associated with congenital abnormalities. Heroin use in pregnancy is associated with premature delivery and low birth weight; often there is a withdrawal syndrome in the baby at birth. Methadone (a long-acting opioid) usually reduces rates of prematurity and low birth weight but still causes as much or more opioid withdrawal in the newborn.

Cancer. Epidemiologic evidence exists for an increased risk of certain types of cancer in association with alcohol consumption. These include cancer of the esophagus, oropharynx (mouth and throat), and liver. Other cancers possibly associated with alcohol consumption include cancer of the breast, stomach, prostate, and colon (Geokas, 1984). Alcohol plays a synergistic (multiplicative) role with smoking tobacco in the development of cancer, particularly with respect to the head, neck, and esophagus. There are several possible mechanisms through which alcohol enhances the onset of cancer. Alcohol appears to modify the immune response to cancers, facilitate delivery of carcinogens (substances which enhance cancer onset), and impair protective responses. Overall, alcohol is considered to act as a co-carcinogen; for example, it increases the likelihood of certain smoking-induced cancers.

Smoking is, of course, well established as a cause of lung as well as other cancers. Smoking is responsible for 85 percent of lung cancers and has been associated with cancers of the mouth, pharynx, larynx, esophagus, stomach, pancreas, uterine cervix, kidney, ureter, and bladder (Bartecchi et al., 1994). Chewing tobacco (smokeless tobacco) is associated with mouth cancer. The chewing of betel nuts with lime is common in Asia and results in the absorption of arecoline (a mild stimulant). This practice also causes cancer of the mouth. It has been suggested that marijuana smoking also causes lung cancer, since high tar levels are present in the smoked products.

alcohol use and abuse among adolescents

Alcohol use among adolescents is a serious worldwide problem. Surveys indicate that up to 54 percent of eighth graders, and up to 84 percent of twelfth graders report having consumed alcohol (O'Malley et al., 1998). There is little doubt that parents' attitudes and habits concerning drinking are important influences on adolescent drinking (Ary et al., 1993). However, there is also evidence that adolescents who abuse alcohol often have coexisting psychopathology such as conduct disorder and bouts of depression and anxiety (Clark & Bukstein, 1998).

Another significant reason for concern about alcohol ingestion by adolescents is the close association of alcohol abuse with the use of other drugs. There is considerable evidence that alcohol use tends to precede the use of illicit drugs, and some researchers argue that, based on long-term studies, alcohol serves as a gateway to the use of illicit substances. Alcohol users were found to have a significantly higher prevalence of cigarette smoking, marijuana use, and cocaine use than non-users of alcohol, as early as the eighth grade. This difference persists through grade 12 and thereafter (Kandel & Yamaguchi, 1993). In one twin study, early use of alcohol by male adolescents (before age 17) was positively correlated with adult alcohol use and dependence and to the use of other drugs of abuse (Grant et al., 2006).

effects of alcohol and other drugs on bodily systems The toxic effects of alcohol on organ systems are pervasive, largely because alcohol mixes easily with water, and is thus distributed widely throughout the body. While alcohol is itself toxic, its effects are also mediated by acetaldehyde, a toxic metabolite. Tobacco also has pervasive toxic effects; when inhaled as cigarette smoke, its components escape metabolism by the liver and are introduced directly and rapidly into the bloodstream. Also like alcohol, the toxic effects of tobacco are due to more than one substance, chief among them nicotine, which is responsible for the cardiotoxic effects of tobacco, and tar, which has its greatest noxious effects on the lungs and mucus membranes. The toxic effects of other drugs of abuse on organ systems are more limited but still not insignificant.

Neurologic Effects. Acute alcohol consumption causes impairment as described above. Alcohol potentiates the action of many drugs that produce acute effects on the brain. High blood-alcohol levels can result in blackouts. This condition is the acute loss of memory associated with intoxication, although the person usually behaves in apparently normal fashion during this period. Blackouts are also seen with the ingestion of other CNS depressants, such as barbiturates and benzodiazepines.

The main adverse neural consequences of chronic alcohol consumption are the following: brain damage (manifested by dementia and alcohol amnestic syndrome); complications of the withdrawal syndrome (seizures, hallucinations); and peripheral neuropathy. Chronic alcohol consumption results in tolerance, followed by an increased long-term consumption that likely leads to tissue damage. Physical dependence may also develop, manifested by a withdrawal syndrome on sudden cessation of drinking. The brain damage, when severe, is usually classified as one of two main disorders. The first is a type of global (general) dementia. It is estimated that 20 percent of those individuals admitted to state mental hospitals suffer from alcohol-induced dementia (Freund & Ballinger, 1988). The second is an alcohol-induced amnestic (memory-loss) syndrome, more commonly known as Wernicke-Kor-sakoff syndrome. This is related to thiamine (Vitamin B1) deficiency. The Wernicke component refers to the acute neurologic signs, which consist of ocular (eye) problems such as a sixth cranial nerve palsy (disturbed lateral gaze), and ataxia (gross incoordination of muscle movements); the Korsakoff component refers to the memory impairment, which tends to be selective for short-term memory and is usually not amenable to treatment once it has become manifest.

Milder forms of these disorders are also detectable with neuropsychologic testing or brain imaging techniques (computed tomography [CT scans]; magnetic resonance imaging [MRI]). Studies of detoxified alcoholics (without other evidence of organic brain damage) reveal that 50 to 70 percent have impairments in neuropsychologic assessment (Eckardt & Martin, 1986). In most of these cases there is reversibility with abstinence from alcohol. Severe liver disease (e.g., acute hepatitis, advanced cirrhosis) may also contribute to this neurologic impairment. CT scans reveal that many alcoholics have cerebral atrophy, which consists of decreased brain weight, an increase in spaces (sulci) between various regions of the brain, and an increase in size of ventricles (spaces filled with cerebrospinal fluid). In a minority of cases, these structural changes are reversible with abstinence. Seizures are associated with heavy alcohol consumption and usually occur in association with alcohol withdrawal. Abstinence from alcohol is usually the only treatment needed for this type of seizure. The hallucinations that are mostly associated with alcohol withdrawal are usually treated with drugs: benzodiazepines and antipsychotics. Peripheral neuropathy is damage to peripheral nerves and is associated with chronic alcoholism. Direct toxic effects of alcohol and concurrent nutritional deficiencies cause this damage.

The neuropathy results in changes in sensation and occasionally motor function, usually in the legs. Sometimes this condition can occur acutely with intoxication. For example, the abnormal posture in association with a drunken stupor can result in radial nerve (so-called Saturday night) palsy (paralysis of a body part that may be accompanied by loss of feeling and uncontrolled body movements). Alcoholics are also at increased risk of subdural hematomas (blood clots due to ruptured intracranial veins secondary to trauma) and of stroke. The neurologic complications associated with the acute use of other drugs of abuse (e.g., cocaine) include seizures (convulsions) and strokes.

Other drugs can also produce neurologic symptoms. High doses of some opioids, such as propoxyphene (Darvon) or meperidine (Demerol) cause seizures. Substances that can cause delirium (reversible disorientation and agitation) include cannabis (marijuana), phencyclidine (PCP), lysergic acid diethylamide (LSD), and atropine. Sudden cessation of use of CNS depressants (benzodiazepines, barbiturates, and alcohol) can result in seizures and hallucinations. Chronic use of other substances of abuse can also result in neurologic complications. Tobacco use is associated with increased rates of stroke (but it appears to be associated with lower rates of Parkinson's disease, a progressive disorder affecting control of movement). Solvent abuse (via inhalation) can cause damage to the cerebellum (the part of the brain controlling movement) and to peripheral nerves. A form of synthetic heroin (MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine), an analog of meperidine (Demerol), has been demonstrated to cause a severe form of Parkinson's disease.

Psychiatric Effects. Alcohol-related diagnoses are common among psychiatric patients. For example, one study (Moore et al., 1989) showed that 30 percent of those admitted to a psychiatric unit had a concurrent alcohol-related diagnosis. Alcohol alone may produce symptoms and signs that mimic psychiatric disorders. Examples include depression, anxiety disorder, psychosis, and antisocial personality disorder. Alternatively, an alcohol-related disorder may coexist with one of these or may aggravate the psychiatric disorder. Alcohol as a CNS depressant tends to cause low mood states (hypophoria) with chronic use. It may cause or worsen clinical depression. If alcohol is the primary cause of a depressed mood state, then abstinence from alcohol, as the sole treatment, rapidly improves the disorder. Hallucinations may occur during alcohol withdrawal, mimicking a psychotic disorder. Similarly, the anxiety associated with alcohol withdrawal may mimic an anxiety disorder. Anxiety and hallucinations may also be seen during withdrawal from sedative-hypnotics. Aggressive, illegal or irresponsible behavior associated with alcoholism may lead to an erroneous diagnosis of antisocial personality disorder.

When alcohol is used for self-medication in some psychiatric conditions, such as anxiety disorders, it tends only to be of short-term help and leads to more long-term problems. Other drugs of abuse, such as the stimulants cocaine and amphetamine, also produce anxiety and occasionally may produce a psychotic state during acute intoxication. This usually disappears rapidly as the drug effects wear off. Withdrawal following chronic use of stimulants may be associated with depression, excessive fatigue, and somnolence (a crash). Tobacco smoking also appears to be associated with depression. (Individuals with a history of depression are more likely to smoke and may develop depression when they try to stop.) Although the nature of the relationship is unclear, patients with psychiatric diagnoses (e.g., schizophrenia) have higher rates of smoking than the general population. Hallucinogens (such as LSD and PCP) commonly cause an acute psychotic disorder that typically disappears as drug effects wear off; however, in some cases there may be longer lasting effects. Antisocial personality disorder is a common pre-existing diagnosis in those who abuse alcohol and drugs.

Endocrine and Reproductive Effects. Alcohol produces both acute and chronic effects on virtually all endocrine organs (hormone-producing glands). Acutely, alcohol raises plasma catechol-amines, which are chemicals released from nerve endings that are responsible for certain emotional reactions: the so-called fear, flight, and fight. Epinephrine (adrenaline) is released from the inside (medulla) of the adrenal gland and norepinephrine (noradrenaline) from sympathetic neurons (nerve cells) and the adrenal glands. Alcohol also causes release of cortisol from the outside (cortex) of the adrenal gland both acutely and chronically.

Cortisol is a hormone (chemical messenger) responsible for multiple effects on the body, including changes in the immune response, glucose regulation, fat breakdown, blood pressure, and mood. Alcohol-induced cortisol excess can mimic Cushing's disease (a condition associated with excess cortisol production, often caused by a tumor on the adrenals) and is known as pseudo-Cushing's disease. Alcohol affects the hypothalamus (an area of the brain), where it modifies chemical-releasing factors, which in turn control release of hormones from the pituitary (a gland in the brain linked to the hypothalamus by a special blood supply), which in turn affect endocrine organs throughout the body. Acutely, alcohol also inhibits the release of antidiuretic hormone (ADH) from the posterior pituitary, which results in increased urine production. The best documented chronic endocrine effect of alcohol is male hypogonadism, a condition resulting from low sex-hormone function. Signs of the condition are small testes and decreased body hair. Symptoms include loss of libido (sex drive) and impotence. Hypogonadism can result from alcohol lowering testosterone levels both by direct effects on the testes and indirectly via the hypothalamus.

Alcoholic liver disease may also produce femi-nization in men, as a result of impaired metabolism (breakdown) of female sex hormones such as estrogen. Signs of such feminization in men include gynecomastia (enlarged breasts) and female fat distribution. In women who drink alcohol excessively, there is a high prevalence of gynecologic disorders (missed periods and problems in functioning of ovaries) and a possibly earlier onset of menopause than in nondrinkers. In women alcohol is metabolized at different rates according to the particular phase of the menstrual cycle. Other hormonal effects have been described in association with acute alcohol ingestion, including the impaired release of growth hormone and increased release of prolactin, a hormone involved in milk production. Thyroid function, which controls the body's rate of metabolism, can be indirectly affected as a result of alcoholic liver disease. This effect occurs from impaired conversion of T4 (a form of thyroid hormone) to T3 (a more active form of thyroid hormone). Furthermore, in alcoholism, there are abnormalities in the proteins to which thyroid hormone binds, making thyroid function tests difficult to interpret. Overall thyroid function is usually normal despite mild abnormalities in the tests.

Other drugs, particularly the opioids, also have multiple effects on the endocrine system. Opioids produce a degree of hypogonadism as a result of lowered testosterone in males and disturbed menstrual function in females. This effect results from opioid inhibition of gonadotropin releasing hormone (GRH) in the hypothalamus, which in turn inhibits release of lutenizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary. Opioids also inhibit corticotropin releasing factor (CRF), which results in decreased adrenocorticotropic hormone (ACTH) and decreased cortisol release. Nicotine causes release of epi-nephrine and norepinephrine, which in turn increase blood pressure and heart rate. Nicotine also enhances the release of ADH from the pituitary, which decreases urine output (i.e., it counteracts alcohol's effects).

Cardiovascular Effects. Alcohol has direct effects on both cardiac muscle and cardiac electrophysiol-ogy (electrical functioning). These effects are also dependent on the prior history of alcohol use (i.e., whether there have been underlying cardiac changes due to chronic use) and whether there is any evidence ofunderlying heart disease. Acutely, alcohol is a myocardial depressant (decreases heart muscle function), and chronically, it may cause a degeneration of cardiac muscle (known as cardiomyopathy), which can lead to heart failure (a condition in which excess body fluids and inadequate pumping function of the heart are present). Abstinence from alcohol leads to improvement in function in some cases. Both acute alcohol intoxication and acute withdrawal can lead to cardiac arrhythmias (abnormal heart rhythms). The most frequent association is with atrial fibrillation (frequent uneven and uncoordinated contraction of the atria, the blood collection chambers of the heart). This condition is usually not life threatening and mostly disappears without specific treatment. Multiple epidemiologic studies have established a relationship between alcohol and high blood pressure (hypertension). Between 5 and 24 percent of hypertension is considered to be alcohol related (Klatsky, 1987). The relationship seems to hold most strongly for white males over the age of 55, consuming at least 3 standard drinks per day on a chronic basis. Many cases resolve with abstinence.

Acute alcohol withdrawal is often associated with hypertension, but this condition usually lasts for only a few days.

High levels of alcohol consumption are associated with increased rates of coronary heart disease (disease of the blood vessels that supply heart muscle), while low levels of consumption (in comparison to complete abstinence) may be associated with a mild protective effect. Evidence for an inverse relationship between moderate alcohol consumption and coronary heart disease is derived from epidemiological and clinical case-control and cohort studies. Early investigators, impressed by the relatively low incidence of coronary heart disease in France despite an intake of saturated fats at least three times that of the United States (the so-called French paradox), focused their studies on the potential cardioprotective properties of red wine (Klatsky et al., 2003). Other studies, however, indicate that all alcoholic beverages—wine, beer, and liquor—when consumed in moderation, are associated with a lower coronary artery disease risk (Rimm et al., 1996). In dose-range studies, the equivalent of two alcoholic drinks per day was associated with a decreased incidence of coronary heart disease compared with no drinks, whereas higher doses result in an increased risk of infarction as well as the well-known problems produced by alcohol excess. Scientists describe this relationship between alcohol intake and coronary heart disease-when shown graphically—as a J-shaped or U-shaped curve, with the greatest benefit accruing at moderate doses, which correlate with the lowest point on the curve. Individuals may find themselves caught in a dilemma between the oft-preached dangers of drinking and these acclaimed benefits. Because most American households already are exposed to alcohol (Thun et al., 1997), advice as to the benefits of moderation may be offered without reserve. However, low levels of consumption are not recommended specifically as a preventive measure against coronary heart disease. In the case of abstainers, the risks of initiating alcohol consumption may outweigh its potential benefits. This reservation is especially applicable in families that include adolescents.

Chronic tobacco use is the most important of the preventable causes of coronary heart disease, and cigarette smoking is a much greater risk factor than is alcoholism. It should be noted, however, that in some studies, 80 to 90 percent of alcoholics are also cigarette smokers, though this high a prevalence of smoking is not universal. Acutely, nicotine results in constriction (narrowing) of blood vessels and an increase in heart rate. The coronary arteries supply the heart muscle. Long-term tobacco use results in an increase in atherosclerosis (build up of fat and other products inside the walls of blood vessels) in most of the arteries throughout the body and increases coagulation (clotting). This has important adverse effects on the coronary arteries (causing angina [chest pain] and infarction [heart attack]); the aorta (causing aneurysms, a ballooning effect on the arterial wall, which can be fatal); the carotid arteries (which can cause strokes); the femoral arteries (causing intermittent claudication, or pain on walking); and the renal arteries (causing kidney failure and some hypertension).

The acute use of cocaine (a stimulant) results in increases in heart rate and blood pressure and causes narrowing of peripheral and coronary arteries. Repeated use of cocaine has been associated with abnormal heart beats, myocardial infarction (heart attack), and possibly myocardial fibrosis (an increase of scar tissue within the heart). Acute use of opioids has minor effects on blood pressure. There are no important chronic adverse effects of opioids on the cardiovascular system. Marijuana acutely causes increases in heart rate and blood flow.

Respiratory System Effects. Acutely, alcohol does not usually interfere with lung function; however, a decrease in cough reflexes and a predisposition to reflux (regurgitate) stomach fluids into the lungs can result in the impairment of bacterial clearance in the respiratory tract after intoxication. Chronic alcohol consumption is associated with several pulmonary infectious diseases; these include pneumonia, lung abscess, and tuberculosis. Aspiration pneumonia occurs in association with high levels of alcohol intoxication; it is thought to be caused by the inhalation of bacteria caused by the impairment of the usual reflexes, such as coughing. For some persons with asthma, alcoholic beverages can induce bronchospasm (airway narrowing). This condition is thought to be related to non-alcoholic components in the beverage. Acute alcohol consumption also has a direct depressant effect on the respiratory center located in the brainstem. Accordingly, an overdose (intentional or unintentional) can result in death from respiratory failure (decreased ability to breathe). Alcohol also contributes to respiratory depression when taken with other central nervous system depressants such as barbiturates and benzodiazepines (minor tranquillizers). Acute alcohol intake worsens sleep apnea, a condition in which breathing ceases for periods of time during sleep. Pancreatitis and alcoholic cirrhosis are associated with pulmonary effusions (buildup of fluid around the lung).

Cigarette smoking causes emphysema, chronic bronchitis, and lung cancer. The smoking of marijuana on a frequent long-term basis may also increase the likelihood of these disorders, though this correlation has not been definitively proven. Acutely, the intravenous injection of opiate drugs may cause pulmonary edema (accumulation of fluid in the lungs), which can be life-threatening. Chronic use of intravenous drugs may cause pulmonary fibrosis (scar tissue in the lung). This effect is probably related to impurities, such as talc, associated with the cutting of the drug (diluting the dose with fillers) prior to its sale and eventual injection.

Effects on the Gastrointestinal Tract and Pancreas. Acutely, alcohol alters motor function of the esophagus. Chronic use of alcohol increases gastroesophageal reflux. Alcohol alone does not appear to cause peptic ulcers (as smoking cigarettes does), but alcohol interferes with healing. Alcohol disrupts the mucosal barrier in the stomach and causes gastritis (inflammation of the stomach), which can lead to hemorrhage, especially when combined with aspirin. Alcohol also interferes with the cellular junctions within the small intestine, which can result in the disturbance of fluid and nutrient absorption, producing diarrhea and malabsorption. Any resulting nutritional deficiencies can further aggravate this process.

Heavy drinking interferes significantly with pancreatic structure and function. Alcohol abuse and gallstone disease are the major causes of pancreatitis, and alcoholism alone is responsible for most cases of chronic pancreatitis. Alcohol changes cellular membranes, disrupting transport mechanisms and the movement of vital ions and nutrients essential for normal cellular function. Acetaldehyde, a breakdown product of alcohol (and also present in cigarette smoke), is toxic to cells and has been proposed as a causative agent in the development of this disorder (Geokas, 1984). Acute pancreatitis is life threatening; patients have abdominal pain, nausea, and vomiting. Increased levels of pancreatic enzymes, such as amylase and lipase, accompany this disorder. Treatment is usually by conservative measures, such as replacement offluids and pain relief. Chronic pancreatitis may occur without symptoms, or it can become evident due to the occurrence of chronic abdominal pain and evidence of malabsorption (weight loss, fatty stools, and nutritional deficiencies) or, uncommonly, with the appearance of diabetes mellitus resulting from the destruction of the endocrine as well as the exocrine function of the pancreas.

Liver Effects. Alcoholic liver disease is a major cause of morbidity and mortality in the United States; in 2004 chronic liver disease and cirrhosis of the liver was the twelfth leading cause of death. Alcohol causes three progressive pathological (abnormal) changes in the liver: fatty liver, alcoholic hepatitis, and cirrhosis. These changes are useful in a prognostic sense but can only be diagnosed with a liver biopsy (in which a needle is inserted in the liver to obtain a small amount of tissue for study), which is not always feasible or practical. More than one pathological condition may exist at any one time in a given patient. Fatty liver, the most benign of the three conditions, is usually completely reversible with abstinence from alcohol; it occurs at a lower threshold of drinking than do alcoholic hepatitis and cirrhosis. Alcoholic hepatitis ranges in severity from no symptoms at all to severe liver failure with a fatal outcome; it can be followed by complete recovery, chronic hepatitis, or cirrhosis. Treatment is primarily supportive.

Similarly, the symptoms and signs of cirrhosis range from none at all to coma and death. Cirrhosis consists of irreversible changes in liver structure resulting from an increase in scar tissue. A consequence of this condition is an abnormal flow of blood through the liver (shunts), which can result in bleeding and the presentation of toxic substances (e.g., ammonia) to the brain. This, in turn, may result in effects ranging from impaired thinking to coma and death. Abstinence from alcohol can prevent progression of cirrhosis and reduces mortality and morbidity (illness) from this condition.

Medications may also help to reduce mortality from alcoholic liver disease. One medication, pro-pothiouracil (an antithyroid drug), is thought to work by reducing oxygen requirements, though its efficacy has yet to be proved. The efficacy of another medication, prednisone (a steroid), which reduces inflammation, appears to be limited. One promising new approach under investigation involves agents that work against tumor necrosis factor, a pro-inflammatory cytokine (chemical messenger) implicated in the pathophysiology of alcoholic liver disease. Women appear to be at higher risk for liver damage than are men.

Opioid use alone has not been associated with liver disease, but some opioids such as morphine can cause spasm of the bile duct, which results in acute abdominal pain. Tobacco use is associated with a more rapid metabolism (breakdown) of certain drugs in the liver, which means that sometimes higher or more frequent dosing of medications is required for smokers. This effect is thought to relate to the tars in tobacco rather than to the nicotine. High doses of cocaine have been associated with acute liver failure.

Acute and chronic viral hepatitis (types B, C, and D) is common in users of intravenous drugs. It is not the drug itself that causes hepatitis (inflammation of the liver) but rather the introduction of the viruses associated with the sharing of needles or other drug paraphernalia. Viruses and bacteria introduced by injecting drugs cause other problems, such as HIV infection and AIDS, endocarditis (infection of heart valves), cellulitis (skin infection), and abscesses.

Immune System Effects. Alcohol affects the immune system both directly and indirectly. It is often difficult to discern the direct effects of alcohol from concurrent conditions, such as malnutrition and liver disease. Alcohol affects host defense factors in a general way; it also seems to predispose those who drink heavily to specific types of infection. With respect to host factors, alcohol alone can reduce both the number and function of white blood cells (both polymorphonuclear leucocytes and lymphocytes). This effect predisposes toward infection while it interferes with the ability to counteract infection. Mechanical factors are also important. For example, alcohol intoxication resulting in a depressed level of consciousness (and depressed cough reflex) predispose toward aspiration pneumonia. Specific infections for which alcoholics are at higher risk, compared to the population at large, include pneumococcal pneumonia (the most common form of pneumonia), other lung infections (e.g., Hemophilus influenzae, Klebsiella), abscesses (anaerobic infections), and pulmonary tuberculosis. Alcoholics with liver disease are at increased risk of spontaneous bacterial peritonitis (inflammation of the lining of the abdominal cavity). Other infections possibly associated with alcoholism include bacterial endocarditis (infection of the heart valves), bacterial meningitis (infection of the covering of the brain), pancreatitic abscess, and diphtheria (an infectious disease). HIV-infected drug abusers are at increased risk of tuberculosis as well as a multitude of other infections. As mentioned above, injecting drug users are also susceptible to a variety of infections associated with the use of non-sterile equipment. Changes in immune function have been reported to occur in users of other drugs of abuse, including heroin, cocaine, and marijuana. The precise relationship of the immune function change to the drug of abuse is not understood as of the early twenty-first century. Lifestyle factors such as poor nutrition are also likely to contribute to this connection.

Nutritional Effects. In heavy alcohol consumers, malnutrition is common and results from several conditions. Alcohol abusers often have poor dietary habits, resulting from the irritating effects of alcohol on the stomach lining. Alcohol also provides a significant number of calories per serving (7.1 kcal/gm), depressing appetite further. In some cases, alcoholics will subsist on alcohol alone without eating food over extended periods of time. In women, heavy alcohol consumption is associated with lower than usual body weight to a degree similar to that also associated with tobacco smoking; there is less weight-lowering effect in men. Specific nutritional disorders associated with alcoholism include anemia (due to iron or folate deficiency); thiamine (Vitamin B1) deficiency, causing beriberi or Wernicke's encephalopathy or neuropathy; malabsorption; and defective immune and hormonal responses. Alcohol also interferes with the absorption of vitamins (such as pyridoxine and Vitamin A), minerals (such as zinc), and other nutrients (such as glucose and amino acids) (Mezey, 1985).

Abuse of other drugs also can lead to malnutrition, though specific syndromes have not been identified as of the early twenty-first century. Tobacco use is associated with depressed appetite as well depletion of Vitamins A and C. Amphetamines and cocaine are stimulants and have the effect of suppressing appetite. Drug-seeking behavior may also result in a general indifference toward food.

Metabolic Effects. Alcohol is metabolized (broken down) in the liver to acetaldehyde and hydrogen and then to carbon dioxide and water. Acetaldehyde is toxic to many different cellular functions. Alcohol affects carbohydrate, lipid (fat), and protein metabolism. Alcohol can cause low blood glucose (hypoglycemia) due to inhibition of glycogen (liver stores of carbohydrate) metabolism. Alcohol also raises blood sugar and acids (alcoholic ketacidosis). By interfering with the elimination of uric acid, alcohol may precipitate acute attacks of gout. Increased urinary excretion of magnesium can result in muscle weakness. Alcohol causes disturbances in blood lipids, mostly increases in triglycerides and high density lipoprotein (HDL) cholesterol.

Acute alcohol consumption can decrease, whereas chronic consumption can increase, the metabolism of certain drugs. Tobacco smoking also increases the metabolism of some drugs, such as theophylline and caffeine. This response results from the increased activity of various liver enzymes as discussed above.

Hematologic (Blood) Effects. The effects of alcohol on the hematologic system can either be direct, or it can be indirect (as a result of liver disease or nutritional deficiencies). Uncommonly, acute consumption of a very large dose of alcohol in a short time has direct effects on the bone marrow, resulting in decreased production of red cells, white cells, and platelets. Anemia is a common problem in alcoholics and may be due to a variety of factors. The most frequent effect seen in alcoholics following chronic consumption is an increase in the size of the red blood cells (macrocytosis). This increase is mainly due to direct toxic effects on the red cell membrane but may also be due to a deficiency of folate, a vitamin found in green vegetables. Folate deficiency in alcoholics is caused mainly by impaired intake and absorption of folate.

Iron deficiency anemia is also seen because of impaired intake of iron and because of frequent bleeding (due to a variety of factors, such as coagulation defects, gastritis, and the impaired healing of peptic ulcer). Iron-overload syndromes are also diagnosed in alcoholics and are due to multiple causes. Chronic alcohol consumption can also lead to hemolytic (excess breakdown of red blood cells) anemia, which is mainly seen in association with liver disease. Platelet production and function can be suppressed by alcohol, resulting in prolonged bleeding times. Other drugs also exert hematologic effects. Experimental addiction to opioids results in a reversible anemia and a reversible increase in erythrocyte sedimentation rate (a nonspecific indicator of the presence of a disease process). Smoking allows carbon monoxide to enter the body and bind to hemoglobin (carboxyhemoglobinemia), which consequently causes an increase in red cell production (erythrocytosis). The hematocrit value (the proportion of blood attributable to red blood cells) and the plasma fibronogen (a clotting factor) rise and increase blood viscosity; platelets (sticky constituents of blood important in wound healing) aggregate more in smokers. These thickening factors, together with damage to the insides of blood vessels, increase the probability of both stroke and heart attack (myocardial infarction) in smokers. White cells are also at increased levels in smokers (leucocytosis).

Skeletal Muscle Effects. Chronic alcohol consumption can result in muscle cell necrosis (death). Two main patterns are seen: (1) An acute alcoholic myopathy (disturbance of muscle function) occurs in the setting of binge drinking, sometimes associated with stupor and immobilization. This condition results in severe muscle pain, swelling, elevated creatine kinase (a muscle enzyme), and myoglobinuria (muscle protein in the urine which can cause kidney failure). (2) This pattern consists of a more slowly evolving syndrome of proximal muscle (those closest to the trunk) weakness and atrophy (decreased size). Milder degrees of muscle injury are quite common and consist of elevated levels of the muscle enzyme creatine kinase. Cocaine use can also cause muscle damage (rhabdomyolysis), resulting in abnormalities of creatine kinase. Most drugs of abuse (especially depressants) may indirectly cause muscle damage as a result of prolonged abnormal posture, for example, sleeping in an intoxicated state on a hard surface.

Renal Effects. Alcohol abuse causes a variety of electrolyte and acid-base (blood chemistry) disorders, which include decreases in the levels of phosphate, magnesium, calcium, and potassium. These abnormalities relate to disorders within the functioning kidney tubules (involved in secretion and reabsorption of minerals). The abnormalities usually disappear with abstinence from alcohol.

Heroin use has been associated with a form of kidney failure known as heroin nephropathy. Its precise relationship to heroin use is unclear and may be due, instead, to adulterants used to dilute the drug or to viral diseases such as hepatitis C or HIV that are spread through intravenous drug use. Secondary effects on the kidneys from drug and alcohol abuse also occur (for example, from the effects of trauma or muscle damage as described above).

See also Crime and Alcohol; Crime and Drugs; Inhalants; Intimate Partner Violence and Alcohol/Substance Use; Social Costs of Alcohol and Drug Abuse; Substance Abuse and AIDS; Tobacco: Medical Complications.

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