Pathology of Drug Abuse


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Smoking

Smoking leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 400,000 deaths each year in the United States and 6 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (Wipfli and Samet, 2009)

Young women who are pregnant and who smoke put their fetuses at increased risk for decreased birth weight, premature birth, placental abruption, and perinatal mortality. The risk for spontaneous abortion is increased with maternal smoking. Fetal deaths late in gestation are increased in mothers who smoke. There is a 4% increase in risk for death during infancy for every 10 cigarettes the mother smoked per day during pregnancy. (Salihu and Wilson, 2007)

  1. Normal lung, gross.
  2. Small cell anaplastic (oat cell) carcinoma of lung, gross.
  3. Squamous cell carcinoma of lung, gross.
  4. Emphysema, centrilobular type, gross.
  5. Emphysema, representing a modern version of "The Masque of the Red Death" in Edgar Allen Poe's short story.
  6. Composite photograph with a narrowed coronary artery at the left and a markedly narrowed coronary artery at the right, microscopic.
  7. Pelvis of kidney, urothelial carcinoma, gross.
  8. Acute gastric ulcerations, gross.
  9. Hyaline membrane disease in the lung of a premature neonate, microscopic.



Alcoholism

The abuse of alcohol contributes to many deaths per year in the United States. One of the most common drug overdoses leading to death is ingestion of a large amount of alcohol.

Chronic alcoholism leads to liver disease. Liver disease can be manifested as fatty change. Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver.

In the brain, chronic alcoholism can lead to Wernicke disease, or to the Wernicke-Korsakoff syndrome. These conditions are linked to nutritional thiamine deficiency. There are problems with coordination of movement, with ataxia and ophthalmoplegia. Higher mental function is affected by confusion and confabulation. (Goforth et al, 2010)

Alcohol use during pregnancy can lead to the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 2 per 1000 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. (May et al 2009)

There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. Anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2007)

  1. Normal liver, gross.
  2. Fatty change of liver, microscopic.
  3. Micronodular cirrhosis of liver, gross.
  4. Micronodular cirrhosis of liver, microscopic.
  5. Hepatocellular carcinoma, liver with micronodular cirrhosis, gross.
  6. Esophageal varices, gross.
  7. Wernicke's disease, hemorrhages in the mammillary bodies, gross.



Opiates

Opiates by themselves have minimal pathologic effects. Higher doses of more powerful opiates can lead to respiratory depression and death. Persons who really need the pain relief that opiate medications can offer do not become addicted, but unfortunately tolerance may develop over time, requiring higher doses to maintain analgesia. The two major problems with opiate abuse are the psychosocial consequences and the infections from route of administration.

Psychosocial problems related to behavioral issues from drug dependence. Drug-seeking behaviors result in lack of concern for oneself or others. The route of administration is typically intraveous, without attention to sterile technique, increasing the risk for infection, with the agents outlined below. Withdrawl from chronic opiate usage typically results in marked physiologic and psychologic disturbances such as agitation, anxiety, nausea, vomiting, diarrhea, and abdominal cramping. (Goforth et al, 2010)

Oxycodone, best known by the trade name OxyContin®, is a controlled release form of opioid analgesic prescribed to treat moderate to severe pain of constant and prolonged duration. Persons abusing this medication risk addiction and death, particularly if oxycodone is used in association with other drugs. Abusers may progress to usage by intravenous injection and to usage of other opiates or drugs of abuse. (Hays, 2004)




Intravenous Drug Abuse

Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections.

Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug.

  1. Normal aortic valve compared with infective endocarditis, gross.
  2. Surface of the brain with acute meningitis, gross.
  3. Viral hepatitis of the liver, gross.
  4. Viral hepatitis of the liver, microscopic.
  5. Macronodular cirrhosis of the liver, gross.
  6. Mycobacterium tuberculosis, lung, cavitary disease, gross.
  7. Glomerulus of kidney demonstrating focal scarring with heroin nephropathy, microscopic.
  8. Talc granulomatosis of the liver, gross.
  9. Talc granulomatosis of the lungs, polarized light, microscopic.



Cocaine

Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010)

Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007)

Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with "excited delerium" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)

  1. Massive intracerebral hemorrhage associated with cocaine use, gross.
  2. Cerebral infarction, gross.
  3. Heart with myocardial contraction band necrosis, microscopic.
  4. Heart with peripheral coronary artery sclerosis, microscopic.
  5. Abruptio placenta with large recent blood clot compressing the parenchyma, gross.



Methamphetamine

Methampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. The myocardial effects are made worse by concomitant ethanol use.

  1. Heart with ischemic changes, microscopic.

Amphetamines also damage both the serotonergic and dopaminergic systems of the central nervous system. Alterations of the dopaminergic system may persist even after years of abstinence from use of methamphetamine and may be associated with deficits in motor and cognitive performance. (Gouzoulis-Mayfrank and Daumann, 2009)

CNS toxicity of methamphetamine may be the result of both hyperthermia as well as direct effects upon individual cells. A dose-related increase in body temperature occurs with acute ingestion of methamphetamine. This can potentiate acute effects of methamphetamine upon the blood-brain barrier and upon neurons, leading to edema. (Kiyatkin and Sharma, 2009)




GHB

Gamma-hydroxybutyrate (GHB) is a metabolite of the neurotransmitter gamma aminobutyric acid (GABA) and also functions as a neurotransmitter by affecting the dopaminergic system. GHB may also potentiate the effects of endogenous or exogenous opiates. GHB was introduced into the U.S. in 1990 as a purported stimulant to muscle growth during sleep, but it was soon banned because of problems with overdose and adverse reactions. Moreover, GHB is no longer used as an anesthetic agent because of the risks. The effects of GHB can be potentiated by alcohol and by benzodiazepines. The ingestion of GHB results in drowsiness and dizziness with the feeling of a "high" within 10 to 20 minutes and lasting up to 4 hours. There are a multitude of adverse effects that can occur within 15 minutes to an hour, including: headache, nausea, vomiting, hallucinations, loss of peripheral vision, nystagmus, hypoventilation, cardiac dysrhythmias, seizures, and short-term coma. These findings generally subside in 2 hours to 4 days. It is difficult to predict how much GHB will produce an overdose. Withdrawl from GHB can have an onset in 12 hours and last up to 12 days. In rare instances, deaths have occurred from these adverse effects. (Olmedo and Hoffman, 2000) (Timby et al, 2000)




Ecstasy

The methylene-dioxy derivatives of amphetamine and methamphetamine are "designer drugs" that generically are termed "ecstasy" and include 3,4-methylenedioxy-methamphetamine (MDMA), also known as "Adam," 3,4-methylenedioxy-ethylamphetamine (MDEA), also known as "Eve," and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), also known as "Methyl-J" or "Eden." A "designer drug" is a compound that is chemically altered from the form of a controlled substance in order to produce special effects and to bypass legal regulations. MDMA and similar compounds are "entactogens" that act upon serotonergic pathways in the brain to give users a feeling of euphoria, energy, and a desire to socialize. These immediate effects last approximately 3 to 6 hours. (Christophersen, 2000)

The adverse effects of ecstasy use may include hyperthermia, liver toxicity, and neuropsychiatric effects. Severe dehydration leading to excessive fluid intake and water intoxication. There can be memory deficits, confusion, depression, and sleep problems even weeks after taking this drug.

MDMA experimentally causes selective and persistent lesions of central serotonergic nerve terminals. MDMA users can have residual alterations of serotonergic transmission, and though at least partial recovery may occur after long-term abstinence, functional sequelae may persist even after longer periods of abstinence. Long term use may be accompanied by long-lasting brain damage and memory impairment. (Carter et al, 2000) (McQuire, 2000) (Gouzoulis-Mayfrank and Daumann, 2009)

A syndrome including hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, hepatic failure, and renal failure has been reported with MDMA use, findings similar to the excited delirium of cocaine use. In addition persons using MDMA may develop acute fulminant hepatitis with liver failure, and possible death, that can occur days to weeks following drug use. (Scully et al, 2001)




Cannabinoids (marijuana)

Some of the most widely used psychoactive agents include derivatives from the hemp plant Cannabis, typically containing the active compound delta-9-tetrahydrocannabinol (THC). The most common form is marijuana. Hashish is stronger, with more active drug. Throughout much of human history for the past 4000 years, preparations of Cannabis contained small amounts of THC, less than 1%. In the latter part of the 20th century, Cannabis plants with higher THC concentrations and processing of the plants to yield more potent products with greater amounts of THC became widely employed. (Hall and Degenhardt, 2009)

The plant products are typically smoked and the drug absorbed into the blood via respiratory tract. The drug acts through cannabinoid receptors in brain and elsewhere in the body. These receptors normally interact with short acting and less potent endogenous compounds that affect brain function. THC induces mild euphoria, relaxation, and perceptual alterations for up to 2 hours following usage. The lifetime risk for THC dependence is about 9% and nearly double that for persons beginning regular use in adolescence. Only tobacco (32%) and alcohol (15%) dependence are more common. (Hall and Degenhardt, 2009)

During adolescence, the brain undergoes modification of neurons with proliferation, migration, differentiation, and pruning of synapses that promote brain development for adulthood. Cannabinoids alter those processes and increase the risk for subsequent development of psychoses, including schizophrenia. (Malone et al, 2010) Adolescent users of Cannabis are less likely to complete schooling and more likely to become unemployed than nonusers. (Hall and Degenhardt, 2009)

Acute adverse reactions to THC include anxiety, panic, and psychosis, more often in persons with no prior use of the drug. Impairments in attention, perception, and motor coordination affect ability to perform critical tasks such as operating a motor vehicle, increasing the risk for accidents. Since Cannabis is smoked, there are irritant effects upon the respiratory tract, with risk for chronic bronchitis and lung cancer. Effects upon the cardiovascular system increase the risk for myocardial infarction in adults. (Hall and Degenhardt, 2009) A high-fat diet and ethanol use upregulate hepatic cannabinoid receptors so that THC may promote development of fatty liver. (Purohit et al, 2010)

Some regular Cannabis users develop severe nausea with vomiting (cannabinoid hyperemesis) and the urge to bathe frequently in warm water for relief of these symptoms. Either the effects of the THC upon cannabinoid receptors near the thermoregulatory center of the hypothalamus, or upon cannabinoid receptors in splanchnic vasculature may play a role. The warm water exposure redirects blood flow to peripheral vasculature. (Patterson et al, 2010)




Synthetic Cannabinoids (spice drugs)

The so-called 'spice drugs' are synthetic cannabinoid compounds that can bind to brain cannibinoid receptors CB1 and CB2. Binding to the CB1 receptor produces strong psychoactive effects and potential complications due to unknown pharmacologic effects and toxicity. Adverse reactions reported include tachycardia, hypertension, tachypnea, chest pain, hallucinations, racing thoughts, and seizures. Psychosis, withdrawl, and death have been reported with usage of these compounds. Users of these drugs are at risk due to their variability as well as their potency that is 4 to 5 times that of cannabis in naturally grown marijuana. (Fattore and Fratta, 2011; Wells and Ott, 2011)




Synthetic Cathiones, or PABS ("bath salts")

The compounds sold as "bath salts" (PABS) have nothing to do with bathing, but instead are psychoactive Ņuppers" that are synthetic forms of cathiones. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of the Catha edulis plant. Derivative synthetic cathinones being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. They mainly contain methylenedioxypyrovalerone (MDPV), which is structurally related to pyrovalerone and pyrrolidinophenone compounds that inhibit norepinephrine-dopamine reuptake. Therefore, they cause central nervous system stimulation and sympathetic stimulation. They are marketed as aphrodisiacs and stimulants. (Prosser and Nelson, 2012)

They are absorbed quickly through mucosal surfaces (nasal, oral, gastric, rectal). Only a few milligrams produce a high, but the quantities marketed may be 100 times that amount, increasing the risk for overdose. Their effects peak at 90 minutes following ingestion and last for 3 or 4 hours before the user "crashes". Long-term users of PABS may develop tolerance, and abstinence can lead to withdrawal and intense craving. (Ross et al, 2011)

The toxicity from PABS may include extreme sympathetic stimulation with tachycardia, hypertension, shortness of breath, blurred vision, dry mouth, and hyperthermia. There can be markedly altered mental status with severe panic attacks, agitation, paranoia, hallucinations, and violent behavior such as self-mutilation, suicide attempts, and homicidal activity. Seizures may occur. Rhabdomyolysis can develop. Deaths have been reported. The toxicity profile includes the worst effects of lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine ("ecstasy"), cocaine, and methamphetamine. Routine drug screens do not detect PABS. (Ross et al, 2011)




Anabolic-Androgenic Steroids

The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 3 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Bahrke and Yesalis, 2004) (Sjöqvist et al, 2008)

There are many adverse effects to AAS use. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, baldness, hypertension, fluid retention, tendon injuries, nosebleeds, more frequent colds, and sleep disorders. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis. The major psychiatric effects of AAS use include increased aggression and major mood disorders including depression and mania. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, anabolic steroids can prevent the very things that they are supposed to enhance. (Hall et al, 2005)

The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 1999) (Fineschi et al, 2001)

  1. Heart with hypertrophy, gross.
  2. Heart with myocardial contraction band necrosis, trichrome stain, microscopic.
  3. Testicular atrophy, gross.
  4. Testicular atrophy, microscopic.
  5. Gynecomastia, gross.



Blood Doping

Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012)





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