Pathology (environmental 3)

• Granulocytopenia, aplastic anemia, pancytopenia: Antineoplastic agents, immunosuppressives, and chloramphenicol
• Hemolytic anemia, thrombocytopenia: Penicillin, methyldopa, quinidine, heparin

• Arrhythmias: Theophylline, hydantoins, digoxin
• Cardiomyopathy: Doxorubicin, daunorubicin

• Glomerulonephritis: Penicillamine
• Acute tubular necrosis: Aminoglycoside antibiotics, cyclosporin, amphotericin B
• Tubulointerstitial disease with papillary necrosis: Phenacetin, salicylates

• Asthma: Salicylates
• Acute pneumonitis: Nitrofurantoin
• Interstitial fibrosis: Busulfan, nitrofurantoin, bleomycin

• Fatty change: Tetracycline
• Diffuse hepatocellular damage: Halothane, isoniazid, acetominophen
• Cholestasis: Chlorpromazine, estrogens, contraceptive agents

• CCL4
• Acetaminophen

• Anaphylaxis: Penicillin
• Lupus erythematosus syndrome (drug-induced lupus): Hydralazine, procainamide

• Tinnitus and dizziness: Salicylates
• Acute dystonic reactions and parkinsonian syndrome: Phenothiazine antipsychotics
• Respiratory depression: Sedatives

• HRT increases the risk of breast cancer after a median time of 5 to 8 years. The risk is highest and the latency times shorter for the development of lobular carcinomas and ductal-lobular cancer.
• HRT has a protective effect on the development of atherosclerosis and coronary disease in women under age 60, but there is no protection in women who started HRT at an older age. Protective effects in younger women depend in part on the response of estrogen receptors that regulate calcium homeostasis in blood vessels.  
• HRT increases the risk of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and stroke. The increase is more pronounced during the first 2 years of treatment and in women who have other risk factors such as immobilization, and hypercoagulable states caused by prothrombin or factor V Leiden mutations

• Increased risk of venous thrombosis and pulmonary thromboembolism. The increased thrombotic risk seems to be a consequence of the generation of an acute-phase response, with increases in C-reactive protein and coagulation factors (factors VII, IX, X, XII, and XIII), and reduction in anticoagulants (protein S and anti-thrombin III).  
• Increase the risk of myocardial infarction in smoking women at all ages and in nonsmoking women over age 35. In women over 35 years of age, the effect is more than ten-fold higher in smokers than nonsmokers
• Reduce the incidence of endometrial and ovarian cancers. They do not increase the lifetime risk for development of breast cancers, although a small increase in incidence has been detected during the first 5 years of use. They increase risk of cervical cancer
• Hepatic adenoma. appears as a large, solitary, and well-encapsulated mass

Breakthrough bleeding

• Anabolic steroids are synthetic versions of testosterone, and for performance enhancement they are used at doses that are about 10 to 100 times higher than therapeutic indications.
• The high concentration of testosterone and its derivatives inhibits production and release of LH and FSH by a feedback mechanism, and increases the amount of estrogens, which are produced from anabolic steroids.
• Anabolic steroids have multiple adverse effects including stunted growth in adolescents, acne, gynecomastia and testicular atrophy in males, and growth of facial hair and menstrual changes in women.
• Other effects include psychiatric problems and premature heart attacks.
• Hepatic cholestasis may develop in individuals receiving orally administered anabolic steroids

Acetaminophen

unintentional overdosage

• At therapeutic doses about 95% of acetaminophen undergoes detoxification in the liver by phase II enzymes and is excreted in the urine as glucuronate or sulfate conjugates.
• About 5% or less is metabolized through the activity of CYPs (primarily CYP2E) to NAPQI (N-acetyl-p-benzoquinoneimine), a highly reactive metabolite

• At therapeutic doses about 95% of acetaminophen undergoes detoxification in the liver by phase II enzymes and is excreted in the urine as glucuronate or sulfate conjugates. About 5% or less is metabolized through the activity of CYPs (primarily CYP2E) to NAPQI (N-acetyl-p-benzoquinoneimine), a highly reactive metabolite.
• NAPQI is normally conjugated with glutathione (GSH), but when taken in larger doses unconjugated NAPQI accumulates and causes hepatocellular injury leading to centrilobular necrosis and liver failure.
• The injury produced by NAPQI involves two mechanisms: (1) covalent binding to hepatic proteins, which causes damage to cellular membranes and mitochondrial dysfunction, and (2) depletion of GSH, making hepatocytes more susceptible to reactive oxygen species–induced injury.
• It should be noted that because alcohol induces CYP2E in the liver, toxicity can occur at lower doses in chronic alcoholics

• Toxicity begins with nausea, vomiting, diarrhea, and sometimes shock, followed in a few days by evidence of jaundice. Overdoses of acetaminophen can be treated at its early stages (within 12 hours) by administration of N-acetylcysteine, which restores GSH.
• In serious overdose liver failure ensues, starting with centrilobular necrosis that may extend to entire lobules, requiring liver transplantation for survival. Some patients show evidence of concurrent renal damage.

• Consists of Microvesicular steatosis, Mallory bodies
• Alcohol Amiodarone

Ethanol, methotrexate, corticosteroids, total parenteral nutrition

• (1) hepatic steatosis (fatty liver disease), (2) alcoholic hepatitis, and (3) cirrhosis

• After even moderate intake of alcohol, microvesicular lipid droplets accumulate in hepatocytes.
• With chronic intake of alcohol, lipid accumulates creating large, clear macrovesicular globules that compress and displace the hepatocyte nucleus to the periphery of the cell.
• Macroscopically, the fatty liver of chronic alcoholism is a large (as heavy as 4 to 6 kg), soft organ that is yellow and greasy. Although there is little or no fibrosis at the outset, with continued alcohol intake fibrous tissue develops around the terminal hepatic veins and extends into the adjacent sinusoids. 
• The fatty change is completely reversible if there is abstention from further intake of alcohol.

• 1.   Hepatocyte swelling and necrosis: Single or scattered foci of cells undergo swelling (ballooning) and necrosis. The swelling results from the accumulation of fat and water, as well as proteins that normally are exported. In some cases there is cholestasis in surviving hepatocytes and mild deposition of hemosiderin (iron) in hepatocytes and Kupffer cells.  
• 2.   Mallory bodies: Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments such as cytokeratin 8 and 18, in complex with other proteins such as ubiquitin. Mallory bodies are visible as eosinophilic cytoplasmic clumps in hepatocytes. These inclusions are a characteristic but not specific feature of alcoholic liver disease, since they also present in NAFLD, PBC, Wilson disease, chronic cholestatic syndromes, and hepatocellular tumors.  
• 3.   Neutrophilic reaction: Neutrophils permeate the hepatic lobule and accumulate around degenerating hepatocytes, particularly those having Mallory bodies. Lymphocytes and macrophages also enter portal tracts and spill into the parenchyma.  
• 4.   Fibrosis: Alcoholic hepatitis is almost always accompanied by prominent activation of sinusoidal stellate cells and portal tract fibroblasts, giving rise to fibrosis. Most frequently fibrosis is sinusoidal and perivenular, separating parenchymal cells; occasionally, periportal fibrosis may predominate, particularly with repeated bouts of heavy alcohol intake

• A, The cluster of inflammatory cells marks the site of a necrotic hepatocyte (arrow). B, Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous (Masson stain) tissue.
• Alcoholic steatohepatitis: Fibrosis, hepatocyte necrosis and swelling, neutrophilic reaction, Mallory bodies

• At first the cirrhotic liver is yellowtan, fatty, and enlarged, usually weighing over 2 kg. Over the span of years, it is transformed into a brown, shrunken, nonfatty organ, sometimes less than 1 kg in weight.
• Initially the developing fibrous septa are delicate and extend through sinusoids from central to portal regions as well as from portal tract to portal tract.
• Regenerative activity of entrapped parenchymal hepatocytes generates uniform micronodules.
• With time the nodularity becomes more prominent; scattered larger nodules create a “hobnail” appearance on the surface of the liver
• As fibrous septa dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks progressively in size.
• Parenchymal islands are engulfed by wider bands of fibrous tissue, and the liver is converted into a mixed micronodular and macronodular pattern.
• Ischemic necrosis and fibrous obliteration of nodules eventually create broad expanses of tough, pale scar tissue (“Laennec cirrhosis”).
• Bile stasis often develops; Mallory bodies are only rarely evident at this stage.
• Thus, end-stage alcoholic cirrhosis comes to resemble, both macroscopically and microscopically, the cirrhosis developing from viral hepatitis and other causes.

Alcoholic cirrhosis. A, The characteristic diffuse nodularity of the surface reflects the processes of nodular regeneration and scarring. The greenish tint of some nodules is due to bile stasis. A hepatocellular carcinoma is present as a budding mass at the lower edge of the right lobe (lower left). B, The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue. The liver capsule is at the top (Masson trichrome)

• Alcohol dose and duration
• Gender. Women > men. This difference may be related to alcohol pharmacokinetics and metabolism, and the estrogen-dependent response to gut-derived endotoxin (LPS) in the liver. Estrogen increases gut permeability to endotoxins, which, in turn, increase the expression of the LPS receptor CD14 in Kupffer cells. This predisposes to increased production of pro-inflammatory cytokines and chemokines.
• Ethnic differences. higher for African Americans than for white Americans.
• Genetic factors. ALDH*2, a genetic variant of aldehyde-dehydrogenase (ALDH), found in 50% of Asians, has a very low activity. Individuals who are homozygous for ALDH*2 are unable to oxidize acetaldehyde and do not tolerate alcohol.  
• Co-morbid conditions. Iron overload and infections with HCV and HBV

• Exposure to alcohol causes steatosis, dysfunction of mitochondrial and cellular membranes, hypoxia, and oxidative stress.
• At millimolar concentrations, alcohol directly affects microtubular and mitochondrial function and membrane fluidity

• (1) shunting of normal substrates away from catabolism and toward lipid biosynthesis, as a result of generation of excess NADH by the two major enzymes of alcohol metabolism, alcohol dehydrogenase and acetaldehyde dehydrogenase;
• (2) impaired assembly and secretion of lipoproteins; and
• (3) increased peripheral catabolism of fat

• Acetaldehyde (the major intermediate metabolite of alcohol) induces lipid peroxidation and acetaldehyde-protein adduct formation, further disrupting cytoskeletal and membrane function.
• Cytochrome P-450 metabolism produces ROS that react with cellular proteins, damage membranes, and alter hepatocellular function.
• In addition, alcohol-induced impaired hepatic metabolism of methionine leads to decreased intrahepatic glutathione levels, thereby sensitizing the liver to oxidative injury.
• The induction of CYP2E1 and other cytochrome P-450 enzymes in the liver by alcohol increases alcohol catabolism in the endoplasmic reticulum and enhances the conversion of other drugs (e.g., acetaminophen) to toxic metabolites

• Alcohol itself is a major source of energy
• chronic gastric and intestinal mucosal damage, and pancreatititis

• Alcohol causes the release of bacterial endotoxin from the gut into the portal circulation, inducing inflammatory responses in the liver, such as the activation of NF-κB, and release of TNF, IL-6, and TGF-α.
• In addition, alcohol stimulates the release of endothelins from sinusoidal endothelial cells, causing vasoconstriction and the contraction of activated stellate cells (“myofibroblasts”), leading to a decrease in hepatic sinusoidal perfusion

• Hepatic steatosis (fatty liver) --> hepatomegaly, with mild elevation of serum bilirubin and ALK levels. Severe hepatic dysfunction is unusual.
• Alcoholic hepatitis --> acute, usually following a bout of heavy drinking. Symptoms vary. nonspecific symptoms of malaise, anorexia, weight loss, upper abdominal discomfort, tender hepatomegaly, hyperbilirubinemia, elevated ALK, and often a neutrophilic leukocytosis. The outlook is unpredictable; each bout of hepatitis incurs about a 10% to 20% risk of death. also may be superimposed on established cirrhosis. may clear or progresses to cirrhosis despite abstinence.

(1) hepatic coma, (2) massive gastrointestinal hemorrhage, (3) intercurrent infection (to which these patients are predisposed), (4) hepatorenal syndrome following a bout of alcoholic hepatitis, and (5) hepatocellular carcinoma

• Accidental in young children; in adults suicidal.
• A source of salicylate poisoning is the excessive use of ointments containing oil of wintergreen (methyl salicylate).

• Acute salicylate overdose causes alkalosis as a consequence of the stimulation of the respiratory center in the medulla.
• This is followed by metabolic acidosis and accumulation of pyruvate and lactate, caused by uncoupling of oxidative phosphorylation and inhibition of the Krebs cycle.
• Metabolic acidosis enhances the formation of non-ionized forms of salicylates, which diffuse into the brain and produce effects from nausea to coma

• Activation of the respiratory center of the medulla results in increased respiratory rate, respiratory alkalosis, increased renal elimination of HCO3, and increased insensible fluid loss.
• Interference with cellular metabolism (uncoupling of oxidative phosphorylation) leads to metabolic acidosis, hyperpyrexia, fluid loss, and hypoglycemia.
• Inhibition of the tricarboxylic acid cycle leads to metabolic acidosis.
• Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes.
• Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting

• Chronic aspirin toxicity (salicylism) may develop in persons who take 3 gm or more daily for long periods of time for treatment of chronic pain or inflammatory conditions.
• Chronic salicylism is manifested by headaches, dizziness, ringing in the ears (tinnitus), hearing impairment, mental confusion, drowsiness, nausea, vomiting, and diarrhea. The CNS changes may progress to convulsions and coma.
• Most often there is an acute erosive gastritis, which may produce overt or covert gastrointestinal bleeding and lead to gastric ulceration.
• A bleeding tendency may appear concurrently with chronic toxicity, because aspirin acetylates platelet cyclooxygenase and irreversibly blocks the production of thromboxane A2, an activator of platelet aggregation.
• Petechial hemorrhages may appear in the skin and internal viscera, and bleeding from gastric ulcerations may be exaggerated

Alkalinization

• Intox: 1. Restlessness, 2. nervousness, 3. Excitement.4. Insomnia.5. Flushed face.6. Diuresis.7. Gastrointestinal disturbance.8. Muscle twitching.9. Rambling flow of thought and speech.10. Tachycardia or cardiac arrhythmia.11. Periods of inexhaustibility.12. Psychomotor agitation.
• Withd: . 1. Headache.2. Marked fatigue or drowsiness.3. Dysphoric mood, depressed mood, or irritability.4. Difficulty concentrating.5. Flu-like symptoms.

• Inhibition of adenosine synthesis and adenosine receptor antagonism;
• stimulation of epinephrine and norepinephrine release;
• inhibition of phosphodiesterase resulting in increased intracellular cyclic adenosine and guanosine monophosphate

• A. A problematic pattern of cannabis use leading to clinically significant impairment or dis­tress, as manifested by at least two of the following, occurring within a 12-month period:
• 1. Cannabis is often taken in larger amounts or over a longer period than was intended.
• 2. There is a persistent desire or unsuccessful efforts to cut down or control cannabis use.
• 3. A great deal of time is spent in activities necessary to obtain cannabis, use canna­bis, or recover from its effects.
• 4. Craving, or a strong desire or urge to use cannabis.
• 5. Recurrent cannabis use resulting in a failure to fulfill major role obligations at work, school, or home.
• 6. Continued cannabis use despite having persistent or recurrent social or interper­sonal problems caused or exacerbated by the effects of cannabis.
• 7. Important social, occupational, or recreational activities are given up or reduced be­cause of cannabis use.
• 8. Recurrent cannabis use in situations in which it is physically hazardous.
• 9. Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by cannabis
• 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of cannabis to achieve intoxication or desired effect.b. Markedly diminished effect with continued use of the same amount of cannabis.
• 11. Withdrawal, as manifested by either of the following:a. The characteristic withdrawal syndrome for cannabis b. Cannabis (or a closely related substance) is taken to relieve or avoid withdrawal symptoms

Antisocial and conduct disorder

Two (or more) of the following signs or symptoms developing within 2 hours of canna­bis use:1. Conjunctival injection.2. Increased appetite.3. Dry mouth.4. Tachycardia.

• 1. Irritability, anger, or aggression.2. Nervousness or anxiety.3. Sleep difficulty (e.g., insomnia, disturbing dreams).4. Decreased appetite or weight loss.5. Restlessness.6. Depressed mood.7. At least one of the following physical symptoms causing significant discomfort: ab­dominal pain, shakiness/tremors, sweating, fever, chills, or headache.

Δ9-tetrahydrocannabinol (THC)

• Treat nausea and pain
• distorts sensory perception and impairs motor coordination (clear in 4 to 5 hours). With continued use these changes may progress to cognitive and psychomotor impairments, such as inability to judge time, speed, and distance, a frequent cause of automobile accidents, euphoria, disinhibition, uncontrollable laughter, changes in perception, and achievement of a dream-like state
• Marijuana increases the heart rate and sometimes blood pressure, and it may cause angina in a person with coronary artery disease.
• The respiratory system is also affected by chronic marijuana smoking; laryngitis, pharyngitis, bronchitis, cough and hoarseness, and asthma-like symptoms
• Marijuana cigarettes contain a large number of carcinogens that are also present in tobacco. Smoking a marijuana cigarette, compared with a tobacco cigarette, is associated with a three-fold increase in the amount of tar inhaled and retained in the lungs, presumably because of the larger puff volume, deeper inhalation, and longer breath holding

• include anadamide and 2-arachidonyl glycerol, are released postsynaptically and act as retrograde messengers to inhibit presynaptic release of conventional transmitters including dopamine
• regulation of the HPA axis, and modulates the control of appetite, food intake, and energy balance, as well as fertility and sexual behavior

• Dronabinol (a controlled-substance formulation of THC): severe nausea. 
• Rimonabant, an agonist at cannabinoid receptors: treatment of obesity.

True

• A pattern of phencyclidine (or a pharmacologically similar substance) use leading toclinically significant impairment or distress, as manifested by at least two of the follow­ing, occurring within a 12-month period:
• 1. Phencyclidine is often taken in larger amounts or over a longer period than was in­tended.
• 2. There is a persistent desire or unsuccessful efforts to cut down or control phency­clidine use.
• 3. A great deal of time is spent in activities necessary to obtain phencyclidine, use the phencyclidine, or recover from its effects.
• 4. Craving, or a strong desire or urge to use phencyclidine.
• 5. Recurrent phencyclidine use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences from work or poor work performance related to phencyclidine use; phencyclidine-related absences, suspensions, or ex­pulsions from school; neglect of children or household).
• 6. Continued phencyclidine use despite having persistent or recurrent social or inter­personal problems caused or exacerbated by the effects of the phencyclidine (e.g., arguments with a spouse about consequences of intoxication; physical fights).
• 7. Important social, occupational, or recreational activities are given up or reduced be­cause of phencyclidine use.
• 8. Recurrent phencyclidine use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by a phencyclidine).
• 9. Phencyclidine use is continued despite knowledge of having a persistent or recur­rent physical or psychological problem that is likely to have been caused or exac­erbated by the phencyclidine.
• 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of the phencyclidine to achieve intoxi­cation or desired effect.b. A markedly diminished effect with continued use of the same amount of the phencyclidine

• Clinically significant problematic behavioral changes (e.g., belligerence, assaultive­ness, impulsiveness, unpredictability, psychomotor agitation, impaired judgment) that developed during, or shortly after, phencyclidine use
• 1. Vertical or horizontal nystagmus.2. Hypertension or tachycardia. 3. Numbness or diminished responsiveness to pain.4. Ataxia.5. Dysarthria.6. Muscle rigidity.7. Seizures or coma.8. Hyperacusis.

• 1) antagonists at the glutamate NMDA receptor
• 2) Unlike most drugs of abuse, they have no actions on dopaminergic neurons in the CNS.
• 2) PCP is probably the most dangerous of the hallucinogenic agents.
• 4) Psychotic reactions are common with PCP, and impaired judgment often leads to reckless behavior. This drug should be classified as a psychotomimetic

BZD

True

• A. Recent use of a hallucinogen (other than phencyclidine).
• B. Clinically significant problematic behavioral or psychological changes (e.g., marked anxiety or depression, ideas of reference, fear of “losing one’s mind,” paranoid ide­ation, impaired judgment) that developed during, or shortly after, hallucinogen use.
• C. Perceptual changes occurring in a state of full wakefulness and alertness (e.g., subjective intensification of perceptions, depersonalization, derealization, illusions, hallu­cinations, synesthesias) that developed during, or shortly after, hallucinogen use.
• D. Two (or more) of the following signs developing during, or shortly after, hallucinogen use:1. Pupillary dilation.2. Tachycardia.3. Sweating.4. Palpitations.5. Blurring of vision.6. Tremors.7. Incoordination

Following cessation of use of a hallucinogen, the reexperiencing of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen (e.g., geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of color, intensified colors, trails of images of moving objects, positive afterimages, halos around objects, macropsia and micropsia)

• A problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
• 1. Opioids are often taken in larger amounts or over a longer period than was in­tended.
• 2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use.
• 3. A great deal of time is spent in activities necessary to obtain the opioid, use the opi­oid, or recover from its effects.
• 4. Craving, or a strong desire or urge to use opioids.
• 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home.
• 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
• 7. Important social, occupational, or recreational activities are given up or reduced be­cause of opioid use.
• 8. Recurrent opioid use in situations in which it is physically hazardous.
• 9. Continued opioid use despite knowledge of having a persistent or recurrent physi­cal or psychological problem that is likely to have been caused or exacerbated by the substance.
• 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of opioids to achieve intoxication or de­sired effect.b. A markedly diminished effect with continued use of the same amount of an opioid.Note: This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision.
• 11. Withdrawal, as manifested by either of the following:a. The characteristic opioid withdrawal syndrome.b. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms

• Remain positive for most opioids (e.g., heroin, mor­phine, codeine, oxycodone, propoxyphene) for 12-36 hours after administration.
• Fentanyl, Methadone, buprenorphine, and LA AM (L-alpha-acetylmethadol) have to be specifically tested

• Infection-->MC
• MDD, other substance/ ASPD, CD

• A. Recent use of an opioid.
• B. Clinically significant problematic behavioral or psychological changes (e.g., initial eu­phoria followed by apathy, dysphoria, psychomotor agitation or retardation, impaired judgment) that developed during, or shortly after, opioid use.
• C. Pupillary constriction (or pupillary dilation due to anoxia from severe overdose) and one (or more) of the following signs or symptoms developing during, or shortly after, opioid use:1. Drowsiness or coma.2. Slurred speech.3. Impairment in attention or memory.

• A. Presence of either of the following;1. Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e., several weeks or longer).2. Administration of an opioid antagonist after a period of opioid use.
• B. Three (or more) of the following developing within minutes to several days after Criterion A:1. Dysphoric mood.2. Nausea or vomiting.3. Muscle aches.4. Lacrimation or rhinorrhea.5. Pupillary dilation, piloerection, or sweating.6. Diarrhea.7. Yawning.8. Fever.9. Insomnia.

• Effects are varied and include euphoria, hallucinations, somnolence, and sedation. Heroin has a wide range of adverse physical effects related to
• (1) the pharmacologic action of the agent,
• (2) reactions to the cutting agents or contaminants,
• (3) hypersensitivity reactions to the drug or its adulterants (quinine itself has neurologic, renal, and auditory toxicity), and
• (4) diseases contracted incident to the use of infected needles

• 1. Sudden death (profound respiratory depression, arrhythmia and cardiac arrest, and severe pulmonary edema)
• 2. Pulmonary injury (moderate to severe edema, septic embolism from endocarditis lung abscess, opportunistic infections, and foreign-body granulomas from talc and other adulterants)
• 3. Infections (skin and subcutaneous tissue, heart valves-->T valve, staph aureus, liver--> viral hepatitis (mc infection) and lungs)
• 4. Skin (Acute changes include abscesses, cellulitis, and ulcerations due to subcutaneous injections. Scarring at injection sites, hyperpigmentation over commonly used veins, and thrombosed veins are the usual sequelae of repeated intravenous inoculations)
• 5. Renal (amyloidosis (generally secondary to skin infections) and focal glomerulosclerosis; both induce heavy proteinuria and the nephrotic syndrome)

Viral hepatitis

• A. Recent use of a sedative, hypnotic, or anxiolytic.
• B. Clinically significant maladaptive behavioral or psychological changes (e.g., inappro­priate sexual or aggressive behavior, mood lability, impaired judgment) that developed during, or shortly after, sedative, hypnotic, or anxiolytic use.
• C. One (or more) of the following signs or symptoms developing during, or shortly after, sedative, hypnotic, or anxiolytic use:1. Slurred speech.2. Incoordination.3. Unsteady gait.4. Nystagmus.5. Impairment in cognition (e.g., attention, memory).6. Stupor or coma.

• I: No medical use; high addiction potential: Flunitrazepam, heroin, LSD, mescaline, PCP, MDA, MDMA, STP
• II: Medical use; high addiction potential barbiturates, strong opioids: Amphetamines, cocaine, methylphenidate, short acting
• III: Medical use; moderate abuse potential: moderate opioid agonists, Anabolic steroids, barbiturates, dronabinol, ketamine
• IV: Medical use; low abuse potential: Benzodiazepines, chloral hydrate, mild stimulants (eg, phentermine, sibutramine), most hypnotics (eg, zaleplon, zolpidem), weak opioids

• Flunitrazepam (Rohypnol), a potent rapid-onset benzodiazepine with marked amnestic properties, has been used in "date rape."
• Added to alcoholic beverages, chloral hydrate or gamma-hydroxybutyrate (GHB; sodium oxybate) also render the victim incapable of resisting rape. The latter compound, a minor metabolites of GABA, binds to GABAB receptors in the CNS. When used as a "club drug" GHB causes euphoria, enhanced sensory perception, and amnesia

• A. Cessation of (or reduction in) sedative, liypnotic, or anxiolytic use that has been pro­longed
• .B. Two (or more) of the following, developing within several hours to a few days after the ces­sation of (or reduction in) sedative, hypnotic, or anxiolytic use described in Criterion A:1. Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100 bpm).2. Hand tremor.3. Insomnia.4. Nausea or vomiting.5. Transient visual, tactile, or auditory hallucinations or illusions.6. Psychomotor agitation.7. Anxiety.8. Grand mal seizures

In addition to the symptoms of classic withdrawal, this syndrome includes weight loss, paresthesias, and headache

• A pattern of amphetamine-type substance, cocaine, or other stimulant use leading to clinically significant impairment or distress, as manifested by at least two of the follow­ing, occurring within a 12-month period:
• 1. The stimulant is often taken in larger amounts or over a longer period than was in­tended.
• 2. There is a persistent desire or unsuccessful efforts to cut down or control stimulant use.
• 3. A great deal of time is spent in activities necessary to obtain the stimulant, use the stimulant, or recover from its effects.
• 4. Craving, or a strong desire or urge to use the stimulant.
• 5. Recurrent stimulant use resulting in a failure to fulfill major role obligations at work, school, or home.
• 6. Continued stimulant use despite having persistent or recurrent social or interper sonal problems caused or exacerbated by the effects of the stimulant.
• 7. Important social, occupational, or recreational activities are given up or reduced be­cause of stimulant use.
• 8. Recurrent stimulant use in situations in which it is physically hazardous.
• 9. Stimulant use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the stimulant.
• 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of the stimulant to achieve intoxication or desired effect.b. A markedly diminished effect with continued use of the same amount of the stimulant.Note: This criterion is not considered to be met for those taking stimulant medica­tions solely under appropriate medical supervision, such as medications for ADHD or narcolepsy.
• 11. Withdrawal, as manifested by either of the following:a. The characteristic withdrawal syndrome for the stimulant. b. The stimulant (or a closely related substance) is taken to relieve or avoid with­drawal symptoms

• Other substances particularly sedatives
• Cocaine users often use alcohol, while amphetamine-type stimulant users often use cannabis

• A. Recent use of an amphetamine-type substance, cocaine, or other stimulant.
• B. Clinically significant problematic behavioral or psychological changes (e.g., euphoria or affective blunting: changes in sociability: hypervigilance: interpersonal sensitivity: anxiety, tension, or anger; stereotyped behaviors: impaired judgment) that developed during, or shortly after, use of a stimulant.
• C. Two (or more) of the following signs or symptoms, developing during, or shortly after, stimulant use:1. Tachycardia or bradycardia.2. Pupillary dilation.3. Elevated or lowered blood pressure.4. Perspiration or chills.5. Nausea or vomiting.6. Evidence of weight loss.7. Psychomotor agitation or retardation.8. Muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias.9. Confusion, seizures, dyskinesias, dystonias, or coma.

• A. Cessation of (or reduction in) prolonged amphetamine-type substance, cocaine, or other stimulant use.
• B. Dysphoric mood and two (or more) of the following physiological changes, developing within a few hours to several days after Criterion
• A:1. Fatigue.2. Vivid, unpleasant dreams.3. Insomnia or hypersomnia.4. Increased appetite.5. Psychomotor retardation or agitation.
• C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

True

physical dependence generally does not occur, the psychologic withdrawal is profound

• The most serious physical effects of cocaine relate to its acute action on the cardiovascular system, where it behaves as a sympathomimetic.
• It facilitates neurotransmission both in the CNS, where it blocks the reuptake of dopamine, and at adrenergic nerve endings, where it blocks the reuptake of both epinephrine and norepinephrine while stimulating the presynaptic release of norepinephrine.
• The net effect is the accumulation of these two neurotransmitters in synapses, resulting in excess stimulation, manifested by tachycardia, hypertension, and peripheral vasoconstriction.
• Cocaine also induces myocardial ischemia, by causing coronary artery vasoconstriction, and enhancing platelet aggregation and thrombus formation.
• Cigarette smoking potentiates cocaine-induced coronary vasospasm. Thus, the dual effect of cocaine, causing increased myocardial oxygen demand by its sympathomimetic action, and, at the same time, decreasing coronary blood flow, sets the stage for myocardial ischemia that may lead to myocardial infarction.
• Cocaine can also precipitate lethal arrhythmias by enhanced sympathetic activity as well as by disrupting normal ion (K+, Ca[2]+, Na+) transport in the myocardium. These toxic effects are not necessarily dose-related, and a fatal event may occur in a first-time user with what is a typical mood-altering dose.

The most common CNS effects are hyperpyrexia (thought to be caused by aberrations of the dopaminergic pathways that control body temperature) and seizures

• In pregnant women, cocaine may cause decreased blood flow to the placenta, resulting in fetal hypoxia and spontaneous abortion. Neurologic development may be impaired in the fetus of pregnant women who are chronic drug users.  
• Other effects. Chronic cocaine use may cause (1) perforation of the nasal septum in snorters, (2) decreased lung diffusing capacity in those who inhale the smoke, and (3) the development of dilated cardiomyopathy

It facilitates neurotransmission both in the CNS, where it blocks the reuptake of dopamine, and at adrenergic nerve endings, where it blocks the reuptake of both epinephrine and norepinephrine while stimulating the presynaptic release of norepinephrine

seizures

Cocaine

• 1)It acts by releasing dopamine in the brain, which inhibits presynaptic neurotransmission at corticostriatal synapses, slowing glutamate release (Robbins).
• Amphetamines inhibit transporters of CNS amines including dopamine, norepinephrine, and serotonin, thus enhancing their actions
• 2) Metamphetamine produces a feeling of euphoria, which is followed by a “crash.” 3) Long-term use leads to violent behaviors, confusion, and psychotic features that include paranoia and hallucinations
• 4) Drugs in this class include dextroamphetamine andmethamphetamine ("speed"), a crystal form of which ("ice") can be smoked.
• 5) Chronic high-dose abuse leads to a psychotic state (with delusions and paranoia) that is difficult to differentiate from schizophrenia. Chronic abuse of amphetamines is associated with the development of necrotizing arteritis, leading to cerebral hemorrhage and renal failure

• MDMA has a more selective action than amphetamine on the serotonin transporter in the CNS. The drug is purported to facilitate interpersonal communication and act as a sexual enhancer.
• PET studies of the brains of regular users of MDMA show a depletion of neurons in serotonergic tracts.
• Overdose toxicity includes hyperthermia, symptoms of the serotonin syndrome, and seizures.
• A withdrawal syndrome with protracted depression has been described in chronic users of MDMA MDMA is generally taken orally.
• MDMA use also reduces the number of serotonergic axon terminals in the striatum and the cortex, and it may increase the peripheral effects of dopamine and adrenergic agents.

• Its effects, which include euphoria and hallucinogen-like feelings that last for 4 to 6 hours, are mainly due to an increase in serotonin release in the CNS.
• This is coupled with interference in serotonin synthesis, causing a reduction in serotonin that is only slowly replenished.

• Anesthetics (nitrous oxide, chloroform, and diethylether-->LOC)
• Industrial Solvents--> toluene causes dementia
• Organic Nitrites--> methemoglobinemia, tachycardia, hypotension, and flushing

first-order (constant half-life)/zero-order (variable half-life) kinetics

• Bupropion--> enhancing noradrenergic and dopaminergic release
• Varenicline--> partial agonist at the alpha-4 beta-2 subunit of the nicotinic acetylcholine receptor, the receptor that appears to produce the reinforcing effects of nicotine and leads to nicotine dependence. As a partial agonist, it binds to and produces partial stimulation of the alpha4beta2 nicotinic receptor, thereby reducing the symptoms of nicotine withdrawal. Secondly, since varenicline binds to the alpha4beta2 receptor subunit with high affinity, it blocks the nicotine in tobacco smoke from binding to the receptor, thereby reducing the rewarding aspects of cigarette smoking

• Antimuscarinic drugs (anticholinergics): Delirium, hallucinations, seizures, coma, tachycardia, hypertension, hyperthermia, mydriasis, decreased bowel sounds, urinary retention--> Control hyperthermia; physostigmine may be helpful, but not for tricyclic overdose
• Cholinomimetic drugs (carbamate or organophosphate cholinesterase inhibitors): Anxiety, agitation, seizures, coma, bradycardia or tachycardia, pinpoint pupils, salivation, sweating, hyperactive bowel, muscle fasciculations, then paralysis--> Support respiration. Treat with atropine and pralidoxime. Decontaminate

• Opioids: Lethargy, sedation, coma, bradycardia, hypotension, hypoventilation, pinpoint pupils, cool skin, decreased bowel sounds, flaccid muscles--> Provide airway and respiratory support. Give naloxone as required
• Salicylates (eg, aspirin): Confusion, lethargy, coma, seizures, hyperventilation, hyperthermia, dehydration, hypokalemia, anion gap metabolic acidosis--> Correct acidosis and fluid and electrolyte imbalance. Alkaline diuresis or hemodialysis to aid elimination
• Sedative-hypnotics (barbiturates, benzodiazepines, ethanol): Disinhibition initially, later lethargy, stupor, coma. Nystagmus is common, decreased muscle tone, hypothermia. Small pupils, hypotension, and decreased bowel sounds in severe overdose--> Provide airway and respiratory support. Avoid fluid overload. Consider flumazenil for benzodiazepine overdose
• Stimulants (amphetamines, cocaine, phencyclidine [PCP]): Agitation, anxiety, seizures. Hypertension, tachycardia, arrhythmias. Mydriasis, vertical and horizontal nystagmus with PCP. Skin warm and sweaty, hyperthermia, increased muscle tone, possible rhabdomyolysis--> Control seizures, hypertension, and hyperthermia
• Tricyclic antidepressants: Antimuscarinic effects. The "3 C's" of coma,convulsions, cardiotoxicity--> Control seizures. Correct acidosis cardiac toxicity (widened QRS, arrhythmias, hypotension) and cardiotoxicity with ventilation, sodium bicarbonate, and norepinephrine (for hypotension). Control hyperthermia

• Acetaminophen: Mild anorexia, nausea, vomiting, delayed jaundice, hepatic and renal failure
• Botulism: Dysphagia, dysarthria, ptosis, ophthalmoplegia, muscle weakness; incubation period 12–36 h
• Carbon monoxide: Coma, metabolic acidosis, retinal hemorrhages
• Cyanide: Bitter almond odor, seizures, coma, abnormal ECG
• Ethylene glycol: Renal failure, crystals in urine, increased anion and osmolar gap, initial CNS excitation; eye examination normal
• Iron: Bloody diarrhea, coma, radiopaque material in gut (seen on x-ray), high leukocyte count, hyperglycemia
• Lead: Abdominal pain, hypertension, seizures, muscle weakness, metallic taste, anorexia, encephalopathy, delayed motor neuropathy, changes in renal and reproductive function
• Lysergic acid (LSD): Hallucinations, dilated pupils, hypertension
• Mercury: Acute renal failure, tremor, salivation, gingivitis, colitis, erethism (fits of crying, irrational behavior), nephrotic syndrome
• Methanol: Rapid respiration, visual symptoms, osmolar gap, severe metabolic acidosis
• Mushrooms (Amanitaphalloides type): Severe nausea and vomiting 8 h after ingestion; delayed hepatic and renal failure
• Phencyclidine (PCP): Coma with eyes open, horizontal and vertical nystagmus

• The osmolar gap is the difference between the measured serum osmolarity (measured by the freezing point depression method) and the osmolarity predicted by measured serum concentrations of sodium glucose and BUN:This gap is normally zero.
• A significant gap is produced by high serum concentrations of intoxicants of low molecular weight such as ethanol, methanol, and ethylene glycol

• The anion gap is the difference between the sum of the measured serum concentrations of the 2 primary cations, sodium and potassium, and the sum of the measured serum concentrations of the 2 primary anions, chloride and bicarbonate:This gap is normally 12–16 mEq/L. A significant increase can be produced by diabetic ketoacidosis, renal failure, or drug-induced metabolic acidosis.
• Drugs that cause an anion gap include cyanide, ethanol, ethylene glycol, ibuprofen, isoniazid, iron, methanol, phenelzine, salicylates, tranylcypromine, valproic acid, and verapamil

• Drugs that cause hyperkalemia include beta-adrenoceptor blockers, digitalis (in suicidal overdose), fluoride, lithium, and potassium-sparing diuretics.
• Drugs associated with hypokalemia include barium,beta -adrenoceptor agonists, methylxanthines, most diuretics, and toluene.

Charcoal does not bind iron, lithium, or potassium, and it binds alcohols and cyanide poorly

polyethylene-glycol electrolyte solution can enhance gut decontamination of iron tablets, enteric-coated pills, and illicit drug-filled packets

Alkalinize: fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates.

Acidify: for weak bases, including amphetamines, nicotine, and phencyclidine

• Phentolamine, a nonselective alpha1-adrenergic receptor antagonist, for severe hypertension due to alpha1-adrenergic agonists;
• propranolol, a nonselective  blocker, for hypotension and tachycardia due to beta2agonists;
• labetalol, a beta blocker with alpha-blocking activity, or phentolamine with esmolol, metoprolol, or other cardioselective blocker for hypertension with tachycardia due to nonselective agents (blockers, if used alone, can exacerbate hypertension and vasospasm due to unopposed  stimulation);

• Amphetamines, cocaine, dextromethorphan, meperidine, MAOI, SSRI, TCA, tramadol, triptans, tryptophan.
• Promotion of serotonin release, inhibition of serotonin reuptake, or direct stimulation of CNS and peripheral serotonin receptors (primarily 5-HT-1a and 5-HT-2), alone or in combination
• Altered mental status (agitation, confusion, mutism, coma, seizures), neuromuscular hyperactivity (hyperreflexia, myoclonus, rigidity, tremors), and autonomic dysfunction (abdominal pain, diarrhea, diaphoresis, fever, flushing, labile hypertension, mydriasis, tearing, salivation, tachycardia). Complications include hyperthermia, lactic acidosis, rhabdomyolysis, and multisystem organ failure.
• Treat with Serotonin receptor antagonist cyproheptadine

• Acetylcysteine: Acetaminophen; best given within 8–10 h of overdose
• Atropine: Cholinesterase inhibitors
• Bicarbonate, sodium: Membrane-depressant cardiotoxic drugs (eg, quinidine, tricyclic antidepressants)
• Calcium: Fluoride; calcium channel blockers
• Deferoxamine: Iron salts
• Digoxin antibodies: Digoxin and related cardiac glycoside
• Esmolol: Caffeine, theophylline, sympathomimetics
• Ethanol: Methanol, ethylene glycol
• Flumazenil: Benzodiazepines, zolpidem
• Fomepizole: Methanol, ethylene glycol
• Glucagon: Beta adrenoceptor blockers
• Glucose: Hypoglycemics
• Hydroxocobalamin: Cyanide
• Naloxone: Opioid analgesics
• Oxygen: Carbon monoxide
• Physostigmine:"Suggested" for muscarinic receptor blockers, NOT tricyclics
• Pralidoxime: Organophosphate cholinesterase inhibitors

fomepizole,

• Alcohols themselves: CNS depression
• Formate causes retinal injury with optic disc hyperemia, edema, and eventually permanent blindness, as well as ischemic or hemorrhagic injury to the basal ganglia 
• Ethylene glycol metabolites target the kidney and lead to reversible oliguric or anuric acute kidney injury (acute renal failure), which in turn slows elimination of ethylene glycol. The renal failure is primarily due to glycolate-induced damage to tubules, although tubule obstruction from precipitated oxalate crystals may contribute . Hypocalcemia in ethylene glycol overdose results from calcium oxalate formation

• With anion gap metabolic acidosis: Ethylene glycol ingestion, Methanol ingestion, ESRD, DKA, Alcoholic ketoacidosis, Lactic acidosis, Formaldehyde, Paraldehyde
• Without metabolic acidosis: Ethanol or isopropyl alcohol, Infusion of nonconductive glycine, sorbitol, or mannitol solutions, Severe hyperproteinemia or hyperlipidemia

• Increased AG: 1. Increased production: KA (diabetes/alcohol), Lactic acidosis, methanol, ethylene glycol, Aspirin 2. decreased excretion: ESRD
• Normal AG: 1. Loss of bicarbonate or bicarbonate precursors: Diarrhea or other intestinal losses (eg, tube drainage), Type 2 (proximal) renal tubular acidosis (RTA), Posttreatment of ketoacidosis, Carbonic anhydrase inhibitors, Ureteral diversion (eg, ileal loop) 2. Decreased acid excretion: Chronic kidney disease and tubular dysfunction (but relatively preserved glomerular filtration rate), Type 1 (distal) RTA, Type 4 RTA (hypoaldosteronism)