Chemical Injury & Metabolism

Chemical Injury & Genetic Influence on Metabolism

• Environmental chemicals enter the body via inhalation, ingestion, or skin absorption
• Chemicals may act at the site of entry or be transported through the bloodstream
• Fat-soluble toxins can accumulate in adipose tissue, leading to prolonged toxicity

Lipophilic Compounds

• Lipophilic compounds dissolve in fat
• Facilitates transport in the blood via lipid-binding proteins
• Allows penetration through plasma membranes into cells
• Lipophilic drugs have extended half-lives and require careful dosage adjustments

Detoxification & Metabolism

• Most external compounds are metabolized into water-soluble forms for excretion through urine, bile, or feces
• Detoxification occurs primarily in the liver
• Impaired liver function increases the risk of drug toxicity
• Some chemicals are converted into reactive metabolites that damage DNA, proteins, and cellular membranes
• Enzyme inactivation by toxins can have short-term or long-term effects

Phases of Chemical Metabolism

Phase 1 Reactions

• Chemicals undergo hydrolysis, oxidation, or reduction
• Converts lipophilic chemicals into primary metabolites
• Phase 1 reactions can create reactive intermediate molecules

Phase 2 Reactions

• Phase 1 metabolites are modified into water-soluble compounds for safe elimination
• Involves glucuronidation, sulfation, methylation, and conjugation with glutathione (GSH)
• Impaired Phase 2 metabolism can lead to toxic accumulation

Cytochrome P450 Enzyme System (CYP)

• Key catalyst in Phase 1 detoxification reactions
• Processes drugs, toxins, and endogenous compounds
• Cytochrome P450 enzymes (CYP)
• Heme-containing proteins specialized for oxidative metabolism
• Primarily located in the endoplasmic reticulum of hepatocytes
• Also present in skin, lungs, and gastrointestinal tract
• CYP system detoxifies environmental chemicals and pollutants
• Can activate pro-drugs into therapeutic compounds or reactive metabolites
• Produces reactive oxygen species (ROS), contributing to oxidative stress

Examples of Chemical Metabolism Via Cytochrome P450

Carbon Tetrachloride (CCl₄)

• Used in dry cleaning and fire extinguishers
• Activated into a toxic free radical (trichloromethyl radical) that causes severe liver damage

Benzene (Cigarette Smoke)

• Metabolized in the lungs, producing DNA-binding carcinogenic metabolites
• Increases the risk of lung cancer

Alcohol & Common Drugs

• Cytochrome P450 metabolizes alcohol, influencing the risk of alcoholic liver disease
• Other drugs metabolized by CYP system include Acetaminophen, Barbiturates, Warfarin, Anticonvulsants

Genetic Variability in Cytochrome P450 Activity

• CYP enzyme function varies significantly between individuals, influencing drug metabolism and toxicity
• Factors influencing CYP activity include Genetic polymorphisms and Drug exposure

Inducers & Inhibitors of Cytochrome P450

CYP Inducers

• Enhance CYP function, leading to faster drug metabolism and clearance
• Examples include Phenobarbital, Rifampin, and Smoking
• Inducers decrease drug efficacy

CYP Inhibitors

• Suppress CYP function, slowing drug metabolism and clearance
• Examples include Omeprazole, Ketoconazole, and Grapefruit juice
• Inhibitors increase drug toxicity

Clinical Considerations

• Genetic variability, diet, and drug interactions affect drug metabolism
• Personalized medicine aims to adjust dosing based on CYP activity
• Patients with altered CYP function require dose adjustments

Pathogenesis of Tobacco Use & Resultant Pathologic Changes in Affected Organs

• Tobacco contains carcinogens and toxins that cause cancers and cardiovascular disease
• Cigarette smoking and smokeless tobacco can both be culprits

Impact of Tobacco Use on Health

• Tobacco smoke contains polycyclic aromatic hydrocarbons (PAHs), nitrosamines, and carbon monoxide
• Main culprit is cigarette smoking, but smokeless tobacco also causes oral cancer

Organs Most Frequently Affected

• Oral cavity, larynx, esophagus, lung, stomach, pancreas, cardiovascular system, and bladder
• Chemicals in tobacco are metabolized in the liver, creating reactive metabolites

Secondhand Smoke Exposure

• Secondhand smoke exposure causes coronary atherosclerosis and myocardial infarction
• Between 30,000 - 60,000 deaths per year in the U.S due to secondhand smoke

Addictive Nature of Tobacco

• Nicotine binds to nicotinic receptors in the brain and peripheral tissues
• Nicotine stimulates dopamine release and increases blood pressure and heart rate
• Withdrawal from nicotine can lead to irritability, anxiety, and increased appetite

Major Diseases Caused by Cigarette Smoking

Pulmonary Diseases

• Affects the lungs, leading to emphysema, chronic bronchitis, and lung cancer
• Smoking can also cause heart attacks
• In pregnant women, it can cause spontaneous abortion, preterm birth, and intrauterine growth restriction (IUGR)

Chronic Obstructive Pulmonary Disease (COPD)

• COPD consists of bronchitis and emphysema
• Smoking activates neutrophils and macrophages, increasing elastase production

Chronic Bronchitis

• Defined as persistent productive cough for at least three consecutive months in at least two consecutive years

Microscopic Features of Emphysema

• Loss of distal air spaces
• Remaining air spaces become dilated
• Loss of lung elasticity and Increased total lung capacity
• Reduced diaphragmatic expansion

Carcinogens in Cigarette Smoke

• Polycyclic hydrocarbons & nitrosamines are carcinogens in tobacco smoke
• Cancer risk increases with cumulative exposure
• Pack-years are used to quantify smoking exposure

Example: Squamous Cell Carcinoma from a Smoker

• Squamous cell carcinoma is a common primary lung malignancy in smokers
• Arises centrally in the lung and is firm with pale white cut surfaces
• Anthracotic Pigment is accumulated carbon deposits

Pathogenesis of Alcohol Use & Resultant Pathologic Changes in Affected Organs

• Excessive acute or chronic ethanol consumption leads to marked physical and psychological damage
• The US estimates ~10 million chronic alcoholics
• Alcohol causes over 100,000 deaths annually

Alcohol Absorption & Metabolism

• Ethanol is absorbed in the stomach and small intestine and distributed through the body
• Less than 10% of ingested alcohol is excreted unchanged in urine, sweat, and breath
• Ethanol is oxidized to acetaldehyde through three major enzymatic pathways, Cytochrome P450 (CYP2E1) system, Alcohol dehydrogenase (ADH), and Catalase
• Acetaldehyde is further converted into acetate by acetaldehyde dehydrogenase (ALDH) in the mitochondria

Role of Cytochrome P450 (CYP2E1) in Alcohol Metabolism

• This system is highly induced in chronic alcoholics, increasing ethanol metabolism
• This metabolic process elevates the production of reactive oxygen species (ROS) & causing oxidative stress

Pathologic Effects of Alcohol on Organs

Direct Toxic Effects (Point of Entry)

• Stomach and small intestine are highly vulnerable to ethanol-induced injury
• Can cause increased intestinal permeability

Indirect Toxic Effects (Metabolism in Liver)

• The liver is the primary site of alcohol metabolism
• Alcohol oxidation by ADH in hepatocytes disrupts cellular redox balance
• Deficiency in NAD+ leads to lipid accumulation in the hepatocytes, resulting in fatty liver (hepatic steatosis)

Fatty Liver (Hepatic Steatosis) Development

• High NADH levels favor lipid accumulation, leading to excess fat deposition in hepatocytes
• Fatty liver appears as a pale, enlarged liver filled with lipid droplets
• Can progress to more severe liver diseases, including alcoholic hepatitis and cirrhosis
• Fatty liver is reversible with alcohol cessation

Acute vs. Chronic Toxicity

Acute Toxicity of Alcohol

• Depresses neural activity in the central nervous system (CNS), impairing motor, sensory, and cognitive function
• Can cause stupor, coma, or death
• Can cause Acute gastritis and ulceration of the stomach

Chronic Toxicity of Alcohol

• Liver is the primary site of chronic injury, may take form of alcohol hepatitis and cirrhosis
• Cirrhosis may lead to portal hypertension

How Alcoholism Leads to Esophageal Varices

• Chronic alcohol leads to Liver Cirrhosis
• Cirrhosis leads to obstructrial blood flow causing Portal Hypertension
• The backed up blood has high pressure, causing Formation of Varices
• Dilation makes them thin and dangerous, leading to possible massive upper GI bleeding

Neurologic Effects of Chronic Alcoholism

• Thymine deficiency is common, leading to Peripheral neuropathy and Wernicke-Korsakoff syndrome
• Can also cause cerebral atrophy, degeneration of the cerebellum, and optic neuropathy

Cardiovascular Effects of Alcohol

• Can damage the myocardium, producing dilated congestive cardiomyopathy
• Can induce fetal alchohol syndrome in developing fetus.

Cocaine and Marijuana: Mechanisms, Effects, and Toxicities

• Cocaine is extracted from the leaves of the coca plant
• Marijuana is made from the leaves of cannabis

Prevalence of Cocaine Use

• An estimated 5.5 million people in the United States used cocaine (2018)
• Cocaine is sold as powder or as crack, which are crystals of cocaine hydrochloride
• Usages include snorting, smoking or injecting

Mechanism of Action

• Cocaine is a sympathomimetic agent, acting on both the central nervous system (CNS) and adrenergic nerve endings
• Blocks dopamine reuptake, leading to dopamine accumulation in the synaptic cleft
• Results in hyperstimulation, causing Euphoria, Paranoia, and Hyperthermia
• Cocaine blocks reuptake of epinephrine and norepinephrine, enhancing sympathetic activity

Acute Toxicity

• Dangerous acute effect of cocaine is on the cardiovascular system, causing Hypertension, tachycardia, peripheral vasoconstriction, and coronary artery vasoconstriction
• May result in Myocardial ischemia or infarction
• Can also experience Seizures, Hyperthermia, and Fetal hypoxia

Chronic Toxicity

• Can cause Nasal septum perforation and Decreased lung diffusing capacity
• Dilated cardiomyopathy is also a result of cocaine use

Cocaine Withdrawal

• Symptoms of withdrawal include Psychological effects, Physiologic crash, depression, and Fatigue
• Treatment includes supportive care and Psychotherapy

Marijuana

• Most widely used illegal drug in the United States, with approximately 44 million users in 2017
• Consists of Delta-9-tetrahydrocannabinol
• Distorts sensory perception, including Time, speed, and distance perception

Prevalence of Marijuana Use

• Approximately 44 million people used marijuana in 2017 in the United States
• Made from the leaves of Cannabis sativa, Cannabis indica, or hybrids of the two species
• This psychoactive substance is Delta nine tetrahydrocannabinol, abbreviated SDHC

Acute Effects

• Distorts sensory perception, including Time, speed, and distance perception and Impaired motor coordination, lasting 4-5 hours
• Cardiovascular effects include Increased heart rate and sometimes blood pressure

Chronic Effects

Respiratory effects can include Laryngitis, bronchitis, and cough

Pathogenesis of Lead Exposure & Resultant Pathologic Changes in Affected Organs

• Lead primarily enters the body via ingestion or inhalation
• Inhalation is a less concern after the ban in in 1996
• Poisoning can come from contaminated foods, water, old house paint, and occupational exposure

Mechanisms of Lead Toxicity & Organ Damage

• Lead binds to sulfhydryl groups in proteins and interferes with cancer metabolism
• This leads to Hematologic, skeletal, neurologic, gastrointestinal and renal toxicity

Why are Children More Vulnerable to Lead Toxicity?

• Children have higher absorption rates and a more permeable blood-brain barrier

Pathologic Changes in Affected Organs

Hematologic System

• Lead interferes with activity of several enzymes that are required for heme synthesis, leading to anemia
• Microcytic, hypochromic anemia associated with punctate and basophilic stipling of red cells

Skeletal System

• Lead accumulation in bones and teeth, altering calcium metabolism
• Lead deposited in epiphysis, gives bright white lines called lead lines

Nervous System

• In children, can lead to brain edema, de minimisation of white matter and neuron destruction
• In adults, it can lead to peripheral demyelinating neuropathy

Renal System

• Lead can lead to proximal tubular damage and chronic to interstitial fibrosis

Diagnosis of Lead Toxicity

Definitive diagnosis is through a blood test

Treatment of Lead Toxicity

Treatment aims to eliminate exposure with Chelation therapy

Toxic Effects of Therapeutic Drugs: Idiosyncratic vs. Dose-Dependent Reactions

Adverse drug reactions are untoward effects of drugs These reactions are extremely common, affecting seven to 8% of patients Estrogen and oral contraceptives are discussed in detail

Menopausal Hormone Therapy (MHT)

• MHT consists of the administration of estrogens together with the progestogen
• This is used primarily to counteract hot flashes and other symptoms of menopause
• MHT may have a protective effect on the development of atherosclerosis and coronary artery disease
• MHD increases the risk of stroke and thromboembolism

Oral Contraceptives

• Usually contain a synthetic stradial and a variable amount of protesting
• Oral contraceptives are associated with small increased risk of breast cancer
• Can have a protective effect against endometrial and ovarian cancers
• Increased risk of cervical carcinomas in women infected with human papillomavirus
• Increasedhepatic synthesis of coagulation factors resulting from increased hepatic synthesis of coagulation factors
• associated with a rare benign hepatic tumor called hepatic adenoma, especially in older women who have used oral contraceptives for prolonged periods of time

Idiosyncratic vs Dose Dependent

• Idiosyncrasy is defined as an abnormal reactivity to a chemical that is particular to a given individual.
• Attributes of being not dose dependent, unpredictable and specific to an individual
• Either the drug itself or a reactive metabolite will bind to a protein
• Can cause Virtually every idiosyncratic response Symptoms usually appear after a long delay between starting the drug and the onset of symptoms

Dose Dependent adversity

These symptoms are directly proportional with the dose predictable, affecting to all who take the drug