Chapter 9 Flashcards
Single leading global cause of health loss (morbidity and premature death)
Malnutrition
Exogenous chemicals in the environment in air, water, food, and soil that may be absorbed into the body through inhalation, ingestion, and skin contact
Xenobiotic
Mechanism of action of cytochrome p450 as it relates to xenobiotics
CYP450 is the most important catalyst in phase I reactions of xenobiotic metabolism
It catalyzes reactions that either detoxify the xenobiotic or (less commonly) convert them into active compounds that cause cell injury
Readily absorbed metal that binds sulfhydryl groups in proteins and interferes with calcium metabolism —> hematologic, skeletal, neurologic, GI, and renal toxicities
Lead
Symptoms of low vs. high level lead poisoning
Low level = subtle defects in intellectual capacity, hyperactivity, poor organizational skills
High level = CNS disturbances, peripheral neuropathy of extensor muscles of wrist and fingers, foot drop, radiodense “lead lines” on x-ray or at gumline, poor fracture healing, microcytic hypochromic anemia, kidney damage including intranuclear inclusions and eventual interstitial fibrosis + renal failure —possible saturnine gout d/t decreases in uric acid secretion
How is lead poisoning definitively diagnosed
Increased blood levels of lead and/or free (or zinc-bound) protoporphyrin
Lead exposure inhibits enzymes involved in heme synthesis. What 2 enzymes are affected?
Delta-aminolevulinic acid dehydratase
Ferrochelatase (catalyzes incorporation of iron into protoporphyrin)
____ binds sulfhydryl groups in certain proteins with high affinity, leading to damage in CNS and kidney; main sources of exposure include contaminated fish, metallic vapors in dental amalgams, and rivers/streams contaminated by gold mining
Mercury
Result of inhalation vs. ingestion of mercury
Inhalation —> tremor, gingivitis, bizarre behavior
Ingestion —> cerebral palsy, deafness, blindness, mental retardation, major CNS defects in fetus (methyl mercury)
Main cellular protective mechanism against mercury
Intracellular glutathione
_____ interferes with several aspects of cell metabolism by replacing phosphates in ATP, leading to toxicities that are most prominent in the GI tract, nervous system, skin, and heart
Arsenic
Arsenic is used as a frontline treatment for what type of cancer?
Promyelocytic leukemia
Effects of arsenic exposure
Acute GI, CV, and CNS toxicities that are often fatal; drinking contaminated water may cause non-malignant respiratory disease
Neurologic effects include sensorimotor neuropathy characterized by paresthesias, numbness, and pain
Skin changes include hyperpigmentation and hyperkeratosis
Most serious consequence of arsenic exposure
Carcinogenesis —> lungs, bladder, skin
What makes arsenic-caused skin cancers distinct from other etiologies?
Often appear in multiple locations and on the palms and soles
____ is preferentially toxic to the kidneys and lungs through uncertain mechansims that may involve increased production of ROS; most important mechanism of exposure is through contaminated food
Cadmium
Principal toxic effects of cadmium exposure
Obstructive lung disease d/t necrosis of alveolar epithelial cells
Renal tubular damage
Skeletal abnormalities d/t calcium loss
Postmenopausal osteoporosis, osteomalacia, and renal disease
Elevated risk of lung cancer
Examples of organic solvents and their potential risks to human health
Chloroform and carbon tetrachloride — dizziness, confusion, CNS depression, coma, kidney and liver toxicities
Benzene and 1,3-butadiene — increased risk of AML
Risks associated with exposure to organochlorines (and halogenated organic compounds in general) like DDT, lindane, aldrin, dieldrin, PCBs, dioxin, etc
Disruption of hormonal balance — antiestrogenic or antiandrogenic activity
Risks associated with polycyclic hydrocarbon exposure
Lung and bladder cancers
Health risks associated with dioxins and PCBs
Chloracne = folliculitis and dermatosis
Abnormalities of liver and CNS
Abnormalities of drug metabolism (these toxins induce CYPs)
Health risks associated with mineral dust inhalation such as coal dust, silica, asbestos, and beryllium
Chronic, nonneoplastic lung diseases = pneumoconiosis
Health risks associated with exposure to bisphenol A (BPA)
Potential endocrine disruptor
Heart disease
Effects of tobacco smoke constituents
Carcinogenesis (tar, polycyclic hydrocarbons, nitrosamine)
Ganglionic stimulation and depression; tumor promotion (nicotine)
Impaired O2 transport and utilization (CO)
Toxicity to cilia and mucosal irritation (formaldehyde, nitrogen oxides)
3 ways that smoking contributes to lung cancer
Direct irritant effect on tracheobronchial mucosa —> bronchitis
Recruitment of leukocytes to lungs —> increased elastase production —> emphysema
Carcinogenesis from hydrocarbons and nitrosamines whose solubility is increased by CYPs and phase II enzymes; some intermediates may mutate DNA directly
Most alcohol in the blood is oxidized to ______ by 3 enzyme systems. What are the 3 enzyme systems?
Acetaldehyde
Alcohol dehydrogenase (primary) - in cytoplasm of hepatocytes
Microsomal ethanol-oxidizing system (CYPs)
Catalase
Oxidation of ethanol produces toxic metabolites and disrupts certain metabolic pathways. What are some examples?
Acetaldehyde: responsible for some acute effects of alcohol and development of oral cancers
Increased NADH: NAD ratio —> lactic acidosis; NAD deficiency
ROS generation —> causes lipid peroxidation in hepatocyte cell membranes and release of endotoxin from gram-negative bacteria in intestinal flora
Vitamin defiency associated with chronic alcoholism; what are the consequences?
Thiamine (B1) deficiency —> peripheral neuropathy, wernicke-korsakoff syndrome, cerebral atrophy, cerebellar degeneration, optic neuropathy
Agents that tend to cause adverse drug reaction in bone marrow and blood cells
Antineoplastic agents, immunosuppressives, chloramphenicol —> granulocytopenia, aplastic anemia, pancytopenia
Penicillin, methyldopa, quinidine, heparin —> hemolytic anemia, thrombocytopenia
Agents that tend to cause adverse drug reaction in skin
Antineoplastic agents, sulfonomides, hydantoins, some abx —> urticaria, papules, vesicles, petechiae, exfoliative dermatitis, fixed drug eruptions, abnormal pigmentation
Agents that tend to cause adverse drug reaction in cardiac system
Theophylline, hydantoins, digoxin —> arrhythmias
Doxorubicin, daunorubicin -> cardiomyopathy
Agents that tend to cause adverse drug reaction in renal system
Penicillamine -> glomerulonephritis
Aminoglycoside abx, cyclosporin, amphotericin B —> acute tubular necrosis
Phenacetin, salicylates —> tubulointerstitial diseases with papillary necrosis
Agents that tend to cause adverse drug reaction in pulmonary system
Salicylates —> asthma
Nitrofurantoin —> acute pneumonitis
Busulfan, nitrofurantoin, bleomycin —> interstitial fibrosis
Agents that tend to cause adverse drug reaction in hepatic system
Tetracycline —> fatty change
Halothane, isoniazid, acetaminophen —> diffuse hepatocellular change
Chlorpromazine, estrogen, contraceptives —> cholestasis
Agents that tend to cause adverse drug reaction in CNS
Salicylates —> tinnitus, dizziness
Phenothiazine antipsychotics —> acute dystonic reactions and parkinsonian syndrome
Sedatives —> respiratory depression
Risk:benefit ratio for menopausal hormone therapy in terms of breast cancer, atherosclerosis, coronary disease, stroke, and embolism
Increases risk of breast cancer after median time of 5-6 years (unless woman had hysterectomy)
May protect from atherosclerosis and coronary disease in women <60
Increases risk of stroke and thromboembolism including DVT and PE
Oral contraceptives impact on cancer risk
Do not increase breast cancer risk; Protective against endometrial and ovarian cancers
May increase risk of cervical cancer in women infected with HPV; increased risk of hepatic adenoma in older women with prolonged OC use
A male adolescent patient presents with the following:
Stunted growth, acne, gynecomastia, testicular atrophy, psychiatric disturbance, and hepatic cholestasis
What agent is likely to cause these adverse effects?
Anabolic steroids
How does acetaminophen detoxification produce liver damage?
5% of it is metabolized via CYP2E to NAPQI, a highly reactive metabolite normally conjugated to glutathione. NAPQI accumulates and causes hepatocellular injury when drug is taken in large doses. Result is centrilobular necrosis and subsequent liver failure
[injury by NAPQI occurs by covalent binding to hepatic proteins and depletion of glutathione]
Effects of acute aspirin overdose
Respiratory alkalosis Metabolic acidosis (causes eventual nausea and coma)
Effects of chronic aspirin toxicity
Headaches, dizziness, tinnitus, hearing impairment, mental confusion, drowsiness, nausea, vomiting, diarrhea, convulsions, coma, acute erosive gastritis
MOA and examples of opioid narcotics
Mu opioid receptor agonists
Heroin Hydromorphone (dilaudid) Oxycodone Methadone Meperidine (demerol)
MOA and examples of sedative-hypnotics
GABA(a) receptor agonists
Barbiturates Ethanol Methaqualone Glutethimide Ethchlorvynol
MOA and examples of psychomotor stimulants
Dopamine transporter antagonists
Cocaine Amphetamines MDMA Ecstasy Meth
MOA and examples of phencyclidine-like drugs
NMDA glutamate receptor channel antagonists
PCP
Ketamine
MOA and examples of hallucinogens
Serotonin 5-HT2 receptor agonists
LSD
Mescaline
Psilocybin
Greatest threats to life in burn patients
Shock
Sepsis
Respiratory insufficiency
Cause and clinical presentation of malignant hyperthermia
Caused by inherited mutation in RYR1
Sweating ceases and core body temp rises to more than 40 C leading to multiorgan dysfunction; marked vasodilation with peripheral pooling of blood and decreased effective circulating blood volume; hyperkalemia, tachycardia, arrhythmias, and other systemic effects, sustained contractions of skeletal muscles exacerbate hyperthermia and lead to muscle necrosis (rhabdomyelosis)
Ionizing radation has what acute effect on hematopoietic and lymphoid systems?
Lymphopenia
Clinical features of Kwarshiorkor
Hypoalbuminemia —> edema “Flaky paint” skin lesions Loss of pigmentation in hair Enlarged fatty liver Apathy, listlessness, loss of appetite Immune defects
Clinical features of marasmus
Growth retardation and loss of muscle and subcutaneous fat d/t catabolism and depletion
Extremities are emaciated, anemia, vitamin deficiencies, immune deficiencies, low leptin production —> lipolysis
Consequences of Vitamin A deficiency
Night blindness, xerophthalmia, bitot spots, corneal ulcers, keratomalacia, squamous metaplasia (long-term), renal stones, vulnerability to infections (measles)
Consequences of vit A toxicity
Headache, dizziness, vomiting, stupor, blurred vision
Weight loss, anorexia, nausea, vomiting, bone and joint pain
Consequences of vitamin D deficiency
Rickets in children — craniotabes, frontal bossing and square head, rachitic rosary (deformation of chest), pigeon chest deformity, lumbar lordosis, bowing of legs
Osteomalacia in adults
Vitamin D toxicity
Metastatic calcifications of soft tissues (kidney) in children
Bone pain and hypercalcemia in adults
Clinical features of vitamin E deficiency
Spinocerebellar degeneration
Clinical features of vitamin K deficiency
Bleeding diathesis
Clinical features of vitamin B1 (thiamine) deficiency
Dry and wet beriberi
Wernicke syndrome
Korsakoff syndrome
Clinical features of vitamin B2 (riboflavin) deficiency
Ariboflavinosis Cheilosis Stomatitis Glossitis Dermatitis Corneal vascularization
Clinical features of niacin deficiency
Pellagra (dementia, dermatitis, diarrhea)
Clinical features of vitamin B6 deficiency
Cheilosis
Glossitis
Dermatitis
Peripheral neuropathy
Clinical features of vitamin B12 deficiency
Megaloblastic pernicious anemia
Degeneration of posterolateral spinal cord tracts
Clinical features of folate deficiency
Megaloblastic anemia
Neural tube defects
Clinical features of zinc deficiency
Rash around eyes, mouth, nose, and anus Anorexia and diarrhea Growth retardation in children Depressed mental function Depressed wound healing and immune response Impaired night vision Infertility
Clinical features of iron deficiency
Hypochromic microcytic anemia (likely d/t GI tract pathology)
Clinical features of iodine deficiency
Goiter
Hypothyroidism
Clinical features of copper deficiency
Muscle weakness
Neurologic defects
Abnormal collagen cross-linking
Clinical features of selenium deficiency
Myopathy
Cardiomyopathy (keshan disease)
What causes obesity in WAGR syndrome?
Haploinsufficiency of BDNF (important component of signaling downstream of MC4R in hypothalamus)
Mechanisms by which obesity may contribute to carcinogenesis
Elevated insulin levels — free IGF-1 is a mitogen that activates RAS and PI3/AKT pathways
Increased synthesis of steroid hormones (estrogen) through effect of adipose tissue aromatases
Proinflammatory state in which cytokines may cause carcinogenesis
