Clinical Chemistry 2 Lecture PDF - Toxicology, Vitamins, & Trace Elements

CLINICAL CHEMISTRY 2 LECTURE II: TOXICOLOGY, VITAMINS, & TRACE ELEMENTS Toxicity Systems correlate dose with harmful Index responses, often using lethal outcomes as a...

CLINICAL CHEMISTRY 2 LECTURE II: TOXICOLOGY, VITAMINS, & TRACE ELEMENTS Toxicity Systems correlate dose with harmful Index responses, often using lethal outcomes as a measure (e.g., a single acute oral dose and TOXICOLOGY its lethality in a 70 kg person). ​ This is the scientific study of the adverse effects of chemical substances or situations on living organisms in the Toxicity Most toxins cause harmful effects at lower environment. Effects doses than death (e.g., liver damage). This can ​ It encompasses a wide range of topics including: be assessed through responses like elevated ○​ Mechanisms of Action serum ALT or GGT. ○​ Nature of Poisons The liver is the organ commonly affected. ○​ Effects of various substances on health ​ In this topic, toxins and toxicants, exposure routes commonly Cumulative A tool to evaluate various toxic responses through inhalation, dermal contact ingestion, and on the Frequency across doses, showing how the population essential thing on dose response relationship (wherein the Histogram reacts differently to the same dose dose makes the poison) that’s fundamental in toxicology, and the mechanisms of toxicity. TD50 (TOXIC DOSE 50) ​ The study of poisons with 4 major disciplines: ​ The dose predicted to cause toxic response in 50% of Mechanistic studies cellular and biochemical effects of the population. Toxicology toxins, aids in therapy design and exposure ​ Morbidity (shows signs and symptoms) tests. LD50 (LETHAL DOSE 50) Descriptive uses animal experiments to predict harm ​ The dose predicted to cause death in 50% of the Toxicology levels in humans (risk assessment). regulatory toxicologists interpret data to population. establish safety standards ​ Mortality Forensic focuses on medicolegal consequences of ED50 (EFFECTIVE DOSE 50) Toxicology toxin exposure and methods used in legal ​ The dose predicted to have therapeutic effects in 50% evidence, such as cause of death. of the population. Clinical examines interrelationships between toxin Toxicology exposure and diseases, with emphasis on Therapeutic Ratio of TD50 to ED50; a large index diagnostic testing and therapeutic intervention Index indicates a drug with few toxic side effects within its therapeutic range EXPOSURE TO TOXINS ​ Intentional Poisoning: 50% of poisoning cases (suicide attempts). ​ Accidental Exposure: 30% of cases, most common in children but also in adults due to drug overdoses. ​ Occupational Exposure: occurs in industrial and agricultural settings. ROUTES OF EXPOSURE ​ Ingestion: Most common in clinical settings ​ Accidental Inhalation and Transdermal Absorption: other common routes ➔​ First curve: represents the therapeutic effect; half of the population showing effectiveness of the dose ABSORPTION OF TOXINS ➔​ Second curve: represents toxic effect; half of the ​ Toxins require entry into circulation, primarily through the population showing signs and symptoms. gastrointestinal tract. ➔​ Third curve: represents lethal effect; half of the ​ Toxins are absorbed by passive diffusion across cell population that have died after ingesting or having an membranes (hydrophobic/water-based substances are absorption of the toxin. absorbed easily compared to non-hydrophobic or liquid soluble substances.) ACUTE & CHRONIC TOXICITY ​ Ionized substances cannot diffuse passively but may be ACUTE CHRONIC absorbed based on pH (substances must appear as weak acids in the stomach, weak bases in the intestine) Results from short-term, Caused by repeated, ​ Other factors influencing absorption: dissolution rate, high-dose exposure lower-dose exposure over causing immediate toxic time, potentially leading to gastrointestinal motility, and interaction with other effects toxic accumulation or substances delayed effects ​ Non-absorbed toxins: may cause local effects (e.g., diarrhea, bleeding, malabsorption) but not systemic effect DOSE-RESPONSE RELATIONSHIP ​ Poison: is any substance causing harmful effects upon exposure, with dose being a key factor in toxicity (fundamental law in toxicology).  ANALYSIS OF TOXIC AGENTS Blood Alcohol 80 mg/dL is the limit for driving in most Screening Tests Simple, qualitative methods with high Concentration states, associated with impaired judgment sensitivity but low specificity, used to (BAC) and motor skills detect specific substances or toxin classes Chronic effects Long-term ethanol use (50g/day for 10 years) damages liver, leading to fatty liver, Trying to see the presence or absence of alcoholic hepatitis, and cirrhosis. a toxin. Metabolic- Acetaldehyde Confirmatory A more specific, second method byproduct Testing confirms the presence of toxins Formed during ethanol metabolism, reacts with proteins and is a key factor in ethanol’s pathologic effects. COMMON ANALYTICAL METHODS IMMUNOASSAYS ​ For screening drugs, often detecting drug classes or METHANOL/ WOOD SPIRIT / METHYL ALCOHOL specific drugs (e.g., THC). ​ Common in solvents and homemade alcohol ​ Leading to acidosis and optic neuropathy, only alcohol that can potentially lead to blindness Metabolic- Formaldehyde and Formic Acid byproduct ISOPROPANOL / RUBBING ALCOHOL ​ With CNS depressant effects similar to ethanol, but acetone has a longer half life, prolonging symptoms THIN-LAYER CHROMATOGRAPHY ​ Simple and inexpensive method for detecting organic Metabolic- Metabolized to Acetone compounds. byproduct ETHYLENE GLYCOL / ANTIFREEZE ​ Found in antifreeze and hydraulic fluids ​ Ingested often by children due to its sweet taste ​ It causes metabolic acidosis, kidney damage from calcium oxalate crystal formation (hallmark). GAS CHROMATOGRAPHY (GC) ​ Widely used for qualitative and quantitative analysis of volatile substances, often combined with mass spectrometry for identification. TOXICOLOGY OF SPECIFIC AGENTS ALCOHOL DETERMINATION OF ALCOHOLS: SPECIMEN TYPES General Toxic Alcohol causes CNS depression ​ Serum, plasma, and whole blood are used for ethanol Effects leading to disorientation, confusion, determination euphoria, unconsciousness, and ​ The sample should be sealed to prevent ethanol evaporation. potentially death. DETERMINATION OF ALCOHOLS: METHODS Mechanism Alcohol depresses the CNS by altering membrane properties; Osmometry Measures serum osmolarity, useful for recovery from CNS effects is screening, but not specific for ethanol. generally quick after cessation. Gas Reference method for ethanol Specific Alcohol is metabolized to aldehydes Chromatography determination; it can also detect other Toxicities and acids, with distinct toxicities from (GC) alcohols like methanol and isopropanol. each type of alcohol, especially through biotransformation. Enzymatic Uses alcohol dehydrogenase (ADH) to Method oxidize ethanol to acetaldehyde, which can be monitored by the reduction of ETHANOL/ETHYL ALCOHOL/ GRADE ALCOHOL NAD to NADH ​ Excessive ethanol consumption leads to major social, economic, and health issues, costing over $100 billion METHOD SENSITIVITY annually. ​ Enzymatic methods are relatively specific for ethanol but ​ It contributes to about 20% of hospital admissions and is a may produce low results for methanol or isopropanol leading cause of premature death (about 80,000 deaths intoxication. annually in the U.S.) ​ Consumption during pregnancy can cause fetal alcohol CHAIN OF CUSTODY syndrome or effects, impacting motor and mental ​ Proper documentation and handling are critical for legal development. ethanol testing, especially in cases like DUI.  TREATMENT CARBON MONOXIDE ​ 100% oxygen therapy is the primary treatment. ​ Severe cases may require hyperbaric oxygen therapy. Properties Colorless Odorless ​ Half-life of COHb: 60–90 minutes on 100% oxygen with Tasteless normal respiratory function. Rapidly absorbed into blood from inspired air. DIAGNOSTIC METHODS Sources Produced by incomplete combustion of Spot Test COHb gives a cherry-red appearance. carbon-containing substances like gasoline engines, improperly ventilated furnaces, A spot test involves adding NaOH to whole and fires. blood. Persistence of a pink solution suggests COHb levels ≥20% Quantitative Gas Chromatography (GC): Reference Assays method. CO is released from hemoglobin and detected by thermal conductivity changes. Spectrophotometry: Measures absorbance at multiple wavelengths to calculate the concentration of COHb and other hemoglobin forms. Common in automated systems CAUSTIC AGENTS Mechanism CO binds to Hgb, forming carboxyhemoglobin Sources: Found in household products and occupational (COHb). setting Affinity CO binds 200–225 times more strongly to Exposure ASPIRATION: Causes pulmonary edema and hemoglobin than oxygen. Risks shock, potentially leading to death. Effect A small amount of CO (e.g., 0.1% in air) can lead to INGESTION: Causes lesions in the esophagus 50% carboxyhemoglobinemia, reducing the and gastrointestinal tract, leading to oxygen-carrying capacity of blood. perforations, hematemesis (vomiting blood), abdominal pain, and possible shock. Note: decreased oxygenation = change in the oxygen hemoglobin dissociation curve (curve METABOLIC EFFECTS: Rapid onset of tends to go leftwards) metabolic acidosis or alkalosis. Oxygen CO shifts the oxygen-hemoglobin dissociation Treatment Dilution is used as a corrective therapy for Delivery curve leftward, reducing oxygen delivery to tissues ingestion (hypoxia), especially affecting high-oxygen-demand organs like the brain and heart. CYANIDE Sources: Exists as a gas, solid, or in solution. It is used in industrial processes and found in insecticides, rodenticides, and as a byproduct of burning plastics (including urea foams). Exposure Can occur via inhalation, ingestion, or transdermal absorption. Cyanide poisoning is often associated with smoke inhalation. Toxic Binds to heme iron and mitochondrial Mechanism cytochrome oxidase, disrupting oxidative phosphorylation. TOXIC EFFECTS ​ HYPOXIA - Decreased oxygen delivery to tissues causes Causes a depletion of ATP due to the significant harm, particularly in the brain and heart. inability of oxygen to accept electrons. ​ SYMPTOMS - Vary depending on COHb concentration. Results in increased oxygen tension in cells and venous PO2 due to lack of oxygen utilization. Symptoms Low-level exposure causes headaches, dizziness, and respiratory depression. Higher doses can lead to seizures, coma, and death Clearance Mediated by enzymatic conversion to thiocyanate, which is nontoxic and rapidly excreted by the kidneys. Toxicity occurs when exposure exceeds clearance rates. Diagnosis Requires rapid evaluation, typically using  industrial processes. Foods may also contain lead, though the ion-specific electrode methods or photometric analysis with microdiffusion separation. average intake for adults (75-120 μg/day) is typically not toxic. Absorption Ingestion is the primary route of exposure. Chronic low-level exposure can be monitored by measuring urinary thiocyanate levels Adults absorb 5%-15% of ingested lead, while children absorb 30%-40%. ARSENIC The lead binds to macromolecules and Sources: Found in both natural and manmade substances, distributes throughout the body, accumulating including air, water, agriculture, and smelting industries. in bone (largest pool) and soft tissue Commonly used in homicide and suicide. Elimination Lead is primarily eliminated by renal filtration, but since most lead is stored in Absorption Organic arsenic compounds are rapidly bones and soft tissues, it has a slow absorbed via passive diffusion. elimination rate, resulting in cumulative body lead levels over time. Other forms are absorbed more slowly. Cleared primarily via renal filtration in the TOXICITY free, ionized state ​ Neurological: Lead exposure can cause encephalopathy, cerebral edema, and ischemia. At high levels, it may cause Toxic Binds to thiol groups in proteins, stupor, convulsions, and coma. Lower levels may cause Mechanism disrupting structure and function. subclinical effects like behavioral changes, hyperactivity, Long half-life due to slow clearance and attention deficits, and reduced IQ. Children are particularly possible accumulation with chronic sensitive. exposure ​ Hematologic: Lead inhibits heme synthesis, causing anemia. Elevated levels of aminolevulinic acid and Symptoms Low-level exposure: Fever, anorexia, protoporphyrin are indicators, and zinc protoporphyrin gastrointestinal distress. fluorescence is used for screening. ​ Renal: Early stages show tubular dysfunction, with High-level exposure: Neurological damage (peripheral and central), renal effects, glycosuria, aminoaciduria, and hyperphosphaturia. Later hematopoietic effects, vascular disease, and stages can result in renal fibrosis and decreased glomerular death filtration rate. ​ Other Effects: Lead exposure is linked to hypertension, Analysis Atomic absorption spectrophotometry is carcinogenesis, birth defects, and compromised commonly used for arsenic analysis. immunity. Blood and urine are used for short-term exposure; hair and fingernail content are Diagnosis Blood testing is the most reliable method to useful for long-term exposure evaluate lead toxicity, with methods like graphite furnace atomic absorption spectrophotometry (AAS) being most common. CADMIUM Sources: Found in industrial processes (especially Urinary testing can also assess recent electroplating and galvanizing), mining, pigments, plastics, and exposure. nickel-cadmium batteries. A significant environmental pollutant. Special care is needed during specimen collection to avoid contamination Exposure Mainly via inhalation in industry and ingestion of contaminated food. Treatment Chelation therapy with agents like EDTA and DMSA is used to remove lead from the body. Toxicity Binds to proteins and other cellular These agents form complexes with lead that components. can be excreted via the kidneys. Mechanism Accumulates in the kidneys, where its toxic Monitoring the urinary concentration of lead effects manifest. helps assess the effectiveness of treatment. Symptoms Early sign of toxicity: Renal tubular Note: Lead toxicity is a significant health concern, especially for dysfunction children, and monitoring and managing exposure is crucial for preventing long-term health effects. Associated conditions include tubular proteinuria, glucosuria, and aminoaciduria. MERCURY Affected Organ: Kidney FORMS Analysis Excessive exposure is typically evaluated by Elemental (Hg₀) Liquid at room temperature. It has measuring blood or urinary cadmium content low vapor pressure and is not easily using atomic absorption spectrophotometry. absorbed if ingested. Inhalation of elemental mercury vapor is unlikely to cause LEAD significant effects Sources: Lead is a common environmental contaminant, found in old household paints (pre-1972), gasoline (until 1978), Inorganic (Hg²⁺) Moderately toxic. It can cause automobile exhaust residues, lead pipes, and various  KEY POINTS localized toxicity in the gastrointestinal tract and has partial absorption into the ​ Chronic Exposure: Results in a cumulative effect, body particularly affecting the kidneys and nervous system ​ Treatment: Focuses on removing the source of exposure Organic (e.g, Highly toxic, especially when and using chelation therapy, though specific treatment Methylmercury,CH absorbed into the body strategies depend on the form of mercury involved. ₃Hg) Note: Mercury toxicity is serious, especially for neurological and ROUTES OF EXPOSURE renal health, and chronic exposure can have long-lasting effects. Inhalation Accidental exposure in industrial PESTICIDES settings, especially with inorganic and organic forms ​ Chemicals designed to kill or harm unwanted organisms such as pests, insects, and weeds Ingestion The most common route for the general ​ Can also harm humans when ingested, inhaled or swallowed population, typically from contaminated ​ These substances are commonly used in agriculture, food (e.g., fish) vector control, and to combat urban pests ​ While they serve beneficial purposes, pesticides can pose Dermal Can also occur but is not as common as significant health risks, especially when there is accidental Absorption inhalation or ingestion or occupational exposure ABSORPTION AND DISTRIBUTION ROUTES OF EXPOSURE Elemental Not significantly absorbed due to its Food The primary route of exposure for the viscous liquid form Contamination general population is through contaminated food Inorganic Partially absorbed and affects the gastrointestinal tract locally. The absorbed It is important to wash vegetables and portion is distributed throughout the body fruits Organic Rapidly and efficiently absorbed through Inhalation and Common in occupational setting passive diffusion, concentrating in dermal hydrophobic tissues, particularly the brain absorption and peripheral nerves. Ingestion Accidental ingestion especially by (hand-to-mouth) children, is a frequent occurrence ELIMINATION particularly in homes where pesticides Primarily occurs through renal filtration of free or are used low-molecular weight mercury species. However, because mercury often binds to proteins, its elimination is slow, leading Intentional Some individuals may intentionally ingest to cumulative effects with chronic exposure Ingestion pesticides often for suicide attempts (farmers) TOXIC EFFECTS CATEGORIES General Mercury binds to proteins, disrupting their Mechanism structure and function, which inhibits enzymes Insecticides The most common type, often used and leads to tissue damage in the control of insect Elemental Typically causes gastrointestinal Herbicides Used to control weeds disturbances when ingested, including ulceration and necrosis. Severe cases may Organophosphates The most abundant insecticides, lead to shock and death responsible for a large percentage of pesticide poisoning Inorganic Affects multiple organs, particularly the kidneys, causing glomerular proteinuria Common in agricultural setting (protein in urine) and renal tubular dysfunction. MECHANISMS OF TOXICITY: ORGANOPHOSPHATES & CARBAMATES Organic Primarily affects the nervous system, causing tremors, behavioral changes, mumbling Acetylcholinesterase Organophosphates and carbamates speech, and loss of balance at low Inhibition inhibit acetylcholinesterase exposure levels. Higher exposure levels (AChE), an enzyme essential for can lead to hyporeflexia, hypotension, breaking down acetylcholine, a bradycardia, and renal dysfunction, neurotransmitter in both insects and potentially leading to death. mammals. Acetylcholine's Role It is involved in nerve transmission DIAGNOSIS and muscle stimulation, and the ​ Whole Blood or 24-Hour Urine: Mercury levels can be enzyme acetylcholinesterase AChE measured using atomic absorption spectrophotometry normally terminates its action or anodic stripping voltammetry. ​ Special techniques are required for elemental mercury Effect of The prolonged presence of analysis due to its volatility. Inhibition acetylcholine at nerve receptors causes overstimulation, leading to  TESTING METHODS toxic effects in the body. TWO-TIERED COMMON ANALYTICAL APPROACH PROCEDURES SYMPTOMS OF EXPOSURE SCREENING Chromogenic reactions, Low-Level Causes salivation, lacrimation (tearing), - Simple, rapid, and immunoassays, and involuntary urination and defecation. inexpensive; detects classes chromatography techniques of drugs based on chemical (thin-layer, GC, liquid Moderate Leads to bradycardia (slow heart rate), similarity chromatography). muscular twitching, cramps, slurred speech, behavioral changes CONFIRMATORY Severe Can result in respiratory failure and death. - Uses highly sensitive and specific methods like GC-MS for accurate results. DIAGNOSIS OF ORGANOPHOSPHATE POISONING ​ Acetylcholinesterase inhibition: inhibition of this enzyme is a sensitive indicator of exposure, because AChE is SPECIFIC DRUGS WITH HIGH ABUSE POTENTIAL membrane-bound, its activity is typically measured in erythrocytes, which have a higher surface activity. AMPHETAMINES ​ Serum pseudocholinesterase (SChE): this enzyme is also METHAMPHETAMINE(METH,ICE,GLASS,CHALK) inhibited by organophosphates but is less specific and ​ Used for narcolepsy and ADHD but have high abuse sensitive for detecting organophosphate poisoning. potential, leading to increased mental and physical ​ Challenges with SChE testing: decreases in SChE can also capacity, restlessness, and irritability. be seen in conditions such as acute infections, pulmonary ​ Potent CNS stimulants: are dopamine and norepinephrine embolism, hepatitis, and cirrhosis, which makes it an releasing agents and reuptake inhibitors. unreliable diagnostic tool on its own.We should not rely only ​ Chronic use leads to tolerance, psychological dependence, on this because it is not specific. and overdose risks (e.g., hypertension, arrhythmias). ​ Normal SChE range: typically between 4,000 and 12,000 ​ Screening for amphetamines involves urine analysis and U/L, with symptoms of toxicity appearing when there is about confirmation via liquid or gas a 40% reduction in activity. ​ Erythrocyte AChE is the preferred test for confirming METHYLENEDIOXYMETHAMPHETAMINE (MDMA) organophosphate poisoning in cases of suspected ECSTASY, MOLLY exposure. ​ A derivative of amphetamines, causing hallucinations, euphoria (euphoric rush), and increased sensitivity TREATMENT (stimulant & psychedelic properties: You hallucinate and see ​ Therapy things) ○​ IMMEDIATE: In suspected cases of ​ An empathogen–entactogen (SEVERELY EMPATHIZE organophosphate poisoning, antidotal treatment can OTHERS) be started based on decreased SChE activity. ​ Adverse effects include seizures, hyperthermia, cardiac ○​ CONFIRMATION: Further testing of erythrocyte and liver toxicity. AChE activity should be conducted to confirm ​ MDMA and analogues require confirmation via GC-MS due poisoning to typical screening limitations. TOXICOLOGY OF DRUG ABUSE ANABOLIC STEROIDS ​ Common in athletes MEDICAL IMPORTANCE ​ Synthetic compounds related to testosterone used to ​ Helps identify substances in overdose situations for increase muscle mass and athletic performance. appropriate treatment ​ Naturally mimic the male sex hormones ​ Provides rationale for treatment of addiction in non-overdose ​ Associated with physical and psychological effects, such as cases heart issues, testicular atrophy, and sterility. ​ Drug abuse testing is commonly done by screening urine ​ Detection challenges exist for newer steroid forms; samples (common sample used in drug testing) testosterone to epitestosterone ratio is used for ​ Screening detects recent drug use but may miss patients screening. with short-term abstinence (false negative result) ​ Positive tests cannot distinguish between casual use and CANNABINOIDS chronic abuse or determine drug dosage or timing (E.G., THC) ​ Psychoactive compounds in marijuana causing euphoria DRUG TESTING IN VARIOUS CONTEXT and memory impairment. ​ Tests must be legally admissible, accurate, precise, and ​ “Bloodshot eyes” secure. ​ Delta-9-tetrahydrocannabinol (THC ) is lipophilic,there is ​ Protocols prevent specimen adulteration and ensure proper an accumulation in the adipose tissue leading to slow specimen handling (e.g., monitoring temperature, pH, elimination and prolonged detection in urine. creatinine). Should be associated with the chain of custody. ​ Urine tests detect the metabolite THC-COOH for 3-5 days There should be a witness so the specimen is not post-use or up to 4 weeks in chronic users. adulterated and no intentional contamination of the result ​ Cannabis refers to the dried leaves, flowers, stems, and done by the patient. seeds of the cannabis plant. ​ Confirmation via GC-MS is sensitive and specific, with ​ Abuse potential: Ranges from high (barbiturates) to low concentration standards to differentiate passive vs. direct (benzodiazepines). inhalation. ​ Overdose: Lethargy, slurred speech, progressing to coma; respiratory depression is most dangerous. COCAINE ​ Toxicity potentiated by ethanol. COCA, COKE, CRACK, CRANK, FLAKE, ROCK, SNOW, SODA ​ Testing: Immunoassays for both barbiturates and COT benzodiazepines, GC or liquid chromatography for ​ Local anesthetic (nasal surgeries) with few adverse effects confirmation. at therapeutic doses. ​ An intense, euphoria-producing stimulant drug with strong VITAMINS addictive potential ​ Organic compounds that are essential for various ​ Comes from the leaves of the coca bush (Erythroxylum physiological functions in the body. coca) ​ Play crucial roles in metabolism, immune functions, cell and ​ At high concentrations, it's a potent CNS stimulant causing tissue health, and maintenance of overall well-being. euphoria and excitement. ​ Categorized into two: ​ Forms of administration: insufflation, intravenous ○​ Fat Soluble Vitamins (A, D, E and K) injection, or smoking in the free-base form (crack). ​ Can be stored in the body’s tissues ​ High abuse potential. ○​ Water Soluble Vitamins ​ Half-life: 0.5–1 hour ​ B - complex ​ Acute toxicity: hypertension, arrhythmia, seizures, ​ Vitamin C - need to be consumed regularly as myocardial infarction. they are not stored in the body ​ Toxicity: more related to dose and route (IV > smoking), not ​ A balanced diet rich in fruits, vegetables, whole grains, and serum concentration. protein typically provides sufficient vitamins but we have ​ Metabolism: rapid hepatic hydrolysis to inactive metabolites. “hypovitaminosis” or deficiencies leading to various health ​ Primary metabolite: benzoylecgonine, detectable in urine issues. for up to 3 days after a single use, 20 days in heavy FUNCTION Act as cofactors in enzymatic reactions, users. enhancing catalytic activity ​ Testing: urine immunoassay for benzoylecgonine, confirmed by GC/MS SOURCES Obtained from food and in some cases bacterial synthesis OPIATES ​ Includes natural substances (morphine, codeine) and DEFICIENCY Occurs when dietary intake or absorption is inadequate modified forms (heroin, oxycodone). ​ Extracted or refined from natural plant matter (poppy sap Hypovitaminosis - dietary intake is and fibers). inadequate ​ Legal in THAILAND incorporated in their cough syrup ​ Are analgesics. HISTORICAL BASIS ​ Common synthetic opiates: fentanyl, methadone, meperidine Scurvy (Vit C) sailors consuming lime ("limeys") ​ Abuse potential: high, leading to tolerance, physical and psychological dependence. Rickets (Vit D) early industrial age (very ​ Acute overdose: respiratory acidosis, myoglobinuria, common) potential cardiac damage. ​ Overdose treatment: naloxone (opioid antagonist)- Brand Beriberi (Thiamine common in alcoholics name: Narcan deficiency) ​ Testing: immunoassay primarily detects morphine and codeine; GC-MS for confirmation. Pellagra (Niacin) associated with vitamin A deficiency and night blindness PHENCYCLIDINE (PCP) / ANGEL DUST Megaloblastic ​ Properties: stimulant, depressant, anesthetic, and anemia (Folic acid hallucinogenic. deficiency) ​ Abuse potential: high, causing agitation, hostility, paranoia. ​ Overdose: stupor, coma. Spina bifida ​ Forms of use: ingested or smoked (PCP-laced substances). ​ Lipophilic: distributes quickly into fat and brain. Pernicious anemia involves neuropathy ​ Elimination: slow, with 10-15% of the dose excreted (Vitamin B12 unchanged in urine. deficiency) ​ Detection: parent drug in urine ​ Chronic use is detectable 7–30 days after use. INSUFFICIENCY DEPENDENCY ​ Testing: urine immunoassay, confirmed by GC/MS Inadequate supply affecting Higher-than-normal demand metabolism for proper physiological SEDATIVES-HYPNOTICS function. (SLEEPING PILLS, TRANQUILIZERS) ​ CNS depressants, used as tranquilizers or sedatives. ​ Common types abused: Barbiturates (e.g., secobarbital, phenobarbital) and benzodiazepines (e.g., diazepam, lorazepam).  INVESTIGATING DIETARY VITAMIN DEFICIENCY TOXICITY (HYPERVITAMINOSIS A) (HYPOVITAMINOSIS) ​ Caused by high doses from supplements, liver, or fish oils. CAUSES ​ Can lead to liver damage and other toxic effects. ​ Inadequate intake or absorption due to dietary sources and ​ Carotenoids are not toxic due to limited practices. absorption/conversion. ​ Palms and side of the eyes look yellow due to excessive NUTRITIONAL GUIDELINES vitamin A. ​ RDAs revised in the 1990s to include chronic disease prevention. DAILY REQUIREMENTS (RDA) ​ 900 μg/day (adult males) ADDITIONAL CATEGORIES ​ 700 μg/day (adult females) ​ EAR (Estimated Average Requirement) ​ AI (Adequate Intake) ASSESSMENT ​ UL (Tolerable Upper Intake Level) ​ Retinol measurement by HPLC is the standard method. ​ Toxicity is assessed by retinyl ester levels in serum METHODS FOR ASSESSING VITAMIN STATUS (HPLC). ​ Measuring active cofactors or precursors in biological fluids or blood cells. VITAMIN E ​ Measuring urinary vitamin metabolites. FORMS AND Generic name: Tocopherol (includes ​ Assessing biochemical functions requiring the vitamin (e.g., ABSORPTION several biologically active isomers). enzymatic activity). ​ Measuring urinary vitamin/metabolite excretion after a test Alpha-tocopherol is the predominant and dose. (Correlated with 2nd bullet point) most potent isomer. ​ Measuring metabolites of substances requiring the vitamin for metabolism. About 40% of ingested tocopherol is absorbed, influenced by dietary fat. CHALLENGES IN DIAGNOSIS Transported via chylomicrons, ​ Low serum vitamin levels don’t always indicate functional VLDL, and chylomicron remnants. deficiency. ​ Normal serum levels may not ensure adequate function. Stored in liver and lipid-rich tissues, ​ Proper interpretation requires biochemical and physiological excreted in feces. knowledge of vitamins. SOURCES Found in vegetable oils, leafy vegetables, egg yolk, legumes, peanuts, and FAT SOLUBLE VITAMINS margarine. VITAMIN A Deficiency risk in diets low in vegetable FORMS AND Found as retinol, retinoic acid, oils, fresh greens, or unsaturated fats. SOURCES and retinyl esters (from animal products). FUNCTIONS Carotenoids (provitamin A), mainly ​ Powerful antioxidant, protects unsaturated lipids from beta-carotene, from pigmented peroxidation. fruits/vegetables. ​ Protects erythrocyte membranes from oxidative stress. STORAGE AND Stored in the liver. ​ Strengthens cell membranes, supports drug metabolism, TRANSPORT heme biosynthesis, and neuromuscular function. Transported in the blood complexed to RBP (retinol binding protein) and DEFICIENCY EFFECTS transthyretin. ​ Hemolytic anemia is the major symptom. ​ Premature newborns are supplemented to stabilize RBCs FUNCTIONS and prevent hemolysis. ​ Vision: Retinol is converted to retinal, forming rhodopsin for ​ May prevent retrolental fibroplasia, intraventricular dim-light vision. hemorrhage, and mortality in preterm infants. ​ Cellular differentiation, growth, reproduction, and immunity. ​ Fat malabsorption disorders (e.g., cystic fibrosis, ​ Regulates cell proliferation via nuclear receptors (along abetalipoproteinemia) increase deficiency risk. with vitamin D) ​ Chronic cholestasis in infants/children linked to neurologic dysfunction. DEFICIENCY EFFECTS ​ Night blindness (nyctalopia), progressing to total ASSESSMENT AND REQUIREMENTS blindness if untreated ​ Measured as alpha-tocopherol via HPLC. ​ Epithelial cell keratinization (skin, GI, respiratory, ○​ Main testing of vitamins is through HPLC urogenital tracts). ​ Indicated in newborns, fat-malabsorption patients, and those ​ Common in children in non-industrialized countries due to on synthetic diets. poor diet ​ Works synergistically with selenium and vitamin C. ​ Can result from chronic fat malabsorption, liver disease, ​ Necessary for maintaining normal vitamin A levels. severe stress, or protein malnutrition. ​ RDA: 15 mg/day for both adult males and females. ​ Premature infants have low retinol and RBP levels, requiring supplementation. TOXICITY AND SUPPLEMENTATION ​ No proven health benefit from high doses. ​ No toxic effects from megadoses, (but excessive ​ Essential of the formation of prothrombin (factor II) and other supplementation in preterm infants may increase sepsis and coagulation proteins (factor VII, IX, X, proteins C & S) necrotizing enterocolitis) ​ Helps convert precursor clotting proteins to functional forms in the liver. VITAMIN D SOURCES & ABSORPTION DEFINITION AND FORMS ​ Synthesized by intestinal bacteria, providing 50% of daily ​ Group of metabolites essential for skeleton formation and needs. mineral homeostasis. ○​ If the intestinal bacteria are killed by antibiotic ​ Produced in our skin therapy then you will also develop hypovitaminosis ○​ Muslim women are at risk for vit D deficiency ​ Absorbed in the terminal ileum and possibly in the colon ​ Synthesized in the skin via UV light exposure, converting ​ Major dietary sources: Cabbage, cauliflower, spinach, leafy 7-dehydrocholesterol to cholecalciferol (vitamin D3). greens, pork, liver, soybeans, vegetable oils. ​ Another major form: Ergocalciferol (vitamin D2), found in ​ Al (Adequate Intake): 120 ug/day (males); 90 ug/day foods. (females) ACTIVE METABOLITES AND FUNCTIONS DEFICIENCY & CAUSES ​ 1,25(OH)₂D₃ (Calcitriol) is the most active form. ​ Rare in healthy children and adults. ​ Stimulates calcium and phosphate absorption for bone ​ Causes of deficiency: growth and metabolism. ○​ Antibiotic therapy (reduces intestinal bacterial ​ Works with parathyroid hormone to mobilize calcium and synthesis). phosphate from bones. ​ One of the major reasons why Vitamin K ​ Has proapoptotic effects through vitamin D receptor binding, deficiency can be developed leading to drug development. ○​ Vitamin K antagonists (e.g., warfarin/Coumadin) prevent functional clotting factor production, SOURCES AND ABSORPTION increasing bleeding risk. ​ UV exposure (recommended 2 hours/day in northern ​ Deficiency can lead to hemorrhagic episodes. climates). ​ Dietary sources: Irradiated foods, fortified milk, butter, egg CLINICAL TESTING & DIAGNOSIS yolks, liver, sardines, herring, tuna, salmon. ​ Prothrombin Time (PT): ​ RDA: 5–15 μg/day (varies by age). ○​ Measures clotting speed after adding thromboplastin ​ Absorbed in the small intestine, requires bile salts for and calcium to plasma. absorption. ○​ Normal range: 11–15 seconds (varies by method). ​ Stored in the liver, excreted in bile. ○​ Prolonged PT in vitamin K deficiency & liver disease. ​ Partial Thromboplastin Time (PTT): Also prolonged in DEFICIENCY AND DISORDERS deficiency. ​ Children: Rickets (failure to calcify cartilage at growth ​ Thrombin Time (TT): Remains normal in vitamin K plates). deficiency. ​ Adults: Osteomalacia (under mineralized bone matrix). ​ Direct vitamin K testing is not common; PT is used as a ​ Low levels associated with anticonvulsants, small bowel functional indicator. disease, chronic renal failure, hepatobiliary disease, pancreatic insufficiency, and hypoparathyroidism. TOXICITY & INTERACTIONS ​ Rare in adults. TOXICITY AND ELEVATED LEVELS ​ Large doses in infants may cause hyperbilirubinemia. ​ Toxic in children; can cause hypercalcemia and ​ Herbal interactions: Garlic, gingko, and ginseng may hypercalciuria, leading to calcium deposits in soft tissues, enhance Coumadin effects, increasing bleeding risk. kidney, and heart damage. ○​ People taking Vitamin K should be very careful in ​ Elevated levels: hyperparathyroidism, hypophosphatemia, taking supplements associated with garlic, gingko, and pregnancy and ginseng supplements, CLINICAL MEASUREMENT AND DIAGNOSIS WATER SOLUBLE VITAMINS ​ Two commonly measured forms: 25(OH)D3 and 1,25 THIAMINE (B1) (OH)2D3 ​ Acts as a coenzyme in carbohydrate metabolism and ​ 25(OH)D3: Major circulating form, best indicator of branched-chain amino acid metabolism. nutritional status and intoxication. ​ Absorbed in the small intestine, excreted in urine. ​ Reference Ranges ​ Deficiency: Causes beriberi, seen in chronic alcoholism ○​ 25(OH)D3 : 22-42 ng/mL due to decreased intake and absorption. ○​ 1,25(OH)2D3 : 30-53 pg/mL ​ RDA: 1.2 mg/day (males); 1.1 mg/day (females). ​ Measured using radioimmunoassay (RIA) or HPLC with ​ Best indicator: Erythrocyte transketolase (ETK) activity; competitive protein binding. >25% increase after thiamine pyrophosphate (TPP) suggests ​ Important in diagnosing hyperparathyroidism, rickets, chronic deficiency. renal failure, and therapy monitoring RIBOFLAVIN (B12) VITAMIN K ​ Component of coenzymes FAD and FMN, involved in ​ Named from the German word “koagulation” due to its role oxidation-reduction reactions. in blood clotting ​ Absorbed in the small intestine, excess excreted in urine (no known toxicity). ​ Found in milk, liver, eggs, meat, leafy vegetables. ​ Found in animal products (meat, eggs, milk); absent in ​ Deficiency causes: Alcoholism, chronic diarrhea, vegetarian diets. malabsorption, drug interactions (phenothiazine, oral ​ Deficiency: contraceptives, tricyclic antidepressants). ○​ Common in the elderly, strict vegetarians, and ​ RDA: 1.3 mg/day (males); 1.1 mg/day (females). those with malabsorption disorders (celiac ​ Best indicator: Reduced glutathione reductase activity >40%. disease, fish tapeworm infection). ○​ Leads to megaloblastic anemia (pernicious anemia) PYRIDOXINE (B6) and neurological disorders. ​ Exists as pyridoxine (plants), pyridoxal, pyridoxamine ​ Pernicious anemia is linked to intrinsic factor antibodies and (animal products) parietal cell antibodies. ​ Sources: Meat, poultry, fish, potatoes, vegetables, dairy, ​ Diagnostic Tests: grains. ○​ Schilling test (assesses absorption using ​ Deficiency is rare but seen in uremia, liver disease, radiolabeled B12). absorption syndromes, malignancies, chronic alcoholism. ○​ Serum B12 levels, methylmalonic acid for definitive ​ High protein intake increases B6 requirements. diagnosis. ​ Deficiency linked to hyperhomocysteinemia. ​ No reported toxicity. ​ Toxicity: Rare but very high doses may cause peripheral ​ RDA: 2.4 μg/day neuropathy. ​ RDA: 1.3–1.7 mg/day (males), 1.3–1.5 mg/day (females) BIOTIN (varies with age). ​ Essential coenzyme for carboxyl transfer reactions. ​ Involved in gluconeogenesis, lipogenesis, and fatty acid NIACIN (B3) synthesis. ​ Derived from dietary tryptophan; exists as nicotinic acid & ​ Sources: Widespread in food, synthesized by gut bacteria. nicotinamide. ​ Deficiency: ​ Functions: Part of NAD & NADP coenzymes, essential for ○​ Caused by raw egg white ingestion (avidin binds metabolism, glycolysis, lipid metabolism. biotin). ​ Absorbed in the small intestine, excess excreted in urine. ○​ Seen in long-term parenteral nutrition and enzyme ​ Deficiency causes pellagra: Symptoms include diarrhea, defects. dementia, dermatitis, death; seen in alcoholism. ​ RDA: 30 μg/day ​ Therapeutic use: Large doses lower lipid levels but can ​ Reference range: 200–500 pg/mL (whole blood and serum). cause flushing and vasodilation. ​ Assays: Microbiologic, chemiluminescent, photometric. ​ RDA: 16 mg/day (males), 14 mg/day (females). PANTOTHENIC ACID (B5) FOLATE (B9) ​ Present in all animal and plant tissues (milk, eggs, whole ​ Functions as a coenzyme in one-carbon transfer reactions. grains, liver). ​ Closely related to Vitamin B12 metabolism; both cause ​ Converted to Coenzyme A, essential for acyl group transfer megaloblastic anemia if deficient. reactions. ​ Sources: Green leafy vegetables, fruits, organ meats, yeast. ​ RDA: 5 mg/day ​ Cooking with water destroys folate. ​ Deficiency is rare but indicated by low blood pantothenate ​ Increased requirements: Pregnancy, lactation, hemolytic (