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臨床生化 Trace Elements ,TDM, Clinical Toxicology. 賴滄海 教授 12-30-2008. Biochemical Functions of Elements. Ion: Hemoglobin, Myoglobin ,Cytochromes, Peroxidase, Catalase, Thyroperoxidase Copper: Ceruloplasmin, cytochrome, c oxidase,
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臨床生化Trace Elements ,TDM, Clinical Toxicology 賴滄海 教授 12-30-2008
Biochemical Functions of Elements • Ion: Hemoglobin, Myoglobin ,Cytochromes, Peroxidase, Catalase, Thyroperoxidase • Copper: Ceruloplasmin, cytochrome, c oxidase, superoxide dismutase, dopamine-β- hydroxylase, tyrosinase, ascorbate oxidase • Zine: Essential for more than 300 enzymesi : alkaline phosphatase, alcohol dehydrogenase, carbonic anhydrase, DNA,RNA polymerase • Cobat: Constitute of Vit B12
Biochemical Functions of Elements • Chromium:Essential activator of insulin • Fluoride:prevent dental caries, enhance bone formation • Manganese:Arginase, pyruvate carboxylase, superoxide dismutase • Molybdenum:Xanthine dehydrogenase/ xanthine oxidase, aldehyde oxidase, sulfite oxidase • Selenium:Cofactor in glutathione peroxidase, iodothyronine diodinase, Has antioxidant property
Reasons for Therapeutic Drug Monitoring • Serious consequences for Overdose • Small therapeutic index (LD50/ED50) • Poor correlation between dose and circulation concentration and therapeutic or toxic effects
There is a change of patient’s physiological states that may affect circulating drug concentration • Drug interaction may be occurring • TDM helps in monitoring patient compliance.
Digoxin: • Absorption of orally administered digoxin is variable. 25% protein bound. Sequestered in muscle cells(15-30 times greater than plasma). T1/2 is 38 hours. • Range:0.8 to 2.0 ng/mL
Digoxin: • Toxicity:Nausea, vomiting, visual disturbance, premature, ventricular contraction(PVC)and AV node blockage. • Interference:Low potassium, Magnesium, Hypothyroidism potentiate digoxin action. • Elimination:Kidney, liver . • Determined by immunoassay. DLIS cause false positive result.
Lidocaine: • Administered IV. 70﹪protein bound. • Range:1.5 to 4.0μg/mL • Toxicity:CNS depression, Seizure, severe decrease in blood pressure and cardiac output. • Elimination:Metabolized in Liver(first pass)to MonoEthylXylidide(MEGX), which is toxic but without therapeutic activity.
Quinidine: • Absorption of orally administered quinidine sulfate is complete. Quinidine gluconate is a slow releasing formulation. 70﹪protein bound. • Range:2 to 5 μg/mL • Toxicity:Nausea, vomiting, abdominal discomfort, premature, ventricular contraction(PVC)and AV node blockage. • Elimination: Liver
Procanamide: • Absorption of orally administered drug is complete. 20﹪protein bound. • Range:4 to 8 μg/mL • Toxicity:Myocardial depression and arrhythmia. • Elimination:Liver metabolism to N-Acetyl procanamide(active metabolite)and Kidney filtration.
Disopyramide: • Absorption of orally administered drug is complete. Protein binding is highly variable. • Range:3 to 5 μg/mL • Toxicity:Dry mouth, constipation(4.5 μg/mL). Bradicardia, AV node blockage(>10 μg/mL) • Elimination:Kidney, liver.
Antibiotics Aminoglycosides:Amikacin, Gentamicin, Kanamycin, Tobramycin. • Administered IV or IM. Effective against gram-negative bacteria. • Toxicity:Orotoxic, disruption of inner ear cochlear and vestibular membranes. • Nephrotoxic, impair the function of proximal tubules of the kidney. • Elimination:Kidney.
Vacomycin: • Administered IV. Protein binding is highly variable. Effective against gram-positive cocci and bacilli. • Range:5 to 10 μg/mL • Toxicity:Red-man syndrome, nephrotoxicity and orotoxicity. • Elimination:Kidney.
Antiepileptic drugs: Phenobarbital, primidone • Absorption of orally administered drug is slow and complete. Protein binding is 50﹪. Long half-life. • Range:15 to 40 μg/mL • Toxicity:Drowsiness, fatigue, reduced mental capacity. • Elimination:Liver(inducer of MFO)and kidney.
Phenytoin, Fosphenytoin • Absorption of orally administered drug is variable and incomplete. Protein binding is 87﹪to 97﹪. • Range:10 to 20 μg/mL • Toxicity:Initiation of seizure. • Hirsutism, gingival hyperplasia, vitamine D and folate deficiency. • Elimination:Kidney(zero order kinetics)
Valproic Acid: • Absorption of orally administered drug is complete. Protein binding is 93﹪. • Range:50 to 120 μg/mL • Toxicity:Nausea, lethargy, weigh gain, pancreatitis, hyperammonemia and hallucinations. • Elimination:Liver metabolism.
Carbamazepine: • Absorption of orally administered drug is variable. Protein binding is 70﹪to 80﹪. • Range:4 to 12 μg/mL • Toxicity:rash, leucopenia, nausea, vertigo, febrile reactions, aplastic anemia. • Elimination:Liver(inducer of enzyme)
Psychoactive drugs Lithium • Absorption of orally administered drug is complete. • Range:0.8 to 1.2 μg/mL • Toxicity:Apathy, lethargy, speech difficulties and muscle weakness(1.2 to 2.0 mmole/L). Muscle rigidity, seizure and coma(>2 mmole/L) • Elimination:Kidney. • Analyzed with ISE, Flame emission photometry or AAS.
Tricyclic antidepressants Impiramine, amitriptyline and active metabolites, doxepin. • Absorption of orally administered drug is variable. Protein binding is 85﹪to 95﹪. • Toxicity:Drowsiness, constipation, blurred vision, memory loss(2X upper limit). Seizure, cardiac arrhythmia and unconsciousness. • Elimination:Liver.
Bronchodilators Theophylline • Absorption of orally administered drug is variable. Protein binding is 50﹪. • Range:10 to 20 μg/mL • Toxicity:Nausea, vomiting and diarrhea. Cardiac arrhythmia, seizure(>30 μg/mL) • Elimination:Kidney and liver.
Immunosuppressive drugs Cyclosporine • Absorption of orally administered drug is variable(5﹪to 50﹪). Sequestered in cells. • Range:100-300 ng/mL • Toxicity:Renal tubular and glomerular dysfunction, hypertension. • Elimination:Liver. • Determined with immunoassays. Whole blood is the specimen of choice.
The categories with the largest number of deaths are as follows:
Salicylate • Aspirin (Acetylsalicylic acid) has analgesic, antipyretic and antiinflammatory properties. Therapeutic concentration: analgesic-antipyretic (lower than 60 mg/L) anti-inflammatory (150 to 300 mg/L) Aspirin interferes with platelet aggregation and thus prolongs bleeding times.
Pharmacologic effect of salicylates • Stimulate central respiratory center • Uncoupling of oxidative phosphorylation • Enhance anaerobic glycolysis, Inhibite Kreb’s cycle and transaminase enzyme. • Respiratory alkalosis predominates in children over age 4 and in adults.
Respiratory alkalosis (19%) • Metabolic acidosis (15%) • Combined (61%) motality was associated with acidemia
Fig.25-13. Nomogram for estimating the severity of acute salicylate intoxication.(From Done, A.K.:salicylate intoxication: Significance of measurements of salicylate in blood in cases of acute ingestion. Pediatrics, 26:800, 1960. Reproduced by permission of Pediatrics.)
Symptoms of salicylate intoxication • Tinnitus (耳鳴) • Diaphoresis (出汗) • Hyperthermia • Hyperventilation • Nausea, vomiting • Acid-base disturbances • CNS effects lethargy, disorientation, coma and seizures.
Treatment • Ipecac to induce vomiting • Correction of acid-base and electrolyte imbalance, activated charcoal to prevent absorption • Hemodialysis
Screening Assay for Acetaminophen and Salicylate • Acetaminophen After acid hydrolysis, the sample was reacted with o-cresol in basic solution to show blue color. • Salicylate Salicylates reacted with Ferric chloride solution to produce a violet color reaction. (Interferant: Diflunisal, labetalol, keto acids)
Methemoglobin • Less than 1.5%of total hemoglobin in normal blood • Caused by methhemoglobin reductase deficiency or ingestion of nitrites, nitrates, phenacetin, phenazopyridine, sulfonamides, sulfones, aniline dyes. • Determined spectrophotometrically at 630 nm
Alcohols • Ethanol • Methanol • Ethyleneglycol • Isopropylalcohol
Effects of Ethanol • Cardiovascular system—Increase high-density lipoprotein • Central nervous system-CNS depression (Respiratory center, coma, death) • Gastrointestinal tract-Stimulate the production of gastric juices • Kidney-Diuretics ( Inhibit the secretion of ADH) • Liver-Fatty liver,Cirrhosis • Fetal alcohol syndrome
Determination of Ethanols • Enzymatic • Headspace-GC • Breath-testing device (amount of ethanol in 1mL of blood equals to 2100mL of breath air) Henry’s law