臨床生化 TDM and Clinical Toxicology

1. 臨床生化TDM and Clinical Toxicology 賴滄海 教授 01-11-2008

2. ` • 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

3. 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.

10. 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

11. 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.

12. 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.

13. 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

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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）

20. 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.

21. 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）

22. 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.

23. 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.

24. 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.

25. 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.

27. The categories with the largest number of deaths are as follows:

32. 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.

33. 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.

34. Respiratory alkalosis (19％) • Metabolic acidosis (15％) • Combined (61％) motality was associated with acidemia

35. 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.)

36. Symptoms of salicylate intoxication • Tinnitus （耳鳴） • Diaphoresis （出汗） • Hyperthermia • Hyperventilation • Nausea, vomiting • Acid-base disturbances • CNS effects lethargy, disorientation, coma and seizures.

37. Treatment • Ipecac to induce vomiting • Correction of acid-base and electrolyte imbalance, activated charcoal to prevent absorption • Hemodialysis

38. 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)

39. 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

40. Alcohols • Ethanol • Methanol • Ethyleneglycol • Isopropylalcohol

42. 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

43. 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

46. Ethyleneglycol 資料來源： 2007年5月7日自由時報

49. Carbon Monoxide

50. Lithium Use to treat manic-depressive illness. It enhances reuptake of neurotransmitters, thus produces sedating effect on the CNS • Toxicity apathy, sluggishness, drowsiness, lethargy, speech difficulties, irregular tremors, muscle weakness, ataxia, epileptic seizures. Determined with ISE or Atomic Absorption Spectrometry, Flame emission photometry