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 p

ositive result.

Lidocaine ：• Administered IV. 70 protein bound.﹪• Range ： 1.5 to 4.0μg/mL• Toxicity ： CNS depression, Seizure, severe decr

ease in blood pressure and cardiac output.• Elimination ： Metabolized in Liver （ first pas

s ） 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 discom

fort, 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 arrhythmi

a.• Elimination ： Liver metabolism to N-Acetyl pro

canamide （ 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.

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.

Antibiotics

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 an

d complete. Protein binding is 50 . Long half-lif﹪e.

• 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 kinetic

s ）

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 A

AS.

Tricyclic antidepressants

Impiramine, amitriptyline and active

metabolites, doxepin.• Absorption of orally administered drug is variabl

e. Protein binding is 85 to 95 .﹪ ﹪• Toxicity ： Drowsiness, constipation, blurred vis

ion, memory loss （ 2X upper limit ） . Seizure, cardiac arrhythmia and unconsciousness.

• Elimination ： Liver.

Bronchodilators

Theophylline• Absorption of orally administered drug is v

ariable. 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 variabl

e （ 5 to 50﹪ ﹪） . Sequestered in cells.• Range ： 100-300 ng/mL• Toxicity ： Renal tubular and glomerular dysfun

ction, 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

1. Enzymatic

2. Headspace-GC

3. Breath-testing device (amount of ethanol in 1mL of blood equals to 2100mL of breath air)

Henry’s law

Ethyleneglycol

資料來源： 2007 年 5月 7日自由時報

Carbon Monoxide

• 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

Lead• Toxicity Inhibits amino levulinic acid dehydratase (causes accu

mulation of protoporphyrin in RBC)

Forms covalent bonds with the-SH group of cysteine in proteins (Nerve cells are particular susceptible)

• Determination whole blood was analyzed with atomic absorption spe

ctrometry

•Fig.25-27. Effects of inorganic lead on children and adults (lowest observable adverse effect levels). (From Royce, S.E., Needleman, H. L., Eds.: Case Studies in Environmental Medicine: Lead Toxicity. U.S. Public Health Service, ATSDR, 1990.)

Iron

• Toxicity Severe irritation of the epithelial lining of the GI tract a

nd results in hemosiderosis, which may develop into hepatic cirrhosis.

• Hemosiderosis A term used to imply iron overload without associated t

issue injury Determined spectrophotometrically after reaction with

Bathophenanthroline or Ferrozine