TDM and Clinical Toxicology
賴滄海 教授11-02-2009
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