Therapeutic Drug Monitoring 

Analysis of a known prescribed drug

what are some reasons for TDM?

What is half-life?

Time it takes for the serum drug concentration to decrease by 50% (half)

Depends on how quickly the drug is eliminated from the body

What is steady state?

• Represents equilibrium between amount of drug administered and amount eliminated
• Takes 5 dosages to reach steady state
• must be achieved before acessing therapeutic levels

What does the "trough" indicate on a graph for TDM

• This is the lowest level that medicine is present in the body
• Good for long half-lives 
• Lack of efficacy towards end of the dosing period
• Just prior to the next dose 

What does the "peak" on a graph for TDM indicate?

What is ED50?

• median effective dose 
• dose at which 50% of the population or sample manifests a given effect

What is TD50?

Median Toxic Dose 

dose at which 50% of the population manifests a given toxic effect

What is LD50

Median Lethal Dose 

Dose which kills 50% of the subject

(rate) way in the which the body handles a drug (absorption, distribution, metabolism, excretion)

What is Pharmacodynamics?

What is bioavailability

• The amount of drug that becomes available for the body
• fraction of drug absorbed by the systemic circulation 
• measurement of the rate and extent to which a drug reaches the systemic circulation

Absorption depends on:

Mechanisms of absorption:

What is volume of distribution?

Volume into which a substrate is distributed

vd=Dose/Plasma conc.

A higher vd would have a slower or faster rate of elimination?

Slower

What is biotransformation?

Biochemical transformation of a chemical to make it more water soluble for excretion

Metabolites can be active, toxic, or nonactive

Drug converted into a more polar compound

(Oxidation/reduction, Hydrolysis, cytochrome P450)

Conjugation with carrier groups in liver or kidney

(acetylation, glucorinide conjugation, glycine conjugation, methylation, sulfate conjugation, mercapturic acid formtion)

• Prescription (controlled by FDA)
• Investigational
• Illicit
• Nonprescription

What are the toxic effects of CO poisoning?

What are the signs/symptoms?

B/c CO has a 210x higher affinity for hb than O2, therefore high concentrations of carboxyhemoglobin limit the oxygen content in the blood.

Results in: 

Tissue Hypoxia

Anoxia

Cherry Red Cheeks

How is CO poisoning tested for in the lab?

• Spec: difference between absorbance spectra of various hemoglobin in whole blood
• Co-Oximeter looks for abs. maxima

What are the references ranges for carboxyhemoglobin in smokers vs nonsmokers

Non-smokers: 0.5-1%

Smokers: ~5% (8% if heavy smoker)

What is the ethanol reaction in the body

Ethanol----->Acetaldehyde 

(in presence of ADH)

Venipuncture site cleansed with alcohol free wipe

Sample is kept capped bc alcohol is volatile 

Enzymatic method is most common. Ethanol measured by oxidation to acetaldehyde  with NAD+

NADH measured at 340 nm...abs increases with concentration 

Methanol-->Formaldehyde-->Formic Acid

(with ADH)

What is the isoporpenol reaction in the body?

Isopropenol-->Acetone 

(ADH)

Ethylene Glycol-->Glycolate-->Glycoxylate--> Formate+Oxalate+Other

(ADH)

Gas Liquid Chromatography

Identified by retention time  compared to standard

Quantitated by comparing peak size to known concentration

Standard: N-propanol

LD: 20-30 grams

Toxic: 10g

• Directly stimulates central respiratory center--> Hyperventilation--> Resp. Alkalosis
  
  
• Inhibition of TCA->enhances anaerobic glycolysis -> Accumulation of organic acids/increased L.A production
    -> Metabolic Acidosis 

How is Salicylates intoxication measured? What are the intereferences?

Trinder Method: Salicylate + Fe⁺-->Colored Complex

Measured at 540nm

Interferences: Salicylate metabolites, endogenous complexes, other drugs 

usually 2 hrs

up to 12 if coated/slow release

7g -adults

3g-children

• Initial: Nausea, vomiting, anorexia, upper right quadrant pain
• 24-36 hrs: Hepatic Necrosis
• 3-5 days: Viral Hepatitis like symptoms

What is the treatment for acetominophen intoxication?

NAC (N-acetylcysteine)

acts as glutathione substitute 

replenishes hepatic glutathione

best if used within 8 hrs of toxic ingestion

Erythropoiesis interruption 

Build up of precursors( ALA, protoporph)

Iron uptake inhibited

Hypochromic microcytic anemia(baso stippling)

What is Anodic Stipping Voltammetry? What does it test for 

Metal Testing-Lead, Mercury

Different metals are stripped at their characteristic oxidation potential and can be detected in nanograms

Digoxin

Disopryramide

Lidocaine

Procainamide

Quinidine

Name some Anticonvulsants measured in lab

Carbamazepine

Clonozepam

Phenobarbitol 

Phenytoin

Name some antibiotics measured in lab

Aminoglycosides (gentamycin)

Vancomycin

Trimethoprim

What are some methods used in drug testing..most common?

Most common-Immunoassays (EIA, EMIT)

Chemiluminesent (ELISA, FIA)

ISE

Anodic stripping 

Atomic Abs

Co-oximetry

What are some seperation techniques used in drug screening 

Mod TLC (initial)

Gas chrom (GC)

GC/ Mass Spec (confirm/quant)

HPLC