MLAB 2401: Clinical ChemistryKeri Brophy-Martinez

Therapeutic Drug Monitoring

Therapeutic Drug Monitoring= TDM

Goal Ensure that a given drug dosage produces

Maximal therapeutic benefit Minimal toxic adverse effects

Must have an appropriate concentration at site of action that produces benefits

Standard dosages derived from healthy population

Only the free fraction of drugs can interact with site of action, resulting in a biologic response

Routes of Administration

Routes Injections

Circulation= IV (intravenous) Muscles=IM (intramuscular) Skin= SC (subcutaneous) Epidermal

Inhaled Absorbed through skin Rectal Oral (most common)

Pharmacokinetics

Involves the dynamics associated with the movement of drugs across cell membranes

Includes biological events: Absorption Distribution Metabolism/Biotransformation Excretion

Relationship of drug concentration to time Process assists in establishing or modifying a

dosage regimen

Absorption

Rate at which drug leaves the site of administration and the extent to which this happens

Mechanism Passive diffusion Active transport

Absorption: Limiting Factors Oral Administration

Absorption depends on.. Formulation of drug

liquid/pill Intestinal motility pH Inflammation Food Presence of other drugs Patient age Pregnancy Concurrent Pathologic Conditions

Distribution

Dependent on Blood flow Capillary permeability

pH gradients Lipid solubility of the drug

Binding of drugs to proteins/Availability of free fractions Free vs. bound drug

Tissue volume

Metabolism

Primarily occurs in the liver Biotransformation of the parent drug molecule

into one or more metabolites Metabolites are:

water soluble easily excreted by kidney or liver Pharmacologically active or inactive

First-Pass Metabolism

Elimination

Elimination Routes Hepatic metabolism Renal filtration Other: skin, lungs, mammary glands and salivary glands

Functional changes in organs can affect rate of elimination i.e. : Hepatic disease with a loss of tissue result in slow

rate of clearance with a longer half-life.

Elimination half-life The time required to reduce the blood level concentration

to one-half after equilibrium is obtained.

Pharmacokinetics Most drugs given on a

scheduled basis not as a single bolus or mass Oscillation between a

maximum(peak) and a minimum (trough)of serum concentration

Goal of dosage regimens Achieve troughs in

therapeutic range and peaks that are non-toxic

Sample Collection Timing of TDM most important

Collaborate with nursing & phlebotomy staff for appropriate timing Trough: right before next dose Peak: one hour post administration of dose (Verify drug

protocol) Random

Specimen Type Serum: no gel Plasma: Heparinized

EDTA, Citrated, Oxalated not acceptable Whole Blood Saliva

Drug Groups Cardioactive Antibiotics Antiepileptic Psychotherapeutic Antiasthmatic Immunosuppressive Antineoplastic Antihypertensive

Drug Groups: Cardioactive

Digoxin Used to treat CHF( congestive heart failure) Peaks draw at 2 hours post dose Inhibits sodium and potassium transport within

the heart Allows for better cardiac muscle contraction and

rhythm

Lidocaine Used to treat premature ventricular

contractions Affects the timing of cardiac contraction

Drug Groups: Cardioactive (2)

Quinidine Used to treat cardiac arrhythmic problems Inhibits sodium and potassium channels Prevents arrhythmias, atrial flutter and fibrillation

Procainamide Used to treat cardiac arrhythmic situations Blocks sodium channels Affects cardiac muscle contraction Often measured with NAPA(N-Acetyl procainamide)

Drug Groups: Antibiotics

Aminoglycosides Used to treat infections with gram-negative

bacteria that are resistant to less toxic antibiotics Inhibits protein synthesis of the micro-organism Examples include: gentamycin, tobramycin,

amikacin and kanamycin

Vancomycin Used to treat infections with more-resistant gram-

positive cocci and bacilli Inhibits cell wall synthesis

Drug Groups: Antiepileptics “AEDs”

Most first and second generation AEDs used to treat seizure disorders and epilepsy

Second Generation

Felbamate

Gabapentin

Levetiracetam

Oxcarbazpine

Tigabine

Topiramate

Zonisamide

First Generation

Phenobarbital•Barbiturate Primidone is a proform

Phenytoin=Dilantin

Valproic Acid= Depakene

Carbamazepine=Tegretol

Drug Groups: Psychotherapeutic

Used to treat manic depression (bipolar disorder) Lithium Tricyclic Antidepressants “TCAs” Clozapine

Drug Group: Antiasthmatic

Used to treat neonatal breathing disorders or respiratory disoders of adults or children, like asthma

Examples include theophylline and theobromine

Drug Group: Immunosuppressive

Monitoring of this group of drugs important to prevent organ rejection (host-versus-graft)

Used to treat autoimmune disease Examples

Cyclosporine Whole blood is the specimen of choice, since it

sequesters in the RBC Tacrolimus (Prograf)

Prevents rejection of liver and kidney transplants

Drug Group: Antineoplastics

Inhibit RNA or DNA synthesis of tumor cells, leading to cell death

Methotrexate Inhibits DNA synthesis

Drug Group: Antihypertensive

Used in treatment of high blood pressure Dilate blood vessels

Sodium nitroprusside Used for short-term control of hypertension

Techniques for Measurement of TDM

Immunoassays Gas chromatography Liquid chromatography Mass spectrometry

References Arneson, W., & Brickell, J. (2007). Clinical

Chemistry: A Laboratory Perspective . Philadelphia, PA: F.A. Davis Company.

Bishop, M., Fody, E., & Schoeff, l. (2010). Clinical Chemistry: Techniques, principles, Correlations. Baltimore: Wolters Kluwer Lippincott Williams & Wilkins.

Sunheimer, R., & Graves, L. (2010). Clinical Laboratory Chemistry. Upper Saddle River: Pearson .