Therapeutic Drug Monitoring (TDM)
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Questions and Answers

Which characteristic primarily defines a substance's ability to undergo reactions within a nonspecific series?

  • Its origin, whether endogenous or exogenous to the system.
  • Its complex molecular structure, allowing for diverse interactions.
  • Its ability to be processed through a variety of enzymatic pathways. (correct)
  • Its capacity to interact with specific, targeted receptors.

How does the broadened scope of molecular genetic testing influence the identification of genetic variants, compared to traditional methods?

  • It allows for the precise detection of complex chromosomal aberrations.
  • It increases the reliance on phenotypic observations for variant detection.
  • It facilitates the discovery of rare variants with significant functional effects.
  • It enhances the recognition of prevalent genetic variants associated with various traits. (correct)

In the context of substance processing, what is the significance of a reaction series being 'nonspecific'?

  • It enables the processing of a wide array of substances, regardless of origin. (correct)
  • It ensures that only targeted substances undergo transformation.
  • It limits the influence of endogenous factors on the reaction outcome.
  • It guarantees a uniform reaction rate for all participating substances.

Which factor most significantly contributes to the increasing application of molecular genetic testing in identifying genetic variants?

<p>The enhanced ability to pinpoint common genetic variations linked to specific traits. (D)</p> Signup and view all the answers

How does the accessibility of a reaction series to both endogenous and exogenous substances affect its potential for metabolic interactions?

<p>It expands the range of potential interactions, increasing complexity. (C)</p> Signup and view all the answers

Why is Therapeutic Drug Monitoring (TDM) commonly employed, considering the characteristics of substances entering biochemical pathways?

<p>To mitigate the challenges arising from the inherent variability in induction processes. (C)</p> Signup and view all the answers

How does the concept of substances 'entering biochemical pathways intended for endogenous substances' relate to drug metabolism and efficacy?

<p>It implies that drugs may compete with or be processed by the same enzymatic systems as natural body chemicals. (C)</p> Signup and view all the answers

Which factor presents the most significant challenge when substances are processed via biochemical pathways?

<p>The potential saturation of metabolic pathways, altering drug clearance rates. (A)</p> Signup and view all the answers

What distinguishes substances that enter biochemical pathways designed for endogenous compounds from those that do not?

<p>They may interfere with or utilize natural metabolic processes, influencing drug potency and duration. (D)</p> Signup and view all the answers

Considering substances in biochemical pathways, how does individual variability impact drug response, and what implications does this have for personalized medicine?

<p>Individual variability can significantly alter drug responses, emphasizing the need for personalized medicine to optimize therapeutic outcomes and minimize adverse effects. (A)</p> Signup and view all the answers

Flashcards

Nonspecific Reactions

Refers to metabolic processes that lack specificity, acting on a wide variety of substances.

Endogenous Substances

Substances originating from within the body.

Exogenous Substances

Substances originating from outside the body.

Molecular Genetic Testing

Analysis of DNA to identify genetic variations.

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Common Genetic Variants

Frequently occurring variations in the genetic sequence.

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Due Substances

Substances that can enter biochemical pathways meant for the body's own substances.

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Therapeutic Drug Monitoring (TDM):

Monitoring drug concentrations in the body to optimize treatment.

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Variability in Induction

Drug levels can vary widely among individuals due to differences in how they absorb, distribute, metabolize, and eliminate drugs.

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TDM Usage

TDM is frequently employed to account for variability in induction when drug effects are variable.

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TDM

Therapeutic Drug Monitoring.

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Study Notes

  • Therapeutic drug monitoring (TDM) involves measuring drug concentrations and/or their metabolites in body fluids to optimize therapeutic benefits.
  • The therapeutic range of a drug is the dose range within which the drug produces the desired effect.
  • Blood concentrations outside the therapeutic range can lead to inefficacy or toxicity.
  • Laboratory personnel play a critical role in TDM by ensuring proper specimen collection timing and accurate drug concentration measurements.

Chapter Objectives

  • Identifying drug characteristics that make therapeutic drug monitoring essential.
  • Identifying influencing factors of orally administered drug absorption.
  • Identify factors that influence the rate of elimination.
  • Defining drug distribution and discuss factors that influence it.
  • Volume of distribution, elimination constant and drug half-life calculation.
  • Correlating drug concentrations to pharmacokinetic and pharmacodynamic parameters.
  • Listing specimen collection and handling requirements for therapeutic drug monitoring.
  • Specifying the therapeutic category or use of each drug presented in this chapter.
  • Describing potential toxic side effects/toxicity of the therapeutic drugs discussed.
  • Applying knowledge of therapeutic drug monitoring to interpret laboratory results.

Pharmacokinetics

  • Pharmacokinetics studies the movement of drugs in the body over time, including absorption, distribution, metabolism, and elimination.
  • Several factors influence drug absorption, distribution, metabolism, and elimination.
  • Optimal therapeutic benefit is achieved when a drug reaches the appropriate concentration at its site of action.
  • Bioavailability refers to the fraction of an administered dose that reaches its site of action.

Routes of Administration

  • Oral administration is the most common route of delivery due to being least invasive.
  • Intravenous (IV) administration provides the most direct and effective delivery.
  • Other methods include intramuscular (IM) injections, subcutaneous (SC) injections, inhalation via a nebulizer, transdermal patches, and rectal suppositories.
  • Each administration method has unique characteristics that affect circulating drug concentrations.

Drug Absorption

  • For orally administered drugs, absorption efficiency depends on dissociation from its administered form, solubility in gastrointestinal fluids, and diffusion across gastrointestinal membranes.
  • Tablets and capsules require dissolution before absorption; liquid solutions are absorbed more rapidly.
  • Hydrophobic drugs are efficiently absorbed in the stomach due to gastric acidity; weak bases are preferentially absorbed in the intestine where the pH is more alkaline.
  • Factors like intestinal motility, pH, inflammation, and the presence of food or other drugs can alter absorption rates.
  • Drug absorption rates may change due to age, pregnancy, or pathologic conditions.
  • Therapeutic oral dosage regimens can be determined when using TDM.

Drug Distribution

  • The free fraction of circulating drug can diffuse out of the vasculature.
  • A drug's ability to leave circulation depends on its lipid solubility.
    • Highly hydrophobic drugs cross cell membranes easily.
    • Polar and nonionized drugs can also cross cell membranes but do not sequester into lipid compartments.
    • Ionized species diffuse out of the vasculature at a slow rate.
  • The volume of distribution (Vd) relates the drug dose to its concentration in the specimen.

Free Versus Bound Drugs

  • Most drugs in circulation bind to serum protein constituents.
  • Usually, only the free (unbound) fraction can interact, resulting in a biologic response.
  • Free drug fraction is also termed the active fraction.
  • Changes in plasma protein content during inflammation, malignancies, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, and acid-base disturbances can alter the active fraction.
  • Albumin is the major transporter of drugs, and its concentration affects free versus bound status.
  • Increased a1-acid glycoprotein during inflammation increases binding of specific drugs.
  • The fraction of free drugs may also be influenced by other drugs/ endogenous substances.
  • Free drug fraction measurement should be considered when clinical signs are inconsistent with the total drug measurement or for highly protein-bound drugs.

Drug Metabolism

  • Substances absorbed enter the hepatic portal system, where circulating blood is routed through the liver before entering general circulation.
  • The first-pass effect reduces drug concentration before reaching the circulatory system.
  • Liver metabolism varies due to genetics, examined in pharmacogenomics.
  • Patients with impaired liver function may have a reduced drug metabolizing capacity.

Drug Elimination

  • Drugs can be cleared from the body through various mechanisms.
  • The free fraction of a drug/metabolites are subject to glomerular filtration, renal secretion, or both.
  • If not secreted/reabsorbed, the elimination rate of the free drug fraction directly relates to the glomerular filtration rate.
  • Decreases in GFR raise drug half-lives and plasma concentrations.
  • Decreases in plasma drug concentration most often occur as a first-order process.
  • First-order elimination follows a general equation, where the rate of elimination is proportional to the drug concentration.
  • The elimination is exponential, declining from high drug concentrations to low drug concentrations.

Elimination Example

  • Formula C₁ = Coe-kt can be used to calculate the amount of drug present after a certain time period.
  • Half-life T½ = 0.693/k refers to the time required for blood concentration to decrease by half.

Drug-drug interactions

  • Can increase drug-like substrate leading to toxicity, but also increase drug levels to make toxic.

Stead State Kinetics

  • After the first oral dose, absorption and distribution occur, followed by elimination.
  • Before the concentration of the drug drops significantly, the second dose is given.
  • The peak of the second dose is added to what remained from the first dose.
  • Because elimination is first-order, the higher concentration results in a larger amount of elimination.
  • The third through the seventh scheduled doses all have the same effect of increasing the blood concentration and the amount of elimination.
  • By the end of the seventh dose, the amount of drug administered in a single dose is equal to the amount eliminated during the dosage period.
  • After the seventh dose, a steady state is established, and the peak and trough concentrations can be evaluated.

Pharmacodynamics

  • Pharmacodynamics studies the biochemical and physiological effects of drugs and their mechanisms of action.
  • It describes the correlation between a drug's concentrations at its site of action and its pharmacological responses which may have a therapeutic and adverse effect.
  • Common mechanisms of action are that a drug activates its receptors.
  • Extent of responses is related to the concentrations of the drug; influenced by demographic factors and the receptor density at the site of action.
  • Maximum effect can be achieved if a drug concentration is high enough.
  • EC50 relates to the 50% effective concentration while consistent exposure to drugs may lead to a reduced response (tolerance).
    • Therapeutic Index = TC50/EC50

Specimen Collection

  • Accurate timing is the most important aspect within specimen collection in TDM; typically, it refers to the amount of time from drug taken, to testing time, to time results have elapsed.
  • Trough concentrations are drawn right before the next dose while peak concentrations are drawn 1 hour after an orally administered aminoglycoside (90 minutes for IV). Serum is appropriate.
  • Follow the container to be used, as some drugs may absorb; calcium-binding anticoagulants or specimen tubes that EDTA, citrate, or oxalate, must be avoided.

Cardioactive Drugs

  • Cardioactive drugs are the most widely used medicines.
  • Many drugs have been developed to treat cardiac complications.
  • Only inotropic agents and antiarrhythmics frequently involve TDM practice.

Pharmacogenomics

  • The effectiveness of a drug within a population depends in part on how patients respond.
  • For any medication, there are responders and nonresponders and their relationship to therapeutic effectiveness has recently been attributed to genetic polymorphisms of the patients' drug metabolism pathways.
  • Pharmacogenomics is studying these variations and developing therapies given the genetic differences.
  • One of the most prominent genes is cytochrome P450 (CYP450) the gene that encodes cytochrome P450 (CYP450), which is a family of enzymes within the MFO system.

Digoxin

  • Digoxin (Lanoxin) is the treatment of cardiac arrythmias as well as congestive heart failure.
  • Influenced by dietary factors, gastrointestinal motility, and formulation of the drug
  • Functions by inhibiting membrane Na+, K+-ATPase, causing a decrease in intracellular potassium, increasing intracellular calcium in cardiac myocytes.
  • The plasma concentration range is 0.8 to 2.0 ng/mL.
  • Low potassium and magnesium potentiate digoxin actions.

Quinidine

  • Quinidine is a natural product extract from the bark of the "fever tree."
  • Commonly used to treat various cardiac arrhythmias.
  • Formulations sulfate and gluconate and administered orally, gastrointestinal absorption is complete and peak blood concentrations occur 2 hours after.
  • Plasma protein (70% to 80%)
  • The half-life is 6 to 8 hours.

Procainamide and N-acetylprocainamide

  • Antiarrhythmic drug that can also be used to treat PVCs
  • Oral route is most common, peak blood about 1 hour, plasma proteins (20%)
  • The most common administration method as its absorption is rapid and complete with peak.
  • NAPA hepatic metabolite demonstrates equal antiarrhythmic potential

Adminoglycosides

  • An antibiotic to treat gram, bacteria that inhibits bacterial protein synthesis (Nephrotoxicity and Ototoxicty)
  • 1-2 hours as peak after administered
  • 2-3 elimination rates.

Antibiotics

  • Poorly absorbed through the gastro tract, administration is limited to intravenous infusion.
  • Aminoglycosides have a half life of approximately 2 -3 hours
  • Elimination by Renal filtration.

Gentamicin

  • 2-3 times given per day by intravenous or intramuscular injections(between 3-12 mcg/mL)
  • Reduced renal function leads to dosing amount
  • The main toxicities associated with Gentamicin from Serum levels and symptoms consistent levels is important

Vancomycin

  • Glycopeptide antibiotic with poor gastro absorption
  • Reaches peak in1 hour
  • Plasma Protein = to 55%
  • Toxic effects - When concentrations exceed , includes Red man sundrome,nephrotoxicitiy, and ototoxcity.

AED

  • Anti Epileptic Drugs are only effective when while drug is their body/ or even if the don't hit concentrations
  • Narrow Therapeutic
  • Can monitor Adherence, and reassess a modified medication Regimen

Phenytoin

  • Slow and can protect brain tissue, also reduce protien, and monitor seziures
  • Adverse effects, and effects, which may include seizures, ataxia, dizziness, and gastrointestinal disturbances.

Lithium

  • Can prevent aggression and treat bipolar
  • Peak Concentrations are reached 2-4 Hours After
  • Excreted Renally with No Protein
  • 0.5 - 1.2 mmol/L, Is a Large Portion of the Patient Population

Theophyline

  • treats Pulmunory diseases with 50-65 bounded protien
  • 10-20 may lead to lead to insomnia, Tachycardia
  • May be used to optimize , TDM - when Suspected

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Therapeutic drug monitoring (TDM) involves measuring drug concentrations to optimize therapeutic benefits. Blood concentrations outside the therapeutic range can lead to inefficacy or toxicity. Laboratory personnel play a critical role in TDM by ensuring proper specimen collection and accurate drug concentration measurements.

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