Therapeutic Drug Monitoring (TDM)

Therapeutic Drug Monitoring (TDM)

• TDM is used by medical providers to maintain therapeutic benefits by monitoring drug/metabolite levels in body fluids, usually blood.
• The therapeutic range is the drug dose or concentration range that produces the desired effect.
• If blood concentration falls outside the therapeutic range, inefficacy or toxicity may occur.
• Laboratory personnel are essential in TDM, due to the importance of specimen collection timing, concentration measurement and timely results reporting.
• TDM helps ensure correct dosages and identify drug-drug interactions.
• Patient-specific factors, such as age, gender, genetics, diet, and co-administered drugs affect drug concentrations and efficacy.
• TDM helps establish appropriate dosing regimens that fit individual situations.
• It identifies nonadherence and reoptimizes drug regimens due to interactions or physiological changes.
• TDM is based on pharmacokinetics and pharmacodynamics studies.

Pharmacokinetics

• Pharmacokinetics studies drug movement within the body.
• Absorption, distribution, metabolism, and excretion influence drug concentrations.
• Achieving therapeutic drug concentrations is complex.

Routes of Administration

• Administering drugs at the appropriate concentration at their site of action yields optimal therapeutic benefit.
• Oral administration is the most common and least invasive.
• Intravenous (IV) administration delivers drugs most directly and effectively.
• Bioavailability defines the fraction of the administered dose that reaches its site of action.
• Other administration methods include intramuscular (IM), subcutaneous (SC) injections, inhalation via nebulizer, transdermal patches, and rectal suppositories (often in infants).
• Each administration method has distinct characteristics affecting drug concentrations.

Drug Absorption

• When administering drugs orally, absorption efficiency depends on dissociation from its form, solubility in gastrointestinal fluids, and diffusion across gastrointestinal membranes.
• Tablets and capsules require dissolution before absorption.
• Liquid solutions absorb more rapidly.
• Most drugs passively diffuse from the gastrointestinal tract into the bloodstream when in a hydrophobic, nonionized state.
• Gastric acidity aids weak acid absorption in the stomach.
• Weak bases are better absorbed in the more alkaline intestine.
• Changes in intestinal motility, pH, and inflammation dramatically alter absorption rates.
• Absorption is affected by food, other drugs, age, pregnancy, and pathological conditions.
• TDM can determine effective oral dosage regimens in these instances.

Drug Distribution

• The free fraction of circulating drug is subject to diffusion out of the vasculature and into interstitial and intracellular spaces.
• Drug distribution is the movement between blood circulation, tissues/organs, and the relative proportion of the drug in those tissues.
• Lipid solubility affects the ability to leave circulation.
  • Highly hydrophobic drugs easily cross cell membranes. They can enter cells or partition into lipid compartments like adipose tissue and nerve cells.
  • Polar, nonionized drugs 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 mathematically relates the dose of the drug in the body to the drug concentration: Va = D/C (V = volume in liters, D = dose in mg or g, C = drug concentration in plasma in mg/L).
• Hydrophobic drugs can have large distribution volumes due to partitioning into hydrophilic compartments.
• Substances that are ionized or primarily bound to proteins in plasma have small distribution volumes due to sequestration in the vasculature.

Free Versus Bound Drugs

• Drugs in circulation often bind with serum protein constituents, forming drug-protein complexes.
• The free or unbound fraction can interact with the site of action, resulting in a biologic response, this is also termed the active fraction.
• A high free fraction or low free fraction can cause toxic adverse effects or no therapeutic benefit, respectively, despite standard doses.
• Alterations in the active fraction can result from changes in plasma protein content from inflammation, malignancies, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, and acid-base disturbances.
• Albumin is the major plasma protein and drug transporter.
• Plasma α1-acid glycoprotein increases during inflammation, increasing the binding of drugs like propranolol, quinidine, chlorpromazine, cocaine, and benzodiazepines.
• Free drug fraction can be influenced by other drugs or endogenous substances like urea, bilirubin, or hormones.
• Measuring the free drug fraction should be considered for highly protein-bound drugs, or if clinical signs are inconsistent with the total drug measurement.

Drug Metabolism

• Substances absorbed from the intestine (except from the rectum) enter the hepatic portal system.
• Blood from the gastrointestinal tract passes through the liver before entering general circulation.
• First-pass effect is a phenomenon where the drug is metabolized, reducing its concentration before reaching circulation.
• The liver is a major site of drug metabolism.
• Liver metabolism varies individually, influenced by genetics. This is studied in pharmacogenomics.
• Impaired liver function reduces the capacity to metabolize certain drugs.
• If a drug's efficacy depends on a therapeutically active metabolite that requires liver enzymes, this is particularly important. This enzymatic process is biotransformation.
• Patients with liver disorders may need dose adjustments due to altered metabolism and elimination.
• Most drugs are xenobiotics that enter biochemical pathways for endogenous substances.
• The hepatic mixed-function oxidase (MFO) system is a biochemical pathway responsible for a large percentage of drug metabolism.
• This system converts hydrophobic substances into water-soluble products through enzymatic reactions. Products then either transport the bile or release into general circulation for renal filtration.
• The MFO system has numerous enzymes in two functional groups or phases.
  • Phase I reactions produce reactive intermediates.
  • Phase II reactions conjugate functional groups like glutathione, glycine, phosphate, and sulfate to intermediates, producing water-soluble products.
• The MFO system is nonspecific, so many substances can undergo this reaction series, with specific products formed.
• For example, acetaminophen is metabolized in the MFO pathway.
• In the case of overdose, acetaminophen leads to the formation of a glutathione conjugate following phase II reactions.
• The MFO system may be overwhelmed and cannot effectively metabolize it to a safe, water-soluble end product for elimination if too much acetaminophen is present.
• The conjugating group becomes depleted in phase II reactions.
• Accumulation of phase I products may result in toxic effects, such as irreversible damage to hepatocytes in acetaminophen overdose.

Drug Elimination

• Drugs can be cleared from the body by various mechanisms, including glomerular filtration and renal secretion of the free fraction or its metabolites.
• For drugs that are not secreted nor reabsorbed, the fraction directly relates to the glomerular filtration rate (GFR).
• Decreases in GFR increases drug half-lives and elevated plasma concentrations.
• Aminoglycoside antibiotics and cyclosporine are examples of drugs that are not secreted or reabsorbed by the renal tubules.
• Decreases in plasma drug concentration occur as a first-order process, an exponential rate of loss that is independent of the clearance mechanism.
• The changing rate of drug concentration (ΔC/ΔT) is directly related to drug concentration (C) and is defined by a constant (k).
• The k value shows the percent change per unit time; also referred to as the elimination constant or the rate of elimination.
• The value is negative because the value decreases.
• The graphic solution is an exponential function that asymptotically approaches zero.
• A semilogarithmic plot can linearize this function.
• Drugs are eliminated through hepatic metabolism, renal filtration, or both.
• Liver-metabolized drugs are excreted in bile for elimination.
• Elimination is highly variable, altered by organ system functional changes. Establishing safe dosage regimens needs the elimination rate and estimated blood concentration over time.

Elimination Example

• C[T] = C[0] e^(kt) can determine elimination rate and concentration after time.
• C[0] is the initial drug concentration, and C[T] is the concentration after time period T, k is the elimination constant, and T is the time period evaluated.
• Measuring the initial drug concentration and the concentration after a period of time (T) can help determine the elimination constant.

Drug Half-Life

• Drug half-life is the time for blood drug concentration to decrease by one-half.
• It can be determined graphically or by converting the elimination constant (k) to drug half-life (T1/2) using the formula T1/2 = 0.693/k.
• 0.693 represents exponential rate of elimination, assuming it is by first order kinetics.
• An ideal plot of drug elimination describes intravenous (IV) bolus assuming no prior distribution of the drug.
• The rapid rate change after the initial IV bolus is due to distribution and elimination.
• The elimination constant (k) can be determined after distribution has completed.
• In oral administration, drug absorption and distribution take place at the same time.
• Concentrations rise when absorption exceeds distribution/elimination and declines when elimination/distribution exceeds absorption.
• Rate of elimination can only be determined after absorption and distribution are complete in oral administration.
• Most drugs are not administered as a single bolus, but on a schedule of certain mg given every so many hours.
• This type of dosage means that blood concentrations oscillate/fluctuate.
• Peak drug is the max level and through drug concentration is the min level.
• Multiple dosages achieve trough and peak concentrations within the therapeutic range.
• Evaluation of the oscillating function cannot be done right away, and needs five to seven doses before achieving steady state oscillation.

Pharmacodynamics

• Pharmacodynamics studies biochemical and physiological drug effects and mechanisms of action.
• It outlines a relationship between a drug's concentration at its site of action and pharmacological responses (therapeutic and adverse).
• The extent of pharmacological response is related to the concentrations of the drug at the site.
• A dose-response curve describes this relationship (plots drug dose/concentration against its pharmacological responses).
• Demographic factors, receptor density, and presence of competing drugs can influence this.
• Tolerance can occur in receptors constantly exposed to drugs.
• As shown in a dose-response curve, an increased amount of EC50 is needed to achieve the same pharmacological response.
• Therapeutic index (TI) indicates the relative safety of a drug, is the ratio between the EC50 and the 50% toxic concentration (IC50).
• Drugs like digoxin, warfarin, insulin, phenytoin, and opioids have low therapeutic indices (<10).
• TDM is employed to titrate the doses of low therapeutic index drugs to maximize therapeutic benefits but avoid adverse effects
• Therapeutic Index = TC50/EC50

Specimen Collection

• Accurate specimen collection timing is most crucial
• Generally, trough concentrations are drawn right before the next dose, and peak concentrations are drawn 1 hour after an orally administered dose.
• IV aminoglycosides have peak levels 90 minutes after completion of infusion.
• Drugs that are absorbed at a slow rate may require several hours before the peak drug concentrations can be evaluated.
• Determining drug peak concentrations should be performed after a steady state has been achieved
• Serum is the typical specimen for measuring circulating drug concentrations
• Containers are specific for each drug and care should be taken with the appropriate container needed for specimen
• Follow manufacturer’s guidance on specimens as well
• Failure to follow manufacturer recommendations results in falsely low values.
• Calcium-binding anticoagulants add cations, which may interfere with analysis or distribution differences with red blood cells and plasma.
• EDTA, citrate, or oxalate tubes are unacceptable for TDM analysis, with one exception: EDTA whole blood is the specimen of choice for measuring immunosuppressive drugs.

Pharmacogenomics

• Drug effectiveness relies on how patients respond. There are responders and nonresponders.
• Responders benefit from therapeutic effects, while nonresponders do not demonstrate beneficial effects.
• Genetic polymorphisms in metabolism recently attribute to variations in therapeutic drug effectiveness.
• Pharmacogenomics are the study of these variations.
• This develops therapies that compensate for any genetic differences.
• One prominent gene that affects drug metabolism is CYP450, encoding for cytochrome P450, a family of enzymes within the MFO system.
• Variations in enzymes result in drug metabolism differences.
• CYP2D6, CYP2C9, and CYP3A4 are three variations linked to differences in drug metabolism.
• Information helps personalize drug doses through the CYP450 profile of a patient.
• For example, patients with genes that slowly metabolize drugs may be given lower doses. Alternatively higher doses will need to be given due to genes predisposing higher rates of metabolism.
• Pharmacogenetic profiling also determines drug-drug interactions or any therapeutic benefit.

Cardioactive Drugs

• Cardioactive drugs are used to treat cardiac complications.
• Inotropic agents like cardiac glycosides and antiarrhythmics frequently involve TDM practice in order to avoid adverse effects to patients.

Digoxin

• Digoxin inhibits the membrane Na+, K+-ATPase, which treats heart failure that increases intracellular concentration
• This improves cardiac contractility, with a plasma concentration range of 0.8-2.0 ng/mL.
• Cardiac arrhythmias and other adverse effects include premature ventricular contractions can result from above 2.0 ng/mL levels.
• Absorption of orally administered Digoxin influenced by: dietary factors, gastrointestinal motility, and formulation of the drug
• Plasma protein binding Rate is approximately: 25%
• Unbound or free form of digoxin is sequestered into muscle cells.
• Tissue concentration is 15 to 30 times great than blood.
• Renal filtration of unbound digoxin eliminated, liver also metabolizes the drug
• Half-life of plamsa is is approximately: 38 hours Extended half-life cause slow release of tissue in the back into circulation.
• Establishing a dosage regimen requires assessment of concentrations after initial dosing
• Effective and nontoxic concentrations are achieved.
• glomerular filtration rate (GFR) affects concentrations
• Patients that suffer from renal disease should have Frequent dose adjustments
• Adjustment of concentrations below the therapeutic range may be necessary to avoid toxic effects
• Serum is the most common tissue used for analysis.
• Hypothyroid patients become To evaluate, timing of specimen collection is needed.
• Concentrations of digoxin occur are between: 2 to 3 hours
• Peak blood concentrations is a slow process it to tissues.
• Peak concentrations do not correlate well with therapeutic effects.
• The therapy to the patient is during the time frame of: 8-10 hours
• Immunoassays, measures total digoxin the drug is: in serum
• Measures both bound and free digoxin, so increased values will be seen in with Digibind
• Digoxin-like immunoreactive factors may: Cause concentration elevations,

Quinidine

• Natural product: Extracted from the bark of the "fever tree" Native to central and south America Treats: cardiac arrhythmias
• Common formulations are: quinidine sulfate and quinidine gluconate
• Administered: orally
• Absorption: rapid and complete
• Peak concentrations occur: 2 hours after administration
• Therapeutic range: 2 to 5 milligram
• Plasma proteins bound: Approximately 70% to 80%
• Half Life is: 6 to 8 hours
• Eliminated by: primarily eliminated by hepatic metabolism Barbiturates: induction of hepatic metabolism Increases the clearance rate of quinidine Liver Disease: impairment
• Adverse effects:nausea, vomiting, and abdominal discomfort.

Procainamide and N-acetylprocainamide

• Procanbid SR, Pronestyl is: antiarrhythmic drug.
• Common method: administration is rapid and complete absorbed
• Peak concentrations occur: Hour after administration
• Approximately: 20% of absorbed is bound to plasma proteins.
• Has a Half- life of approximately: 4 hours Eliminated by a combination of : renal filtration and hepatic metabolism N-acetylprocainamide is: (NAPA), a hepatic metabolite of procainamide,
• Demonstrates similar antiarrhythmic: potential to the parent drug. Therapeutic range for Procainamide: 4-10 milligram Therapeutic range for NAPA: 12-18 milligram
• Renal or hepatic function: increased concentration plasma concentration results in myocardial depression and arrhythmia. Both Procainamide and an active measured by: Immunoassay Determine total antiarrhythmic

Disopyramide

• Norpace is: antiarhythmic drug, treats cardiac abnormalities
• May be administered as: a quinidine substitute when the adverse effects of quinidine are unacceptable
• Administered: orally
• Absorption: completely and rapidly
• Plasma concentration occurs about : 1 to 2 hours, is highly variable between individuals and is concentration dependent
• Therapeutic range; 3 to7 micrograms
• Interpretation of results: should take the clinical perspective into consideration.
• Adverse effects: dose dependent.
• concentration about 4.5 micro liters/mL: Anti-cholinergic effects, such as dry mouth.
• Cardiac effects of drug: concentrations about 10 micro liters bradycardia and atrioventricular node blockage.
• Half-life: 7 hours
• Primarily eliminated: renal filtration, to a lesser extent, by hepatic metabolism. GFR, the drug half-life is prolonged, and the blood concentrations are elevated. Commonly determined by: serum or plasma.

Antibiotics Aminoglycosides

• Treats: gram-negative and some gram-positive bacterial infections.
• Antibiotics within this classification, gentamicin, tobra-mycin, amikacin, and kanamycin
• Share pharmacological mechanism: inhibiting bacterial protein, also varies in effectiveness
• Blood concentrations, cause toxicities: especially nephrotoxicity and ototoxicity.
• Hearing and balance impairment: aminoglycosides disrupt inner ear cochlear and vestibular membranes
• Irreversible ototoxic effects
• results in: Electrolyte imbalance and proteinuria.
• Reversible effects: however, extended high-level exposures may result in necrosis of renal tubular cells and subsequent renal failure.
• Drug administration; IV infusion or intramuscular injection
• Outpatient setting: due to drug route.
• Peak concentrations: administered 1 to 2 hours after injection
• Approximately: half-life of 2 to 3 hours

Gentamicin

• An Antibiotic used in blood infections
• Antibbitoics is used to treat life-threatening blood infections or by gram
• Conventional dosing of gentamicin is usually: 2 to 3 times per day
• Antibiotics doses 2.0 to 12.0 micrograms
• May be administered higher doses 5-7 mg/kg once per day
• Dosing: reduced in patients with renal function
• The Trough level is 3.0 milligram (peak)

Tobramycin

• Used to: treat blood infections
• Adverse effects is due to: Ototoxicity and Nephrotoxic effects
• monitoring of serum levels, renal function important due to: toxicity Therapeutic goal trough levels the goal is 2.0 miligram 12.0 milligram

Amikacun

• An aminoglycoside
• Treats: severe blood infections
• Results in the death of bacteria
• Administered by: Intravenous and Intramuscular
• 2-3 hours: serum half lofe

Digoxin

• Used for cardiac arrythmia and heart failure
• Inhibits the membrane-sodium and Potassium ATP
• Oral admin with 2-3 hours (peak blood concentrations)
• Kidney and Livers also play a role in elimination
• Therapeutic effects last 8-10 hours

Quindine

• Oral admin
• Extracted from the bark of Cinchora spp.
• Treats cardiac arrhythmia
• Hepatic elimintaion

Procainamide

• treats cardiac conditions
• elimination through Renal

Disopyramide

• adverse effects is due to the toxicity

Adminoglycosides

• treat blood infections
• not adminstered orally

Pharmacogenomics

• effectiveness relies in genes and enzymes