MODULE 8: THERAPEUTIC DRUG MONITORING C.

Other drugs
● Requires active transport mechanism
● Weak acids - stomach
THERAPEUTIC DRUG MONITORING (TDM) ● Weak bases - intestine
● measurement of drugs prescribed by medical
providers Factors that alter absorption rates in GI tracts:
● also measures drug metabolites in body fluids to ● Motility of intestine
maintain therapeutic benefits (in serum, plasma, ● pH
or whole blood) ● Inflammation
● Therapeutic range - dosage range of a drug ● Presence of food or other drug
which produces the desired therapeutic effect ○ antacids, fiber, kaolin, sucralfate,
○ drug therapy leads to inefficacy or toxicity cholestyramine, and antiulcer medications
if the blood concentration is outside of the ○ Morphine – slows GI motility
therapeutic range ● Age
● used to identify patients who are non adherent or ● Pregnancy
to reoptimize a dosing regimen ● Pathologic conditions
● performed based on studies of
pharmacokinetics and pharmacodynamics
DRUG DISTRIBUTION
How to achieve safe and effective pharmaceutical ● Involves the transfer of a drug between the
therapies? bloodstream and various organs or tissues, as well
1. Appropriate timing of specimen collection as the proportion of the drug present in each
2. Accurate measurement of drug concentrations tissue or organ.
3. Timely reporting of results ● Lipid solubility is necessary in the ability of the
drug to leave circulation
Main Purpose of TDM:
● ensure correct drug dosages for the therapeutic DRUG CLASSIFICATION:
range A. Highly hydrophobic drugs
● identify drug-drug interactions if multiple drugs ● Readily pass through cell membranes and enter
are taken together cells. They can also distribute into lipid-rich
compartments, such as adipose tissue and nerve
cells.
PHARMACOKINETICS ● Have a large Vd due to partitioning into
● It is the study of how drugs move through the hydrophobic compartments
body
● It offers a timeline of how the concentration of a B. Ionized Drugs
drug changes within the body over a period of ● Diffuse out of the vasculature but at a slower rate
time. This process is influenced by absorption, ● Have a small Vd due to sequestration in
distribution, metabolism, and excretion. vasculature

C. Polar and not ionized drugs

ROUTES OF ADMINISTRATION ● Also capable of crossing cell membranes, but they
● Oral do not accumulate in lipid compartments.
● Intravenous
● Intramuscular injection Volume of distribution
● Inhalation ● The relationship between the amount of a drug
● Transcutaneous present in the body after administration and the
● Rectal delivery concentration of the drug that is detected in a
biological sample.
* Optimal therapeutic benefit is achieved when a drug is ● This relationship can be expressed mathematically
in its appropriate concentration when in its site of action. using this formula:
Vd=D/C
Bioavailability Where:
● refers to the proportion of the dose of a drug that ● Vd is the volume of distribution in liters
ultimately reaches and is available at its intended ● D is the dose of the drug (mg or g)
site of action ● C is the drug concentration in plasma (mg/L or
g/L)

DRUG ABSORPTION

Absorption in the GI tract depends on: FREE VERSUS BOUND DRUGS

● Dissociation from its administered form
● Solubility in GI fluids A. Free or unbound fraction:
● Diffusion across GI membranes ● aka “active fraction”
● Standard dose – within therapeutic range
Types of drugs: ● High free fraction – toxic adverse effect
A. Tablet and Capsules – requires dissolution ● Low free fraction – no therapeutic effect
B. Liquid solutions – readily absorbe
Alteration in active fraction may occur secondary to reactions, allowing for excretion via bile or renal
changes in plasma protein content during: filtration.
● Inflammation
● Malignancies Enzymes involved in the MFO system
● Pregnancy ● Phase I reactions - produce reactive intermediates
● hepatic disease ● Phase II reactions - produce water-soluble
● nephrotic syndrome metabolites through the conjugation of functional
● malnutrition groups, such as glutathione, glycine, phosphate,
● acid–base disturbances and sulfate, to drug intermediates.

B Bound Fraction Induced MFO system

● aka “inactive fraction” ● Seen in increased synthesis and activity of
● Forms a drug–protein complexes enzymes
● Albumin is the primary protein component found ● This induction typically results in accelerated drug
in plasma and plays a crucial role in transporting clearance and a shorter half-life
drugs. Variations in the concentration of albumin ● In Hepatic disease it results in slower clearance
can influence the balance between bound and and a longer half-life of drugs. In this case drugs
unbound (free) forms of numerous drugs. may not be effectively metabolized, increasing the
● Increase in α1-acid glycoprotein can result in risk of toxicity
enhanced binding of drugs like:
○ Propranolol Alteration in the rate of elimination of the involved
○ Quinidine drugs is due to:
○ Chlorpromazine ● Drug-drug interaction
○ Cocaine (competitive/noncompetitive)
○ Benzodiazepines ● Drug-food interaction

Drugs or endogenous substance that competes for

binding sites of proteins:
● Urea DRUG ELIMINATION
● Bilirubin ● Free fraction of a drug or its metabolites are
● Hormones subject to:
a. glomerular filtration
b. renal secretion
DRUG METABOLISM c. both
● Drugs that are not secreted or reabsorbed shows
Hepatic Portal System direct relationship between the elimination rate
● In this system, blood that is flowing through the of the free drug fraction and the glomerular
gastrointestinal tract is directed through the liver filtration rate (GFR)
prior to entering the overall circulation of the ○ Decreased GFR: ↑ drug half- lives and
body. elevated plasma concentration
● First Pass Effect - refers to the process where a ○ Exs. (drugs): aminoglycoside antibiotics,
drug undergoes metabolism in the liver, leading to cyclosporine
a decrease in its concentration before it enters the ● Elimination through:
systemic circulation. ○ hepatic metabolism
● The liver, being a primary site of drug metabolism, ○ renal filtration
can extensively metabolize certain drugs as they ○ combination of the two
pass through it.
FIRST- ORDER ELIMINATION
Drug metabolism is influenced by: ● decrease in the plasma drug concentration
● Genetic ● indicates an exponential rate of loss
● Impaired liver function ● ∆𝐶/∆𝑇 = − 𝐾𝑐

Pharmacogenomics Where:
● Study of the genetic variation in drug metabolism ● k - proportionality factor that describes the
percent change per unit time
Biotransformation ○ referred as “elimination constant” or “rate
● Refers to the enzymatic processes in the body of elimination”
that convert drugs into metabolites ○ negative value (as it is a decreasing
● facilitate the elimination of drugs from the body, value)
as well as to convert them into forms that are
more easily excreted −𝑘𝑡
𝐶𝑇 = 𝐶0𝑒
Hepatic mixed-function oxidase (MFO) system Where:
● Responsible for a large portion of drug metabolism ● 𝐶0- initial concentration of drug
● Non-specific but the product produce from each
● 𝐶𝑇 - drug concentration after the time period
substance is specific
● Converts hydrophobic substances into ● k - elimination constant
water-soluble products through enzymatic ● T - time period evaluated
Note: DRUG HALF - LIFE (T½)
● most useful form of elimination constant ● time needed for the blood concentration of the
● k - determined by measuring the initial drug drug to decrease by one-half
concentration and the concentration after a period 1
● 𝑇 2 = 0. 693/𝑘
of time
○ 0.693 - logarithm of 2
○ known k - amount of drug that will be
■ represents the exponential rate of
present after a certain time period can be
elimination
determined

Elimination Example 𝑇
1
= 0. 693/𝑘
2
1
𝑇 2
= 0. 693/(0. 13/ℎ)
1. The concentration of gentamicin is 10 μg/mL at 1
12:00. At 16:00, the gentamicin concentration is 6 𝑇 2
= 5. 33 ℎ𝑜𝑢𝑟𝑠
μg/mL. What is the elimination constant (k) for
gentamicin in this patient? Interpretation: The gentamicin concentration in the
blood would be one-half of the initial concentration after
Given: 5.33 hours.
● C0 = 10 μg/mL
● CT = 6 μg/mL
Multiple-Dosage Regimen
● T = 4 hours
● Purpose: achieve trough and peak concentrations
● k=?
−𝑘𝑡 within the therapeutic range
𝐶𝑇 = 𝐶0𝑒 ● Steady-state oscillation - achieved after 5 -7
−𝑘 (4ℎ) doses
6 µ𝑔/𝑚𝐿 = (10µ𝑔/𝑚𝐿) 𝑒
6 µ𝑔/𝑚𝐿 10 µ𝑔/𝑚𝐿 −𝑘 (4ℎ)
10µ𝑔/𝑚𝐿
= 10µ𝑔/𝑚𝐿
𝑒 A. Peak Drug Concentration
−𝑘 (4ℎ) ● happens when drugs are delivered on a scheduled
0. 6 = 𝑒 basis and blood drug concentration oscillates
−𝑘 (4ℎ)
𝑙𝑛 (0. 6) = 𝑙𝑛 (𝑒 ) between a maximum level
− 0. 51 = − 𝑘(4ℎ)
B. Trough Drug Concentration
(− 0. 51 = − 𝑘(4ℎ))(− 1)
● happens when drugs are delivered on a scheduled
0. 51 = 𝑘(4ℎ) basis and blood drug concentration oscillates
0.51 𝑘 (4ℎ)
4ℎ
= 4ℎ
between a maximum level
0. 13/ ℎ = 𝑘
PHARMACODYNAMICS
Interpretation: Patient is eliminating gentamicin at a ● Study of the biochemical and physiological effects
rate of 13% per hour of drugs and their mechanisms of action

Dose-Response Curve
2. In this same patient on the same day, what would ● Plots the drug dose against its pharmacological
the predicted blood concentration of gentamicin be at responses
midnight (24:00)?

For C0, either the 12:00 or 16:00 value can be used as

long as the correct corresponding time duration is used.

In this example, the 16:00 value of 6 μg/mL will be

used.

Given:
● C0 = 10 μg/mL
● CT = ?
● T = 4 hours
● k = 0.13/h ● Affecting factors:
−𝑘𝑡
𝐶𝑇 = 𝐶0𝑒 ○ Demographic factors
−0.13 (8ℎ)
○ Density of receptors at the site
𝐶𝑇 = (6µ𝑔/𝑚𝐿) 𝑒 ○ Presence of other drugs that compete for
−1.04 binding at the same receptor
𝐶𝑇 = (6µ𝑔/𝑚𝐿) 𝑒
𝐶𝑇 = (10µ𝑔/𝑚𝐿) (0. 35) 50% effective concentration (𝐸𝐶50)
𝐶𝑇 = 2. 1 µ𝑔/𝑚𝐿 ● Concentration at which 50% of the maximum
effect is seen
● Important determinant of drug activities
Interpretation: There is 2.1 µ𝑔/𝑚𝐿 serum gentamicin
concentration in the patient at midnight (24:00).
 PHARMACOGENOMICS
● Science of studying variations on how patients
respond to a certain medication
● For any medication, there are patients who are
responders and nonresponders.
○ Responders- benefits from the
therapeutic and desired effects of a drug
○ Nonresponders- do not demonstrate a
beneficial effect from a given drug

Tolerance CYP450
● reduced response due to constant exposure of ● Gene that encodes for cytochrome (CYP450)
receptors to drugs ● One of the most prominent genes that affect drug
metabolism
● Three variations most often linked to differences
in drug metabolism:
○ CYP2D6
○ CYP2C9
○ CYP3A4

CARDIOACTIVE DRUGS
● used to treat cardiac complications
Therapeutic Index (TI) ● only the inotropic agents (cardiac glycosides) and
● Ratio between the 𝐸𝐶50 and the 50% toxic antiarrhythmics are involved in TDM
concentration (𝑇𝐶50) A. Digoxin
● Most drugs have TIs of greater than 100, except: ● Brand name: Lanoxin
○ Digoxin ● a cardiac glycoside
○ Warfarin ● used in the treatment of cardiac arrhythmias and
○ Insulin congestive heart failure
○ Phenytoin ● it functions by inhibiting membrane Na+, K+
○ Opioids -ATPase
● Formula: ○ ↓ intracellular K+ = ↑ intracellular Ca2+ in
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥 = 𝑇𝐶50 /𝐸𝐶50 cardiac myocytes
■ ↑ intracellular Ca2+ improves cardiac
contractility
● Administration: oral
○ Bound to proteins: about 25%
○ Free form is sequestered into muscle cells,
and at equilibrium
■ tissue conc.: 15-30x > blood
○ remains are metabolized by the liver
● Half-life: 38 hours (adult)
● timing of specimen collection is crucial
○ peak conc.: 2-3 hours
○ significant effects occur at: 8-10 hours
SPECIMEN COLLECTION ● Therapeutic range: 0.8 to 2.0 ng/mL
● ACCURATE TIMING of specimen collection ● Dosage requirements:
○ Single most important factor in TDM ○ should assess blood concentrations before
initial dosing
Trough concentration Peak concentration ○ GFR: affects the concentrations of digoxin
○ patients with renal diseases: should
● Drawn right ● Drawn 1 hour after an have frequent adjustments to avoid
before the next orally administered
toxicities
dose dose
● Should only be ○ hyperthyroid patients: resistant to
performed only after a digoxin actions
steady state has been ○ hypothyroid patients: sensitive to digoxin
achieved ● Toxic level: >2.0 ng/mL
● Specimen: Serum ○ but it can be used to control ventricular
○ Must not use: tachycardia
■ Serum separator collection tubes ○ mimics cardiac arrhythmias
■ Calcium-binding anticoagulants ● Toxic adverse effects:
(EDTA, citrate, oxalate) ○ premature ventricular contractions (PVCs)
○ One notable exception: EDTA whole blood ○ atrioventricular node blockage
is the specimen of choice for measuring ○ nausea
immunosuppressive drugs ○ vomiting
○ visual disturbances
 ● Eliminated by: renal filtration of unbound digoxin D. Disopyramide
● Antidote: Digibind ● aka Norpace
● Interfering conditions: ● an antiarrhythmic drug used in the treatment of
○ Newborns cardiac abnormalities
○ Pregnant women ● used as a quinidine substitute
○ Patients with renal and hepatic failure ○ when the adverse effects of quinidine are
■ produces endogenous digoxin-like unacceptable
immunoreactive factors (DLIF) ● its pharmacodynamics have not been fully
○ Biotin determined
● Method: immunoassays ● Administration: oral
○ measure total digoxin (digoxin + its ○ plasma conc.: 1-2 hours after
metabolites) administration
● Therapeutic range: 3.0–7.5 μg/mL
B. Quinidine ● Half-life: approx. 7 hours
● Common brands: Quinidex Extentabs, ○ if ↓ GFR and ↑ blood conc.: prolonged
Cardioquin, or Quinora half-life
● commonly used to treat various cardiac ● Toxic levels:
arrhythmias ○ >4.5 μg/mL: anticholinergic effects (dry
● Extracted from: bark of “fever tree” (Cinchona mouth and constipation)
spp.) ○ >10 μg/mL: bradycardia and
● Two most common formulations: atrioventricular node blockage
○ quinidine sulfate ● Eliminated by: renal filtration and hepatic
○ quinidine gluconate metabolism
● Administration: orally ● Method: chromatographic methods or
○ peak blood conc.: 2 hours immunoassay
○ bound to plasma proteins: approx.
70-80%
● Therapeutic range: 2 to 5 μg/mL ANTIBIOTICS
● Half-life: 6 to 8 hours
● Toxic adverse effects: A. Aminoglycosides
○ nausea ● group of antibiotics
○ vomiting ● treatment for gram-negative and some
○ abdominal discomfort gram-positive bacterial infections
○ thrombocytopenia and tinnitus ● Most frequently prescribed aminoglycosides:
■ more serious side effect ○ gentamicin, tobramycin, amikacin, and
○ cardiovascular toxicity kanamycin
■ eg. PVCs – seen in 2x >5 μg/mL ● disrupts inner ear cochlear and vestibular
● Eliminated by: hepatic metabolism membranes
○ barbiturates – ↑ clearance rate of quinidine ○ resulting to hearing and balance
● Method: immunoassays impairment
● Increased Aminoglycosides:
C. Procainamide and N-Acetylprocainamide ○ Ototoxicity: irreversible and seen with
Procainamide repeated high-level exposures
● Common brands: Procanbid, Procan SR, ○ Nephrotoxicity: damage the renal
Pronestyl tubules
● also an antiarrhythmic drug ■ May cause: electrolyte imbalance
● Administration: oral route and proteinuria
○ peak blood conc.: 1 hour after oral ● High-level exposures:
administration ○ necrosis of renal tubular cells
○ bound to plasma proteins: approx. 20% ○ subsequent renal failure
● Half-life: approx. 4 hours ● Absorption: GIT
● Therapeutic range: 4–10 μg/mL ● Administration: IV infusions or IM injections
● Eliminated by: a combination of both renal ○ Peak concentration: 1-2 hrs after
filtration and hepatic metabolism ● Half-life: ~ 2-3 hours
● Elimination: Renal filtration
N-acetylprocainamide (NAPA) ● Method: Immunoassay
● a hepatic metabolite of procainamide
● also an antiarrhythmic drug B. Gentamicin
● Therapeutic range: 12–18 μg/mL ● used to treat life-threatening blood infections
● Alteration in either renal or hepatic function can caused by gram-negative bacilli
lead to increased plasma concentrations ○ bacteremia and septicemia
○ resulting to myocardial depression and ○ Gram-negative bacilli:
arrhythmia Enterobacteriaceae, Acinetobacter and
Pseudomonas species
NOTES (for both): ● used in combination with Staphylococcus aureus
● Toxic level: >40 μg/mL (sum of procainamide ● Administration: 2-3x/ day by IV or IM injection
and NAPA) ● Pulse dosing: 5-7 mg/kg
● Method: immunoassay
 ● Primary Toxicities: ototoxicity and ANTIEPILEPTIC DRUGS
nephrotoxicity ● Used for:
○ Associated with ototoxicity: ○ Treating seizure disorders
■ monitoring serum levels ○ Suppressing seizures
■ symptoms ■ BUT only effective while the drug
● Therapeutic range: metabolites are still inside the
○ Trough level: <2.0 µg/mL body
○ Peak target: 3.0 - 12.0 mcg/mL ● Therapeutic ranges depends on the concentration
■ conventional dosing that will give no or minimal acceptable adverse
effects
C. Tobramycin ● Complicated pharmacokinetics
● used to treat bacteremia and septicemia by ○ Causes interindividual variability
gram-negative bacilli
○ GNB: Enterobacteriaceae and Therapeutic ranges:
Pseudomonas aeruginosa a. First generation AEDs: narrow therapeutic
● Toxicities: ototoxicity and nephrotoxicity ranges
○ Associated with ototoxicity: b. Second generation AEDs: not yet identified
■ monitoring serum levels
■ renal function Therapeutic Drug Monitoring (TDM) on Antiepileptic
■ symptoms Drug
● Baseline: audiology testing ● Used for:
● Therapeutic goal: ○ to establish the therapeutic baseline
○ Trough levels: < 2.0 µg/mL ○ to reassess a modified medication
■ conventional dosing regimen
○ Peak levels: 3.0 - 12.0 µg/mL ○ to assess patient adherence
○ Toxic: >2.0 µg/mL ● Prefers a trough concentration measured at the
end of the dosing interval
D. Amikacin
● used to treat severe blood infections caused by Analyzation of AEDs
susceptible strains of gram-negative bacteria ● Uses immunoassay or chromatography
● induce bacterial death by irreversibly binding ● Normal physiologic state: total AED
bacterial ribosomes to inhibit protein synthesis concentration is sufficient for TDM purposes
● excreted by the kidneys ● Change in physiologic state: free drug
○ accumulate in the kidney at 50-100x the measurement (for causes with change in plasma
serum concentration protein concentrations)
● Administration: oral (to reduce intestinal flora) ○ Examples:
○ Peak serum conc.: seen 30 mins after Iv ■ Pregnancy
infusion / 60 mins after IM administration ■ late-stage renal or hepatic disease
● Serum half-life: 2-3 hours ■ Malnutrition
● Toxicity: Nephrotoxicity ■ A known drug–drug interaction
○ Present as: dizziness, vertigo
○ If severe: ataxia and Meniere disease-like A. Primidone
syndrome ● used for control of grand mal seizures
○ Manifestation: transient proteinuria or ● rapidly absorbed after oral administration
azotemia ○ peak: after 2 hours of administration
● Auditory manifestations: ○ half-life: 8 hours
○ simple tinnitus ● not highly protein bound(only 10%)
○ any degree of hearing loss ● converted to its metabolites (phenobarbital and
● Therapeutic range: phenylethylmalonamide) by the liver
○ Trough level: <8.0 µg/mL ● Steady state:
○ Peak levels: 20.0 - 35.0 µg/mL ○ preferred over phenobarbital (when
needed quickly)
E. Vancomycin ○ happens 2 weeks after initiation
● glycopeptide antibiotic ○ For adults: 5.0 - 12.0 ug/mL
● used against gram-positive cocci and bacilli ● Monitoring: collect specimen before the next
infections dose
● Administration: IV infusion ● Toxicity: due to accumulation of phenobarbital
○ Peak conc.: 1 hour after dosing ● Done to assess the total AED potential
● Plasma protein binding level: ~55% ● Method: Homogeneous Enzyme Immunoassay
● Therapeutic range: 10 - 20 µg/mL
● Adverse effects: B. Phenobarbital
○ Red Man syndrome ● Brand name: Luminal or Solfoton
○ Nephrotoxicity: trough= 20 µg/mL ● slow-acting barbiturate (control several types of
○ Ototoxicity: peak = 40 µg/mL seizures)
● Half-life: 4-6 hours ● absorption of oral dose is slow but complete
● Elimination: renal filtration and secretion ○ Peak: 10 hours after oral dose
● Method: Immunoassay ○ 50% is bound to plasma proteins
○ Half-life: 70 - 100 hours
 ● Blood concentrations do not change dramatically ● Administration: Oral and Gastrointestinal
● Toxic adverse effects: absorption (rapid and complete)
○ drowsiness ● eliminated by hepatic metabolism
○ fatigue ○ induced by other AEDs
○ depression ○ inhibited by felbamate
○ reduced mental capacity ● Adverse effects:
● Eliminated by hepatic metabolism and renal ○ Nausea
filtration ○ Lethargy
● Potential inducer of the hepatic MFO system ○ Weight gain
○ clearance occurs by the hepatic MFO ● Hepatic dysfunction
system ○ still seen in therapeutic levels
● Dosage: ○ markers should be checked during the
○ adjusted after completed induction period first 6 months
○ usually 10-15 days after initial dose ● Therapeutic range: 50-120 ug/mL
● Therapeutic range: 20.0 - 40.0 ug/mL (adults) ● Toxic level: >120 ug/mL (blood concentration)
● Method: Immunoassay techniques ○ elevated (>200 ug/mL): causes
pancreatitis, hyperammonemia, and
hallucinations
C. Phenytoin And Free Phenytoin
● Brand name: Dilantin Circulating Valproic Acid
● for treatment of seizure disorders and short-term a. Protein-bound Valproic acid:
prophylactic agent ○ highly protein-bound (93%)
○ during brain injury to prevent loss of ○ peak: 1 - 4 hours
functional tissue ○ half-life: 11-17 hours (without
● administration: Oral and Gastrointestinal coadministration of other drugs)
absorption (incomplete) ○ decreases in cases of:
○ Peak: 3-12 hours after dosage ■ renal failure
○ Half-life: 6-24 hours ■ in late liver disease
● Eliminated by hepatic metabolism ■ coadministration of drugs that
○ also an inducer of the hepatic MFO compete for its binding sites
pathway
● reduced protein binding is seen in patients with: E. Carbamazepine
○ anemia ● Brand name: Tegretol
○ hypoalbuminemia ● treatment for seizure disorders
○ when coadministered with other drugs ● Serious adverse effects:
with similar binding properties ○ Agranulocytosis
● symptoms of toxicity may still be seen even if ○ Aplastic anemia
dosage is within therapeutic range ● Administration: Oral
● Adverse effects: ● eliminated by hepatic metabolism
○ seizures (most seen) ○ inducer of hepatic metabolism
○ hirsutism ○ Hepatic dysfunction: causes
○ gingival hyperplasia accumulation of carbamazepine
○ vitamin D deficiency ● Dosage adjustments: done by monitoring serum
○ folate deficiency levels
● Small changes in dosage or elimination can have ● Toxicity: diverse and variable
dramatic effects on blood drug concentrations ○ idiosyncratic effects: rashes, leukopenia,
● Therapeutic levels: nausea, vertigo, and febrile reactions
○ Serum: 10-20 ug/mL ● Baseline: Leukocyte count and Liver function
○ Free Phenytoin: 1-2 ug/mL tests
○ Leukopenia and Liver markers are most
Circulating Phenytoin Types: serious and usually seen and result of
a. Free/Unbound Phenytoin discontinuation
○ 10% of phenytoin ● Therapeutic levels: 4-12 ug/mL
○ Biologically active form ○ Toxicity: >15 ug/mL (serum
○ can easily be replaced by high concentratiol)
protein-bound drugs ■ results to aplastic anemia
○ produces an enhanced pharmacological
effect Circulating Carbamazepine
○ readily available to be metabolized to the a. Protein-bound Carbamazepine
liver and cleared quickly ○ 70% - 80% of Carbamazepine
b. Protein-bound drug ○ peak: 4-8 hours
○ usually 87%-90% of phenytoin ○ half-life: 10 - 20 hours
○ mostly bound to albumin
F. Ethosuximide
D. Valproic Acid ● Brand name: Zarontin
● also known as Valproate; brand name: Depakote ● Used for controlling petit mal seizures
● treatment of petit mal and absence of seizures ○ Absence seizure
○ Brief, sudden lapses of consciousness
 ● Oral administration half-life as they eliminate the drug
○ Therapeutic range: 40-100 µg/mL faster than adults
○ Peak concentration: 2-4 hours after dose ● Adverse effects:
● Toxicity associated with high plasma ○ Generally mild
concentrations are rare, tolerable, and ○ Fatigue, ataxia, dizziness, weight gain
self-limiting.
○ Adverse effects: nausea, vomiting, I. Lamotrigine
anorexia, dizziness, lethargy ● Brand name: Lamictal
● Less than 5% is bound to plasma proteins ● Used to treat patient with partial and generalized
● Half-life: 40-60 hours seizures
○ Metabolized in the liver ● Oral administration
○ 20% is excreted through renal infiltration ○ Rapidly and completely absorbed by the
GIT
G. Felbamate ○ Therapeutic range: 2.5-15 µg/mL
● Brand name: Felbatol ○ Peak concentration: 3 hours after
● Used in severe epilepsies in children administration
○ Examples: ● 55% are protein-bound and biologically inactive
(1) Mixed Seizure Disorder ● Half-life: 15-30 hours
(2) Lennox-Gastaut Syndrome ○ Patient undergoing monotherapy
(3) Refractory Epilepsy ● Elimination:
● Oral administration (most common) ○ Hepatic metabolism (majority)
○ Completely absorbed by the GIT ■ Younger infants metabolize slower
○ Therapeutic range: 25-60 µg/mL than older infants
○ Peak concentration: 1-4 hours after dose ■ Children metabolize two (2)
● 30% is bound to plasma proteins times quicker than adults
● Half-life: 14-22 hours ○ Rate of elimination is highly dependent on
○ Eliminated by renal and hepatic patient age and physiologic condition
metabolism ● Clearance:
■ Renal and hepatic function ○ Markedly increase during pregnancy
impairment can cause increased ■ Peak: 32 weeks of gestation
half-life ○ Enzyme-inducers:
○ Enzyme inducers- enhances hepatic ■ Phenobarbital
metabolism and results in decrease ■ Primidone
half-life ■ Phenytoin
■ Phenobarbital ■ Carbamazepine
■ Primidone ○ Inhibitor: Valproic Acid
■ Phenytoin ■ Increase half-life to 60 hours
■ Carbamazepine ● Adverse effects: rash, neurological effects
● Adverse effects: aplastic anemia, hepatic failure (dizziness), GI disturbances

H. Gabapentin J.Levetiracetam
● Brand name: Neurontin ● Brand name: Keppra
● Most frequently used in patients with: ● Used in partial and generalized seizures
(1) Liver disease ● Does not bind to plasma proteins
(2) Acute Intermittent Porphyria ● Completely bioavailable
■ As treatment for partial-onset ● Oral administration
seizures ○ Therapeutic range: 12.0-35.0 µg/mL
● May be administered as a monotherapy or in ○ Peak concentration: 1 hour after dose
conjunction with other AEDs ● Elimination:
○ For patients with complex partial seizures ○ 65% is excreted unchanged by the
and pain management kidneys
● Oral administration ○ Increased: children and pregnant
○ Maximum bioavailability: 60% females
■ Fraction of an administered drug ○ Decreased: elderly
that reaches the systemic NOTE:
circulation ● The need for TDM is of levetiracetam is not as
■ Reduced when antacids are are pronounced as other AEDs due to its lack of
administered concurrently pharmacokinetic variability
○ Therapeutic range: 12-20 µg/mL
○ Peak concentration: 2-3 hours after K. Oxcarbazepine
dosage ● Brand name: Trileptal
● Does not bind to plasma proteins ● Metabolized to licarbazepine
● Half-life: 5-9 hours ● Used in partial seizures and secondarily in
○ Not metabolized in the liver generalized tonic–clonic seizures
○ Eliminated unchanged by the kidneys ● 40% is bound to plasma proteins
■ Children require higher dose than ● Half-life
adults to maintain a comparable ○ Adults: 8-10 hours
○ Children: Higher clearance rate
 ○ Elderly: reduced by 30% ○ Therapeutic failure
● Marked renal dysfunction – reduced
metabolism and clearance N. Zonisamide
● Two active enantiomeric forms: ● Brand name: Zonegran
○ (R)-licarbazepine ● An anticonvulsant used in adjunctive therapy for
○ (S)-licarbazepine partial and generalized seizures
● Adverse effect is similar to carbamazepine ● 60% is bound to plasma proteins and accumulate
● Oral administration in RBC
○ Therapeutic Range: 12 – 35 µg/mL ● Half-life:
○ Peak Concentration: 8 hours after dosing ○ Patients receiving monotherapy: 50 – 70
● Metabolism is sensitive to: hours
○ Phenytoin ○ Together with other enzyme-inducing
○ Phenobarbital AEDs: 25 – 35 hours
● TDM indication: ● Administration: Oral
○ Therapeutic Failure ○ Therapeutic range: 10 – 40 μg/mL
○ Suspected drug-drug interaction ○ Peak concentration: 4 – 7 hours
○ During pregnancy ● Metabolism in the liver:
○ Acetylation
L. Tiagabine ○ Oxidation
● Brand name: Gabitril ○ Glucuronide conjugation
● Used for partial seizures ○ Renal excretion
● Approximately 96% are protein bound ● Symptoms of toxicity:
● Half-life: 4-13 hours ○ Difficulty
● GI absorption is rapid and nearly complete ○ Breathing
● Highly metabolized by hepatic MFO pathway ○ Low blood pressure
● Hepatic dysfunction – increase half life ○ Slow heart rate
● Factors that affect the ratio of free to bound drug: ○ Possible loss of consciousness
○ Valporic acid ● TDM indication:
○ naproxen ○ Steady state is reached
○ salicylates ○ Detect drug-drug interaction
○ pregnancy ○ Therapeutic failure
● Administration: Oral Note:
○ Therapeutic range: 20 to 100 ng/mL ● Clinicians should use caution when treating
○ Peak Concentration: 1 – 2 hours after patients with liver or kidney disease because
dosing blood zonisamide concentrations may rise in
● Adverse CNS side effect: direct proportion to the severity and type of organ
○ Stuttering dysfunction.
○ Mild sedation
○ Paresthesia
● TDM indication: PSYCHOACTIVE DRUGS
○ intraindividual and interindividual
variations A. Lithium
● Mood-altering drug
M. Topiramate ● Cationic metal that does not bind to proteins
● Brand name: Topamax ● Lithium is orally administered
● Used for partial and generalized seizures ○ Rapidly absorbed by the GI
● 15% bound to plasma proteins and almost ○ Peak blood conc. After 2 to 4 hours after
completely bioavailable administering lithium
● Half-life: 20 – 30 hours ● Half-life: 10 - 35 hours
● Majority is eliminated by renal filtration ○ Eliminated predominantly by the renal
● Administration: Oral filtration
○ Therapeutic range: < 25 mg/L ● Primarily Uses:
○ Peak concentration: 1 – 4 hours after ○ Bipolar disorder
dosing ○ Recurrent depression
● Dose-to-blood concentration ratio ○ Aggressive or self-mutilating behavior
○ Children: lower concentration ● Other uses:
○ Adults: higher concentration ○ Preventative treatment for migraines and
● Increased in blood concentration is secondary to cluster headaches
secondary to renal insufficiency ● Compromises in renal function
● Decreased in blood concentration when used with ○ resulting lithium accumulation
other enzyme-inducing AEDs
● Adverse CNS side effects: Therapeutic Drug Monitoring for Lithium
○ change of taste (e.g., diet soda and beer) ● Therapeutic range: 0/5 - 1.2 mmol/L
○ sensation of “pins and needles” in the ● Avoid toxic effects associated with high blood
extremities concentration
● TDM indication: ● Lithium conc.: 1.5 to 2 mmol/L
○ Steady state is reached ○ Can cause:
○ Detect drug-drug interaction ■ Apathy Lethargy
 ■ Speech difficulties ○ Approximately 97% circulating drug is
■ Muscle weakness bound to plasma proteins
● Lithium conc.: >2 mmol/L ● Peak: 2 hours of administration
○ Can cause: ● Half-life: 8 to 16 hours
■ Renal impairment ● Beneficial effect of Clozapine: 350 – 420
■ Hypothyroidism ng/mL
■ CNS disturbances ● TDM can indicate to check for adherence and
patient with altered pharmacokinetics
Laboratory Analyses ● TDM can be used to avoid the toxicity of the
● Colorimetric method Clozapine
○ most commonly used
○ Replaced by the older methods: D. Olanzapine
■ Flame photometry ● Olanzapine (Zyprexa) is a
■ ISE thienobenzodiazepine derivative
■ AAS ● Effectively treats:
○ Interference: Lithium anticoagulants ○ Schizophrenia
○ Acute manic episodes
B. Tricyclic antidepressants (TCAs) ○ Recurrent of bipolar disorder
● Drugs that are mainly use for antidepressant ● Administration of Drugs though:
● Class of drugs that are used to treat: ○ Fast acting intramuscular injection
○ Depression ○ Orally – more common
○ Insomnia ● Absorbed well in the GI Tract
○ extreme apathy ○ 40% is inactivated by first-pass
○ loss of libido metabolism
● Most commonly monitored TCAs: ● Peak: 5 – 8 hours
○ Desipramine and Nortriptyline ○ Approximately 93% is bound to plasma
● Peak: 2-12 hours proteins in circulation
● Approximately 85% to 95% TCAs are protein ● Half-life: 21 to 54 hours
bound
● Half-life: 17 to 14 hours Therapeutic Drug Monitoring of Olanzapine
● TCAs are orally administered but varying degree ● Olanzapine (Zyprexa) is a thienobenzodiazepine
of absorption ● Therapeutic range: 20 – 50 ng/mL
● The rate of elimination can also be influenced by ● Adverse effects of Olanzapine:
coadministration of other drugs ○ Tachycardia
○ TCAs are eliminated by Hepatic ○ Decreased consciousness
metabolism ○ Possible coma

Therapeutic Drug Monitoring for TCAs

● Toxicities of TCAs are dose dependent IMMUNOSUPPRESSIVE DRUGS
● Serum concentration twice the upper limit of the ● used to prevent organ rejection
therapeutic range can cause: ● it require establishment of individual dosage
○ Drowsiness regimens
○ Constipation ○ to optimize therapeutic outcomes and
○ Blurred vision minimize toxicity
○ Memory loss
● Even higher levels can cause: A. Cyclosporine
○ Seizure ● Brand name: Gengraf, Neoral, Sandimmune
○ Cardiac arrhythmia ● a cyclic polypeptide
○ Unconsciousness ● has a potent immunosuppressive activity
● Clinical use: suppression of host-versus-graft
Laboratory Analyses rejection of heterotopic transplanted organs
● TCAs should not be evaluated until a steady state ● Administration: oral
has been achieved ○ absorption rate: 5-50%
● Immunoassay ○ peak conc.: 1-6 hours
○ Use polyclonal antibodies ○ poor oral dosage and blood concentration
○ It is used for TCA screening rather than relationship
TDM ● >98% of circulating cyclosporine is protein-bound
● Chromatographic Methods ○ cyclosporine appears to sequester in cells,
○ Provide simultaneous evaluation of both including erythrocytes
parent drugs and their metabolites ○ evaluation of blood cyclosporine
○ Provides basis for unambiguous concentrations requires rigorous control of
interpretation of results specimen temperatures (highly temperature
dependent RBC content)
C. Clozapine ● whole blood specimens are used
● Brand name: (Clozaril/FazaClo) ● Half-life: approx. 12 hours
● Clozapine is an antipsychotic used in the ● Trough conc.: 100 to 400 ng/mL
treatment-refractory schizophrenia ● Toxic level: >400 ng/mL
● Absorption is rapid and almost complete ● Toxic adverse effects:
 ○ renal tubular and glomerular dysfunction ● Therapeutic range:
■ may result in hypertension ○ 4 to 12 μg/L – sirolimus with cyclosporine
● Eliminated by: hepatic metabolism ○ 12 to 20 μg/L – used if cyclosporine therapy
● Methods: is not used or discontinued
○ immunoassays ● Methods:
○ chromatographic methods ○ chromatographic methods
■ provide separation and quantitation of ○ HPLC-MS
the parent drug from its metabolites
D. Everolimus
B. Tacrolimus ● derived from sirolimus (rapamycin)
● aka Tacrolimus FK-506 ● allows rapid achievement of steady-state
● Brand name: Astagraf, Envarsus, Hecoria, pharmacokinetics
Prograf ● metabolized by CYP3A4
● 100x more potent than cyclosporine ● Adverse effect:
○ both drugs appear to have comparable ○ hyperlipidemia
degrees of nephrotoxicity ○ thrombocytopenia
● whole blood is the preferred specimen for ○ nephrotoxicity
tacrolimus TDM ● FDA approved for prophylaxis of graft rejection in
● Bound to proteins: >98% solid organ transplant
● Administration: orally ● Target trough level: between 3 and 8 ng/mL
○ peak conc.: 1-3 hours ● Method: Liquid chromatography-Tandem Mass
● Half-life: 10-12 hours spectrometry
● Therapeutic range: 5–15 ng/mL ● Sample: Whole blood
● Toxic level: >15 ng/mL
○ thrombus formation E. Mycophenolic Acid
● Toxic adverse effects: ● active form of Mycophenolate mofetil
○ anemia ○ Mycophenolate mofetil - prodrug
○ leukopenia converted in the liver
○ thromobocytopenia ● lymphocyte proliferation inhibitor
○ hyperlipidemia ● used as supplemental therapy with cyclosporine
● Eliminated: exclusively by hepatic metabolism and tacrolimus
○ its metabolites are primarily secreted into ● Administration: oral
bile for excretion ○ Peak conc.: 1-2 hours after dosing
● ↑ immunoreactive tacrolimus: cholestasis ● Circulation: MPA is 95% protein-bound
● Methods: ● Elimination:
○ HPLC-MS (most common) ○ Renal excretion: >90%
○ immunoassays ● Half-life: ~ 17 hours
● Therapeutic range: 1 - 3.5 µg/mL
C. Sirolimus ● Increased levels effects:
● aka Rapamune ○ nausea
● an antifungal agent with immunosuppressive ○ vomiting
activity ○ diarrhea
● used to prevent graft rejection in patients ○ abdominal pain
receiving a kidney transplant ● Method:
● extremely potent and requires TDM due to its ○ LC-MS/MS
inherent toxicity ○ immunoassay (common, less specific)
● Bound to lipoproteins (rather than plasma):
approx. 92%
● Administration: oral ANTINEOPLASTICS
○ peak conc.: 1-2 hours ● Pharmacodynamics are hard to establish
○ metabolized in the liver ● rapidly metabolized or incorporated into cellular
● To increase the therapeutic efficacy, it is structures within seconds to minutes
coadministered with: ● administered intravenously
○ cyclosporine – bioavailability of sirolimus is ○ as a single bolus
15% ○ actual delivered dose is more relevant
○ tacrolimus than circulating dose
● Half-life: 62 hours
● Toxic adverse effects: A. Methotrexate
○ thrombocytopenia ● Brand name: Otrexup, Rasuvo
○ anemia ● Inhibits DNA synthesis
○ leukopenia ● Administration: Oral
○ infections ○ peak: 1 hour
○ hyperlipidemia ○ half-life: 5-9 hours
● whole blood is the ideal specimen for analysis ● Protein-bound methotrexate (50%)
● Subsequent monitoring is performed by ● Effective therapy: high-dose methotrexate and
collecting trough specimens on a weekly basis for leucovorin
the first month, followed by a biweekly sampling ○ involves the relative rate of mitosis of
pattern in the second month normal versus neoplastic cells
 ○ dependent on controlled inhibition
○ Leucovorin: reverses action of
methotrexate (Leucovorin rescue)
● Neoplastic cells
○ divide more rapidly
○ higher requirement for DNA
○ susceptible to depravation
● Evaluation:
○ done after the inhibitory time
○ determines how much leucovorin is
needed to counteract toxic effects of
methotrexate
● High dose therapy:
○ 24 hours: >10 umol/L
○ 48 hours: >1 umol/L
○ 72 hours: >0.1 umol/L
● Trough serum specimen:
○ preferred for determination of
methotrexate concentrations
○ 48 hours: <1 umol/L

BRONCHODILATORS
A. Theophylline
● Also known as:
○ Theo-Dur
○ Theo-24
○ Uniphyl
● Used in the treatment of:
○ Asthma
○ Stable COPD
● Peak: 1-2 hours
● Approximately 50% to 65% circulating drugs is
bound to plasma proteins
● Half-life: 3 to 8 hours
● Predominantly metabolized in the liver
○ 20% eliminated through the renal system

Therapeutic Drug Monitoring of Theophylline

● Beneficial effects: 10 to 20 ug/L
● Serious adverse effects: >20ug/L
○ Insomnia
○ Tachycardia
○ Seizures
○ Arrhythmias
○ Cardiorespiratory arrest

SPECIMEN CONSIDERATIONS
1. Trough concentration are drawn immediately or 30
mins before the next dose
● Trough concentration reflects the lowest
level of drug in the blood
● The trough level is affected by the drug
clearance rate - ( if clearance increase,
then trough level decrease)
2. Peak concentration are drawn one hour after an
orally administered dose
● Except: Digoxin
● The peak blood sample (sample after
absorption and distribution is complete) is
the best specimen for initial investigation
of therapeutic drug toxicity
● For IV drugs, peak levels are determined
after the infusion is completed