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Therapeutic Drug Monitoring

Definition: analysis, assessment, & evaluation of circulating

concentrations of drugs in serum, plasma, or whole blood
Purpose: to ensure that a given drug dosage produces maximal
therapeutic benefit & minimal toxic adverse effects
Used when safe dosage regimens have not been established & a
trial & error approach is not appropriate
Standard dosage derived from observations in healthy population.
Involves quantitative evaluation of circulating drug concentration
Key factors: route of administration, rate of absorption,
distribution of drug within body, rate of elimination
Overview of factors that influence the circulating concentration of an
orally administered drug

Intravenous (IV): injected directly into
Intramuscular (IM): injected into muscle
Subcutaneous (SC): injected just under skin
Transcutaneous: inhaled or absorbed through
Suppository: rectal delivery
Oral Administration: by mouth

For orally administered drugs, efficiency of
absorption from GI tract depends on many
Formulation of drug: tablets, capsules, liquid solutions
Uptake by transport mechanisms intended for dietary constituents
vs. passive diffusion
Changes in intestinal motility, pH, inflammation, food, other drugs
Variation among population
Age, pregnancy, pathologic conditions

Free vs. Bound
Only free (unbound) fraction of drug can interact with site of
action & cause biologic response.
Percentage free depends on physiologic & biochemical
Inflammation, malignancies, pregnancy, hepatic disease,
nephrotic syndrome, malnutrition, acidbase disturbances
Concentration of other substances competing for binding sites
Drug Distribution
Ability of drug to diffuse out of circulation
Depends on lipid solubility of drug

Rate of change of drug concentration over
time varies continuously in relation to
concentration of drug.
Elimination equation: C/T = -kC
Metabolic Clearance
Hepatic mixed function oxidase (MFO) system
Converts hydrophobic substances into water-soluble ones
Transports them into bile or circulation, eliminates them by
renal filtration
Renal Clearance

First-order drug elimination

Mathematic modeling of drug concentration in circulation
Assists in establishing or modifying a dosage regimen
Takes into account all factors that determine concentration of a
serum drug & its rate of change (absorption, distribution,
elimination, etc.)
Sample Collection
Timing is critical: trough concentrations, right before next dose;
peak concentrations, 1 hour after oral dose
Serum or plasma is specimen of choice.

Responders: patients benefitting from
therapeutic & desired effects of drug
Non-responders: patients not benefitting
from therapeutic & desired effects of drug
Therapeutic effectiveness of drugs has been
attributed to inter-individual variation in
genetic polymorphisms of drug metabolism
Cytochrome P450: gene group family that
affects drug metabolism

Cardiac Glycosides
Purpose: used in treatment of congestive heart failure
Function: inhibits membrane Na-K-ATPase
Absorption: variable, influenced by dietary factors, GI motility,
formulation of drug
Elimination: renal filtration of plasma free form
Half-life (plasma): 38 hours in average adult
Measurement: immunoassay to determine total concentration in

Most common formulations are quinidine sulfate & quinidine
Used as a quinidine substitute when quinidines adverse effects
are excessive

A group of chemically related antibiotics used for treatment of
infections with gram-negative bacteria that are resistant to less
toxic antibiotics
Most common: gentamicin, tobramycin, amikacin, kanamycin
A glycopeptide antibiotic that is effective against gram-positive
cocci & bacilli

First Generation
A slow-acting barbiturate that effectively controls several types
of seizures
A commonly used treatment for seizure disorders
Used as a short-term prophylactic agent in brain injury to
prevent loss of functional tissue
Valproic acid
Used as a monotherapy for treatment of petit mal & absence

First Generation
An effective treatment in various seizure disorders
Because of its serious toxic adverse effects, it is less frequently
Used for control of petit mal seizure
Second Generation
An orally administered drug that is nearly completely absorbed
by the GI tract
Known for its toxicity & is primarily indicated in severe
epilepsies such as Lennox-Gastaut syndrome (children) &
refractory epilepsy (adults)
May be indicated as monotherapy or in conjunction with other
antiepileptic drugs in patients suffering from complex partial
seizures with or without generalized seizures
Second Generation
Indicated in partial & generalized seizures
A pro-drug that is almost immediately metabolized to
Indicated for monotherapy of partial seizures & in secondarily
generalized tonic-clonic seizures
Second Generation
Indicated in partial seizures
Indicated in partial & generalized seizures
Indicated in partial & generalized seizures
Lithium: orally administered; used to treat manic
Tricyclic Antidepressants: a class of drugs used
to treat depression, insomnia, extreme apathy, &
loss of libido
Clozapine: an atypical antipsychotic used to treat
otherwise treatment-refractory schizophrenia
Olanzapine: a thienobenzodiazepine derivative
that effectively treats schizophrenia, acute manic
episodes, & recurrence of bipolar disorders

Cyclosporine: Primary clinical use is suppression
of host-versus-graft rejection of heterotropic
transplanted organs.
Tacrolimus: 100 times more potent that
Sirolimus: an antifungal agent with
immunosuppressive activity; FDA approved for
patients receiving kidney transplants
Mycophenolic Acid: a lymphocyte proliferation
inhibitor; used most commonly as supplemental
therapy with cyclosporine & tacrolimus in renal
transplant patients
One of few antineoplastic drugs in which TDM offers benefits to a
therapeutic regimen
High-dose methotrexate followed by leucovorin rescue has been
shown to be an effective therapy for various neoplastic conditions.
Basis of this therapy involves relative rate of mitosis of normal vs.
neoplastic cells.
Neoplastic cells divide more rapidly than normal cells, have higher
requirement for DNA, and are susceptible to deprivation of this
essential constituent before normal cells.
Efficacy depends on controlled period of inhibition, accomplished
by leucovorin.