Therapeutic Drug Monitoring
Therapeutic drug monitoring (TDM), or simply drug monitoring, is the measurement of drug levels in the blood.
TDM is employed to measure blood drug levels so that the most effective dosage can be determined and toxicity can be prevented. Drug monitoring is not needed for most drugs. Many drugs have a wide therapeutic window, meaning that the difference between the therapeutic and toxic level is large. Often, the physician can measure an expected outcome to see if a drug is working. For example, body temperature can be measured to evaluate an antipyretic drug. Monitoring is mainly used for drugs that can be toxic or cause severe side effects. Examples are antiepileptic drugs, antiarrhythmic agents, oral anticoagulants, theophylline, tricyclic antidepressants, lithium, antineoplastics, aminoglycoside antibiotics, cardiac glycosides, and drugs to prevent transplant rejection. TDM is also utilized to identify noncompliant patients (i.e., those patients who, for whatever reason, either cannot or will not comply with drug dosages as prescribed by the physician).
Many different factors influence blood drug levels, and the following points should be taken into consideration during TDM: the age, sex, and weight of the patient; the route of administration of the drug; the drug's absorption rate, excretion rate, delivery rate, and dosage; other medications the patient is taking; other diseases the patient has; the patient's compliance regarding the drug treatment regimen; and the laboratory methods used to measure the drug.
Drugs taken orally should not be measured until the processes of absorption and elimination have nearly reached a steady state. The steady state is reached when the drug in the next dose is sufficient to replace the drug that is eliminated. This requires approximately five drug
TDM is a practical tool that can help the physician provide effective and safe drug therapy in patients who need medication. Monitoring can be used to confirm that a blood drug concentration is within the therapeutic range. If the desired therapeutic effect of the drug is not as expected, two blood levels can be used to determine the drug's half-life in the body. This data along with dose information can be used to calculate the change in dose or dosing interval needed to bring the concentration into the therapeutic range.
Blood drug levels are influenced by five processes: liberation, absorption, distribution, metabolism, and excretion. Liberation is the release of the drug in the body (usually the gastrointestinal tract) and absorption is the transport of the drug to the blood. These variables determine the fraction of the dose that is bioavailable. Many drugs are absorbed by the portal circulation and transported directly to the liver, where they are partly metabolized to inactive forms. This process reduces the amount of drug available to the target tissues. Distribution refers to the volume of body fluids in which the drug becomes diluted. Metabolism refers to the chemical transformation of the drug performed by the liver. Most drug metabolites are water soluble and removed by the kidneys. Individual differences in any of these processes alters the relationship between dose and drug blood levels, called drug pharmacokinetics. For example, persons with decreased renal function will have a longer drug half-life (decreased clearance) causing the blood level (and tissue level) of drug to be higher than expected. Drugs in the blood are mainly protein-bound, and therefore, inactive. Decreased albumin, abnormal blood pH, or displacement of one drug by another may alter protein binding increasing the blood level of free (active) drug. Persons may metabolize a drug more slowly than expected due to genetic factors or liver disease. Smoking, stress, and drug formulation (generic versus trade name) can alter pharmacokinetic properties, making some drugs ineffective or toxic at usual doses. In such cases TDM can explain the discordance between dose and outcome and provide data needed to safely make changes in drug administration.
Blood specimens for drug monitoring can be taken at two different times, called peak and trough levels. Blood for peak level is collected at the drug's highest therapeutic concentration within the dosing period. For drugs given intravenously, the peak level is drawn 30 minutes after completion of the dose. For drugs given orally, this time varies with the drug because it is dependent upon the rates of absorption, distribution and elimination. For intravenous drugs, peak levels can be measured immediately following complete infusion. Trough levels (occasionally called residual levels) are measured just prior to administration of the next dose, and are the lowest concentration in the dosing interval. Too low a dose or too great a dose interval will produce a trough level that is below the therapeutic range, and too great a dose or too close a dose interval will show a peak level greater than the therapeutic range. Most therapeutic drugs have a narrow trough to peak difference, and therefore, only trough levels are needed to detect blood levels that are too low or too high. Peak levels are needed for some drugs, especially aminoglycoside antibiotics. A concentration below the therapeutic range will not resolve the bacterial infection. However, too high a level can cause damage to the kidneys, bone marrow, and acoustic nerves.
Many methods are available to measure the concentration of specific drugs. The most widely used methods are immunoassay and chromatography.
In preparing for this test, the following guidelines should be observed:
- For patients suspected of symptoms of drug toxicity, the best time to draw the blood specimen is when the symptoms are occurring.
- If there is a question as to whether an adequate dose of the drug is being achieved, it is best to obtain trough levels.
- Peak (highest concentration) levels are usually obtained 30 minutes after an intravenous dose, one hour after intramuscular (IM) administration, and approximately one to two hours after oral dosing. However, slow-release formulas for many drugs will not produce peak levels for several hours after ingestion.
|THERAPEUTIC DRUG MONITORING: THERAPEUTIC AND TOXIC RANGE|
|Drug Level*||Use||Therapeutic Level*||Toxic|
|* Values are laboratory-specific.||**Concentration obtained 30 minutes after the end of a 30-minute infusion.|
|Aceteminophen mg/ml||Analgesic, antipyretic||Depends on use||>250|
|Amikacin mg/ml||Antibiotic||12-25 mg/ml**||>25|
|Aminophylline ng/ml||Bronchodilator||10-20 mg/ml||>20|
|Amitriptyline ng/ml||Antidepressant||120-150 ng/ml||>500|
|Carbamazepine mg/ml||Anticonvulsant||5-12 mg/ml||>12|
|Chloramphenicol mg/ml||Antibiotic||10-20 mg/ml||>25|
|Digoxin ng/ml||Cardiotonic||0.8-2.0 ng/ml||>2.4|
|Gentamicin||Antibiotic||4-12 mg/L||>12 mg/L|
|Lidocaine||Antiarrhythmic||1.5-5.0 mg/ml||>5 mg/ml|
|Lithium mEq/L||Antimanic||0.7-2.0 mEq/L||>2.0|
|Nortriptyline ng/ml||Antidepressant||50-150 ng/ml||>500|
|Phenobarbital mg/ml||Anticonvulsant||10-30 mg/ml||>40|
|Phenytoin mg/ml||Anticonvulsant||7-20 mg/ml||>30|
|Procainamide mg/ml||Antiarrhythmic||4-8 mg/ml||>16|
|Propranolol ng/ml||Antiarrhythmic||50-100 ng/ml||>150|
|Quinidine mg/ml||Antiarrhytmic||1-4 mg/ml||>10|
|Theophylline mg/ml||Bronchodilator||10-20 mg/ml||>20|
|Tobramycin mg/ml||Antibiotic||4-12 mg/ml**||>12|
|Valproic acid mg/ml||Anticonvulsant||50-100 mg/ml||>100|
Absorption—Uptake of drug into the circulation.
Bioavailability—The amount of drug in a dosage that can be absorbed by the patient.
Distribution—The division of the drug into different parts of the body such as the liver, blood, spinal fluid, and urine.
Elimination—The final excretion of a drug and its metabolites.
Half-life—The amount of time that is needed to reduce a drug level to one half of what was absorbed in the blood.
Maintenance dose—The amount of drug that is needed to keep the patient's blood levels at a steady state.
Metabolism—The breakdown of a drug into its metabolites.
Metabolites—Compounds that the drug is broken down into, usually done by the liver.
Peak concentration—The highest level of drug reached in the blood.
Slow release—A preparation of the drug that allows for slow absorption, over hours or days.
Therapuetic range—Levels of a drug that will yield the desired effect without toxicity.
Toxic—Poisonous, a drug is toxic when levels in the body are too high.
Trough concentration—The lowest level of a drug in the plasma, usually seen right before the next dose is given.
Risks for this test are minimal, but may include slight bleeding from the blood-drawing site, fainting or feeling lightheaded after blood is drawn, or accumulation of blood under the puncture site (hematoma).
Bruising may occur at the puncture site or the person may feel dizzy or faint. Pressure should be applied to the puncture site until the bleeding stops to reduce bruising. Warm packs can also be placed over the puncture site to relieve discomfort. Drug dose, dosing schedule, or medication changes may be required, if the blood drug level is outside the therapeutic range.
Health care team roles
Physicians will determine the initial dose of drug. A nurse or phlebotomist collects the specimen by venipuncture documenting the time of draw. Pharmacists may assist by providing information about drug half-life, recommended peak collection time, therapeutic ranges, side-effects, and drug interactions. Clinical laboratory scientists, CLS (NCA)/medical technologists, MT (ASCP) or clinical laboratory technicians, CLT (NCA) or medical laboratory technicians, MLT (ASCP) perform drug assays. They are responsible for notifying the physician when critical values are exceeded.
Patients should be educated on the importance of complying with their physician's orders for medications, and should be told to report any complications or side effects they may experience. Patients should also be told about the frequency of their drug monitoring tests, and why keeping their appointment is important.
Burtis, Carl A. and Edward R. Ashwood. Tietz Fundamentals of Clinical Chemistry, Fourth Edition. Philadelphia: W.B. Saunders, 1999.
Kaplan, Lawrence A. and Amadeo J. Pesce. Clinical Chemistry, Theory, Analysis and Correlation, Third Edition. St. Louis: Mosby Publishing, 1996.
Lane, Keryn A.G. The Merck Manual of Medical Information. Merck Research Laboratories, 1997.
Pagana, Kathleen D. Mosby's Manual of Diagnostic and Laboratory Tests. Mosby, Inc., 1998.
Jane E. Phillips