CLINICAL CHEMISTRY THERAPEUTIC DRUG MONITORING (TDM) OUTLINE • Therapeutic Drug Monitoring o Adsorption o TDM Drugs o Therapeutic Drug Monitoring o Laboratory Methods for Substance of Abuse THERAPEUTIC DRUG MONITORING • Therapeutic drug monitoring (TDM) involves the coordinated effort of several health professionals to measure and monitor circulating drug levels primarily in serum, plasma, or whole blood. After the physician has ordered TDM, laboratory personnel involved in the timing of blood collection, the measurement of drug levels, and reporting of these data play a critical role in achieving safe and effective patient drug therapy. • Must be monitored to determine what doses are inadequate or excessive in the treatment of the patient. Often, th e ingested drug (called the “parent” drug) is metabolized to form an active metabolite that produces an effect similar to the parent drug. ADSORPTION • The efficiency of absorption from the gastrointestinal tract to its bioavailability in the bloodstream is dependent on many factors including: o dissociation from its administered form o solubility in gastrointestinal fluids and o diffusion across gastrointestinal membranes. Tablets & capsules require dissolution before being absorbed. TDM DRUGS CARDIOACTIVE DRUGS • Are divided into two categories: the cardiac glycosides and the antiarrhythmic drugs. These agents serve to maintain normal heart function. • Digoxin is the major cardiac glycoside and alters the force of contraction through its effect on the ATPase pump in heart muscle. o Blood specimens must be collected 8 hours after a dose of digoxin is administered, because its peak concentration in tissue occurs 6 to 10 hours after administration. o Digoxin toxicity produces symptoms of nausea, rapid heart rate, and visual impairment. Digoxin is excreted as digoxigenin in the urine. • The anti arrhythmic drugs are prescribed to treat irregular heart beat that produces inappropriate ventricular contraction or tachycardia (increased heart rate). o Lidocaine is used for the treatment of faulty ventricular contractions and arrhythmias. It binds to α1-acid glycoprotein and is metabolized in the liver, producing two active metabolites, monoethylglycinexylidide and glycinexylide. o Procainamide is used to treat inappropriate eventricular contractions and tachycardia. ▪ Procainamide is metabolized in the liver to form an active metabolite, Nacetylprocainamide, which produces the same effect as its parent drug. Therefore, serum levels of both drugs must be analyzed. o Disopyramide stabilizes the heartbeat. It is both excreted by the renal system as the unchanged drug and is metabolized in the liver to form an inactive metabolite. o Quinidine is a myocardial depressant that decreases the heart’s ability to conduct current. It is metabolized in the liver to produce several active metabolites, including 3-hydroxyquinidine. If quinidine is added to a digoxin therapy regimen, an interaction occurs that induces an increase in digoxin concentration. o Propranolol is prescribed for atrial and ventricular arrhythmias and hypertension. It is considered to be a beta-blocker. ANTICONVULSANTS • Function to alter transmission of nerve impulses within the brain to minimize the seizures of epilepsy. • Phenobarbital is used to treat all types of seizures except absence seizures. It is effective in children and neonates. It is metabolized in the liver, and serum concentrations increase during the administration of valproic acid or salicylic acid. • Phenytoin corrects grand mal seizures. It is metabolized by the liver and can interact with several drugs that induce increased serum concentration or increased metabolism of phenytoin. • Valproic acid is prescribed for absence (petit mal) seizures. Valproic acid affects many others anticonvulsants by inhibiting their metabolism in the liver, thus increasing serum concentration. • Primidone is metabolized in the liver to form phenobarbital. Therefore, dual analyses must be performed to determine the proper dosage of this drug. It is used to treat both grand mal and complex-partial seizures. • Carbamazepine is typically used for treatment of various seizures and facial pain. • Ethosuximide is prescribed for the treatment of petit mal seizures. BRONCHODILATORS • Act to relax bronchial smooth muscle for relief or prevention of asthma. Theophylline is the most common in this category of therapeutic drugs and is metabolized in the liver to produce several metabolites, including caffeine. PSYCHOTROPIC OR ANTIPSYCHOTIC DRUGS • Are used to treat psychotic patients. They can be categorized in two classes: lithium and the antidepressants. • Lithium treats manic-depressive illness. The mechanism of action of lithium as a mood stabilizer remains unknown, although effects on synaptic neurotransmission are thought to be the cause.
o Lithium is ﬁltered by the renal glomerulus and eliminated as the unchanged drug. • Antidepressants, or tricyclic antidepressants , are used to treat depression that has no apparent organic or social cause. Antidepressants include imipramine, nortriptyline, amitriptyline, and desipramine, all of which are metabolized by the liver to form active metabolites. o The active metabolites include desipramine (parent is imipramine), nortriptyline (parent is amitriptyline), and 2-hydroxy-desipramine (parent is desipramine). • Fluoxetine is not chemically related to the tricyclic antidepressants, but has a similar effect by blocking serotonin uptake by nerve terminals in the CNS and by platelets. ANTINEOPLASTIC DRUGS • Are used in the management of certain tumors, including those found in breast, testicular, pharyngeal, and sometimes lung cancer. • These agents work by inhibiting DNA synthesis. THERAPEUTIC DRUG MONITORING (TDM) • Is performed to determine patient compliance to the drug-taking regimen, to monitor drug interactions, and to monitor drugs that are used for a preventive effect. • Liberation is the release of this ingredient, followed by the process of the drug passing into solution. • Absorption is the process by which the drug molecule is taken up into systemic circulation. Following absorption through the intestinal mucosa, a drug traverses the hepatic system, where some drugs undergo substantial metabolism and elimination. This is called ﬁrst-pass elimination or metabolism. • Drug molecules can be conﬁned to the blood, leave the bloodstream, and enter the extravascular space, or they can migrate into various tissues. This is referred to as distribution , a process that typically occurs between a period of 30 minutes and 2 hours. o The bioavailability of a drug is the amount of drug that is absorbed into the system and is available for distribution. • Metabolism is the process of transformation of the parent drug molecule to its metabolite(s). Metabolites are usually water soluble and can be easily excreted. o Most of metabolism occurs in the liver, where enzymes catalyze oxidation, reduction, or hydrolysis of the drug. • Elimination is the process of excretion of the drug from the body. Drugs are typically excreted in the urine but also can be eliminated in the feces, sweat, expired air, and saliva. BASIC PRINCIPLES. • TDM measures drug concentrations during therapy with pharmaceutical agents. • A steady-state drug level (complete with peaks and troughs) exists for each drug. When a single dose of a drug is administered orally, the blood level changes markedly over time and, at some time, the concentration in the plasma reaches its peak (highest point) and then declines. Immediately before the next dose of medication, a trough level occurs. • For single-dose administration, the rate of decline in concentration is expressed in terms of half-life, which is the time required for the concentration of the drug to decrease by 50% (Figure 1 –6). • The half-life is different for each drug. (2) At steady-state levels, the rate of administration of the drug is equal to the rates of metabolism and excretion, allowing the drug level to remain constant. PHARMACOKINETICS • Pharmacokinetics is the mathematical interpretation of drug disposition overtime to determine proper dosing amounts of a therapeutic drug. Pharmacokinetic responses are typically graphic plots of blood concentration of the drug versus time, such as a dose-response curve (see Figure 1 –6). • Three kinetic processes are used to describe the fate of drugs in the body over a period of time and can be illustrated in a dose-response curve. o First-order kinetics describe absorption, distribution, and elimination of drugs. This means that the rate of change of concentration of a drug is dependent on the drug concentration. It is represented by the ﬁrst phase of the dose-response curve. o Zero-order kinetics describe the rate of change of concentration of a drug that is independent of the concentration of the drug. That is, a constant amount of drug is eliminated per unit of time. This typically depends on the ability of the liver to metabolize the drug. This is illustrated by the second phase of the curve. o Michaelis-Menten kinetics state that if a drug concentration in a system exceeds the capacity of the system, the rate of change of concentration proceeds according to the Michaelis-Menten equation. LABORATORY METHODS FOR SUBSTANCE OF ABUSE • Include a variety of compounds that, when found in high levels in the urine or serum, can incriminate an individual. It is mandatory in substance-of-abuse analysis to obtain a satisfactory specimen and to process the specimen in a secure part of the laboratory. • Laboratory analysis of therapeutic drugs includes enzyme immunoassays and ﬂuorescence-polarized immunoassays. • Gas chromatography and high-pressure liquid chromatography are also used, particularly as conﬁrmatory tests when a screening test is positive. • Serum is typically the specimen of choice for drug analysis, but urine metabolites are measured in some cases, particularly in screening tests.