Tiêu đề 10. TDM OF DRUGS USED IN CARDIOVASCULAR DISEASE.pdf ✅

PHARMD GURU Page 1 INTRODUCTION:  Therapeutic drug monitoring refers to the individualization of dosage by maintaining plasma or blood drug concentrations within a target range (Therapeutic range, therapeutic window).  It manages the drug therapy in individual patient often requires evaluation of response of the patient to the recommended dosage. FUNCTIONS:  Select drug.  Design dosage regimen.  Evaluate patient response.  Determine need for measuring serum concentration.  Assay for drug concentration in biological fluids.  Perform pharmacokinetic evaluation of drug concentration.  Re-adjust the dosage regimen. CONCEPT OF THERAPEUTIC DRUG MONITORING:  TDM is based on the principle that for some drugs there is close relationship between the plasma level of the drug and its clinical effect.  The main aim of therapeutic drug monitoring is to find out an effective medication against the disease without any dangerous toxic action.  The purpose of TDM is to individualize the dosage to achieve maximum efficacy of a drug and at the same time minimize adverse drug reactions. ANALYTICAL METHODOLOGYOF TDM:  The fundamental procedures necessary for the quantification of the drug in the body are: recovery from body fluids, tissues, and organs, separation from the biological components, identification of the species concerned and finally quantification.  The analytical methodology employed should ideally:  Distinguish between compounds of similar structure unchanged drug and metabolites. TDM OF DRUGS USED IN CARDIOVASCULAR DISEASE
PHARMD GURU Page 2  Detect small amounts.  Be simple enough to use as a routine assay and  Be unaffected by other drugs administered simultaneously. SPECTROPHOTOMETRY AND FLUORIMETRY:  Prior to advent of GLC and HPLC, drug samples were analyzed by spectro- photometric methods.  Solvent extraction schemes coupled with a spectro-photometric finish can still provide a much derived simplicity in assay procedure when the level of sensitivity required is not too low. i.e., in the μg/ml range. However the drawbacks are:  large volume of samples,  complex extraction procedures,  Interference by other compounds. THIN LAYER CHROMATOGRAPHY (TLC): TLC possesses adequate resolutions for identifying many drugs but it suffers from inability to quantify these drugs accurately and time consuming technique with inadequate sensitivity. However it is a useful technique in toxicology laboratory. HPLC & GLC: These methods are highly specific, precise and sensitive. Besides multiple analyses can be done. RADIO IMMUNE ASSAY (RIA): It is sensitive, reasonably precise but requires the use of radionuclide. Cross reactivity with other closely reacted drugs is a potential problem with this technique. The hazard of using radioactive material is a considerable limitation of this method. ENZYME IMMUNE ASSAY: These techniques offer some advantages over RIA in that no radioactive tracer is required; there is no need to separate the bound from the unbound fractions. However the potential for cross reactivity still exits.
PHARMD GURU Page 3 THERAPEUTIC DRUG MONITORING FOR CARDIOVASCULAR DRUGS DIGOXIN: GENERAL INTRODUCTION:  Group V anti-arrhythmics, Inotropic agents  Digoxin is used to treat heart failure.  Digoxin is also used to treat atrial fibrillation, a heart rhythm disorder of the atria (the upper chambers of the heart that allow blood to flow into the heart). USES:  Digoxin is the most widely used of the digitalis glycosides.  Its primary actions on the heart are those of increasing the force of contraction and decreasing conduction through the atrioventricular node.  Currently, its main role is in the treatment of atrial fibrillation by slowing down the ventricular response, although it is also used in the treatment of heart failure in the presence of sinus rhythm.  The primary method of monitoring its clinical effect in atrial fibrillation is by measurement of heart rate but knowledge of its pharmacokinetics can be helpful in predicting a patient's dosage requirements. MECHANISM OF ACTION: • Digoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium. • Sodium calcium exchanger (NCX) in turn tries to extrude the sodium and in so doing, pumps in more calcium. • Increased intracellular concentrations of calcium may promote activation of contractile proteins. • Digoxin also acts on the electrical activity of the heart. Increasing the slope of phase 4 depolarization and shortening the action potential duration, and decreasing the maximal diastolic potential.
PHARMD GURU Page 4 PHARMACOKINETIC PROFILE: ABSORPTION:  Completely absorbed from the gut.  In some patients, absorption may be decreased due to digoxin inactivation by gut bacteria (Eubacterium lenium).  Also by some drugs like antacids, cholestyramine, tetracycline, neomycin and kaolin.  For patients with normal absorption:  Digoxin tablets: 50-90%  Digoxin elixir: 80%  Digoxin liquid filled capsules: 100% DISTRIBUTION: • Digoxin distributes into lean body tissue but not appreciably into adipose or fatty tissues. • For this reason ideal body weight should be used to dose digoxin. • 20-30% bound to albumin. • Vd : 6- 7 L/kg • Distributive phase is 6 to 8 hour. • Two clinical implications:  Loading doses of digoxin need to be administered in divided doses 6 hour apart.  Serum digoxin levels should be determined at least 8 hr after administration. METABOLISM: • Takes place in stomach and intestine. • Involves:  Deglycosylation.  Reduction of the lactone ring.  Oxidation.  Epimerization.  Conjugation to polar metabolites. EXCRETION:  Excreted largely unchanged in the urine.