Dictionary of Related Terms
Active Metabolite
It is important to emphasize that one must be concerned with the disposition of potentially active metabolites in addition to the handling of the parent drug.
AUC (Area Under the Curve)
A plot of the concentration of a drug against time, after a single dose of medicine, produces a standard shape curve.
Bioavailability
The percentage of drug that is detected in the systemic circulation after its administration. Detection of drug can be accomplished pharmacodynamically or pharmacokinetically.
Cirrhosis
A condition in which scar tissue forms in the liver and may keep the liver from functioning normally.
Clearance
Elimination is expressed in terms of clearance and half life. Clearance (Cl) is presented as ml/min/kg. As with volume of distribution, some of the data were derived presuming studies in adults to represent 70 kg of body weight. In patients with renal disease, values for elimination parameters or a qualitative statement are presented; end stage renal disease (ESRD) represents ClCr less than 20, moderate represents ClCr greater than 20 and less than 50, and mild represents ClCr greater than 50 ml/min/1.73 m2. In the regressions, entering ClCr corrected in terms of body weight computes the clearance as ml/min/kg. From the regressions, one may calculate a half-life at a specific level of renal function:
Half life = 0.693 x (volume of distribution) x 1000
clearance x 60
Clinical Pharmacology
Clinical pharmacology is studying pharmacology in relation to clinical science. It is a science which deals with the study of drugs in healthy volunteers and in patients. By its study the action and adverse affects of drugs can be compared.
Cytochrome P450
A system that metabolizes drugs and other foreign substances in the liver by means of enzymes (eg, CYP3A4) that inhibit or promote metabolic reactions.
Dialysis
The reader may wish to use specific calculations of pharmacokinetic parameters to derive dosage modification for an individual patient. Dialyzability is expressed in terms of half life and the percent of a dose removed by the dialytic procedure. It is important to emphasize that for dialysis to be considered important for dose adjustment or as a therapeutic maneuver, it must contribute to overall clearance in a clinically meaningful amount, usually increasing clearance at least 30 percent over that without dialysis.
In the dialysis comments, specific mention may not be made about drug removal by hemofiltration. The increment in dosing needed in this setting can be calculated assuming that the only drug available for removal is that which is unbound.
Dosing Guidelines
Specific comments are directed toward dosing guidelines, which, for the most part, are expressed as a fraction of the "normal dose" rather than as specific recommendations on a mg/kg. This approach was deemed most useful, because the "normal dose" in a patient may differ depending on the treatment strategy. With many drugs, I have arbitrarily elected to suggest guidelines for the following categories of renal function: ClCr greater than 50, ClCr less than 50 but greater than 20, ClCr less than 20, and dialysis. With each category, a range is suggested as a fraction of the normal dose, the smallest fraction applying to the lowest renal function in that category and the largest fraction to the highest level of renal function. To obtain intermediate levels of renal function, the clinician should interpolate within the suggested range. For drugs that have a narrow therapeutic index, more precise guidelines are offered.
The user must remember that these recommendations are based on data derived from populations of patients and extrapolated to the individual. Inter individual variability is great, and as a consequence, these guidelines do not achieve the predicted drug concentration in all patients -in fact, only for the idealized "average" patient.
The guidelines are best used as a starting point with more precise dose adjustment based on determinations of serum concentrations and evaluation of clinical end points in the individual patient.
Drug Interaction
The effect that can occur when two or more drugs are used together. These include changes of absorption in the digestive tract, changes in rate of the drugs' breakdown in the liver, new or increased side effects, and changes in the drugs' activity.
Enzyme
A protein that accelerates the rate of chemical reactions. Enzymes are catalysts that promote reactions repeatedly, without being damaged by the reactions.
ESRD (End Stage Renal Disease)
Severe kidney disease or chronic kidney failure that has reduced the kidney function to 10 percent or less of normal function, requiring the patient to have either dialysis or a transplant in order to live. Also called renal failure.
Excreted Unchanged
In general, the degree to which accumulation of a drug may occur in uremia is directly related to the percent excreted unchanged in the urine. Unless about 40 percent or more of a parent drug or its active metabolite is eliminated by the kidney, renal dysfunction is unlikely to mandate dose adjustment.
Half-life
The time required for half the amount of a drug to be eliminated from the body.
Metabolism
Metabolism is the biochemical modification or degradation of drugs, usually through specialized enzymatic systems.
Metabolite
Metabolites are the intermediates and products of metabolism. An active metabolite can be effective in controlling a disease state or can cause or contribute to the drug's adverse effects.
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect.
Pharmacokinetics
The study of the metabolism and action of drugs with particular emphasis on the time required for absorption, duration of action, distribution in the body and method excretion.
Protein Binding
The degree of a drug's protein binding can lead to certain predictions about its handling and possible changes with renal and hepatic dysfunction. Drugs, usually acidic, that are bound to albumin in excess of 90 percent are subject to displacement by other tightly bound drugs or by accumulated endogenous products in uremia. In addition, protein binding decreases as albumin levels decline with age or disease. The increased unbound drug in either scenario is then available to the distribution space or to pathways of elimination. The net effect of these factors is an increased volume of distribution (based on concentrations of total drug) and a lower serum concentration of total drug in the face of a concentration of free drug the same as occurs in normal subjects. The unchanged concentration of free drug means that pharmacologic effect is the same. The clinical importance of this effect is that the "therapeutic range," expressed in terms of total drug concentration, may decrease; therefore, a low total concentration should not necessarily be misinterpreted as subtherapeutic.
The degree of protein binding may also influence dialyzability. Drugs tightly bound to proteins are unable to cross dialysis membranes. However, these same drugs might still be extracted from blood by resin hemoperfusion.
Renal Insufficiency (Failure)
Renal insufficiency or failure is the condition where the kidneys fail to function properly. It can broadly be divided into two categories: acute renal failure and chronic renal failure.
Volume of Distribution
Volume of distribution is expressed in L/kg. Data In these tables that are gleaned from studies in adults but have been reported solely as volume not factored for body weight have been assumed to represent those of a 70 kg subject. The volume of distribution in the ensuing data represents Vd beta or Vd area and is the total volume into which drug distributes in the body; therefore, clearance equals the product of Vd and the elimination rate constant.
Drugs with a large volume of distribution have a large clearance, and as a consequence, hemodialysis is less likely to contribute to overall elimination in a significant manner.
A change in the volume of distribution caused by a disease process or by aging may mandate a compensatory change in the loading dose of a drug. It does not affect the maintenance dose.