Drug Elimination

Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers. A patient in renal failure may undergo extracorporeal dialysis, which removes small molecules such as drugs. 

A. Renal elimination of a drug

1. Glomerular filtration: 

Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into Bowman's space as part of the glomerular filtrate 

(Figure :Drug elimination by the kidney.)

The glomerular filtration rate (125 mL/min) is normally about twenty percent of the renal plasma flow (600 mL/min). [Note: Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate] 

2. Proximal tubular secretion:

Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport (carrier-requiring) systems, one for anions (for example, deprotonated forms of weak acids) and one for cations (for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds; thus, competition between drugs for these carriers can occur within each transport system

[Note: Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the glomerular filtrate.] 

3. Distal tubular reabsorption:

As a drug moves toward the distal convoluted tubule, its concentration increases, and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the pH of the urine to increase the ionized form of the drug in the lumen may be used to minimize the amount of back-diffusion, and hence, increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called œion trapping.

 For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. If overdose is with a weak base, such as cocaine, acidification of the urine with NH4Cl leads to protonation of the drug and an increase in its clearance.

 4. Role of drug metabolism: 

Most drugs are lipid soluble and without chemical modification would diffuse out of the kidney's tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space. To minimize this reabsorption, drugs are modified primarily in the liver into more polar substances using two types of reactions: Phase I reactions that involve either the addition of hydroxyl groups or the removal of blocking groups from hydroxyl, carboxyl, or amino groups, and Phase II reaction,that use conjugation with sulfate, glycine, or glucuronic acid to increase drug polarity. The conjugates are ionized, and the charged molecules cannot backdiffuse out of the kidney lumen 

(Figure  Effect of drug metabolism on reabsorption in the distal tubule.)

 B. Quantitative aspects of renal drug elimination

Plasma clearance is expressed as the volume of plasma from which all drug appears to be removed in a given time—for example, as mL/min. Clearance equals the amount of renal plasma flow multiplied by the extraction ratio, and because these are normally invariant over time, clearance is constant.

 1. Extraction ratio: This ratio is the decline of drug concentration in the plasma from the arterial to the venous side of the kidney. The drugs enter the kidneys at concentration C1 and exit the kidneys at concentration C2. The extraction ratio = C2/C1. 

2. Excretion rate: The excretion ratio is determined the equation:

The elimination of a drug usually follows first-order kinetics, and the concentration of drug in plasma drops exponentially with time. This can be used to determine the half-life, ½, of the drug (the time during which the concentration of a drug at equilibrium decreases from C to ½C): 

where ke = the first-order rate constant for drug elimination from the total body and CL = clearance. 

C. Total body clearance

The total body (systemic) clearance, CLtotal or CLt, is the sum of the clearances from the various drug-metabolizing and drug-eliminating organs. The kidney is often the major organ of excretion; however, the liver also contributes to drug loss through metabolism and/or excretion into the bile. A patient in renal failure may sometimes benefit from a drug that is excreted by this pathway, into the intestine and feces, rather than through the kidney. Some drugs may also be reabsorbed through the enterohepatic circulation, thus prolonging their half-life. Total clearance can be calculated by using the following equation:

It is not possible to measure and sum these individual clearances. How-ever, total clearance can be derived from the steady-state equation: 

D. Clinical situations resulting in changes in drug half-life

When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. It is important to be able to predict in which patients a drug is likely to have a change in half-life. The half-life of a drug is increased by:

 1) diminished renal plasma flow or hepatic blood flow for example, in cardiogenic shock, heart failure, or hemorrhage;
 2) decreased extraction ratio for example, as seen in renal disease; and
 3) decreased metabolism for example, when another drug inhibits its biotransformation or in hepatic insufficiency, as with cirrhosis.

On the other hand, the half-life of a drug may decrease by:

1) increased hepatic blood flow,
2) decreased protein binding, and
3) increased metabolism.

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1 comment:

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