Drug elimination

 Drug elimination

Drugs are cleared primarily by the liver and kidneys. Excretion into the urine is a major route of elimination for metabolites and unchanged drug.


organs that excrete drugs eliminate water soluble  .

Lipid soluble drugs are not readily eliminated until they are metabolized to more polar compounds.

Possible sources of excretion include:

Breath -Urine -Saliva -Perspiration -Feces -Milk -Bile-Hair.

- kidney is the most important organ that eliminate drugs and their metabolites.

-Substances excreted in the feces are the orally ingested unabsorbed drugs or metabolites excreted in the bile that are not reabsorbed from the intestinal tract.

- Pulmonary excretion  is important as it pertains to the elimination of anesthetic gases and vapors, as well as alcohol.

 

 A. Renal elimination of a drug

1- Glomerular filtration:

Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus.
 no bound to albumin drugs flows through the capillary slits into Bowman's space as part of the glomerular filtrate . 
The glomerular filtration rate (125mL/min) is normally about twenty percent of the renal plasma flow (600 mL/min). 
(it is not affected by PH and lipid solubility.)

 

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:

drug concentration increases when it  moves toward the distal convoluted tubule, and exceeds that of the perivascular space.
  if The drug is uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. to minimize the amount of back-diffusion, increasing the ionized form of the drug in the lumen may be used , 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.

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 reactions .

 that use conjugation with sulfate, glycine,( or) glucuronic acid to increase drug polarity.
 The conjugates are ionized, and the charged molecules cannot back-diffuse out of the kidney lumen.