Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (630 page)

   Excretion or elimination

Changes in these parameters affect drug concentrations.

Absorption

Absorption describes the process in which the drug or xenobiotic enters the bloodstream. For intravenous/intra-arterial administration, there is no absorption. Other common routes of administration include oral, intramuscular, subcutaneous, inhalation, rectal, intrathecal, oral mucosa, dermal, and intranasal. The following factors affect the bioavailability (amount absorbed compared with amount administered):

   Surface area

   Solubility

   Blood supply

   Concentration

   pH

   Molecular size and shape

   Degree of ionization

Distribution

This describes the transfer of the drug from site of administration throughout the body. This is generally movement from the bloodstream to tissues. Therefore, it is a function of the blood supply to the tissues. A drug may rapidly be distributed to highly perfused tissues such as brain, heart, liver, and kidney, whereas slower distribution will occur for muscle, fat, and bone. Factors affecting drug absorption are also relevant to distribution. Plasma protein binding is an additional factor to consider.

Metabolism

Drugs are chemically altered to facilitate removal from the body. This process is performed mainly in the liver by enzymes. Other sites of enzyme activity include the GI tract, blood, kidney, and lung. Phase I metabolism describes transformation of functional groups on the drug molecule. Phase II are known as conjugation reactions and involve addition of endogenous substances to render the compound more water soluble. The most common conjugation reaction involves the addition of uridine diphosphate-glucuronic acid with hydroxyl or amino groups to form glucuronides. Opiates and benzodiazepines are highly glucuronidated prior to excretion.

Excretion

Removal of drug from the body typically occurs in urine from the kidney, feces from the liver, and breath from the lung. Drugs are also eliminated in sweat, breast milk, and sebum. Removal of drug by the liver, clearance, depends on blood flow to the liver, which may be increased in the presence of food, the presence of phenobarbital, and decreased during exercise, dehydration, disease (cirrhosis, CHF), and the presence of anesthetics. Removal of drug also depends on the ability of the liver to extract drug from the bloodstream. This includes diffusion and carrier systems. Renal excretion is a function of filtration, secretion, and reabsorption. Again the processes that affect transfer across biologic membranes must be considered.

   Conclusions

In general, increases in serum/plasma drug concentrations may be observed in

  1.  Overdose

  2.  Coingestion of drugs that compete for metabolic enzymes

  3.  Liver and renal failure/insufficiency

  4.  Age-related increases due to loss in enzyme activity, decreases in absorption, blood flow, intestinal motility

  5.  Genetic polymorphisms—slow metabolizers

  6.  Movement of drugs from tissue depots

In general, decreases in serum/plasma drug concentrations may be observed in

  1.  Decreased oral bioavailability

  2.  Increased metabolism due to coingestion of drugs that induce metabolic enzymes such as phenobarbital, phenytoin

  3.  Increased renal clearance

  4.  Increases in plasma proteins (results in decreases in observed serum drug concentrations, since most tests measure unbound or free drug concentrations)

   Alternate Matrices

Drugs may be detected in nontraditional matrices

   Meconium