To gain access to their receptors most drugs must first be absorbed into the systemic circulation. This requires that drugs translocate across biological membranes. There are several mechanisms by which this can be achieved, but the most important one is passive diffusion. Primary determinants of passive diffusion include the drug’s molecular weight; its concentration gradient, pKa, and lipid solubility; and, to some extent, the drug’s formulation and route of administration.
Most drugs are weak acids or weak bases. In an aqueous environment they exist as a mixture of protonated (positively charged) and deprotonated (neutral) molecules. Only the deprotonated or neutral (unionized) form of drug molecules can translocate across biological membranes. The ratio of protonated (ionized) to deprotonated (unionized) forms of a drug is predicated on the drugs’ dissociation constant (pKa) and the pH of the drug’s milieu (environment).
The pKa is that pH at which a drug is 50% ionized and 50% unionized (Figure 8). When the pH of the environment is increased above the pKa of a weak acid, over 50% of the drug will be ionized. Conversely, when the pH of the environment is decreased below the pKa of a weak acid, over 50% of the drug will be unionized. Generally, the pKa of weak acids (e.g., aspirin, penicillin) is 3 to 5; and the pKa of weak bases (e.g., local anesthetics) is 6 to 10.
When lidocaine with a pKa of 7.9 is deposited into an infected (acidic) site more than 50% of its molecules will be ionized. Since only the neutral form of the drug can translocate across biological membranes, the protonated or charged forms of the drug will accumulate at the site. This phenomenon is known as ion trapping. Ion trapping also explains the accumulation of weak acids (e.g., aspirin) in an alkaline environment, i.e., when placed in the mucobuccal fold.
The oral route is the most common, convenient, and economical method of drug administration. It is also the least predictable. When a drug is administered orally (an enteral route) its rate of absorption into the systemic circulation is greatly influenced by the pH of the gastrointestinal tract, gastric motility, splanchnic blood flow, the presence of food in the stomach, and importantly, patient adherence to the prescribed drug regimen.
Gastric motility (emptying) moves a drug from the stomach into the upper small intestine. The larger surface area of the small intestine and its more specialized epithelial lining promote absorption. Consequently, rapid gastric emptying leads to more rapid drug absorption. Conversely, factors that slow gastric motility (e.g., fatty foods in the stomach) tend to delay gastric emptying, slow the rate of absorption, and, predictably, delay a drug’s onset of action.
Following oral administration of a drug, an important determinant of its bioavailability is first-pass metabolism by the liver. Bioavailability is the extent and rate at which the active drug or its active metabolite enters the systemic circulation and becomes available for distribution to the drug’s site of action. In general, drugs given enterically that are efficiently removed and/or extensively metabolized by the liver at the time of first-pass will have low bioavailability.
Intravenous (IV) administration (a parenteral route) provides for accurate and immediate deposition of drugs into the systemic circulation unaffected by hepatic first-pass metabolism. The dose can be adjusted to patient response; however, once a drug is injected into the circulation there is no recall. Sterile formulations of soluble substances and an aseptic technique are required. Local irritation and thromboembolic complications may occur with some drugs.
Subcutaneous (SC) injections provide for a rate of drug absorption that is sufficiently constant to maintain steady-state concentrations. Local tissue irritation such as sloughing, necrosis, and severe pain may occur. Intramuscular (IM) injections allow for rapid absorption of aqueous solutions, while oily or other nonaqueous vehicles provide for slow, constant absorption. Drugs that are too irritating when administered IV or SC may be given IM.
Gaseous, volatile agents administered by inhalation may act locally, cross the alveoli, or travel in the systemic circulation and then act at distant receptor sites. Concentration is controlled at the alveolar level, since most of these drugs are exhaled immediately. The rectal route of drug administration may be useful in young children and for unconscious or vomiting patients, however, absorption, as with the oral route of drug administration, is unpredictable.
Following topical application, drugs are absorbed across skin and mucosa by passive diffusion as a function of their concentration, molecular size, lipid solubility, and pKa. Sublingual drug administration, because of venous drainage from the mouth is via the superior vena cava, allows for direct absorption into the systemic circulation and has the advantage of circumventing first-pass metabolism in the liver.