Pharmacokinetics: Absorption

PHARMACOKINETICS

Pharmacokinetics defines the relationships among drug dosing, drug concentration in body fluids and tissues, and time. It consists of four linkedprocesses: absorption, distribution, biotransforma-tion, and excretion.

Absorption

Absorption defines the processes by which a drug moves from the site of administration to the blood-stream. There are many possible routes of drug administration: oral, sublingual, rectal, inhalational, transdermal, transmucosal, subcutaneous, intra-muscular, and intravenous. Absorption is influenced by the physical characteristics of the drug (solubility, pK_a, diluents, binders, and formulation), dose, and the site of absorption (eg, gut, lung, skin, muscle). Bioavailability is the fraction of the administered dose reaching the systemic circulation. For example, nitroglycerin is well absorbed by the gastrointestinal tract but has low bioavailability when administered orally. The reason is that nitroglycerin undergoes extensive first-pass hepatic metabolism as it transits the liver before reaching the systemic circulation.

Oral drug administration is convenient, inex-pensive, and relatively tolerant of dosing errors. However, it requires cooperation of the patient, exposes the drug to first-pass hepatic metabolism, and permits gastric pH, enzymes, motility, food, and other drugs to potentially reduce the predictability of systemic drug delivery.

Nonionized (uncharged) drugs are more readily absorbed than ionized (charged) forms. Therefore, an acidic environment (stomach) favors the absorp-tion of acidic drugs (A^–+ H⁺→ AH), whereas a more alkaline environment (intestine) favors basic drugs (BH⁺→ H⁺+ B). Most drugs are largely absorbed from the intestine rather than the stomach because of the greater surface area of the small intestine and longer transit duration.

All venous drainage from the stomach and small intestine flows to the liver. As a result, the bioavailabil-ity of highly metabolized drugs may be significantly reduced by first-pass hepatic metabolism. Because the venous drainage from the mouth and esophagus flows into the superior vena cava rather than into the portal system, sublingual or buccal drug absorption bypasses the liver and first-pass metabolism. Rectal administration partly bypasses the portal system, and represents an alternative route in small children or patients who are unable to tolerate oral ingestion. However, rectal absorption can be erratic, and many drugs irritate the rectal mucosa.

Transdermal drug administration can provide prolonged continuous administration for some drugs. However, the stratum corneum is an effec-tive barrier to all but small, lipid-soluble drugs (eg, clonidine, nitroglycerin, scopolamine, fentanyl, and free-base local anesthetics [EMLA]).

Parenteral routes of drug administration include subcutaneous, intramuscular, and intrave-nous injection. Subcutaneous and intramuscular absorption depend on drug diffusion from the site of injection to the bloodstream. The rate at which a drug enters the bloodstream depends on both blood flow to the injected tissue and the injectate formu-lation. Drugs dissolved in solution are absorbed faster than those present in suspensions. Irritating preparations can cause pain and tissue necrosis (eg, intramuscular diazepam). Intravenous injections completely bypass the process of absorption.