Pharmacokinetics defines the relationships among drug dosing, drug concentration in body fluids and tissues, and time. It consists of four linked processes: absorption, distribution, biotransformation, and excretion.
Absorption defines the processes by which a drug moves from the site of administration to the bloodstream. There are many possible routes of drug administration: inhalational, oral, sublingual, transtracheal, rectal, transdermal, transmucosal, subcutaneous, intramuscular, intravenous, perineural, peridural, and intrathecal. Absorption is influenced by the physical characteristics of the drug (solubility, pKa, diluents, binders, formulation), dose, the site of absorption (eg, gut, lung, skin, muscle), and in some cases (eg, perineural or subcutaneous administration of local anesthetics) by additives such as epinephrine. Bioavailability defines the fraction of the administered dose that reaches 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 before reaching the systemic circulation.
Nonionized (uncharged) drugs are more readily absorbed than ionized (charged) forms. Therefore, an acidic environment (stomach) favors the absorption of acidic drugs (A– + H+ → AH), whereas a more alkaline environment (intestine) favors basic drugs (BH+ → H+ + B).
All venous drainage from the stomach and small intestine flows to the liver. As a result, the bioavailability 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 effective barrier to all but small, lipid-soluble drugs (eg, clonidine, nitroglycerin, scopolamine, fentanyl, free-base local anesthetics [EMLA]).
Parenteral routes of drug administration include subcutaneous, intramuscular, and intravenous 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 formulation. 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 bypass the process of absorption.
Once absorbed, a drug is distributed by the bloodstream throughout the body. Highly perfused organs (the so-called vessel-rich group) receive a disproportionate fraction of the cardiac output. Therefore, these tissues receive a disproportionate amount of drug in the first minutes following drug administration. These tissues approach equilibration with ...