Clinical Pharmacology and Therapeutics. Группа авторов

Figure 1.2 Schematic diagram of the dose–response relationship for the desired effect (dose–therapeutic response) and for an undesired adverse effect. The therapeutic index is the extent of displacement of the two curves within the normal dose range.

Principles of pharmacokinetics

      Absorption

      Drug absorption after oral administration has two major components: absorption rate and bioavailability. Absorption rate is controlled partially by the physicochemical characteristics of the drug but in many cases is modified by the formulation. A reduction in absorption rate can lead to a smoother concentration–time profile with a lower potential for concentration‐dependent adverse effects and may allow less frequent dosing.

Bioavailability is the term used to describe the fraction of the oral dose that is absorbed into the systemic circulation. It can range from 0 to 100% and depends on a number of physicochemical and clinical factors. Low bioavailability may occur if the drug has low solubility or is destroyed by the acid in the stomach. Changing the formulation can affect the bioavailability of a drug and it can also be altered by food or the co‐administration of other drugs. For example, antacids can reduce the absorption of quinolone antibiotics, such as ciprofloxacin, by binding them in the gut. Other factors influencing bioavailability include metabolism by gut flora, the intestinal wall or the liver.

      First‐pass metabolism refers to metabolism of a drug that occurs en route from the gut lumen to the systemic circulation. For the majority of drugs given orally, absorption occurs across the portion of gastrointestinal epithelium that is drained by veins forming part of the hepatoportal system. Consequently, even if they are well absorbed, drugs must pass through the liver before reaching the systemic circulation. For drugs that are susceptible to extensive hepatic metabolism, a substantial proportion of an orally administered dose can be metabolised before it ever reaches its site of pharmacological action, e.g. insulin metabolism in the gut lumen is so extensive that it renders oral therapy impossible. Other drugs which undergo extensive hepatic metabolism include propranolol, lidocaine and morphine.

      First‐pass metabolism has several clinical implications:

      Distribution

      Once a drug has gained access to the bloodstream, it begins to distribute to the tissues. The extent of this distribution depends on a number of factors including plasma protein binding, lipid solubility and regional blood flow. The volume of distribution, V_D, is the apparent volume of fluid into which a drug distributes based on the amount of drug in the body and the measured concentration in the plasma or serum. If a drug was wholly confined to the plasma, V_D would equal the plasma volume – approximately 3 L in an adult. If, on the other hand, the drug was distributed throughout the body water, V_D would be approximately 42 L. In reality, drugs are rarely distributed into physiologically relevant volumes. If most of the drug is bound to tissues, the plasma concentration will be low and the apparent V_D will be high, while high plasma protein binding will tend to maintain high concentrations in the blood and a low V_D will result. For the majority of drugs, V_D depends on the balance between plasma binding and sequestration or binding by various body tissues, for example, muscle and fat. Volume of distribution can therefore vary considerably.

      Clinical relevance of volume of distribution

      Knowledge of volume of distribution (V_D) can be used to determine the size of a loading dose if an immediate response to treatment is required. This assumes that therapeutic success is closely related to the plasma concentration and that there are no adverse effects if a relatively large dose is suddenly administered. It is sometimes employed when drug response would take many hours or days to develop if the regular maintenance dose was given from the outset, e.g. digoxin.

      In practice, weight is the main determinant to calculating the dose of a drug where there is a narrow therapeutic index.

      Plasma protein binding

      In the blood, a proportion of a drug is bound to plasma proteins – mainly albumin (acidic drugs) and α₁‐acid glycoprotein (basic drugs). Only the unbound, or free, fraction distributes because the protein‐bound complex is too large to pass through membranes. It is the unbound portion that is generally responsible for clinical effects – both the target response and the unwanted adverse effects. Changes in protein binding (e.g. resulting from displacement interactions) generally lead to a transient increase in free concentration but are rarely clinically relevant. However, a lower total concentration will be present and the measurement might be misinterpreted if the higher free fraction is not taken into account. This is a common problem with the interpretation of phenytoin concentrations, where free fraction can range from 10% in a normal patient to 40% in a patient with hypoalbuminaemia and renal impairment.

      Clearance

      Clearance is the sum of all drug‐eliminating processes, principally determined by hepatic metabolism and renal excretion. It can be defined as the theoretical volume of fluid from which a drug is completely removed in a given period of time.

When a drug is administered continuously by intravenous infusion or repetitively by mouth, a balance is eventually achieved between its input (dosing rate) and its output (the amount eliminated over a given period of time). This balance gives rise to a constant amount of drug in the body which depends on the dosing rate and clearance. This amount is reflected in the plasma or serum as a steady‐state concentration (Css). A constant rate intravenous infusion will yield a constant Css, while a drug administered orally at regular intervals will result in fluctuation between peak and trough concentrations (Figure 1.3).