Pharmacokinetics is the arithmetic description of the movement of a substance through the various body compartments. It reflects a time-dependent relationship between drug dosage and the measurable concentration of drug that results, usually in the serum or plasma. Measurement of blood levels is usually easier than the measurement of tissue levels.
Pharmacodynamics is the study of how chemicals produce their pharmacologic effects on living tissue when a drug is administered. Drug concentrations must always be considered within the context of the therapeutic goals for which they are used. Therapeutic success or failure is not determined by drug concentrations, but by the physiologic or biochemical changes produced by that specific drug in the concentration achieved at the target site. The circulation is rarely the target site but is often the route used to deliver drugs to the target site within a tissue.
- Receptor concept: the principle that assumes drugs act by forming a complex with a specific macromolecule in a way that alters that molecule's function. This alteration in function may include inhibition or potentiation of the macromolecule's activity in a way that creates the desired drug effect. The drug's affinity for binding to the receptor plays a large part in the determination of the concentration of the drug required to achieve the desired response. The individual characteristics of the receptor are responsible for the selective nature of drug response. The receptor theory of drug action allows an explanation of drug antagonists. The antagonist drug may alter the characteristics of the receptor molecule in a way that then limits or inhibits the response to the original drug. Some drugs do not appear to act through receptors. Their action is related to a direct response in the recipient.
- General mechanisms of drug actions are based on the nature of the receptor/drug complex.
- There are receptor/drug complexes that regulate gene expression. They act by mediating a response that ultimately involves gene expression and new protein synthesis. These drugs do not generally have a rapid effect after initial administration.
- There are receptor/drug complexes that change cell membrane permeability. These drugs have a very short time lag between administration and response.
- There are receptor/drug complexes that increase the intracellular concentration of a second messenger molecule. These drugs increase the production and activity of enzyme systems within the cell. They can stimulate a rapid response to changing cell characteristics.
- The relationship between drug dose and clinical response may be very different. Idiosyncratic drug response is an abnormal response to a drug that is not usually observed and may include:
- Low sensitivity – usual dose results in a less intense response than usual.
- Extreme sensitivity – more intense than expected.
- Unpredictable adverse reaction – drug reaction substantially different than would have been expected or not usually seen.
- Tolerance – diminished response to drug-related to long-term administration of the drug.
- Tachyphylaxis – rapidly diminished drug response without drug dosage change.
- Desired versus undesired effects of drugs can be grouped as desired or therapeutic effects, side effects, and toxic effects. It is the responsibility of the health care provider to weigh the benefits against the undesirable side effects or toxic risk and adjust accordingly.8
The volume of distribution refers to an imaginary space into which a drug distributes once it reaches the bloodstream and assumes equal distribution of the drug throughout all body compartments. The volume of distribution is the mathematical relationship between the dose administered and the serum concentration of the drug. The volume of distribution for a drug depends on the chemical properties of the drug itself and the physiologic state of the patient. Some physiologic factors can alter the volume of distribution:
- Extent of plasma and tissue binding
- Lipid solubility
- Increased volume of distribution for a drug that distributes into body water
- Increases in a patient's intravascular and extravascular fluid
- Changes in protein concentration and binding capacity
- Fat content in the body
If a drug is already present in the circulation, the volume of distribution is calculated from the change in concentration produced from by the dose.
Volume of distribution (Vd) =
dose (mg/kg)/Peak concentration (mg/L)
If a 2.5 mg dose of gentamicin raises the serum trough concentration of 1.5 mg/L to a peak of 3.5 mg/L the volume of distribution can be calculated from the following equation:
3.5 - 1.5 (mg/L) =
2.5 (mg/kg)/volume of distribution (L/kg)
Volume of distribution (mL/kg) =
2.5 (mg/kg)/2.0 (mg/L)
= 1.25 (L/kg)
Dose adjustments are dependent upon knowledge of the volume of distribution. If the desired peak concentration is 6.0 mg/L, and the same trough level occurs after the current dose, the volume of distribution can be used to calculate the appropriate change in the next dose to reach the desired concentration.
Half-life describes the time it takes for the serum concentration of a drug to decrease by one half of its original concentration. Half-life may be influenced by other drugs, tissue perfusion, and organ function.9
t1/2 = .693 x VD (volume of distribution)/CL (clearance)
Clearance refers to the amount of drug cleared from the bloodstream per unit of time. The clearance of a drug depends on many factors, including the volume of distribution, the half-life, the physiologic status of the patient, blood flow to the organs, organ function, and the properties of the drug itself. In clinical practice, clearance is generally referred to as linear or nonlinear. For a drug whose clearance follows linear pharmacokinetics, an increase in the dose will proportionately and predictably increase the serum proportional to the concentration of drug achieved at steady state. The majority of drugs used in neonates follow this type of elimination.
A drug that follows nonlinear pharmacokinetics may have a rapid rise in serum concentration in response to a small increase in dose. This unpredictable dose response is a result of enzyme saturation in the liver. Elimination now becomes dose-dependent. All drugs cleared hepatically follow nonlinear pharmacokinetics; however, elimination may appear linear over the therapeutic range and change to nonlinear elimination when levels exceed the therapeutic range. An increase in dose yields a predictable increase in serum concentration unless the serum concentration exceeds what is normally considered therapeutic.
Clearance (Cl) =
0.693 X Vd/T1/2
Steady-state refers to the point in time at which for each dosing interval, the patient is receiving the same amount of drug that is being excreted by the body; the rate of drug administration equals the rate of drug elimination. In clinical practice, the steady-state is considered to be achieved after about four to five half-lives of the drug have passed. Although drug concentrations will be the same after each dose at steady-state, constant drug concentration does not define a steady state. The use of loading dose may lead to rapid attainment of constant circulating drug concentrations, but drug equilibration continues among body compartments for at least five half-lives. The collection of the drug eliminated from the body or sampling of tissue compartments will reveal this continued equilibrium. The time required to reach steady-state concentration is dependent upon the elimination rate, which is inversely related to the half-life. Concentration increases with increasing infusion rate, or increasing dose and decreases with larger distribution volume. Doubling the infusion rate doubles the steady-state concentration but the time to reach the steady-state concentration remains constant.10