Pharmacokinetics

Bioavailability

• This is the amount of drug taken that reaches the systemic circulation i.e. the fraction of an administered dose of unchanged drug that reaches the systemic circulation.
• If a medication is administered IV then the bioavailability is 100%. If however medication is administered via other routes e.g. orally then its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism and may vary from patient to patient.
• Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. In both pharmacology and nutrition sciences.
• Bioavailability is measured by calculating the area under the curve (AUC) of the drug concentration-time profile. Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs.

Bioequivalence

• Term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug.
• If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.

Volume of distribution

• The apparent volume of distribution is the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma. The volume of distribution is a theoretical concept and has nothing to do with the actual volume of the body or its fluid compartments.
• For a drug that is highly tissue-bound, very little drug remains in the circulation; thus, plasma concentration is low and volume of distribution is high. Drugs that remain in circulation tend to have a low volume of distribution. VOD provides a reference for the plasma concentration expected for a given dose but provides little information about the specific pattern of distribution.
• Each drug is uniquely distributed in the body. Some drugs distribute mostly into fat, others remain in extracellular fluid, and others are bound extensively to specific tissues.
• Many acidic drugs (eg, Warfarin, Aspirin) are highly protein-bound and thus have a small apparent volume of distribution.
• Many basic drugs (eg, amphetamine, meperidine) is extensively taken up by tissues and thus have an apparent volume of distribution larger than the volume

  Volume of distribution = Total amount of drug in body / plasma concentration of the drug

Binding

• Drug distribution into tissues depends on the degree of plasma protein and tissue binding. Some drugs may be transported partly in solution as free (unbound) drug and partly reversibly bound to blood components (eg, plasma proteins, blood cells).
• The main plasma proteins that can interact with drugs, are albumin, alpha-1 acid glycoprotein, and lipoproteins. Acidic drugs are usually bound more extensively to albumin; basic drugs are usually bound more extensively to alpha-1 acid glycoprotein, lipoproteins, or both.
• Only unbound drug can passively diffuse to extravascular or tissue sites where the pharmacologic effects of the drug occur. Therefore, the unbound drug concentration in systemic circulation typically determines drug concentration at the active site and thus efficacy.
• At high drug concentrations, the amount of bound drug approaches an upper limit determined by the number of available binding sites. Saturation of binding sites is the basis of displacement interactions among drugs Drugs bind to many substances other than proteins. Binding usually occurs when a drug associates with a macromolecule in an aqueous environment but may occur when a drug is partitioned into body fat. Because fat is poorly perfused, equilibration time is long, especially if the drug is highly lipophilic.
• Accumulation of drugs in tissues or body compartments can prolong drug action because the tissues release the accumulated drug as plasma drug concentration decreases. For example, thiopental is highly lipid-soluble, rapidly enters the brain after a single IV injection, and has a marked and rapid anaesthetic effect; the effect ends within a few minutes as the drug is redistributed to more slowly perfused fatty tissues.
• Thiopental is then slowly released from fat storage, maintaining subanesthetic plasma levels. These levels may become significant if doses of thiopental are repeated, causing large amounts to be stored in fat. Thus, storage in fat initially shortens the drug effect but then prolongs it.
• Some drugs accumulate within cells because they bind with proteins, phospholipids, or nucleic acids. For example, chloroquine concentrations in WBCs and liver cells can be thousands of times higher than those in plasma. The drug in cells is in equilibrium with the drug in plasma and moves into plasma as the drug is eliminated from the body.

Loading Dose

Dose of the drug that must be given to achieve the desired plasma concentration

Loading dose = Volume of distribution X plasma concentration

Steady State

• The time to achieve a steady-state concentration is 4.5 x half-life of the drug

First order kinetics

• This is shaped like a decay curve with a drop over time of concentration.
• The half-life is the time taken for the concentration to fall by half.

Zero order kinetics

• There is a linear-shaped fall of concentration. The concentration does not matter. The same amount of lost irrespective of the drug concentrations.
• Seen with higher dose phenytoin, Theophylline and alcohol. The reverse is that as the dose goes up in small amounts the plasma concentration can rise quickly.

Clearance

• The amount of plasma from which the substance is removed per unit time. Eg creatinine excretion and clearance which is used as a marker of GFR.