Principles of Pharmacology

Pharmacology: The Science of Drug Action

Pharmacokinetic Factors Determining Drug Action

Therapeutic Drug Monitoring

• A placebo is an inert substance that produces effective therapeutic response and side effects. Placebo response depends on the ritual of the therapeutic treatment, which has neurobiological and behavioral effects. Multiple explanations for the effectiveness of placebos include Pavlovian conditioning and expectation of outcome.
• The effects of a drug are determined by (1) how much of the drug reaches its target sites, where it has biological action, and (2) how quickly the drug reaches those sites.
• Interacting pharmacokinetic factors that determine how much free drug is in the blood (bioavailability) include method of administration, rate of absorption and distribution, binding at inactive sites, biotransformation, and excretion.
• The route of administration determines both onset and duration of drug action.
• The method of administration influences absorption of the drug because it determines the area of the absorbing surface, the number of cell layers through which the drug must pass, and the extent of first-pass metabolism.
• Oral and rectal routes of administration are enteral because they involve the gastrointestinal tract; all other methods are called parenteral.
• Each method of administration provides distinct advantages and disadvantages involving rate of onset, blood level of drug achieved, duration of action, convenience, safety, and special uses.
• Absorption is dependent on method of administration, solubility and ionization of the drug, and individual differences in age, sex, and body size.
• Lipid-soluble drugs are not ionized and readily pass through fatty membranes at a rate dependent on the concentration gradient.
• Drugs that are weak acids tend to remain nonionized (lipid soluble) in acidic body fluids such as stomach juices; they are more readily absorbed there than in the more alkaline intestinal fluid. Drugs that are weak bases are more ionized in the acidic stomach fluid, so they are absorbed less readily there than from the more basic intestine, where ionization is reduced.
• Drug distribution is determined by the volume of blood flow to the tissue, but drug concentration in the CNS is limited by the blood–brain barrier that is formed by specialized brain capillaries that have few pores to allow drugs to leave the circulation. Only lipid-soluble drugs readily enter the brain.
• The placental barrier separates maternal circulation from fetal circulation, but it does not impede passage of most drug molecules.
• Drug molecules bound to inactive depots, including plasma proteins, cannot act at target sites, nor can they be metabolized, so the magnitude, onset, and duration of drug action are affected.
• Drug clearance from the blood usually occurs by first-order kinetics such that a constant fraction (50%) of the free drug is removed during each time interval. This interval is called the drug half-life. Some drugs are cleared according to zero-order kinetics, in which clearance occurs at a constant rate regardless of drug concentration.
• The steady state plasma level is the desired blood concentration of drug achieved when the absorption/distribution phase is equal to the metabolism/excretion phase. The steady state plasma level is approached after a period of time equal to five half-lives.
• Enzymatic drug metabolism or biotransformation occurs primarily in the liver and produces chemical changes in the drug molecule that make it inactive and more water soluble. The cytochrome P450 family of enzymes consists of the most important type of liver enzyme for transforming psychotropic drugs.
• Drug metabolism occurs in two steps. Phase I consists of oxidation, reduction, or hydrolysis and produces an ionized metabolite that may be inactive, as active as, or more active than the parent drug. Phase II metabolism involves conjugation of the drug with a simple molecule provided by the body, such as glucuronide or sulfate. Products of phase II metabolism are always inactive and are more water soluble.
• The kidney is most often responsible for filtration of metabolites from the blood before excretion in the urine. Alternatively, metabolites may be excreted into bile and eliminated with the feces.
• Factors that change the biotransformation rate may alter the magnitude and duration of drug effects or cause drug interactions, and they may explain variability in individual response to drugs. Chronic use of some drugs can induce (increase) the quantity of liver enzymes, thereby decreasing bioavailability. Drugs that inhibit liver enzymes increase the blood levels of a drug, enhancing its action. Competition among drugs for metabolism by the same enzyme increases blood levels of one or both drugs. Genetic differences and individual differences in age, sex, nutrition, and organ function may influence the rate of drug metabolism.
• Therapeutic drug monitoring involves taking multiple blood samples to directly measure plasma levels of drug after a drug has been administered. Monitoring is done to identify the optimum dosage for a patient to maximize therapeutic potential and minimize side effects. It is especially important for drugs with serious side effects and when there are changes in an individual’s pharmacokinetics due to aging, hormonal changes, stress, the addition of new medications, or other events.

Pharmacodynamics: Drug–Receptor Interactions

Biobehavioral Effects of Chronic Drug Use

Pharmacogenetics and Personalized Medicine in Psychiatry

• Drugs have biological effects because they interact with receptors on target tissues.
• Drugs or ligands that bind and are capable of changing the shape of the receptor protein and subsequently altering cell function are called agonists.
• Ligands that attach most readily are said to have high affinity for the receptor.
• Antagonists are capable of binding and may have high affinity while producing no physiological change; hence they have little or no efficacy. Antagonists “block” agonist activity by preventing agonists from binding to the receptor at the same moment.
• Inverse agonists bind to a receptor and initiate a biological action that is opposite that produced by an agonist.
• In general, binding of the specific ligand to a receptor is reversible.
• Receptor number changes to compensate for either prolonged stimulation (causing downregulation) or absence of receptor stimulation (causing up-regulation).
• Dose–response curves show that with increasing doses, the effect increases steadily until the maximum effect is reached.
• The ED₅₀ is the dose that produces a half-maximal (50%) effect. The more potent drug is one that has the lower ED₅₀.
• Comparison of the TD₅₀ (50% toxic dose) with the ED₅₀ (50% effective dose) for a single drug provides the therapeutic index, which is a measurement of drug safety.
• Competitive receptor antagonists reduce the potency of an agonist; this is shown by a parallel shift of the dose–response curve to the right with no change in the maximum effect.
• Biobehavioral interactions of drugs can produce physiological antagonism, additive effects, or potentiation.
• Chronic drug use may lead to a reduction in biobehavioral effects called tolerance, but in some circumstances, drug effects increase with repeated use—a phenomenon called sensitization.
• Cross-tolerance may occur if repeated use of one drug reduces the effectiveness of a second drug.
• Tolerance is generally a reversible condition that depends on dose, frequency of use, and the drug-taking environment. Not all drugs induce tolerance, and not all effects of a given drug undergo tolerance to the same extent or at the same rate.
• Metabolic tolerance occurs when drugs increase the quantity of the liver’s metabolizing enzymes; this more rapidly reduces the effective blood level of the drug.
• Pharmacodynamic tolerance depends on adaptation of the nervous system to continued presence of the drug by increasing or decreasing receptor number or by producing other compensatory intracellular processes.
• Behavioral tolerance occurs when learning processes and environmental cues contribute to the reduction in drug effectiveness. Pavlovian conditioning and operant conditioning can contribute to the change in drug response.
• Sensitization is dependent on dose, intervals between treatments, and the drug-taking environment. Cross sensitization with other drugs in the same class can occur. Unlike tolerance, sensitization is not readily reversible, and it persists for long periods of abstinence caused by long-term physiological changes to cells.
• Pharmacogenetics strives to identify genetic polymorphisms in individuals that predict good or poor therapeutic response to a specific drug or susceptibility to specific side effects. Genetic variation in pharmacokinetic factors such as rate of drug metabolism is responsible for determining drug blood level and subsequent biobehavioral effects. Genetic polymorphisms may influence the targets for drugs such as receptors and transporters.