Dr. Steven I. Dworkin Pharmacology for the Health Sciences Lecture 2a
Dr. Steven I. Dworkin Lecture 1 Review
Dr. Steven I. Dworkin Drug Effects Are Determined By (1) how much of the drug reaches its target sites, where it has biological action (2) how quickly it reaches those sites
Dr. Steven I. Dworkin Pharmacokinetic Factors Determine Bioavailability Method of administration The route of administration is significant because it determines both onset and duration of drug action. The method of adminis tration influences absorption of the drug because it deter-mines the area of the absorbing surface, the number of cell layers the drug must pass through, and the extent of first-pass metabolism –Rate of absorption and distribution –Binding at inactive sites, –Biotransformation –Excretion. These factors interact, so that as a drug is being absorbed and distrib uted throughout the body to act at target sites, some of its molecules are simultaneously being bound to inactive sites, while others are metabolized and excreted.
Dr. Steven I. Dworkin Absorption Absorption is dependent on administration method and the solubility and ionization of the drug. Addition Considerations and Influences –Individual differences in age, sex, and body size, which contribute to the concentration of the drug. –Lipid solubility- 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 unionized (lipid soluble) in acidic body fluids like stomach juices; they are more readily absorbed there than in the more alkaline intestinal fluid, where ionization of weak acids increases and absorptibon is reduced. 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 and the drugs become more lipid soluble.
Dr. Steven I. Dworkin Degradation and Elimination In addition to the absorption and distribution of a drug in the body, the rate of degradation and elimination is equally important in determining bioavailability. Drugs are most often biotransformed by liver enzymes (e.g., cytochrome P450) that produce products for excretion that are inactive and more water soluble. – Phase I metabolism involves oxidation, reduction, or hydrolysis and produces an ionized metabolite that may be inactive, equally active, or more active than the parent drug. – Phase II metabolism involves the 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 more water soluble. The kidney is most often responsible for filtration of metabolites from the blood before excretion with the urine. Alternatively, the metabolites maybe excreted into bile and eliminated with the feces.
Dr. Steven I. Dworkin Psychopharmacology Several factors that influence drug metabolism and elimination are significant to psychopharmacologists because they are responsible for many drug interactions and also explain why some individuals respond differently to drugs. –1. Liver enzymes can be induced (increased) by some class-es of drugs given repeatedly. More enzyme means more-efficient metabolism, which reduces blood levels of drug and reduces the intensity and/or duration of its effects. –2. Some drugs directly impair liver enzyme action, so any drug normally metabolized by that enzyme will remain in the body for longer periods of time, producing pro-longed drug effects. –3. The limited number of enzymes also means that if two drugs share a metabolic system, then the two will compete for biotransformation, causing elevated blood levels of one or the other or both drugs. –4. Individuals who are very sensitive or very resistant to drug effects may differ genetically in the efficiency of the metabolic enzymes. Rapid metabolizers will appear to be less responsive to the drug, while slow metabolizers may show greater response, increased side effects, or toxicity. –5. In addition to genetic differences, differences in age, sex, nutrition, and organ (e.g., kidney and liver) function also are responsible for varying rates of biotransformation.
Dr. Steven I. Dworkin Pharmacology for the Health Sciences Lecture 2 Pharmacodynamics: Drug-Receptor Interactions
Dr. Steven I. Dworkin Pharmacodynamics –The study of the physiological and biochemical interaction of drug molecules with the target tissue that is responsible for the ultimate drug effects. – Drugs can be classified into a wide variety of categories (see next slide). –Many of the drugs we are concerned with affect cell function in target tissue by acting on receptors. –Knowing which receptors a drug acts on and where the receptors are located is crucial to understanding what actions and side effects will be produced.
Dr. Steven I. Dworkin
Receptors –Large protein molecules located either on the surface of or within cells, Initial sites of action of a biologically active agent including Neurotransmitters, hormones, or drugs (all referred to as ligands). –A ligand is any molecule that binds to a receptor with some selectivity. Because most drugs do not readily pass into neurons, neuropharmacology is most often interested in receptors found on the outside of cells that relay information through the membrane to affect intracellular processes (see next slide). –There are many possible intracellular changes that a ligand can produce depends upon whether the receptor is coupled to an ion channel (ionotropic receptor) or to a G protein (metabotropic receptor). –The essence of neuropharmacology is to identify drugs that can act at neurotransmitter receptors that either enhance or reduce the normal functioning of the cell..
Dr. Steven I. Dworkin Most drugs and neurotransmitters remain outside the cell and bind to receptors on the exterior cell surface. When these receptors are activated,they initiate changes in an effector,which causes intracellular changes, such as movement of ions or changes in enzyme activity
Dr. Steven I. Dworkin Structure and function of ionotropic receptors
Dr. Steven I. Dworkin Functions of metabotropic receptors
Dr. Steven I. Dworkin Receptors A second type of receptor is found within the target cell –In the cytoplasm (as for the glucocorticoids) –In the nucleus (e.g., sex steroid receptors). Most of the hormones that act on the brain to influence neural events utilize this type of receptor. » Hormonal binding to intracellular receptors alters cell function by triggering changes in the expression of the genetic material within the nucleus, producing differences in protein synthesis. »Sex hormones act in this way to facilitate mating behavior and other activities related to reproduction.
Dr. Steven I. Dworkin Many hormones are capable of entering the cell before acting on an intracellular receptor that changes the expression of specific genes within the nucleus.The altered protein synthesis in turn leads to changes in cell function.
Dr. Steven I. Dworkin Extracellular and intracellular receptors have several common features The ability to recognize specific molecular shapes is one very important characteristic. –Only a limited group of neurochemicals or drugs can bind to a particular receptor protein to initiate a cellular response. These neurochemicals are called agonists. – Molecules that have the best chemical "fit" (have the highest affinity) attach most readily to the receptor. – Ligand maybe recognized by a receptor (attach to the receptor) without initiating a biological action. Such ligands are considered to have low efficacy. These molecules are called antagonists because not only do they produce no cellular effect after binding, but by binding to the receptor they prevent an "active" ligand from binding and "block" the receptor from interacting with high efficacy ligands. A second significant feature of receptors is that the binding or attachment of the specific ligand is usually temporary. –Most ligands dissociates (i.e., separates) from the receptor.
Dr. Steven I. Dworkin Extracellular and intracellular receptors have several common features Third, ligands binding to the receptor produce a physical change in the three- dimensional shape of the protein, –Initiating a series of intracellular events that ultimately generates a biobehavioral effect. – How much intracellular activity occurs depends on the number of interactions with the receptor as well as the ability of the ligand to alter the shape of the receptor, which reflects its efficacy. –Fourth, although we tend to think about receptors as a permanent characteristic of cells, these proteins in fact have a life cycle just as other cell proteins do –Both increased and decreased concentrations of ligands can modified both the number (long-term regulation) and in sensitivity (more rapid regulation via second messengers) of receptors. Long-term regulation, called up-regulation when receptor numbers increase or down-regulation when receptors are reduced in number, reflects compensatory changes following prolonged absence of recep tor agonists or chronic activation of the receptor, respectively
Dr. Steven I. Dworkin
Dose-response Curves The dose-response curve –Used to evaluate receptor activity is which describes the amount of biological or behavioral effect (response) for a given drug concentration (dose). –When plotted on semilog scale, the curve takes on a classic S-shape. –At low doses, the drug-induced effect is slight, because very few receptors are occupied. The threshold dose is the smallest dose that produces a measurable effect. – As the dose of the drug is increased, more receptors are activated and a greater biological response occurs. The ED50 (50% effective dose) is the dose that produces half the maximal effect. The maximum response occurs at a dose at which we assume the receptors are fully occupied (ED 100).