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Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
NR565 Week 1 Study Outline
Chapter 2: Review of Basic Principles of Pharmacology
How Drugs are Developed
Drugs are developed by pharmaceutical companies to help patients and to make money The early part of the drug development process is called the preclinical stage Pharmaceutical companies will identify a drug target, starting sometimes with ingredients isolated from a plant (or organism in the case of antibiotics) with desirable medicinal properties, sometimes with a molecular target identified in the body to produce the desired response, and sometimes with a disease in need of treatment. Many drugs are examined as pharmaceutical companies seek the elusive perfect drug with just the right combination of properties. Preclinical studies are performed on cells, isolated tissues and organs, and in laboratory animals to identify promising compounds Drugs approved by the Food and Drug Administration (FDA) must be both safe and effective and are screened by pharmacologists specializing in various aspects of drug activity. Ideally, drugs will produce their desired effects at dosages well below those needed to produce toxicity. During the clinical stage of new drug development, pharmaceutical companies must establish the safety and effectiveness of new products in humans. Phase I clinical trials typically establish biological effects as well as safe dosages and pharmacokinetics in a small number of healthy patients. o During phase II clinical trials, new drugs are used to treat disease in a small number of patients and to establish the n potential of the drug to improve patient outcomes. If the drug still looks promising, phase III clinical trials will compare the new medication to standard therapy in a larger number of patients studied by at sites across the country. New drugs must be at least as good as, and it is hoped better than, other available therapies. Throughout the process, pharmaceutical companies work with the FDA. After being approved by the FDA, drugs are continuously monitored through post-marketing surveillance, in which health professionals are encouraged to report adverse events, which are studied by both pharmaceutical companies and the FDA.
Drug Responses
Homeostasis is the tendency of a cell, tissue, or the body not to respond to drugs but instead to maintain the internal environment by adjusting physiological processes. Before a medication can produce a response, it often must overcome homeostatic mechanisms. Drug effects depend on the amount of drug that is administered. o If the dose is below that needed to produce a measurable biological effect, then no response is observed; any effects of the drug are not sufficient to overcome homeostatic capabilities. o If an adequate dose is administered, there will be a measurable biological response. With an even higher dose, we may see a greater response. At some point, however, we will be unwilling to increase the dosage further, either because we
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
have already achieved a desired or maximum response or because we are concerned about producing additional responses that might harm the patient. Because pharmacology is the study of substances that produce biological responses, measurement of what happens when we administer medications is important. Two types - these responses differ in how they are measured and dictate dosing decisions to achieve the desired effect.
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
Drug Selectivity o An inability to tolerate the adverse effects of a medication, generally at therapeutic or subtherapeutic doses o The most reasonable way to express selectivity is as a ratio of the dose or concentration producing the undesired effect to the dose or concentration producing the desired effect.
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
o This is the same as determining how many times the therapeutic dosage needs to be increased to produce the undesired effect. o A medication that requires one tablet to produce the desired response and does not produce undesirable effects unless five tablets are used would have a selectivity ratio of
o The therapeutic index is a special ratio describing drug selectivity. The therapeutic index is the ratio of the lethal dose of a drug to the therapeutic dose of a drug. There are some limitations to the therapeutic index: it uses death, a really unacceptable adverse effect, and it uses data from animal studies. But the therapeutic index provides a fixed comparison for drug safety. The therapeutic index of drugs on the market is, of course, always greater than 1; a therapeutic index of less than 1 means that the drug kills before it cures.
Receptors (understand how they function and examples): Ion channel receptors, receptors coupled to G proteins, transmembrane receptors, intra-cellular receptors regulating gene expression
Enzymes
Agonists o Drugs that produce receptor stimulation and a conformational change every time they bind o A chemical that binds to a receptor and activates the receptor to produce a biological response o Some agonists can produce their maximum response by binding to less than 10% of the available receptors. The receptors that are left over and not needed for a response are called spare receptors. Antagonists o Blocks the action of the agonist; produce no direct response o Drugs that occupy receptors without stimulating them o Antagonists occupy a receptor site and prevent other molecules, such as agonists, from occupying the same site and producing a response o The response we see following administration of antagonists results from their inhibiting receptor stimulation by agonists ie: beta blockers - act as antagonists at the beta-adrenoceptor
Pharmacokinetics
The branch of pharmacology dealing with the absorption, distribution through the body, metabolism, and excretion of drugs. Ideally, drugs will enter the body readily, go directly to their site of action, and have a favorable combination of metabolism and excretion that will make it easy to manage patients, even in the presence of kidney or liver disease. Absorption o To produce a biological effect, drugs must enter the body. Once inside the body, drugs
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
o Parenteral Administration Medications may be administered parenterally, or by injection, when immediate effect is required, when the active ingredients are destroyed or not absorbed in the gastrointestinal tract or other routes, or when the patient is unable to take an oral medication. A major limitation of parenteral administration is that it requires needles, syringes, and sterile technique. Intravenous (IV) injection - greatest drug absorption → all the drug enters the bloodstream immediately Advantage - rapid or complete absorption and immediate drug action Disadvantage - once administered, the dosage cannot be slowed or removed o Oral Administration Most convenient and common Following oral administration, dosages, as tablets, capsules, or liquid, make their way to the stomach and continue to move into and through the small and large intestines on their way to the colon. Tablets or capsules must break apart, and their drug contents must dissolve in stomach acid or intestinal fluid before the drug can be absorbed → This takes time, so orally administered drugs may not act as fast as some other routes of administration. Sublingual administration (under the tongue) and buccal administration (between the cheek and gum, as with chewing tobacco) allow drugs to have a more rapid onset of action and to avoid liver metabolism as they enter the bloodstream Enteric-coated formulations protect the medication in the stomach and only disintegrate and dissolve when they reach the gentler conditions of the intestinal tract. Sustained-release preparations allow a drug to dissolve slowly in the intestines so that medication is absorbed over a period of time. It is important not to crush these preparations before administration because that would destroy the formulation and speed absorption. o Site of Administration Topical administration allows medication to be concentrated in the skin when patients need an anti-inflammatory (e.g., hydrocortisone) or an antifungal (e.g., clotrimazole) medication for a skin condition. This is particularly advantageous in that drugs pass more easily through damaged skin, so more drug is available to the areas of the skin that need the medication. Multidose inhalers and nebulizers are commonly used to administer drugs (e.g., albuterol) directly into the lungs. Ophthalmic preparations are sterile preparations suitable for administration to the eye. Because the eye is particularly sensitive, ocular medications are typically buffered and isotonic so that they do not cause discomfort when administered. Aural preparations, intended for administration into the ear canal, do not meet the
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
buffering and isotonicity requirements for ophthalmic administration. o Bioavailability Because not all of the administered dosage may be dissolved or absorbed or survive liver passage, only a fraction of an administered dosage makes it to the bloodstream → this percentage of the administered dose that does enter the bloodstream is called the bioavailability of the dosage form.
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
At higher acidity, or lower pH, carboxylic acid groups are uncharged, but amine groups are charged. At low acidity, at higher pH under basic conditions, the amine groups are uncharged, but the carboxylic acid groups are charged Each drug is unique, and the pH at which it exists half in the charged state and half in the uncharged state is defined as its pKa.
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
Since the pH of body fluids is limited to a relatively narrow range and the pKa is a fixed property for an individual drug, we can calculate the percentage of charged and uncharged molecules for a drug if we know its pKa. The pKa can be an important drug property that influences absorption, distribution, and excretion of the drug. Passive diffusion is a process by which drugs cross some type of biological barrier, such as a cell membrane or through a layer of cells, based on the concentration difference on the two sides of the barrier We expect that passive diffusion will proceed until the concentration of drug is equal on both sides, but that is not quite what happens. Instead, passive diffusion proceeds until the concentration of unionized drug is the same on both sides. As a result of this, pH differences can cause more drug to accumulate based on the fraction of unionized and ionized molecules → called ion trapping Protein Binding o Drugs passively diffuse and distribute when they are unbound and uncharged. o Drugs can bind to a variety of proteins that are present in the bloodstream → plasma proteins Many plasma proteins are produced in the liver, and their presence in the blood reflects liver function, nutritional status, and the effect of aging and disease. Albumin is a major protein in the blood and is measured as part of a typical blood analysis o Binding to plasma proteins serves several important functions Drugs bound to plasma proteins can freely circulate in the bloodstream rather than be distributed by passive diffusion from their site of absorption, so plasma protein binding helps normalize concentrations throughout the body. Drugs that are bound to plasma protein can be protected from metabolism in the liver and from excretion by the kidneys, so plasma protein binding can extend the period of time that drugs remain in the body. o Binding to plasma proteins can protect drugs from metabolism and excretion, extending the time the drugs remain in the body → but remember the general principle that drug action occurs through free, unbound drug. o Protein binding, which may include binding to proteins that are not in the plasma, also prevents the interaction of drug molecules with their site of action. o Plasma protein binding creates a reservoir of bound drug molecules that can unbind at any time to interact with drug receptors and produce responses o Plasma protein binding occurs in the plasma and encourages retention of drug in the systemic circulation. So it may appear that blood levels of a drug are high, even if the drug is not at its active site → ie: digoxin o Drugs bound to plasma proteins cannot interact with their receptor. If a drug is very strongly bound to plasma proteins, then even a small change in the fraction that is bound can have significant pharmacological effects Transport Systems o Drug distribution is also influenced by transporters, membrane proteins that facilitate the movement of molecules across the cell membranes o Transport systems are often directional, and they can transport drugs into (influx) or out of (efflux) cells
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
o Transport systems also form the basis for distribution into protected tissues. p- Glycoprotein, an efflux secretory transporter, is widely distributed and limits the entry of drugs into the brain, testes, intestines, and other sites. Depending on the site, inhibition of p-glycoprotein can result in increased intestinal absorption or distribution into the brain or testes o Also affect distribution to sites of metabolism Transport or diffusion of a drug into cells is required for intracellular metabolism, and transport systems can control how much of a drug is available to an intracellular enzyme for metabolism. Metabolism (i ncluding first-pass and Phase I and II) o Important factor in determining drug activity o When drugs are metabolized, they are chemically altered by enzymes into new molecules → metabolites o Definition - the process of changing one chemical into another Process usually either creates or uses energy o Metabolism of drugs can occur in every biological tissue but mostly occurs in the smooth endoplasmic reticulum of cells in the liver o Liver → a major organ for drug metabolism because it contains high amounts of drug- metabolizing enzymes and because it is the first organ encountered by drugs once they are absorbed from the GI tract o Metabolism by the liver following oral administration is called first-pass metabolism and is important in determining whether a drug can be orally administered. o Cytochrome P450 → family of enzymes that metabolizes drugs Each of these CYP enzymes is responsible for a single type of metabolic rxn Phase I reactions - “non-synthetic reactions” Involve oxidation, reduction, and hydrolysis reactions - prepares the drug molecule for further metabolism Introduces or unmask polar groups that, in general, improve water solubility and prepare drug molecules for further metabolic rxns Can result in metabolites with greater or lesser pharmacological activity Many phase I metabolites are rapidly eliminated, whereas others go on to phase II rxns Phase II reactions - “synthetic or conjugation reactions” Drug molecules are metabolized and something is added to the drug to synthesize a new compound Metabolites are linked, or conjugated, to highly polar molecules such as glucuronic acid, glycine, sulfate, or acetate by specific enzymes. Conjugation to these molecules makes metabolites more water soluble and more easily excreted by the kidneys → so the presence or activity of these enzymes can influence the pattern of drug activity and the duration of action for drugs.
Excretion: Renal, Biliary, Other (ex: for volatile drugs)
Definition - the process in which drugs are transferred from inside the body to outside the body Kidney and gallbladder - site where drugs are excreted but not absorbed
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
The principal organs for drug elimination → kidneys, lung, biliary system, and intestines Renal Excretion o Kidney - primary organ of excretion for most drugs o General theme of metabolism - to produce drug metabolites that are more water soluble and more easily removed by the kidneys
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
For example, low doses of salicylates, such as aspirin, inhibit tubular secretion and decrease total urate excretion, whereas higher doses inhibit tubular reabsorption and result in increased excretion of uric acid. Tubular Secretion o The nephron also contains active secretory systems that transport drugs from the blood into the lumen of the nephron.
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
o There is a transport system that secretes organic anions and a transport system that secretes organic cations. o The transporters are present on the plasma side of the tubular cells of the nephron, where they actively pump anions or cations into the cell → The substances then pass into the lumen by passive transport. o The secretory capacity of these transporters can be saturated so that less drug is excreted at high drug concentrations. When two drugs are substrates for the same transporter, they compete with one another and decrease the rate at which each is excreted. o Tubular secretion often contributes to the renal elimination of drugs that have short half- lives. o Hydrochlorothiazide, furosemide, penicillin G, and salicylates are among the substrates for the organic anion transport system. The organic cation transport system actively secretes atropine, cimetidine, morphine, and quinine. Renal Excretion of Drugs o The rate at which a drug is excreted by the kidneys depends on several factors. Renal blood flow influences the GFR, which is how much plasma is filtered per minute by the glomerulus. Filtration in the glomerulus depends on the molecular size, the charge, and the degree of protein binding, each of which influences how much drug passes through the glomerular basement membrane. Tubular acidity will influence the degree of reabsorption. Active reabsorption or active secretion into the urine may also influence excretion rate o Renal function is typically assessed from patient serum creatinine along with height, weight, age, and gender. Biliary Excretion o The liver secretes about a liter of bile each day o Drugs can enter the bile and be excreted into the intestinal tract when bile is released to help digest food. o Only small amounts of drug enter the bile by diffusion; instead, biliary excretion contributes to removal of some drugs. o The biliary system includes three types of active transport: organic cation, organic anion transporters, and bile acid transport system o Conjugated metabolites of drugs generally have enhanced biliary excretion o Cardiac glycosides, such as digoxin, are an example of drugs secreted into the bile. o Some drugs that are excreted in bile can be reabsorbed in the intestine → enterohepatic cycling → drug is excreted in the bile, absorbed from the intestines, and then excreted in the bile again Other Sites of Excretion o Pulmonary excretion can occur for any volatile material present in the body Important for anesthetic gases, such as nitrous oxide Also important following alcohol consumption Ethanol distributes throughout the body and is readily excreted each time we breathe → because the amount of ethanol exhaled in each breath is proportional to blood level, the Breathalyzer can be used to estimate blood
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
Excretion of drugs into sweat and saliva is of minor importance for most drugs and depends on the diffusion of uncharged drug across the epithelial cells of sweat and salivary glands Excretion into hair, sweat, and saliva is quantitatively unimportant but can be used to noninvasively detect drugs in the body Interestingly, some drugs excreted into saliva can produce changes in taste Excretion into saliva might help explain part of the pharmacological action of certain drugs, such as antibiotic erythromycin, in throat infections. o Breast milk of nursing mothers The concentration in the breast milk depends on drug properties such as lipid solubility and the degree of ionization and on patient properties such as the extent of active secretion into breast milk and the blood level of the drug in the mother Low-molecular-weight drugs that are unionized can passively diffuse across the epithelial cells of the mammary gland and enter the breast milk. Because breast milk is more acidic than plasma, it tends to accumulate basic drugs Infants can be exposed to drugs through breast milk. The risk to the infant from drug exposure in breast milk depends on the amount and type of drug involved and the ability of the infant to metabolize the drug. Breastfeeding is discouraged when there is a potential for drug toxicity in the infant.
Chapter 7: Cultural and Ethnic Influences in Pharmacotherapeutics
Health disparities in the U.S. Cultural influences on care
Standards of cultural competency: National standards of culturally and linguistically appropriate standards
Eliminating health disparities
Ethnopharmacology including pharmacokinetic factors the potentially exhibit racial differences
African Americans, Native groups, Asian Americans, Hispanic Americans
Cultural Influences on Care
Understanding health disparities is having knowledge of cultural factors that may impact the well- being of patients
Who makes the decisions in the family about health care?
Does this person support the use of the prescribed drug and the plan of care?
How does the patient and family members view health and illness and their views on the management plan?
Cultural factors that may create challenges in adhering to the treatment plan are all important to
Chapter 2: Review of Basic Principles of Pharmacology
Comprehensive Exam Study Guide Latest Updated 2024
helping clients improve and/or maintain their health
- It is important to know what is common to members of the group and in particular what risk factors the group shares
