NUR 613 Advanced Pharmacology and Therapeutics Exam 1 PDF

NUR 613: Advanced Pharmacology and Therapeutics: MODULE 01: Virtual Classroom 01 SPRING 2025 Pharmacology: The Basics Drug Any chemical that can a?ect living processes Pharmacology (pharmakon-poison; ology-study of) The study of drugs and their interactions with living systems Clinical Pharmacology The study of drugs in humans Therapeutics (also known as Pharmacotherapeutics) The use of drugs to diagnose, prevent or treat disease or to prevent pregnancy or, the medical use of a drug Pharmacology: The Therapeutic Objective The objective of drug therapy is to provide maximum beneﬁt with minimum harm In order to meet this challenge, there must be: Skill Judgement Knowledge The desire to provide greater good than harm How does this happen? STUDY, LEARN, and APPLY Properties of an Ideal Drug: The Big 3 ENectiveness The most important property a drug can have Safety There is no such thing as a safe drug Selectivity There is no such thing as a selective drug ALL drugs have side eNects The Ideal Drug: The Other Properties Why is all of this important? Reversible Action Predictability Ease of Administration Freedom from Drug Interactions Low Cost Chemical Stability Simple Generic Names WHY IS EACH OF THESE IMPORTANT? Terms Related to Adverse Drug Reactions Allergic reaction Immune response (Type I and Type IV Hypersensitivity Rxns) Determined primarily by the degree of sensitization of the immune system NOT by drug dosage Patient’s sensitivity to a drug can change over time Very few drugs cause severe allergic reactions Penicillins are the most common Allergies may also be induced by sulfonamides (as well as diuretics, other antibiotics, and oral hypoglycemic agents) Terms Related to Adverse Drug Reactions Idiosyncratic eNect An uncommon drug response resulting from a genetic predisposition Succinylcholine-induced paralysis Usually brief but may last for hours in genetically predisposed patients (acetylcholinesterase deﬁciency) Paradoxical eNect The opposite of the intended drug response For example, when using benzodiazepines for sedation to treat insomnia, excitement may occur instead (especially in children and older adults) Terms Related to Adverse Drug Reactions Physical dependence Develops during long-term use of certain drugs (opioids, alcohol, barbiturates, and amphetamines) A state in which the body has adapted to drug exposure in such a way that an abstinence syndrome will result if drug is discontinued It is important to warn patients against abrupt discontinuation of any medication without ﬁrst consulting a knowledgeable health professional (i.e., the nurse practitioner responsible for the patient’s care) Iatrogenic disease Iatrogenic: Literally, “a disease produced by a healer”; also used to refer to a disease produced by drugs (e.g., drugs for antipsychotic disorders can cause Parkinson’s-like symptoms) Sometimes also called drug-induced disease Essentially identical to naturally occurring pathology ENects of Drugs (Kinetics and Dynamics) Drug-Drug Interaction Addition (potentiation) drugs of similar action-e?ect are additive: 1 + 1 = 2 (Diuretic + 𝛽-blocker) Synergism di?erent drugs enhance the action of another drug: 1 + 1 = > 2 (Bactrim→ two abxs combined) Inhibition the use of one drug antagonizes the e?ect of another drug: 1 + 1 < 2 (Morphine + naloxone) Drug-Drug Interactions (KINETICS) Intensiﬁcation of e?ects Increased therapeutic e?ects Sulbactam and ampicillin Increased adverse e?ects Aspirin and warfarin Reduction of e?ects Inhibitory: Interactions that result in reduced drug e?ects Reduced therapeutic eNects Propranolol and albuterol Reduced adverse eNects Naloxone to treat morphine overdose Factors That Determine the Intensity of Drug Responses (Much more on this later!) How the drug is administered Pharmacokinetics What the BODY DOES TO THE DRUG Pharmacodynamics What the DRUG DOES TO THE BODY Sources of Individual Variation Varies from PERSON TO PERSON Factors that Determine the Intensity of Drug Responses Stages of New Drug Development Phase I: The objective is to evaluate drug metabolism, pharmacokinetics, and biologic eNects. Phase II and III: The objective is to determine therapeutic eNects, dosage range, safety, and eNectiveness. Phase IV: the new drug is released for general use, permitting observation of its eNects in a large population. 18 months of COVID-19 VACCINE NEXT phase of COVID-19 VACCINE Exercise Discretion Regarding New Drugs Be neither the ﬁrst to adopt the new nor the last to abandon the old Balance potential beneﬁts against inherent risks New drugs generally present > risks than older ones Why would you think this? Pharmaceutical reps are in the business of selling drugs Do your due diligence before prescribing a new drug Drugs: “What is in a name? That which we call a rose by any other name would smell as sweet.” (Shakespeare Romeo and Juliet, Act 2, Scene 2) How do we name drugs? Chemical formula 3,3-Dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2- carboxylic acid Chemical name Phenoxymethylpenicillin Generic name (o?icial name: Only name used on national board exams) penicillin v Trade name Propicillin® (just one of many trade names) Which Name to Use: Generic or Trade? The little problems with generic names More complicated than trade names The big problems with trade names Single drug can have multiple trade names Adalat CC®, Nifedical XL®, Nifediac CC®, Procardia®, Procardia XL® are all the same drug (nifedipine, a calcium channel blocker) U.S. drugs and drugs outside the United States may have di?erent active ingredients Products with the same generic name may have di?erent active ingredients and di?erent bioavailability For example, Kaopectate® (kayolen) Ways to Classify Drugs Therapeutic Classiﬁcation Pharmacologic Classiﬁcation Drugs grouped by what they treat Grouped by the chemical structure/mechanism of action (MOA) → how they work –Drugs to lower plasma volume –Diuretics –Drugs for high blood pressure (BP) –Calcium channel blockers –Drugs for depression –Selective serotonin reuptake inhibitors (SSRIs) Ways to Classify Drugs Other forms of classiﬁcation are used for speciﬁc purposes. Controlled substances morphine Over-the-counter (OTC) medications Tylenol Homeopathic drugs pollen for treatment of hay fever Herbal remedies rosemary tea SuNixes are helpful (Do Not Learn Yet) Identifying Therapeutic Use Pharmacologic Class Drug Name SuNix Infection Penicillin antibiotic -cillin Amoxicillin Amoxil High cholesterol HMG-CoA reductase inhibitor -statin Simvastatin Zocor Peptic Ulcer Proton pump inhibitor -prazole Omeprazole Prilosec Disease Anticoagulation Low-molecular-weight heparin -parin Enoxaparin Lovenox Diazepam Valium Alprasolam Anxiety Benzodiazepines -epam -olam Xanax Phosphodiesterase type 5 Erectile dysfunction -aﬁl Sildenaﬁl Viagra inhibitor Over-the-Counter Drugs Americans spend about $30 billion annually on over-the-counter (OTC) drugs OTC drugs account for 60% of all doses administered 40% of Americans take at least one OTC drug every 2 days 4x as many illnesses are treated by a consumer using an OTC drug as by a consumer visiting a physician or nurse practitioner The average home medicine cabinet contains 24 OTC preparations Pharmacologic Classiﬁcations: Controlled Substances Abuse Deﬁnitions for Schedule I – V Drugs Potential High potential for abuse Schedule No currently accepted medical use in the United States I* Lack of accepted safety for due of the drug under medical supervision High potential for abuse Schedule Currently accepted medical use in the United States II Abuse may lead to severe psychological or physical dependence Potential for abuse less than schedule I and II drugs Schedule Currently accepted medical use in the United States III Abuse may lead to moderate or low physical dependence or high psychological dependence Lower potential for abuse than schedule III drugs Schedule Currently accepted medical use in the United States IV Abuse may lead to limited physical or psychological dependence relative to schedule III substances Low potential for abuse relative to schedule IV substances Schedule Currently accept4ed medical use in the United States V Abuse may lead to limited physical or psychological dependence relative to schedule IV substances *N indicates that the drug is a non-narcotic. For example, a Schedule III-N drug, such as anabolic steroids has potential for abuse greater than a Schedule IV or Schedule IV-N drug. Sources of Drug Information (information only) Newsletters The Medical Letter on Drugs and Therapeutics: bimonthly Prescriber's Letter: monthly Reference Books Physicians' Desk Reference based upon package inserts Drug Facts and Comparison very comprehensive reference; updated monthly Saunders Nursing Drug Handbook - annual Mosby's Drug Guide for Nurses - annual The Internet If it is on the internet, it must be true, right?! Pharmacokinetics (MOTION) or WHAT THE BODY DOES TO THE DRUG) Factors That Determine the Intensity of Drug Responses: KINETICS (κίνησις→kinetikos – Greek for putting in motion) Pharmacokinetics: Impact of the BODY ON THE DRUG: The FOUR PHASES Absorption → blood GI tract, skin, mucous membranes, direct injection into the blood, muscle Distribution site of absorption to site of action Metabolism liver, kidney, site of action Excretion kidney, bile, stool The 4 Basic Pharmacokinetic Processes (A di?erent visual) Figure 4.1, p. 25., Burchum & Rosenthal All phases of pharmacokinetics depend upon the drug crossing a membrane Channels or pores –smallest of the drugs Transport active—requires energy passive—requires no energy p-glycoprotein: transports a wide variety of drugs OUT of cells Direct—lipid (fat) soluble Di?usion P-Glycoprotein P-glycoprotein: Transmembrane protein that transports a wide variety of drugs out of cells Liver: Transports drugs into the bile for elimination Kidney: Pumps drugs into the urine for excretion Placenta: Transports drugs back into the maternal blood Brain: Pumps drugs into the blood to limit the drug’s access to the brain The 4 Basic Pharmacokinetic Processes (A di?erent visual) Figure 4.1, p. 25., Burchum & Rosenthal Passage of Drugs Across Membranes (Kinetics) For most drugs, movement throughout the body is dependent on the drug’s ability to penetrate membranes directly Most drugs are too large to pass through channels or pores Most drugs lack transport systems that help them cross all the membranes that separate them from their sites of action, metabolism, and excretion Passage of Drugs Across Membranes (Kinetics) A general rule in chemistry states that “like dissolves like” Water dissolves water-soluble materials Fat dissolves lipid-soluble materials Cell membranes are composed primarily of lipids therefore, to directly penetrate membranes, a drug must be lipophilic→lipid soluble (lipo-fat; philic-loving) Absorption (Kinetics) Movement of a drug from its site of administration into the blood The rate of absorption determines how soon e?ects will begin The amount of absorption helps determine how intense the e?ects will be Factors aNecting drug absorption (Think of the pathophysiologic factors that a4ect each of the following) Rate of dissolution Surface area Blood ﬂow Lipid solubility pH partitioning Site of administration How Does the Drug Get There? What Are the Barriers? Absorption Is the medication given correctly? Is the patient adherent to the drug regimen? How is the medication given? orally (PO) rectally (PR) intravenous (IV) subcutaneous (SQ) intramuscular (IM) lungs transdermal transvaginal sublingual (SL) buccal (BUCC) nasal ophthalmic Movement of Drugs Following GI Absorption (Kinetics) Distribution (Kinetics) Movement of drugs throughout the body Blood ﬂow to tissues Exiting the vascular Drug system distribution is Entering cells determined by these three factors: How Does the Drug Get Where It Is Supposed To? (Kinetics) DISTRIBUTION—Transport of the drug from the site of absorption to the site of action (absorption may be direct or indirect) Factors A?ecting Distribution Organ blood ﬂow brain, heart, liver, kidney, placenta: highly perfused-rapid onset of action Plasma Protein Binding almost all drugs are reversibly bound to plasma proteins→WHY IS THIS IMPORTANT albumin Molecule Size Lipid Solubility Blood Flow to Tissues (Kinetics) Drugs→blood→tissues and organs of the body Blood ﬂow determines the rate of delivery Abscesses and tumors Low regional blood ﬂow a?ects therapy Pus-ﬁlled pockets rather than internal blood vessels Solid tumors have a limited blood supply Distribution: Special Circumstances (Kinetics) DISTRIBUTION— Blood-Brain Barrier unique anatomy of capillaries in the central nervous system (CNS)—tight junctions vascular junctions are so tight that they prevent drug passage drugs MUST BE lipid soluble AND have a transport system that allows passage through the cells of the capillary wall the good: prevents passage of toxins the bad: prevents the delivery of helpful therapies for CNS disorders (e.g., antibiotics, chemotherapy) poorly developed in the newborn→babies are particularly sensitive to drugs that act on the brain Capillaries; The Blood-Brain Barrier Typical capillary Blood-brain barrier Large gaps allow drug passage Tight junction prevents drug passage Distribution: Special Circumstances (Kinetics) DISTRIBUTION— The Placenta separates maternal circulation from fetal circulation NOT an absolute barrier to drugs and other toxins lipid soluble, non-ionized substances freely cross Possible consequences for the fetus »mental retardation »drug dependence »fetal malformations ion trapping-the fetal compartment is more acidic than the mother; non-ionized substances that cross can become ionized in lower pH environments and then get “trapped” in the fetal compartment How Does the Drug Get Where It Is Supposed To? Special Circumstances (Kinetics) DISTRIBUTION— Protein binding: albumin is a HUGE molecule; because of the size, albumin always (well, almost always) remains in the blood (Where have you seen this information before?) Drug molecules reversibly* bind with albumin for TRANSPORT bound drugs-INACTIVE unbound drugs-ACTIVE or FREE dynamic state between inactive and active form of drug-molecules are always leaving and attaching to the transport molecule % of binding is unique to each drug disorders that decrease or increase albumin production will change the free and bound concentrations of drugs (What are some of these disorders?) *This would make sense because a drug molecule that is irreversibly bound to a carrier molecule would serve no purpose. Free at last..... Drug Therapy During Pregnancy: Ion Trapping Protein Binding A. Albumin is the most prevalent protein in plasma and the most important of the proteins to which drugs bind. B. Only unbound (free) drug molecules can leave the vascular system. Bound molecules are too large to ﬁt through the pores in the capillary wall. FIG. 4.10 Movement of drugs after gastrointestinal (GI) absorption. What Does the Body Do to Make the Drug Work? (Kinetics) METABOLISM or BIOTRANSFORMATION –drug is converted to a less active or more active form –ﬁrst pass eNect drugs absorbed from the intestine are transported to the liver where the drug is metabolized to decrease or increase the amount of active drug –metabolites active inactive The Liver (Kinetics) Metabolism: Special Considerations (Kinetics) Induction of drug-metabolizing enzymes –certain drugs may induce liver enzymes that speed the metabolism of the inducing drug as well as other drugs Cytochrome P450 Malnutrition –metabolism may be compromised Infants –Limited drug metabolism due to immature liver because liver enzymes not fully active –Liver is fully mature at one year –Smaller dosages required –May be a?ected by milk Metabolic competition –if the same system metabolizes two drugs, one will compete with the other; drug levels may not be predictable Special Considerations: The Elderly (Kinetics) THE ELDERLY Absorption Decreased gastric acidity Slowed gastric emptying Slower movement through the GI tract –Delayed absorption Reduced blood ﬂow to the GI tract –Decreased ﬁrst pass Distribution Decreased cardiac output Vascular disease Competition of other drugs for receptor sites Metabolism Decreased liver function –Active drug levels may be too low or too high Excretion Decreased kidney function Competition of multiple drugs for tubular excretion What are comorbid conditions that the elderly experience that would cause these issues? REMEMBER (Kinetics) DRUG Possible increased toxicity secondary to inhibition of the Cytochrome P450 system Special Considerations in Drug Metabolism (Kinetics) Age Induction of drug-metabolizing enzymes First-pass e?ect Nutritional status Competition among drugs What Does the Body Do to Get Rid of the Drug? (Kinetics) EXCRETION: the removal of drugs from the body Renal (kidney): majority of drug excretion healthy vs unhealthy kidneys older vs younger kidneys pH dependence Other bile (liver), sweat, saliva, breast milk, lungs Renal Routes of Drug Excretion Steps in renal drug excretion Glomerular ﬁltration Passive tubular reabsorption Active tubular secretion Factors that modify renal drug excretion pH-dependent ionization Competition for active tubular transport Age (why?) Time Course of Drug Responses (Kinetics) Plasma Drug Levels: Clinical Signiﬁcance drug level of e?ectiveness Minimum E?ective Concentration (MEC) the plasma drug level below which therapeutic e?ects will not occur Toxic Concentration (TC) the plasma drug level above which harm occurs Therapeutic range- The objective of drug dosing is to maintain plasma drug levels within the therapeutic range the AREA BETWEEN MEC and TC (SEE NEXT SLIDE) Time Course of Drug Responses (Kinetics) Single-dose Time Course Latent phase: time from administration to minimal e?ective concentration (MEC) Durationofaction: timefromMECto MEC FIG. 4.13 Single-dose time course, p. 41, Burchum & Rosenthal Time Course of Drug Responses (Kinetics) Drug Half-life (t1/2) the time required for the amount of drug in the body to decrease by 50% T1⁄2 is independent of the amount of drug given Drug half-life (t1/2) gives many students a challenge. Do what it takes to understand this. (The videos are helpful.) Time Course of Drug Responses (Kinetics) When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant, and plateau has been reached. Plateau is reached in approximately four half-lives. When drug is discontinued, 94% reduction in plasma level occurs in four half-lives and ~97% is removed in ﬁve half-lives. Make sure you understand the concept of plateau and half-life!!! (I cannot be any more direct than this.) Time Course of Drug Responses (Kinetics) After repeated doses, –highest level→peak –lowest level→trough Fluctuation reduction –continuous infusion –administer depot prep –reduce dose size and decrease time of dose frequency Why is the concept of peak and trough important? (Think about your clinical experience.) Initial peak At At plateau, plateau, 2 gms trough peak is 2x ~ = initial initial MEMORY TRICK→ peak 2 gms peak 4g Time Course of Drug Responses (Kinetics): The Numbers gms Question Drug X with T(1/2) of 12 hrs is given q 12 hrs. If the initial drug peak is 500 mcg/L, what is the drug level just before dose 31 is given? 250 mcg/L 500 mcg/L 1000 mcg/L 2000 mcg/L Question Drug X with T(1/2) of 12 hrs is given q 12 hrs. If the initial drug peak is 500 mcg/L, what is the drug level just before dose 31 is given? 250 mcg/L 500 mcg/L 1000 mcg/L 2000 mcg/L The trick as discussed in the VC, at plateau, the trough is ~ = initial dose peak; peak is 2x initial dose peak. Knowing this allows you to know peak and trough before or after any dose after plateau is reached. What Can Change the Kinetics of a Drug? (Kinetics) Food impact on Drug Absorption ↓ absorption Decreases rate Drug is kept in the stomach for a longer time Decreased extent Example: milk binds tetracycline, ﬁber binds digoxin ↑ absorption Some foods increase the absorption of a medication to increase its therapeutic e?ect High-calorie meal more than doubles the absorption of Invirase (saquinavir), a drug for HIV Factors That Determine the Intensity of Drug Responses: DYNAMICS Pharmacodynamics: Impact of DRUGS ON THE BODY The drug must FIRST bind to a RECEPTOR --Important concept!!! A DRUG-RECEPTOR INTERACTION must take place --Important concept!!! A cellular response occurs BECAUSE of the DRUG-RECEPTOR INTERACTION Receptor A receptor is any functional macromolecule in a cell to which a drug binds to produce its e?ects Receptors can include enzymes, ribosomes, and tubulin The term receptor is generally reserved to refer to the body’s own receptors for hormones, neurotransmitters, and other regulatory molecules Drugs produce their therapeutic eNects by helping the body use its preexisting capabilities Types of Receptors (p. 48, Burchum & Rosenthal) First and Second Messengers Figure 2.9, p. 23, Norris (11th ed.) Porth’s Pathophysiology Factors That Determine the Intensity of Drug Responses: DYNAMICS Drug-receptor interaction Simple Occupancy Response is related to the number of receptors occupied Modiﬁed Occupancy The higher the aGinity of a drug to the receptor, the higher the potency The lower the aGinity of a drug to the receptor, the lower the potency FIG. 5.6 Model of simple occupancy theory, p. 50, Burchum & Rosenthal Factors That Determine the Intensity of Drug Responses: DYNAMICS Drug-receptor interaction Agonist Molecule that activates receptors Partial agonist Molecule that produces a response but not as great as an agonist Antagonist Molecule that blocks the activation of a receptor Interaction of Drugs with Receptors Under physiologic conditions, cardiac output can be increased by the binding of norepinephrine (NE) to receptors (R) on the heart. Norepinephrine is supplied to these receptors by nerves. These same receptors can be acted on by drugs, which can either mimic the actions of endogenous NE (and thereby increase cardiac output) or block the actions of endogenous NE (and thereby reduce cardiac output). Figure 5.3, p. 47, Burchum & Rosenthal, 12th ed. Dose-Response Relationships As the dosage increases, the response becomes progressively larger Treatment is tailored by increasing or decreasing the dosage until the desired intensity of response is achieved Very high maximal eNicacy is not always more desirable Maximum ENicacy & Relative Potency A ENicacy, or maximal e?icacy, is an index of the maximal response a drug can produce. The e?icacy of a drug is indicated by the height of its dose-response curve. In this example, meperidine has greater e?icacy than pentazocine. ENicacy is an important quality in a drug B Potency is an index of how much drug must be administered to elicit a desired response. In this example, achieving pain relief with meperidine requires higher doses than with morphine. We would say that morphine is more potent than meperidine. Note that, if administered in su?iciently high doses, meperidine can produce just as much pain relief as morphine. Potency is usually not an important quality in a drug. Receptor Binding The binding of a drug to its receptor is usually reversible Receptor activity is regulated by endogenous compounds When a drug binds to a receptor, it will mimic or block the action of the endogenous regulatory molecules and increase or decrease the rate of physiologic activity normally controlled by that receptor Receptors and Selectivity of Drug Action IMPORTANT CONCEPTS The more selective a drug is, the fewer side e?ects it will produce Receptors make selectivity possible Each type of receptor participates in the regulation of just a few processes Agonists – know the deﬁnitions – you will see this for the entire course Agonists are molecules that activate receptors Endogenous regulators are considered agonists Agonists have both a?inity and high intrinsic activity Example: Dobutamine mimics norepinephrine at cardiac receptors Agonists can make processes go “faster” or “slower” depending upon the eNect of the agonist on a particular cell Antagonists Do not cause receptor activation but cause pharmacologic eNects by blocking the activation of receptors by agonists VERY IMPORTANT CONCEPT If no agonist is present, an antagonist will have no observable e?ect Noncompetitive vs. Competitive Antagonists (see notes section) Noncompetitive antagonists Bind irreversibly to receptors Irreversible binding is equivalent to reducing the total number of receptors available for activation Reduce the maximal response that an agonist can elicit (fewer available receptors) Impact not permanent (cells are constantly breaking down “old” receptors and synthesizing new ones) Competitive antagonists Compete with agonists for receptor binding Bind reversibly to receptors Equal a?inity: Receptor occupied by whichever agent is present in the highest concentration Noncompetitive vs. Competitive Antagonists (Figure 5.7, Burchum & Rosenthal, p. 51, 12ed.) Interpatient Variability in Drug Responses Clinical implications of interpatient variability The initial dose of a drug is necessarily an approximation Subsequent doses must be “ﬁne tuned” based on the patient’s response ED50* in a patient may need to be increased or decreased after the patient response is evaluated * ED50 – The e?ective dose for 50% of people Therapeutic Index—It’s Just a Number*! Measure of a drug’s safety Ratio of the drug’s LD50 (average lethal dose to 50% of the animals treated) to its ED50 (average e6ective dose to 50% of the animals treated) Since we are dealing with humans, we look at TD50 rather than the LD50 (It doesn’t look good if we kill 50% of our study patients!) The larger/higher the therapeutic index, the safer the drug The smaller/lower the therapeutic index, the less safe the drug *Actually, think of Therapeutic Index as a ratio. FIG. 5.9, p. 53, Burchum & Rosenthal Chapter 6: Drug Interactions 1.Discuss the consequences of drug-drug interactions, the basic mechanisms of drug-drug interactions, and the critical steps in minimizing adverse drug- drug interactions. 2.Focus on the liver as an example of a drug-metabolizing system and explain why it is such a crucial organ in many drug-drug interactions. 3.Discuss the e?ect of food on drug absorption, on drug metabolism (e.g., grapefruit juice), and on drug toxicity and action, as well as the timing of drug administration with respect to meals. Drug-Drug Interactions Intensiﬁcation of e?ects Increased therapeutic e?ects Sulbactam and ampicillin Increased adverse e?ects Aspirin and warfarin Reduction of e?ects Inhibitory: Interactions that result in reduced drug e?ects Reduced therapeutic e?ects Propranolol and albuterol Reduced adverse e?ects Naloxone to treat morphine overdose Pharmacokinetic Interactions Altered absorption – which factors ↑ absorption and which ↓ absoprtion Elevated gastric pH Laxatives Drugs that depress peristalsis Drugs that induce vomiting Adsorbent drugs Drugs that reduce regional blood ﬂow Pharmacokinetic Interactions Altered distribution Competition for protein binding Alteration of extracellular pH Altered renal excretion Drugs can alter: Filtration Reabsorption Active secretion Pharmacokinetic Interactions Altered metabolism Most important and most complex mechanism in which drugs interact Cytochrome P450 (CYP) group of enzymes Example of inducing agent: Phenobarbital Increase rate of metabolism two- to three-fold over 7 to 10 days Resolve over 7 to 10 days after withdrawal Inhibition of CYP isoenzymes Usually undesired Clinical Signiﬁcance of Drug-Drug Interactions Drug interactions have the potential to signiﬁcantly a?ect the outcome of therapy Responses may be increased or reduced The risk for serious drug interaction is directly proportionate to the number of drugs a patient is taking Interactions are especially important for drugs with low therapeutic indices Many interactions are yet to be identiﬁed Minimizing Adverse Drug-Drug Interactions Minimize the number of drugs a patient receives Take a thorough drug history Be aware of the possibility of illicit drug use Adjust the dosage when metabolizing inducers are added or deleted Adjust the timing of administration to minimize interference with absorption Be especially vigilant when a patient is taking a drug with a low therapeutic index Organ-Speciﬁc Toxicity Many drugs are toxic to speciﬁc organs Common examples include: Kidneys: Amphotericin B (antifungal) Heart: Doxorubicin (anticancer) Lungs: Amiodarone (antidysrhythmic) Inner ear: Aminoglycoside (antibiotic) Hepatotoxic Drugs Leading cause of liver failure in the United States More than 50 drugs are known to be hepatotoxic As some drugs undergo metabolism, they are converted to toxic products that can injure liver cells Combining hepatotoxic drugs may increase the risk for liver damage (e.g., acetaminophen and alcohol) Monitor aspartate aminotransferase (AST) and alanine aminotransferase (ALT) for liver injury Watch for signs of liver injury; educate patients about jaundice, dark urine, light-colored stools, nausea, vomiting, malaise, abdominal discomfort, and loss of appetite QT Interval Drugs: More Than 100 Are Known QT interval: Measure of the time required for the ventricles to repolarize after each contraction QT drugs: Drugs that prolong the QT interval on electrocardiography (ECG) Creates serious risk of life-threatening dysrhythmias Examples: Torsade's de pointes, ventricular ﬁbrillation Minimizing the risk: Most patients are at higher risk, including women, older adults, and patients with bradycardia, congestive heart failure (CHF), congenital QT prolongation, low potassium, and low magnesium Do not use two QT drugs concurrently Adverse Reactions to New Drugs Half of all new drugs have serious ADRs that are not revealed during Phase II and Phase III trials Drugs that are suspected of causing a previously unknown adverse e?ect should be reported to MedWatch, the FDA Medical Products Reporting Program Patients with chronic disorders are especially vulnerable to ADRs Boxed Warnings Also known as black box warnings Strongest safety warning a drug can carry and still remain on the market Purpose of this warning is to alert prescribers to: Potentially severe side e?ects (for example, life- threatening dysrhythmias, suicidality, major fetal harm) Ways to prevent or reduce harm (for example, avoiding a teratogenic drug during pregnancy) Pediatric Patients Children ARE NOT little adults ▪Ongoing growth and development ▪Di?erent age groups have di?erent challenges ▪ Two-thirds (66%)of drugs used in pediatrics have never been tested in pediatric patients ▪Twenty percent (25%) of drugs were ine?ective for children even though they were e?ective for adults ▪Thirty percent (30%) of drugs caused unanticipated side e?ects, some of which were potentially lethal Pharmacokinetics: Neonates and Infants Absorption Oral administration Gastric emptying time Prolonged and irregular Adult function at 6 to 8 months Gastric acidity Very low 24 hours after birth Does not reach adult values for 2 years Low acidity: Absorption of acid-labile* drugs is increased *Low acidity (higher pH) delays the breakdown certain drugs making the drug more easily absorbable. Pharmacokinetics: Neonates and Infants Distribution Protein binding Amount of serum albumin is relatively low Binding of drugs to albumin and other plasma proteins is limited in the infant Endogenous compounds compete with drugs for available binding sites Limited drug/protein binding in infants Reduced dosage are needed Adult protein binding capacity develops by 10 to 12 months of age Blood-brain barrier Not fully developed at birth Drugs and other chemicals have relatively easy access to the central nervous system (CNS) Infants especially sensitive to drugs that a?ect CNS function Dosage should also be reduced for drugs used for actions outside the CNS if those drugs are capable of producing CNS toxicity as a side e?ect Pharmacokinetics: Neonates and Infants Hepatic metabolism drug-metabolizing capacity of newborns is low Neonates are especially sensitive to drugs that are eliminated primarily by the hepatic metabolism The liver’s capacity to metabolize many drugs increases rapidly about 1 month after birth The ability to metabolize drugs at the adult level is reached a few months later Complete liver maturation occurs by 1 year of age Renal excretion Signiﬁcantly reduced at birth Signiﬁcantly reduced at birth Low renal blood ﬂow, glomerular ﬁltration, and active tubular secretion Drugs eliminated primarily by renal excretion must be given in reduced dosage and/or at longer dosing intervals Adult levels of renal function achieved by 1 year Metabolism: Infants vs Adults Fig. 12.1 A. Plasma drug levels following IV injections. Dosage was adjusted for body weight. Note that plasma levels remain above the minimum e?ective concentration much longer in the infant. B. Plasma drug levels following sub-Q injection. Dosage was adjusted for body weight. Note that both the maximum drug level and the duration of action are greater in the infant. (p. 103, Burchum & Rosenthal, 12th ed.) Pharmacokinetics: Children One Year and Older Most pharmacokinetic parameters are like those of adults Drug sensitivity more like that of adults than for children younger than 1 year old One important diNerence: Children in this age group metabolize drugs faster than adults Markedly faster until the age of 2 years, then a gradual decline Sharp decline at puberty (Can you think of a reason why this might happen? See the notes!!!) May need to increase dosage or decrease interval between doses Adverse Drug Reactions Children are vulnerable to unique adverse e?ects related to organ immaturity and ongoing growth and development Age-related eNects: Growth suppression (caused by glucocorticoids) Discoloration of developing teeth (tetracyclines) Kernicterus (sulfonamides) in neonates Promoting Adherence Provide patient/caregiver education in writing Dosage size and timing Route and technique of administration Duration of treatment Drug storage Demonstration techniques should be included as appropriate Drug Therapy in Geriatric Patients 1. Identify the main age-related physiologic, pathophysiologic, and pharmacologic factors that inﬂuence how older adults respond di?erently to drugs and state how those di?erences could (or likely will) a?ect drug responses. 2. Identify the most important factors that predispose older patients to adverse drug reactions. 3. Describe common reasons for noncompliance and nonadherence that are particularly relevant to older adults and list some approaches for minimizing those problems and improving compliance. Older Adult Patients The Beers Criteria When prescribing medications to older patients, it is important to check recommendations in the Beers Criteria→important to know about Altered pharmacokinetics More sensitive to drugs than younger adults and with greater variation in pharmacokinetics Multiple and severe illnesses Severity of illness, multiple pathologies Multiple-drug therapy Excessive prescribing Poor adherence Pharmacokinetics: Distribution Increased percentage of body fat Storage depot for lipid-soluble drugs Decreased percentage of lean body mass Decreased total body water Distributed in smaller volume; concentration increased and e?ects more intense Reduced concentration of serum albumin May be signiﬁcantly reduced in malnourished patients Causes decreased protein binding of drugs and increased levels of free drugs Pharmacokinetics: Metabolism Hepatic metabolism declines with age Reduced hepatic blood ﬂow, reduced liver mass, and decreased activity of some hepatic enzymes occur The half-lives of some drugs may increase, and responses are prolonged Responses to oral drugs (for example, those that undergo extensive ﬁrst-pass e?ect) may be enhanced Pharmacokinetics: Excretion Renal function undergoes progressive decline beginning in early adulthood (Another pathophysiology reference!) Reductions in renal blood ﬂow, glomerular ﬁltration rate, active tubular secretion, and number of nephrons Drug accumulation because of reduced renal excretion is the most important cause of adverse drug reactions in older adults Fig. 32.14 Relationship between the percentage of renal function and serum creatinine levels. (Norris, Porth’s Pathophysiology, 11h ed, p. 1104.) Pharmacokinetics: Excretion Renal function should be assessed with drugs that are eliminated primarily by the kidneys In patients who are older adults: Use creatinine clearance rather than serum creatinine to assess this, because lean muscle mass (source of creatinine) declines in parallel with kidney function (Remember module 05 last semester?) Creatinine levels may be normal even though kidney function is greatly reduced Summary of Pharmacokinetics in Older Adults (How much of this could you predict from Pathophysiology? I hope you are beginning to see how these courses are really coming together!) Increased Gastric pH ABSORPTION of Decreased absorptive surface area Decreased splanchnic blood ﬂow Drugs Decreased GI motility Delayed gastric emptying Increased body fat DISTRIBUTION of Decreased lean body mass (LBM) Decreased total body water Decreased Drugs serum albumin Decreased cardiac output (CO) METABOLISM of Decreased hepatic blood ﬂow Decreased hepatic mass Drugs Decreased activity of hepatic enzymes Decreased renal blood ﬂow EXCRETION of Decreased glomerular ﬁltration rate (GFR) Decreased tubular secretion Drugs Decreased number of nephrons Pharmacodynamic Changes in Older Adult Patients Alterations in receptor properties may underlie altered sensitivity to some drugs Drugs with more intense e?ects in older adults Warfarin and certain central nervous system depressants Beta blockers less eNective in older adults, even in the same concentrations Reduction in number of beta receptors Reduction in the a?inity of beta receptors for beta-receptor blocking agents Adverse Drug Reactions (ADRs) 7x more likely in the elderly Account for 16% of hospital admissions Account for 50% of all medication-related deaths Majority are dose-related rather than idiosyncratic* Symptoms in older adults are often nonspeciﬁc May include dizziness and cognitive impairment *What does this word mean? Factors That Contribute to Poor Adherence in Older Adults (Much of this is intuitive but some are surprising.) Multiple chronic disorders Multiple prescription medications Multiple doses per day for each medication Drug packaging that is di?icult to open Multiple prescribers Changes in the regimen (addition of drugs, changes in dosage size or timing) Cognitive or physical impairment (reduction in memory, hearing, visual acuity, color discrimination, or manual dexterity) Factors That Contribute to Poor Adherence in Older Adults (Much of this is intuitive but some are surprising.) Consider the social determinants of health that a?ect populations Living alone Recent discharge from hospital Low literacy Inability to pay for drugs Personal conviction that a drug is unnecessary or the dosage too high Presence of side e?ects Promoting Adherence with Unintentional Nonadherence Simpliﬁed drug regimens Clear and concise verbal and written instructions based on the health literacy of the patient* Appropriate dosage form Clearly labeled and easy-to-open containers Daily reminders Support system Frequent monitoring * This is why “TEACHING POINTS” are important. Intentional Nonadherence Most cases (75%) of nonadherence are intentional Reasons include the following: High cost of drugs*, side e?ects, and the patient’s belief that the drug is unnecessary or that the dosage is too high *Later in the course you will see why we stress the most e6ective drug at the lowest cost. Newest is not always better.

NUR 613 Advanced Pharmacology and Therapeutics Exam 1 PDF

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