2024 Introduction to the Principles of Pharmacology Lecture Notes PDF

INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY Block: Foundations Block Director: James Proffitt, PhD Session Date: Tuesday, July 30, 2024 Time: 11:00 – 12:00 pm Instructor: Todd Vanderah, PhD Department: Pharmacology, Anesthesiology & Email: vanderah@ema...

INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY Block: Foundations Block Director: James Proffitt, PhD Session Date: Tuesday, July 30, 2024 Time: 11:00 – 12:00 pm Instructor: Todd Vanderah, PhD Department: Pharmacology, Anesthesiology & Email: [email protected] Neurology INSTRUCTIONAL METHODS Primary Method: IM13: Lecture ☐ Flipped Session ☐ Clinical Correlation Resource Types: RE18: Written or Visual Media (or Digital Equivalent) DIRECTIONS Please review the Cell Signaling Basics Independent Learning materials, the learning objectives and notes attached to the session within MedLearn prior to attending session. READINGS RECOMMENDED Reading: Chapters 1-4. Katzung BG & Vanderah TW. Basic & Clinical Pharmacology, 15ed, (2021). McGraw-Hill Medical. [AccessMedicine] CHAPTER 1: Introduction: The Nature of Drugs & Drug Development & Regulation, CHAPTER 2: Drug Receptors & Pharmacodynamics, CHAPTER 3: Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action, CHAPTER 4: Drug Biotransformation SESSION OBJECTIVES 1. Define the terms Pharmacology, Pharmacokinetics, Pharmacodynamics, Toxicology and Pharmacotherapeutics. 2. Define the three general mechanisms of drug actions. 3. Define what it takes for a drug to have affinity for a receptor. 4. Compare and contrast therapeutic index vs therapeutic window. CURRICULAR CONNECTIONS Below are the competencies, educational program objectives (EPOs), disciplines and threads that most accurately describe the connection of this session to the curriculum. Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #1 MK-01: Core of basic sciences Pharmacology N/A CO-01 LO #2 MK-01: Core of basic sciences Pharmacology N/A CO-01 LO #3 MK-01: Core of basic sciences Pharmacology N/A Block: Foundations | VANDERAH [1 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #4 MK-09: Critical thinking about Pharmacology EBM: Patient medical science and about the Safety diagnosis and treatment of disease INTRODUCTION CASE STUDY (from Katzung BG & Vanderah TW, Basic & Clinical Pharmacology, McGraw-Hill, 15th edition) A 51-year-old man presents to the emergency department due to acute difficulty breathing. The patient is afebrile and normotensive but anxious, tachycardic, and markedly tachypneic. Auscultation of the chest reveals diffuse wheezes. The physician provisionally makes the diagnosis of bronchial asthma and administers epinephrine by intramuscular injection, improving the patient’s breathing over several minutes. A normal chest X-ray is subsequently obtained, and the medical history is remarkable only for mild hypertension that is being treated with propranolol. The physician instructs the patient to discontinue use of propranolol, and changes the patient’s antihypertensive medication to verapamil. Why is the physician correct to discontinue propranolol? Why is verapamil a better choice for managing hypertension in this patient? What alternative treatment change might the physician consider? Pharmacology is the science basic to medicine that is about the effects of chemicals on living systems at all levels of organization (molecular to the whole body). The chemicals may be drugs used to prevent, diagnose or treat disease. Drugs modify physiological processes-they do not create new processes or effects. The relationship between the dose of a drug given to a patient and the utility of that drug in treating that patient’s disease is described by a drug’s pharmacokinetics and pharmacodynamics. Pharmacokinetics deals with the absorption, distribution, biotrans- formation and excretion of drugs. Pharmacodynamics deals with the study of the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacokinetics is thought of as the body having actions on the drug whereas pharmacodynamics is thought of the drug having effects on the body. Toxicology is an aspect of pharmacology that deals with the adverse effects of drugs and chemicals. Pharmacotherapeutics is the use of drugs in the prevention and treatment of disease. Many drugs stimulate or depress biochemical or physiological function in human beings in a sufficiently reproducible manner to provide relief of symptoms or, ideally, to alter favorably the course of disease. Conversely, chemotherapeutic agents are useful in therapy because they have minimal effects on human beings but can destroy or eliminate pathogenic cells and organisms. What is important to remember is that virtually all drugs result in more than one effect. In general, one effect predominates over a particular dose range, i.e., the therapeutic window and, within this dose range the drug may be termed selective. Block: Foundations | VANDERAH [2 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY If a drug resulted in one and only one effect the drug would be termed specific. It is the goal of pharmacotherapeutics to achieve specificity, however is most often unachievable. Toxicity may result if the dose range is exceeded. It has often been emphasized that there is only a quantitative difference between a drug and a poison. GENERAL MECHANISMS OF DRUGS Drugs are used therapeutically to correct defects in physiology. Deficiency of some essential component of a normally functioning body - for example, this might be iron, a vitamin, a neurotransmitter or a hormone. The obvious treatment in this case is simply replacement therapy. An excellent example of this type of therapy is in the case of diabetes mellitus, which is essentially insulin deficiency - this is treated by injection of insulin. Replacement therapy may also occur by a drug inhibiting the breakdown or uptake of an endogenous chemical. For example selective serotonin reuptake inhibitors (SSRIs) (i.e., fluoxetine) decrease the degradation of the endogenous neurotransmitter serotonin by blocking a selective transporter responsible for the uptake of serotonin in the neuronal synapse, resulting in an overall increase in the serotonin neurotransmitter. Excess action of some normal or even essential, ingredient of the organism can promote physiological difficulties - thus the appropriate treatment might be to use a chemical antagonist. For example, if gastric acidity is producing heartburn, then the appropriate therapy is the administration of antacids, which are essentially alkaline compounds, designed to neutralize the acid. Excess action may also result from activity of exogenous substances. In such cases, specific (i.e., receptors) antagonists may be called for. An obvious example is the situation of heroin overdose and the use of an opioid antagonist such as naloxone. The physiochemical environment of a specific part of the body may be altered by a drug. For example, laxatives or antacids act by changing the characteristics of the gastrointestinal tract allowing more water to accumulate in the lumen of the GI or neutralize the acid, respectively. These drugs are taken orally and are effective treatment for constipation or gastro esophageal reflux disease (GERD), respectively. Drugs which act simply because of their presence are termed nonspecific. The onset, intensity and duration of responses to chemicals are determined by factors that govern chemical concentration at the site of action. In addition, in the great majority of cases, the drug molecule interacts with a selective molecule in the biological system that plays a regulatory role, i.e., a receptor molecule. In order for a drug to interact Block: Foundations | VANDERAH [3 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY with its receptor, a drug molecule must have the appropriate size, electrical charge, shape and atomic composition (Figure 1 – next page) A drug’s “attractiveness” to a receptor is referred to as affinity (figure 1). A drug must also have the necessary properties to be transported from its site of administration to its site of action (KADME). Kinetics, Absorption, Distribution, Metabolism and Excretion examines the properties of chemicals and characteristics of biologic processes that influence tissue concentration of drugs and toxins. Most Drugs act at Receptors to produce and effect In order for drugs to interact “bind” with receptors they should have: -Shape -Size -Charge Affinity -Atomic Composition CH3 Drug N+ CH2 CH2 O C CH3 CH3 CH3 Ionic Bond Van der Waals’ O Hydrogen Bond Forces AA - Receptor H+ Figure 1. Illustration demonstrating how drugs fit into receptors based on size, shape, electrical charge and atomic composition. Block: Foundations | VANDERAH [4 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY DRUG DISPOSITION (covered in more detail in Pharmacokinetics Chapter) The components of drug disposition include absorption, distribution, metabolism and elimination/excretion. Disposition rates influence tissue drug concentration, with the elimination/excretion rate having the greatest influence on tissue concentration (Figure 2). Figure 2. Drug administration, distribution to the plasma and tissue and elimination. DRUG SAFETY Comparison of two dose-response curves, one for a desired therapeutic effect and one for an adverse effect (unwanted side effect), can be used to calculate a drug's therapeutic index. The therapeutic index is a relative measure of dose that a drug can achieve a therapeutic effect without producing a side effect, calculated as the ratio of the TD50 (toxic dose) to the ED50 (effective dose) for the desired effect. TD50 (adverse effect) Therapeutic window = ---------------------------- ED50 (desired effect) Block: Foundations | VANDERAH [5 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY Drug Safety Therapeutic Index 100 TD50 500 ia = = 250 g es c al xi % Response 75 ED50 2 an To 50 25 0 0.001 0.01 1.0 10.0 100.0 1000.0 ED50 (2mg/kg) TD50 (500mg/kg) Log Morphine (mg/kg) Therapeutic index of less than 1 would suggest that the drug will have side effects and could produce toxicity in patients at doses that are needed to produce the therapeutic effect. The safest and most desirable drugs are drugs with a large therapeutic index, particularly if the side effect is a serious one. Most if not all drugs come with side effects resulting in undesirable biological effects. Therefore, it is always important to inform patients that drugs produce more than one effect. Do you think that a drug can have a therapeutic index less than 1? Therapeutic 100 Window s ia ge n al x ic 75 A To % Response Therapeutic Index 50 25 0 0.001 0.01 1.0 10.0 100.0 1000.0 Minimum Minimum effective dose toxic dose Log Morphine (mg/kg) Another useful term you will need to know is the therapeutic window. Since all humans are different due to many factors (i.e., genetics, epigenetics, surgical or device alterations, etc.) it is impossible to know with precision the exact numbers for ED50 and TD50. Therefore, clinical trials and real patient data result in more of a range or “window” of the relatively effective (therapeutic) dose and a range – and sometimes overlapping range – of possible toxic or unwanted effects.. Hence, the Block: Foundations | VANDERAH [6 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY range between the minimum toxic dose and the minimum therapeutic dose is the therapeutic window. The medications to know that have a very narrow therapeutic index and are often material for USMLE Step I of Boards are: Lithium mood stabilizer Phenytoin epilepsy Carbamazepine epilepsy Warfarin anticoagulant Cyclosporine antibiotic Levothyroxine thyroid hormone deficiency Digoxin heart failure/atrial fibrillation Theophylline COPD/Asthma (not used often anymore) SUMMARY In summary the pharmacologic response to drugs and toxins is determined by those characteristics of the drug or toxin and the body’s ability to affect the rate of appearance, concentration and duration of drug at the site of action. In this sense the biologic processes that control absorption, distribution, metabolism and excretion are important determinants of pharmacologic effect or toxicity (all topics that will be discussed in the next several lectures/notes). The choice of the pharmaceutical formulation and the route of administration can influence the rate and extent of absorption. The properties of drugs that favor passage across body membranes include low degree of ionization at physiologic pH, low protein binding and high lipid solubility. Most drugs cross membranes by passive diffusion but there are instances of carrier- mediated transport including active transport. The concentration gradient of lipid soluble molecules across body membranes governs the rate of passive diffusion. Drug distribution is influenced by regional blood flow and the extent of drug-protein binding. Drug distribution into the central nervous system is limited by the presence of anatomical barriers. Water soluble and ionized compounds do not enter the brain readily. Distribution across the placenta and into milk is influenced by the same factors that affect membrane transport elsewhere in the body. In many instances fetal drug exposure equates with maternal exposure. Hepatic metabolism usually converts lipid soluble molecules into more polar water-soluble molecules that are more amenable to elimination by the liver or kidney. Renal elimination is the net of the processes of glomerular filtration and tubular secretion as modified by the extent of renal tubular reabsorption of drug. Glomerular filtration and tubular reabsorption are favored by the same physicochemical properties that govern the passage of drugs across other membranes. Renal elimination rates may be influenced by clinical manipulations that effect the pH of plasma and urine and hence the degree of drug ionizations. Renal function is diminished in newborns, neonates, infants and the elderly. The use of drugs eliminated primarily by the kidney in patients at the extremes of the age range may require Block: Foundations | VANDERAH [7 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY downward dosage adjustment. Drugs are also eliminated in the bile, breath, milk and saliva. Drug disposition is influenced by many factors, the variation of which may cause qualitative or quantitative changes in pharmacologic response. The importance of inter-individual variations in drug disposition is reflected in studies that show the wide variation in doses required to maintain a given therapeutic response, the variation in plasma levels following identical doses and the variation in rate of drug elimination in persons with normal function of the organ of elimination. Drugs can harm and even result in death. Always seek advice on what drugs to prescribe, start with low doses and be sure to check for drug-drug interactions. Be sure to inform your patients of what to expect (drug effects and SIDE EFFECTS) and make sure you checkup with your patients after writing a prescription. Variation in response MUST be anticipated and handled by the individualization of therapy using careful formulation of therapeutic objectives and appropriate monitoring of response. In other words, “HAVE A PLAN”. This is especially important when treating serious illness with drugs whose action is characterized by a steep dose-response relationship, (i.e., a small therapeutic index – dose range between therapeutic effect and the drugs lethal dose) and where the clinical endpoints are indistinct. Block: Foundations | VANDERAH [8 of 9] INTRODUCTION TO THE PRINCIPLES OF PHARMACOLOGY CASE STUDY ANSWER Propranolol, a beta-adrenoceptor antagonist, is a useful antihypertensive agent because it reduces cardiac output and probably vascular resistance as well. However, it also prevents beta-adrenoceptor–induced bronchodilation and therefore may precipitate bronchoconstriction in susceptible individuals. Calcium channel blockers such as verapamil also reduce blood pressure but, because they act on a different target, rarely cause bronchoconstriction or prevent bronchodilation. An alternative approach in this patient would be to use a more highly selective adrenoceptor antagonist drug (such as metoprolol) that binds preferentially to the beta1 subtype, which is a major beta adrenoceptor in the heart, and has a lower affinity (ie, higher Kd) for binding the beta2 subtype that mediates bronchodilation. Selection of the most appropriate drug or drug group for one condition requires awareness of the other conditions a patient may have and the receptor selectivity of the drug groups available. Block: Foundations | VANDERAH [9 of 9]