General Principles of Pharmacology_ Approach to Learning Pharmacology by Marc Imhotep Cray, M.D.

GENERAL PRINCIPLES OF PHARMACOLOGY Approach to Learning Pharmacology Marc Imhotep Cray, M.D.

Pedagogical Approach ď ą This course sets out to provide an understanding of scientific and clinical pharmacology within the framework of biochemistry, physiology and pathophysiology, travelling from drug effects on molecular targets to their effects on the whole-organism.

In other words, ď ą You will be learning pharmacology using an approach that integrates the actions of medications (drugs) starting from the level of molecular targets (biologic effects) to the level of the clinical patient (therapeutic and adverse effects), relying on kindred basic medical sciences as the scaffolding. Marc Imhotep Cray, M.D.

“What Is Pharmacology?” …“Medical pharmacology is a bridge between basic medical science and clinical medicine. It makes use of all the disciplines that comprise the scientific foundation of clinical medicine; including anatomy, physiology, pathophysiology, pathology and immunology biochemistry, molecular and cell biology, epidemiology, genetics and genomics. Hence…it is particularly useful for pre-clinical student to view and engage the subject as a major horizontal and vertical integrator, as it pulls together all the different strands of the basic medical science years and simultaneously introduces one to the cornerstone of modern clinical therapeutics, i.e. drugs”… Cray MI. Integrated Scientific and Clinical Pharmacology: A Course Syllabus and Digital Guidebook for Medical Students. Atlanta, Georgia: IVMS, 2015; 4. Marc Imhotep Cray, M.D.

The Scope of Pharmacology Psychology

Clinical Medicine & Therapeutics

Psychopharmacology

Clinical Pharmacology

Veterinary Medicine

Pharmacy Pharmaceutical Science

Veterinary Pharmacology

Biotechnology

Pathology

Chemistry

Biopharmaceutics

Toxicology

Medicinal Chemistry

Pharmacokinetics & Pharmacodynamics

Biochemical pharmacology

PHARMACOLOGY Molecular pharmacology

Chemotherapy Systems pharmacology

Neuropharmacology

Immunopharmacology

Cardiovascular Gastrointestinal Respiratory Endocrine pharmacology pharmacology pharmacology pharmacology

Pharmacogenetics

Genetics

Pharmacogenomics

Pharmacoepidemiology

Genomics

Clinical Epidemiology

Pharmacoeconomics Health Economics

Importance of the GPs of Pharmacology ď ą The general principles of pharmacology are absolutely key to gaining an understanding of how drugs exert their therapeutic and adverse effects ď ą General principles are at the core of organ-systems pharmacology, as you will be applying these principles during the study of drug classes/organ-systems pharmacology ď&#x201A;§

Therefore, a strong knowledge of general principles will help you most with your study of organ-systems pharmacology, as well as the prudent application of pharmacotherapeutics during your clinical medicine training

Marc Imhotep Cray, M.D.

Learning Objectives 1. To understand some key terms and concepts related to the general principles of pharmacology (pharmacokinetics and pharmacodynamics). 2. To understand the approach to the study of disease within a medical pharmacology and therapeutics framework. 3. To understand how one should approach the study of pharmacology and the rational underlying. (Main Objective) Note: The terms, concepts and mechanisms provided herein are not intended as complete discussions. Rather, they are only introduced here as â&#x20AC;&#x153;stair-stepsâ&#x20AC;? and to encapsulate Objective 3. They will be explored in more detail further in the course of study. Marc Imhotep Cray, M.D.

Lecture Outline  Approach to Learning Pharmacology o o

Key Terms and Concepts Mechanisms of Drug Action •

4 Levels of complexity

 Approach to Disease  Approach to Reading & Studying Pharmacology o

“The seven key questions”

 Key Points Capsule  Comprehension Q & A  Further Study: IVMS Tools and Resources Marc Imhotep Cray, M.D.

1. Approach to Learning Pharmacology Pharmacology is best learned by a systematic approach  understanding physiology of body  recognizing every medication (drug) has desirable and undesirable effects and  being aware biochemical and pharmacologic properties of a drug affects its characteristics such as… o o o o o

duration of action volume of distribution passage through blood-brain barrier mechanism of elimination, and route of administration

Marc Imhotep Cray, M.D.

Approach to Learning Pharmacology (2)  Rather than memorizing characteristics of a medication, one should strive to learn underlying rationale for example  Second-generation antihistamine agents are less lipid soluble than first-generation antihistamines  therefore 2nd Gen. agents do not cross blood-brain barrier (BBB) as readily thus, 2nd Gen. antihistamines are not as sedating  b/c they both bind histamine H1 receptor, efficacy is same in treating conditions for which they are indicated (e.g., allergic rhinitis ) Marc Imhotep Cray, M.D.

Key Terms and Concepts  Pharmacology: The study of substances that interact with living systems through biochemical processes.  Drug (medication): A substance used in prevention, diagnosis, or treatment of a disease or prevention of reproduction.  Toxicology: A branch of pharmacology that studies undesirable effects of chemicals on living organisms.  Food and Drug Administration (FDA): Federal agency responsible for safety & efficacy of all drugs in U.S, as well as food & cosmetics.  Adverse effect: Also known as side effect; all unintended actions of a drug that result from lack of specificity of drug action. N.B. All drugs are capable of producing adverse effects>>>toxicity Marc Imhotep Cray, M.D.

Key Terms and Concepts(2) Classically there are two major divisions of pharmacology: pharmacodynamics and pharmacokinetics  Pharmacodynamics (PD): The actions of a drug on a living organism, including mechanisms of action and receptor interaction. 

How the drug affects the body

 Pharmacokinetics (PK): The actions of the living organism on the drug, including absorption, distribution, and elimination. 

How the body affects the drug

Third emerging division  Pharmacogenomics: study of how genomic makeup affects PD &PK 

affects drug selection and application to individual patients based on interindividual variations in the handling of drugs based on genetics

Marc Imhotep Cray, M.D.

Pharmacogenomics “Pharmacogenomics may hold the opportunity of allowing practitioners to integrate a molecular understanding of the basis of disease with an individual's genomic makeup to prescribe personalized, highly effective, and safe therapies.” Roden DM. (2012) Ch. 5 Principles of Clinical Pharmacology. In: Longo DL, Fauci AS, et al. Harrison's Principles of Internal Medicine,18th Ed., McGraw-Hill 2012, 33. NB “Drug-gene testing is also called pharmacogenomics, or pharmacogenetics. All terms characterize the study of how your genes affect your body's response to medications.” Link to see animation and transcript: http://mayoresearch.mayo.edu/centerfor-individualized-medicine/drug-gene-testing.asp Marc Imhotep Cray, M.D.

Major PD and PK Components & Parameters

Trevor AJ, Katzung BG, Kruidering-Hall M , Masters SB. Katzung & Trevor's Pharmacology Examination & Board Review 10th Ed. New York: McGraw-Hill, 2013. Marc Imhotep Cray, M.D.

Relationship between PK and PD Pharmacokinetics

Dose of drug

Pharmacodynamics

Drug concentration in target organ over time

Absorption Distribution Biotransformation Excretion

Mechanism and magnitude of drug effect

Receptor binding Signal transduction Physiological effect

Redrawn after Brenner GM and Stevens CW. Pharmacology 4th ed. Sanders, 2014. Marc Imhotep Cray, M.D.

Key Terms and Concepts(4)  Potency of drug (x-axis on dose-response curve): Relative amount of drug needed to produce a given response  determined by amt. of drug that reaches site of action and by affinity of drug for receptor  Efficacy (y-axis on dose-response curve): Drug effect as maximum response it is able to produce  determined by number of drug-receptor complexes and ability of receptor to be activated once bound (intrinsic activity) • •

EC50 [also ED50 in many text] refers to drug concentration that produces 50 percent of maximal response (Graded curve); whereas ED50 (Quantal curve) refers to drug dose that is pharmacologically effective in 50 percent of population

NB-There are two types of dose-response curves--graded and quantal-each provides useful information for therapeutic decisions…see next slide

Dose-Response (Concentration) Curves Quantal dose-response curve:

Graded dose-response curve

A graph of the fraction of a population that shows a specified response at progressively increasing doses

A graph of increasing response to increasing drug concentration or dose

Bardal KS, Waechter JE, Martin DS. Applied Pharmacology. St. Louis: Saunders, 2011. Marc Imhotep Cray, M.D.

Key Terms and Concepts(5)  Agonist: A drug that activates its receptor upon binding 

Affinity and intrinsic activity; whereas, antagonists have affinity but no IA

Antagonist: A drug that attenuates effect of an agonist  Can be competitive or non-competitive each of which can be reversible or irreversible

 Pharmacologic antagonist: A drug that binds without activating its receptor and thereby prevents activation by an agonist  Competitive antagonist: A pharmacologic antagonist that can be overcome by increasing conc. of agonist  Non-competitive antagonist: binds to an allosteric (non-agonist) site on receptor to prevent activation of receptor Marc Imhotep Cray, M.D.

Key Terms and Concepts(6)  Reversible antagonist: binds non-covalently to receptor therefore can be “washed out” 

A pharmacologic antagonist that can be overcome by increasing agonist conc.

 Irreversible antagonist: binds covalently to receptor and cannot be displaced by either competing ligands or washing 

A pharmacologic antagonist that cannot be overcome by increasing agonist conc.

 Physiologic antagonist: A drug that counters effects of another by binding to a different receptor and causing opposing effects Marc Imhotep Cray, M.D.

Potential mechanisms of drug interaction with a receptor  Ligand: A substance that forms a complex with a biomolecule (receptor) to serve a biological purpose  Receptor: A molecule to which a ligand (drug) binds to bring about a change in function of biologic system  Receptor site: Specific region of receptor molecule to which drug binds  Effector: Component of a system that accomplishes biologic effect after receptor is activated by an agonist  often a channel or enzyme molecule may be part of receptor molecule itself

Possible effects resulting from these interactions are diagrammed in doseresponse curves at right Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012; Fig. 1–3.)

Key Terms and Concepts(7) Routes of administration (RoA) Path by which a drug, fluid or poison is taken into body  Routes can also be classified based on where target of action is  Action may be topical (local)  Enteral (system-wide effect, but delivered through GIT), or  Parenteral (systemic action, but delivered by routes other than GI tract)

Marc Imhotep Cray, M.D.

Key Terms and Concepts(8)  Route of administration: Drug may be delivered  intravenously (IV) for delivery directly into bloodstream  intramuscularly (IM), and  subcutaneously (SC)  Medication may be  depot and slow release  inhalant for rapid absorption & delivery to bronchi & lungs  sublingual to bypass first-pass effect  intrathecal for agents that penetrate BBB poorly  rectal to avoid hepatic first-pass effect and for N/V, and  topical administration when local effect is desired such as dermatologic or ophthalmic agents Lippincott Illustrated Reviews: Pharmacology Sixth Ed. Wolters Kluwer, 2015. 21

Key Terms and Concepts(9) Absorption: Movement of a drug from administration site into blood stream usually requiring crossing of one or more biologic membranes Important parameters include • lipid solubility • ionization • size of molecule and • presence of a transport mechanism

Marc Imhotep Cray, M.D.

Key Terms and Concepts(10)  Bioavailability: The percentage of an ingested drug that is actually absorbed into bloodstream  By definition, intravascular doses have 100% bioavailability, f = 1.  Factors that influence bioavailability: o o o o

First-pass hepatic metabolism Solubility of the drug Chemical instability Nature of the drug formulation

Marc Imhotep Cray, M.D.

Lippincott Illustrated Reviews: Pharmacology Sixth Ed. Wolters Kluwer, 2015. 23

Key Terms and Concepts(11)  Volume of distribution (Vd): The size of “compartment” into which a drug is distributed following absorption  ratio of amt. of drug in body to drug conc. in plasma or blood Units=liters  determined by equation: Vd = Dose (mg) drug administered/Initial plasma concentration (mg/L)

Marc Imhotep Cray, M.D.

Key Terms and Concepts(12)  Elimination: Process by which a drug is removed from body, generally by either metabolism (biotransformation) or excretion  Elimination=biotransformation (liver…) + excretion (kidneys…)

 Elimination follows various kinetic models For example  First-order kinetics describes most circumstances means that rate of drug elimination depends on concentration of drug in plasma as described by equation: Rate of elimination from body = Constant × Drug concentration  Zero-order kinetics: It is less common (PEA) means that rate of elimination is constant does not depend on the plasma drug concentration • consequence of a circumstance such as saturation of liver enzymes or saturation of kidney transport mechanisms Marc Imhotep Cray, M.D.

Key Terms and Concepts(13)  Clearance: Ratio of rate of elimination of a drug to concentration of drug in plasma or blood  Units: volume/time, eg, mL/min or L/h

 Half-life: Time required for amount of drug in body or blood to fall by 50%  For drugs eliminated by first-order kinetics this number is a constant regardless of concentration  Units: time

Marc Imhotep Cray, M.D.

Mechanisms of Drug Action Drug effects are produced by altering normal functions of cells and tissues via one of four general mechanisms: 1. Interaction with receptors (major) Ligand-activated ion channels G-protein–coupled receptors  Gαs-coupled receptors  Gαi (Ginhibitory)-coupled receptors  Gq (and G11)-coupled receptors Intracellular nuclear receptors Receptor-activated tyrosine kinases

2. Nonspecific chemical or physical interactions (least common)  e.g., antacids 3. Antimetabolite action  e.g., ChemoTx agents 4. Alteration of the activity of enzymes  increasing or decreasing

Important Notes: • Drugs do not produce new function/s in body, but rather augment nml physiologic and biochemical mechanisms • No drug has a single action, but rather, both therapeutic & adverse actions or multiple effects • Drug vs poison is dose related, as all drugs are poisons when introduced at a high enough dose Marc Imhotep Cray, M.D.

Mechanisms of Drug Action (2) ď ą Drugs act at four different levels: 1) Molecular: protein molecules are immediate targets for most drugs. Action here translates into actions at next level 2) Cellular: biochemical and other components of cells participate in the process of transduction 3) Tissue: the function of heart, skin, lungs, etc., is then altered 4) System: the function of the cardiovascular, nervous, gastrointestinal system, etc., is then altered Marc Imhotep Cray, M.D.

Mechanisms of Drug Action (3)  To most clearly understand pharmacologic actions of drugs (agonist and antagonist) it is necessary to know:  which molecular targets are affected by the drug,  nature of this molecular interaction,  nature of the transduction system (the cellular response),  types of tissue that express the molecular target and  mechanisms by which the tissue influences the body system NB. It is important to consider MOA of drugs at each of the four levels of complexity.

Marc Imhotep Cray, M.D.

The four levels of MOA illustrated Propranolol, a Î˛ adrenergic antagonist used to treat several diseases including angina pectoris, a cardiac condition resulting from localized ischemia (i.e. insufficient blood flow) in heart: ď ą At the molecular level, propranolol is a competitive and reversible antagonist to action of epinephrine (Epi) and norepinephrine (NE) on cardiac Î˛ adrenoceptors

Marc Imhotep Cray, M.D.

Four levels of MOA cont.  At the cellular level, propranolol prevents β adrenergic agonism from elevating intracellular cyclic adenosine monophosphate (cAMP), initiating protein phosphorylation, Ca2+ mobilization and oxidative metabolism  At the tissue level, propranolol prevents β adrenergic agonism from increasing contractile force of heart and heart rate, i.e. it has negative inotropic and negative chronotropic effects Marc Imhotep Cray, M.D.

Four levels of MOA cont.  At a system level, propranolol improves cardiovascular function  It reduces heart's β adrenergic responses to sympathetic nervous system activity thereby decreasing requirements for blood flow (O2 demand) in heart tissue useful if blood supply is limited (e.g. in coronary artery disease)

Marc Imhotep Cray, M.D.

2. Approach to Disease Physicians approach clinical situations by    

taking a history (asking questions) performing a physical examination obtaining selective laboratory and imaging tests, and then formulating a diagnosis

The synthesis of history, physical examination, and imaging or laboratory tests is called the clinical database After reaching a diagnosis a treatment plan is initiated, and patient is followed for a clinical response Marc Imhotep Cray, M.D.

Approach to Disease (2) ď ą Rational understanding of disease (pathologic, microbiologic, immunologic and (or) behavioral) and plans for treatment (therapeutics) are best acquired by learning about normal human processes on a basic science level (physiology, biochemistry neuro and behavioral science) ď ą likewise, being aware of how disease alters normal physiologic processes is also best understood on a basic science level (pathology, pathogenesis & pathophysiology) ď&#x192; Sn & Sx of disease Marc Imhotep Cray, M.D.

Approach to Disease (3)  Pharmacology and therapeutics require also ability to tailor correct medication (drug) to patient’s situation and awareness of medication’s adverse effect profile 

Sometimes, a patient has an adverse reaction to a drug as chief complaint one must be able to identify medication as culprit

 Again, an understanding of underlying basic science allows for more rational analysis and drug (medication) choices Marc Imhotep Cray, M.D.

3. Approach to Reading & Studying Pharmacology ď ą There are seven key questions that help to stimulate application of basic science information to clinical setting These are: 1. Which medications is most likely to achieve desired therapeutic effect and/or is responsible for described symptoms or signs? 2. What is likely mechanism for clinical effect(s) and adverse effect(s) of medication? 3. What is basic pharmacologic profile (e.g., absorption, elimination) for medications in a certain class, and what are differences among the agents within the class? Marc Imhotep Cray, M.D.

Approach to Reading and Studying Pharm (2) 4. Given basic pharmacologic definitions such as therapeutic index (TI) or certain safety factor (TD1/ED99), or median lethal dose (LD50), how do medications compare in their safety profile? 5. Given a particular clinical situation with described unique patient characteristics, which medication is most appropriate? 6. What is best treatment toxic effect of a medication? 7. What are drug-drug interactions to be cautious about regarding a particular medication? ď śIn the following slides we will discuss a bit more about each of these seven key questions, explaining how they help to stimulate application of basic science information to the clinical setting. Marc Imhotep Cray, M.D.

1. Which drug is most likely responsible for described symptoms or signs?  One must be aware of various effects, both desirable (therapeutic) and undesirable (ADR), produced by particular medications  Knowledge of desirable therapeutic effects is essential in selecting appropriate drug for particular clinical application  Likewise, an awareness of its adverse effects (AE) is necessary, b/c patients may present with a complaint caused by a drug effect unaware that their symptoms are b/c of the prescribed drug 

only by being aware of common and dangerous effects can one arrive at correct diagnosis

 Learners are encouraged not to merely memorize comparative adverse effect profiles of drugs but rather to understand underlying biochemical and physiological mechanisms Marc Imhotep Cray, M.D.

2. What is mechanism for clinical effect(s) and adverse effect(s) of drug? As noted one should strive to learn underlying physiologic, biochemical, and (or) cellular explanation for drug effect  allows for rational choice of an alternative agent or reasonable choice of an agent to alleviate symptoms or explanatory advice to pt. regarding behavioral changes to diminish any adverse effects o For example, if a 60-year-old woman who takes medications for osteoporosis complains of severe “heartburn” one may be suspicious, knowing that bisphosphonate medication alendronate can cause esophagitis •

Marc Imhotep Cray, M.D.

Instruction to patient to take medication while sitting upright and remaining upright for at least 30 minutes would be proper course of action, b/c gravity will assist in keeping alendronate in stomach rather than allowing regurgitation into distal esophagus 39

3. What is basic pharmacologic profile for drugs in a certain class, and what are differences among agents within said class?  Understanding pharmacologic profile of medications allows for rational therapeutics   instead of memorizing separate profiles for every medication, grouping drugs together into classes allows for more efficient learning and better comprehension  Excellent starting point is to study how a prototype drug within a drug class organized by structure or mechanism of action may be used to treat a condition (such as hypertension)  o Then within each category of agents, one should try to identify important subclasses or drug differences Marc Imhotep Cray, M.D.

Pharmacologic profile of a drug and differences among agents within class (2)  For example, anti-hypertensive agents can be categorized as  diuretic agents  β-adrenergic-blocking agents  calcium-channel-blocking agents, and  renin-angiotensin system inhibitors= ACEI & ARBs  Within subclassification of renin-angiotensin system inhibitors, angiotensin converting enzyme inhibitors (ACEI) can cause adverse effect of a dry cough caused by increase in bradykinin brought about by enzyme blockade  instead, angiotensin-1 receptor blockers (ARBs) do not affect bradykinin levels and so do not cause cough as often Marc Imhotep Cray, M.D.

4. Given basic pharmacologic definitions such as (TI) or (TD1/ED99), or (LD50), how do medications compare in their safety profile?  Therapeutic index (TI): Defined as TD50/ED50 (ratio of dose that produces a toxic effect in half population to dose that produces desired effect in half population)  Certain safety factor (TD1/ED99): Defined as ratio of dose that produces toxic effect in 1 percent of population to dose that produces desired effect in 99 percent of population also known as standard safety measure  Median lethal dose (LD50): Defined as the median lethal dose, the dose that will kill half the population Marc Imhotep Cray, M.D.

TI or TD1/ED99, or LD50 (2) ď ą Based on these definitions, a desirable medication would have a high therapeutic index (toxic dose is many times that of efficacious dose), high certain safety factor, and high median lethal dose (much higher than therapeutic dose) ď ą Likewise, medications such as digoxin that have a low therapeutic index require careful monitoring of bld levels and vigilance for adverse effects Marc Imhotep Cray, M.D.

5. Given a particular clinical situation with described unique patient characteristics, which medication is most appropriate? One must weigh various advantages and disadvantages, as well as different patient attributes Some of those may include  compliance with medications  allergies to medications  liver or renal insufficiency  age  coexisting medical disorders, and  other medications Marc Imhotep Cray, M.D.

Unique patient characteristics (2) One must be able to sift through medication profile and identify most dangerous adverse effects For example,  if a patient is already taking a monoamine-oxidaseinhibiting agent (Selegiline) for depression then adding a serotonin reuptake inhibitor [Fluoxetine (Prozac)] would be potentially fatal, b/c serotonin syndrome may ensue (hyperthermia, muscle rigidity, death)

Marc Imhotep Cray, M.D.

Unique patient characteristics (3)  Clinical pharmacology is a complex interaction betw. pt. and drug Patient profile Patient profile  The patient is a unique individual, with many distinguishing features that need Age to be taken into account during prescribing Weight Drug profile  The drug, likewise, is unique, with its own distinguishing features  Good prescribing involves tailoring drug and dosing regimen to unique patient o Clinical pharmacology provides basis of this pharmacotherapeutic principle

Sex Race Allergies Smoking history Alcohol history Diseases Pregnant/lactating Current therapy Intelligence

Drug profile Name (generic) Class Action Pharmacokinetics Indications Contraindications/ precautions Interactions Adverse effects Dosing regimen Monitoring Overdose/Antidote 46

6. What is best treatment for toxic effect of a medication?  If complications of drug therapy are present one should know proper treatment  best learned by understanding drug MOA For example, a pt. who has taken excessive opioids may develop respiratory depression, caused by either a heroin overdose or pain medication may be fatal o Tx of an opioid overdose includes • ABCs (airway, breathing, circulation) and • administration of naloxone, which is a competitive antagonist of opioids Marc Imhotep Cray, M.D.

7. What are the drug-drug interactions to be concerned with regarding a particular medication?  Patients are often prescribed multiple medications, from same practitioner or different clinicians  Pts may not be aware of drug-drug interactions thus, a clinician must compile pt. to maintain a current list of all medications (Rx, OTC, and herbal) taken by patient  Thus, one should be aware of most common and dangerous drug-drug interactions  again, understanding underlying mechanism allows for lifelong learning rather than short-term rote memorization of facts that are easily forgotten Marc Imhotep Cray, M.D.

Drug-drug interactions (2)  For example, magnesium sulfate to stop preterm labor should not be used if patient is taking a calcium-channel blocking agent such as nifedipine  Magnesium sulfate acts as a competitive inhibitor of calcium and by decreasing its intracellular availability it slows down smooth muscle contraction such as in uterus  Calcium-channel blockers potentiate inhibition of calcium influx and can lead to toxic effects such as respiratory depression Marc Imhotep Cray, M.D.

Key Points Capsule ❖ Understanding the pharmacologic mechanisms of drugs allows for rational choices for therapy, fewer medication errors, and rapid recognition and reversal of toxic effects ❖ The therapeutic index, certain safety factor (TD1/ED99), and median lethal dose are various methods of describing the potential toxicity of medications ❖ There are seven key questions to stimulate the application of basic science information to the clinical arena Marc Imhotep Cray, M.D.

Key Points Capsule (2) Focus of study for each drug:      

Classification and class prototype/s (as applicable) Mechanism of action-biologic, therapeutic and adverse Indications (therapeutic use) Adverse effects (common vs dangerous) Drug-drug interactions, cautions and contraindications Pharmacokinetic properties, drug-disease interactions and other patient-specific considerations  Toxicities and antidotes (or) treatment Marc Imhotep Cray, M.D.

“What Is Pharmacology?” A Capsule …“Medical pharmacology is a bridge between basic science and clinical medicine. It makes use of all the disciplines that comprise the scientific foundation of clinical medicine; including anatomy, physiology, pathophysiology, pathology and immunology biochemistry, molecular and cell biology, epidemiology, genetics and genomics. Hence…it is particularly useful for pre-clinical student to view and engage the subject as a major horizontal and vertical integrator, as it pulls together all the different strands of the basic medical science years and simultaneously introduces one to the cornerstone of modern clinical therapeutics, i.e. drugs”… Cray MI. Integrated Scientific and Clinical Pharmacology: A Course Syllabus and Digital Guidebook for Medical Students. Atlanta: IVMS, 2015; 4. Marc Imhotep Cray, M.D.

Comprehension Q & A

Question 1. Bioavailability of an agent is maximal when the drug has which of the following qualities? A. Highly lipid soluble B. More than 100 Daltons in molecular weight C. Highly bound to plasma proteins D. Highly ionized

Marc Imhotep Cray, M.D.

Answer 1. A. Transport across biologic membranes and thus bioavailability is maximal with high lipid solubility.

Marc Imhotep Cray, M.D.

Question 2. An agent is noted to have a very low calculated volume of distribution (Vd). Which of the following is the best explanation? A. The agent is eliminated by the kidneys, and the patient has renal insufficiency. B. The agent is extensively bound to plasma proteins. C. The agent is extensively sequestered in tissue. D. The agent is eliminated by zero-order kinetics. Marc Imhotep Cray, M.D.

Answer 2. B. The volume of distribution is calculated by administering a known dose of drug (mg) IV and then measuring an initial plasma concentration (mg/L). The ratio of the mass of drug given (mg) divided by the initial plasma concentration (mg/L) gives the Vd. A very low Vd may indicate extensive protein binding (drug is sequestered in the bloodstream), whereas a high Vd may indicate extensive tissue binding (drug is sequestered in the tissue).

Marc Imhotep Cray, M.D.

Question 3. Which of the following describes the first-pass effect? A. Inactivation of a drug as a result of the gastric acids. B. Absorption of a drug through the duodenum. C. Drug given orally is metabolized by the liver before entering the circulation. D. Drug given IV accumulates quickly in the central nervous system (CNS).

Marc Imhotep Cray, M.D.

Answer 3. C. The first-pass effect refers to the process in which following oral administration a drug is extensively metabolized as it initially passes through the liver, before it enters the general circulation. Liver enzymes may metabolize the agent to such an extent that the drug cannot be administered orally.

Marc Imhotep Cray, M.D.

Question 4. A laboratory experiment is being conducted in which a mammal is injected with a noncompetitive antagonist to the histamine receptor. Which of the following best describes this agent? A. The drug binds to the histamine receptor and partially activates it. B. The drug binds to the histamine receptor but does not activate it. C. The drug binds to the receptor, but not where histamine binds, and prevents the receptor from being activated. D. The drug irreversibly binds to the histamine receptor and renders it ineffective.

Marc Imhotep Cray, M.D.

Answer 4. C. A noncompetitive antagonist binds to the receptor at a site other than the agonist-binding site and renders it less effective by preventing agonist binding or preventing activation.

Marc Imhotep Cray, M.D.

Question 5. A 25-year-old medical student is given a prescription for asthma, which the physician states has a very high therapeutic index. Which of the statements best characterizes the drug as it relates to the therapeutic index? A. The drugâ&#x20AC;&#x2122;s serum levels will likely need to be carefully monitored. B. The drug is likely to cross the blood-brain barrier. C. The drug is likely to have extensive drug-drug interactions. D. The drug is unlikely to have any serious adverse effects.

Marc Imhotep Cray, M.D.

Answer 5. D. An agent with a high therapeutic index means the toxic dose is very much higher than the therapeutic dose, and it is less likely to produce toxic effects at therapeutic levels.

Marc Imhotep Cray, M.D.

Question 6. A drug M is injected IV into a laboratory subject. It is noted to have high serum protein binding. Which of the following is most likely to be increased as a result? A. Drug interaction B. Distribution of the drug to tissue sites C. Renal excretion D. Liver metabolism

Marc Imhotep Cray, M.D.

Answer 6. A. High protein binding means less drug to the tissue, the kidney, and the liver. Drug interaction may occur if the agent binds to the same protein site as other drugs, thus displacing drugs and increasing serum levels.

Marc Imhotep Cray, M.D.

Question 7. A bolus of drug K is given IV. The drug is noted to follow first-order kinetics. Which of the following describes the elimination of drug K? A. The rate of elimination of drug K is constant. B. The rate of elimination of drug K is proportional to the patientâ&#x20AC;&#x2122;s renal function. C. The rate of elimination of drug K is proportional to its concentration in the patientâ&#x20AC;&#x2122;s plasma. D. The rate of elimination of drug K is dependent on a nonlinear relationship to the plasma protein concentration. Marc Imhotep Cray, M.D.

Answer 7. C. First-order kinetics means the rate of elimination of a drug is proportional to the plasma concentration.

Marc Imhotep Cray, M.D.

Further study tools and resources: IVMS Online Medical Pharmacology Course (5 components): Instructor: Marc Imhotep Cray, M.D. Course Website: Link  Integrated Scientific and Clinical Pharmacology: A MS1 & MS2 Course Syllabus and Digital Guidebook (2015) • Medical Pharmacology: Core Concepts and Learning Objectives • Medical Pharmacology Case Studies •

Medical Pharmacology Unit e-Notes

• Medical Pharmacology Glossary of Terms

e-Learning resource center: IVMS Medical Pharmacology Cloud Folder Marc Imhotep Cray, M.D.