Pharmacodynamics 2 (Mayers-Aymes) PDF

Turning point ID: pharmmcqs Pharmacodynamics 2 Natalie Mayers-Aymes [email protected] Calendy Link: https://calendly.com/nmayers-aymes/office-hours ◼ Practice questions available on Canvas ◼ Recommended reading:  Chapter 2: Drug Receptors and Pharmacodynamics, in Basic & Clinical Phar...

Turning point ID: pharmmcqs Pharmacodynamics 2 Natalie Mayers-Aymes [email protected] Calendy Link: https://calendly.com/nmayers-aymes/office-hours ◼ Practice questions available on Canvas ◼ Recommended reading:  Chapter 2: Drug Receptors and Pharmacodynamics, in Basic & Clinical Pharmacology, ed. 15. by Trevor Katzung ◼ ◼ Available through Canvas, Student Resources, Access Medicine, Books, Library There is a long list of terms to understand. Make sure you work the practice questions, to practice using these terms. A bit of practice goes a long way 2 Learning Objectives 1. 2. Explain how one drug can affect the actions of another. a. Describe drug interactions that are additive, potentiating, or synergistic Explain how one drug can counteract or antagonize the effects of another. a. Define and explain partial agonist, competitive antagonist, non-competitive antagonist, physiological antagonist, functional antagonist, chemical antagonist Explain what is meant by “pharmacokinetic antagonism” 3. b. Explain how drug responses in a population are described. a. Describe a quantal dose response curve. Draw a frequency distribution curve. Draw a cumulative frequency distribution curve. Define ED50, LD50, TD50. Define therapeutic index and therapeutic window. Use experimental data to calculate these values. 4. 5. b. c. Explain how a drug response may change over time. a. Describe desensitization and supersensitivity b. Compare receptor up-regulation and receptor down-regulation. c. Describe pharmacodynamic processes for drug tolerance d. Describe pharmacokinetic processes for drug tolerance Explain how a patient’s expectations can affect drug response a. Define placebo and “nocebo” 3 Learning Objectives 1. 2. Explain how one drug can affect the actions of another. a. Describe drug interactions that are additive, potentiating, or synergistic Explain how one drug can counteract or antagonize the effects of another. a. Define and explain partial agonist, competitive antagonist, non-competitive antagonist, physiological antagonist, functional antagonist, chemical antagonist Explain what is meant by “pharmacokinetic antagonism” 3. b. Explain how drug responses in a population are described. a. Describe a quantal dose response curve. Draw a frequency distribution curve. Draw a cumulative frequency distribution curve. Define ED50, LD50, TD50. Define therapeutic index and therapeutic window. Use experimental data to calculate these values. 4. 5. b. c. Explain how a drug response may change over time. a. Describe desensitization and supersensitivity b. Compare receptor up-regulation and receptor down-regulation. c. Describe pharmacodynamic processes for drug tolerance d. Describe pharmacokinetic processes for drug tolerance Explain how a patient’s expectations can affect drug response a. Define placebo and “nocebo” 4 A drug interaction is a measurable modification of the action of one drug by the administration of another substance (drug, food, or environmental agent). Drug interactions can increase or decrease drug effects. Type of Interaction Mathematical “model” Addition -The response elicited by combined drugs is equal to the combined responses of the individual drugs. 1+1=2 Synergism -The response elicited by combined drugs is greater than the combined responses of the individual drugs. 1+1>2 Potentiation -A drug which has no effect by itself enhances the effect of another drug. 0+1>1 Antagonism -The response elicited by combined drugs is lower than the response of the individual drug. 0+1<1 1+1<1 LO 1 Explain how one drug can affect the actions of a second drug. 5 Application Exercise:1 ◼ A bronchiole smooth muscle cell has an intracellular concentration of cAMP of 1 nM. Drug A and Drug B are added, separately or together. The results are shown in the table: 1 2 3 4 No drug 1 nM 1 nM 1 nM 1 nM Drug A 20 nM 20 nM 20 nM 20 nM Drug B 20 nM 1 nM 20 nM 1 nM Drug A+B 80 nM 5 nM 40 nM 40 nM Of conditions 1, 2, 3 and 4, which is an example of: Addition? Potentiation? Synergy? Antagonism? LO 1 Explain how one drug can affect the actions of a second drug. 6 Learning Objectives 1. 2. Explain how one drug can affect the actions of another. a. Describe drug interactions that are additive, potentiating, or synergistic Explain how one drug can counteract or antagonize the effects of another. a. Define and explain partial agonist, competitive antagonist, non-competitive antagonist, physiological antagonist, functional antagonist, chemical antagonist Explain what is meant by “pharmacokinetic antagonism” 3. b. Explain how drug responses in a population are described. a. Describe a quantal dose response curve. Draw a frequency distribution curve. Draw a cumulative frequency distribution curve. Define ED50, LD50, TD50. Define therapeutic index and therapeutic window. Use experimental data to calculate these values. 4. 5. b. c. Explain how a drug response may change over time. a. Describe desensitization and supersensitivity b. Compare receptor up-regulation and receptor down-regulation. c. Describe pharmacodynamic processes for drug tolerance d. Describe pharmacokinetic processes for drug tolerance Explain how a patient’s expectations can affect drug response a. Define placebo and “nocebo” 7 Drug Binding Sites on Drug Target ◼ Many drug targets (e.g., receptors) have  Orthosteric site: binding site for natural ligand  Allosteric site: additional site that influences receptor activity LO 2 Explain how one drug can counteract or antagonize the effects of another. 8 The Binding Sites of Receptors and the Types of DrugReceptor Interaction Application: 2 Is positive allosteric modulator (C): additive, synergistic or potentiating? The terminology for (D) is confusing: -allosteric inhibitor, negative allosteric modulator, uncompetitive antagonist or non-competitive antagonist LO 2 Explain how one drug can counteract or antagonize the effects of another. On this diagram, where is the orthosteric site? Where is the allosteric site(s)? 9 Competitive Antagonist Consider: Haloperidol, 1 micromolar concentration • dopamine is added at increasing concentrations • dopamine can still have maximal effect, but curve is shifted to right • more dopamine is needed to get the effect Effect (% max) Dopamine acts at D2 receptor • increased effect with increasing concentration of dopamine Haloperidol, 100 micromolar concentration • dopamine is added at increasing concentrations • dopamine can still have maximal effect, but curve is shifted to the right • more dopamine is needed to get the effect LO 2 Explain how one drug can counteract or antagonize the effects of another. EC50 Dopamine concentration (log) 10 Competitive Antagonist Agonist Competitive antagonist LO 2 Explain how one drug can counteract or antagonize the effects of another. Non-Competitive Antagonist Antiadrenergic Consider: Phenoxybenzamine, 1 micromolar concentration • Phenoxybenzamine binds covalently to alpha 1, decreasing the number of available receptors • NE is added at increasing concentrations • NE can not have maximal effect as there are fewer receptors available Effect (% max) Norepinephrine (NE) acts at alpha 1 receptor • increased effect with increasing concentration of NE Phenoxybenzamine, 100 micromolar concentration • Phenoxybenzamine binds covalently to alpha 1, decreasing the number of available receptors • NE is added at increasing concentrations • NE can not have maximal effect as there are fewer receptors available LO 2 Explain how one drug can counteract or antagonize the effects of another. Norepinephrine concentration (log) 12 Le, Tao, et al. First Aid for the USMLE Step 1 2022. Available from: VitalSource Bookshelf, (32nd Edition). McGraw-Hill Professional, 2022. Non-Competitive (Irreversible) Antagonists Agonist Non-competitive (irreversible) antagonist LO 2 Explain how one drug can counteract or antagonize the effects of another. Application Exercise: 3 What does the receptor binding curve look like? Dopamine only, then  Dopamine plus haloperidol (1 micromolar)  NE only, then  NE plus phenoxybenzamine (1 micromolar)  Receptors bound (% max) by Dopaimen or NE ◼ 100 75 50 25 0 Dopamine or NE concentration 14 Functional Antagonist, Physiological Antagonist Consider: ◼ Cocaine increases dopamine levels and haloperidol blocks D2 receptors  ◼ The actions of cocaine are opposed by haloperidol, but the drugs act at different sites ◼ In bronchiole smooth muscle   Muscarinic agonists (e.g., Ach) promote contraction of smooth muscle, whereas beta-2 agonists (e.g., albuterol, epinephrine) promote relaxation of smooth muscle Opposing actions through activation of different receptors Amphetamine is a stimulant and ethanol is a CNS depressant  The actions of amphetamine are opposed by ethanol, but the drugs act at different sites LO 2 Explain how one drug can counteract or antagonize the effects of another. 16 Chemical Antagonist ◼ ◼ ◼ ◼ “antagonist” physically binds to the “agonist” and prevents “agonist” from having its effect e.g., antacids are used to prevent the actions of stomach acid e.g., heavy metal toxicity is treated with a drug to chelate the heavy metal and prevent its toxic actions e.g., protamine sulfate is positively charged and is used to treat toxicity due to the anticoagulant heparin (which is negatively charged) LO 2 Explain how one drug can counteract or antagonize the effects of another. 17 Partial Agonist ◼ Partial agonist has agonist activity but also antagonizes effect of full agonist (e.g., endogenous ligand) ◼ ◼ ◼ Purple – concentration response curve to full agonist (FA) Green – concentration response curve to partial agonist (PA) Red, yellow – full agonist is inhibited by antagonist (red) or partial agonist (yellow) FA concentration-effect PA concentration-effect 10-7 M FA + increasing PA 10-7 M FA + increasing antagonist LO 2 Explain how one drug can counteract or antagonize the effects of another. 18 Additional Application Question “Pharmacokinetic Antagonism” ◼ ◼ Many drug interactions occur because one drug affects metabolism of another drug Consider:     Drug B Drug B, altered by Drug A Drug A increases the metabolism of Drug B, Drug B will have reduced plasma concentration and shorter duration of action Drug A is inhibiting the effects of Drug B Drug A is a “pharmacokinetic antagonist” of Drug B FM2 Pharmacokinetics LO 2 Explain how one drug can counteract or antagonize the effects of another. 20 Application Exercise: 4 ◼ Drug A is a full agonist, how is its potency (EC50) and efficacy affected (↑ increased; ↓ decreased; 0 no change) by: Potency High [Drug A] + Competitive antagonist High [Drug A] + Partial agonist Drug A + Irreversible antagonist Drug A + Positive allosteric modulator Drug A + Negative allosteric modulator Efficacy Learning Objectives 1. 2. Explain how one drug can affect the actions of another. a. Describe drug interactions that are additive, potentiating, or synergistic Explain how one drug can counteract or antagonize the effects of another. a. Define and explain partial agonist, competitive antagonist, non-competitive antagonist, physiological antagonist, functional antagonist, chemical antagonist Explain what is meant by “pharmacokinetic antagonism” 3. b. Explain how drug responses in a population are described. a. Describe a quantal dose response curve. Draw a frequency distribution curve. Draw a cumulative frequency distribution curve. Define ED50, LD50, TD50. Define therapeutic index and therapeutic window. Use experimental data to calculate these values. 4. 5. b. c. Explain how a drug response may change over time. a. Describe desensitization and supersensitivity b. Compare receptor up-regulation and receptor down-regulation. c. Describe pharmacodynamic processes for drug tolerance d. Describe pharmacokinetic processes for drug tolerance Explain how a patient’s expectations can affect drug response a. Define placebo and “nocebo” Quantal Dose Response Curve Outcome is defined in advance • e.g., zero virus detected • e.g., drop of 10 mm Hg in blood pressure • e.g., admitted to hospital Quantal – did the individual have an outcome: yes or no? Frequency distribution curve Cumulative frequency distribution curve Percent individuals with defined outcome LO 3 Explain how drug responses in a population are described. Katzung, Bertram, G. and Anthony J. Trevor. Basic and Clinical Pharmacology. Available from: VitalSource Bookshelf, (15th Edition). McGraw-Hill Professional, 2020. 23 Relationship Between the Dose of a Drug and the Pharmacological Response If the chosen effect is a lethal one, a toxic one, or a therapeutic one, the doses, which produce that effect in 1%, 50% or 99% percent of the individuals, can be estimated from the quantal log dose-response curve as follows: Dose The minimum The median Lethal LD1 LD50 Toxic TD1 TD50 Effective ED1 ED50 The maximum LD99 TD99 ED99 Definition: LD50 is the dose that will kill 50% of those who take it; TD50 is the dose that will give a specific adverse effect in 50% of those who take it (usually the most common or most problematic adverse effect) LO 3 Explain how drug responses in a population are described. 24 Relationship Between the Dose of a Drug and the Pharmacological Response Therapeutic Index: the ratio between a median harmful dose and a median effective dose of a drug. Examples: LD50 / ED50 ; TD50 / ED50 Therapeutic Window: the range between the minimum therapeutic dose (or plasma concentration) and the minimum toxic dose (or plasma concentration) of a drug ◼ the range of doses that have the highest probability of therapeutic success LO 3 Explain how drug responses in a population are described. 25 Additional Application Question Five new antihypertensive drugs were tested in healthy volunteers. All of the drugs were found to be equally effective in controlling hypertension. The minimum effective plasma concentrations and the minimum toxic plasma concentrations were determined for each drug. The results are reported below. Which of the drugs has the highest probability of therapeutic success? Drug Plasma Concentration (mg/L) Minimum effective Minimum toxic P 5 20 Q 1 10 R 30 60 S 0.6 3 T 20 80 Quantal Dose Response Curve Note: ED50 is dose at which 50% of test subjects get a specific therapeutic effect Application -5 If ED50 is 4 mg and LD50 is 120 mg, then Therapeutic index is ? Therapeutic window is ? LO 3 Explain how drug responses in a population are described. 27 Quantal vs Graded ◼ Quantal: all-or-none e.g., yes or no  e.g., did event happen?  How many participants experienced the event?  ED50 – dose at which 50% of participants experienced the event  ◼ Graded: all, none, and everything in between e.g., How big of a response was observed?  e.g., concentration-effect curve  LO 3 Explain how drug responses in a population are described. 25 Learning Objectives 1. 2. Explain how one drug can affect the actions of another. a. Describe drug interactions that are additive, potentiating, or synergistic Explain how one drug can counteract or antagonize the effects of another. a. Define and explain partial agonist, competitive antagonist, non-competitive antagonist, physiological antagonist, functional antagonist, chemical antagonist Explain what is meant by “pharmacokinetic antagonism” 3. b. Explain how drug responses in a population are described. a. Describe a quantal dose response curve. Draw a frequency distribution curve. Draw a cumulative frequency distribution curve. Define ED50, LD50, TD50. Define therapeutic index and therapeutic window. Use experimental data to calculate these values. 4. 5. b. c. Explain how a drug response may change over time. a. Describe desensitization and supersensitivity b. Compare receptor up-regulation and receptor down-regulation. c. Describe pharmacodynamic processes for drug tolerance d. Describe pharmacokinetic processes for drug tolerance Explain how a patient’s expectations can affect drug response a. Define placebo and “nocebo” 26 Regulation of Receptor Number Activation (1) Desensitization (2) Internalization (3) Resensitization (4, 5) Down-regulation (6) LO 4 Explain how a drug response may change over time. 30 Regulation of Receptor Number Chronic activation of receptors ◼ When receptors are chronically activated by an agonist drug, the pharmacological response can decrease with time, a process called desensitization or down-regulation. Chronic inhibition of receptors ◼ ◼ When receptors are chronically inhibited by an antagonist drug, the pharmacological response can increase with time, a process called sensitization or supersensitivity. This increased response can be evident once the antagonist drug is suddenly removed. Mechanisms include the up-regulation of receptors that are increased in number due to either decreased destruction or increased synthesis LO 4 Explain how a drug response may change over time. 31 Drug Tolerance ◼ Definition : A decreased response to a drug, caused by prior exposure to that drug or to a related drug ➔tolerance is a decrease in sensitivity to a drug; Features 1. Tolerance is evident only with some drugs. 2. Tolerance can be overcome by increasing the dose 3. The amount of tolerance can vary widely LO 4 Explain how a drug response may change over time. 32 Mechanisms of Tolerance PHARMACOKINETIC TOLERANCE → Also called METABOLIC tolerance ◼ Tolerance is due to a decrease in the effective concentration of the drug at the site of action (e.g., the drug increases its own rate of biotransformation by inducing drug metabolizing enzymes). FM2 Pharmacokinetics LO 4 Explain how a drug response may change over time. 33 Mechanisms of Tolerance PHARMACODYNAMIC TOLERANCE → Also ◼ called FUNCTIONAL tolerance Tolerance to a drug whose concentration at the site of action is not modified, is due to: 1. 2. 3. Homeostatic adaptive changes (neurophysiological or biochemical) that counteract the drug effect Changes in a number of receptors of the drug (changes in number of receptors i.e, down-regulation, is the most common mechanism. Changes in receptor signaling (e.g., signal transduction pathway). LO 4 Explain how a drug response may change over time. 34 Application Exercise: 6 Draw a concentration - effect curve for a drug before and after development of pharmacodynamic tolerance  Does tolerance cause an increase or decrease in the EC50 value? Drug effect (% max) ◼ 100 75 50 25 0 Drug concentration LO 4 Explain how a drug response may change over time. 32 Learning Objectives 1. 2. Explain how one drug can affect the actions of another. a. Describe drug interactions that are additive, potentiating, or synergistic Explain how one drug can counteract or antagonize the effects of another. a. Define and explain partial agonist, competitive antagonist, non-competitive antagonist, physiological antagonist, functional antagonist, chemical antagonist Explain what is meant by “pharmacokinetic antagonism” 3. b. Explain how drug responses in a population are described. a. Describe a quantal dose response curve. Draw a frequency distribution curve. Draw a cumulative frequency distribution curve. Define ED50, LD50, TD50. Define therapeutic index and therapeutic window. Use experimental data to calculate these values. 4. 5. b. c. Explain how a drug response may change over time. a. Describe desensitization and supersensitivity b. Compare receptor up-regulation and receptor down-regulation. c. Describe pharmacodynamic processes for drug tolerance d. Describe pharmacokinetic processes for drug tolerance Explain how a patient’s expectations can affect drug response a. Define placebo and “nocebo” 33 Placebo, “Nocebo” ◼ Placebo: any substance whose beneficial effects are attributable to its use, but not to its specific pharmacodynamic properties   ◼ On average 35% of benefit of drug is a placebo effect Influenced by many factors, e.g. physician attitude, environment of drug use, size/color/taste of medicine “nocebo”: any substance whose harmful effects are attributable to its use, but not to its specific pharmacodynamic properties LO 5 Explain how a patient’s expectations can affect drug response. 34 Turning point ID: pharmmcqs Summary ◼ ◼ Drug-drug interactions: can increase or decrease clinical response Many types of antagonists     ◼ Drug response in population – frequency distribution curves  ◼ ◼ Competitive - competes with agonist for binding site Non-competitive – covalently binds to agonist binding site Negative allosteric modulator Chemical, physiological/functional Therapeutic index, safety Mechanisms of drug tolerance Placebo response 35 Turning point ID: pharmmcqs Learning Objectives 1. 2. Explain how one drug can affect the actions of another. a. Describe drug interactions that are additive, potentiating, or synergistic Explain how one drug can counteract or antagonize the effects of another. a. Define and explain partial agonist, competitive antagonist, non-competitive antagonist, physiological antagonist, functional antagonist, chemical antagonist Explain what is meant by “pharmacokinetic antagonism” 3. b. Explain how drug responses in a population are described. a. Describe a quantal dose response curve. Draw a frequency distribution curve. Draw a cumulative frequency distribution curve. Define ED50, LD50, TD50. Define therapeutic index and therapeutic window. Use experimental data to calculate these values. 4. 5. b. c. Explain how a drug response may change over time. a. Describe desensitization and supersensitivity b. Compare receptor up-regulation and receptor down-regulation. c. Describe pharmacodynamic processes for drug tolerance d. Describe pharmacokinetic processes for drug tolerance Explain how a patient’s expectations can affect drug response a. Define placebo and “nocebo” 36 Turning point ID: pharmmcq Question # 1 A new hypnotic drug was tested in laboratory animals. It was found that the ED50 for inducing sleep was 2 mg/kg. Which of the following best explains the meaning of that dose? A. The mean dose able to elicit sleep induction B. The dose with a 50% probability of causing sleep C. The dose that elicits sleep in 50% of animals D. The mean dose with a good probability of sleep induction E. The dose that elicits a median therapeutic sleep response in most animals Pharmacology Test Prep. 1500 USMLE-Style Questions & Answers. Babbini M, Thomas M, ed. 1st Edition. New York: Thieme; 2014. doi:10.1055/b-005-148823 Question # 1 Answer A new hypnotic drug was tested in laboratory animals. It was found that the ED50 for inducing sleep was 2 mg/kg. Which of the following best explains the meaning of that dose? A. The mean dose able to elicit sleep induction B. The dose with a 50% probability of causing sleep C. The dose that elicits sleep in 50% of animals D. The mean dose with a good probability of sleep induction E. The dose that elicits a median therapeutic sleep response in most animals Question # 2 A 2-year-old girl was rushed to the emergency department after ingesting several tablets of a medication containing iron. An emergency treatment was started that included the intravenous administration of deferoxamine. This drug is able to combine with iron in plasma to form an inactive complex and therefore to antagonize iron effects. Which of the following terms best defines this antagonism? A.Competitive B.Noncompetitive C.Functional D.Chemical E.Pharmacokinetic Pharmacology Test Prep. 1500 USMLE-Style Questions & Answers. Babbini M, Thomas M, ed. 1st Edition. New York: Thieme; 2014. doi:10.1055/b-005-148823 Question # 2 Answer A 2-year-old girl was rushed to the emergency department after ingesting several tablets of a medication containing iron. An emergency treatment was started that included the intravenous administration of deferoxamine. This drug is able to combine with iron in plasma to form an inactive complex and therefore to antagonize iron effects. Which of the following terms best defines this antagonism? A.Competitive B.Noncompetitive C.Functional D.Chemical E. Pharmacokinetic Question # 3 A 45-year-old woman recently diagnosed with a urinary tract infection started therapy with a trimethoprim–sulfamethoxazole combination. Both trimethoprim and sulfamethoxazole are bacteriostatic drugs when given alone. However, a bactericidal effect is obtained when the two drugs are given in combination. Which of the following terms best defines this drug interaction? A. Additive effect B. Potentiation C. Synergism D. Reverse tolerance E. Sensitization Pharmacology Test Prep. 1500 USMLE-Style Questions & Answers. Babbini M, Thomas M, ed. 1st Edition. New York: Thieme; 2014. doi:10.1055/b-005-148823 Question # 3 Answer A 45-year-old woman recently diagnosed with a urinary tract infection started therapy with a trimethoprim–sulfamethoxazole combination. Both trimethoprim and sulfamethoxazole are bacteriostatic drugs when given alone. However, a bactericidal effect is obtained when the two drugs are given in combination. Which of the following terms best defines this drug interaction? A. Additive effect B. Potentiation C. Synergism D. Reverse tolerance E. Sensitization Office Hours Do you need help with…? ◼ Application Exercises ◼ Practice Questions Calendy Link: https://calendly.com/nmayers-aymes/office-hours 46