PCTH 325 Lecture 2 Pharmacodynamics Part 2 (1) PDF

Rational Basis of Drug Therapy Dr. Alasdair M. Barr Associate Professor...

Rational Basis of Drug Therapy Dr. Alasdair M. Barr Associate Professor Department of Anesthesiology, Source Image: www.drugabuse.gov Pharmacology & Therapeutics PCTH 325 Fall Term 2024 University of British Columbia Alasdair M. Barr  Receptor Concept & Importance Receptors largely determine the quantitative relations between dose/concentration of drug and effect ─ Receptors affinity for a drug determines the concentration of drug required ─ Total number of receptors can limit the maximal effect a drug produces Receptors are responsible for selectivity of drug action ─ Molecular size, shape, electrical charge of drug determines whether it can bind to a selective receptor site ─ Slight changes in chemical structure can dramatically increase/decrease drug binding for additional receptors Receptors mediate the actions of agonists and antagonists 2 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Receptor Concept & Importance Receptors largely determine the quantitative relations between dose/concentration of drug and effect ─ Receptors affinity for a drug determines the concentration of drug required ─ Total number of receptors can limit the maximal effect a drug produces Receptors are responsible for selectivity of drug action ─ Molecular size, shape, electrical charge of drug determines whether it can bind to a selective receptor site ─ Slight changes in chemical structure can dramatically increase/decrease drug binding for additional receptors Receptors mediate the actions of agonists and antagonists 3 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Receptor Concept & Importance Receptors largely determine the quantitative relations between dose/concentration of drug and effect ─ Receptors affinity for a drug determines the concentration of drug required ─ Total number of receptors can limit the maximal effect a drug produces Receptors are responsible for selectivity of drug action ─ Molecular size, shape, electrical charge of drug determines whether it can bind to a selective receptor site ─ Slight changes in chemical structure can dramatically increase/decrease drug binding for additional receptors Receptors mediate the actions of agonists and antagonists 4 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response Concentration-Effect Curves ─ Responses to low dose usually increase in direct proportion to dose ─ Response increment diminishes as dose increases ─ Doses may be reached at which no further increase in response is noted xC E = C + EC50 ─ E = Effect observed ─ C = Concentration ─ = maximal response that can be produced by drug ─ EC50 = concentration of drug that produces 50% of maximal effect 5 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response Fitting of complex receptor-response can be complex Focus on key terms needed to understand specialized pharmacology 6 Source: https://www.nature.com/articles/s41598-020-70220-w Alasdair M. Barr  Relation Between Drug Concentration & Response EC50: Half maximal effective concentration (EC50) is a measure of the concentration of a drug which induces a response halfway between the baseline and maximum (Emax) Commonly used to determine potency of a drug 7 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response Concentration-Effect Curves ─ The linear scale has a very steep increase which flattens out with increasing concentration. If you wish to compare two drugs for say the EC50, the space between the two drugs may be very small and tricky to differentiate. Typically drug doses reported on log scale. 8 Source: https://www.quora.com/Why-do-I-need-to-log-my-concentrations-in-a-dose-response-curve Alasdair M. Barr  Relation Between Drug Concentration & Response Concentration-Effect Curves ─ The linear scale has a very steep increase which flattens out with increasing concentration. If you wish to compare two drugs for say the EC50, the space between the two drugs may be very small and tricky to differentiate. Typically drug doses reported on log scale. 9 Source: https://www.quora.com/Why-do-I-need-to-log-my-concentrations-in-a-dose-response-curve Alasdair M. Barr  Drug Dose & Clinical Response Drug-receptor interactions underlie the relations between dose and response in patients To choose among drugs and to determine appropriate dose of a drug: Pharmacologic Potency ─ The concentration (EC50) of a drug required to produce 50% of that drug's maximal effect ─ Based on the relative position of their dose-response curves along the dose axis (typically x-axis) Maximal Efficacy ‒ Based on the relative position of their dose-response curves along the response axis (typically y-axis) 10 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Drug Dose & Clinical Response 50% 11 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Drug Dose & Clinical Response Drugs A, C and D are more efficacious than Drug B because they elicit a larger response than Drug B [Purple arrow] 50% 12 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Drug Dose & Clinical Response Drugs A, C and D are more efficacious than Drug B because they elicit a larger response than Drug B [Purple arrow] 50% Drug A is more potent than drugs C and D because the dose that elicits 50% of the response is much smaller than the doses of drugs C and D 13 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Drug Dose & Clinical Response - antagonists Competitive Competitive antagonist shifts curve to the right, increasing EC50 14 Source: https://quizlet.com/145854517/pharmacology-pharmacodynamics-drug-receptor-interactions-and-dose-response-relationships-flash-cards/ Alasdair M. Barr  Drug Dose & Clinical Response Non-competitive antagonists bind to the active site of the receptor, permanently reducing the number of receptors available to the agonist. -A non-competitive antagonist causes a downward shift of the Emax, with no shift of EC50 Competitive values. -In contrast to competitive antagonists, addition of more agonist does not overcome the effect of irreversible antagonists. -Irreversible antagonists and allosteric antagonists both have these effects 15 Source: https://quizlet.com/145854517/pharmacology-pharmacodynamics-drug-receptor-interactions-and-dose-response-relationships-flash-cards/ Alasdair M. Barr  Relation Between Drug Concentration & Response Concentration-Effect Curves Emax x C E = C + EC50 ─ E = Effect observed at concentration C ─ C = Concentration ─ Emax = maximal response that can be produced by drug ─ EC50 = concentration of drug that produces 50% of maximal effect 16 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response EC50 versus ED50: EC50 is the dose required for an individual to experience 50% of the maximum effect. ED50 is the dose for 50% of the population to obtain the therapeutic effect. 17 Sourcehttps://www.emedsa.org.au/MedicalPBL/AdvancedPharmacology.html & https://medicoapps.org/dose-response-curve-3/ Alasdair M. Barr  Relation Between Drug Concentration & Response IC50: The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function by 50% Tumor growth in 2D cell cultures 18 Source: https://www.biorxiv.org/content/10.1101/2020.05.05.079285v1.full Alasdair M. Barr  Relation Between Drug Concentration & Response IC50: The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function by 50% 19 Source: https://www.biorxiv.org/content/10.1101/2020.05.05.079285v1.full Alasdair M. Barr  Relation Between Drug Concentration & Response Kd = equilibrium dissociation constant Concentration (molar) of free drug at which half-maximal receptor binding is observed ‒ Characterizes the receptor’s affinity for binding the drug If the If P = protein (receptor) L = ligand (drug) 20 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response Kd = equilibrium dissociation constant Concentration of free drug at which half-maximal binding is observed ‒ Characterizes the receptor’s affinity for binding the drug If the Kd value is low, binding affinity is high If Kd is high value, binding affinity is low 21 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response Kd = equilibrium dissociation constant Concentration of free drug at which half-maximal binding is observed ‒ Characterizes the receptor’s affinity for binding the drug If the Kd value is low, binding affinity is high If Kd is high value, binding affinity is low 22 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response Maximal occupation of the receptors = Bmax 23 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Relation Between Drug Concentration & Response EC50 and Kd are not necessarily the same…. 24 Source: https://basicmedicalkey.com/pharmacodynamics-6/ Alasdair M. Barr  Relation Between Drug Concentration & Response Spare receptors: Occurs when the maximal drug response (Emax) is obtained at less than maximal occupation of the receptors (Bmax) In a system with spare receptors, the EC50 is lower than the Kd, indicating that to achieve 50% of maximal effect, less than 50% of the receptors must be activated Occurs when i) duration of the activation of the effector may be much greater than the duration of the drug-receptor interaction ii) the actual number of receptors may exceed the number of effector molecules available 25 Source: https://basicmedicalkey.com/pharmacodynamics-6/ Alasdair M. Barr  Drug Dose & Clinical Response - Toxicity ED50 = median effective dose; the dose at which 50% of individuals exhibit the specified effect TD50 = the dose at which 50% of individuals exhibit a toxic side-effect (LD50 = lethal effect) 26 Source https://tmedweb.tulane.edu/pharmwiki/doku.php/basic_principles_of_pharm Alasdair M. Barr  Drug Dose & Clinical Response LD50 = dose at which half of subjects die 27 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Drug Dose & Clinical Response Relates dose of a drug required to produce a desired effect to that which produces an undesired effect TD50 TI = ED50 28 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Drug Dose & Clinical Response Relates dose of a drug required to produce a desired effect to that which produces an undesired effect TD50 TI = ED50 Therefore, drugs with a high TI are considered safe, while drugs with a low TI are less safe Generally, ideal to have drugs with a TI of at least 10 29 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Drug Dose & Clinical Response 30 Sourcehttps://www.slideserve.com/gladys/therapeutic-drug-monitoring Alasdair M. Barr  Signaling Mechanisms & Drug Action Molecular Mechanisms by which a drug acts – Important clinical implications Why do some drugs produce effects for min, hours, days after drug is no longer present on receptor? Why do responses to other drugs diminish rapidly after prolonged or repeated administration? Why do chemically similar drugs exhibit selectivity in their actions? Do these mechanisms provide targets for developing new drugs? 31 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Signaling Mechanisms & Drug Action Molecular Mechanisms by which a drug acts – Important clinical implications Why do some drugs produce effects for min, hours, days after drug is no longer present on receptor? Why do responses to other drugs diminish rapidly after prolonged or repeated administration? Why do chemically similar drugs exhibit selectivity in their actions? Do these mechanisms provide targets for developing new drugs? 32 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Signaling Mechanisms & Drug Action Molecular Mechanisms by which a drug acts – Important clinical implications Why do some drugs produce effects for min, hours, days after drug is no longer present on receptor? Why do responses to other drugs diminish rapidly after prolonged or repeated administration? Why do chemically similar drugs exhibit selectivity in their actions? DETERMINED BY TRANSMEMBRANE DRUG SIGNALING MECHANISMS 33 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Signaling Mechanisms & Drug Action Known transmembrane signaling mechanisms: 1: A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene transcription); 2: the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain; 3: the signal binds to the extracellular domain of a transmembrane receptor bound to a separate protein tyrosine kinase, which it activates; 4: the signal binds to and directly regulates the opening of an ion channel; 5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. (A, C, substrates; B, D, products; R, receptor; G, G protein; E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.) 34 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Signaling Mechanisms & Drug Action 1. A lipid-soluble ligand that crosses the membrane and acts on a intracellular receptor Most common example: Steroids (corticosteroids, mineralocorticoids, sex steroids, Vitamin D) Receptors stimulate the transcription of genes through binding to DNA sequences Effects occur after a ‘lag’ period (several hours – days time required to synthesize new proteins) Effects can persist for hours-days (slow turnover of proteins) 35 Source: https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/66-hormones-homeostasis-and/types-of-hormones.html Alasdair M. Barr  Signaling Mechanisms & Drug Action 1. A lipid-soluble ligand that crosses the membrane and acts on a intracellular receptor Effects occur after a ‘lag’ period (several hours – days time required to synthesize new proteins) Effects can persist for hours-days (slow turnover of proteins) Effects occur after a ‘lag’ period (several hours – days time required to synthesize new proteins) Effects can persist for hours-days (slow turnover of proteins) 36 Source: https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/66-hormones-homeostasis-and/types-of-hormones.html Alasdair M. Barr  Signaling Mechanisms & Drug Action 2 & 3. A transmembrane receptor protein that has intracellular enzymatic activity or stimulates a protein tyrosine kinase Common example: Cytokine receptors 1. Ligand (cytokine) binds to receptor 2. Receptor conformational change 3. Activation of intracellular enzymatic domain, or separate protein (enzyme) bound to receptor becomes activated (e.g. Janus kinases JAK) 4. Phosphorylation engages downstream signaling proteins (e.g. STAT) 37 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Signaling Mechanisms & Drug Action 4. A ligand-gated transmembrane ion channel that can be induced to open or close Common example: acetylcholine nicotinic receptor is a pentamer made up of four different polypeptide subunits (eg, two α chains plus one β, one γ, and one δ chain, all with molecular weights ranging from 43,000 to 50,000). Neurotransmitters, when bound to ion channel, regulate the flow of ions through plasma membrane channels 38 Effect is relatively instant (milliseconds) Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Signaling Mechanisms & Drug Action 4. A ligand-gated transmembrane ion channel that can be induced to open or close Neurotransmitters, when bound to ion channel, regulate the flow of ions through plasma membrane channels Effect is relatively instant (milliseconds) E.g. Acetylcholine binds to nAchR, which allows sodium to flow down concentration gradient into cells = produce excitatory postsynaptic potential Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors 39 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Signaling Mechanisms & Drug Action 5. A transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G-protein) that modulates a intracellular second messenger GPCR signaling is initiated when a ligand binds to the extracellular surface of the GPCR. This results in a conformational change in the GPCR causing the activation of the Gα subunit. The activated Gα exchanges bound GDP with GTP, resulting in the disassociation of the Gα subunit from the Gβγ dimer. The Gα and Gβγ subunits then induce or inhibit intracellular signaling cascades as a response to the extracellular stimuli. 40 Source: https://blog.addgene.org/gpcrs-how-do-they-work-and-how-do-we-study-them Alasdair M. Barr  Common Intracellular Second Messengers Phosphorylation Almost all second messenger signaling involves reversible phosphorylation Amplification of signal ─ When phosphorylated, usually activation (kinases) ─ Dephosphorylation usually terminates effect 42 Source: Katzung BG, Masters SB, Trevor AJ: Basic & Clinical Pharmacology, 12 e Alasdair M. Barr  Review The history and major classes of pharmacology ‒ Pharmacodynamics (what the drug does to the body/tissue) The general principles of pharmacology The nature and characteristics of drugs ‒ Size, charge, lipophilicity etc To identify the drug-receptor interactions ‒ Agonist versus antagonist To review signaling mechanisms & drug action ‒ Ion-channel versus G-protein To understand the relation between drug dose and clinical response ‒ Potency, efficacy, EC50, LD50, TI 43 Alasdair M. Barr Questions? 44 Alasdair M. Barr