Fundamentals of Pharmacology-COM5082 Lecture 2 PDF

Fundamentals of Pharmacology-COM5082 Lecture 2: Dose Response Relationships Receptor Theory 1 Hoang Nguyen, M.D., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for questions or appoin...

Fundamentals of Pharmacology-COM5082 Lecture 2: Dose Response Relationships Receptor Theory 1 Hoang Nguyen, M.D., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for questions or appointment: [email protected] Learning Objectives After Completion of this section of Dose-Response Receptor Theory, first year M1 students will be able to identify and explain: 1. State the basic assumption that govern receptor theory 2. Analyze LDR curves to distinguish a drug as an agonist, partial agonist, competitive antagonist, or non-competitive antagonist 3. Define ED50, LD50, therapeutic index, potency, efficacy, and affinity, and determine these parameters from LDR curves. Drug Receptors • Drug delivered into system • Affects cells that have receptors  Drugs, as well as hormones, neurotransmitter, and toxins can transfer information to cells by interaction with specific receptive molecules called “receptors”. • Desired effect = therapeutic effect • All other effects = side effects (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Theory of Drug-Receptor Interactions  Relationship between the drug concentration and response.  For drugs that exhibit a direct and reversible effect, the following diagram describes what occurs at the level of the drug receptor: • When a specific receptor site for a drug is known, that receptor site becomes the site of action for that particular drug. • e.g. Morphine, an analgesic drug; the receptor for morphine is located in the brain and are known as opioid receptors. When morphine binds to its receptors, it produces cell changes that reduce the perception of pain. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Law of Mass Action  Ligand=a substance that forms a complex with a biomolecule to serve a biological purpose.  Receptor=typically glycoproteins located in cell membranes that specifically recognize and bind to ligands.  Binding occurs when ligand and receptor collide.  Once binding has occurred, the ligand and receptor remain bound together for a random amount of time influenced by the affinity of the ligand for the receptor.  Affinity=a measure of the tightness with which a drug binds to the receptor.  After dissociation, the ligand and receptor are the same as they were before binding.  At equilibrium, ligand receptor complexes form at the same rate that they dissociate: Law of Mass Action describe the concentration of drug and association/dissociation of the drug-receptor complex Receptor Occupancy    The dose -response relationship suggests that the magnitude of pharmacologic effects produced by ligands is proportional to fractional receptor occupancy f As the dose of drug increases, the fractional occupancy increases, and this results in an increase in the response. The maximal number of receptors bound is termed Bmax Receptor Occupancy  Michaelis-Menten equation Binding of drug to receptor = drug to enzyme • The amount of drug bound at any time is determined by: – the number of receptors – the concentration of drug added – the affinity of the drug for its receptor Affinity  Affinity= strength of binding between drug and receptor.  It is quantified by the dissociation constant Kd ,the concentration of ligand that produces 50% receptor occupancy at equilibrium.  Affinity = KD Affinity and Dissociation constant are inversely proportional. If the affinity is low, a higher concentration of ligand is required to produce receptor occupancy. An individual with a higher % body fat may experience a greater drug effect, because the drug is dissolved in a smaller volume of body fluids and would result in a longer duration of action. Therefore, the affinity of the drug is greater. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Potency  Potency= a measure of strength, or concentration, of a drug required to produce a specific effect.  The dose that will produce an effect that is half of the maximal response is referred to as the Effective Dose (ED50) Potency is proportional with affinity (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Efficacy  Efficacy=the magnitude of response a drug causes when it interacts with a receptor.  Efficacy is more clinically useful characteristic than potency, since a drug with greater efficacy is more therapeutically beneficial than one that is more potent.  Ceiling effect: reflects the limit of some drug classes to produce a particular effect. Above the certain dosage no further increase in effect is observed (e.g: Amoxillicin x14 days for Strep Pneumonia) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Clinical Vignette  A 65 years old male with a history of hypertension is to be treated with an antidiuretic drug. Drugs A and B have the same mechanism of diuretic action. Drug A in a dose of 2 mg produces the same magnitude of antidiuresis as 200mg of drug B. Which of the following statements can be made? A. Drug B is less efficacious than drug A B. Drug A will have a shorter duration of action than drug B because less of drug A is present for a given effect. C. Drug A is 100 times more potent than drug B D. Toxicity of drug A is less than that of drug B E. Drug A has a wider therapeutic window than drug B Time-Plasma Drug Concentration Curve     Onset of action: the time from drug administration to the first observable effect Duration of action: the length of time that a drug continues to produce its effect. Termination of drug action: when the plasma drug concentration falls below the therapeutic range. Time-Plasma Drug concentration curves are used for predicting the frequency with which a drug must be administered in order to maintain an effective drug response. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Therapeutic Index  ED50 (median effective dose): dose that produces therapeutic effect in 50% of population.  TD50 (median toxic dose): dose that produces toxic effect in 50% of population.  LD50 (median lethal dose): dose that produces lethal effect in 50% of population The results of the LD50 and other test are used to predict the safety of a drug. Therapeutic Window  The concentration of drug between the effective and the toxic concentration; window where most safe and effective treatment will occur. Therapeutic Index  The therapeutic index (TI), also called therapeutic ratio is a quantitative measure of the relative safety of a drug. It compares the amount of therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. Drug with low TI: Warfarin, Theophylline, Digoxin, Gentamicin, Lithium (Warning! These Drugs are Getting Lethal!) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Agonist  Drugs that bind to specific receptors and produce a drug action are called agonists.  Full Agonist: produce complete activation of a receptor at high drug concentration.  Partial Agonist: binding results in less than 100% activation, even at very high concentration.  Inverse Agonist: activates the receptor, but produces opposite effects of endogenous ligand (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Drug Receptors – Agonist Epinephrine Beta Adrenergic Receptor Target Cell Drug Response Antagonist  Antagonist= type of receptor ligand or drug that block or dampens a biological response by binding and blocking a receptor, rather than activating it like an agonist.  Example: Naloxone, a morphine antagonist, is administered to prevent, or antagonize, the effects of morphine in cases of morphine overdose. Protamine Sulfate, an unfractionated heparin antagonist  There are two type of antagonist drugs: Competitive Antagonist and Noncompetitive Antagonist Competitive Antagonist  When both agonist and antagonist drugs bind to the same receptor and are administered together, they compete with each other for the same receptor site. This effect is known as competitive antagonism.  Presence of a competitive antagonist, shifts the log dose response curve to higher doses (i.e. horizontally to the right on the dose axis) but the same maximal effect isreached May be reversible or irreversible  • Competitive antagonists the ED50 (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Non-competitive Antagonist   Non-competitive antagonism occurs when the antagonist drug interferes with the agonist drug action, without binding to the same receptor. Non-competitive antagonists cause a downward shift in the dose-response curve = reduced efficacy Agent A=Diazepam Agent B=Picrotoxin (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Comparison: Competitive and Non-competitive Antagonist (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Resources  1. Basic and clinical pharmacology by Katzung, 15th edition.  2. Videos: https://sketchy.com/