Introduction To Pharmacology Fall 2024 PDF

1 INTRODUCTION TO PHARMACOLOGY & PHARMACODYNAMICS PHRM 6200 Fall 2024 Kathleen Frey, Ph.D. Aug 26 & 28, 2024  2 Announcements Office hours: Mondays and Wednesdays, 11am–12:30pm (by appointment) Email: [email protected] ...

1 INTRODUCTION TO PHARMACOLOGY & PHARMACODYNAMICS PHRM 6200 Fall 2024 Kathleen Frey, Ph.D. Aug 26 & 28, 2024  2 Announcements Office hours: Mondays and Wednesdays, 11am–12:30pm (by appointment) Email: [email protected]  3 Learning Objectives After the next 2 classes, you should be able to: Describe major concepts in pharmacology. Explain the difference between pharmacodynamics (PD) versus pharmacokinetics (PK). Identify the major components of pharmacodynamics (PD). Provide examples of drug targets. Describe the various concepts in receptor theory: receptors, ligands, agonists, antagonists. Define intrinsic drug activity and its measurements: affinity, inhibition, potency, efficacy, and specificity.  4 Lecture Outline Introduction to Pharmaceutical Sciences & Pharmacology Major Concepts in Pharmacology Principles of Pharmacodynamics (PD) o Drug Targets o Receptor Theory & Effectors o Agonism and Antagonism  5 PHARMACEUTICAL SCIENCES: PHARMACOLOGY  6 How to Interpret my Notes Any concept highlighted in bold colored = important concept; bold and underlined = very important concept. Anything highlighted in red = correction to notes; I will point out any corrections to you in lecture. Answers to any practice problems or exercises covered in class will be uploaded to Blackboard. FYI slides are only for your information; they may help you understand big picture concepts but will not be tested on quizzes/exams.  7 Pharmaceutical Sciences Pharmacology/ Toxicology Pharmaceutical sciences are a group of Drug interdisciplinary sciences that deal with the Design/Discovery Pharmacodynamics design, action, delivery, disposition, and Pharmacogenomics Drug Properties SAR & use of drugs. Pharmacophores Pharmaco- kinetics Major topics in pharmaceutical sciences include: Biochemistry/ Chemistry Medicinal Biology Biochemistry/Medicinal Chemistry (6100) Chemistry Pharmacology/Pharmacodynamics (6200) Pharmacokinetics (6200) Stability ADME Pharmaceutics Physical properties & Chemistry Formulation, This field continues to expand with the Delivery development of new advancements and technology. Pharmaceutics  8 Pharmaceutical Sciences Each discipline focuses on drug behavior in a different manner. Biochemistry/ Pharmaceutics Medicinal Chemistry Molecular Biological & Physical Behavior: Behavior: Physiological Formulation, Drug Structure & Behavior: Cell, Disposition, Delivery Target Organ System, Body Pharmacology/Pharmacokinetics  9 Pharmaceutical Sciences: Pharmacology Pharmacology is the scientific study of biochemical and physiological effects of drugs on organisms. This discipline will cover drug action in the body in addition to molecular and cellular mechanisms of action. For many drug classes, pharmacology will also cover the mechanisms of drug toxicity, side effects, and adverse effects. Pharmacology focuses on the science of how drugs work as opposed to clinical or patient decisions.  10 Major Concepts in Pharmacology 1. Review of general physiology and pathophysiology of disease state. 2. Pharmacodynamics (PD) or “what the drug does to the body.” 3. Mechanism of drug therapeutic action (molecular, cellular, and whole organ system). 4. Mechanism of adverse drug reactions, toxicity and/or drug-drug interactions.  11 Major Concepts in Pharmacology: Example Case Drug Example: Ibuprofen Clinical Indication: Anti-inflammatory Drug used for headache, fever, inflammation, mild pain. Chemistry Description: Arylalkanoic acid; propionic acid IUPAC Name: 2-[4-(2-methylpropyl)phenyl]propanoic acid  12 1. Review of General Physiology & Pathophysiology Normal Wrong Fixed Physiology Pathophysiology Treatment Inflammation triggered Painless Reduce Pain & Inflammation by injury/stimuli resulting No Inflammation in pain. No Injury/Stimuli  13 2. Pharmacodynamics (PD) Ibuprofen (NSAID) – Competitive Inhibitor COX Enzyme (Target)  14 3. Mechanism of Therapeutic Action Specific Mechanism of Action (MOA): Ibuprofen is an reversible, competitive inhibitor of both COX-1 and COX-2. Inhibition of COX enzymes results in decreased production of pro- inflammatory and pro-aggregatory prostaglandins and thromboxane. Therapeutically, this reduces inflammation, pain, and fever.  15 4. Mechanism of Adverse Drug Reactions Adverse effect: GI bleeding of ibuprofen Mechanism: NSAIDs cause mucosal damage to the GI leading to breaks and/or bleeding.  16 PHARMACOLOGY: PRINCIPLES OF PHARMACODYNAMICS (PD) PD - What the drug does to the body  17 Pharmacology: PD & PK Pharmacology Pharmacodynamics Pharmacokinetics (PD) (PK) What the drug does to the body What the body does to the drug Relationship Between PD and PK Pharmacodynamics (PD) vs. Pharmacokinetics (PK) Receptors/Targets Pharmacodynamics “What the drug does to the body.” Binding Sites/Affinity Nature of Drugs Absorption Distribution Pharmacokinetics “What the body does to the drug.” Metabolism Excretion Relationship Between PD and PK Pharmacodynamics (PD) Pharmacodynamics Receptor Theory Signaling Mechanisms & Dose-Response Drug Targets Agonism/Antagonism Relationships & Effectors Mechanism of Action Pharmacodynamics (PD) refers to “what the drug does to the body.” Major components of PD include receptor-ligand theory; agonism/antagonism; signaling mechanisms; receptor regulation and dose-response relationships. Drug Targets & Interactions Drug target refers to the primary macromolecule in the body (proteins, nucleic acids) that the drug binds to and produces a biological response. Major drug targets in the body are proteins: receptors, enzymes, ion channels, transporters; other less common targets include nucleic acids or lipids. For protein targets, drugs physically interact with the amino acids (residues) in a specific binding site (i.e. agonist binding site; catalytic site). The number and strength of bonds made between the drug and target will influence affinity. Drug Targets: Enzymes Enzyme + Substrate Enzyme:Substrate Complex Enzyme + Product Example Enzyme: Protease Enzymes are proteins that catalyze reactions by lowering activation energy required in a chemical reaction. Typical cellular effect of enzymes: E + S ⇌ ES → P (E = enzyme; S = substrate; P = product) To lower activation energy, the enzyme must bind a specific substrate and catalyze its conversion to product. Example enzyme drug target: Proteases/HIV protease Drug Targets: Physiological Receptors & Signaling Physiological receptors are transmembrane proteins capable of transmitting a “signal” involved in cellular processes (signal transduction). Signal transduction is an important Ligand process for regulation of gene transcription, cell growth, proliferation, and biochemical cascades. Effectors These receptors in the body have endogenous ligands that bind an extracellular domain, induce a conformational change, and initiate a cascade with downstream effects. Physiological Receptors: GPCRs GPCRs are structurally similar receptors: 7 transmembrane helices with defined extracellular and intracellular domain. Ligand binding site is located within the extracellular region (red). Common GPCRs of pharmacological interest include H1; Rho; β1 adrenergic, Adenosine A2A, and CXCR4. Important Physiological Receptors Structural Family Functional Endogenous Effectors & Example Drugs Family Ligands Transducers G-Protein Coupled Adrenergic (α or β) Norepinephrine; dopamine; G-proteins; adenylyl Alpha blockers; Beta Receptors (GPCRs) receptors epinephrine cyclase Blockers Cholinergic (muscarinic) Acetylcholine G-proteins; adenylyl Atropine; Scopolamine receptors cyclase; ion channels. Eicosanoid receptors Prostaglandins; G-proteins Montelukast thromboxanes; leukotrienes Ion Channels Ligand-gated Acetylcholine; GABA; Na+, Ca2+, K+, Cl- Nicotine; Gabapentin serotonin Voltage-gated N/A (depolarization) Na+, Ca2+, K+, other ions Lidocaine; Verapamil Transmembrane Receptor tyrosine kinases Growth factors PTB/SH2 signaling proteins Imatinib; Herceptin Enzymes Transmembrane Non- Cytokine receptors Interleukins (ILs); other JAK/STAT; soluble tyrosine Antibodies (biologics) Enzymes cytokines kinases Nuclear Receptors Steroid receptors estrogen; testosterone; Co-activators Estrogens; androgens; aldosterone; cortisol corticosteroids Thyroid hormone receptors Thyroid hormone Thyroid hormone Intracellular Many enzymes Nitric oxide (NO); Ca2+ Cyclic GMP Nitrodilators (cytosolic) Enzymes Guanylyl cyclase Pharmacodynamics (PD) Pharmacodynamics Receptor Theory Signaling Dose-Response Drug Targets Agonism/Antagonism Mechanisms Relationships & Effectors Pharmacodynamics (PD) refers to “what the drug does to the body.” Major components of PD include: receptor-ligand theory; agonism/antagonism; signaling mechanisms; receptor regulation and dose-response relationships. PD Principles: Drug Binding and Effects Most drugs bind to a specific receptor to produce a biological effect. Once the drug binds the receptor, the following cellular effects are possible: D + R-effector (R) ⇌ D-R-effector complex → effect D + R ⇌ D-R complex ⇌ effector molecule → effect D + R ⇌ D-R complex ⇌ activation of coupling molecule ⇌ effector molecule → effect Inhibition of metabolism of endogenous activator → increased activator action on an effector molecule → increased effect An effector is another molecule in the cascade that must be “signaled” or activated to produce the biological/therapeutic effect. Effectors translate the drug-receptor interaction into a change in cellular activity; example: G-protein coupled receptors (GPCRs; receptors) -> G-proteins (effectors) -> other proteins. Receptor Theory: Ligands & Receptor Interactions Ligands refer to any molecule that binds the receptor and has a specific biological effect. Ligands may be generally classified as agonists, antagonists, inhibitors, competitive, non-competitive, or allosteric. Drugs are also considered ligands Dose-response Curve that bind the receptor to produce a particular response. Dose-response curves relate a ligand/drug dose/concentration to the % response/effect. Receptor Theory: Endogenous Ligands Endogenous ligands synthesized in the body commonly activate receptors to initiate signal cascades; examples include acetylcholine, norepinephrine, and histamine. Some endogenous ligands may be used therapeutically. The use of endogenous ligands as drugs is limited by short duration of action (due to rapid metabolism) or poor physiochemical properties; example: acetylcholine. Many drugs mimic endogenous ligands but have better properties (i.e. cholinomimetics have longer duration of action). Pharmacodynamics (PD) Pharmacodynamics Receptor Theory Signaling Dose-Response Drug Targets Agonism/Antagonism Mechanisms Relationships & Effectors Pharmacodynamics (PD) refers to “what the drug does to the body.” Major components of PD include: receptor-ligand theory; agonism/antagonism; signaling mechanisms; receptor regulation and dose-response relationships. Receptor Theory: Full Agonists Primary or Competitive Allosteric Dose-Response Curve full Endogenous agonist Endogenous agonist effect * * Drug agonists bind the receptor (preferably active state) to produce a biological effect. Typical cellular effect of agonist on receptor: D + R* ⇌ DR* → full effect (R* = active state) Agonists can be further sub-categorized based on their specific action: 1. Primary or competitive agonists: bind the same site as endogenous agonist. 2. Allosteric agonists: bind a different site from the endogenous agonist. Full agonists (primary or allosteric) will reach a maximal effect (100%) with increasing drug concentration. Receptor Theory: Partial Agonists full effect Endogenous agonist partial effect Partial agonists bind the receptor (preferably in inactive state) and only partially produce a biological effect. Typical cellular effect of partial agonist on receptor: D + R ⇌ DR → partial effect (R= inactive state) Partial agonists will only reach a partial effect (