Histamine Pharmacology - MA 2025 PDF

ONGROUND HYBRID Thursday, 1/16, at 8:30 AM Friday, 1/17, at 8:30 AM In-Class Cases will be released by Wednesday. Patient Cases Participate for the whole duration with accurate response rate of >90% for >90% of the questions....

ONGROUND HYBRID Thursday, 1/16, at 8:30 AM Friday, 1/17, at 8:30 AM In-Class Cases will be released by Wednesday. Patient Cases Participate for the whole duration with accurate response rate of >90% for >90% of the questions.  Pharmacology of Histamine and Anti-Histamines Maha Abdalla, PharmD, PhD, RPh Associate Professor of Pharmaceutical Sciences Email: [email protected] Office Room#276 Phone: (865)288-5837 *Office Hours: Tuesday & Thursday 9 am - 12 pm or by appointment 2  *Big Picture: Histamine and Anti-Histamines Histamine − Biosynthesis & Metabolism − Histamine Receptors − GPCR: H 1 - 4 receptors 1. H1 receptor antagonists − 1st generation: − Allergy: Diphenhydramine HCl (Benadryl), Chlorpheniramine, Cyproheptadine − Various indications (including CNS disorders): − Hydroxyzine HCL (Vistaril, Atarax), Promethazine HCl (Phenergan), Doxepin HCl (Sinequan), Cyproheptadine, Diphenhydramine − 2 generation nd − Cetirizine HCl (Zyrtec), Piperidines: Loratadine (Claritin) − 3rd generation (sometimes referred to as 2nd gen) − Levocetirizine (Xyzal), Desloratadine (Clarinex) − 2nd/3rd gen Fexofenadine (Allegra) − Ophthalmic and/or Nasal: Olopatadine (Patanase), ketotifen (Zaditor), Azelastine 2. H2 receptor antagonist − Famotidine (Pepcid, Zantac 360), cimetidine (Tagamet), nizatidine (Axid) − Ranitidine (Zantac): all RX and OTC withdrawn from the market per the FDA (04/2020) 3. H3 receptor antagonist − Pitolisant (Wakix) Orphan drug for narcolepsy (EDS, Cataplexy) –FDA approved 8/2019 4. H4 receptors antagonists − Investigational agents for inflammatory diseases 3  Lecture Objectives 1. Describe the role of histamine and anti-histamine agents 2. Explain the different H-receptor subtypes 1. Location, signaling pathways, and physiological effects 3. Explain the mechanism of action for each drug class 4. Relate the mechanisms of action of different classes of drugs to their potential adverse effects; 5. Using the information below, be able to explain the “why” and “how” a drug is effective, adverse events occur, and interaction occurs 1. Drugs in the class, key structural differences, mechanism of action, pharmacokinetic aspects (t1/2, metabolism, etc.), side /adverse effects, mechanisms of drug interactions and outcomes of such interactions, contraindications 6. Application of concepts using patient cases: Evaluate patient cases and demonstrate knowledge of therapeutic implications of specific drugs and drug classes. 1. Evaluate and interpret relevant patient/disease state/lab values/and medication(s) information that contributes to developing a therapeutic plan and impact patient outcomes 2. Discuss, compare and contrast, drugs within and across classes including mechanism(s) of action, therapeutic indications, potential adverse effects, contraindication, drug interactions, and therapeutic implications. 4 Primer Histamine A natural constituent in plants, animal and human tissues First autacoid (hormone-like substance) to be discovered. (Greek: autos=self; akos=cure) Synthesized in 1907 Demonstrated to be a natural constituent of mammalian tissues (1927) Involved in inflammatory and anaphylactic reactions. Local application causes swelling redness, and edema, mimicking a mild inflammatory reaction. Large systemic doses leads to profound vascular changes similar to those seen after shock or anaphylactic origin The Triple Response: intradermal administration of histamine A localized “red-spot” Appears within a few seconds & extends rapidly to a few mm around injection site Due to direct vasodilatory effect of histamine (H1-mediated NO production) A “flush”/“flare” Develops slowly, extends 1cm or more beyond the original “red spot” Brighter red than the original “red spot” & general sensation of heat Due to release of other mediators including kinins, PGs etc. and activation of localized axon reflexes A “wheal” Appears in a couple of minutes at the same spot as original red-spot Due to increased capillary permeability & accumulation of plasma exudates 5  Primer Histamine: Biosynthesis and Metabolism Synthesis From L-histidine to histamine via L-histidine decarboxylase Storage and release Mast cells of tissues (skin, mucosal membranes of bronchial tree & intestines), basophils in blood, high in CSF Non-mast cell sites (epidermis, gastric mucus, CNS neuron) Pharmacodynamics Histamine acts on 4 histamine receptors, all are G protein coupled (GPCRs) *Metabolism: 1^ pathway in central histamine: Ring methylation by histamine-N- methyltransferase *MAO-B In peripheral histamine Oxidative deamination by diamine oxidase → imidazole acetic acid Phosphoribosyl transferase 6 Primer Histamine – Receptors and Effects 7 Primer Histamine Receptors All 4 histamine receptors are GPCRs *H1 receptors: 487 aa Coupled to Gq/11, activate PLC-IP3-Ca2+ pathway → PKC, PLA2 Smooth muscle & endothelial cells, CNS (stimulate wakefulness) H1 receptors → immunological response (allergy symptoms) Urticaria, redness, edema, hypotension *Blocked by classical anti-histamines *H2 receptors: 359 aa Both H1 and H2 can act like ntm Coupled to Gs,  cAMP → activate PKA in CNS and play a role in reg body Gastric parietal cells (gastric acid secretion), temp, BP, appetite, pain, thirst, and cardiac muscle, mast cells, CNS secretion of antidiuretic hormone *Antagonists block gastric acid secretion *H3 receptors: 373, 445, 365 aa Coupled to Gi/o,  cAMP, activates MAPK CNS: presynaptic autoreceptors (feedback inhibition) H3R Agonist:  histamine release H3R ANTAgonist:  histamine release H4 receptors: 390 aa, 35-40% homologous with H3 receptors *Coupled to Gi/o,  cAMP,  Ca2+ Cells of hematopoietic lineage (blood) 8 Primer Histamine & Histamine Receptors Use and Warnings Precaution: rash, allergic reaction, hives, may occur Contraindicated in those with histamine hypersensitivity (refer to each product for more info) Use: Allergy testing (e.g. skin test/ scratch test) Europe: Adjunct in the treatment of acute myeloid leukemia (AML) EpiCept (Ceplene) Not FDA approved U.S. - OTC: topical, pain relief, arthritis 9  *Big Picture: Histamine and Anti-Histamines Histamine − Biosynthesis & Metabolism − Histamine Receptors − GPCR: H 1 - 4 receptors 1. H1 receptor antagonists − 1st generation: − Allergy: Diphenhydramine HCl (Benadryl), Chlorpheniramine, Cyproheptadine − Various indications (including CNS disorders): − Hydroxyzine HCL (Vistaril, Atarax), Promethazine HCl (Phenergan), Doxepin HCl (Sinequan), Cyproheptadine, Diphenhydramine − 2 generation nd − Cetirizine HCl (Zyrtec), Piperidines: Loratadine (Claritin) − 3rd generation (sometimes referred to as 2nd gen) − Levocetirizine (Xyzal), Desloratadine (Clarinex) − 2nd/3rd gen Fexofenadine (Allegra) − Ophthalmic and/or Nasal: Olopatadine (Patanase), ketotifen (Zaditor), Azelastine 2. H2 receptor antagonist − Famotidine (Pepcid, Zantac 360), cimetidine (Tagamet), nizatidine (Axid) − Ranitidine (Zantac): all RX and OTC withdrawn from the market per the FDA (04/2020) 3. H3 receptor antagonist − Pitolisant (Wakix) Orphan drug for narcolepsy (EDS, Cataplexy) –FDA approved 8/2019 4. H4 receptors antagonists − Investigational agents for inflammatory diseases 10 H1 H1Receptor and its Antagonists Physiology& Pathophysiology: *H1 receptors Distribution: endothelium, smooth muscle, CNS (stimulate wakefulness) H1 receptors → immunological response (Allergy symptoms) Urticaria, redness, edema, hypotension Blocked by classical anti-histamines Pharmacology: *H1 Receptor Antagonists: *MOA: reversible competitive inh. of histamine Indications: varies by agent and can include allergic reactions , hypersensitivity reactions, anaphylaxis. Some 1st gen. agents can be used for motion sickness, vertigo, N/V, loss of appetite, or to manage psychotic depressive disorders Pharmacological effects: Anti-histamine effects Inhibit histamine mediated vascular vasodilation Suppresses capillary permeability Prevent histamine induced bronchoconstriction Suppress secretions from exocrine glands (but not gastric acid secretion-gastric acids are secreted by H2 not H1) Sedation Sedative effects are related to brain distribution of H1-R o Degree of sedative effect varies between generations of drugs (Benadryl vs Zyrtec) Anti-cholinergic **1st gen. agents: Beers Criteria – caution or avoid use in elderly patients Anti-emetic actions 11 H1 1st Generation H1 Receptor Antagonists Indication: Allergic reaction Agents: RX/OTC: Diphenhydramine HCl (Benadryl), Chlorpheniramine **RX ONLY: Cyproheptadine indications: Anaphylaxis, allergic reaction. Off-label: loss of appetite, serotonin syndrome Other indications & Agents Ethanolamines Piperazines Phenothiazines Tricyclic Dibenzoxazepines **Diphenhydramine HCl *Hydroxyzine HCl *Promethazine HCl *Doxepin HCl (Sinequan) (Benadryl) (Vistaril, Atarax) (Phenergan) doxepin motion sickness; insomnia, Anxiety, pruritus, allergic Motion sickness, vertigo, Anxiety, insomnia, psychotic parkinsonism rhinitis, sedation N/V, post-op pain, depressive disorders Avoid in Pregnancy Avoid in Pregnancy Avoid in Pregnancy ***Side Effects (1st Generation Agents) - **Cross BBB **1st gen. agents: Beers Criteria – caution or avoid use in elderly patients **CNS depression – (somnolence, sedation, impaired cognition, impaired coordination) Some patients can experience CNS excitation: insomnia, hallucination, seizures **Anticholinergic effects are most prominent (some can stimulate if OD!) – Beers Criteria Sedation, dry mouth, blurred vision, constipation, tachycardia, urinary retention GIT disturbances (V/D) - Take with food to minimize this effect Weight gain 12 H1 2nd and 3rd Generation H1 Receptor Antagonists Indications: hypersensitivity reactions & allergic reactions **2nd Generation **3rd Generation H1 receptor antagonists H1 receptor antagonists: Think: derived from 2nd gen. Cetirizine HCl (Zyrtec) Levocetirizine (Xyzal) Loratadine (Claritin) Desloratadine (Clarinex) Terfenadine Fexofenadine (Allegra) – 2nd/ 3rd gen Withdrawn: prolonged QT- cardiac arrhythmias Derived from terfenadine cetirizine loratadine fexofenadine *ADME profile for 2nd and 3rd generations: Better absorption, peak concentration in 2-3 hrs, effect lasts for 4-6 hrs,  BBB ***Degree of AE is LESS than 1st gen. and have longer duration of action ***Less CNS depression, sedation, anticholinergic effects compared to 1st gen. agents their effect is limited to the periphery (not CNS, which is where most 1st generation antihistamines mediate their sedating effects) Distributed widely in all tissues, excreted as metabolites in urine 2nd generation usually metabolized to active constituents by CYP enzymes 13 H1 1st, 2nd, 3rd Generation H1 Receptor Antagonists Alcohol dehydrogenase Levocetirizine Hydroxyzine R-enantiomer of the cetirizine cetirizine racemate. CYP 3A4 Terfenadine (Pro-drug) Fexofenadine CYP 3A4 CYP 2D6 Loratadine 14 H1 Topical H1 Receptor Antagonist Indication: rhinitis, erythema and conjunctival congestion associated with seasonal allergic conjunctivitis Formulation: Nasal spray and/or ophthalmic solution Azelastine (Astelin, Astepro) – Nasal also available as an ophthalmic solution Olopatadine (Patanol; Pataday; Patanase) Short onset Long duration of action Olopatadine Due to slow rate of dissociation Ketotifen (Zaditor; Alaway; Zyrtec Itchy Eye; Claritin Eye) Piperidine Mast cell stabilizer Ophthalmologic agent Ketotifen Emedastine (Emedine) 15  H1 Anti-histamine drugs 16  *Big Picture: Histamine and Anti-Histamines Histamine − Biosynthesis & Metabolism − Histamine Receptors − GPCR: H 1 - 4 receptors 1. H1 receptor antagonists − 1st generation: − Allergy: Diphenhydramine HCl (Benadryl), Chlorpheniramine, Cyproheptadine − Various indications (including CNS disorders): − Hydroxyzine HCL (Vistaril, Atarax), Promethazine HCl (Phenergan), Doxepin HCl (Sinequan), Cyproheptadine, Diphenhydramine − 2 generation nd − Cetirizine HCl (Zyrtec), Piperidines: Loratadine (Claritin) − 3rd generation (sometimes referred to as 2nd gen) − Levocetirizine (Xyzal), Desloratadine (Clarinex) − 2nd/3rd gen Fexofenadine (Allegra) − Ophthalmic and/or Nasal: Olopatadine (Patanase), ketotifen (Zaditor), Azelastine 2. H2 receptor antagonist − Famotidine (Pepcid, Zantac 360), cimetidine (Tagamet), nizatidine (Axid) − Ranitidine (Zantac): all RX and OTC withdrawn from the market per the FDA (04/2020) 3. H3 receptor antagonist − Pitolisant (Wakix) Orphan drug for narcolepsy (EDS, Cataplexy) –FDA approved 8/2019 4. H4 receptors antagonists − Investigational agents for inflammatory diseases 17 H2 H2 Receptor and its Antagonists Physiology& Pathophysiology: *H2 receptors (Gαs) Distribution in gastric mucosa (enterochromaffin cells), mast cells, CNS Histamine activation of H2R on parietal cells stimulates the cAMP pathway that results in release of gastric acid into the stomach (GER and GERD) Pharmacology: *H2 Receptor Antagonists (H2RA) Treat gastrointestinal-esophageal reflux disease (GERD) Inhibit gastric acid secretion, useful for treating ulcers *Agents: Famotidine (Pepcid, Zantac 360) Cimetidine (Tagamet) - DDIs Nizatidine (Axid) **Ranitidine (Zantac) Note: all RX and OTC withdrawn from the market per the FDA (04/2020) https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market H2RAs will be discussed in depth in iMCP3 18 H 3 and H 4 H3 and H4 Receptors Physiology& Pathophysiology: *H3 receptors (Gαi) → ↓ cAMP Inhibits adenylyl cyclase , activates K+ channels &  Ca 2+ Autoreceptors - feedback inhibition H3 Receptor Antagonists/Inverse Agonist: *Pitolisant -Orphan drug for narcolepsy management treatment of excessive daytime sleepiness/somnolence and cataplexy in patients with narcolepsy 5/2018: received FDA Breakthrough Therapy and Fast Track Designations. 8/2019: FDA approved *MOA: H3 Receptor antagonist/inverse agonist complete mechanism is unclear. modulates neurotransmitter systems →  acetylcholine, norepinephrine, and dopamine release Effect:  attention & arousal, wakefulness, anticonvulsant activity H4 receptors: Gαi →  cAMP H4 Receptor Antagonists (In clinical development) 19 Top 200 Drugs H1 Receptor Antagonist diphenhydramine (Benadryl) fexofenadine (Allegra) loratadine (Claritin) levocetirizine (Xyzal) cetirizine (Zyrtec) azelastine (Astelin, Astepro) - Nasal hydroxyzine pamoate (Vistaril) hydroxyzine HCl (Atarax) Antiemetic-Histamine Antagonist promethazine (Phenergan) H2 Receptor Antagonist famotidine (Pepcid) 20 Supplementary Information 21 22 Reminders 23  Adapted from “Intro to iMCPI” 5 Tips on Learning and Understanding Topics for Long-Term Success Improving patient outcomes is your number 1 priority 1. Be able to adapt – Pharmacy profession is constantly changing and constantly moving Observe and monitor changes in your performance You notice that you now struggle answering questions (homework, worksheets, class discussions, exams, etc.) despite using the same style of studying that worked in this course and/or in previous courses (in undergrad, pharmacy etc.) Be willing to learn, identify the root cause, and adjust you approach accordingly Once you observe that there is an issue, address it – the sooner the better. Meet with the faculty, bring your notes, discuss how you approached their material, identify the root cause, identify how to improve your study approach Constantly re-evaluate and adapt Do NOT get complacent. Each course brings new challenges, being able to adapt is a key skill to have. Avoid procrastination 2. Time management is essential Studying for iMCP3 should not overshadow other courses. If you devote all your time to iMCP3 and your academic performance in another class –regardless of its credit hour- is below passing, it will negatively impact your progression through the program. 3. Keep your study guides (electronic copy is preferred) Remember, as you go through the program, the curriculum builds on what you learn previously. Keep your study guides and tables, and add to them as you move through the curriculum For example, when you take Pharmacotherapy in P2 year, instead of having to re-learn all the pharmacology parameters of antibiotics or heart failure meds all over again (drug class, MOA, AEs, CI, DDIs, special consideration, boxed warning, etc), you just have brush up on your notes from iMCP and that will give you time to focus on learning the new parameters specific to pharmacotherapy and the appropriate use of medications to optimize patient care: (assessment, plan, evidence-based and guideline-driven recommendations, dosing regimen, dose adjustments, monitoring parameters, follow-up plan, patient counseling, etc.). 24  Adapted from “Intro to iMCPI” 5 Tips on Learning and Understanding Topics for Long-Term Success 4. Having a diverse toolkit of study resources to help you understand concepts helps increase your chances for success Learning antibiotics and oncology can be challenging because it requires diverse knowledge base and to be well- versed in various: physiology and pathophysiology concepts, diseases, drugs within and across drug classes and their unique facts and places in therapy, patient- and drug- specific factors, and the many exceptions to some “rules” 5. Rewrite the material in a way that you understand it and make your own study guides/tables/graphics Explain what you learn in class and explain the “how” and “why” of concepts to a family member or friend in a way that is accurate, and they understand it. Ultimately, you will be working with patients, who have different levels of education and different backgrounds - effective communication is essential. Don’t simply memorize slides. Remember each Faculty has their own teaching style, it’s up to you to rewrite the material in a way that you understand it (see item 3 in previous slide). Memorization is not the same as knowledge. Memorization may only help in the short term. Take the time to think out relationships in order to truly understand concepts. If a concept doesn’t make sense, try to research the answer using available resources, and do not hesitate to contact the Faculty who taught that concept. It’s best to contact the respective Faculty via email first to schedule an appointment, this will ensure that they set adequate time to discuss these points with you and fully address your concerns. 25  Adapted from “Intro to iMCPI” Resources 1. Canvas iMCP3 – Study Resources and Videos/Illustrations (duration range: approx. 1 – 8 min) 2. Online via South College Library: http://library.south.edu/ 1. SOP: http://library.south.edu/c.php?g=843137 1. Guidelines, AccessPharmacy, Micromedex, Lexicomp 2. For literature search: PubMed, Discover search (SC library) 3. Textbooks: Required Recommended RxPrep Course Basic & Clinical Foye’s Principles of Goodman & Pharmacogenomics: An Review of Organic Book for NAPLEX Pharmacology, 15th Medicinal Gilman’s Introduction and Functional Licensure Exam Ed. (2021) Chemistry, 8th Pharmacological Clinical Perspective Groups: Preparation by Katzung BG. Ed. (2019) Basis of (2013) by Joseph S. Introduction to Note: in P1/P2 year- Available on by Roche VF Therapeutics, 13th Bertino Jr, et al. Medicinal you may buy a used AccessPharmacy et al. Ed. (2018) by Available on Organic book released after Brunton LL, Lazo AccessPharmacy Chemistry, 5th 2020. In P3 year: you’ll JS, and Parker KL. Ed. (2012) have the latest released Available on by Lemke TL. book and online AccessPharmacy package. 26  Adapted from “Intro to iMCPI” Resources - Top Medications Top 300 Medications document available on Canvas iMCPI Course AccessPharmacy https://accesspharmacy.mhmedical.com/ Multimedia Study Tools Flashcards Review Questions 27