[01.31b] Autacoids & Anti-Inflammatory Agents 2 (V2) (TG17-CG09) - Daniel Carlos Salipsip.pdf

Autacoids & Anti-Inflammatory Agents 2 Module 01: Principles and Perspectives II Henrietta Teresa de la Cruz, MD, MS, MPH | Asynchronous TABLE OF CONTENTS I. VASOACTIVE AUTACOIDS.................................................................. 1 A. VASOCONSTRICTORS....................................

Autacoids & Anti-Inflammatory Agents 2 Module 01: Principles and Perspectives II Henrietta Teresa de la Cruz, MD, MS, MPH | Asynchronous TABLE OF CONTENTS I. VASOACTIVE AUTACOIDS.................................................................. 1 A. VASOCONSTRICTORS....................................................................1 B. VASODILATORS............................................................................. 5 C. MIXED VASODILATOR & VASOCONSTRICTOR...............................9 QUESTIONS......................................................................................... 9 ANSWER KEY..................................................................................... 10 RATIONALE........................................................................................10 LEARNING OBJECTIVES 1. To be familiar with the various autacoids & their antagonists according to the Pharmacodynamic and Pharmacokinetic criteria 2. Advise patients on the monitoring, adverse reactions, and integrations of autacoids and their antagonists 3. Be familiar with the pharmacodynamic and pharmacokinetic properties of natural and synthetic vasoactive polypeptides 4. Discuss the therapeutic applications of vasoactive polypeptides I. VASOACTIVE AUTACOIDS ● Polypeptides acting on the vasculature ● Diverse set of naturally occuring polypeptides ● Clinical significance involves its effects on the body and clinical implications ○ E.g. Antagonists to vasoactive polypeptides are gradually emerging ● The significance of some of these peptides lie in the production of newer antagonists which target the action of these drugs Figure 2. Renin-Angiotensin-Aldosterone System (RAAS) RENIN ● Initially triggered by a decrease in blood pressure which is sensed at the macula densa ● Renin Mechanism of Action: ○ Cleaves angiotensinogen to form angiotensinogen to angiotensin I in response to sympathetic stimulation ● Release of renin ○ Low Na, NO, & PGE2 with low blood pressure → increased cGMP, cAMP, and Ca → release of renin ● Renin release will trigger a cascade of events leading to the conversion of angiotensinogen to angiotensin, and the release of aldosterone ○ All of these events work to restore blood pressure ● While these downstream events have a longer duration of action, the release of renin is immediate ○ Peak release of renin is noted as early as 1 minute ○ Short lived action ▸ Decrease in levels are noted even after 30 minutes ○ Despite its short duration, the target of renin inhibitors (i.e. Aliskiren) is effective due to its ability to control the downstream events leading to hypertension Figure 1. Classification of Vasoactive Peptides According to their Dominant Effects A. VASOCONSTRICTORS RAAS OVERVIEW ● RAAS system ○ In the presence of low pressure, renin triggers the conversion of angiotensinogen → angiotensin I ○ Angiotensin I is converted by angiotensin converting enzyme (ACE) (in the lungs) to Angiotensin II ▸ Results in vasoconstriction and stimulation of adrenal cortex to produce aldosterone ○ With Sodium retention from aldosterone, water follows which increases blood volume to restore normal blood pressure YL6:01.31b Figure 3. Juxtaglomerular Cell with Renin at the Center Surrounded by Various Triggers TG17: Angeles, Ayop, Basa, Dy, Layco, Lim, Medel, Ocampo, Regio, Salipsip, Simpao CG09: Barin, Choudhry, Cu, Jamisola, Sanota, Simbulan, So, Tagulob, Umil, Urrutia, Velasco, Yu 1 ● PK: synthesized in JG cells as preprorenin cleaved to pro-renin: pro-renin previously thought to be inert has distinct binding sites in various tissues ● Inhibition of renin release is signalled by a negative feedback loop; in stress studies, plasma levels peaked at 1 minute after stimulus and decreased by 30 mins ● Note: renin inhibitors; Aliskiren is used as an antihypertensive ANGIOTENSIN II ● RAAS system is capable of restoring blood pressure in hypotension (volume depletion) via Angiotensin II ● Angiotensin II ○ Mechanism of action: vasoconstrictor; increases sodium reabsorption via aldosterone, triggering sodium/water retention via vasopressin ▸ direct vasoconstriction mediated by sympathetic activity ▸ Augmented by increased sodium reabsorption via activation of aldosterone ▸ Increase in ADH secretion → increase in vasopressin → sodium/water retention ▸ Increases water retention and restores blood pressure ○ Main effects mediated by specific G protein coupled receptors, angiotensin receptor 1 or AT-1 where strong vasoconstriction can occur ▸ Rapid onset 10-15 sec effect at ATII is ½ < 1 min. ⎻ Angiotensin II activity recorded at 10 to 15 with a very short half life Figure 4. Prorenin Receptor ANGIOTENSINOGEN AND ANGIOTENSIN I ● Angiotensinogen ○ Circulating protein synthesized in the liver ○ Angiotensinogen is cleaved to form Angiotensin I ○ Increased in the presence of corticosteroids (mineralocorticoids and androgens like estrogen), thyroid hormones, ANG II, oral contraceptive use ○ Sympathetic activity with thyroid hormones and ANG II can increase its presence in circulation but it is quickly converted to Angiotensin I via ACE inhibitor ● Angiotensin I ○ Little to no biologic activity Figure 5. Angiotensinogen and Angiotensin I YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 Figure 6. Angiotensin II ● Mechanism of Angiotensin II, less active pathway and more prominent in fetal development ○ Adult tissue has very minimal AT II receptor activity ● AT II receptor activity is counter-regulatory mediating vasodilation, anti-inflammatory, antiproliferative, anti hypertrophic, antifibrotic, proapoptotic, and vasodilatory effects ○ Activation of the AT II receptor pathway is counter-regulatory to the effects of AT I receptor binding as they can reverse these primary effects ● PK: Route; IV ● Angiotensin II effects are short acting because they are rapidly degraded ● Metabolism: aminopeptidase A and M/ACE 2 ○ 1st pathway for Angiotensin II degradation is through ACE 2 ▸ ACE 2 by-products include AT 1 to 7 mediated by a Mas receptor: vasodilation, antiproliferative, anti remodelling, natriuresis ▸ May be active in counter-regulatory mechanisms 2 ○ 2nd pathway for Angiotensin II degradation is through Aminopeptidase A ▸ AP A byproducts: AT III and AT IV actively binds with AT-4 receptors → peripheral effects in learning, memory, long term potentiation, and glucose uptake ● Angiotensin II actions may have a myriad of effects ○ Excessive Angiotensin II reactions may lead to hypertension and hypertrophy of the vasculature and cardiomyocytes ● Antagonists of angiotensin II are now available ○ Angiotensin converting enzyme inhibitors ▸ Captopril ▸ Enalapril ○ Angiotensin receptor blockade ▸ Losartan ▸ Valsartan ○ Commonly used as antihypertensives and reducing glomerular pressure in diabetic nephropathy and idiopathic membranous nephropathy ● Receptors ○ ET-A receptors ▸ Most dominant receptor for ET-1 ▸ Less affinity for ET-3 ▸ Most active in smooth muscles ▸ Initial response of endothelin is a transient vasodilation ⎻ Due to PGI2 and NO pathways ▸ Sustained response is vasoconstriction ○ ET-B receptor ▸ Equal affinity for ET-1 and ET-3 ▸ May also produce transient vasodilation due to PGI2 and NO ▸ Sustained response is vasoconstriction ○ Other ET-A and ET-B effects ▸ Proliferation ▸ Fibrosis ▸ Repair mechanisms Figure 7. Angiotensin II ENDOTHELIN ● ● ● ● Vasoconstrictor Found in vascular endothelium Typically a response to injury in the vasculature Subtypes ○ ET-1 (most widespread) ▸ Found in vascular endothelium, neurons, astrocytes, endometrial cells, renal mesangial cells, Sertoli cells, breast epithelial cells ○ ET-2 ▸ Found in kidney and intestine ○ ET-3 ▸ Found in brain ● Triggers ○ Physical, mechanical, and chemical stress ○ Hormones ○ Acidosis ○ Tissue injury ▸ Proinflammatory enzymes and cytokines ○ Hypertension, cardiac hypertrophy, heart failure, coronary artery disease, myocardial infarction, atherosclerosis, asthma ○ Renal disease ○ Ovarian cancer YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 Figure 8. Endothelin ● Effects of Endothelin ○ Primary effect: Initial vasodilation followed by vasoconstriction (endothelial vasoconstriction) ○ Other effects ▸ Repair ⎻ Positive inotropic and chronotropic actions on the heart ⎻ Potent mitogen for vascular smooth muscle, cardiac myocytes, and glomerular mesangial cells ▪ Leads to cardiac repair, remodeling, and hypertrophy ⎻ Increasing the secretion of renin, aldosterone, AVP, and ANP → Increase in intravascular volume ● Excessive endothelin can contribute to progression of chronic kidney disease, hypertension, and atherosclerosis ● Endothelin antagonists ○ Bosentan, ambrisentan, macitentan → ET receptor antagonist ▸ Used in pulmonary hypertension ○ Phosphoramidon → Inhibits endothelin converting enzyme leading to decreased formation of endothelin ▸ Used in pulmonary hypertension 3 ○ Common adverse effects ▸ Systemic hypotension ▸ Increased heart rate ▸ Facial flushing or edema ▸ GI effects including nausea, vomiting, constipation ▸ Hepatotoxicity ▸ Teratogenic effects Figure 9. The Role of Endothelin-1 in Chronic Kidney Disease (CKD) and Cardiovascular Disease NEUROPEPTIDE Y ● A big family of multi-ligand/multi-receptor system consisting of three polypeptide agonists (NPY, PP, PYY) ○ Pancreatic polypeptide (PP) - secreted by islets of Langerhans ▸ Acts as a neurohormone ▸ Promotes appetite suppression ▸ Inhibits gastric emptying ▸ Increase energy expenditure ○ Peptide YY (PYY) - secreted by enteroendocrine cells of distal gut ▸ Acts as an anorexigenic neurohormone ○ Neuropeptide Y (NPY) is the one included in the vasoconstrictor family ▸ Acts as a neurotransmitter ▸ Functions as a cerebral vasoconstrictor and co-transmitter of norepinephrine ⎻ One of the most potent orexigenic molecules in the brain ▪ Increases feeding behavior ▸ Actions are mediated by subtypes of NPY receptors, which are all G Protein Coupled Receptors (GPCR) ▪ Y1, Y2 & Y5 mediate cardiovascular effects and vasoconstrictive properties ▪ These are the targets of antagonists which seek to mediate the abnormal repair mechanism that lead to damage ▪ Y4 is for pancreatic polypeptide (PP) activity ▪ Y5 is in the CNS for orexigenic properties Effects of Neuropeptide Y Figure 10. Endothelin Function YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 ● Myocardial Infarction ○ NPY recruits myocardial stem cells and initiating angiogenesis ▸ Via promotion of Vascular Endothelial Growth Factor (VEGF) expression ⎻ Important in cardiomyocyte remodeling and angiogenesis ● Renal ○ Potent renal vasoconstrictor ○ Suppresses renin secretion ○ Can cause diuresis and natriuresis ● Initiation of hematopoietic stem cells ○ Important in repair of osteoporosis ● Adipocyte stem cell recruitment and proliferation ● Inhibition of both sympathetic and parasympathetic neurotransmitter release ● Implicated in various pathologic states ○ Excessive secretion of NPY ▸ States of obesity & eating disorders ▸ Anxiety ▸ Epilepsy ▸ Pain ▸ Cancer ▸ Bone pathologies 4 VASOPRESSIN (AVP & ADH) & SYNTHETIC ANALOGUES ● A.k.a. Arginine vasopressin or antidiuretic hormone ○ Together with its agonists, are active in hypotension and volume depletion ▸ Restores blood pressure by increasing water absorption ▸ Induces vasoconstriction via two receptors: ⎻ V1a ⎻ V2 ▸ Release of ACTH by pituitary corticotrophs is handled by V1b receptors ● Vasopressin is triggered by the following situations ○ Dehydration and hemorrhage ○ Reynaud’s disease ○ Hypertension and heart failure ○ Brain edema ○ Motion sickness ○ Cancer ○ Preterm labor ○ Anger reduction ● Broken down by: ○ Angiotensin Converting Enzyme (ACE) ○ Neuropeptidases ○ Aminopeptidases ○ Carboxypeptidases Agonists of Vasopressin ● Synthetic Agonists ○ Selepressin: V1a agonist ○ Terlipressin: V1a agonist Antagonists of Vasopressin ● Tolvaptan - V2 antagonist ● Conivaptan - targets V1a and V2 receptors ○ Approved for treatment of hyponatremia (Katzung, 2021) Active Recall Box 1. Angiotensin II undergoes two pathways of degradation, through ET-A receptors and M/ACE 2 2. These are the NPY receptors which mediate the vasoconstrictive and cardiovascular effects. Answers: 1F, 2 Y1, Y2, & Y5 B. VASODILATORS BRADYKININ & KALLIDIN ● Part of the vasodilator family ● Present in the heart, skeletal muscles, kidney, liver, and intestines ● 10x more potent than histamine ● Kallidin can be converted into bradykinin by an arginine aminopeptidase ● In the presence of tissue injury or activation of blood coagulation factors: ○ Kallikreins will act on kininogens ▸ Plasma kallikrein will act on high molecular weight kininogen (Katzung, 2021) ⎻ Results in bradykinin ▸ Tissue kallikrein will act on low molecular weight kininogen (Katzung, 2021) ⎻ Results in kallidin ● Vasodilatory effects are mediated by: ○ Nitric oxide ○ Prostaglandins (PGE2 & PGI2) ● Venoconstrictor effect is mediated by PGF2 alpha ○ Predominant effect of kinins on veins is contraction (Katzung, 2021) ● Inactivated by kininases I and II UROTENSIN (UII) ● A potent vasoconstrictor ○ 10x of endothelin ● Produced in various tissues such as the heart, lungs, liver and kidneys ● Mediated by a GPCR, referred to as UT receptor ○ Widely distributed in brain, spinal cord, heart, vascular smooth muscle, skeletal muscles and pancreas (Katzung, 2021) ○ Leads to its vasoconstrictive effect ● Urotensin II (UII) levels are increased in: ○ Hypertension ○ Heart failure ○ Atherosclerosis ○ Diabetes mellitus ○ Renal failure ● Antagonized by synthetic drugs ○ Urantide - a penicillamine-substituted derivative of UII ○ Palosuran - orally active nonpeptide antagonist to the UII receptors ▸ Has displayed beneficial effects in animal models of renal failure but not in hypertensive patients with type 2 diabetic nephropathy (Katzung, 2021) YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 Figure 11. Kallikrein-Kinin System 5 Effects of Kinins ● Inflammation ○ Increases vascular permeability, vasodilation, pain stimulation, and smooth muscle contraction ▸ Produces the classic symptoms of inflammation – redness, local heat, swelling, and pain ○ Effects are mediated by B2 receptors ▸ More ubiquitous than B1 receptors ▸ B1 receptors are more inducible in times of injury ● Can play a protective role in certain cardiovascular diseases and ischemic stroke-induced brain injury ● Excessive secretion of kinins leads to excessive inflammatory changes ○ Angioedema ▸ There can be compromise to breathing ⎻ Bradykinin increases vascular permeability and causes recurrent angioedema of the airways (Katzung, 2021) Antagonists of Kinins Table 1. Antagonists of Kinin Receptors Antagonist Type Effect Icatibant B2 receptor antagonist for hereditary angioedema Aprotinin Kallikrein inhibitor Ecallantide Recombinant plasma kallikrein inhibitor, is also effective Lanadelumab Monoclonal antibody against kallikrein ● Arrest of the effects may be mediated by receptor antagonism at the B2 receptors for Icatibant, an antagonist ● Other targets for antagonists to kinins will be targeting the kinin precursor, kallikrein via: ○ Aprotinin ○ Ecallantide (an antagonist) will target the plasma kallikrein inhibition ○ Lanadelumab is a monoclonal antibody against kallikrein ● The effect of these proteins are triggered by volume expansion ○ General response would be to correct situations where there is volume overload (i.e. treatment of congestive heart failure) by: ▸ Vasodilation ▸ Natriuresis ▸ Inhibition (blocks the counter-regulatory mechanism) of the renin-angiotensin system ● Effects are mediated by specific receptors: ○ NPR A for ANP and BNP a ○ NPR B for CNP ○ NPR C binds all 3 ● Human pro-CNP ○ Consists of 103 AA residues ○ Processed by furin ▸ Intracellular endoprotease to the mature 53-AA CNP ⎻ CNP-53 is found primarily in the brain, heart, and endothelial cells; may be further cleaved to CNP-22 ● Pharmacokinetics: ○ Short half life (effects are short-lived) ○ Rapidly metabolized by the enzyme, neprilysin, or ○ Bound to ANPC receptors, which internalize the natriuretic peptide for eventual degradation ● Synthetic Agonists: ○ Recombinant ANP: Carpreitide, M-ANP ○ Recombinant BNP: Nesiritide ○ CNP analogue: Vosoritide ● ACE inhibitors + neprilysin inhibitors include omapatrilat, sampatrilat, and fasidotrilat - omapatrilat less used due to angioedema ○ “alat” means salt in Filipino → increases salt in urine from natriuresis ● Ace receptor and neprilysin inhibitor (ARNI) to lower BP: Valsartan-Sacubitril - CHF with reduced ejection fraction ○ Combined effects are apparently higher than individual effects of either ace receptors or neprilysin NATRIURETIC PROTEINS: ANP, CNP & BNP Table 2. 3 Natriuretic Proteins Name Source Atrial Natriuretic Produced in atrium in response to Peptide (ANP) stretch of myocytes or atrial fibrillation B-type Natriuretic Produced in ventricles in response to Peptide (BNP) volume expansion Figure 12. Natriuretic Hormone Receptors, Intracellular Signaling, and Degradation Processes (Katzung, 2018) C-type Natriuretic Found in vascular endothelium Peptide (CNP) ● ANP, BNP, and CNP are secreted/synthesized as preprohormones ○ Split and converted into their active secretion (prohormones) by proteolytic cleavage of an N-terminal signal peptide YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 6 VASOACTIVE INTESTINAL PEPTIDE NEUROTENSIN (NTS) ● A peptide neurotransmitter ● Misnomer ○ Vasoactive → causes vasodilation ○ However, it is not only active or produced in the intestines ● Sites: ○ G protein-coupled receptors ○ VPAC1 and VPAC2 receptors ▸ In the central nervous system ▸ In the heart ○ Blood vessels ○ Lungs ○ Gastrointestinal and urogenital tracts ○ Skin ○ Eyes ○ Ovaries ○ Thyroid gland ○ Other tissues ● Effects on various metabolic processes: ○ Induces secretion of endocrine and exocrine glands ○ Cell differentiation ○ Smooth muscle relaxation ○ General modulation of the immune response ● Use (therapeutic agent): ○ Vasodilation for treatment of systemic and pulmonary hypertension and heart failure ○ Its therapeutic value is limited by its short half-life ● Long acting form: Vasromera ○ Alternative vasodilator ○ Targets VPAC2 receptors for the treatment of heart failure & pulmonary hypertension ● Dual function as a neurotransmitter or neuromodulator in the central nervous system and as a local hormone in the periphery (heart, lungs, liver, spleen) via NTS1 > NTS2 or NTS3 ○ Both a neurotransmitter and a neuromodulator in the CNS ○ Acts via the NTS1, which has the highest binding affinity and is the most widespread compared to NTS2 and NTS3 receptor ▸ NTS3 receptor does not contribute to the actions of neurotensin ○ Apart from CNS effects, neurotensin is also active in the heart, lungs, liver, and spleen ● Effects: ○ Main effect: vasodilation ○ Associated with common pro-inflammatory effects ▸ Hypotension ▸ Increased vascular permeability ○ Also has effects related to tension or stress ▸ Hyperglycemia ▸ Inhibition of gastric acid and pepsin secretion ▸ Inhibition of gastric motility ○ Suppressive effects on the immune system ● NTS2 is associated with disorders involving dopamine pathways ○ Explored for use in schizophrenia, Parkinson’s disease, and drug abuse Figure 14. Effects of Neurotensin ADRENOMEDULLIN (AM) Figure 13. Vasoactive Intestinal Peptide (VIP) YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 ● Hormone found in the adrenal medulla ● Secreted as preproAM, which is later cleaved to form mature AM: ○ ProAM N-terminal 20 peptide (PAMP) ○ Mid-regional AM (MR-proAM) ● Mediated by AM1 and AM2 receptors ○ Found in vascular and smooth muscles ● Downstream Effects: ○ Mediated by NO and in Phosphokinase A → vasodilation → Increased Heart Rate, Cardiac Output, Norepinephrine, and Renin ○ Effect on angiogenesis and vascular remodelling ▸ Inhibition of Fibrosis and remodelling is helpful in vascular injury ● Half-life: 22 Minutes ○ Short due to being metabolized by neprilysin ● Antagonist: Adrecizumab ○ Humanized, monoclonal, non-neutralizing antibody against the N-terminus of AM ▸ For treating patients with early septic shock where vasodilation is not beneficial 7 RELAXIN ● RLX-1, RLX-2, RLX-3 ○ RLX-2 : most active form ● Receptor: RXFPR 1 ● Members of Insulin family ○ Mainly a hormone of pregnancy ○ Can also be found in the brain, heart, kidneys, lungs, liver ● Effects: ○ Vasodilation → increased cardiac output, renal blood flow (GFR), decreased collagen ● Analogs: ○ Serelaxin (RLX030) ▸ Recombination form of human RLX ▸ Used for suppression of arrhythmia and inflammation and for reversal of fibrosis ○ Insulin Like 3 peptide ▸ Produced by gonads, acts via RXFP3 for bone and reproductive remodelling Figure 15. Adrenomedullin Mode of Action CALCITONIN GENE RELATED PEPTIDE (CGRP) ● Produced by the C cells of the thyroid gland in large quantities ● Widely distributed on the CNS, PNS, Cardiovascular, Respiratory, and Gastrointestinal systems ● Effects: Hypotension, tachycardia, suppression of feeding ● Protective roles in: ○ Patients with hypertension and extensive remodelling in heart failure ○ Patients with migraine and headaches ● Antagonists: ○ Olcegepant and telcagepant ▸ Used for Migraines ○ MAB ▸ Receptor MAB: Erenumab ▸ CGRP MAB: Eptizenumab, Fremazenumab, Galcazenumab ▸ Expensive drugs given subcutaneously Figure 17. Relaxin Mode of Action UROCORTIN Figure 16. CGRP Mode of Action YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 ● Members of the corticotropin-releasing hormone (CRH) family of peptides ○ UCN1 (40 amino acids) - Largest ○ UCN2 (39 aa) ○ UCN3 38 (aa) ● Receptors: CRHR1 and CRHR2 ○ G protein-coupled receptors ● Expressed in the CNS, Cardiovascular, Digestive, and Immune systems, Kidneys adrenals and other tissues ○ Also found in the circulation and urine ● Stress hormones ○ Involved in anxiety, depression, and drug abuse 8 ● Effects: ○ All 3 forms cause renal vasodilation ○ UCN2 ▸ Controls gastric emptying via sympathetic pathway and the hypothalamic pituitary-adrenal axis ○ UCN3 ▸ Contributes to control of food intake ● UCNs modulate actions of other vasoactive peptides such as ANG II, endothelins, and natriuretic peptides ● Uses: ○ Heart failure, Pulmonary hypertension ● Drug: Stresscopin (RT-400) ○ Used for acute decompensated heart failure Figure 18. Urocortin Mode of Action C. MIXED VASODILATOR & VASOCONSTRICTOR ● Some vasoactive amines can have both vasodilator and vasoconstrictor effects. SUBSTANCE P ● 11-amino acid chain peptide belonging to tachykinins ● Found in the CNS, PNS, CVS and enteric tissue ● Receptor: Neurokinin ○ Binding affinity: NK1> NK2, NK3 ● Implicated in nociception, stress, nausea, and emesis ● Effects: ○ Vasoconstriction, bronchoconstriction ▸ Can mediate vasodilation on endothelial cells ● Antagonists: ○ Aprepitant/Fosaprepitant ▸ Prevention of post-chemotherapy emesis; anti-tumor QUICK REVIEW QUESTIONS 1. Loratadine is an example of a third generation antihistamine. Desloratadine is a metabolite of loratadine. A. Statement 1 is true B. Statement 2 is true C. Both statements are true D. Both statements are false 2. T/F: Aspirin needs to be taken in high doses in order to elicit its antithrombotic/antiplatelet effect. 3. T/F: First generation H1 antihistamines can cross the blood-brain barrier, interfering with histamine brain functions and subsequently causing side effects like drowsiness. 4. LTD4 is responsible for the inflammatory effects of monocyte migration, neutrophil chemoactivation, and T-cell trafficking. LTB4 is pro-inflammatory. A. Only statement 1 is true B. Only statement 2 is true C. Both statements are true D. Both statements are false 5. Which of the following 5-HT agonist drugs are correctly paired with the receptor that they interact with? A. Sumatriptan – 5-HT1B B. Cisapride – 5-HT3 C. Ergotamine – 5-HT2 D. Trazodone – 5-HT4 6. Among all the triptans, which of the following has the fastest onset of efficacy?. A. Zolmitriptan B. Eletriptan C. Rizatriptan D. Frovatriptan 7. Plasma kallikrein acting on high molecular weight kininogen will result in kallidin formation. Tissue kallikrein will act on low molecular weight kininogen in order to produce bradykinin. A. Statement 1 is true. Statement 2 is false. B. Statement 1 is false. Statement 2 is true. C. Both statements are true. D. Both statements are false. 8. The toxic metabolite of N-acetyl-para-aminophenol (acetaminophen). A. NAPQI B. Phenacetin C. Acetanilide D. Acetaldehyde Figure 19. Substance P’s Mode of Action YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 9 9. Which receptor does not contribute to the actions of neurotensin? A. NTS1 B. NTS2 C. NTS3 D. AOTA E. NOTA 10. Which of the following would be an antagonist for adrenomedullin? A. Adrecizumab B. Eptizenumab C. Fremazenumab D. Galcazenumab Concerns and Feedback form: http://bit.ly/YL6CFF2027 How’s My Transing? form: https://bit.ly/2027YL6HMT Mid-Semester Evaluation form: https://bit.ly/2027YL6MidSem End-of-Semester Evaluation form: https://bit.ly/2027YL6EndofSem Errata Points Trackers: https://bit.ly/YL62027EPT ANSWER KEY 1B, 2F, 3T, 4B, 5A, 6C, 7D, 8A, 9C, 10A RATIONALE 1. B. Statement 2 is true. Loratadine is an example of a 2nd generation antihistamine. Desloratadine is an example of a 3rd generation antihistamine which is a metabolite of loratadine. 2. False. Only a low dose of aspirin (160mg) is needed to elicit its antithrombotic/antiplatelet effect. 3. True. This is why some of these drugs are used as sedatives. Other side effects include cognitive impairment and increased appetite. 4. B. Only statement 2 is true. LTB4 is the leukotriene being described in statement 1. 5. A. Sumatriptan – 5-HT1B. The following are the correct 5-HT agonists – receptor pairs for the rest of the choices: Cisapride – 5-HT4 and Trazodone – 5-HT2. Ergotamine is a non-selective agonist for 5-HT receptors. 6. C. Rizatriptan. It has the fastest onset of efficacy that occurs within 30 minutes. Meanwhile, it takes 45-60 minutes for Zolmitriptan to take effect, 60 minutes for Eletriptan, and up to 4 hours for Frovatriptan. 7. D. Both statements are false. Kallidin comes from tissue kallikrein acting on low molecular weight kininogen. Bradykinin is produced by plasma kallikrein acting on high molecular weight kininogen. 8. A. NAPQI. NAPQI is the hepatotoxic metabolite of acetaminophen biotransformation. It is produced when all glutathione donors are depleted. 9. C. NTS3. No study has mentioned a possible role for the NTS3 receptor in pain. 10. A. Adrecizumab. Eptizenumab, Fremazenumab, and Galcazenumab are all antagonists for CGRP, not adrenomedullin. YL6 TransMap: https://bit.ly/2027YL6TransMap FREEDOM SPACE REFERENCES REQUIRED ● 📄 De la Cruz, H. T. (2023). Autacoids & Anti-Inflammatory Agents [Lecture slides]. YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 10 MASTER TABLES Table A. Antagonists of Kinin Receptors Antagonist Type Effect Icatibant B2 receptor antagonist for hereditary angioedema Aprotinin Kallikrein inhibitor Ecallantide Recombinant plasma kallikrein inhibitor, is also effective Lanadelumab Monoclonal antibody against kallikrein Table B. 3 Natriuretic Proteins Name Source Atrial Natriuretic Peptide (ANP) Produced in atrium in response to stretch of myocytes or atrial fibrillation B-type Natriuretic Peptide (BNP) Produced in ventricles in response to volume expansion C-type Natriuretic Peptide (CNP) Found in vascular endothelium YL6:01.31b Autacoids & Anti-Inflammatory Agents 2 11