[01.31a] Autacoids & Anti-Inflammatory Agents 1 (V2) (TG17-CG09) - Daniel Carlos Salipsip.pdf

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

Autacoids & Anti-Inflammatory Agents 1 Module 01: Principles and Perspectives II Henrietta Teresa de la Cruz, MD, MS, MPH | Asynchronous TABLE OF CONTENTS I. AUTACOIDS OVERVIEW.....................................................................1 II. AMINE AUTACOIDS..........................................................................1 A. ANTIHISTAMINES......................................................................... 1 B. SEROTONIN: AGONISTS/SSRIs & ANTAGONISTS.......................... 4 III. ONSET OF ACTION.......................................................................... 4 A. SEROTONIN PATHWAYS................................................................ 4 B. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)..................4 C. MECHANISM OF ACTION..............................................................5 D. SEROTONIN AGONISTS.................................................................5 E. SEROTONIN ANTAGONISTS...........................................................6 IV. LIPID-BASED AUTACOIDS (EICOSANOIDS)........................................7 A. ARACHIDONIC ACID PATHWAY..................................................... 7 B. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)...........7 C. ANTI-LEUKOTRIENES.................................................................. 12 QUESTIONS....................................................................................... 14 ANSWER KEY..................................................................................... 14 RATIONALE........................................................................................14 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. AUTACOIDS OVERVIEW ● Auto = self + Acos = medical agent ● Substances released from cells in response to various stimuli to elicit local responses ● May have diverse pharmacological activities including: ○ Inflammation ○ Hypersensitivity ○ Behavior regulation ● Lecture will be organized according to chemical structures Table 1. Classification of Autacoids according to Chemical Structures Group Autacoid Bioamines ● ● Histamine Serotonin (5 HTA) Polypeptides ● ● ● Angiotensin Bradykinin Kallidin Lipid-Derived Substances ● ● ● Prostaglandins Leukotrienes Platelet Activating Factor (PAF) Nitric Oxide ● Vasodilator YL6:01.31a Take Note! ● Nitric Oxide was included as a group, functioning as a vasodilator ○ Will be discussed separately in the Respiratory Module II. AMINE AUTACOIDS ● Diverse group with unrelated drugs ● Include: ○ Histamines & Antihistamines ○ Serotonin & Selective Serotonin Reuptake Inhibitors (SSRIs) ○ Serotonin antagonists A. ANTIHISTAMINES Take Note! ● The following section includes information taken from a video on antihistamines included in Doc Henri’s lecture HISTAMINE ● Known as mediator of allergic reactions ● Also involved in important physiological processes such as: ○ Immune response, gastric acid secretion, sleep and wake cycle, cognitive ability, and food intake ○ Functions as a neurotransmitter in the hypothalamus (histaminergic neurons) whose axons project throughout the brain ● Synthesized from the amino acid histidine ● Present in all tissues but most abundant in: ○ Skin ○ Lungs ○ Gastrointestinal Tract ● Most are stored as granules in mast cells ● Allergies ○ Most occur upon repeated exposure to allergen ○ Mast cells that were previously sensitized to the allergen are activated releasing histamine and other inflammatory chemicals ○ Histamine causes: ▸ Dilation ▸ Increased permeability of blood vessels ▸ Stimulation of sensory nerves ▸ Contractions of smooth muscles ○ Histamine is also responsible for most allergic symptoms ▸ E.g. watery eyes, runny nose, sneezing, swelling, hives, and difficulty breathing due to bronchospasms ○ When histamine is released systemically, it can cause extensive vasodilation and bronchoconstriction which may lead to life-threatening anaphylaxis 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 HISTAMINE AND ITS RECEPTORS ● Exerts its binding to H-receptors, all of which are G-protein Coupled ● Four H-receptors with different functions and patterns Table 2. Types of H-Receptors H-Receptor H1 Location ● ● ● ● Smooth muscle Endothelial cells Nerves Respiratory epithelium ● Gastric parietal cells H2 H3 H4 Function ● Involved in allergic reactions ● Only H1 antihistamines are currently available in the market ● Stimulate gastric acid secretion ● H2 antihistamines are used to treat gastric acid disorders (gastric acid reflux, peptic ulcers) ● CNS ● Immune Cells ● Involved in allergic reactions CLASSES OF ANTIHISTAMINES ● Most H1 antihistamines are not similar to histamine in structure and do not compete with it for binding to H1 receptors ○ They bind to a different site on the receptor and stabilize it to an inactive state instead First Generation H1 Antihistamines ● Derived from the same chemical class as muscarinic, adrenergic, and serotonin antagonists ○ E.g., Diphenhydramine (Benadryl), Promethazine, Chlorpheniramine ● Side effects include anticholinergic, antiadrenergic, and anti-serotonin effects ● Can cross the blood-brain barrier interfering with histamine functions in the brain causing: ○ Drowsiness/sedation ○ Cognitive impairment ○ Increased appetite ● Some of these drugs are used for their sedative side effects (such as sleeping aid medications) YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 Table 3. 1st Generation H1 Antihistamines and their Uses Treat Examples Acute allergic reactions (marked potential for producing drowsiness or sedation) ● ● ● ● ● ● ● ● Brompheniramine Chlorpheniramine Clemastine Cyproheptadine Diphenhydramine Doxylamine Hydroxyzine Promethazine Treat motion sickness due to the anticholinergic properties of its structures ● ● ● ● ● ● Cyclizine Diphenhydramine Dimenhydrinate Hydroxyzine Meclizine Promethazine Motion sickness and vestibular disturbances ● ● ● Dimenhydrinate Meclizine Promethazines ● Cyclizines Nausea and vomiting of pregnancy Second Generation H1 Antihistamines ● Less capacity to cross the blood-brain barrier and are minimally or non-sedating ● Highly selective for H1 receptors ● No anticholinergic effects Potential Adverse Effects of First Generation H1 Antihistamines ● Before we use antihistamines lightly, we have to know they myriad of effects that can complicate its use Table 4. Potential Adverse Effects of 1st (Old) Generation H1 Antihistamines Receptors Effects ● CNS H1-Receptors ● Decreased alertness, cognition, learning, memory, and psychomotor performance May cause impairment with or without sedation Muscarinic Receptors ● ● ● Dry mouth Urinary retention Sinus tachycardia Serotonin Receptors ● ● Increased appetite Weight gain ɑ-Adrenergic Receptors ● ● Dizziness Postural hypotension Cardiac Ion Channels ● ● Increased QT interval Ventricular arrhythmias 2 Comparison of First and Second Generation Antihistamines Take Note! ● Some histamines are used as anti-suppressants Chemical Classification of Antihistamines Take Note! (Table 5) ● Non-bolded: Classical or 1st generation H1 antihistamines ● Bolded: 2nd generation H1 antihistamines ● Examples from Alkylamines, Ethanolamines, Ethylenediamines, and Phenothiazines are used for the acute allergic reactions ● More 2nd generation H1 antihistamines in the Piperazines and Piperidines group Table 5. Chemical Classification of H1 Antihistamines Classification Examples ● ● ● ● ● ● ● Brompheniramine Chlorpheniramine Dexchlorpheniramine Pheniramine Dimethindene Triprolidine Acrivastine ● ● ● ● ● ● Carbinoxamine Clemastine Dimenhydrinate Diphenhydramine Doxylamine Phenyltoloxamine Ethylenediamines ● ● ● Antazoline Pyrilamine Tripelennamine Phenothiazines ● ● ● Promethazine Mequitazine Trimeprazine Piperazines ● ● ● ● ● ● ● Buclizine Cyclizine Meclizine Oxatomide Hydroxyzine Cetirizine Levocetirizine ● ● ● ● ● ● ● ● ● ● ● ● Azatadine Cyproheptadine Ketotifen Loratadine Desloratadine Blastine Ebastine Terfenadine Fexofenadine Levocabastine Mizolastine Rupatadine Alkylamines Ethanolamines Piperidines YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 ● Shorter onset of actions for the 2nd generation but a comparable T concentration (or Tmax) ● Many of the 2nd generation will have longer durations of action ● Advantage of second generation antihistamines ○ Modification of 1st generation antihistamines to eliminate side effects ○ More selective for peripheral H1 receptor ○ Some metabolites derivatives or active enantiomers of pre-existing drugs ○ Safer, faster acting, or more potent: better side effect profile ● Examples of non-sedating 2nd generation antihistamines: ○ Loratadine ○ Fexofenadine ○ Desloratadine ● Examples of 2nd generation antihistamines with weak potential for producing sedation: ○ Levocetirizine ○ Cetirizine ○ Acrivastine Third Generation Antihistamines ● Derivatives of 2nd generation ● Advantage: less sedation and adverse effects ● Examples: ○ Desloratadine: metabolite of loratadine ○ Fexofenadine: metabolite of terfenadine ○ Levocetirizine: enantiomer of cetirizine Table 6. Classification of Antihistamines First Generation Antihistamines Second Generation Antihistamines These are highly lipid soluble hence effects both CNS as well as periphery These are large molecules and less lipophilic and thus less affect the brain Sedative in nature Non-sedative in nature It also shows as anticholinergic and antiadrenergic effect No effect as anticholinergic and antiadrenergic Short duration of action hence more intake of tablets Long duration of action hence it can be given once daily It results in sleepiness It results in little or no sleepiness Common side effects: drowsiness, impaired thinking, dizziness Common side effects: headache, dry mouth, dry nose E.g.: alimemazine, promethazine E.g.: cetirizine, fexofenadine 3 B. SEROTONIN: AGONISTS/SSRIs & ANTAGONISTS ● Serotonin: natural neurotransmitter produced by serotonergic cells which convert tryptophan to the active 5-hydroxytryptamine ○ Affects regulation of mood and social behavior, appetite and digestion, sleep, memory, and sexual desire and function ○ Serotonergic cells in the medullary area are responsible for: ▸ Cerebellar regulation ▸ Motor control ▸ Emesis ▸ Respiratory drive ▸ Body temperature ● Figure 1: distribution of serotonergic neurons (red), projections from medullary area, cortical-limbic midbrain, hindbrain regions Figure 2. Serotonin Pathways B. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI) Figure 1. Serotonergic Pathway ● Serotonin receptors in the GI ○ Most of the body’s serotonin is found in the GI tract, where it regulates bowel function and movements ○ Plays a part in reducing appetite while eating ● Serotonin receptors on platelets ○ Released by platelets when there is a wound ○ Results in ▸ Vasoconstriction, or narrowing of the blood vessels ▸ Reduces blood flow ▸ Helps blood clots to form ● Class of drugs ● Increase presence of serotonin by reducing its uptake from the synapse ● Use of SSRI: ○ Serotonin deficit: ▸ OCD-like symptoms ▸ Impulsivity ▸ Depression ▸ Craving ○ Dopamine deficit: ▸ Parkinson-like symptoms ▸ Anhedonia (lack of pleasure) III. ONSET OF ACTION A. SEROTONIN PATHWAYS ● Serotonin pathways: commonly autoregulated, ○ Lower levels of serotonin ▸ Reuptake by SERT (serotonin reuptake transporters) in nerve terminals ▸ Breakdown by MAO (monoamine oxidase) or aldehyde dehydrogenase to produce hydroxyindole acetic acid products YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 Figure 3. Use of SSRI ● Many of SSRIs in the market have analogous chemical structures to the parent 5-hydroxytryptamine ● Generally used for their mood stabilizing effects: ○ Citalopram (Celexa) ○ Escitalopram (Lexapro) ○ Fluoxetine (Prozac) ○ Paroxetine (Paxil, Pexeva) ○ Sertraline (Zoloft) ○ Vilazodone (Viibryd) ● Usually prescribed once daily because of prolonged duration of action ○ Fluoxetine has the longest half-life (96-144 hours) ○ Escitalopram has the shortest time to peak (5 hours) 4 Non-Selective Agonists Drug Ergotamine LSD Figure 4. Examples of SSRI Drugs ● Pharmacokinetic considerations: ○ All of the SSRIs are orally active ○ Once-daily dosing ○ Hepatic metabolism: CYP2D6 ▸ CYP1A2, 2D6, 2C9, 3A4 ▸ Used in caution with other drugs such as warfarin, antidepressants, and paclitaxel ○ Escitalopram has a somewhat faster onset of action than the others do, due to its activity on serotonin 5HT1A autoreceptors ○ Fluvoxamine, paroxetine, and citalopram are metabolized to inactive products ○ Fluoxetine is metabolized to norfluoxetine which is pharmacologically active, and like its parents compound, has a long half-life ○ Fluvoxamine is less protein-bound than the other SSRIs ○ Sertraline is only well absorbed when taken with food. Differences are also apparent in the suitability of individual SSRIs in special patient groups C. MECHANISM OF ACTION ● Dependent on receptor selectivity ● 5-HT receptors are scattered throughout the brain and body ANTAGONISTIC EFFECTS ● Antagonistic effects are mainly associated with 5-HT2 and 5-HT3 receptors AGONISTIC EFFECTS ● Agonistic effects are mainly associated with 5-HT1 and 5-HT4 receptors Table 7. Summary of 5-HT Receptor Agonists and their Clinical Application (Selective and Nonselective) Selective Agonists 5-HT Receptor Drug 5-HT1A Buspirone Clinical Application Vasoconstrictor Migraine headache Psychotropic D. SEROTONIN AGONISTS SUMATRIPTAN ● Mechanism of action: A 5HT1D receptor agonist at vascular receptors → vasoconstrictor effect on cranial blood vessels ● Therapeutic effect: relieve migraine headache ● Pharmacokinetics: Well-absorbed after PO administration ○ Metabolized by the liver into an inactive metabolite ○ Eliminated in the urine ● Half-life: 26 hours (increase in hepatic impairment) ● NOTE: The drug is reserved for recalcitrant headaches not susceptible to ordinary analgesics OTHER SELECTIVE 5-HT 1B/1D AGONISTS ● Mechanisms of action: ○ Induce vasoconstriction ○ Inhibit neurotransmitter release which mediate nociceptive and inflammatory effects ● Remembered as -triptans: ○ Almotriptan ○ Eletriptan ○ Naratriptan and Frovatriptan ▸ Longer onset of efficacy ▸ Shorter duration of action ○ Rizatriptan ▸ Fastest onset ○ Zolmitriptan ● Heptically metabolized by the monoamine oxidase (MAO) system and cytochrome enzymes (CYP) ○ More active in Sumatriptan, Rizatriptan, Zolmitriptan, and Almotriptan ● Long acting drugs with once daily preparations except for Naratriptan and Frovatriptan Refer to Table H in Master Tables for the pharmacokinetic properties of the different triptans. Clinical Application Anxiety Depression 5-HT1B and 5-HT1D Triptans Migraine headaches 5-HT2 Trazodone Somnorific (Sleep-inducing) 5-HT4 Cisapride Cholinergic GI motility Decrease cardiac toxicity Active Recall Box 1. Which generation of H1 antihistamines is known for its better side effect profile? A. First generation H1 antihistamines B. H2 antihistamines C. Second generation H1 antihistamines 2. T/F: H1 antihistamines are used for allergic reactions. 3. T/F: At low concentrations, breakdown of 5-hydroxytryptamine (serotonin) is handled by SERT and reuptake is managed by MAO. Answers: 1C, 2T, 3F YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 5 SEROTONIN SYNDROME ● Use of triptans should be limited to those resistant to analgesia to prevent occurrence of serotonin syndrome ● Constellation of mental status change, autonomic instability, and neuromuscular abnormalities: ○ Mental Status Changes ▸ Agitation ▸ Pressure Speech ○ Autonomic Instability ▸ Tachycardia ▸ Diarrhea ▸ Shivering ▸ Diaphoresis ▸ Mydriasis ○ Neuromuscular Abnormalities ▸ Clonus ▸ Hyperreflexia (lower > upper) ▸ Tremor ▸ Seizure ● Treatment: ○ Neuromuscular abnormalities and mental status changes require benzodiazepine treatment ○ Hydration and cooling may be needed to address rare hot or cold sensations ○ Cyproheptadine (an antihistamine) may be needed in drying of secretions due to diaphoresis ● Side effects: ○ Occasional (4-8%): dizziness, paresthesia, fatigue, flushing ○ Rare (2-3%): hot or cold sensation, dry mouth, dyspepsia ● Serious reactions: ○ Cardiac Reactions ▸ Ischemia ▸ Coronary artery vasospasm (CAV) ▸ Myocardial infarction ○ Noncardiac vasospasm-related reactions (rare occurrences) ▸ Cerebral hemorrhage ▸ Cerebrovascular accident (CVA) ● Contraindications: ○ When there are prior conditions such as CVA, CAV, or ischemic heart disease: ▸ Basilar or hemiplegic migraine ▸ Cerebrovascular or peripheral vascular disease ▸ Coronary heart disease ▸ Ischemic heart disease (including angina pectoris, history of MI, silent ischemia, Prinzmetal’s angina) ○ Severe hepatic impairment (Child-Pugh grade C) ○ Uncontrolled hypertension ○ Prior use of serotonin agonists ▸ Use within 24 hours of ergotamine-containing preparations or another serotonin receptor agonist ○ Use within 14 days of monoamine oxidase inhibitors (MAOIs) ERGOTAMINE ● Mechanism of action: agonist at serotonin receptors ○ 5-HT1B and 5-HT1D ○ Ergot Alkaloid Alpha receptor ○ Dopamine receptor ● Use: severe migraine headaches, wherein the usual use of analgesics are rendered ineffective ○ After onset of an attack, one 2 mg tablet is placed under the tongue ○ If necessary, another tablet should be taken at half-hour intervals thereafter ▸ NOTE: Dosage must not exceed three tablets in any 24 hours period ● Adverse effects: ○ Cardiovascular effects (e.g., low/fast/irregular heartbeat) ○ Neurologic effects (e.g., tingling/pain/coldness in the fingers/toes, loss of feeling in the fingers/toes) ○ Whitish fingers/toes/nails and bluish hands/feet ○ Muscle pain/weakness ○ Stomach/abdominal pains ○ Lower back pain ○ Kidney problems (e.g., change in urine amount) ○ Vision changes ○ Confusion ○ Slurred speech E. SEROTONIN ANTAGONISTS ● Some of the 5-HT receptors also produce symptoms that require regulation ● Block 5-HT receptors ● Mechanism of serotonin action is dependent on receptor selectivity Table 8. Serotonin Antagonists Drug 5-HT Receptor Uses Cyproheptadine H1, 5-HT 2α ● Sedative and anticholinergic ● Increases appetite ● Carcinoid and post gastrectomy dumping syndrome Ketanserin 5-HT 2A and alpha (-) Antihypertensive Odansetron and Granlsetron 5-HT 3 Antiemetics Clozapine and Olanzapine (atypical antipsychotics) 5-HT 2 Schizophrenia Methysergide 5-HT 2A/2C Tegaserod YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 5-HT 4 Prophylaxis of migraine Inhibit peristalsis on patients with irritable bowel disease 6 Take Note! ● It is important that an adequate balance of serotonin be achieved to ensure the proper functions of the CNS, GI, and platelet regulation. IV. LIPID-BASED AUTACOIDS (EICOSANOIDS) ● Eicosanoids include ○ Non-steroidal anti-Inflammatory drugs ○ Anti-Leukotrienes A. ARACHIDONIC ACID PATHWAY Figure 5. Conversion of membrane Arachidonic Acid to a Free Form by Phospholipase 2 ● Arachidonic Acid ○ Parent structure of most non-steroidal anti-inflammatory drugs (NSAIDs) ○ A normal component of membranes ○ In the presence of inflammatory stimuli: ▸ Phospholipase A2 will activate and convert arachidonic acid in the membrane to a free form ○ Steroids ▸ Have the capacity to inhibit both phospholipase A2 and cyclooxygenase pathways [Clinical Correlation] Aspirin and Cyclooxygenase ● Video link: https://www.youtube.com/watch?v=0YZ1vDzi_SM&t=185s ● Functions of prostaglandins: ○ Stimulate hypothalamus to increase body temperature ○ Stimulate immune cells to cause inflammation ○ Sensitize nerves to pain ○ Initiates blood clotting ○ Constrict or dilate blood vessels ○ Produce protective mucous in stomach ● Aspirin inhibits cyclooxygenase at the enzyme level ○ Blocks prostaglandin synthesis ○ Relieves prostaglandin-induced pain, fever, and inflammation until ○ Can also treat inflammation from some autoimmune diseases ● Aspirin use also inhibits other body functions ○ Blocks thromboxane A2 synthesis (involved in platelet activation) ▸ A low dose of aspirin everyday will make it harder for blood to clot ⎻ Extremely useful in preventing diseases caused by blood clots (MI and stroke) ○ Aspirin decreases production of protective mucus in the stomach ▸ Stomach acid is allowed to burn through the stomach and lead to gastric ulcers and bleeding ● Taking aspirin is not recommended for those with ○ Low risk of MI or stroke ○ History of gastric ulcers ○ Hemophilia B. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Figure 6. Two Pathways of Arachidonic Acid Breakdown ● Arachidonic acid breakdown has two pathways (both are pro-inflammatory) ○ Lipoxygenase pathway: generates leukotrienes which are pro-inflammatory ○ Cyclooxygenase (COX-1 and COX-2) pathway: generates many prostaglandins ▸ Prostaglandins are active in various organs and are also pro-inflammatory ● Inhibition of the pro-inflammatory pathways of arachidonic acid breakdown ○ Lipoxygenase pathway inhibition ▸ Done at the level of the enzyme lipoxygenase ▸ Can also be done through the inhibition of leukotriene receptors (via leukotriene receptor inhibitors) ○ COX-1 and COX-2 inhibition ▸ Done at the level of the enzyme (via NSAIDs, acetaminophen, COX-2 inhibitors, and aspirin) YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 ● NSAIDs and anti-leukotrienes block the pro-inflammatory products of oxidation and arachidonic acid ● Inhibit the cyclooxygenase enzyme ● Stop inflammation, vasodilation, and water excretion ● Inhibit platelet aggregation to prevent clotting ● Larger group of drugs inhibited by your cyclooxygenase enzyme ● Globally, the highest prescribed category of drugs Active Recall Box 4. Which of the following enzymes is tasked with converting arachidonic acid to a free form? A. Lipoxygenase B. Phospholipase A2 C. Cyclooxygenase 5. T/F: Arachidonic acid breakdown has two pathways, one pro-inflammatory and one anti-inflammatory. Answers: 4B, 5F 7 Figure 7. Prostaglandin and Arachidonic Metabolism Figure 7 ● In the presence of inflammatory stimuli, the following will occur: ○ Activation of Phospholipase A2 ○ Conversion of arachidonic acid in the membrane which frees arachidonic acid ● The 2nd breakdown pathway of arachidonic acid via cyclooxygenase yield prostaglandins ○ Enzymes responsible for the breakdown of prostaglandin G2 are cyclooxygenase 1 and cyclooxygenase 2 ● Both breakdown pathways generate various prostaglandin products that are active in several organs: ○ Prostacyclin (PGI2) ○ Thromboxane A2 ○ Prostaglandin E2 ○ Prostaglandin F ○ Thromboxane and prostacyclin are generated for this purpose ○ COX-1 and COX-2 inhibition or abolishing their conversion would make patients more prone to stroke and myocardial infarction ● Adverse effects are common to the use of all NSAIDs ○ Central Nervous system: Headaches, tinnitus, dizziness ▸ Rarely: aseptic meningitis ○ Cardiovascular: fluid retention, hypertension, edema ▸ Rarely: myocardial infarction and congestive heart failure ○ Gastrointestinal: abdominal pain, dyspepsia, nausea, vomiting ▸ Rarely: ulcers or bleeding ○ Hematologic: rarely thrombocytopenia, neutropenia, or aplastic anemia ○ Hepatic: abnormal liver function test results ▸ Rarely: liver failure ○ Pulmonary: asthma ○ Skin: rashes, all types, pruritus ○ Renal: renal insufficiency, renal failure, hyperkalemia, and proteinuria Table 9. Adverse Effects of NSAIDs System Central Nervous System ● ● ● ● Cardiovascular ● ● ● ● Gastrointestinal ● ● ● ● ● Hematologic ● Rare Thrombocytopenia ● Neutropenia ● Aplastic Anemia Hepatic ● Abnormal liver function ● Rare Liver Failure Pulmonary ● Asthma Skin ● Rashes ● Pruritus Renal ● ● ● ● SIDE EFFECTS OF NSAIDs ● Various prostaglandins can be active in the GI, the kidney, and the heart and cardiovascular system ● GI mucosa: ○ Conversion by your COX-1 will result in gastroprotective prostaglandins including PGE2, which will increase ▸ Mucus secretion ▸ Bicarbonate secretion ▸ Mucosal blood flow ○ COX-1 inhibition will have the opposite effect and make patients more prone to the following abolishment of gastroprotective mechanisms ▸ Peptic ulcers ▸ GI bleeding ● Kidney: ○ COX-1 and COX-2 inhibition will result in the afferent arteriolar vasodilation, sodium, and water excretion ○ Prostaglandin (E2 and I2) inhibition will result in sodium and water retention, hypertension, and hemodynamic-induced acute kidney injury ● Cardiovascular system: ○ Conversion by COX-1 and COX-2 is important for: ▸ Vasodilation ▸ Inhibition of platelet aggregation YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 Adverse Effects Headaches Tinnitus Dizziness Rarely, Aseptic Meningitis Fluid retention Hypertension Edema Rarely, Myocardial Infarction ● Congestive Heart Failure (CHF) Abdominal pain Dyspepsia Nausea Vomiting Rarely, Ulcers or Bleeding Renal insufficiency Renal Failure Hyperkalemia Proteinuria 8 TYPES OF NSAIDs NSAID SELECTIVITY AND EFFICACY Non-Selective NSAIDs Selectivity ● Inhibit COX-1 and COX-2 ● Properties ○ Anti-inflammatory ▸ Analgesic ▸ Antipyretic ● Common also to this class would be the inhibition of platelet aggregation ● There is comparable efficacy across NSAIDs but not so much in terms of COX-2 selectivity and GI toxicity (See Figure 9) Table 10. Traditional-Nonselective COX inhibitors System Adverse Effects Salicylic acid • Aspirin Propionic acids • Naproxen • Ibuprofen • Ketoprofen • Oxaprozin • Flurbiprofen Anthranilic acids • Mefenamic acid Aryl-acetic acid derivative • Diclofenac • Aceclofenac Oxicam derivatives • Piroxicam • Tenoxicam Pyrrolo-pyrrole derivative • Ketorolac • Indomethacin • Nabumetone Indole derivatives • Sulindac • Indomethacin Pyrazolone derivative • Phenylbutazone • Oxyphenbutazone ● Common to all these groups is the chemical structure belonging to Aspirin (Figure 8) ○ Other COX-1 and selective COX-2 inhibitors will share these features Figure 9. GI Toxicity and COX-2 Selectivity ● Based on selectivity (from highest to lowest): ○ High selectivity: ▸ Rofecoxib ▸ Celecoxib ○ Intermediate selectivity: ▸ Meloxicam ▸ Piroxicam ▸ Diclofenac ○ Non-selective: ▸ Ibuprofen ▸ Nabumetone ▸ Indomethacin ▸ Ketoprofen ▸ Ketorolac ● Based on GI toxicity (from greatest to least): ○ Greatest toxicity ▸ Ketoprofen ▸ Piroxicam ○ Least toxicity (safest) ▸ Ibuprofen Efficacy ● Oxford league study ○ Compares the relative efficacy of NSAIDs with the standard tramadol opioid antagonists (morphine and paracetamol/codeine preparations) ○ Shows that there is an advantage to the more selective COX-2 inhibitors ▸ E.g. etoricoxib, valdecoxib, celecoxib ▸ Has a higher capacity to achieve its effects compared to diclofenac, naproxen, and ibuprofen Figure 8. Aspirin, COX-1 and selective COX-2 inhibitors YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 9 ○ Very effective at preventing coronary and cerebral thrombosis ○ May prevent colon cancer ● Adverse effects (rare at antithrombotic doses) ○ Gastric upset (intolerance) ○ Duodenal ulcers ○ Hepatotoxicity ○ Asthma ○ Rashes ○ GI bleeding ○ Renal toxicity Figure 10. The Oxford League Table of Analgesic Efficacy (Commonly Used and Newer Analgesic Doses) ● There is an advantage to remembering which class the NSAID belongs to ○ Efficacy is greatest with: ▸ Selective COX-2 inhibitors ⎻ Celecoxib ⎻ Etoricoxib ⎻ Parecoxib ▸ Preferential COX-2 inhibitors (have some COX-1 activity) ⎻ Nimesulide ⎻ Diclofenac ⎻ Aceclofenac ⎻ Meloxicam ⎻ Nabumetone ● Advantage of selective COX-2 inhibitors: ○ GI safety may be improved ○ Selective COX-2 inhibitors do not affect platelet function at their usual doses ● Selective COX-2 inhibitors increase the incidence of: ○ Edema ○ Hypertension ○ Possible risk for myocardial infarction (MI) ● Increased risk of serious bleeding and cardiovascular events after an MI is greatest with celecoxib and diclofenac ASPIRIN ● A prototype for NSAIDs ● MOA: Desired effect is through the nonselective inhibition of cyclooxygenase ○ It is effective in low doses in inhibiting the thromboxane A2 and prostacyclin (PGI2) pathways ● Use is limited to its anti-platelet ability ○ Aspirin is hardly used anymore for its anti-inflammatory properties ● Mechanism ○ Covalently bind and irreversibly inhibits cyclooxygenase ○ Interferes with thromboxane A2 (TXA2) and prostacyclin (PGI2) pathways ▸ Induces platelet aggregation and prostacyclin ○ Irreversibly binds to platelets ▸ Effects of aspirin on bleeding tendencies are also irreversible ▸ Effects last for the duration of the platelet’s life (8-10 days) ● Use: a low dose (160mg) is needed for its antithrombotic/ antiplatelet effect YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 Figure 11. Arachidonic Acid Derivatives; Note that aspirin (NSAIDs) will inhibit the synthesis of TXA2 and PGI2 at the COX enzyme level ACETAMINOPHEN (N-ACETYL-PARA-AMINOPHENOL) ● The most commonly taken analgesic worldwide ● Mechanism is unclear ○ Believed to inhibit cyclooxygenase pathways ▸ Does not inhibit cyclooxygenase in peripheral tissues (has no peripheral anti-inflammatory effects) ▸ The specific enzyme may be the variant of cyclooxygenase enzymes (COX-3) ● Pharmacokinetics ○ Well absorbed ○ Peak levels: 90 minutes ○ Half-life: 2.5 hours ○ Hepatic metabolism via Cytochrome P450 to phenacetin and acetanilide (leads to urinary excretion) ● Marketed as the safest drug ○ Adverse effects still present ▸ Skin rash ▸ Hypersensitivity ▸ Nephrotoxicity ▸ Anemia ▸ Leukopenia ▸ Hyperuricemia ▸ Increased serum glucose ▸ Elevation of liver enzymes ▸ Metabolic problems ⎻ Hyperuricemia ⎻ Decreased bicarbonate ⎻ Hepatotoxicity 10 Toxic Effects of Paracetamol ● At normal doses, paracetamol is broken down to its nontoxic metabolites which are readily excreted in urine ○ Phenacetin ○ Acetanilide ● At very large doses (toxic doses), there is depletion of the glutathione donors ○ Shifts the metabolism of acetaminophen towards an alternate (toxic) pathway ▸ Increases the hepatotoxic metabolite: N-acetyl-benzoquinoeimine (NAPQI) ● Signs of toxicity due to accumulation of NAPQI ○ Renal tubular necrosis ○ Hypoglycemic coma ○ Thrombocytopenia ○ Liver necrosis (leads to death) ● Treatment ○ Administration of N-acetylcysteine ▸ Donates a sulfhydryl group necessary for converting acetaminophen to its less toxic metabolites Table 11. Types of NSAIDs NSAID Type Example Agents Non-COX-2-Selective NSAID ● ● ● ● ● NSAIDs with some COX-2 Activity ● Diclofenac (not traditionally considered a COX-2-specific agent, but has been associated with a cardiovascular risk profile similar to the COX-2-specific agent) ● Piroxicam ● Diflunisal ● Meclofenamate COX-Selective NSAIDs ● ● ● ● Ibuprofen Naproxen Indomethacin Ketoprofen Ketorolac Celecoxib (Celebrex, Pfizer) Meloxicam Etodolac Valdecoxib (no longer available) ● Etoricoxib (investigational) ● Rofecoxib (no longer available) ● Lumiracoxib (investigational) Figure 12. Metabolites of Paracetamol; NAPQI is hepatotoxic NSAID SUMMARY ● Products that inhibit the breakdown of arachidonic acid via lipoxygenase and cyclooxygenase pathways can arrest inflammatory processes that can be damaging to patients ● Knowing the different classes of selective and non-selective NSAIDs can determine the safety, efficacy, and adverse effects expected in each class Active Recall Box 6. What is the highest prescribed category of drugs? 7. NSAID with the highest selectivity? Answers: 6 NSAIDs, 7 Rofecoxib Figure 13. Products that Inhibit Arachidonic Acid Breakdown YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 11 Table 12. Prostaglandin-Specific Effects that May Arise from Selective Inhibition of Pathways for Anti-Inflammatory Effects Drug Preparation Use Dinoprostone Vaginal tab/gel ● Induction of labor ● Midterm abortion Dinoprost Intra-amniotic injection ● Midterm abortion Carboprost IM, Intra-amniotic injection Gemeprost Vaginal pessary ● Cervical priming in early pregnancy Alprostadil IV infusion, IV injection, Intracavernosal injection ● Maintenance of a patent ductus arteriosus in neonates ● Erectile dysfunction ○ Leukotrienes C4, D4, and E4 are responsible for many of the allergic reactions related to asthma (see Figure 15) ▸ Increased mucus production ▸ Recruitment of mast cells and other pro-inflammatory cells ▸ Plasma edema from epithelial shedding ▸ Smooth muscle hyperplasia or hypertrophy ● Midterm abortion ● Control of PPH Misoprostol Oral ● Abortion Enprostil Oral ● Peptic ulcer Epoprostenol IV infusion ● Pulmonary hypertension Latanoprost Topical Iloprost IM Figure 14. Significant Leukotrienes of the Arachidonic Acid Pathway ● Glaucoma ● Decrease infarct size when given IM after MI C. ANTI-LEUKOTRIENES ● When the breakdown of arachidonic acid is inhibited in the cyclooxygenase pathway, less prostaglandins are generated ○ Pathway is shunted to the 5-lipoxygenase pathway, leading to the production of pro-inflammatory leukotrienes ○ The blockage of prostaglandin production pathways by NSAIDs direct more arachidonic acid toward leukotriene production ▸ This negatively affects asthmatic patients ● Significant leukotrienes and their functions (see Figure 15) ○ LTB4: responsible for many of the inflammatory effects of monocyte migration, neutrophil chemoactivation, and T-cell trafficking ○ LTD4: responsible for the effects of inducing mucus secretion, inflammatory cell infiltration, tissue edema, and severe bronchoconstriction ▸ These are the hallmarks of an asthmatic reaction YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 Figure 15. Effects of Leukotrienes C4, D4, and E4 Take Note! ● In Dr. Henri’s lecture video, she mentions that LTB4 inhibits the effects listed. However, the figure in the slide, as well as that in Katzung, will show that LTB4 is what causes the effects, and not inhibit them 12 CONTROLLER MEDICATIONS: LEUKOTRIENE PATHWAY INHIBITORS 5-Lipoxygenase Inhibitors ● Targets pathways responsible for production of all leukotrienes ○ ZILEUTON ▸ Inhibits arachidonic acid breakdown by inhibiting 5-lipoxygenase ▸ Use: prophylaxis and chronic treatment of asthma in all adults and children older than 12 years of age ⎻ For mild to moderate asthma and should be avoided in severe asthma ○ Well tolerated preparation ▸ Peak: 1-2 hours ▸ Half-life: 2.5 hours ▸ DoseL 600 mg q.i.d. with meals and at bedtime Figure 17. Leukotriene Receptor Agonists (LTRAs): Montelukast Comparing Montelukast and Zileuton Side Effects Figure 16. Zileuton, Montelukast, Pranlukast, and Zafirlukast Sites of Inhibition in the Arachidonic Acid Pathway Leukotriene Receptor Antagonists (LTRAs) ● Represented by MONTELUKAST/PRANLUKAST/ZAFIRLUKAST ○ LTD4 receptor antagonists, inhibitors of LTD4 receptor binding ○ Use: maintenance treatment for those with mild to moderate asthma ▸ Modestly effective for maintenance treatment of adults and children with intermittent/persistent asthma ▸ No use in acute exacerbations of asthma ▸ Only leukotriene approved for use in children 6-12 years old ▸ Less effective than inhaled steroids ▸ May be added to oral/inhalation corticosteroids to improve asthma patients with aspirin-tolerant asthma ● LTRA: Montelukast ○ Inhibits the pro-inflammatory leukotrienes ▸ This effect has no evidence of benefit when the damage is more from fibrosis in the terminal airways with COPD ○ Effect is generally less than that of low-dose inhaled corticosteroids ▸ Therefore, it cannot be a substitute for low-dose corticosteroid therapy for those on corticosteroid therapy ○ Requires monitoring for hepatic toxicity YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 ● Both Montelukast and Zileuton share similar adverse effects, which are mild ○ >10%L headache, and increased ALT (liver enzymes) ○ 1-10%: ▸ Chest pain ▸ Dizziness ▸ Fever ▸ Insomnia ▸ Malaise ▸ Nervousness ▸ Dyspepsia ▸ Nausea ▸ Abdominal pain ▸ Constipation ▸ Flatulence ▸ Myalgia ▸ Arthralgia ▸ Weakness ▸ Conjunctivitis ▸ Low WBC count ○ Rare: severe neuropsychiatric adverse effects (agitation, aggressive behavior, anxiousness, depression, dream abnormalities, hallucinations, insomnia, irritability, restlessness, suicide and suicidal thinking, and tremors) Take Note! ● Between both LTRAs (Montelukast and Zafirlukast) and Zileuton: Churg Strauss vasculitis is more common in Zileuton 13 QUICK REVIEW QUESTIONS 1. Which of the following pharmaceuticals is not classified as an NSAID? a. Aspirin b. Paracetamol c. Ibuprofen d. Loratadine 2. T/F: Acetaminophen being the safest drug means that it has no adverse reactions. 3. T/F: Montelukast may be given to patients with persistent asthma or COPD to help them breathe. 4. Which of the following is important for neutrophil and monocyte migration during inflammation? a. LTB4 b. LTC4 c. LTD4 d. LTE4 5. All of the following are examples of 2nd generation antihistamines with weak potential for producing sedation EXCEPT: a. Levocetirizine b. Cetirizine c. Acrivastine d. Loratadine 6. T/F: Toxicity due to ibuprofen can be remedied by administration of N-acetylcysteine. 7. Antazoline and Pyrilamine are examples of ethylenediamines. Cetirizine and Levocetirizine are examples of piperidines. a. Only statement 1 is true b. Only statement 2 is true c. Both statements are true d. Both statements are false 8. Muscarinic receptors can have the following adverse effects, except? a. Dry mouth b. Urinary retention c. Sinus tachycardia d. Weight gain 9. Where is most of the body’s serotonin found? a. Brain b. GI Tract c. Heart d. D. Lungs 10. SSRIs are usually prescribed multiple times a day because of their short half-life. Sertraline is only well absorbed when taken with food. 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. YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 ANSWER KEY 1D, 2F, 3F, 4A, 5D, 6F, 7A, 8D, 9B, 10B RATIONALE 1. D. Loratadine. Loratadine is an antihistamine, not an NSAID. 2. False. Although rare, acetaminophen can still manifest adverse reactions. 3. False. Montelukast is effective in persistent asthma but not in fibrosis-related damage such as COPD. 4. A. LTB4. The function described is that of LTB4; the other choices are responsible for allergic reactions related to asthma. 5. D. Loratadine. Loratadine is an example of a non-sedating 2nd generation antihistamine. 6. False. N-acetylcysteine is for treating paracetamol toxicity. 7. A. Only statement 1 is true. Cetirizine and Levocetirizine are examples of piperazines. 8. D. Weight gain. This is a potential adverse effect of serotonin receptors 9. B. GI Tract. Most of the body’s serotonin is found in the GI tract, where it regulates bowel function and movements 10. B. Statement 1 is false. Statement 2 is true. SSRIs are usually prescribed once daily because of prolonged duration of action. 14 REFERENCES FREEDOM SPACE REQUIRED ● 📄 De la Cruz, H. T. (2023). Autacoids & Anti-Inflammatory Agents [Lecture slides]. 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 YL6 TransMap: https://bit.ly/2027YL6TransMap YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 15 MASTER TABLES Table A. Classification of Autacoids according to Chemical Structures Group Autacoid Bioamines ● ● Histamine Serotonin (5 HTA) Polypeptides ● ● ● Angiotensin Bradykinin Kallidin Lipid-Derived Substances ● ● ● Prostaglandins Leukotrienes Platelet Activating Factor (PAF) Nitric Oxide ● Vasodilator Table B. Types of H-Receptors H-Receptor Location ● ● ● ● H1 Function ● Involved in allergic reactions ● Only H1 antihistamines are currently available in the market Smooth muscle Endothelial cells Nerves Respiratory epithelium ● Gastric parietal cells ● Stimulate gastric acid secretion ● H2 antihistamines are used to treat gastric acid disorders (gastric acid reflux, peptic ulcers) H2 H3 ● CNS H4 ● Immune Cells ● Involved in allergic reactions Table C. 1st Generation H1 Antihistamines and their Uses Treat Examples Acute allergic reactions (marked potential for producing drowsiness or sedation) ● ● ● ● ● ● ● ● Brompheniramine Chlorpheniramine Clemastine Cyproheptadine Diphenhydramine Doxylamine Hydroxyzine Promethazine Treat motion sickness due to the anticholinergic properties of its structures ● ● ● ● ● ● Cyclizine Diphenhydramine Dimenhydrinate Hydroxyzine Meclizine Promethazine Motion sickness and vestibular disturbances ● ● ● Dimenhydrinate Meclizine Promethazines Nausea and vomiting of pregnancy ● Cyclizines YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 16 Table D. Potential Adverse Effects of 1st (Old) Generation H1 Antihistamines Receptors Effects ● ● Decreased alertness, cognition, learning, memory, and psychomotor performance May cause impairment with or without sedation Muscarinic Receptors ● ● ● Dry mouth Urinary retention Sinus tachycardia Serotonin Receptors ● ● Increased appetite Weight gain ɑ-Adrenergic Receptors ● ● Dizziness Postural hypotension Cardiac Ion Channels ● ● Increased QT interval Ventricular arrhythmias CNS H1-Receptors Table E. Chemical Classification of H1 Antihistamines Classification Examples Alkylamines ● ● ● ● Brompheniramine Chlorpheniramine Dexchlorpheniramine Pheniramine ● ● ● Dimethindene Triprolidine Acrivastine Ethanolamines ● ● ● Carbinoxamine Clemastine Dimenhydrinate ● ● ● Diphenhydramine Doxylamine Phenyltoloxamine Ethylenediamines ● ● ● Antazoline Pyrilamine Tripelennamine Phenothiazines ● ● ● Promethazine Mequitazine Trimeprazine Piperazines ● ● ● ● Buclizine Cyclizine Meclizine Oxatomide ● ● ● Hydroxyzine Cetirizine Levocetirizine Piperidines ● ● ● ● ● ● Azatadine Cyproheptadine Ketotifen Loratadine Desloratadine Blastine ● ● ● ● ● ● Ebastine Terfenadine Fexofenadine Levocabastine Mizolastine Rupatadine Table F. Classification of Antihistamines First Generation Antihistamines Second Generation Antihistamines These are highly lipid soluble hence effects both CNS as well as periphery These are large molecules and less lipophilic and thus less effect the brain Sedative in nature Non-sedative in nature It also shows as anticholinergic and antiadrenergic effect No effect as anticholinergic and antiadrenergic Short duration of action hence more intake of tablets Long duration of action hence it can be given once daily It results in sleepiness It results in little or no sleepiness Common side effects: drowsiness, impaired thinking, dizziness Common side effects: headache, dry mouth, dry nose E.g.: alimemazine, promethazine E.g.: cetirizine, fexofenadine YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 17 Table G. Summary of 5-HT Receptor Agonists and their Clinical Application (Selective and Nonselective) Selective Agonists 5-HT Receptor Drug Clinical Application 5-HT1A Buspirone 5-HT1B and 5-HT1D Triptans 5-HT2 Trazodone Somnorific (Sleep-inducing) 5-HT4 Cisapride Cholinergic GI motility Decrease cardiac toxicity Anxiety Depression Migraine headaches Non-Selective Agonists Drug Clinical Application Ergotamine Vasoconstrictor Migraine headache LSD Psychotropic Table H. Pharmacokinetic Properties of the Different Triptans Drug Onset of Efficacy (Minutes) Time to Pike levels (hours) Lipophilicity Bioavailability (%) Elimination Half-live (hours) Elimination Routes Maximum Daily Doses (mg) Sumatriptan 45-60 2–3 Low 14 2-2 – 5 Hepatic, MAO 200 Rizatriptan 30 1 Moderate 45 2 – 2.5 Hepatic, MAO, renal 30 Zolmitriptan 45-60 1 – 1.5 Moderate 40 – 48 2.5 – 3 Hepatic (active metabolite), MAO, CYP 10 Almotriptan 45-60 1.5 – 2.5 Unknown 80 3.5 Hepatic (active metabolite), renal, MAO, CYP 25 Eletriptan 60 1.3 – 2.8 High 50 4–5 Hepatic (active metabolite), CYP 80 Naratriptan Up to 4 hours 2 – 3.5 High 63 – 73 5–6 Hepatic, CYP, renal 5 Frovatriptan Up to 4 hours 2–4 Low 24 – 30 26 Hepatic, CYP 7.5 Table I. Serotonin Antagonists Drug Cyproheptadine Ketanserin 5-HT Receptors Uses H1, 5-HT 2α ● Sedative and anticholinergic ● Increases appetite ● Carcinoid and post gastrectomy dumping syndrome 5-HT 2A and alpha (-) 5-HT 3 Antiemetics Clozapine and Olanzapine (atypical antipsychotics) 5-HT 2 Schizophrenia Tegaserod YL6:01.31a 5-HT 2A/2C 5-HT 4 Autacoids & Anti-Inflammatory Agents 2 ● Dry mouth ● Drowsiness ● Weight gain Antihypertensive Odansetron and Granlsetron Methysergide Side Effects Prophylaxis of migraine Chronic use causes abdominal and pulmonary fibrosis Inhibit peristalsis on patients with irritable bowel disease 18 Table J. Adverse Effects of NSAIDs System Adverse Effects Central Nervous System ● ● ● ● Headaches Tinnitus Dizziness Rarely, Aseptic Meningitis Cardiovascular ● ● ● ● ● Fluid retention Hypertension Edema Rarely, Myocardial Infarction Congestive Heart Failure (CHF) Gastrointestinal ● ● ● ● ● Abdominal pain Dyspepsia Nausea Vomiting Rarely, Ulcers or Bleeding Hematologic ● Rare Thrombocytopenia ● Neutropenia ● Aplastic Anemia Hepatic ● Abnormal liver function ● Rare Liver Failure Pulmonary ● Asthma Skin ● Rashes ● Pruritus Renal ● ● ● ● Renal insufficiency Renal Failure Hyperkalemia Proteinuria Table K. Traditional-Nonselective COX inhibitors System Adverse Effects Salicylic acid • Aspirin Propionic acids • Naproxen • Ibuprofen • Ketoprofen • Oxaprozin • Flurbiprofen Anthranilic acids • Mefenamic acid Aryl-acetic acid derivative • Diclofenac • Aceclofenac Oxicam derivatives • Piroxicam • Tenoxicam Pyrrolo-pyrrole derivative • Ketorolac • Indomethacin • Nabumetone Indole derivatives • Sulindac • Indomethacin Pyrazolone derivative • Phenylbutazone • Oxyphenbutazone YL6:01.31a Autacoids & Anti-Inflammatory Agents 2 19 Table L. Types of NSAIDs NSAID Type Example Agents Non-COX-2-Selective NSAID ● ● ● ● ● NSAIDs with some COX-2 Activity ● Diclofenac (not traditionally considered a COX-2-specific agent, but has been associated with a cardiovascular risk profile similar to the COX-2-specific agent) ● Piroxicam ● Diflunisal ● Meclofenamate COX-Selective NSAIDs ● ● ● ● ● ● ● Ibuprofen Naproxen Indomethacin Ketoprofen Ketorolac Celecoxib (Celebrex, Pfizer) Meloxicam Etodolac Valdecoxib (no longer available) Etoricoxib (investigational) Rofecoxib (no longer available) Lumiracoxib (investigational) Table M. Prostaglandin-Specific Effects that May Arise from Selective Inhibition of Pathways for Anti-Inflammatory Effects YL6:01.31a Drug Preparation Dinoprostone Vaginal tab/gel ● Induction of labor ● Midterm abortion Dinoprost Intra-amniotic injection ● Midterm abortion Carboprost IM, Intra-amniotic injection ● Midterm abortion ● Control of PPH Gemeprost Vaginal pessary Alprostadil IV infusion, IV injection, Intracavernosal injection Misoprostol Oral ● Abortion Enprostil Oral ● Peptic ulcer Epoprostenol IV infusion Latanoprost Topical Iloprost IM Autacoids & Anti-Inflammatory Agents 2 Use ● Cervical priming in early pregnancy ● Maintenance of a patent ductus arteriosus in neonates ● Erectile dysfunction ● Pulmonary hypertension ● Glaucoma ● Decrease infarct size when given IM after MI 20