Ch 36 Part 1 - NSAIDs, Paracetamol, Drugs Used in Gout - Slides v2024 PDF

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Disease-Modifying Anti-Rheumatic Drugs (DMARDs), Nonopioid Analgesics, & Drugs used in Gout Prepared by: ABIGAIL L. GO, MD AUGUST 2024  REFERENCE...

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Disease-Modifying Anti-Rheumatic Drugs (DMARDs), Nonopioid Analgesics, & Drugs used in Gout Prepared by: ABIGAIL L. GO, MD AUGUST 2024  REFERENCE Kafaja TK, Anwar S, Furst DE. Nonsteroidal Anti -Inflammatory Drugs, Disease - Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout ( Chapter 36). In: Katzung ’s Basic And Clinical Pharmacology, 16th Edition (Vanderah TW, editor), McGraw-Hill, 2024.  PART 1: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Other Analgesics Drugs used in Gout Prepared by: ABIGAIL L. GO, MD AUGUST 2024  1. Differentiate in terms of MOA, PK, I/CI, AEs (& antidote to toxicity*) a. NSAIDs: non-selective COX inhibitors LEARNING vs. selective COX-2 inhibitors b. other analgesics: Paracetamol*, OUTCOMES Ketorolac, Tramadol c. drugs used in gout (acute, chronic, refractory) d. DMARDs: conventional synthetic vs. At the end of the lecture, biologic DMARDs the 2nd year medical 2. Discuss the WHO analgesic ladder for student should be able to: cancer patients 3. Choose the most appropriate drug using the ESSC criteria given a case of pain and/or inflammation © ALG 2024 4  INFLAMMATION response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from circulation to the sites where they are needed (Robbins and Cotran, 9th Ed, p. 69) © ALG 2024 5  WITHOUT INFLAMMATION Infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores. (Robbins and Cotran, 9th Ed, p. 69) © ALG 2024 6 5 CARDINAL SIGNS OF INFLAMMATION REDNESS SWELLING LOSS OF HEAT PAIN FUNCTION 7  INFLAMMATION However, there are diseases in which the inflammatory reaction is misdirected against self such as in autoimmune diseases (e.g., RA), occurs against harmless environmental substances (e.g., in allergies), or is inadequately controlled. (Robbins and Cotran, 9th Ed, p. 70) © ALG 2024 8  PRIMARY THERAPEUTIC GOALS IN PATIENTS WITH INFLAMMATION 1. RELIEF OF SYMPTOMS MAINTENANCE OF FUNCTION 2. SLOWING OR ARREST OF TISSUE-DAMAGING PROCESSES © ALG 2024 9  NON- STEROIDAL ANTI- INFLAMMATORY A DRUGS NSAIDs  INTRODUCTION Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed to improve aspirin’s efficacy profile and decrease its toxicity. © ALG 2024 11  What do NSAIDs have in COMMON? All but one of the NSAIDs are weak organic acids; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug. © ALG 2024 12  PHARMACOKINETICS of NSAIDs Absorption Well absorbed; Food does not substantially change bioavailability Distribution Highly protein-bound (~98%), usually to albumin; Found in synovial fluid after repeated dosing; * drugs w/ short T½ remain longer in joints than predicted from T½ * drugs w/ longer T½ are as predicted © ALG 2024 13  PHARMACOKINETICS of NSAIDs Metabolism Highly metabolized in the LIVER, by phase I-II, by phase II (direct glucuronidation) alone, by CYP3A or CYP2C families of P450 enzymes. Excretion RENAL: most important for final elimination Biliary excretion and reabsorption (via enterohepatic circulation) © ALG 2024 14  MOA of NSAIDs NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis. Additional possible MOAs: 1. inhibition of chemotaxis 2. downregulation of IL-1 production 3. decreased production of free radicals & superoxide 4. interference w/ Ca2+-mediated intracellular events © ALG 2024 15  MOA NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostanoid biosynthesis by inhibiting cyclooxygenase (COX). Katzung 2024 Figure 36-2 16  PHARMACODYNAMICS of NSAIDs © 2019, Katzung & Trevor’s Pharmacology Examination & Board Review © ALG 2024 17  CYCLOOXYGENASE (COX) isozymes 1. COX-1 generates prostanoids for “housekeeping” functions, such as gastric epithelial cytoprotection 2. COX-2 = major source in inflammation and cancer - Endothelial COX-2 is the primary source of prostacyclin - Renal COX-2 is important for normal renal development © ALG 2024 18  Non-selective COX inhibitors © ALG 2024 © 2012, American Association for the Advancement of Science 19  PHARMACODYNAMICS of NSAIDs NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T-lymphocytes, and reverse the vasodilation of inflammation. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the selective COX-2 inhibitors and the non-acetylated salicylates) inhibit platelet aggregation. THERAPEUTIC © ALG 2024 EFFECTS of NSAIDs 20  Non-selective COX inhibitors “cardioprotective” © ALG 2024 © 2012, American Association for the Advancement of Science 21  Selective COX-2 inhibitors “not cardioprotective” © ALG 2024 © 2012, American Association for the Advancement of Science  Non-selective COX vs selective COX-2 Older NSAIDs = variable selectivity for COX-1 vs COX-2 synthesis of selective COX-2 inhibitors equally efficacious do not affect housekeeping functions in GIT ❖ ↑ GIT safety do not counter thromboxane’s effect on platelet aggregation ❖ (-) cardioprotection ❖ ↑ incidence of edema, hypertension, myocardial infarction © ALG 2024 23  Clinical Uses of NSAIDs Although not all NSAIDs are approved by FDA for the whole range of rheumatic disorders, most are effective in RA, PsA, arthritis in IBD, OA, localized MSK syndromes, and gout (except tolmetin). There is no evidence that NSAIDs alter the course of arthritic disorders. Several NSAIDs (including aspirin) reduce the incidence of colon cancer (50% reduction in relative risk when taken for > 5 years). © ALG 2024 24  PRIMARY THERAPEUTIC GOALS IN PATIENTS WITH INFLAMMATION 1. RELIEF OF SYMPTOMS NSAIDs MAINTENANCE OF FUNCTION 2. SLOWING OR ARREST OF TISSUE-DAMAGING PROCESSES © ALG 2024 25  Toxicity of NSAIDs NSAIDs are all gastric irritants and can be associated with GI ulcers and bleeding as well, although as a group, the newer agents tend to cause less GI irritation than aspirin. Nephrotoxicity is due in part to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins. Hepatotoxicity also can occur. © ALG 2024 26  Adverse Effects of NSAIDs 1. Central nervous system: Headaches, tinnitus, dizziness, (rarely) aseptic meningitis. 2. Cardiovascular: Fluid retention, hypertension, edema, (rarely) myocardial infarction (MI) and congestive heart failure (CHF). 3. Gastrointestinal: Abdominal pain, dyspepsia, nausea, vomiting, (rarely) ulcers or bleeding. 4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. 5. Hepatic: Abnormal liver function test results and (rarely) liver failure. 6. Pulmonary: Asthma. 7. Skin: Rashes, all types, pruritus. 8. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria. NSAIDs interfere with autoregulation of renal blood flow modulated by prostaglandins © ALG 2024 27  ! BLACK BOX WARNINGS ! Cardiovascular: "NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk." FDA RELEASES BLACK-BOX TEMPLATE FOR NSAIDS © ALG 2024 June 27, 2005 28  ! BLACK BOX WARNINGS ! Gastrointestinal: "NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk." FDA RELEASES BLACK-BOX TEMPLATE FOR NSAIDS © ALG 2024 June 27, 2005 29  Previously… FDA recommended avoiding use of NSAIDs in pregnancy at 30 weeks or later because of the risk of premature closure of the fetal ductus arteriosus. October 15, 2020 Exception: patients on low-dose 80 mg aspirin for pregnancy-related conditions (e.g., pre-eclampsia) © ALG 2024 30  A. A NSAIDs A. ASPIRIN (ACETYLSALICYLIC ACID; ASA) B. NON-ACETYLATED SALICYLATES C. SELECTIVE COX-2 INHIBITORS D. NON-SELECTIVE COX INHIBITORS © ALG 2024 31  A. A NSAIDs 1. NON-SELECTIVE COX INHIBITORS a) SALICYLATES i. ASPIRIN (ACETYLSALICYLIC ACID; ASA) ii. NON-ACETYLATED SALICYLATES b) NEWER NON-SELECTIVE COX INHIBITORS 2. SELECTIVE COX-2 INHIBITORS © ALG 2024 32  A 1a-i ASPIRIN The original NSAID Pharmacokinetics: Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 metabolism: rapidly hydrolyzed (serum half-life of 15 mins) by tissue and blood esterases to acetic acid and salicylate (bound to albumin) excretion: alkalinization of urine increases the rate of excretion Katzung 2024 Figure 36-3 © ALG 2024 33  A 1a-i ASPIRIN The original NSAID Pharmacokinetics: Aspirin (acetylsalicylic acid; ASA) In case of aspirin poisoning: has a pKa of 3.5 administer IV sodium metabolism: rapidly hydrolyzed bicarbonate to achieve urine (serum half-life of 15 mins) by tissue pH 7.5 and enhance and blood esterases to acetic acid and elimination of aspirin salicylate (bound to albumin) (Mirrakhimov et al. excretion: alkalinization of urine 2017 Int J Nephrol) increases the rate of excretion © ALG 2024 34  A 1a-i ASPIRIN rarely used as anti-inflammatory medication used for its antiplatelet effects (dose: 80–325 mg OD) MOA: irreversibly inhibits platelet COX such that its antiplatelet effect lasts 8–10 days (lifespan of platelet). In other tissues, it lasts 6–12 hours. Clinical Uses: decreases the incidence of coronary artery thrombosis with myocardial infarction, thrombosis after coronary bypass grafting, transient ischemic attacks, unstable angina © ALG 2024 35  aspirin > 100 mg/day inhibit systemic COX-1 & COX-2 ASPIRIN ANTIPLATELET (80-325 mg/day) ANALGESIA (325-650 mg/dose, max 4 g/day) ANTI-INFLAMMATORY EFFECTS (4-6 g/day) © ALG 2024 © 2012, American Association for the Advancement of Science  A 1a-i ASPIRIN in GOUT? Review: Aspirin achieves ANALGESIA at 325-650 mg/dose, every 4–6 hours, max 4 g/day Aspirin causes RENAL RETENTION OF URIC ACID at ≤2.6 g/day, only increasing its excretion at >3.6 g/day ∴ Do NOT use aspirin as analgesic for gout © ALG 2024 37  A 1a-i ASPIRIN versus OTHER NON- SELECTIVE COX INHIBITORS Aspirin irreversibly acetylates and blocks platelet COX, while the (other) non-COX-selective NSAIDs are reversible inhibitors. ASPIRIN: THE IRREVERSIBLE © ALG 2024 38  A 1a-i ASPIRIN + CLOPIDOGREL Dual Antiplatelet Therapy (DAPT) The combination is more effective than aspirin alone in reducing MI, stroke, CV death BUT has greater risk for major bleeding. © ALG 2024 39  A 1a-i FINDING THE BALANCE with ASPIRIN THROMBOSIS BLEEDING © ALG 2024 40  A 1a-i ASPIRIN before SURGERY When do we discontinue? Perform risk-benefit analysis for the patient: Do the benefits (↓ intraoperative bleeding in major surgery) outweigh the risks (↑ CV events from thrombosis)? If yes, then discontinue. How long is the lifespan of the platelet? Discontinue aspirin for 1 week before the elective surgery © ALG 2024 41  A 1a-i Adverse Effects of ASPIRIN Main AEs: gastric upset (intolerance), gastric & duodenal ulcers Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses. ❖ Reye’s syndrome (rare but serious; swelling of liver & brain) in children with viral infections (Influenza, Varicella) do NOT use aspirin to treat fever in pediatric patients © ALG 2024 42  A 1a-i Contraindications of ASPIRIN Hypersensitivity to aspirin, salicylates, NSAIDs (e.g., ibuprofen) History of asthma attacks precipitated by aspirin or NSAIDs Active or history of peptic ulcers or GI bleeding Bleeding disorders (e.g., hemophilia) Severe liver or renal impairment Children with influenza or varicella infections Pregnancy (20 weeks or later)* © ALG 2024 43  A. A NSAIDs 1. NON-SELECTIVE COX INHIBITORS a) SALICYLATES i. ASPIRIN (ACETYLSALICYLIC ACID; ASA) ii. NON-ACETYLATED SALICYLATES b) NEWER NON-SELECTIVE COX INHIBITORS 2. SELECTIVE COX-2 INHIBITORS © ALG 2024 44  A 1a-ii Non-Acetylated Salicylates effective anti-inflammatory drugs, but rarely used examples: o magnesium choline salicylate o sodium salicylate o salicyl salicylate weak COX inhibitors that do NOT inhibit platelet aggregation (no cardioprotective effect) have less toxicity so may be preferable in patients with asthma, bleeding tendencies, renal dysfunction © ALG 2024 45  A 1a-ii Non-Acetylated Salicylates more commonly used: TOPICAL methyl salicylate The most concentrated and toxic form of salicylate is oil of wintergreen; ingestion of 5 mL is equivalent to 7 g aspirin, which can kill a young child. www.msdmanuals.com © ALG 2024 46  A. A NSAIDs 1. NON-SELECTIVE COX INHIBITORS a) SALICYLATES i. ASPIRIN (ACETYLSALICYLIC ACID; ASA) ii. NON-ACETYLATED SALICYLATES b) NEWER NON-SELECTIVE COX INHIBITORS 2. SELECTIVE COX-2 INHIBITORS © ALG 2024 47  A 1b NON-SELECTIVE COX INHIBITORS For PAIN & INFLAMMATORY CONDITIONS (e.g., arthritis) IBUPROFEN NAPROXEN The only non-acid NSAID 1. 3. 2. FLURBIPROFEN PROPIONIC INDOLE / ACID KETONE NABUMETONE INDENE derivatives prodrug derivatives naphthylacetic acid metabolite KETOPROFEN OXAPROZIN INDOMETHACIN SULINDAC DEXKETOPROFEN sulfide metabolite © ALG 2024 48  A 1b NON-SELECTIVE COX INHIBITORS For PAIN & INFLAMMATORY CONDITIONS (e.g., arthritis) IBUPROFEN NAPROXEN 1. PROPIONIC FLURBIPROFEN ACID derivatives KETOPROFEN OXAPROZIN DEXKETOPROFEN © ALG 2024 49  A 1b NON-SELECTIVE COX INHIBITORS For PAIN & INFLAMMATORY CONDITIONS (e.g., arthritis) IBUPROFEN NAPROXEN Incidence of upper GI bleeding FLURBIPROFEN 1. PROPIONIC with NAPROXEN is 2x that of ACID derivatives IBUPROFEN but it has a more favorable CV risk profile. KETOPROFEN OXAPROZIN DEXKETOPROFEN © ALG 2024 50  A 1b NON-SELECTIVE COX INHIBITORS For PAIN & INFLAMMATORY CONDITIONS (e.g., arthritis) IBUPROFEN NAPROXEN IBUPROFEN 1. PROPIONIC FLURBIPROFEN ACID derivatives analgesia: < 1600 mg/day anti-inflammatory: > 2400 mg/day KETOPROFEN OXAPROZIN DEXKETOPROFEN © ALG 2024 51  A 1b NON-SELECTIVE COX INHIBITORS INDOMETHACIN or IBUPROFEN can be IBUPROFEN NAPROXEN used to close patent ductus arteriosus (PDA) FLURBIPROFEN 1. PROPIONIC in preterm infants 3. INDOLE / ACID INDENE derivatives derivatives KETOPROFEN OXAPROZIN INDOMETHACIN SULINDAC DEXKETOPROFEN sulfide metabolite © ALG 2024 52  A 1b NON-SELECTIVE COX INHIBITORS Overall: INDOMETHACIN is more toxic than IBUPROFEN INDICATION ADVERSE EFFECT/S IBUPROFEN closure of patent higher bilirubin levels INDOMETHACIN ductus arteriosus (PDA) lower urine output in preterm infants more fluid retention This indication is limited to these 2 drugs among the NSAIDs © ALG 2024 53  A 1b NON-SELECTIVE COX INHIBITORS PIROXICAM long half-life 4. MEFENAMIC of 57 hours but higher FENAMATE ACID incidence of GI bleeding 6. ENOLCARBOX PIROXICAM AMIDE derivatives 5. PHENYL ACETIC DICLOFENAC multiple ACID derivatives 7. PYRROLE formulations; more ALKANOIC TOLMETIN hepatotoxic than others ACID derivatives DICLOFENAC KETOROLAC TOLMETIN rarely used, short half-life of 1-2 h; KETOROLAC analgesia not effective for gout only; more nephrotoxic © ALG 2024 54  A. A NSAIDs 1. NON-SELECTIVE COX INHIBITORS a) SALICYLATES i. ASPIRIN (ACETYLSALICYLIC ACID; ASA) ii. NON-ACETYLATED SALICYLATES b) NEWER NON-SELECTIVE COX INHIBITORS 2. SELECTIVE COX-2 INHIBITORS © ALG 2024 55  A2 SELECTIVE COX-2 INHIBITORS “coxibs” (e.g., celecoxib, etoricoxib*, parecoxib*) *not FDA-approved in USA, but available in PH inhibit pain & inflammation induced by COX-2 PGE2 & PGI2 without affecting COX-1 in platelets, GIT, kidneys. ∴ ↑ GIT safety inhibit endothelial COX-2 PGI2 which if present would have countered the platelet aggregation mediated by COX-1 TXA2 ∴ (-) cardioprotection © ALG 2024 56  A2 SELECTIVE COX-2 INHIBITORS One report: ↑ incidence of acute pancreatitis 1. 2. BENZENE CELECOXIB PYRANO- SULFON INDOLE ETODOLAC AMIDE 10-20x more SELECTIVE ACETIC ACID derivative for COX-2 “PREFERENTIAL” COX-2 INHIBITORS prefers COX-2 over COX-1 Indications: osteoarthritis, rheumatoid arthritis, juvenile RA 3. ENOLCARBOX AMIDE MELOXICAM Adverse Effects: Fewer GI symptoms derivative inhibits COX-1 TXA2 but not enough than non-selective COX inhibitors to inhibit platelet function © ALG 2024 57  A2 IMBALANCE by COX-2 INHIBITORS COX-2 PGI2 THROMBOSIS COX-1 TXA2 © ALG 2024 58  A CHOICE OF NSAID: EFFICACY All NSAIDs are equally efficacious. Few exceptions: Tolmetin : not effective for gout Aspirin : o less effective for ankylosing spondylitis o not for gout o not for fever in children with viral infections © ALG 2024 59  A CHOICE OF NSAID: SAFETY Surveys on toxicity of non-selective NSAIDs: indomethacin and tolmetin = most toxic salsalate, aspirin, ibuprofen = least toxic diclofenac and sulindac = liver function test abnormalities ketorolac = more nephrotoxic Choice of NSAID for patients with renal insufficiency: nonacetylated salicylates high risk for GI bleed: celecoxib, OR low dose non-selective NSAID + omeprazole high risk for CV disease: non-selective NSAID © ALG 2024 60  A CHOICE OF NSAID: ESSC “The choice of an NSAID requires a balance of efficacy, safety, cost-effectiveness, and suitability numerous personal factors (e.g., other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no best NSAID for all patients.” © ALG 2024 61  OTHER ANALGESICS B  B OTHER ANALGESICS 1. PARACETAMOL / ACETAMINOPHEN 2. KETOROLAC – NSAID 3. TRAMADOL – WEAK OPIOID © ALG 2024 63  B 1 PARACETAMOL / ACETAMINOPHEN UK USA para-aminophenol derivative active metabolite of phenacetin (withdrawn in 1983 due to nephrotoxicity) one of the most important drugs used to treat mild to moderate pain when an anti-inflammatory effect is not necessary MOA: weak COX-1 and COX-2 inhibitor in peripheral tissues. Its antinociceptive effects are also due to interactions with the endogenous opioid, cannabinoid, and serotonergic systems. NO significant Therapeutic Effects: Analgesia, Antipyresis anti-inflammatory effects effect on platelet function effect on uric acid levels © ALG 2024 64  B 1 Indications of PARACETAMOL acute pain & fever: pedia 10-15 mg/kg/dose adult 325-500 mg q4-q6 (max: 4 g/day) mild to moderate pain (e.g., headache, myalgia, postpartum pain) o paracetamol has been combined with NSAID for better pain control, but can potentiate GI toxicity of NSAID For mild pain, paracetamol is preferred to aspirin in patients: ✓ who are allergic to aspirin or unable to tolerate aspirin ✓ with hemophilia, or history of peptic ulcer ✓ in whom bronchospasm is precipitated by aspirin ✓ children with fever © ALG 2024 65  B 1 PARACETAMOL / ACETAMINOPHEN Available preparations: oral, IV, rectal (suppository) Pharmacokinetics: o A: peak plasma in 30–60 mins (oral administration) o D: poorly bound to plasma proteins o M: partially metabolized by liver microsomal enzymes to inactive sulfate and glucuronide o E: 2x increase in liver disease); relatively unaffected by renal function © ALG 2024 66  B 1 Metabolism of PARACETAMOL RECAP/EMPHASIS: o 95% is metabolized by liver microsomal enzymes to nontoxic metabolites (sulfate and glucuronide) o < 5% excreted unchanged in urine o Remainder undergoes CYP450 metabolism and is converted to a highly reactive metabolite (N-acetyl-p-benzoquinone imine NAPQI), which is neutralized in the liver by glutathione conjugation. Consider paracetamol poisoning. In large doses, glutathione will be depleted, NAPQI accumulates and damages the liver. Antidote: N-acetylcysteine (NAC) © ALG 2024 67  B 1 METABOLISM of PARACETAMOL NONTOXIC NONTOXIC sulfhydryl groups Antidote: N-acetylcysteine within 8-10 hours (NAC) TOXIC sulfhydryl groups oxidative NONTOXIC stress © Tittarelli et al. 2017 HEPATOTOXICITY Eur Rev Med Pharmacol Sci © ALG 2024 68  B 1 In case of LIVER DISEASE, MALNUTRITION, ALCOHOLISM REDUCE dose or AVOID use of paracetamol NONTOXIC NONTOXIC sulfhydryl groups CYP-450 TOXIC oxidative NONTOXIC stress © Tittarelli et al. 2017 HEPATOTOXICITY Eur Rev Med Pharmacol Sci © ALG 2024 69  B 1 Hepatotoxicity of PARACETAMOL Therapeutic doses: mild reversible ↑liver enzymes 4 g may cause liver function test abnormalities 7 g (adult), 150-200 mg/kg (pedia) → potential toxicity 15 g may be fatal, death being caused by severe hepatotoxicity (centrilobular necrosis) + acute renal tubular necrosis Early symptoms of hepatic damage include nausea, vomiting, diarrhea, and abdominal pain (GIT). High doses: can promote oxidative stress and damage cells in the brain (hepatic encephalopathy: drowsiness, confusion, disorientation) Overdose can cause renal failure after significant hepatic impairment (hepatorenal syndrome) © ALG 2024 70  B 1 Adverse Effects of PARACETAMOL Usual doses: cases of renal damage without hepatic damage (but not to the extent of interstitial nephritis or papillary necrosis – serious AEs of phenacetin) Very rare: hemolytic anemia, methemoglobinemia, anaphylaxis, serious skin reactions © ALG 2024 71  B OTHER ANALGESICS 1. PARACETAMOL / ACETAMINOPHEN 2. KETOROLAC – NSAID 3. TRAMADOL – WEAK OPIOID © ALG 2024 72  B 2 KETOROLAC analgesic NSAID MOA: inhibitor of COX-1 and COX-2, but used exclusively as an analgesic Indications: adjuvant with opioids, other nonopioid analgesics, or local anesthetics for short-term treatment of mod-to-severe pain, postop pain Pharmacokinetics: It can be administered IV, IM, intranasally, orally, or as an ophthalmic; it has a half-life of 5–6 hours. It is partly metabolized by the liver and about 90% is excreted by the kidneys, with 60% unchanged. Adverse Effects: similar to those of other NSAIDs. Renal toxicity is more common with chronic use. It has less toxicity than morphine, but its use should not exceed 5 days. All doses should be halved in those older than 65, with a body mass less than 50 kg, or with renal impairment. © ALG 2024 73  B OTHER ANALGESICS 1. PARACETAMOL / ACETAMINOPHEN 2. KETOROLAC – NSAID 3. TRAMADOL – WEAK OPIOID © ALG 2024 74  B 3 TRAMADOL weak opioid analgesic MOA: centrally acting synthetic analgesic with a weak affinity for μ-opioid receptors. It also acts on serotonin (5-HT) and norepinephrine receptors by reuptake inhibition. Indications and Dosage: acute and chronic pain at 50-100 mg q8 IV or oral (capsule or tablet or in combination with paracetamol, up to 300 mg/day) FEWER adverse effects and LOWER addiction potential than classic opioids o Most common AEs (initial Tx period): nausea, vomiting, vertigo, dizziness, tiredness, sedation, dry mouth, constipation, sweating o Other AEs: serotonin syndrome (when combined with antidepressants), seizures (use with caution in patients with history), exacerbated anticoagulant effect, angioedema © ALG 2024 75 © ALG 2024 76 DRUGS USED IN C GOUT  GOUT metabolic disease characterized by: recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage uric acid renal calculi, tophi, interstitial nephritis © CREAKYJOINTS.ORG © ALG 2024 78  HYPERURICEMIA & GOUT serum uric acid > 6.8 mg/dL Most individuals with hyperuricemia never develop clinical symptoms of gout. The efficacy of long-term drug treatment in a patient with asymptomatic hyperuricemia person is unproven. However, gout is associated with hyperuricemia; its deposits of monosodium urate are formed by uric acid and sodium ions. © ALG 2024 79  HYPERURICEMIA & GOUT There are data suggesting a clear relationship between the degree of uric acid elevation and the likelihood of clinical gout, BUT in some individuals, uric acid levels may be elevated up to 2 standard deviations above the mean for a lifetime without adverse consequences. © ALG 2024 80  GOUTY JOINT NLRP3 activation KATZUNG 2024 FIGURE 36–5 © ALG 2024 81  PRIMARY THERAPEUTIC GOALS IN PATIENTS WITH GOUT 1. RELIEVE ACUTE GOUTY ATTACKS 2. PREVENT RECURRENT GOUTY EPISODES 3. PREVENT URATE LITHIASIS © ALG 2024 82  PATIENT NONCOMPLIANCE Many different agents have been used for the treatment of acute and chronic gout. However, nonadherence to these drugs is exceedingly common; adherence has been documented to be 18–26% in younger patients. Providers should be aware of compliance as an important issue. © ALG 2024 83  C DRUGS USED IN GOUT 1. Acute Gout 2. Intercritical & Chronic Gout a) NSAIDs a) NSAIDs b) COLCHICINE b) COLCHICINE c) Glucocorticoids c) ALLOPURINOL d) FEBUXOSTAT e) PROBENECID f) PEGLOTICASE © ALG 2024 84  C 1a NSAIDs ibuprofen, indomethacin, naproxen MOA: inhibit phagocytosis of urate crystal inhibit PG synthesis to reduce inflammation/pain in acute gout flare Indication: All NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes. All effective and safe. Adverse Effects: GIT, CVS, renal, etc. EXCEPTION: aspirin is not used for gout because it causes renal retention of uric acid at lower doses (≤2.6 g/day); uricosuric at doses >3.6 g/day © ALG 2024 85  C 1b COLCHICINE alkaloid isolated from the autumn crocus, Colchicum autumnale. MOA: o main: binds to tubulin and prevents its polymerization into microtubules, resulting in inhibition of leukocyte migration and phagocytosis (ANTI-INFLAMMATORY) o disrupts the function of caspase-1-activating cryopyrin inflammasome such as NLRP3 (thus decreasing formation of IL-1β and IL-18), inhibits formation of LTB4, decreases levels of IFN-α and IL-6, and decreases TNF-α receptor expression on macrophages ↓ INFLAMMATORY MEDIATORS © ALG 2024 86  C 1b Indications of COLCHICINE acute gout (1 mg followed by 500 mcg 1 hour later, initiate treatment within 24 hours of onset, not later than 36 hours) intercritical gout (between acute attacks) for prolonged prophylaxis of flares (500 mcg TID, starting 12 hours after the initial dosing) others: pseudogout, Behçet disease, epidermolysis bullosa acquisita, leukocytoclastic vasculitis, Sweet syndrome, pericarditis, pleurisy, CAD acute Mediterranean fever for prophylaxis of attacks sarcoid arthritis, hepatic cirrhosis (mild beneficial effect) © ALG 2024 87  C 1b COLCHICINE Therapeutic Effects: relieves the pain and inflammation of gouty arthritis in 12–24 hours w/o altering urate metabolism or excretion and w/o other analgesic effects. PK: o A: good oral absorption; peak plasma levels: 2 hours o D: large volume of distribution, extensively bound to tissues o M: metabolized by CYP3A4 in the liver o E: biliary, large intestines, kidney; with half life of 9 hours © ALG 2024 88  C 1b Adverse Effects of COLCHICINE CAUTION in patients on often causes diarrhea CYP3A4 inhibitors which occasionally nausea, vomiting, abdominal pain may inhibit colchicine pharyngolaryngeal pain metabolism and increase its adverse effects. CNS symptoms (fatigue, headache), seizures hepatic necrosis, increase in LFTs Dose reductions are recommended for acute renal failure patients with hepatic or renal impairment. disseminated intravascular coagulation (rarely) hair loss, bone marrow depression, peripheral neuritis, myopathy, rhabdomyolysis, death (associated with IV) © ALG 2024 89  C 1c Glucocorticoids in ACUTE GOUT MOA: o decrease activation, proliferation, survival of various inflammatory cells o decrease the migration of neutrophils o inhibit prostaglandins and proinflammatory cytokines such as IL-1β Routes: oral (prednisone); intraarticular (triamcinolone, methylprednisolone) Indication: good alternative for patients o in whom NSAIDs or colchicine are contraindicated o with renal impairment or chronic kidney disease AEs: immunosuppression (very rare if given for 24 hours so that allopurinol is given once a day o E: renally cleared © ALG 2024 95 C 2c Katzung 2024 Figure 36–7 96  C 2c Indications of ALLOPURINOL first-line agent for the treatment of chronic gout in the period between attacks (it tends to prolong the intercritical period) during initiation of allopurinol, NSAID or colchicine should be used concurrently for 3-6 months (to prevent flare) until serum urate < 6 mg/dL in patients with gout and < 5 mg/dL in tophaceous gout Dosage: 100 mg/day, titrated upward by 100 mg/day every 2–5 weeks until serum uric acid 80% absorbed following oral administration; max concentration in 1 hour o although half-life of 4–8 hours, once-daily dosing is effective o extensively metabolized in the liver, excreted in the urine Most common AEs: liver function abnormalities, diarrhea, headache, and nausea. Like allopurinol, febuxostat can precipitate gout, so concomitant use of NSAID or colchicine should be given at the start. © ALG 2024 101  C 2d FEBUXOSTAT vs ALLOPURINOL Like allopurinol, febuxostat has: urate-lowering effect (regardless of hyperuricemia due to overproduction or underexcretion) renoprotective effect over long treatment periods Unlike allopurinol: febuxostat appears safe in patients with moderate chronic kidney disease febuxostat has a black box warning (↑ risk for CV death) © ALG 2024 102  LESINURAD: C 2e withdrawn in 2019 PROBENECID uricosuric / urate transporter 1 (URAT1) inhibitor for business reasons MOA: inhibits active transport sites for reabsorption & secretion of uric acid in the proximal convoluted tubule, ↓ net reabsorption in the PCT and overall urate burden, but does not do much for serum urate Additionally: reduces tubular secretion of penicillin (prolongs its plasma T ½) Indications: decreases the body pool of urate in patients with tophaceous gout or in those with increasingly frequent gouty attacks AE: increase in uric acid excretion → formation of renal stones, THEREFORE increase oral fluid intake to maintain high urine output Contraindications: patients who excrete large amounts of uric acid patients with known renal calculi or moderate-to-severe CKD (stage >3) © ALG 2024 103  C 2e PROBENECID PK: organic acid; completely reabsorbed by renal tubules; metabolized slowly with a terminal serum half-life of 5–8 hours Indications: Gouty patients with underexcretion of uric acid when XO inhibitor is CI or when tophi are present. Initiate 2–3 weeks after acute attack. Monotherapy or in combination with XO inhibitor. Start at 250 mg BID for 1 week → 500 mg BID AEs: GI irritation, rash, nephrotic syndrome, (rarely) aplastic anemia © ALG 2024 104  C 2f PEGLOTICASE absent in human MOA: recombinant mammalian urate oxidase (uricase; converts uric acid to allantoin – easily eliminated by kidneys) that is covalently attached to a methoxy polyethylene glycol (mPEG) to prolong the circulating half-life and diminish immunogenic responses PK: rapid-acting drug, peak effect within 24–72 hours, serum half-life 6–14 days Indication: Monotherapy and combination with methotrexate are FDA approved as urate-lowering therapy in symptomatic gout and effectively decrease tophi 8 mg IV every 2 weeks, lowers urate levels for up to 21 days after single IV infusion Pre-meds (glucocorticoid & H1 receptor blocker) prevent infusion reactions © ALG 2024 105  C 2f PEGLOTICASE for chronic refractory gout 2020 American College of Rheumatology (ACR) Guidelines: ❖optimal trial of oral medication would be appropriate prior to pegloticase due to cost differences and potential adverse effects of pegloticase. ❖Switching to pegloticase over continuing current urate-lowering therapy is strongly recommended for patients with gout for whom XO inhibitors, uricosurics, and other interventions have failed to achieve the SU target, and who continue to have frequent gout flares (≥2 flares/year) OR who have non-resolving subcutaneous tophi. © ALG 2024 106  C 2f Adverse Effects of PEGLOTICASE Gout flare can occur during the first 3–6 months (give NSAID or colchicine) Infusion reactions can be avoided (give glucocorticoid & H1RB before Tx) Combination with methotrexate: ↑efficacy + ↓most allergic reactions Other AEs: Nephrolithiasis, arthralgia, muscle spasm, h/a, anemia, nausea Less common: URTI, UTI, peripheral edema, diarrhea Avoided in patients with G6PD deficiency (potential hemolytic anemia from formation of hydrogen peroxide by uricase) © ALG 2024 107  Before I end… ▪ NSAIDs (for fever, pain, inflammation) ▪ Other analgesics: ▪ Non-selective COX inhibitors : aspirin (irreversible), ▪ Paracetamol (for fever & pain; toxic doses non-acetylated salicylates, diclofenac, ibuprofen, deplete glutathione, produce NAPQI that indomethacin, nabumetone (non-acid), naproxen, damages LIVER – antidote: N-acetylcysteine) piroxicam, sulindac, tolmetin ▪ Ketorolac: NSAID but used exclusively for ▪ Selective COX-2 inhibitors : celecoxib, etodolac, pain relief; nephrotoxic; use < 5 days only meloxicam ▪ Tramadol: weak opioid, less addicting than ▪ Black box warnings of NSAIDs: classic opioids; seizures as relative CI ▪ CVS (more with selective COX-2 inhibitors due to ▪ Drugs for acute gout: NSAIDs, colchicine, COX-2 prostacyclin inhibition) glucocorticoids ▪ GIT (more with non-selective COX inhibitors due to ▪ Drugs for chronic gout: XO inhibitors (allopurinol, COX-1 PGE inhibition) febuxostat), uricosuric (probenecid) – NSAID or colchicine during initiation to control/avoid flare ▪ Drugs for chronic refractory gout: pegloticase © ALG 2024 108 THANK YOU! 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