Pharmacotherapy Review - OA and RA-2

NSAIDs work by inhibiting cyclooxygenases (COX), which leads to a decrease in prostaglandins. This results in a reduction of pain and inflammation.

• COX-1 inhibition: Potential renal and gastrointestinal insult.
• COX-2 inhibition: Potential for thrombus formation.

NSAIDs are used for:

1. Pain relief
2. Anti-inflammatory effects

However, they do not have any effects on disease modification or progression.

Arachidonic acid is metabolized into prostaglandins, which bind to various receptors, leading to inflammation and pain.

Corticosteroids, specifically annexin A1, inhibit the enzyme phospholipase A2, which prevents the conversion of membrane phospholipids to arachidonic acid.

NSAIDs and aspirin inhibit the activity of COX-1 and COX-2 enzymes, which are responsible for converting arachidonic acid into prostaglandins.

Thromboxane (TxA₂) leads to vasoconstriction and increased platelet aggregation, contributing to thrombosis.

Prostaglandins E₂ and I₂ provide gastric protection in the gastric mucosa.

Prostaglandins E₂ and I₂ are associated with pain and inflammation in joints.

Prostacyclin (PGI₂) causes vasodilation and decreases platelet aggregation.

COX-2 Selective NSAIDs (e.g., Celecoxib):

• Increased risk for cardiovascular (CV) events
• Decreased risk for gastrointestinal (GI) side effects

Semi-selective NSAIDs (e.g., Meloxicam, Diclofenac):

• Increased affinity for COX-2 but still retain activity for COX-1
• Use with caution in patients at increased CV risk

Nonselective NSAIDs (e.g., Ibuprofen, Naproxen):

• Decreased risk for cardiovascular (CV) events
• Increased risk for gastrointestinal (GI) side effects

Aspirin:

• Irreversible nonselective NSAID
• Cardioprotective at low doses
• Increased risk for GI side effects

Inhibition of COX-1 leads to:

• Peptic ulcers
• GI bleeding

Inhibition of COX-1 and COX-2 results in:

• Sodium and water retention
• Hypertension
• Hemodynamic acute kidney injury

COX-2 inhibition leads to:

• Increased risk of stroke
• Increased risk of myocardial infarction

PGE2 is responsible for:

• Gastric protection
• Increased mucus secretion
• Increased bicarbonate production
• Increased mucosal blood flow

Low dose aspirin irreversibly inhibits platelet COX-1, which affects platelet aggregation and vasoconstriction.

The serious cardiovascular risks associated with NSAIDs include myocardial infarction (MI) and stroke.

The gastrointestinal risks highlighted include serious gastrointestinal bleeding, ulcerations, and perforation. Elderly patients and those with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for these serious gastrointestinal events.

NSAIDs inhibit COX-1 and COX-2, resulting in decreased formation of PGE2 and PGI2. These prostaglandins are responsible for afferent arterial vasodilation. The decrease in PGE2 and PGI2 leads to vasoconstriction, which in turn causes decreased blood flow to the kidney.

The risk of NSAID Induced AKI is increased when NSAIDs are taken with other medications that can:

1. Cause AKI
2. Cause hypoperfusion to the kidney

The risk factors for NSAID induced peptic ulcer disease (PUD) include:

1. Older age: Greater than 65 years
2. History of PUD: Previous occurrences of peptic ulcer disease
3. Existing infection: Presence of H. Pylori infection
4. NSAID usage: High dose, prolonged use, and use of multiple NSAIDs
5. Concurrent medications: Use of steroids, warfarin, or clopidogrel

The addition of a Proton Pump Inhibitor (PPI) can lower the risk of NSAID induced peptic ulcer disease (PUD) by reducing gastric acid secretion, thereby providing a protective effect on the gastric mucosa.

The mechanism involves excessive production of leukotrienes C, D, and E from arachidonic acid precursors, with leukotriene E being particularly responsible for anaphylaxis.

The types of reactions include:

1. Angioedema
2. Urticaria
3. Anaphylaxis
4. Drug rash with eosinophilia and systemic symptoms (DRESS)

Patients are at increased risk if they have Samter's triad, which includes:

1. Asthma
2. Nasal polyps
3. Aspirin sensitivity

Ibuprofen is a reversible inhibitor of COX-1 and COX-2 enzymes.

Ibuprofen is used as an analgesic, anti-inflammatory, and antipyretic.

The recommended dosing for Ibuprofen is 200-600 mg orally every 4-6 hours as needed, with a maximum dosing of 3.2 grams/day.

Adverse effects of Ibuprofen include:

• Increased risk of cardiovascular events
• Gastrointestinal bleeding/ulcer
• Prolonged bleeding time
• Increase in liver function tests (LFTs)
• Acute kidney injury (AKI)

Clinical pearls for Ibuprofen include:

• It has a short half-life and is dosed every 6 hours as needed.
• Patients should be counseled to take it with food to decrease the risk of GI bleeding.

Celecoxib is a selective inhibitor of COX-2, which helps reduce inflammation and pain without affecting COX-1, thus minimizing gastrointestinal side effects.

Celecoxib is used as an analgesic and a potent anti-inflammatory medication.

For chronic pain management, Celecoxib is typically dosed at 100-200 mg PO every 24 hours. For acute pain, it is dosed every 12 hours.

The major adverse effects of Celecoxib include:

• Increased risk of cardiovascular events
• GI bleeding/ulcer
• Prolonged bleeding time
• Increase in liver function tests (LFTs)
• Acute Kidney Injury (AKI)

Clinical pearls for Celecoxib include:

1. Prescription only medication, mainly used as an anti-inflammatory.
2. Has a longer half-life, allowing for dosing every 12-24 hours.
3. Use with caution in patients with a sulfa allergy.

Naproxen works by reversibly inhibiting COX-1 and COX-2, which are enzymes involved in the inflammatory process.

Naproxen is indicated for use as an analgesic, antipyretic, and anti-inflammatory agent, and is also used for dysmenorrhea.

The recommended dosing for Naproxen is 250-500 mg PO every 12 hours as needed, with a maximum dosing of 1.5 grams per day.

Adverse effects of Naproxen include an increased risk of cardiovascular events, gastrointestinal bleeding/ulcers, prolonged bleeding time, increased liver function tests (LFTs), and acute kidney injury (AKI).

Naproxen can be obtained by prescription and over-the-counter (OTC). It is longer acting than ibuprofen but has a slower onset, which may not be ideal for acute settings.

Meloxicam exerts its effects through reversible inhibition of COX-2, which is more pronounced than its inhibition of COX-1.

• Oral (PO): 7.5 – 15 mg once daily (maximum = 15 mg/day)
• IV: 30 mg daily

Meloxicam is indicated for use as an analgesic and anti-inflammatory agent.

Common adverse effects include:

• Increased risk of cardiovascular events
• Gastrointestinal bleeding/ulcer
• Prolonged bleeding time
• Increase in liver function tests (LFTs)
• Acute Kidney Injury (AKI)

• Meloxicam has a slow onset of action.
• Other NSAIDs are recommended for acute pain management due to this slow onset.

Etodolac works by reversibly inhibiting COX-1 and COX-2, which are enzymes involved in the inflammatory process.

Etodolac is indicated for analgesic and anti-inflammatory purposes, particularly in cases of acute pain and osteoarthritis/rheumatoid arthritis (OA/RA).

The recommended dosing for Etodolac is 200 – 400 mg PO every 6-8 hours as needed, with a maximum of 1 gram per day.

The potential adverse effects of Etodolac include:

• Increased risk of cardiovascular events
• Gastrointestinal bleeding/ulcer
• Prolonged bleeding time
• Increase in liver function tests (LFTs)
• Acute kidney injury (AKI)

Some clinical pearls for Etodolac include:

• It is prescription only.
• It is not as commonly used as other NSAIDs.
• It is indicated for acute pain and osteoarthritis/rheumatoid arthritis (OA/RA).

Indomethacin works by reversibly inhibiting COX-1 and COX-2, which are enzymes involved in the inflammatory process.

Indomethacin is used as an analgesic and has potent anti-inflammatory effects.

The recommended dosing for Indomethacin immediate release capsules/suppositories is 25-50 mg BID-TID, with a maximum of 200 mg/day.

Adverse effects of Indomethacin include:

• Increased risk of cardiovascular events
• Gastrointestinal bleeding/ulcer
• Prolonged bleeding time
• Increase in liver function tests (LFTs)
• Acute kidney injury (AKI)

Clinical pearls for Indomethacin include:

• It has a short half-life and is available by prescription only.
• Supplied as oral and rectal suppositories.
• It may have more adverse effects than other NSAIDs.

Diclofenac works by reversibly inhibiting COX-1 and COX-2 enzymes, which are involved in the inflammatory process.

Diclofenac is typically used as a topical formulation such as gel, patch, or solution. For the 1% gel, a dosing card is used to measure the dose, with 2 grams corresponding to a strip 2.25 inches long, applied to the affected area.

Diclofenac is indicated for use as an analgesic and anti-inflammatory medication.

The most common adverse effect of Diclofenac is an application site reaction.

Diclofenac can be obtained by prescription (Rx) and over-the-counter (OTC). It has a slow onset of action, so other NSAIDs are recommended for acute pain management.

Ketorolac works by reversibly inhibiting COX-1 and COX-2, which are enzymes involved in the inflammatory process.

IV/IM dosing: 15-30 mg IV every 6 hours as needed (maximum 120 mg/day).
PO dosing: 10 mg PO every 4-6 hours as needed (maximum 40 mg/day).

Ketorolac is indicated for use as an analgesic and anti-inflammatory medication.

Adverse effects of Ketorolac include:

• Increased risk of cardiovascular events
• GI bleeding/ulcer
• Prolonged bleeding time
• Increase in liver function tests (LFTs)
• Acute Kidney Injury (AKI)

Key clinical pearls for Ketorolac include:

1. Short term use only (up to 5 days).
2. Avoid in renal impairment.
3. It is a highly potent NSAID, indicated only for patients with severe pain.

Aspirin irreversibly inhibits COX-1 and COX-2, leading to the inhibition of thromboxane A2 formation, which in turn inhibits platelet aggregation.

The recommended daily dosing of Aspirin is 81 mg taken orally.

Common adverse effects of Aspirin include:

• GI bleeding/ulcer
• Prolonged bleeding time
• Increase in liver function tests (LFTs)
• Acute Kidney Injury (AKI)

Clinical considerations for Aspirin use include:

• It takes >= 1 week to reconstitute platelet function.
• Use caution in patients with Gout.
• Avoid in:
  • Breastfeeding and 3rd trimester of pregnancy
  • Bleeding disorders
  • Surgery (stop 7-10 days prior)
  • Children (due to association with Reye's syndrome)

Salicylates are found in various over-the-counter products, including:

• Aspirin (acetylsalicylic acid)
• Salicylic Acid (used in wart removers and Neutrogena acne wash)
• Methyl salicylate (found in oil of wintergreen)

The toxic dose is between 150-300 mg/kg.

Toxicity affects multiple organ systems by causing:

1. Inhibition of the citric acid cycle
2. Inhibition of amino acid synthesis
3. Accumulation of organic acids

1. Uncoupling of oxidative phosphorylation
2. Increase in fatty acid metabolism
3. Increase in lactic acid and ketone production

1. Direct stimulation of CNS respiratory center
2. Hyperventilation
3. Decrease in pCO2

1. Airway, breathing, circulation: Ensure the patient has a clear airway, is breathing adequately, and has stable circulation.

2. Decontamination: Administer activated charcoal at a dose of 1 gram/kg PO (up to 50 grams), ensuring the patient is alert or mechanically ventilated with an orogastric tube.

3. Alkalinization with sodium bicarbonate: Maintain serum pH between 7.45-7.5 and urine pH between 6-8 to enhance salicylate excretion.

4. Glucose administration: Provide glucose as toxicity may decrease cerebral glucose levels, even if blood glucose levels are normal.

5. Hemodialysis: Consider hemodialysis for severe cases.

The mechanism of action of acetaminophen is not well understood, but it is thought to impair prostaglandin (PG) synthesis.

The recommended dosing for acetaminophen is 500 – 1000 mg QID as needed, with a maximum dosing of 4000 mg/day.

The major adverse effects associated with acetaminophen include hepatic toxicity/liver failure, which is contraindicated in patients with liver disease, and caution is advised in patients with chronic alcohol use. Other adverse effects include nausea and vomiting.

Some clinical pearls regarding acetaminophen use include:

• There is no risk of gastrointestinal ulceration or acute kidney failure.
• It is considered safe for pregnant and nursing mothers.

APAP toxicity is one of the leading causes of acute liver failure in the U.S., with over 100,000 overdoses and approximately 160 deaths annually, accounting for 5.4% of fatal exposures.

The toxic intermediate formed is N-acetyl-p-benzoquinoneimine (NAPQI).

The enzyme primarily responsible for the conversion of acetaminophen into NAPQI is Cytochrome P-450.

The main detoxification pathways for acetaminophen metabolism include:

1. UDP-glucuronosyltransferase (40-67%) leading to O-Glucuronide
2. Phenolsulfotransferase (20-46%) leading to sulfate conjugates
3. Glutathione-S-transferase (5-15%) leading to APAP-mercaptate for renal excretion.

Approximately 40-67% of acetaminophen is metabolized through the UDP-glucuronosyltransferase pathway.

The clinical significance of NAPQI in acetaminophen overdose is that it can cause hepatotoxicity, leading to liver damage and potentially liver failure if not treated promptly.

N-acetylcysteine (NAC) acts as a substrate/precursor of glutathione (GSH), detoxifying NAPQI to prevent hepatotoxicity.

Oral (PO) dosing regimen:

1. 140 mg/kg PO x1
2. 70 mg/kg PO every 4 hours for 17 doses

Intravenous (IV) dosing regimen:

1. 150 mg/kg IV x1
2. 50 mg/kg IV over 4 hours
3. 100 mg/kg IV over 16 hours

• Low risk medication: The risk vs benefit usually favors administration.
• Poor tasting: The oral formulation is very poor tasting.
• Timing: Maximum benefit if administered within 8 hours of ingestion; late administration may still be beneficial.

Tramadol acts as a mu-opioid receptor agonist and is a weak inhibitor of norepinephrine and serotonin reuptake.

The recommended dosing for Tramadol is 50-100 mg PO every 4-6 hours as needed, with a maximum dosing of 400 mg per day.

Common adverse effects of Tramadol include constipation, vertigo, and headache.

Contraindications for Tramadol include:

1. Significant respiratory depression
2. Gastrointestinal obstruction
3. Concomitant use within 14 days of a MAO inhibitor

Corticosteroids are non-specific anti-inflammatory agents that inhibit both the innate and adaptive immune response. They achieve this through:

• Glucocorticoids: Binding to the GC receptor inhibits pro-inflammatory mediators such as macrophages and eosinophils.
• Mineralocorticoids: Binding to the MC receptor increases sodium and water retention.

Synthetic corticosteroids differ in:

• Glucocorticoid potency: Their effectiveness in inhibiting inflammation.
• Mineralocorticoid potency: Their effectiveness in promoting sodium and water retention.
• Route of administration: The method by which they are delivered to the body, which can affect their efficacy and side effects.

Fludrocortisone has a glucocorticoid activity of 10 and a mineralocorticoid activity of 125.

Fludrocortisone has the highest mineralocorticoid activity at 125 among the listed corticosteroids.

Betamethasone has a glucocorticoid activity of 25 and a mineralocorticoid activity of 0.

Methylprednisolone has a mineralocorticoid activity of 0.5.

Equivalent Dose: 20 mg Route: IV, PO

Dexamethasone is anti-inflammatory and is used when water retention is not desirable due to its lack of mineralocorticoid activity. It is typically used for short-term severe, acute conditions.

Prednisone is suitable for long-term treatment as an anti-inflammatory and immunosuppressant due to its high glucocorticoid activity.

Equivalent Dose: 0.6 mg Route: IV, PO, Topical

• Increased Blood Pressure
• Increased Glucose Levels
• Increased Appetite
• Insomnia
• Mood Changes
• Irritability/Jitters

• Osteoporosis
• Hypertension
• Weight Gain/Round Face
• Glaucoma
• Risk of Infection
• Thinning of Skin/Bruising Easily
• Diabetes
• Hirsutism

Colchicine prevents microtubule assembly and modulates multiple pro and anti-inflammatory pathways.

The recommended dosing for colchicine is 1.2 mg at the first sign of a flare, followed by 0.6 mg in one hour, totaling 1.8 mg.

A common adverse effect associated with colchicine is diarrhea.

Colchicine does not lower uric acid levels; it is used for management of acute flare-ups and/or prevention. Additionally, watch for drug-drug interactions as it is a substrate for CYP3A4 metabolizing enzyme and p-gp, interacting with azoles, clarithromycin, HIV medications, and statins.

Allopurinol is a xanthine oxidase inhibitor that prevents the formation of uric acid. It lowers urate levels within 7-14 days.

Allopurinol is used in combination with an anti-inflammatory agent (NSAID or colchicine) for 3-6 months to prevent flare-ups in chronic gout.

The initial dosing for allopurinol is 100 mg PO daily. It should be titrated by 100 mg every 1-4 weeks until reaching a target of 400-600 mg daily, with a goal uric acid level of <6.

The primary adverse effect of allopurinol is acute cutaneous reactions.

It is important to test for the HLA-B*5801 allele prior to starting allopurinol in Southeast-Asian and African American populations.

Allopurinol is generally preferred over febuxostat in the management of chronic gout.

Febuxostat is a xanthine oxidase inhibitor that prevents the formation of uric acid.

Febuxostat is used as a second line treatment to allopurinol in chronic gout.

The recommended dosing for Febuxostat is 40 mg PO daily, with titration every 2 weeks to a maximum of 80 mg per day. The goal uric acid level is < 6 mg/dL.

Febuxostat has a black box warning linked to heart-related deaths. It is important to monitor AST/ALT levels during treatment.

• Febuxostat is more expensive ($$$$) compared to allopurinol, which is preferred as a first line treatment if possible.
• There is an increased CVD risk associated with its use.

Probenicid prevents the reabsorption of uric acid in the renal proximal tubules, promoting the excretion of uric acid.

Probenicid is generally used for chronic gout management in patients with low or normal values for urinary uric acid excretion but serum hyperuricemia.

The recommended dosing for Probenicid is 250 mg PO BID (twice a day).

Adverse effects of Probenicid include an increased risk of nephrolithiasis, rash, gastrointestinal upset, and headache.

Clinical pearls for Probenicid include:

1. Avoid in acute gout flares.
2. Avoid in sulfa allergy.
3. Avoid in patients with CrCL < 50 ml/min.

Methotrexate inhibits dihydrofolate reductase, which leads to the inhibition of proliferation of rapidly dividing cells.

Methotrexate is the first line treatment for moderate to severe disease activity in RA and studies suggest it reduces cardiovascular mortality compared to other DMARDs.

The typical dosing for Methotrexate in RA is 7.5 - 15 mg orally once weekly, with a maximum of 25 mg weekly.

Contraindications for Methotrexate include chronic liver disease, alcoholism, immunodeficiency, preexisting blood disorders, and pregnancy or breastfeeding.

The onset of action for Methotrexate is typically 2-3 weeks.

• Elevated liver enzymes (discontinue if >2 x ULN)
• Cirrhosis

• Stomatitis
• Diarrhea
• Nausea
• Vomiting

• Thrombocytopenia
• Leukopenia

• Pulmonary fibrosis
• Pneumonitis

Folic Acid 5 mg PO once weekly, taken the day after Methotrexate administration.

The mechanism of action of Hydroxychloroquine (HCQ) is poorly understood, but it may interrupt antigen-antibody interactions at inflammation sites.

Hydroxychloroquine is a first-line treatment for low disease activity in rheumatoid arthritis (RA) patients and is also used in the treatment of lupus.

The onset of action for Hydroxychloroquine in treating rheumatoid arthritis (RA) is approximately 6 weeks.

The recommended dosing for Hydroxychloroquine in RA patients is 200-400 mg daily, either as a single dose or in 2 divided doses. However, due to the risk of retinal/ocular toxicity, patients should not exceed 5 mg/kg/day of actual body weight or 400 mg, whichever is lower.

Adverse effects associated with Hydroxychloroquine include:

• Nausea/Vomiting/Diarrhea
• Retinal/Ocular toxicity
• Bone marrow suppression
• Myopathy
• Cardiomyopathy
• Hemolytic anemia
• Skin hyperpigmentation

Leflunomide inhibits pyrimidine synthesis, leading to decreased lymphocyte proliferation and modulation of inflammation.

The recommended dosing for Leflunomide in RA is 20 mg orally daily. The onset of action is approximately 1 month.

Adverse effects of Leflunomide include pancytopenia, liver toxicity, interstitial lung disease (ILD), and hypertension.

Contraindications for Leflunomide include:

1. Pre-existing liver disease
2. Pregnancy

Sulfasalazine's mechanism of action is not well understood. It is a prodrug that is cleaved to sulfapyridine, which possesses antirheumatic properties.

The typical dosing for Sulfasalazine in rheumatoid arthritis is 0.5 to 1 gram taken orally daily. The onset of action is approximately 2 months.

Common adverse effects of Sulfasalazine include:

• Nausea/Vomiting/Diarrhea (start low and titrate)
• Rash
• Discoloration of urine and skin
• Pancytopenia
• Elevated liver function tests (LFTs)

The primary contraindication for Sulfasalazine is hypersensitivity to sulfa.

TNF Alpha Inhibitors block the pro-inflammatory cytokine TNF-alpha, which plays a key role in inflammatory processes.

The available TNF Alpha Inhibitors include:

• Etanercept
• Infliximab
• Adalimumab

All are considered to have similar efficacy in treating inflammatory arthritis, both for primary and secondary treatment failure.

TNF Alpha Inhibitors are reserved for treating moderate to severe inflammatory arthritis.

Common adverse effects include:

• 30% discontinuation due to adverse effects or lack of efficacy
• Worsening or new onset heart failure
• Increased risk of infection (e.g., TB, Hep B)
• Increased risk of lymphoma

Tofacitinib is a janus kinase (JAK) inhibitor that inhibits signal transduction from pro-inflammatory cytokines and increases B cells. It is classified as a targeted synthetic DMARD.

The recommended dosing for Tofacitinib is 5 mg orally twice daily (BID) or 11 mg extended-release (ER) once daily.

The major adverse effects of Tofacitinib include:

• Increased risk of infection, malignancy, and thrombosis (DVT, PE) - noted in the US Black Box Warning.
• Immunosuppression affecting lymphocytes, neutrophils, and hemoglobin.
• Elevated liver function tests (LFTs) and lipids.
• Bradycardia.