02-20 Anti-Inflammatory PHARM

Question 1

Physiologic/pathophysiologic mediators of acute inflammation

—which ones do what actions?

—Which are targeted by NSAIDs?

Answer 1

(see image)

NSAIDs target prostaglandins which are involved in all mechanisms:

1. vasodilation +++
2. chemotaxis +++
3. increasing vasc perm +
4. pain +

Question 2

Re-cap of arachodonic acid metabolism

• Where do non-selective NSAIDs work?
• Coxibs?
• Glucocorticoids?

Answer 2

1. Phospholipids in plasma membrane —Phospholipase A2→ arachadonic acid
2. arachadonic acid →
   
   • lipoxygenase→ leukotrienes
   • COX 1 → PGE2, PGI2 (prostacyclin), TXA2 (thromboxane)
     
     • GI Protective
   • COX 2 → PGE2, PGI2, TXA2
     
     • Anti-clot

GLucocorticoids block phospholipase A2 and COX2

NSAIDS: COX 1 & 2

Coxibs: COX 2 only

Question 3

Physiologic/homeostatic effects of cyclo-oxygenase (COX) products

Answer 3

• .GI Protection
  
  • PGE2 (Prostaglandin E2) and PGI2 (Prostacyclin) are produced in gut epithelia → G-PCRs → signal cascade ‪↓‬ activity of proton pumps
  • This is mostly mediated by COX1, thus COX2 inhibitors have fewer GI side effects
  • You can prevent GI side effects of non-Coxib NSAIDS by co-prescribing a PPI.
• Clotting
  
  • TXA2 is produced by COX1 in platelets, mediates initiation of clotting
    
    • blocking COX1 (irreveribly w/ ASA or reverisbly with other NSAIDs) therefore decreased clotting
      This can be good or bad
• Renal Effects
  
  • COX1 fxns control renal hemodynamics and GFR
  • COX2 fxns effect salt and water excretion.
  • PGE2 and PGI2 regulate renal blood flow
  • Inhib of COX fxn that:
    
    • ‪↓‬s PGE2 → Na retention, ↑ BP, ↑ wt (H2O retention) and rarely CHF
    • ↓s PGI2 → hyperkalemia and ARF

Question 4

Pathophysiologic effects of COX products

Answer 4

• Inflammation
  
  • PGE2 → vasodilates → Redness, warmth & ↑ fluid transudation across leaky capillary beds → swelling
• Pain
  
  • PGE2 accounts for pain in acute inflammation and for propagating inflammation.
    
    • It’s constituatively synthesized by COX-1.
    • But during acute inflam COX-2 gene expression ↑s and → ↑ed PGE2 prod
• Fever
  
  • Prostaglandin signaling at the hypothalamus is believed to contribute to fever.
  • Mech unknown.
  • believed to underlie NSAIDs’ anti-pyretic effects

Question 5

Introduction to NSAIDS

• Common Themes
• Uses
  
  • Mechanism?
• Side-effects
• Contra-indications
• Drug-drug interactions

Answer 5

• Common Themes
  
  • All reversible compet inhibs of COXs (except ASA) which work by blocking binding of arachadonic acid to to COX
  • Most don’t inhibit leukotriene synthesis
• Uses
  
  • Anti-pyretic
    
    • CNS COX inhib → decrease PGE2
    • Decrease IL-1 activity
  • Anti-inflammatory
    
    • Blocks COX metabolites
    • Salicylates also scavenge free radicals
  • Anti-thrombotic
    
    • Inhib (irreversibly in case of ASA) platelet COX1
    • Inhibition of COX activity in Vascular endothelia
  • Analgesic
    
    • Peripheral effects mediated through effects on inflammation
    • May inhibit pain stimuli at a subcortical site.
• Side-effects
  
• Contra-indications
  
• Drug-drug interactions
  *

Question 6

NSAID Pharmacokinetics

*

Answer 6

General Common Properties:

• Weak organic acids → Well absorbed
• Hepatic metab via CYP3A or CYP2C.
• Nearly all undergo some biliary excretion
  
  • reabsorption of which correlates w/ degree of lower GI irritation.
• Renal Excretion is the primary mode of clearance.

Question 7

NSAID ADRs

• Side effects
• Drug-Drug Interactions

Answer 7

SIDE EFFECTS

• GI toxicity is combination of acidity and COX inhibition
• Increased Bleeding
• CNS Toxicity
• Salicylism: acute aspirin toxicity
  
  • ringing in the ears, nausea, vomiting
  • Mixed acid-base disturbance
    
    • 1° resp alkalosis (b/c ↓ resp ctrs)
    • followed by concomitant 2° metab acidosis from lactic acid, metabolites, other organic acids.
  • The presence of this finding should raise the suspicion of the possibility of an aspirin overdose.
• Anaphylactic shock.
• Rare: r/o Reyes Syndrome
  
  • Children with viral fever
• Contraindicated in third trimester of pregnancy
• Fluid retention and renal distress/failure.

DRUG-DRUG INTERACTIONS

• Additive analgesia with opioids.
• Caffeine enhances kinetics slightly.
• Exacerbate GI complications of other drugs.
  
  • Caution should be excercised with patients who are taking other medications that cause GI upset.
• Anticoagulants: Excessive bleeding
• Reduce the effectiveness of diuretics and some antihypertensives
• Cimetidine can affect the metabolism (use famotidine or proton pump inhbitor).
• anti-virals: Concomitant admin (e.g. w/ cidofovir) → potential for ↑ nephrotoxicity.
  
  • D/c NSAIDs 7 days before beginning cidofovir.
• Lithium: NSAIDs interfere w/ excretion, may ↑ [Li]
• Corticosteroids

Question 8

NSAID Class: Salicylic Acid Derivatives

• Prototype example
• Preventative Effects

Answer 8

• Prototype: Aspirin
• irreversibly inhibits COX by acetylation of specific Ser moiety
  
  • 170-times more potent in inhibiting COX-1 than COX-2.

Preventative Effects

• antithrombotic: aspirin useful in reducing the risk of MI in pts w/ h/o:
  
  • myocardial infarction
  • coronary bypass
  • angioplasty
  • angina
  • stroke
  • transient ischemic attacks (TIAs)
  • peripheral vascular disease
• reduces the risk of colorectal cancer.
• may also decr progression of atherosclerosis by:
  
  • protecting LDL from oxidative modification and
  • improve endothelial dysfunction in atherosclerotic vessels.

Question 9

Para-aminophenol derivatives

• Prototype
• Uses
• Comparison w/ NSAIDs
• Toxicity
• Pregnancy?

Answer 9

Prototype = Acetaminophen

Uses

• Possesses analgesic and antipyretic activity

Comparison w/ NSAIDs

• Has no peripheral anti-inflammatory activity
• effects on platelet function.
• Fewer GI and renal negative side effects.
• Preferred analgesic/antipyretic for patients in whom aspirin is contraindicated.

Toxicity

• Acute overdose leads to dose-dependent hepatotoxicity and acute renal failure.
• Chronic ingestion may also lead to hepatotoxicity or chronic analgesic nephropathy.
  
  • Alcoholic hepatic disease, viral hepatitis or alcoholism are risk factors for acetaminophen-induced hepatotoxicity.
• Agents which induce CYP2E1 and CYP1A2 increase the risk for acetaminophen-induced hepatotoxicity.

Pregnancy

• Use during pregnancy or breast-feeding only if the benefits to the mother outweigh the potential risks to the fetus or infant.

Question 10

Indole and Indene Acetic Acids

• Prototype
• Uses
• Mechanism
• Route of Delivery Options
• Toxicity

Answer 10

Prototype

• indomethacin

Uses

• Possesses analgesic anti-inflammatory and antipyretic effects
• used primarily for tx of rheumatoid and osteoarthritis.
• In premature neonates, used to accelerate closure of PDA
  
  • reduces circulating prostaglandins that maintain the duct in a dilated state. A decrease in their production permits the ductus to close.

Mechanism

• Competitively inhibits COX-1 and COX-2, by blocking arachidonate binding.

Route of Delivery

• Can be delivered orally, rectally or intravenously.

Toxicity

• Increased adverse gastrointestinal effects are possible if indomethacin is used with other NSAIDs, ethanol, corticosteroids, or salicylates.

Question 11

Name this queen who won season 2 of Drag Race.

Answer 11

Tyra Sanchez

Question 12

Arylproprionic acids

• Prototypes
• Uses
• Pharmacokinetics

Answer 12

Prototypes

• ibuprofen, naproxen

Uses

• Indicated for the treatment of rheumatoid arthritis, osteoarthritis, and dysmenorrhea.
• Used for its antipyretic effects and for the alleviation of mild to moderate pain.

Pharmacokinetics

• Ibuprofen is administered orally and is approximately 80% absorbed from the gut.
  
  • Plasma half-life is between 2 and 4 hours. Excreted in urine, 50—60% as metabolites and approximately 10% as unchanged drug.
  • Excretion is usually complete within 24 hours of oral administration.
  • The elimination half-life of ibuprofen is significantly prolonged in patients with moderate to severe cirrhosis.

Question 13

Heteroaryl acetic acids

• Prototype
• Uses

Answer 13

Prototype = diclofenac

Uses

• Rapid-release form indicated for pain and dysmenorrhea.
• Delayed-release form approved for osteoarthritis, RA, and ankylosing spondylitis.
• 3% topical gel for treatment of actinic keratosis.
• Analgesic Activity: Diclofenac is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia).
• PgE and PgF, sensitizepain receptors; therefore, diclofenac has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
• Ophthalmic Activity:
  
  • Topically inhibits miosis by inhib synth of ocular prostaglandins.
  • In the eye, prostaglandins also have been shown to disrupt the blood-aqueous humor barrier, cause vasodilation, increase vascular permeability, promote leukocytosis, and increase intraocular pressure (IOP).
  • Doesn’t affect intraocular pressure or interfere with the action of ACh given during ocular surgery.

Question 14

Anthranilic Acids

• Prototype
• Contra-indications

Answer 14

Prototype

• Meclofenamate (does anyone use this anymore??)

Contra-Indications

• Contraindicated for patients with preexisiting renal disease or active ulceration or chronic inflammation of the upper or lower gastrointestinal tract; meclofenamate should be used with extreme caution (if al all) in these patient populations.
• Mefenamic acid should be discontinued if a rash or diarrhea develops.
• Meclofenamate should be discontinued and the patient should have a complete ophthalmologic examination if visual symptoms occur.
• Patients with hepatic impairment: Although specific guidelines are not available, dosage reduction may be necessary in patients with hepatic dysfunction.

Question 15

Enolic Acids

• Prototypes
• Pharmacokinetics
• Contraindications

Answer 15

Prototypes = meloxicam and piroxicam

Uses

• Piroxicam is indicated in the treatment of osteoarthritis and rheumatoid arthritis.

Pharmacokinetics

• Piroxicam has a long half-life and may be administered as a single daily dose, which can be an advantage over other NSAIDs.

Contraindications

• Patients with hepatic impairment: Although specific guidelines are not available, dosage reduction may be necessary in patients with hepatic impairment.
• Patients with renal impairment: Although specific guidelines are not available, dosage reduction may be necessary in patients with renal impairment.
• Piroxicam is not recommended for patients with severe renal impairment.

Question 16

Alkanones

• Prototype
• Info from drug card

Answer 16

Prototype = Nabumetone

Info from drug card

• Nabumetone is a prodrug that requires conversion to an active metabolite (6-MNA) for its anti-inflammatory, analgesic, and antipyretic activity.
• At lower doses, 6-MNA is COX-2 selective.
• 6-MNA is a competitive inhibitor of arachidonic acid binding to COX-1 and COX-2.
• Nabumetone is the only NSAID of the acetic acid class with a half-life long enough to support once daily administration.
• Nabumetone may cause fewer adverse GI effects than do other anti-inflammatory drugs in clinical use.
• Due to extensive hepatic metabolism, nabumetone should be used with caution in patients with hepatic dysfunction.

Question 17

NSAID Class: COX-2 selective inhibitors

• Prototype example
• Uses
• Toxicity

Answer 17

Prototype = celecoxib (Celebrex)

Uses

• efficacy = to other NSAIDs in RA and osteoarthritis.
• Adjuvant tx for familial adenomatous polyposis (FAP).
• Being studied in pts w/:
  
  • sporadic adenomatous polyps (SAP) of colon
  • Barrett’s
  • actinic keratosis
  • superficial bladder cancer

Toxicity

• Due to celecoxib’s specificity for the COX-2 cyclooxygenase pathway, it has the potential to cause less gastropathy and risk of GI bleeding; however, severe GI adverse events have occurred in patients receiving celecoxib.

Question 18

Selective COX-2 inhibitors Cardiovascular risks of selective COX-2 inhibitors

Answer 18

• inhibition of prostacyclin synthesis causes vascular constriction and platelet aggregation.
  
  • B/c prostacyclin:
    
    • Eases blood flow by relaxing blood vessels.
    • Prevents vascular endothelia from synthesizing adhesion molecules that serve as nucleation sites for platelet clumping.

Question 19

APAP

Answer 19

Not an NSAID

• Acetaminophen is equally effective as analgesic or antipyretic.
• COX-3 is expressed predominately in the brain. Thus, acetaminophen is effective on processes in the CNS.
• Acetaminophen is destroyed in inflamed tissue.
• Acetaminophen is not active in the periphery.
• Acetaminophen has no effect on COX-1 in platelets.
• Acetaminophen has few or no effects on the gut, kidneys, or cardiovascular system.

Question 20

Only NSAID that can be given IV or IM?

Answer 20

ketorolac (Toradol)

Question 21

Only NSAID approved to close patent PDA in neonate?

Answer 21

indomethacin

Question 22

How does the immune response mediate the transition from acute to chronic inflammation?

• Include the physiologic/pathophysiologic mediators of chronic inflammation

Answer 22

1. Key step in initiation of chronic inflammation is migration of cells to site
   a. Usu, cells leave the blood and migrate to site via leukotriene-mediated chemotaxis.
   b. First: Traverse endothelium (Leukocytes express (CAMs) which allow binding to endothelium
   c. Chemotactic cytokines (chemokines) attract additional cells to tissue
2. M0s accumulate at site at ~24 hours
   a. They predominate over neutrophils after 48 hours
   b. Include Kupfer, Alveolar, Synovial, Microglia, splenic macrophages, osteoclasts
3. M0 activation accompanied is by prod of IL1, TNFa; PGDF, FGF, CSFs (mediators of chronic inflam)
4. Ts and Bs migrate to the site after M0s.

Question 23

Diagnostic distinction between acute and chronic inflammation

Answer 23

.

Question 24

Pathophysiology of Chronic Inflammation

Answer 24

.

Question 25

Pharmacologic Strategies for Tx of Chronic Inflamm

Answer 25

.

Question 26

MTX

• Class
• MoA
• Uses
• Side-effects
• Contra-indications
• Drug-drug interactions

Answer 26

• Class = DMARD
• MoA
  
  • Inhibits folate metabolism which leads to decreased DNA synthesis.
  • Alleviates acute inflammation by acting as an immunosuppressive drug.
• Uses
  
  • Low-dose methotrexate is now first-line Rx for the tx of RA
• Side-effects
  
  • Though MTX for autoimm dzs is taken in lower doses than for cancer, ADRs e.g. hair loss, nausea, h/a, and skin pigmentation are still common
  • Common: GI distress, oral ulcerations, and progressive dose-related hepatotoxicity.
  • Rare: pulm fibrosis, hepatic fibrosis, severe hypersensitive pneumonitis in pre-existing lung dz.
• Contra-indications
  
  • Contraindicated in pregnancy, lactation, alcoholism, blood disorders, immunodeficiency.
• Drug-drug interactions
  *

Question 27

Leflunomide

• Class
• MoA
• Uses
• Side-effects

Answer 27

• Class: DMARD Immunosuppressive drug that is orally active.
• MoA
  
  • Metabolite, A77 1726, is the active compound and has long half life.
  • Major action is inhibition of dihydroorotate dehydrogenase and blockade of pyrimidine biosynthesis.
  • Prevents histamine release and COX-2 expression.
• Uses
  
  • Similar efficacy for Rheumatoid Arthritis patients as methotrexate.
• Side Effects
  
  • Similar GI side effects as Methotrexate.
  • Slightly more common hepatic side effects than Methotrexate

Question 28

Sulfasalazine

• Class
• MoA
• Uses
• Side-effects
• Contra-indications
• Drug-drug interactions

Answer 28

• Class = DMARD
  
  • Prodrug combo of sulfapyridine and 5-aminosalicylic acid (mesalamine).
• MoA
  
  • Colonic bacteria metabolize prodrug → allows accum of mesalamine w/o GI complications.
  • mesalamine inhib of arach. acid metab in bowel mucosa by inhib of COX.
    
    • also inhibits leukotriene synthesis, possibly thru inhib of lipoxygenase
  • Sulfapyridine is more active metabolite in joints
    
    • functions as a free radical scavenger.
    • Reduces tissue damage
    • blocks immune-modulatory signaling.
• Uses
  
  • UC & Crohn’s most commonly
  • Alternative for juvenile RA or women of child bearing age.
  • RA to reduce bone deterioration.
• Side-effects
  
  • More toxic than MTX or leflunomide
  • rashes, n/v, dizziness, and h/a
  • occasionally: leukopenia.
• Contra-ind
  
  • Not given to patients with sulfa drug or salicylate allergies.
• Drug-Drugs Interactions
  
  • You can give this w/ NSAIDS

Question 29

Glucocorticoids

• MoA
• Uses
• Side-effects
• Contra-indications

Answer 29

• MoA
  
  • inhibs WBC infiltration at the site
  • interferes w/ inflamm mediator fxn
  • suppresses humoral immune responses.
  • Inhib COX2 expression
  • reduction in edema or scar tissue
  • general suppression in immune response.
  • anti-inflam action thought to involve phospholipase A2 inhib proteins, or “lipocortins”
    
    • Lipocortins control biosynthesis of prostaglandins and leukotrienes by inhib arachidonic acid (their precursor)
• Uses
• Side-effects
  
  • Cushing Syndrome (hypercorticism)
  • physiological dependence due to HPA suppression
  • exert neg feedback on pit, inhibs ACTH
    
    • results in ‪↓‬ synth of endogen corticosteroids and androgens
  • Metab effects: Protein catab and diversion of AAs to glucose metab
    
    • increased need for insulin.
    • thus weight gain, visceral fat, muscle wasting and hyperglycemia.
  • cortisone and hydrocortisone → sodium and fluid retention, hypokalemia
  • ulcers
  • hypomania or acute psychosis, depression
  • Hyperhidrosis
  • Telangeictasia
• Contra-indications
  
  • Peptic ulcer
  • Heart dz or HTN w/ CHF
  • Infections (especially HSV), DM, osteoporosis
  • Psychoses
  • Hepatic dysfunction

Question 30

Actions of TNF-α

Answer 30

TNF-α = central cytokine in mediating the chronic inflam

• signaling mediated by cell surface receptors TNFR1 and TNFR2.
• TNF-α is produced in M0s and stimulates activation of T-lymphocytes and other pro-inflammatory events.

1. Induces pro-inflam cytokines (e.g. IL-1 & IL-6)
2. Enhances leukocyte migration.
3. Increases endothelial layer permeability
4. Increases synth of endothelial and WBC adhesion molecules
5. Activates PMNs and eos.
6. Stimulates prolif of synovial fibroblasts.
7. ↑ Synthesis of prostaglandins.
8. ↑s expression & release of extracellular proteases → tissue destruction and remodeling.
   
   • This is the sx that leads to the highest degree of long-term suffering and debilitation in RA patients.

Question 31

Infliximab (Remicade) and Adalimumab (Humira)

• Class
• MoA
• Pharmacokinetics
• Uses
• Contra-indications
• Drug-drug interactions
• Cost

Answer 31

Class

• Both are anti-TNF-α
• Similar drugs; main difference is that:
  
  • infliximab is composed of human constant and murine variable regions whilst
  • adalimumab is recombinant human antibody (more thoroughly humanized → greater stability of the antibody and improved clinical tolerance)
  • Pts treated w/ infliximab may develop human anti-chimeric Abs (HACA).
  • This is less likely with adalilumab.

MoA

• TNF-α is a naturally occurring cytokine that is involved in normal inflammatory and immune responses.
  
  • Activated M0s release TNF-α, which acts on chondrocytes, fibroblasts, and osteoclasts to release metalloproteinases (MMP) and other effector molecules that induce the migration of PMNs.
• Both infliximab and adalimumab neutralize TNF-α by binding to it and blocking its interaction with the p55 and p75 cell surface TNF receptors.
• ↑ [TNF-α] is found in synovial fluid of pts w/ RA
  
  • plays important role in both pathologic inflam and joint destruction

Pharmacokinetics

• Infliximab is administered IV
  
  • predom distrib w/in vasc compartment.
  • may also enter site of inflam
• Adalimumab is admin SC

Uses

• Used alone or in combo w/ MTX
• Infliximab
  
  • ankylosing spondylitis

  • Juvenile RA
  • Psoriasis
  • Psoriatic arthritis
  • RA
  • Bechet’s Syndrome
  • Crohn’s
    
    • unique to inflix
• Single infliximab infusion induces a clinical response or remission in 65% of pts w/ mod-to-severe tx-resistant Crohn’s!
• Adalimumab
  
  • ankylosing spondylitis
  • 
Juvenile RA
  • Psoriasis
  • Psoriatic arthritis
  • RA

Contra-indicaitons

• Caution should be used for patients who have recently received vaccines.

Drug-Drug

• On-going trial to determine effects of combination with anti-inflammatory steroids.

Cost

• 100 mg vial: $600.00—699.99/ea. Annual costs approach $15,000 for a patient with rheumatoid arthritis.

Question 32

etanercept (Remicade)

• Class
• Structure
• MoA
• Pharmacokinetics
• Uses
• Contra-indications
• Drug-drug interactions
• Cost

Answer 32

Class

• Anti-TNF-α

Structure

• Recombinant fusion prot: consisting of the human IgG1 heavy chain fused to the extracellular domain of TNFR1 (no light chains!)
• Favored over Infliximab of Adalimumab for treatment of chronic pain due to a longer half-life.

MoA

Pharmacokinetics

• Administered SC or IV

Uses

• Used alone or with methotrexate to manage mod-to-severe chronic inflam:
  
  • ankylosing spondylitis

  • Juvenile RA
  • Psoriasis
  • Psoriatic arthritis
  • Rheumaoid arthritis

Contra-indications

• Caution when prescribing Etanercept w/ myelosuppressive anti-rheumatic agents e.g. azathioprine, cyclophosphamide, leflunomide, or methotrexate.
  
  • These combos have been assoc’d w/ pancytopenia, incl aplastic anemia
• Caution should be used for patients who have recently received vaccines.

Drug-drug interactions
Cost

• Annual cost: $10,400 to 15,600
• NOTE: Anti-etanercept antibodies have been noted in ~16% of patients, but do not seem to interfere with efficacy or alter toxicity profile.*

Question 33

Bechet’s Syndrome

Answer 33

• Infliximab can tx
• classically characterized as a triad:
  
  1. Recurring crops of mouth ulcers (aphthous ulcers),
  2. Genital ulcers
  3. Inflammation of the uvea (area of eye around pupil) a.ka. uveitis.