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Pharmacology Gout/OA/RA Month 3 Week 3
Pharmacology Gout Osteoarthritis and Rheumatoid Arthritis
79
Pharmacology
Graduate
07/20/2018

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Cards

Term
Nonselective NSAIDs
Definition
Ketorolac, Diclofenac, Ibuprofen, Indomethacin, Nabumetone, Aspirin, Naproxen
Term
NSAID MOA
Definition
[image]
Term
NSAID toxicities based on body system
Definition
-Central Nervous System
• Headaches
• Tinnitus
• Dizziness
-Cardiovascular
• Fluid retention, edema
• Hypertension
• Myocardial infarction (rare)
• Congestive heart failure (rare)
-Gastrointestinal
• Abdominal pain
• Dysplasia
• Nausea/vomiting
• Ulcers and/or bleeding
-Hematologic (rare)
• Thrombocytopenia
• Neutropenia
• Aplastic anemia
-Hepatic
• Abnormal liver function tests
• Liver failure (rare)
-Pulmonary
• Asthma
-Skin
• Rashes (all types)
• Pruritis
-Renal
• Renal insufficiency
• Renal failure
• Hyperkalemia
• Proteinuria
Term
Aspirin indications
Definition
-Risk reduction of:
• Transient ischemic attacks
• Unstable angina
• Myocardial infarction
• Thrombosis post CABG (coronary artery bypass graft) and stent placement
Term
Diclofenac indications
Definition
• Osteoarthritis, rheumatoid arthritis
• Ankylosing spondylitis
• Migraine
• Analgesia
Term
has toxicities of • Liver function test abnormalities
Definition
esp Diclofenac
Term
Ibuprofen indications
Definition
• Osteoarthritis, rheumatoid arthritis
• Analgesia
• Pericarditis
Term
Has toxicities of:
• Rare
• Aseptic meningitis
• Agranulocytosis
• Aplastic anemia
Definition
Ibuprofen
Term
Indomethacin MOA
Definition
• Potential inhibition of:
• Phospholipase A/C
• Decreased neutrophil migration
• Decreased T/B cell proliferation
Term
Indomethacin Indications
Definition
• Inflammatory/rheumatoid disorders
• Closure of patent ductus arteriosus • Acute gouty arthritis
• Many off-label trials
Term
Has toxicities:
• Pancreatitis
• Headache (15–25%)
• Dizziness, confusion, depression
• Renal papillary necrosis
Definition
Indomethacin
Term
Ketorlac Indivations
Definition
Analgesia, IV or Oral
Term
Has toxicities:
• Headache
• Injection site pain
• GI bleeding (>5 days of therapy)
• Renal function abnormality

-maximum duration in therapy is 5 days
Definition
Ketorolac
Term
Nabumetone Indications
Definition
Arthritis
Term
Has Toxicities:
rare:
• Pseudoporphyria
• Photosensitivity
Definition
Nabumetone
Term
Naproxen indications
Definition
• Osteoarthritis, rheumatoid arthritis
• Analgesia
• Acute gouty flare
• Migraine
• Ankylosing spondylitis
Term
Has toxicities:
• Upper GI bleeding
- Rare:
• Allergic pneumonitis
• Leukocytoclastic vasculitis
• Pseudoporphyria
Definition
Naproxen
Term
Celecoxib Indications
Definition
• Osteoarthritis
• Rheumatoid arthritis
• Acute pain
• Ankylosing spondylitis
Term
has side effects/toxicities:
• Associated with fewer ulcers
• Does not inhibit platelet aggregation
• Toxicities - Rash
Definition
Celecoxib (COX-2 selective)
Term
Indications for Meloxicam
Definition
Osteoarthritis, rheumatoid arthritis

• Note: preferential selection for COX-2 vs. COX-1
Term
Acetaminophen MOA
Definition
• Weak COX-1 and COX-2 inhibitors
• Block prostaglandin synthesis in the CNS
• No significant anti-inflammatory effects
• Major metabolites
- Nontoxic sulfate and glucoronide
- Reactive: N-acetyl-p-benzoquinone
Term
Has Toxicities:
Therapeutic doses
• Mild hepatic enzyme elevations
Larger doses
• Dizziness
• Excitement
• Disorientation
>15grams
• Severe hepatotoxicity
• Acute renal tubular necrosis
• Death
Definition
Acetaminophen/APAP
Term
APAP/Acetaminophen: Toxicity Timeline
Definition
Stage 1 (Days 0–1)
N/V
Abdominal pain
Sweating
General discomfort
Pale color

Stage 2 (Days 1– 3)
Liver injury develops
Upper right quadrant pain
Rise in LFTs

Stage 3 (Days 3– 5)
Hepatotoxicity peak
Rapid/severe liver failure
Glucose, lactate, phosphate abnormalities
Coma and death
Term
Considerations for choosing an NSAID
Definition
• Similar efficacy
• Key considerations
• Toxicities
- Indomethacin, ketorolac, diclofenac
- Celecoxib, meloxicam
• Cost-effectiveness
Term
Rheumatoid Arthritis
Definition
• Progressive immunologic disease
• Outcomes
-Systemic effects (joint)
- Shortens lifespan
- Reduces mobility and quality of life
Term
Treatment for Rheumatoid arthritis
Definition
DMARDs
Term
Rheumatoid arthritis MOA diagram
Definition
[image]
In rheumatoid arthritis, we have a pretty complicated system occurring. So first, we have some type of antigen, hypothesized, maybe a microbe. It's going to be going and attaching to the CD4 T cell. That CD4 T cell will go on to have B cell activation, macrophage activation, as well as activation of the endothelial lining. Ultimately, a series of cascading events will occur with cytokine activation, formation of auto-antibodies. Ultimately, bottom line, we're going to have pannus formation in the joints. We're going to have destruction of the bone occurring at that joint, as well as cartilage, fibrosis, as well as ankylosis occurring.

We want to prevent that from occurring. This is where our DMARDs come in, the first being methotrexate. By far, it's probably the first agent that will be prescribed by rheumatologists for the management of rheumatoid arthritis.
Term
Methotrexate: MOA
Definition
AICAR inhibits intracellular AMP deaminase ->
Increased AMP levels ->
AMP exits cell -> adenosine ->
Adenosine = inhibits inflammation

• Secondary effects on PMN chemotaxis
• Immune-inflammatory cells
- Inhibitory effects on proliferation - Increased apoptosis
• Inhibits proinflammatory cytokines
Term
Methotrexate: Indications
Definition
• Rheumatoid arthritis
• Juvenile chronic arthritis • Psoriasis
• PA
• AS
• Polymyositis
• SLE
Term
Has toxicities:
- Hematologic
• Anemia • Leukopenia
- Gastrointestinal
• Nausea • Mucosal ulcers • GI ulcerations • Stomatitis
- Hepatic
• Elevated liver function tests • Cirrhosis (rare)
- Pulmonary
• Hypersensitivity-like reaction
Definition
Methotrexate
Term
Nonbiologic DMARDs
Definition
Methotrexate, Azathioprine (a wrath of pine), Cyclosporine, Leflunomide (Left in time), Sulfasalazine, Tofacitinib (Total kit of bibs)
Term
Azathioprine: MOA
Definition
• Major metabolite = 6-thioguanine
• 6-thioguanine suppresses:
- Inosinic acid synthesis
- B-/T-cell function
- Immunoglobulin production
-IL-2 secretion
Term
Azathioprine: Indications
Definition
• Rheumatoid arthritis
• Prevention of organ transplant rejection
• PA
• Reactive arthritis
• Polymyositis
• SLE
Term
Has toxicities:
- Bone marrow suppression
- GI disturbances
- Rare
• Acute allergic reactions with: • Fever • Rash • Hepatoxicity
Definition
Azathioprine
Term
Cyclosporine: MOA
Definition
• Inhibits IL-1 and IL-2 receptor production
• Secondarily inhibits:
- Macrophage-T-cell interaction - T-cell responsiveness
• Impairs T-cell-dependent B-cell function
Term
Cyclosporine: Indications
Definition
• Rheumatoid arthritis
• SLE
• Polymyositis
• Juvenile chronic arthritis • Solid organ transplant
Term
Has Toxicities:
• Hematologic
- Leukopenia - Thrombocytopenia - Anemia
• Cardiotoxic
• Infertility
Definition
Cyclosporine
Term
Leflunomide: MOA
Definition
• Active metabolite: A77-1726
• Inhibits: dihydroorotate dehydrogenase •-Decreased ribonucleotide synthesis - Arrests cell growth in stimulated cells
• Inhibits T-cell proliferation
• Decreases production of autoantibodies by B-cells

- Secondary effects:
• Increases in IL-10 receptor mRNA
• Decreased IL-8 receptor type A mRNA
• Decreased TNF-alpha dependent nuclear factor kappa B activation
Term
Leflunomide: Indications
Definition
Rheumatoid arthritis
Term
Has Toxicities:

• Diarrhea
• Elevated LFTs
• Mild alopecia
• Weight gain
• Increased blood pressure
• Leukopenia, thrombocytopenia
• Contraindications: pregnancy
Definition
Leflunomide
Term
Sulfasalazine: MOA
Definition
• Active agent: sulfapyridine
• Suppresses T-cell response to concanavalin
• In-vitro studies show inhibition of:
- B-cell proliferation
- Inflammatory cytokine release from monocytes and macrophages
Term
Sulfasalazine: Indications
Definition
• Rheumatoid arthritis
• Juvenile chronic arthritis
• Psoriatic arthritis
• IBD
Term
Has Toxicities:
• Nausea/vomiting • Headache
• Rash
• Rare
- Hemolytic anema
- Methemoglobinemia
- Neutropenia
- Thrombocytopenia
Definition
Sulfasalazine
Term
Tofacitinib: MOA
Definition
Inhibits Janus kinase (JAK) enzymes
- JAK stimulates: • Hematopoiesis • Immune cell function
- Reduced cytokine or growth factor mediated gene expression
- Reduced intracellular immune cell activity
• Includes: CD15/56+, NK cells, serum IgG, IgM, IgA, CRP
Term
Tofacitinib: Indications
Definition
• Rheumatoid arthritis
• IBD
• Spondyloarthritis • Psoriasis
• Dry eyes
Term
Has toxicities:
• Increased infection risk
• Malignancy
- Lymphoma, lung, breast cancer
• Lipid panel changes
• Neutropenia, anemia
Definition
Tofacitinib
Term
Biologic DMARDs
Definition
T-cell modulation, B-cell cytotoxic, Anti-IL-6 Receptor Antibody, IL-1 Inhibition, TNF-a Blockade

Generally, there's five different categories of biologic DMARDs. And what are biologic DMARDs compared to non-biologic? Well, generally, these medications are large protein molecules that are often produced by recombinant DNA technology.
Term
Abatacept: MOA
Definition
[image]
T-cell modulator
The first medication class is the T-cell modulators. Here the medication is Abatacept. It's a pretty unique mechanism of action. So here we have an antigen presenting cell in the bottom left-hand corner.

It has a major histocompatibility receptor in its cell surface, as well as CD80/86 receptor. In the upper right-hand corner, we have the T-cell. It has a T-cell receptor as well as a CD28 receptor.

When these two cells combine, well, the overall result is activation, proliferation, and production of inflammatory mediators. We do not want this to occur in our rheumatoid arthritis patients. So this is where Abatacept comes in.
Abatacept will bind with CD80/86 receptor. What happens here is blockade of this activation, proliferation, and production of inflammatory mediators, just exactly what we wanted. We don't want that T-cell to be activated.
Term
Abatacept: Indications
Definition
• Rheumatoid arthritis
• PJIA
• Psoriatic arthritis
Term
Abatacept: Toxicities
Definition
• Increased risk of infection
• Infusion related reactions
• Hypersensitivity reactions
• Increased lymphoma risk
Term
Rituximab: MOA
Definition
B-cell cytotoxic
Targets CD20 B lymphocytes ->
1. Cell-mediated/complement mediated cytoxicity
2. Stimulation of cell apoptosis ->
Reduced inflammation
Term
Rituximab: Indications
Definition
• Rheumatoid arthritis (moderate-severe)
• Granulomatosis with polyangitis
• Vasculitis
Term
Rituximab: Toxicities
Definition
• Rash
• Increased risk of infection
• Hepatitis B reactivation
• Hematologic - Cytopenias
Term
Tocilizumab: MOA
Definition
Anti-IL-6 Receptor Antibody

• Binds to soluble/membrane bound IL-6 receptors
• IL-6 = proinflammatory cytokine
- Physiologic processes: • T-cell activation • Hepatic acute-phase protein synthesis • Stimulation of inflammatory processes
Term
Tocilizumab: Indications
Definition
• Rheumatoid arthritis
• SJIA (Systemic juvenile idiopathic arthritis)
• PJIA (Polyarticular juvenile idiopathic arthritis )
Term
Has Toxicities:
• Increased risk of serious infections
• Hematologic - Neutropenia, thrombocytopenia
• Lipid panel abnormalities
• Common - Headache - Hypertension - Elevated LFTs
Definition
Tocilizumab
Term
Interleukin-1 Inhibition Biologic DMARDs
Definition
Interleukin-1 is very interesting. So it was one of the first biologic DMARDs. However, it really doesn't have a clinical role anymore in the management of rheumatoid arthritis. But historically, I felt it was necessary to include in our talk of biologic DMARDs.
Term
Adalimumab: MOA
Definition
TNF-a Blockade (biggest group)
• Fully humanized IgG anti-TNF monoclonal antibody
- Prevents TNF interaction with p55 and p75 cell receptors
• End Result
- Downregulation of macrophage and T-cell
function
Term
Adalimumab: Indications
Definition
• Rheumatoid arthritis
• Plaque psoriasis
• Ulcerative colitis
• Crohn disease
• Ankylosing spondylitis
Term
Etanercept: MOA
Definition
TNF-a Blockade (biggest group)
• Recombinant fusion protein comprised of:
- Two soluble TNF p75 receptor moieties
- Fc portion of human IgG
• Binds to TNF-α and inhibits lymphotoxin α
Term
Etanercept: Indications
Definition
• Rheumatoid arthritis
• Plaque psoriasis
• Ankylosing spondylitis
• Psoriatic arthritis
Term
Infliximab: MOA
Definition
TNF-a Blockade (biggest group)
• Chimeric IgG1 monoclonal antibody:
- Binds with high affinity to TNF-α
- Prevents TNF interaction with p55 and p75 cell receptors
Term
Infliximab: Indications
Definition
• Rheumatoid arthritis
• Crohn disease
• Plaque psoriasis
• Psoriatic arthritis
• Ulcerative colitis
Term
Has Toxicities:
• Bacterial infections
• Activation of latent TB
• Reactivation of HBV
• Increased risk of skin cancer • SLE
• Antidrug antibodies
• Injection site reactions
• GI ulcers, bowel perforation
Definition
TNF-α Blockers (Adalimumab- a day of mobs, Etanercept- etan intercept, Infliximab- inflict a mob)
Term
Gout
Definition
• Metabolic disease characterized by:
- Acute arthritis in joints and cartilage • Due to monosodium urate deposits
• Usually associated with ↑ serum uric acid levels
Term
Gout: Pathophysiology
Definition
[image]

Taking a closer look at the pathophysiology of gout, you'll see that we have the synovial site. It's absorbing those urate crystals. This is going to result in an inflammatory response where we'll have prostaglandin release, and it will affect our neutrophil cells.

Then we'll also have formation of interleukin-1. And you'll see the MNP cell at the bottom. That's a macrophage. That's going to become activated. It's going to result in inflammation and pain at that specific affected joint.
So looking here at this diagram, you can see there's potentially areas where we can have interventions to reduce that inflammation. We could use colchicine to block neutrophils. We can potentially use indomethacin, which is a nonselective NSAID, to also reduce that inflammation as well, to provide some acute pain relief in our patients that are suffering with gout.
Term
Gout Management
Definition
1. Treat the acute gout attack
2. Prevent future attacks
3. Hypouricemic therapy
Term
Colchicine: MOA
Definition
Binds to intracellular tubulin in neutrophils ->
Prevents polymerization into microtubules ->
Inhibits activation, degranulation, migration, and phagocytosis ->
Reduced inflammation
Term
Colchicine: Indications
Definition
• Gout
• Flare treatment: 1.2 mg once followed by 0.6 mg one hour later
• Prophylaxis: 0.6 mg daily, twice daily • Maximum 1.2 mg/day
• Familial Mediterranean fever(FMF)
• Pericarditis(off-label)
• Postpericariotomy syndrome(off-label)
Term
Has Toxicities:
- Gastrointestinal
• Diarrhea, nausea, vomiting, abdominal pain
- Rare
• Hematologic
• Hepatic necrosis
• Acute renal failure • Peripheral neuritis • Myopathy
Definition
Colchicine
Term
Probenecid: MOA
Definition
• Inhibits reabsorption of uric acid in the proximal renal tubule
• Increased excretion of uric acid
• Reduced urate pool
- Reabsorption of tophaceous deposits
Term
Probenecid: Indications
Definition
• Gout (under excretion of uric acid)
• Prolong penicillin serum levels
Term
Has Toxicities:

• Acute gouty flare
• GI irritation
• Hematologic - Anemias - Leukopenia
• Rash
• Nephrotic syndrome • Hepatic necrosis
Definition
Probenecid
Term
Allopurinol: MOA
Definition
[image]

Allopurinol is a very popular option in the management of gout. So first off, we have allopurinol being metabolized by xanthine oxidase into alloxanthine. Then further below you'll see hypoxanthine being converted by xanthine oxidase to xanthine, which then gets further metabolized into uric acid. Well, allopurinol will come in and will block this final step of xanthine oxidase converting xanthine into uric acid. And again, alloxanthine, that's going to be the metabolite of allopurinol and the active agent that's ultimately blocking that uric acid formation.
Term
Allopurinol: Indications
Definition
• Chronic gout
• Cancer-induced hyperuricemia
Term
Has Toxicities:
• Acute gouty flare
• GI intolerance
• Hypersensitivity reaction -Drug rash
• Hepatic toxicity
• Interstitial nephritis
Definition
Allopurinol
Term
Indomethacin: MOA
Definition
• Inhibits prostaglandin synthase
• Inhibits urate crystal phagocytosis
Term
Indomethacin: Indications
Definition
• Gout
• Inflammatory/rheumatoid disorders
• Bursitis/tendonitis of the shoulder
• Acute pain
Term
Has Toxicities:
• Standard NSAIDs toxicities
• Pancreatitis
• Headache (15–25%)
• Dizziness, confusion, depression
• Renal papillary necrosis
Definition
Indomethacin
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