Pain, Inflammation, & Arthritis Drugs

Question 1

Rhematoid arthritis vs osteoartheritis

Answer 1

RA

Onset:

Speed: Rapid (weeks-months)

Age: Juvenile

Gender Prevalence; (Women:Men): 3:1

Joints:

Most common affected: Small joints

Symptoms: Pain, swelling, warmth, stiffness

Inflammation: Local & Systemic

Osteoarthritis:

Onset:

Speed: Slow (Years)

Age: >50

Gender Prevalence; (Women:Men): 1:1

Joints:

Most common affected: Large joints

Symptoms: Pain, bony enlargement

Inflammation: none or mild (Local)

Question 2

ID drug SoA for RA

MoA of RA:

1. Costimulation of Dendritic cells & Tcell
2. Tcell stimulation of Bcells & Macrophages
3. Macrophage secretion of cytokines;
   
   1. TNFa
   2. IL1
   3. IL6

Answer 2

1. Costimulation of Dendritic cells & Tcell: Abatacept
2. Tcell stimulation of Bcells & Macrophages: Methotrexate & Leflunomide
3. Macrophage secretion of cytokines;
   
   1. TNFa: Etanercept
   2. IL1: Anakinra
   3. IL6: Tocilizumab

Question 3

Describe the MoA of Aspiring

How do Salicylates compare?

Answer 3

Irreversible inactivation by covalent modification (acetylation) of COX1 and COX2

Salicylates are competitive inhibitors of COX

Question 4

Describe how Inhibition of COX 1 is different from COX 2

Answer 4

COX1 produces Thromboxane (TxA2) which promotes Vasoconstriction & Platelet aggregation (thrombosis)

Inhibition reduces the risk of thrombosis, but also inhibits gastroprotective effects of PGE2 & PGl2, thereby disposing to gastric ulcers & bleeding.

COX2 produces Prostacyclin (PGl2) which promotes Vasodilation & inhibits platelet aggregation

Inhibition reduces pain & inflammation, but also blocks vasodilatory & anti-platelet effects, predisposing to thrombus formation

Question 5

Aspirin toxicities w/ increasing dosage

Answer 5

80-160mg: Antiplatelet

650-975mg: Analgesic & antipyretic effects

3-6g: Antiinflammatory effect & Tinnitus

6-10g: Hyperventilation & respiratory alkalosis

10-20g: Fever, dehydration, & Metabolic acidosis

20-30g: Shock, coma, respiratory & renal failure, & death

Question 6

Describe the metabolism & hepatotoxicity of Acetaminophen

Answer 6

Normal MAJOR metabolic pathways:

Acetaminophen is converted to Sulfate & Glucuronide & excreted

Minor, toxic pathway:

Acetaminophen is converted to a toxic intermediate (via P450)

If Glutathione is present, it is tagged and renally excreted

If Glutathione is absent (used up), it is not excreted, and promotes Hepatic necrosis

Question 7

Describe the pathophysiology of Gout

Answer 7

1. Urate cyrstals form in joints
2. Synoviocytes phagocytose Urate crystals & secrete inflammatory mediators which attract & activate PMN’s & MNP’s

Drugs active in gout:

• Inhibit crystal phagocytosis
• PMN & MNP release of inflammatory mediators

Question 8

Describe Uric acid metabolism

Answer 8

1. Purines are converted to Hypoxanthine
2. Xanthine Oxidase:
   
   1. Hypoxanthine -> Xanthine
   2. Xanthine -> Plasma uric acid
3. Plasma Uric acid->
   
   1. Urate crystal deposits in joints (Gout)
   2. Renal tubule
      
      1. Resorption
      2. Secretion
   3. Excretion

Question 9

Describe SoA’s of drugs for Gout

1. Purines are converted to Hypoxanthine
2. Xanthine Oxidase:
   
   1. Hypoxanthine -> Xanthine
   2. Xanthine -> Plasma uric acid
3. Plasma Uric acid->
   
   1. Urate crystal deposits in joints (Gout)
   2. Renal tubule
      
      1. Resorption
      2. Secretion
4. Excretion

Answer 9

Allopurinol: Inhibits Xanthine Oxidase

High-dose Salicylates: Inhibits Tubular reabsorption

***Diuretics & Low-dose salicylates inhibit Tubular Secretion & makes Gout Worse

Question 10

A 52-year-old woman reports soreness in her knees and wrists that is not related to physical activity. Her physician notes that both right and left joints are affected and appear reddened and swollen. She has round, painless nodules under the skin and tells her physician that the pain is worse in the morning. The physician orders joint radiographs, a synovial fluid draw, and a blood test for rheumatic factor. All three studies come back positive for rheumatoid arthritis (RA), so the doctor prescribes celecoxib for the pain and inflammation and methotrexate to slow the progression of the disease.

Answer 10

RA is a common disease, affecting more than 2 million people in the United States; it is three times more likely to be found in women than in men. RA is an autoimmune disease that causes chronic, symmetrical inflammation of the joints. The disease can begin at any age but most often starts after age 40 and before age 60. There are two main classes of medications used in treating RA: the antiinflammatory agents, such as celecoxib, aspirin, and cortisone, used to reduce pain and inflammation; and the disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, hydroxychloroquine, and others, which promote disease remission and prevent progressive joint destruction. Newer immunomodulating DMARD agents are administered by the intravenous route and include infliximab, anakinra, adalimumab, and others. Methotrexate is the most common DMARD used to treat RA, and the use of the selective COX-2 inhibitor celecoxib is warranted given no stated history of cardiovascular disease in the patient.