MSK Drugs

Question 1

Two main pathways for arachidonic acid metabolism

Answer 1

1. Lipoxygenase –> Leukotrienes

2. COX pathways (COX-1, COX-2) –> Prostaglandins, Thromboxane

Question 2

LBT4

Answer 2

Attracts neutrophils

Question 3

LTC4, LTD4, LTE4

Answer 3

Function in bronchoconstriction, vasoconstriction, contraction of smooth muscle and increase in vascular permeability

• Target of anti-leukitriene medications in asthma

Question 4

PGI2

Answer 4

Inhibits platelet aggregation and promotes vasodilation

PGI = “Platelet Gathering Inhibitor”

Question 5

Prostaglandins (PGE2, PGF2)

Answer 5

• Increase uterine tone
• Decrease vascular tone
• Decrease bronchial tone

** Aspirin causes wheezing because these prostaglandins are blocked due to COX inhibiton so only bronchoconstriction causing leukotrienes are left

Question 6

Thromboxane

Answer 6

• Increase platelet aggregation
• Increase vascular tone
• Increase bronchial tone

Question 7

Aspirin: Mechanism

Answer 7

IRREVERSIBLY inhibits COX-1 and COX-2 by acetylation which decreases thromboxane and prostaglandins

• Increase bleeding time
• No effect on PTT, PT

Question 8

Aspirin: Clinical Use

Answer 8

Low dose (< 300 mg/day): decreased platelet aggregation

Intermediate dose (300 - 2400 mg/day): antipyretic and analgesic

High dose (2000 - 4000 mg/day): anti-inflammatory

Question 9

Aspirin: Toxicity

Answer 9

Gastric ulceration (due to COX-1 inhibition which maintains GI mucosa)

• Tinnitus
• Chronic use can lead to renal failure, interstitial nephritis and upper GI bleeding
• Reye’s syndrome when used in children for tx of viral infection
• Aspirin- induced asthma, Hyperventilation (respiratory alkalosis)

Question 10

NSAIDS

Answer 10

Ibuprofen, Naproxen, Indomethacin, Ketorolac, Diclofenac

Question 11

NSAIDs: Mechanism

Answer 11

REVERSIBLY inhibit cyclooxyenase (both COX-1 and COX-2). Block prostaglandin synthesis

Question 12

NSAIDs: Clinical Use

Answer 12

Antipyretic, analgesic, anti-inflammatory

Question 13

Tx for PDA closure

Answer 13

Indomethacin

Question 14

NSAIDs: Toxicity

Answer 14

Interstitial nephritis
Gastric ulcer
Renal ischemia (PG vasodilate afferent arteriole

Question 15

COX-2 inhibitors

Answer 15

Celecoxib

Question 16

COX-2 Inhibitors (Celecoxib) : Mechanism

Answer 16

Reversibly inhibit COX-2, which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain

• Spares GI lining (normally maintained by COX-1
• Spares platelet function as platelet normally associated with COX-1

Question 17

Celecoxib (COX-2 inhibitor): Toxicity

Answer 17

Increased risk of thrombosis (can lead to acute MI). Sulfa allergy

Question 18

Acetaminophen

Answer 18

Reversibly inhibits COX, mostly in CNS. Inactivated peripherally

Question 19

Acetaminophen: Clinical use

Answer 19

Antipyretic, Analgesic, but not anti-inflammatory. Used instead of aspirin to avoid Reye’s syndrome in children with viral infection

Question 20

Acetaminophen: Toxicity

Answer 20

Overode produces hepatic necrosis as acetaminophen depletes glutathione (which protects against free radicals) and form toxic liver tissue.

Question 21

Tx for acetaminophen overdose

Answer 21

N-acetylcysteine - regenerates glutathione depleted with acetaminophen use

Question 22

Bisphosphonates

Answer 22

ends in -dronates

Alendronate

Question 23

Bisphosphonate: Mechanism

Answer 23

• Pyrophosphate analog (critical component of hydroxyapatite in bone)
• Bind hydroxyapatite in bone
• Inhibits osteoclast activity

Question 24

Bisphosphonate: Clinical Use

Answer 24

Osteoporosis
Hypercalcemia
Paget’s disease of bone

Question 25

Bisphosphonate: Toxcity

Answer 25

``` Corrosive esophagitis (advise patients to sit up when taking) - Osteonecrosis of jaw (contraindicated during dental work) ```

Question 26

Chronic gout drugs

Answer 26

Allopurinol, Febuxostat, Probenecid, Colchicine

Question 27

Allopurinol

Answer 27

Inhibits xanthine oxidase which decreases conversion of xanthine to uric aic - Used in lymphoma and leukemia to prevent tumor lysis - associated with urate nephropathy - Increase concentrations of azathioprine and 6-MP (both normally metabolized by xanthine oxidase)

Question 28

Discuss salicylates and drug use

Answer 28

Don't give salicylates. All but high doses suppress uric acid clearance.

Question 29

Febuxosate

Answer 29

Inhibit xanthine oxidase

Question 30

Probenecid

Answer 30

Inhibits reabsorption of uric acid in PCT (also inhibits secretion penicillin)

Question 31

Colchicine

Answer 31

Binds and stabilizes tubulin to inhibit polymerixation, impairing leukocyte chemotaxis and degranulation ** GI side effects, especially if given orally

Question 32

Acute gout drugs

Answer 32

NSAIDs, Glucocorticoids (can be given orally or intraarticular)

Question 33

TNF-alpha inhibitors

Answer 33

Etanercept, Infliximab, Adalimumab

Question 34

Discuss TNF-alpha inhibitors and Infection

Answer 34

Can predispose to infection including reactivation of latent TB since TNF blockage prevents activation of macrophages and destruction of phagocytosed microbes

Question 35

Etanercept

Answer 35

Fusion protein (receptor for TNF-alpha + IG1Fc) produced by recombinant DNA - Is a decoy TNF receptor - used for Rheum Arthritis, Psoriasis, Ankylosing Spondylitis

Question 36

Infliximab, Adalimumab

Answer 36

Anti-TNF-alpha monoclonal antibody - Used for Crohn's, Rheum Arthritis, Ankylosing Spondyltis, Psoriasis