MSK Drugs Flashcards
Two main pathways for arachidonic acid metabolism
- Lipoxygenase –> Leukotrienes
2. COX pathways (COX-1, COX-2) –> Prostaglandins, Thromboxane
LBT4
Attracts neutrophils
LTC4, LTD4, LTE4
Function in bronchoconstriction, vasoconstriction, contraction of smooth muscle and increase in vascular permeability
- Target of anti-leukitriene medications in asthma
PGI2
Inhibits platelet aggregation and promotes vasodilation
PGI = “Platelet Gathering Inhibitor”
Prostaglandins (PGE2, PGF2)
- 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
Thromboxane
- Increase platelet aggregation
- Increase vascular tone
- Increase bronchial tone
Aspirin: Mechanism
IRREVERSIBLY inhibits COX-1 and COX-2 by acetylation which decreases thromboxane and prostaglandins
- Increase bleeding time
- No effect on PTT, PT
Aspirin: Clinical Use
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
Aspirin: Toxicity
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)
NSAIDS
Ibuprofen, Naproxen, Indomethacin, Ketorolac, Diclofenac
NSAIDs: Mechanism
REVERSIBLY inhibit cyclooxyenase (both COX-1 and COX-2). Block prostaglandin synthesis
NSAIDs: Clinical Use
Antipyretic, analgesic, anti-inflammatory
Tx for PDA closure
Indomethacin
NSAIDs: Toxicity
Interstitial nephritis
Gastric ulcer
Renal ischemia (PG vasodilate afferent arteriole
COX-2 inhibitors
Celecoxib
COX-2 Inhibitors (Celecoxib) : Mechanism
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
Celecoxib (COX-2 inhibitor): Toxicity
Increased risk of thrombosis (can lead to acute MI). Sulfa allergy
Acetaminophen
Reversibly inhibits COX, mostly in CNS. Inactivated peripherally
Acetaminophen: Clinical use
Antipyretic, Analgesic, but not anti-inflammatory. Used instead of aspirin to avoid Reye’s syndrome in children with viral infection
Acetaminophen: Toxicity
Overode produces hepatic necrosis as acetaminophen depletes glutathione (which protects against free radicals) and form toxic liver tissue.
Tx for acetaminophen overdose
N-acetylcysteine - regenerates glutathione depleted with acetaminophen use
Bisphosphonates
ends in -dronates
Alendronate
Bisphosphonate: Mechanism
- Pyrophosphate analog (critical component of hydroxyapatite in bone)
- Bind hydroxyapatite in bone
- Inhibits osteoclast activity
Bisphosphonate: Clinical Use
Osteoporosis
Hypercalcemia
Paget’s disease of bone
Bisphosphonate: Toxcity
Corrosive esophagitis (advise patients to sit up when taking) - Osteonecrosis of jaw (contraindicated during dental work)
Chronic gout drugs
Allopurinol, Febuxostat, Probenecid, Colchicine
Allopurinol
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)
Discuss salicylates and drug use
Don’t give salicylates. All but high doses suppress uric acid clearance.
Febuxosate
Inhibit xanthine oxidase
Probenecid
Inhibits reabsorption of uric acid in PCT (also inhibits secretion penicillin)
Colchicine
Binds and stabilizes tubulin to inhibit polymerixation, impairing leukocyte chemotaxis and degranulation
** GI side effects, especially if given orally
Acute gout drugs
NSAIDs, Glucocorticoids (can be given orally or intraarticular)
TNF-alpha inhibitors
Etanercept, Infliximab, Adalimumab
Discuss TNF-alpha inhibitors and Infection
Can predispose to infection including reactivation of latent TB since TNF blockage prevents activation of macrophages and destruction of phagocytosed microbes
Etanercept
Fusion protein (receptor for TNF-alpha + IG1Fc) produced by recombinant DNA
- Is a decoy TNF receptor
- used for Rheum Arthritis, Psoriasis, Ankylosing Spondylitis
Infliximab, Adalimumab
Anti-TNF-alpha monoclonal antibody
- Used for Crohn’s, Rheum Arthritis, Ankylosing Spondyltis, Psoriasis
