MSK: 439 - 441 Flashcards
What pathway produces leukotrienes?
Lipooxygenase
How is arachidonic acid formed?
From membrane lipids (e.g. phosphatidylinositol) via the action of phospholipase A2
What class of drugs inhibits phospholipase A2?
Corticosteroids
What are the 2 pathways that arachidonic acid can take?
- Lipoxygenase
2. Cyclooxygenase
What drug inhibits lipoxygenase?
Zileuton
What is the intermediate between arachidonic acid and leukotrienes?
Hydroperoxides (HPETEs)
What are the four leukotrienes produced in the lipoxygenase pathway?
LTB4, LTC4, LTD4, LTE4
Differentiate LTB4, C4, D4, E4 by their effects.
LTB4 - neutrophil chemotaxis
LTC4, LTD4, LTE4 - bronchoconstriction, vasoconstriction, contraction of smooth muscle, increased vascular permeability
What do zafirlukast and montelukast inhibit?
LTC4, LTD4, LTE4
Remember they are asthma drugs so it makes sense that you would want to inhibit the leukotrienes that are increasing bronchial tone
How many cyclooxygenases are there?
COX-1, COX-2
What are the three things produced in the cyclooxygenase pathway?
- Prostacyclin (PGI2)
- Prostaglandins (PGE2, PGF2)
- Thromboxane (TXA2)
What is the intermediate between arachidonic acid and the ultimate products of the cyclooxygenase pathway?
Endoperoxides (PGG2, PGH2)
Which drugs inhibit cyclooxygenase?
- NSAIDs
- Aspirin
- Acetaminophen
- COX-2 inhibitors
What are the effects of prostacyclin?
Decreased:
- Platelet aggregation
- Vascular tone
- Bronchial tone
- Uterine tone
What are the effects of prostaglandins?
- Increased uterine tone
2. Decreased bronchial tone
What are the effects of thromboxane?
Increased:
- Platelet aggregation
- Vascular tone
- Bronchial tone
Is aspirin a selective or non-selective COX inhibitor?
Non-selective; inhibits both 1 and 2
How does aspirin inhibit COX?
Covalent acetylation
How does aspirin affect bleeding time, PT, and PTT?
Increased bleeding time until new platelets are produced (around 7 days)
No effect on PT, PTT
What category of drug does aspirin fall in?
NSAID
What are the three clinical uses for aspirin and their doses?
Low dose (< 300 mg/day): decrease platelet aggregation
Intermediate dose (300 - 2400 mg/day): antipyretic and analgesic
High dose (2400 - 4000 mg/day): anti-inflammatory
What are the two main side effects of aspirin use?
- Gastric ulceration
2. Tinnitus (CN VIII)
What can chronic use of aspirin lead to (toxicities)?
- Acute renal failure
- Interstitial nephritis
- Upper GI bleeding
When would you worry about Reye syndrome with aspirin?
In children treated with aspirin for viral infection
How can aspirin affect acid-base balance?
Can stimulate respiratory center and cause hyperventilation leading to a respiratory alkalosis
Name 5 NSAIDs that are not aspirin.
- Ibuprofen
- Naproxen
- Indomethacin
- Ketorolac
- Diclofenac
Are NSAIDs selective or non-selective COX inhibitors?
Non-selective
What are the three clinical uses for NSAIDs?
- Antipyretic
- Analgesic
- Anti-inflammatory
What can we use indomethacin for?
Close a PDA
What are 3 toxicities of NSAIDs?
- Interstitial nephritis
- Gastric ulcer
- Renal ischemia
Why are gastric ulcers a potential toxicity for NSAIDs?
NSAIDs inhibit the production of prostaglandins which normally protect the gastric mucosa
Why is renal ischemia a potential toxicity for NSAIDs?
NSAIDs inhibit the production of prostaglandins which normally vasodilate the afferent arteriole
What is celecoxib?
Selective COX-2 inhibitor
Where do we find COX-2?
Inflammatory cells and vascular endothelium
What functions does celecoxib target/spare?
Targets functions of COX 2 - inflammation and pain
Spares functions of COX 1 - maintenance of gastric mucosa, platelet function
Why is platelet function spared by celecoxib?
TXA2 production depends on COX 1
What are 3 clinical indications for celecoxib?
- Rheumatoid arthritis
- Osteoarthritis
- Patients with gastritis or ulcers
What are the 2 major toxicities of celecoxib?
- Increased risk of thrombosis
2. Sulfa allergy
For aspirin, NSAIDs, celecoxib, acetaminophen, which are reversible inhibitors and which are irreversible?
Aspirin - irreversible
NSAIDs, celecoxib, acetaminophen - reversible
Where does acetaminophen act?
Mostly in CNS; inactivated peripherally
What are the 2 clinical uses for acetaminophen?
- Antipyretic
- Analgesic
NOT anti-inflammatory
When would you preferentially use acetaminophen over aspirin?
Children with viral infection - to avoid Reye syndrome
What does an overdose of acetaminophen cause and why?
Hepatic necrosis - acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue adducts in the liver
What is the antidote for acetaminophen overdose?
N-acetylcysteine (regenerates glutathione)
What are bisphosphonates?
Pyrophosphate analogs that bind hydroxyapatite in bone and inhibit osteoclast activity
Give an example of a bisphophonate.
Alendronate (+ other -dronates)
What are 3 clinical indications for bisphosphonates?
- Osteoporosis
- Hypercalcemia
- Paget disease of bone
What are 2 toxicities of bisphosphonates?
- Corrosive esophagitis
2. Osteonecrosis of the jaw
How do you prevent corrosive esophagitis as a bisphosphonate toxicity?
Patients are advised to take the medication with water and to remain upright for 30 minutes
