NSAIDs Flashcards
(26 cards)
What are the major mediators of inflammation, fever and pain?
Prostaglandins
How do we deal with excess prostaglandins?
PGs act on multiple types and subtypes of of G-protein-couple receptors
- there are no good selective receptor anatgonists available
- so we deal with excess PGs by inhibiting ezymes that make them
What are PGs synthesized from?
Arachidonic acid (AA) and by cyclo-oxygenase enzymes (COX)
How do NSAIDs mediate their theraputic effects?
by inhibiting the COX enzyme that generate PGs
- this makes NSAIDs anti-inflammatory, anti-pyretic, and analgesic
COX enzymes convert AA to _____ and _____, the precursors of all other PGs adn the thromboxanes (TXs); COXs are also known as ______
- PG-G2 and PG-H2
- PG-H synthase (PGHSs)
____ is expressed:
In CNS, here it mediates fever and pain
In the stomach, where it protects the mucosal lining
In platelets, where it increases platelet aggregation and blood clotting by making TXs
COX-1
____ is expressed:
- some role in CNS to mediate pain
- in stomach, where it protects the mucosal lining
- in endothelial cells, where it decreases platelet aggregation by making prostaclyins
COX-2
____ also has an inducible isozyme:
- induced by injury, infection, other stresses
- critical enzyme for inflammation, and the key target for anti-inflammatory effects of NSAIDs
- Probaly also important in wound healing after injury or infection
COX-2
- it can irreversibly inactivate COXs in some tissues and cells by covalently acetylating the enzyme
- platelets with irreversibly inactivated COX circulate throughout the body, affecting the entire circulation, for clinical benefit
- distributed throughout the body
- 80% protein bound in plasma
Asprin
- 325 mg tablets
anti-inflammatory actions of asprin are mediated by its ______, after it has lost its ______
Salicylate metabolite
acetyl group
At low to moderate doses, salicylate is metabolized in the liver by _____, with______, and ______
Is metabolized in the liver by conjugation with glycine or glucoronic acid, with first-order kinetics, and saturable
At higher doses, salicylate is excreted unmetabolized, by ____, with ______, and a _____
by organic ion transporters (OATs) in the kidneys, with zero-order kinectics and a half-life that increases with increasing dose
- High enough dose to saturate liver metabolism and exceed renal elimination capacity are required for salicylate to achieve theraputic levels for inhibition of COX-2 and inflammation
- a longer time is need to achieve this and is associated with toxicity
How much Asprin is needed for analgesia?
- Antipyresis?
- Anti-inflammatory?
- reduce MI and stroke risk?
Analgesia–pain: 650-1000 mg (2-3 tablets)/4 hrs
Antipyresis–fever: 650-1000 mg (2-3 tablets)/4 hrs
Anti-inflammatory: 1300 mg+ (4 or more tablets)/4 hrs
MI/Stroke: 75-81 mg/day “asprin regimen”
Platelets use COX-1 to make TXs which
Increase clotting and thrombosis risk
Endothelial cells use COX-2 to make prostacylcins (PGIs) which
Decrease clotting and thrombosis risk
How do other salicylates differ from asprin?
- they share analgesic, anti-pyretic, and anti-inflammatory effects
- DO NOT share platelet-related anti-thrombotic effects and uses, becasue they are not irreversible inhibitors like asprin and do not have long-lasting effects on platelets
What are adverse effects of salicylates? (Asprin and others)
- GI–> because PGs are major protectors of the GI mucosa from acid damage, and because salicylates are acids!
- allergic reactions
- may induce asthma attacks
- Interactions with other drugs due to displacement from plasma binding proteins
- reye’s syndrome–> asprin should not be used in children under 16
- premature closure of ductus arteriosus
- renal and hepatic toxicity–> primarily with long term use
Drug group:
- effective analgesics, antipyretics, and anti-inflammatory agents
- similarly effective as asprin, with somewhat fewer side effects and less toxicity
- same mechanism as asprin, but only cause reversible and competitive inhibiton of COXs
- Specifically approved for dysmenorrhea
Propionic acid derivatives: Ibuprofen, Naproxen, others
What are some adverse effects of propionic acid derivatives like Ibuprofen and Naproxen?
- similar GI as asprin but to a lesser extent
- inpart because of higher potency, lower doses
- most prolong bleeding time–> but a short term effect do not permantly change
- bind very highly to albumin and can displace other drugs–>98% for ibuprofen
- cross-senstivity to salciylates
- reversible COX inhibitors can prevent low dose asprin from exerting its desirder anti-platelet effects –> so take 8hr before or 30 min after asprin
- 200 mg/4-6 hr for analgesia and antipresis
- 400 mg/ 4-6 hr for anti-inflammatory effects
- higher doses require a prescription
- also approved for treatment of patent ductus arteriosis
Ibuprofen (Advil, Motrin, others)
- NeoProfen for PDA
Generally 200-250 mg bid; longer half-life allows twice per day use; higher doses require a prescription
- enteric-coated delayed-release and extended release preparations, often 1/day
- additional approvals for gout and migrane
Naproxen
- Aleve, Anaprox, Naprosyn, others
- 10-20x more potent than asprin
- 25mg/ 4-6 hr
- limited use for analgesia and antipresis, except in severe cases, because of its severe side effects
- because it is so potent it will autmatically start interfering with COX2
- severe headaches, vertigo, confusion, seizures, psychosis, serious GI problems, pancreatitis, hepatitis
- mainly used in severe inflammation such as RA or gouty arthrisits–> with careful attention to toxicities
- specifically approved for PDA given IV
Indomethacin
- a selective COX 2 inhibitor
- most inflammation effects are due to COX-2, and the serious GI adverse effects are due to COX-1 inhibition, so selective COX2 inhibition should treat inflammation and reduce most serious adverse effects
- 100-200 mg bid, rapidly absorbed
- metabolized by liver, half life 12 hours
- approved for osteoarthritis, RA, juvenile idiopathic arthritis, ankylosing sponylitis, relief of acute pain and primary dysmenorrhea
- poorer than naproxen for acute pain
- metabolized by CYP 2C9 and may inhibit 2D6 in those with genetic variants
- can slow metabolism of tricyclic antidepressents, SSRIs, antiarrhythmics
Celecoxib
- Celebrex
- adverse effects:
- edema is most common–> because of kidney function due to renal roles of both COX-1 and COX-2 inhibition
- GI problems
- patients allergic to sulfonamides should not take celecoxib
- not approved for use during pregnancy
- Mechanism of action–inhibition of COXs and PG synthesis
- 325 mg tablets; typically 650-1000mg (2-3 tablets/4 hr)
- absorbed well from the GI tract, distrubted uniformly
- anaglesia and antipyresis comparable to asprin
- CNS effects like asprin–> relaxation, drowsiness, euphoria
- BUT NO ANTI-INFLAMMATORY action
Acetaminophen–Tylenol
- Asprin dangers that do not occur with acetaminophen:
- no GI, hematological, cardiovascular, respiratory, effects on acid-base balance, reye syndrom effects
- max dose: 4g/ day
- hepatic damage with chronic use
- skin rash, drug fever, mucosal lesions
