NSAIDs Flashcards
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
