NSAIDs

Question 1

What are the major mediators of inflammation, fever and pain?

Answer 1

Prostaglandins

Question 2

How do we deal with excess prostaglandins?

Answer 2

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

Question 3

What are PGs synthesized from?

Answer 3

Arachidonic acid (AA) and by cyclo-oxygenase enzymes (COX)

Question 4

How do NSAIDs mediate their theraputic effects?

Answer 4

by inhibiting the COX enzyme that generate PGs

• this makes NSAIDs anti-inflammatory, anti-pyretic, and analgesic

Question 5

COX enzymes convert AA to _____ and _____, the precursors of all other PGs adn the thromboxanes (TXs); COXs are also known as ______

Answer 5

• PG-G2 and PG-H2
• PG-H synthase (PGHSs)

Question 6

____ 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

Answer 6

COX-1

Question 7

____ 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

Answer 7

COX-2

Question 8

____ 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

Answer 8

COX-2

Question 9

• 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

Answer 9

Asprin

• 325 mg tablets

Question 10

anti-inflammatory actions of asprin are mediated by its ______, after it has lost its ______

Answer 10

Salicylate metabolite

acetyl group

Question 11

At low to moderate doses, salicylate is metabolized in the liver by _____, with______, and ______

Answer 11

Is metabolized in the liver by conjugation with glycine or glucoronic acid, with first-order kinetics, and saturable

Question 12

At higher doses, salicylate is excreted unmetabolized, by ____, with ______, and a _____

Answer 12

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

Question 13

How much Asprin is needed for analgesia?

• Antipyresis?
• Anti-inflammatory?
• reduce MI and stroke risk?

Answer 13

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”

Question 14

Platelets use COX-1 to make TXs which

Answer 14

Increase clotting and thrombosis risk

Question 15

Endothelial cells use COX-2 to make prostacylcins (PGIs) which

Answer 15

Decrease clotting and thrombosis risk

Question 16

How do other salicylates differ from asprin?

Answer 16

• 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

Question 17

What are adverse effects of salicylates? (Asprin and others)

Answer 17

• 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

Question 18

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

Answer 18

Propionic acid derivatives: Ibuprofen, Naproxen, others

Question 19

What are some adverse effects of propionic acid derivatives like Ibuprofen and Naproxen?

Answer 19

• 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

Question 20

• 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

Answer 20

Ibuprofen (Advil, Motrin, others)

• NeoProfen for PDA

Question 21

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

Answer 21

Naproxen

• Aleve, Anaprox, Naprosyn, others

Question 22

• 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

Answer 22

Indomethacin

Question 23

• 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

Answer 23

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

Question 24

• 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

Answer 24

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

Question 25

The most serious concern with acetaminophen is hepatoxicity–> what does it form?

Answer 25

A reactive electrophile metabolite that can modify and inactivate liver protiens if it is not adequalty removed by endogenous glutathione

Question 26

• a reactive sulfhydryl compound to capture reactive acetaminophen and/or replace the depleted glutathione levels
• Oral dose: 140mg/kg plus 70 mg/kg every 4 hr for 16 more doses (2-3 days)
• IV therapy: 150 mg/kg loading dose over 15-60 min; 50 mk/kg over 4 hr; 6-25 mg/kg/hr for 16 hours
• monitor blood levels and liver funciton in hospitals for 3 days
• typically an 8 hour window to prevent serious liver damage, but time window depends on level of overdose also

Answer 26

N-Acetylcysteine (Acetadote)