3220: NSAIDs

Non Steroidal Anti-inflammatory Agents

• - inhibit the synthesis of prostaglandins by inhibiting cyclooxygenase [COX]
• - Inhibit the synthesis of leukotrienes by inhibiting 5-lipooxygenase

- mostly local hormones [found everywhere in the body]

- control release of inflammatory mediators 

- mediate fecrile response in CNS

- synthesized by cyclooxygenase [COX]

- is considered the good COX

- synthesis prostaglandins in stomach [increases mucus production, protective effect on the lining of the stomach]

- synthesis of prostoglandins in kidneys [promote voasodilation and renal perfusion]

- synthesis of thromboxane [promotes platelet aggregation]

- is considered the bad COX

- synthesis prostaglandins in joints [pain and inflammation]

- synthesis of prostaglandins in brain [pain and fever]

- synthesis of prostaglandins in kidney [promote vasodilation and renal perfusion]

• - protects stomach from ulceration 
• - protective inflammatory responses to tissue
• - increase kidney profusion
• - decrease blood pressure
• - stops bleeding with injury, by causing platelet aggregation

• - increase bleeding and stomach ulcers
• - decreased pain
• - decrease flow to kidneys

• - gastric ulceration
• - inhibited platelet aggregation [bleeding]
• - decreased renal perfusion
• - pain reduction 
• - suppressed inflammation

• - pain reduction 
• - suppressed inflammation

• - dose dependent 
• - decrease inflammation [but NOT OTC doses]
• - decrease pain
• - reduce pain [analgesic]
• - reduce platelet aggregation [low-dose ASA]
• - alter GI smooth muscle activity [decreases activity]
• - decrease uterine contraction 
• - cause bronco-constriction

does not have anti-inflammatory effects

• - fever
• - inflammatory disorders like arthritis [high doses, not OTC]
• - dysmenorrhea [menstrual cramps]
• - minor pain [OTC dose]
• - vascular headaches, migraine

FALSE

• - thrombosis[ASA]
• - preventing gallstones [ASA]
• - preeclampia [ASA] - type of HTN developed during pregnancy
• - closing ductis in preterm newborns
• - decreasing risk of colon, breast cancer [COX-2 inhibitor]
• - lowering risk of diabetic rerinopathy - due to change in circulation in the eyes with diabetes

20 %

• - type 2 diabetes
• - type 1 diabetes [counteracts ACEIs]
• - hypertension
• - cirrhosis [diclodenac inc. risk of hepatoxicity]
• - bone and ligament injury [use with caution]

• includes
• 1. rhinitis: watery runny nose
• 2. nasal polyps: allergy to inhalants 
• 3. bronchospastic disease [asthma]

• - NSAIDs are cross-reactivem but do NOT ACETAMINOPHEN
• - treat with EPINEPHRINE

- can cause acute renal failure, nephrotic syndrome

- fenoprofen [Nalfon] caused 48% of cases of acute renal failure due to NSAIDs

- combo NSAID + acetaminophen more nephrotoxic than either alone [multiply effect] 

- ACEI/ARB + diuretics + NSAIDs - "triple whammy risk"

- NSAIDs + acetaminophen (> 2g daily or 6 regular strength doses) inc. risk 4x NSAID alone 

- NSAIDs +SSRIs [med that changes availability of serotonin in the body] inc. risk 12x NSAID alone

- NSAIDs + Prilosec [anacid] inc. risk 5x NSAID alone [more chance of bleeding]

• - NSAID + antacid  inc. risk 4x NSAIDS alone

- "nonselective NSAIDS and COX-2 selective inhibitors can be considered rarely, with caution, in highly selected individuals"

their ok for a SHORT while, but not for a long period of time

• - give NSAIDs with glass of water, milk, or food!
• - careful if NPO after surgery 
• - do not crush enteric coated [dumping syndrome]
• - warn no alcohol, smoking 
• - avoid with ASA allergies [remember triad]
• - avoid with high risk patients [kidney, liver, diabetes problems]
• - stop taking NSAIDs before surgical procedure, esp aspirin

- drug of choice in treating peptic ulcer disease [not systemically absorbed] [no acid rebound]

- BUT, prolonged high doses can cause hypermagnesemia 

- those taking NSAIDs have inc. hospitalization for ulcers

they do NOT prevent NSAID-induced ulcers

- 50% of those with H. pylori + low dose ASA will get ulcers

- 16% with low dose ASA get ulcers [no H. pylori] 

you should test and treat for H. pylori before starting NSAID therapy 

- misoprostol [cytotec]

- similar to prostaglandin 

- its mucotropic [produces mucus in the stomach]

- decreases/inhibits gastric acid secretion

• - diarrhea 
• - uterine stimulant, abortifacient 
• - decreased bone density 
• - spotting

cannot use while pregnant b/c it can induce labor and can also cause a miscarriage

+ first-generation NSAIDs: aspirin

+ first-generation NSAIDs: all other [ibuprofen, naproxen, etc.] OTC

+ second-generation NSAIDs: Coxibs [specific developed to only effect COX-2]

- aspirin 

• - Aspirin (low-dose) only NSAID with
• selectivity against COX-1 synthesis of thromboxane (platelet aggregation)

- Higher doses inhibit COX-1, COX-2

• - Risk GI bleeding, other bleeding
• due to irreversible COX-1 inhibition – takes 8 days for new
• platelets to f

• If a platelet gets exposed to ASA it permentally loses its ability to make cox-1
• and cox-2

- thus not being able to coagulate blood

- platelet aggregation inhibition via thromboxane [TXA2], prostacyclin 

- low dose [81mg]

- used in [post MI - second prevention], [primary prevention stroke, MI], [atrial fibrillation - also 325 mg]

- some patients with high platelet counts are resistant to antiplatelet effects of low-dose ASA

- NSAIDs cause ASA resistance 

- no simple lab test for efficacy of ASA on platelet aggregation inhibition

- platelet aggregation inhibitor for those who cannot take ASA

- for those with thrombotic stoke, TIA

- as effective as low-does ASA 

- is bioactivated by hepatic P450 3A4, 2C19

- most common cause of poisening in children

- no antidote: supportive treatments, eliminate aspirin

- causes respiratory alkylosis with metabolic compensation then hyperthermia, dehydration, respiratory depression, and respiratory acidosis 

- 

- there is NO antidote but you CAN give syrup of ipecac first to induce vomiting; charcoal after vomiting to absorb ASA

- give bicarb to alkyllinize urine, inc. excreation in urine

tinnitus or ringing of the ears

- include ibuprofen, naproxen 

- reversible COX-1 inhibition

- increase B/P, counteract antihypertensives 

- counteract ability of aspirin to inhibit platelet aggregation

- NSAIDS with analgesic efficacy ~ morphine

- not a narcotic

- 10 mg ketorolac IM ~ to 6mg morphine

- may decrease risk post-op ileus

- peptic ilceration with IM doses

- do not use more than 5 days

- PO only after IM or IV

- use with prophylactic PPI

- no greater than 40mg/day PO

- max daily IV, IM= 120 mg [60mg in elderly]

- not for post prartum: b/c of possible bleeding

- do not use patch in Rx naive pt

less gastric ulceration and bleeding

- include coxibs

- inhibit only COX-2 at first, but, lose selectivity for COX-2 with dose and time

- still associated with gastric ulcers and renal impairment 

- associated with increased risk cardiovascular events

- only celecoxib [celebrex] still on market

•Blood loss (microcytic anemia)

•Tinnitus (esp. ASA) – “salicyslism”

•Gastric ulceration (ALL routes - PO, topical, IM, enteric coated)

•Prolonged bleeding time

•Decreased gastric ETOH metabolism

• •Decreased FOLATE status (macrocytic
• anemia)

• •Inhibits synthesis prostaglandins
• in CNS

•No anti-inflammatory activity

• •Pain and fever relief efficacy
• equal or better than OTC ibuprofen, naproxen

• •HIGH doses have antiplatelet
• activity

•Wide therapeutic range

• •More risk of stomach bleeding ONLY
• when combined with NSAIDs (synergistic)

• •Overdose is leading cause liver
• failure in U.S.

• •Analgesic ceiling is 1 gram (1000
• mg) [ the amount that actually works to relieve pain]

•Nephrotoxic (kidney) ONLY with NSAIDS

about 5 days

• •Acetaminophen is Drug of Choice
• (DOC) for pain, fever in patients on warfarin

• •BUT, > 6 regular strength doses
• acetaminophen/week increases INR with inc. risk intra-cerebral bleeding in patients
• on warfarin!

4 gm

•Two metabolic paths for processing acetominophen

• •ETOH induces metabolism of
• acetaminophen to toxic metabolite

• •Glutathione detoxifies
• acetaminophen

• •Fasting depletes glutathione
• reserves

• •Those who use ETOH more than 3 x a
• day should use < 2 g acetaminophen/day

• •Day 1: Nausea, vomiting, diarrhea,
• cramps

•Early on Day 2: RELIEF

• •Later on Day 2: IRREVERSIBLE
• hepatic necrosis

•Day 3-5: DEATH

• - consume 3 + drinks/day
• - are fasting
• - take the HIV/AIDS medication AZT

• N-acetylcysteine (Mucomyst) is antidote if given within 12 hrs
• - causes vomiting oral and IV

• •Rx formulations may have no more
• than 325 mg/tablet or capsule (down from 750 mg)

•Boxed warning on label:   4g/day max., liver injury if exceeded

• •Boxed warning on label: liver
• injury if consumed with alcohol