Pharm: NSAIDs Flashcards
aspirin
- acetylsalicylic acid (ASA)
** covalently binds COX, and is non-reversible, this is important with platelets - results in inhibiting platelet function! (provides CV protection)
- has most SE’s of GI, but also has antiplatelet effects!
provides:
1. analgesic effect
2. antipyresis
3. anti-inflammatory
4. anti-platelets
5. increased apoptosis
6. GI effects :/
7. possible kidney effects
CI: children, people with gout, women in third trimester pregnancy
ibuprofen
- Advil, Motrin - “propionic acid”
- still has platelet effects, but GI effects are diminished
Naproxen
- aleve, Naprosyn - “propionic acid”
** best tolerated drug in pain relief of morning stiffness
Ketoprofen
- orudis
- priopionic acid similar to naproxen
indomethacin
- indocin
**Indomethacin is more potent than aspirin
Very efficacious anti-inflammatory agent
***Toxicity (worse than aspirin) limits its usefulness
Not used for routine analgesia
Can be used in resistant rheumatoid disease
Suppression of uterine contraction in preterm labor and ** closure of patent ductus arteriosus **
etodolac
lodine
- NSAID, similar to indomethacin
- newest drug with lesser incidence of GI irritation
- also relatively COX2 specific
ketorolac
toradol
Potent analgesic
Weak antiinflammatory effect
***Can be used orally, IM, or IV
**Used for post-operative pain, as an alternative to opioids (not obstetrics)
Unlike opioids, it is not associated with tolerance, withdrawal effects, or respiratory depression.
celecoxib
“celebrex” selective COX-2 inhibitor
- much less GI ulcers!!!
- Do not effect platelets and bleeding time.
- Originally approved for dysmenorrhea, osteoarthritis, and rheumatoid arthritis, acute post-operative pain
- Contraindicated in aspirin allergy & 3rd trimester pregnancy (others were removed for increased MI/stroke)
acetaminophen
- tylenol : non-narcotic aneglesic (no-anti-inflammatory activity)
- Antipyretic
- Very weak anti-inflammartory activity
- Not an NSAID, not effective for inflammation
- Well tolerated, lacks GI and platelet side effects
Useful analgesic, antipyretic for children and those with contraindications to aspirin
Initial drug of choice for treatment of pain in ***osteoarthritis
Combined with opioid agonists for additive postoperative pain relief [Percocet, Lortab, Vicodin, Darvocet, Tylenol with Codeine]
Acute Overdose: can be fatal due to delayed liver damage - hepatic necrosis
analgesic
pain relief
- PGE2 sensitizes pain nerve endings to the action of bradykinin, histamine, and substance P. Aspirin blocks PGE2 formation.
- NSAIDs are mild analgesics effective against pain of low-to-moderate intensity.
- NSAIDs can be superior to opioids for relief of some forms of post-operative pain and pain associated with inflammation.
- Efficacy of pain relief provided by NSAIDs is lower than opioids.
- NSAIDS lack opiod effects of : respiratory depression, and development of physical dependence
- Pain from integumental structures is relieved but not pain from hollow viscera.
antipyretic
anti-fever
- Temperature control center in hypothalamus regulates body temperature.
- Pyrogens (cytokines) from lymphocytes lead to higher temperature set point, i.e., fever.
- Heat generation (metabolism) increases and heat loss (vasodilation) decreases.
- NSAIDs that can cross BBB effectively suppress this response.
MOA of NSAID’s
inhibit the enzyme cyclooxygenase (COX) –> results in stopping synthesis of prostaglandins (which contribute to number of inflammatory processes)
all are analgesics, antipyretics, and anti-inflammatory
COX 1 is always (constitutively) active and in all tissues
COX2 is seen in inflammatory conditions
- This enzyme is the “real” target for anti-inflammatory effects
Traditional NSAIDs non-selectively inhibit both COX-1 and COX-2.
NSAID’s vs. Aspirin
Advantages: some NSAIDs are marginally superior to aspirin because they:
- are more potent
- are more efficacious at tolerated doses.
- cause less gastrointestinal irritation or other side effects
- have longer duration of action so taken less frequently (qd or bid)
Disadvantages
- Newer NSAIDs are more expensive than aspirin
- Some are more toxic than aspirin.
anti-inflammatory effects of NSAID’s
- PGE2 and PGI2 cause vasodilation are important mediators of localized erythema and edema in inflammation. NSAIDs inhibit PG formation.
- NSAIDs inhibit activation and function of inflammatory cells, may stabilize lysosomal membranes and inhibit phagocytosis.
GI effects of NSAID’s
** increased acidity, less protection, and ulcers !!! (most commonly seen in aspirin!)
PGI2 inhibits gastric acid secretion.
PGE2 and PGF2a stimulate synthesis of bicarbonate and mucus.
PGE2 promotes mucosal blood flow.
NSAIDs inhibit all of these effects which leads to GI irritation.
GI Side effects: Epigastric distress Nausea Vomiting Microhemorrhage Ulceration Anemia
can still get this irritation from enteric coated
Effects on Platelets and the CV system?
Platelets have thromboxane synthetase and make TXA2, a potent vasoconstrictor and activator of platelet aggregation and release.
Endothelial cells make PGI2 (prostacyclin) an inhibitor of platelet aggregation and a vasodilator.
Low doses of aspirin irreversibly inhibit COX and platelet aggregation for the life of the platelet (8-11 days)
- 1 baby aspirin a day, dampens down platelet aggregation
prophylactic use of aspirin:
- coronary artery disease
- deep vein thrombosis
- unstable angina
- prophylaxis and treatment of MI and stroke
effects on the kidney
Little effect in normal subjects.
PGs normally cause vasodilation - and maintain renal blood flow in the presence of vasoconstrictors
In situations where there are high levels of circulating vasoconstrictors, e.g., compensated congestive heart failure, chronic renal disease, NSAIDs can reduce renal blood flow.
Can cause acute renal failure, Retention of sodium and water.
Reduced effectiveness of hypertensive regimens.
*** NSAIDs and COX-2s should be used with caution in patients with reduced renal function, heart failure, liver dysfunction, or in patients on ACE inhibitors or diuretics, especially elderly patients.
Reye’s syndrome
Reye’s syndrome is a rare but often fatal consequence of infection with chicken pox, varicella and influenza viruses. Liver damage and encephalopathy.
Use of aspirin and salicylates are associated with the development of Reye’s syndrome.
The use of salicylates in children or adolescents with chicken pox or influenza is contraindicated.
give kids tylenol!!!! or ibuprofen….
therapeutic uses of NSAIDs
pain and fever: Headache Dysmenorrhea Arthralgia Myalgia Neuralgia Arthritis
anti-inflammatory agents: Rheumatoid Arthritis Osteoarthritis Gout and Crystal Arthritis Systemic Lupus Erythematosus Seronegative Spondyloarthropathy Arthralgia Myalgia Bursitis, Tendonitis
- ** NSAIDs other than aspirin are typically used for chronic treatment of inflammation, e.g., ibuprofen or naproxen
- less serious GI and SE
how do NSAIDs work on dysnmenorrhea
Prostaglandins released by the endometrium during menstration contribute to severe cramps and pain.
NSAIDs have proven very effective for treatment.
PDA
patent ductus arteriosus
PGE2 keeps ductus arteriosus open following birth.
Indomethacin is the NSAID often used to stimulate closure of the patent ductus arteriosus.
FAP
familial adenomatous polyposis
reduction in number of polyps with COX-2 inhibitors
COX-2 is overexpressed in several human cancers
** Increasing evidence suggest that COX-2 inhibitors, and perhaps NSAIDs in general, may be effective for prevention or treatment of certain cancers, especially for colorectal cancer
AE’s of NSAIDs
GI irritaiton
prolonged bleeding time (anti-platelet effect)
hypersensitivity - “aspirin allergy” :
- asthma, nasal polyps, chronic urticaria predisposed
- progresses from hives, nasal secretion and edema to acute asthma attack, severe dyspnea, hypotension, and shock
- Hypersensitivity to aspirin is a contraindication to therapy with any NSAID.
reye’s syndrome
DDI’s:
- antacids
- risk of bleeding w/ anticoags
- uricosuric effect in gout pts.
toxicity of aspirin?
Salicylism - mild intoxication
nausea, vomiting,*** tinnitus, hyperventilation, headache, mental confusion, dizziness
Overdose = acute medical emergency
- fever, dehydration, delirium, hallucination, convulsions, coma, respiratory and metabolic acidosis, death
- children are especially vulnerable!
aspirin and pregnancy?
Avoid use during third trimester unless absolutely necessary
low birth weight increased perinatal mortality anemia antepartum and postpartum hemorrhage prolonged gestation premature closure of ductus arteriosus
NSAID metabolism
liver is main site of metabolism for most nsaid’s
howevere there are mixed order kinetics of aspirin - at high doses the liver conjugation pathways become saturated and zero-order kinetics of elimiatnion exist
** under zero-order conditions, small increments in dose produce disproportionate increases in plasma concentration that can lead to toxicity
