Block 2_5 - NSAIDs Flashcards
Ibuprofen, Naproxen
- Mechanism of Action
- Pharmacokinetics
- Pharmacologic Effects
- Adverse Effects/Toxicity
- Therapeutic Applications
Propionic Derivative
- reversible inhibition of COX-1 and COX-2
- a. Ibuprofen - plasma half life 2 hrs
b. naproxen - plasma half life 14 hrs(both drugs are highly bound to plasma proteins)
- anti-inflammatory, analgesic, and anti-pyretic
4.
- GI effects, though less than seen with aspirin
- Hypersensitivity
- Kidney
- Blood
- Drug interactions
- Both - inflammatory disease and rheumatoid diseases including juvenile rheymatoid arthritis, mild to moderate pain, fever, dysmenorrhea, osteoarthritis
Ibuprofen only: iburpoefen lysine injections to induce closure of patent ductus arteriosus (PDA) in premature infants
Naproxen only - management of ankylosing spondylitis, *acute gout; tendonitis, bursitis *
Indomethacin
- Mechanism of Action
- Pharmacokinetics
- Pharmacologic Effects
- Adverse Effects/Toxicity
- Therapeutic Applications
Acetic Acid Derivative
- reversible inhibitor of COX-1, -2
- plasma half life 3 hrs
- 90% bound to plasma proteins
- anti-inflammatory, analgesic and anti-pyretic
- frequently adverse reactions; GI toxicity; CNS effect (severe frontal headache)
-
Acute gouty arthritis, acute bursitis/tendonitis, moderate to severe osteoarthritis, rheumatoid arthritis, ankylosing spondylitis
- IV form - closure of patent ductus arteriosus in neonates
- not routinely used to treat pain and fever
unalabeled/investigational use - pre-term labor
Ketorolac
- Mechanism of Action
- Pharmacokinetics
- Pharmacological Effects
- Adverse Effects/Toxicity
- therapeutic applications
Acetic Acid Derivative
- Reversible inhibitor of COX-1,-2
- absorbed orally and intramuscularly; highly plasma protein bound
- analgesic and anti-pyretic, less anti-inflammatory activity
- None
- oral, injection: short term (<5 days) management of moderate-to-severe acute pain requiring analgesia at the opioid level
**Nabumetone **
- Mechanism of Action
- Pharmacokinetics
- Pharmacological Effects
- Adverse Effects/Toxicity
- therapeutic applications
Acetic Acid Derivative
- active metabolite is a reversible inhibitor of COX-2 > COX-1
- converted to active metabolite, 6-methoxy-2-naphthylacetic acid; long half life
- analgesic, anti-inflammatory
- well tolerated; less GI effects; more “like” a COX-2 inhibitor
- osteoarthritis, rheumatoid arthritis
Piroxicam
- Mechanism of Action
- Pharmacokinetics
- Pharmacological Effects
- Adverse Effects/Toxicity
- therapeutic applications
Oxicam Derivative
- reversible inhibitor of COX-1, COX-2
- plasma half life of 50 hrs (long half life)
- 99% bound to plasma proteins - anti-pyretic, analgesic, anti-inflammatory
- GI toxicity
- symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis
- may offer advantage in treatment of osteoarthritis because of long half-life
Sulfasalazine
- Mechanism of Action
- Pharmacokinetics
- Pharmacological Effects
- Adverse Effects/Toxicity
- therapeutic applications
other salicylate -
- 5-aminosalicyclic acid (5-ASA) linked to sulfapyridine by an azo bond
- mesalamine (5-aminosalicylic acid - is the active component of sulfasalazine)
1. unclear in relation to inhibition to COX - potential sites of action:
- inhibition of production of IL-1 and TNFα
- inhibition of the lipoxygenase pathway
- scavenging of free radicals and oxidants
- inhibition of NF-kB
- oral drug delivered effectively to the distal GI tract
- given individually, 5-ASA or sylfapyridine absorbed in the upper GI tract
- azo linkage in sulfasalazine prevents absorption in the stomach and small intestine, and the individual components are not liberated for absorption until colonic bacteria have cleaved the bond
- given either as delayed-release formulation or a pH sensitive coating - anti-inflammatory - local effect in GI
-
headache, nausea, fatigue
- Allergic reactions: rash, fever, hepatitis, pneumonitis, hemolytic anemia, and bone marrow suppression
- reversibly decreases the number and motility of sperm but does not impair female fertility.
- inhibits intestinal folate absorption and is usually administered with folate - mild or moderately active ulcerative colitis
- rhematoid arthritis and akylosing spondylitis
Celecoxib
- Mechanism
- Pharmacokinetics
- Pharmacologic Effects
- Adverse Effects/Toxicity
- Contraindications
- Therapeutic Use
1. Mechanism
- inhibition of COX-2
- binds tightly to a distinct hydrophilic side pocket region on COX-2 that isn’t present in COX-1
2. Pharmacokinetics
- oral administration (peak concentration 3 hrs)
- highly bound to plasma proteins
- - metabolized by CYP 2C9 to inactive metabolite
3. Pharmacologic Effects
anti-pyretic, analgesic, anti-inflammatory
4. Adverse Effects/Toxicity
- hypersensitivity
- counterintuitive: increased risk of GI irritation, ulceration, and bleeding
- - increase risk of adverse CV thrombotic events, including MI and stroke
- anemia (rare
5. Contraindications
- pts with sulfonamide toxicity
- prior NSAID hypersenitivity
- pre-existing CV risk factors or disease
- Do not use in patients after coronary artery bypass graft surgery
- patient with deficiency in CYP2C9
6. Therapeutic Use
- signs/symptoms of rheumatoid arthritis and osteoarthritis
- treatment of primary dysmenorrhea
- acute pain management
- **reduce # of intestinal/colorectal polyps **
Aspirin Toxicity/ Adverse Effects - GI
gastric irritation wihch can lead to gastric ulcers and bleeding
mechanism: inhibition of COX-1 in GI prevents production of cytoprotective prostaglandins (PGE2, PGI2)
Aspirin Toxicity/Adverse Effects - Blood
increase bleeding time
mechanism: inhibition of COX-1 in platelet blocks production of platelet thromboxane (TXA2) and decreases platelet aggregation
Aspirin Toxicity/Adverse Effects - Hypersensitivity (intolerance to aspirin and other NSAIDs)
- bronchoconstriction, edema (increased vascular permeability) – think: leukotrienes
- cross-sensitivity with other NSAIDs
- mechanism: due to action of luekotrienes because of shunting Arachidonic Acid from COX to Lipoxygenase pathway
Aspirin Toxicity/Adverse Effects - Renal
decreased renal blood flow and GFR; salt and water retention
mechanism: inhibit COX-1 (and 2) derived vasodilatory prostaglandins (PGE2, PGI2)
note: renal perfusion more dependent on production of vasodilatory PGs in patients with congestive heart failure, chronic renal disease, or liver disease compared to normal inidividuals
Aspirin Toxicity/Adverse Effects - Pregnancy
- Fetus?
- Ductus arteriosus?
Decreased uterine contractions, may prolong labor
mechanism: inhibition of COX prevents prostaglandin (PGE2, PGF2) production necessary for cervical ripening and stimulating uterine contraction
- crosses the placenta and can affect the fetus
- intrauterine closure of ductus arteriosus without prostaglandin (PGE2) production since you are blocking COX
Aspirin toicity/Adverse Effects - Salicylism
- Mechanism
- Treatment
aspirin overdose, fatal if not treated
- initial effects: slight respiratory stimulation, N/V, tinnitus, deafness
- increased doses: confusion, fever, dehydration, electrolyte imbalance, metabolic acidosis
_Mechanism :_Saturdation of enzymes responsible for converting salicylic acid to inactive metabolites = buildup of salicylic acid (increased half life of drug)
Treatment:
- gastric lavage
- activated charcoal to prevent absorption
- replacement fluid and electrolytes
- alkalization of urine (IV bicarbonate)
Aspirin toicity/Adverse Effects - Reye’s Syndrome
What is Reye’s syndrome? - illness directly related to viral epidemics, can result in liver failure and death
- in children linked between viral infection and taking aspirin
Mechanism: mitochondrial damage?
Aspirin - Therapeutic Use
- fever (325 mg/day)
- low intensity pain (325 mg/day)
- inflammatory disorders (5-8 GRAMS/day)
- cancer
- as anti-platelet in cardiovascular disease (80 mg/day)
80 mg/day - low dose
325 mg/day → 1 gram/day - intermediate dose
5-8 grams/day - high dose
