NSAIDs Flashcards
NSAID characteristics
- Reduce inflammation non-specifically
o Don’t include drugs that decrease source or cause of inflammation (i.e. antibiotics) - Not steroids
- Act peripherally at site of tissue damage
- Are palliative, not curative (i.e. don’t affect course or cause of disease
- By decreasing inflammation, NSAIDs may lower body’s defense mechanisms
Prostaglandins
DRG nociceptors release substance P and promote inflammation when active.
PG do not cause pain by themselves. PGE2 and PGF2alpha sensitize pain receptors to other mediators like histamine and bradykinin, creating a feed-forward cycle of inflammation and pain
NSAIDs interrupt the feed-forward cycles of inflammation and pain. They give major pain relief through interruption of nociceptor sensitization.
Aspirin therapeutic uses
- Therapeutic uses – pain, inflammation, fever, prophylaxis against platelet aggregation
a. Prophylactically prevent of stroke and heart attack – daily baby aspirin (80mg) recommended for all men over age 45 and women over age 55
b. Irreversibly blocks COX enzyme in platelets, which have no protein synthesis -> can not make more COX -> needs to make new platelets -> takes 8-11 days for turnover and new platelets
Aspirin mechanism of action
- Mechanism of action – unique among all NSAIDs because it irreversibly inhibits COX enzymes (the acetyl group!!)
a. in periphery, inhibits COX1 and COX2 to block prostaglandin (PG) synthesis
b. in CNS, some effect on COX inhibition within the CNS, affect febrile patients only, resets temperature control center in hypothalamus
Aspirin pharmacokinetics, absorption
a. Absorption – taken orally, rapidly absorbed from stomach and small intestine
i. Rate-limiting step is disintegration and dissolution of tablet
ii. Acetylsalicylic acid has a 15-minute half-life, metabolized by gastric and plasma esterases to salicylate
- Salicylate can also block COX
iii. Salicylate distributed throughout most body fluids and tissues, easily crosses placenta
Aspirin pharmacokinetics, excretion
i. Elimination half-life of salicylate is 2-3 hrs after single analgesic dose
- Liver main site and conjugation main biotransformation
- Excretion by glomerular filtration and proximal tubular secretion in kidney
- Metabolism of salicylate is capacity limited – so large repeated doses or single toxic ingestion results in plasma half-lives of 5-30 hrs
Aspirin adverse effects
a. Gastrointestinal tract – most common and most quickly developing ADR, especially with chronic use
i. Symptoms: dyspepsia, nausea, gastric bleeding, peptic ulcers
ii. Mechanism: PGs normally mediate cytoprotective mechanisms (make mucus layer) in gastric mucosal cells to resist penetration by acid
b. Kidney
i. Acute ischemia – produced when PGI2 and PGE2 synthesis inhibited due to loss of vasodilator effect of PG on renal arterioles
ii. Chronic use of aspirin and other NSAIDs associated with nephrotoxicity
c. Blood
i. Increases bleeding time by inhibiting platelet aggregation (stop using aspirin a week before surgery)
d. Reye’s syndrome
i. Most common in 3-16 year old, during recovery from a viral infection
ii. Rapidly developing encephalopathy (20-30% fatality) and fatty degeneration of viscera
iii. Cause is unknown (probably mitochondrial dysfunction) but aspirin is statistically associated with Reye’s syndrome
- Acetaminophen should be recommended instead when children or teenagers have or have recently had a viral infection
Aspirin acute toxicity: “Salicylism”
i. Diagnosed by four early symptoms: tinnitus (ringing in ears), loss of hearing (reversible), headache, confusion -> worse, becomes respiratory stimulation and depression (dose time dependent), acid-base imbalance, coma, death
ii. Overdose treatment – most palliative and supportive
Aspirin contraindications
a. Presence of ulcers – can worsened problem, lead to ulcer
b. Compromised liver function – poor metabolism
c. Asthma – 20% of patients have intolerance to salicylates and other NSAIDs
d. Diabetes – low doses recommended
e. Gout – aspirin competes with uric acid for excretion
f. Hypocoagulation states
g. Pregnancy – prolong labor (inhibit PG synthesis), increase blood loss during dilvery, teratogenic effects possible with only very high doses
Acetaminophen (Tylenol) therapeutic uses
- Used for mild to moderate pain, most frequently used antipyretic in children, but not anti-inflammatory
- Often packaged with other drugs, like opiods or caffeine
Acetaminophen mechanism
reversibly blocks COX indirectly, mostly in the CNS
a. Effective in brain and endothelial cells – good for headache
b. Weak prostaglandin inhibitor in peripheral tissues, including platelets and immune cells
Acetaminophen toxicity
a. Acute overdose: shuts down liver
i. Accounts for 4.1% deaths from poisoning
ii. Accounts for 39% of liver failure cases in US
iii. Used in suicide attempts because of availability in large doses
iv. Acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue byproducts in the liver -> heptatic necrosis
b. Overdose antidote – N-acetylcysteine (regenerates glutathione)
Propionic acid derivatives
aspirin alternatives among NSAIDs, substituted phenylpropionic acids
Propionic acid derivatives names
Ibuprofen (Advil, Motrin), Fenoprofen, Ketoprofen, Naproxen (Aleve)
Propionic acid therapeutic uses
a. OTC for headache, fever, mild to moderate musculoskeletal and postoperative pain
b. Rheumatoid arthritis and osteoarthritis
c. Dysmenorrhea (menstrual cramps)
