Eicosinoid NSAID and Acetaminophen Pharmacology

Question 1

Describe the major treatment properties of NSAIDs and conditions in which NSAIDs are indicated.

Answer 1

anti -inflammatory, antipyretic, analgesic (non-neurogenic pain); carry black box warning about increased risk of CV and GI adverse effects

indicated for mild to moderate pain, arthritis, fever, dysmenorrhea, gout; prophylaxis of thrombosis (aspirin) and polyps/colon cancer

Question 2

Describe the mechanism of action of NSAIDs and the different forms of COX enzymes.

Answer 2

inhibition of cyclooxygenase enzymes involved in prostaglandin biosynthesis (decreases prostaglandins)

COX-1 constitutively expressed in almost all tissues
COX-2 constitutively expressed in brain, kidney and bone but is inducible in response to inflammation mediators.

Question 3

If NSAIDS are about equally efficacious, how does one choose a drug to prescribe?

Answer 3

differentiated on basis of toxicity and cost-effectiveness, several forms are pegged for a given niche condition

Question 4

What is the mechanism of NSAIDs adverse GI effects?

Answer 4

PGE2 interacts with EP3 receptors to produce mucous and bicarbonate to protect the stomach lining

Question 5

Aspirin (ASA; Bayer, generic)

Answer 5

used for thrombosis prevention, reduces risk for patients with hx of MI, coronary event, stroke etc.

mechanism: irreversible inhibitor of COX enzymes, 5x COX-1 v. COX-2 **Note COX enzyme in platelets cannot be restored until platelets are replaced

adverse reactions include GI disturbance, hypersensitivity and anaphylaxis, precaution giving to s syndrome or clotting disorders

Question 6

Ketorolac (toradol)

Answer 6

strong analgesic (opioid level)

MOA: competitive inhibitor of COZ enzymes 100x COX-1 vs. COX-2 (GI adverse effects)

renal clearance is important as 90% excreted in urine;

Question 7

Indomethacin (Indocin)

Answer 7

NSAID of the indole and indene acetic acid classes- used in premature infants to accelerate closure of the patent ductus arteriosus

competitive inhibitor of COX enzymes, 3-5x selective COX-1 v. COX-2

undergoes enterohepatic recirculation

adverse CNS reaction due to indole molecule (cleaves to a molecule to seratonin) and GI disturbance; pregnancy risk category D in 3rd trimester

Question 8

Naproxen (Aleve, Anaprox)

Answer 8

used for analgesic and anti-inflammatory properties, long lasting
competitive inhibitor of COX enzymes, x3-5 COX-1 v COX-2

significant renal metabolism

risk of gastric bleeding is double that of ibuprofen and possible DERM adverse reactions

Question 9

Ibuprofen (Advil)

Answer 9

competitive inhibitor of COX enzymes 2x COX-1 v. COX-2 used to treat pain, fever;

less GI disturbance and shortened duration compared to naproxen

Question 10

Meloxican (Mobic)

Answer 10

NSAID indicated for arthritis (very potent); selective x10 COX-2 v. COX-1

significant metabolism by 2C9, 3A4

Question 11

Celecoxib (Celebrex)

Answer 11

selective COX-2 inhibitor (10-20x selective)

almost entirely metabolized by 2C9

(market concern due to CV risk, which was found to be true for most NSAIDs)

Question 12

Diclofenac (generic)

Answer 12

competitive inhibitor of COX enzymes, possibly more COX-2 selective than Celecoxib

available in an extended QD dose

mostly 2C9 metabolized, followed by glucuronidation or sulfation

Question 13

Acetaminophen (Tylenol)

Answer 13

analgesic and antipyretic but no anti-inflammatory activity and no platelet effects

useful when aspirin is contraindicated

competitive inhibitor of COX-1, COX-2 enzymes within the CNS but not the periphery; binds cannabinoid receptors in spinal cord

important 10-15% metabolism converted by 2E1, 1A2 or 3A4 to a reactive, hepatotoxic metabolite

contraindicated in hepatic disease and alcoholism

Question 14

Discuss the metabolism of acetaminophen in more detail.

Answer 14

possible to under go glucorondiation and sulfonation and 3 CYP pathways

of the pathways the CYP pathways can lead to a reactive species which is toxic because sulfydryls react with proteins causing cell death

this can be avoided by conjugation with glutathione via GST forming a mecapturic acid derivative

Question 15

Alporstadil (Caverject)

Answer 15

synthetic PGE1 use to tx ED or to maintain potency of ductus arteriosus before corrective surgery

acts as a agonist at the EP receptors to increase cAMP production and vasodilation; indicated for men who cannot tolerate nitro compounds to treat ED

AR: mild to moderate penile pain, prolonged erection, penile fibrosis, in PEDs fever, apnea and flushing (infuse smallest dose for shortest amount of time

Question 16

Latanoprost (Xalatan)

Answer 16

synthetic PGF2a analog prodrug used to reduce elevated IPO in open angle glaucoma or ocular hypertension

acts as a selective FP receptor agonist, increases outflow of aqueous humor, hydrolyzed by esterase’s in the cornea to biologically active acid

can cause increased iris pigmentation and eyelash increase

contraindicated for intraocular inflammation and make sure to remove contact lenses for 15min.

Question 17

Misoprostol (Cytotec)

Answer 17

potent synthetic prostaglandin for prevention of gastric ulcers and following mifepristone as an abortifacient or to induce labor

acts as an agonist in EP receptors in parietal cells (cAMP decrease causes decreases acid secretion) as well as uterus (stimulate and increases contractions, dilates cervix)

AR headache, diarrhea, pain and NV, pregnancy risk X
(negative serum pregnancy test, effective use of contraception, oral and written warnings and initiate therapy on 2nd or 3rd day of next normal period

Question 18

Zileuton (Zyflow)

Answer 18

indicated for the prophylaxis and chronic treatment of asthma

acts as a specific 5-LOX inhibitor, inhibiting neutrophil and eosinophil migration, leukocyte adhesion and decreased capillary permeability along with less leukotriene-induced smooth muscle contractions

metabolism by 1A2, 2C9 and 2A4; can causes dyspepsia and elevated liver function tests

LFT should be checked before treatment and during treatment ~3mo, does not treat acute episodes of asthma

Question 19

Zafirlukast (Accolate)

Answer 19

selective peptide leukotriene receptor antagonist indicated for the prophylaxis and chronic asthma treatment

antagonist at G protein coupled cysteinyl leukotriene receptor of airway smooth muscle, mast cells and neutrophils, inhibits bronchoconstriction, edema, mucous secretion

food can reduce bioavailability, highly bound to plasma proteins; extensive metabolism at 3A4 AND 2C9

few adverse reactions, not a bronchodilator, caution with hepatic status

Question 20

Montelukast (Singulair)

Answer 20

use for asthma maintenance therapy and allergic rhinitis

acts as a antagonist at Gprotein coupled cysteinyl leukotriene receptors in airway, sm. muscle, mast cells and neutrophils

extensive metabolism by 3A4, 2C9, excreted almost exclusively in bile

rare fever, indigestion and gastritis, precaution with hepatic status, not a bronchodilator

preferred as maintenance because it is easier to dose

Question 21

What is oleocanthal?

Answer 21

compound in extra virgin olive oil shown to have some anti inflammatory effects