Lectures 16-17: NSAIDS

Inflammatory Response

Damage associated with inflammation acts on cell membranes to release lysosomal enzymes

Arachidonic acid (AA) is released from phospholipids → Inflammation

Lipoxygenase pathway - promotes bronchoconstriction and inflammation (asthma)

Cyclooxygenase (COX) pathway - Leads to prostaglandins and thromboxane which promote inflammation and bronchoconstriction

Aspirin/NSAIDS inhibit COX enzymes → Aspirin asthma

COX-1

Constitutive: regulates body homeostasis

Synthesizes thromboxane

GI mucosal protection

Renal blood flow

Platelet aggregation

Vasoconstriction

COX-2

Inducible

Synthesizes prostacyclin

Inflammatory pathway

Tumor invasion, angiogenesis, cell proliferation

Pain, Inflammation, Fever

General Properties of NSAIDS

Most NSAIDS are highly metabolized in the liver by CYP450

Renal excretion

Some undergo biliary excretion and reabsorption (enterohepatic circulation)

High degree of plasma protein binding

Analgesic, anti-inflammatory, anti-antipyretic, anti-platelet aggregation (aspirin only)

Inhibition of chemotaxis

General Adverse Effects of NSAIDS

Headaches, tinnitus, dizziness, aseptic meningitis

Hypertension, myocardial infarction

Ulcers or bleeding

Thrombocytopenia, neutropenia, or even aplastic anemia

Abnormal liver function test results and liver failure

Asthma

Pruritic rashes

Renal insufficiency, renal failure, hyperkalemia, and proteinuria

Aspirin (Acetylsalicylic acid)

Nonselective, irreversible inhibitor of COX-1 and COX-2; acetylates COX enzymes

Analgesic

Antipyretic

Anti-inflammatory

Antiplatelet inhibits platelet aggregation

Platelets can not synthesize new enzyme

Effect lasts for 8-10 days

NSAIDS will reduce the antiplatelet effect of aspirin

Acid- competition with other acidic compounds

Concentration in mucosal cells 20x higher than in the lumen of the stomach – results in gastritis, ulceration, Peptic Ulcer Disease

Lipid soluble

Crosses placental barrier and blood brain-barrier

Binds to plasma proteins

Low doses: first order kinetics

High doses: zero order kinetics (above 600 mg body burden)

Renal excretion - alkalinization of the urine promotes excretion

Aspirin (Acetylsalicylic acid) Adverse Effects

Alkalosis, then metabolic and respiratory acidosis (high doses)

Aspirin asthma – increased leukotriene synthesis

Aspirin inhibits platelet aggregation → Doubles bleeding time

Aspirin avoided in hypoprothrombinemia, vitamin K deficiency, hemophilia, severe hepatic damage,

Aspirin therapy should be stopped at least one week before elective surgery or labor

Low doses (1-2 grams/day) - decreases uric acid excretion + elevates plasma urate concentration

Large doses (over 5 grams/day) - enhances uric acid excretion (uricosuria) + lowers the plasma urate levels

Minimal cardiovascular effects in regular doses

Increased acid production + inhibit the secretion of protective gastric mucus → ulceration and/or bleeding + GI issues

Renal damage, acute renal failure, interstitial nephritis

Aspirin (Acetylsalicylic acid) and pregnancy/children

No teratogenic effect

Reye’s Syndrome – do not use in children

Aspirin Toxicity

Fatal dose - approximately 20 grams (10-30 grams) of aspirin

Tinnitus, restlessness, irritability, confusion, dizziness, hallucinations, loss of consciousness

Double vision

Fever, Burning throat

Emesis

Uncontrollable shaking; seizures

Renal/respiratory failure

Aspirin has many drug interactions

Beta-blockers/ACE inhibitors: decreases antihypertensive effects

Aminoglycosides: increases nephrotoxicity

Penicillin: competition for plasma protein binding; increases toxicity

Lithium: Increase uptake and toxicity

Antacids: changed absorption

Corticosteroids: Increases gastric ulceration

Diuretics: Increases effect and increases nephrotoxicity

Nonspecific reversible inhibitors of COX-1 and COX-2

First choice drug/best adverse effect profile: ibuprofen

Potent/worst adverse effect: Indomethacin

GI pain, bleeding, ulcer, pancreatitis, diarrhea

Nephrotoxicity - acute renal failure, interstitial nephritis, nephrotic syndrome

Cardiovascular – thrombosis, MI, stroke

CNS - headache, dizziness, confusion, depression

Lung – bronchoconstriction (leukotrienes)

Bone marrow - agranulocytosis, aplastic anemia

Hepatotoxicity - enzyme elevation, hepatitis

Hypersensitivity reactions

Ibuprofen

Drug of first choice; lowest incidence of side effects

High dose - more potent anti-inflammatory effects than aspirin

Lower dose - used for analgesia; limited effects on inflammation

Liver metabolism; renal excretion

Overall toxicity is low

Nausea, vomiting, diarrhea, constipation, heartburn

Gastrointestinal bleeding

Dizziness, light headiness, headache, hyperuricemia, edema

Indomethacin

Inhibits phospholipase A2 (reduce release of arachidonic acid), reduce neutrophil (PMN) migration, and decreases T-cell and B-cell proliferation

Anti-inflammatory + anti-rheumatic

Accelerate closure of patent ductus arteriosus (by inhibiting PGE2; ibuprofen alternate); juvenile RA

Headache, vomiting

Piroxicam

Inhibits PMN migration, lymphocyte function; decreases oxygen radical production

Long t1/2 55 hours; once daily dosing

Diclofenac

Decreases arachidonic acid bioavailability; increases reincorporation of AA into triglycerides, thereby decreasing lipoxygenase pathway and leukotriene synthesis

GI ulcerations may be less frequent than others

Impairs renal blood flow in some patients

Ketorolac

Short-term analgesic in postsurgical pain (can replace morphine)

After 5 days of use frequent GI side effects

May be combined with opioids; decreases dose of opioid

Naproxen

Long t1/2 = ~13 hours, once daily dosing

Extensively bound to plasma proteins

GI disturbances, heartburn, dyspepsia, abdominal pain, constipation, diarrhea

Gastric bleeding is less severe than with aspirin

Management of NSAID GI effects

Proton pump inhibitor (PPI)

H2 receptor antagonist

Misoprostol (prostaglandin E1 analogue, less tolerable)

Celecoxib

Selective, reversible cyclooxygenase-2 (COX-2) inhibitor

Inhibits prostaglandin synthesis and inflammation

Less GI side effects

Rash, edema, hypertension, and myocardial infarction

Increased risk of cardiovascular diseases

Contraindications: breast feeding, pregnancy, renal failure

Acetaminophen

Analgesic and Antipyretic

Fatal hepatic necrosis

Metabolized in the liver by CYP450s

Glucuronidation conjugation, renal excretion

Dose-dependent free radical production and oxidative damage (hepatoxicity) - eliminated by GSH (reduced glutathione)

Adverse effects:

Skin rash and allergic response

Hepatotoxicity occurs after ingestion of the 10-15 grams of acetaminophen at once

25 grams may be fatal (hepatic necrosis)

Hepatotoxicity may progress into encephalopathy, coma and death

Intermediate metabolite NAPQI

Chronic alcohol consumption increases toxicity – chronic alcohol consumption induces P450

Specific antidote is N-acetylcysteine (precursor to glutathione; free radical scavenger)

No history of PUD

any NSAID

PUD in history but not active

celecoxib; some NSAIDS w/ gastroprotective agent

Active PUD

acetaminophen and/or opioids

Metabolized by CYP450

Acetylsalicylic Acid (Aspirin)

Ibuprofen

Indomethacin

Diclofenac

Ketorolac

Naproxen

Piroxicam

Celecoxib

Acetaminophen