NSAIDs + Glucocorticoids

Aspirin, Ibuprofen

Non-Selective NSAIDs - (2)

Celecoxib

Selective COX-2 Inhibitor - (1)

Acetaminophen

Non-NSAID Antipyretic - (1)

Hydrocortisone, Methylprednisone, Prednisone

Short-Acting Glucocorticoids - (3)

Cyclooxygenase (COX)

Enzyme family leading to formation of prostaglandins formed via endoperoxides

COX-1

Enzyme always expressed in platelet and stomach

COX-2

Enzyme always expressed in brain, kidney, and vascular endothelial cells; inducible at site of inflammation

Prostaglandins

Mediator of inflammation

Glucocorticoids

Drug class that inhibit phospholipase A2

COX-2, lipoxygenase, inflammation, asthma

Glucocorticoids

• Eventually block __ (prostaglandins) and __ (leukotrienes)

• Tx __ and __ respectively with blockage

NSAIDS

Drug class that inhibit COX-1 and COX-2 non-selectively

COX-2, COX-1

NSAIDS inhibit COX-1 and COX-2 non-selectively

• Tx inflammation (block __)

• But can lead to kidney and stomach damage (block __)

NSAIDS and Ibuprofen

Reversible COX Inhibitors that work at substrate-binding site and can easily dissociate

Acetaminophen

Non-NSAID with NO anti-inflammation and Inhibits CNS COX only

Aspirin

Does irreversible inhibition due to covalent acetylation of COX-1 and COX-2

Covalent acetylation, nucleus, 4 g/d, 2,1

Aspirin

• Irreversible inhibition due to __ __ of COX-1 and COX-2

• Platelets cannot synthesize new enzymes as they have no __

• Follows Zero-Order elimination at dose higher than _ __

• Higher dose blocks COX-__ > COX-__

Rheumatic fever

Higher dose aspirin clinical use - (1)

Anti-inflammatory, analgesic, antipyretic

NSAID clinical uses - (3)

81-325 mg

Aspirin of low dose

Angina, MI, TIA

Low dose aspirin clinical uses - (3)

*by irreversible inhibitor of COX-1-TXA2

Gastritis, peptic ulcers, analgesic nephropathy, renal papillary necrosis, CV, ductus arteriosis, asthma, allergic

Side Effects of NSAIDS

• Gastric damage - __ and __ __

• Kidney damage - __ __ and __ __ __

• __ Effects - Seen with all NSAIDS except low-dose aspirin

• __ __ Constriction - Closure in fetuses or neonate vasculature prematurely

• Precipitation of __ via increase in leukotrienes

• __ Reactions - Among cross NSAIDS (do not pair NSAID together)

Low-dose aspirin, celecoxib, 32 weeks, leukotrienes

Side Effects of NSAIDS

• CV Effects - Seen with all NSAIDS except ___

  • __ has higher risk of angina, MI, stroke

• Ductus Arteriosus Constriction

  • NSAIDs contraindicated for patients pregnant over __ __

• Precipitation of asthma

  • Via increase of __

Symptoms of Analgesic Nephropathy from NSAID use (Analgesic Nephropathy)

Back pain, cloudy urine, tissue pieces in urine, fever

Symptoms of Interstitial Nephritis from NSAID use (Interstitial Nephritis)

Fever, eosinophiluria, tubular function damage, polyuria, chronic renal failure

COX-1, thromboxane, 8-11, 1 week, thrombosis

Aspirin Low Dose

• Irreversibly inhibit __

  • Reducing __ → Inhibition of platelet aggregation

• One dose inhibits the life of the platelet (_-_ days)

• Aspirin should be stopped _ __ before surgery

• Used for prophylaxis of __, angina, MI, stroke

Salicylism

Overdose on aspirin with initial tinnitus, vertigo, respiratory alkalosis

Severe Sx of Salicylism

Respiratory acidosis, metabolic acidosis, respiratory and vasomotor collapse

Reye’s Syndrome

Rare but often fatal infection for children while using aspirin

Encephalopathy, liver failure, viral infection

Reye’s Syndrome

• Complications from Reye’s Syndrome - __ and __ __

• Aspirin contraindicated in children or adolescents with a __ __

Celecoxib

COX-2 Inhibitor with less GI irritation and NO effect on COX-1

Cardiovascular thrombosis risk, kidney damage

Side Effects of Celecoxib - (2)

Peripherally, CNS, anti-inflammatory, anticoagulant, GI

Acetaminophen (Tylenol)

• Non-specific COX inhibitor that does NOT inhibit COX __

• Inhibits COX-1/2/3 and other __ targets

• No __ or __ effects, no __ irritation

p450, GSH, liver

Acetaminophen

• Toxic metabolites - __ (enzyme) forms reactive intermediate product needing __ to inactivate

• In overdose - Toxic metabolites can cause irreversible and fatal __ failure

Cholesterol, cortex

Glucocorticoids are synthesized from __ in the adrenal __

COX-2, phospholipase-2, leukotrienes

Glucocorticoids Inhibit Immunity and Inflammation

• Reduce __ (enzyme) transcription, inhibit __ (enzyme)

• Reduce __

Stimulate gluconeogenesis and increase plasma glucose

Glucocorticoids lead to Metabolic Effects - (2)

Muscle, bone, lymphoid, skin, protein (catabolism)

Glucocorticoids lead to Catabolic Effects - (5) Things broken down

Catecholamines

Glucocorticoids maintain vascular response to __ (i.e. NE)

Mineralo, Cushing’s syndrome

Cortisol’s __corticoid property

• Responsible for HTN in __ __ (endocrine disorder)

Hydrocortisone

Topical rapid-acting glucocorticoid with equal gluco- and mineralo- corticoid activity

Prednisone

Oral prodrug glucocorticoid with no biologic activity until converted to prednisolone

4, 1/3

Prednisolone

• _x potent and __ (fraction) salt retaining than cortisol

Methylprednisolone

IV or oral glucocorticoid that is 5x potent than cortisol

Short-acting Glucocorticoids

Have half-lives of 12 hours and preferred to be used as morning dose matches to physiological peak

Addison’s disease (Adrenal insufficiency)

Clinical Use for Glucocorticoids - (1)

ACTH, HPA, syndrome, diabetes, osteoporosis, avascular necrosis, wound healing, peptic, muscle, psychosis

Adverse Effects of Glucocorticoids

• Adrenal Suppression - Suppression of __ and __ axis

• Cushing’s __: Moon face, buffalo hump, weight gain

• New onset __ and or New onset __ (decrease bone density)

• Femur head __ __

• Reduced immunity and Inhibition of __ __

• __ ulcers

• __ wasting

• CNS/Behavioral - __

Cushing’s Syndrome

Glucocorticoid excess with moon face, buffalo hump, weight gain

Cataract - ulcer - skin thinner - Hypertension - Infection - Necrosis of femoral head - Glycosuria - Osteoporosis/Obesity - Immunosuppression - Diabetes

“Cushingoid” Pneumonic for Glucocorticoid Adversities

HPA suppression, morning dose, 2 weeks, taper

Principles of Corticosteroid Therapy

• Alternative day therapy to prevent __ __

• OR Single __ __ if long-term use

• Long-term treatment greater than __ __ leads to HPA suppression

• Should not be stopped suddenly if more than 2 weeks of use, must __