NSAIDS Flashcards
What explains the GI complaints associated with aspirin use?
Decreased production of PGs that promote mucus secretion
Why does aspirin increase bleeding time
TXA2 production in platelet decreases
General properties of NSAIDS
- Anti-inflammatory
- Anti-pyretic
- Analgesic
Mechanism of action of all NSAIDS
Inhibition of cyclooxygenase
Acetylsalicylic Acid/Aspirin mechanism of action
Irreversible inhibitor of Cox 1 and 2
Acetylation of a serine moiety - Serine 230
Why doesn’t protein synthesis occur in both Endothelial cells AND platelets
Platelets have no nucleus - once inhibited, cannot create more protein
Aspirin
Absorption:
Distribution:
Absorption: Oral absorption
- Rapidly absorbed from stomach and small intestine
- limited by dissolution rate (chewing increases)
- Buffered (substances which neutralize acid) vs. enteric coated (dissolves in intestines)
Distribution:
- Highly bound to plasma proteins
- Crosses BBB and placental barrier
Aspirin Metabolism
Renal Elimination
Plasma half life is dose-dependent
Unique effects specific to Aspirin/Salicylates
Uric Acid Excretion
CNS
Respiration
Uricosuric Effects
- Any agent that increases rate of excretion of uric acid
- Uptake of uric acid from renal tubules via a transporter that acts as an anion exchanger
- Uriosuric agents compete with the urate transporter
What is the dose dependent Uricosuric effect of Aspirin?
Low doses - decrease uric acid exretion
- Secretory component for urate sensitive to low concentrations of salicylates
Large doses - Increase uric acid excretion
- Normal mechanism to block reabsorption via interaction with transpoter (OAT)
CNS effects of high doses of Salicylates (Toxicity)
- Stimulation followed by depression
- Tinnitus, high tone deafness, confusion, dizziness, delirium, psychosis, coma
- Nausea and vomiting
_________ are a major limitation to long term therapy with NSAIDs
GI side effects
PGs and their function in the GI
- Inhibit acid secretion by the stomach
- Promote secretion of cytoprotective mucus in the intestine
NSAID GI Side Effects
Block the production of cytoprotective PGs
- GI ulceration and irritation
NSAIDs and Platelets
- All NSAIDs increase bleeding time by inhibiting platelet TXA2
- Platelets lack nucleus so new COX only with new platelets since ASA irreversible inhibition of COX
Aspirin Hypersensitivity
Blocking COX forces arachidonic acid to follow other pathways leading to products which promote allergy, bronchoconstriction. inflammation and mucus production
- Treated as analphylactic shock (epinephrine)
NSAID renal side effects
- Decrease renal blood flow
- Promote salt and water retention
- Effects more prominant in individuals dependent on vasodilatory PGs
- Elderly
NSAIDs and pregnancy
- Prolongation of gestation
- Prolonged labor
- Increased risk of postpartum hemorrhage
- Intrauterine closure of the Patent Ductus Arteriosus
- NSAIDS still used
Dose needed for Salicylate poisoning
Asprin:
Methyl Salicylate:
Aspirin: dose 10 to 30 grams
Methyl Salicylate: dose of 4.7 grams in children
Aspirin Half Life During Over Dose
15-30 hours
Reye’s Syndrome
- Specific to aspirin
- Most often in children (6-11)
- Acute encephalopathy; Liver degeneration
- Often follows a viral illness
- Mechanism unknown (Mitochondrial damage?)
Drug Interactions for NSAIDs
- Alcohol
- NSAIDS
- Steroids
- Anticoagulants
- Methotrexate
NSAID therapeutic uses:
- Low Dose:
- Intermediate Dose:
- High Dose:
Low Dose (80 mg/day): CV disease
Intermediate Dose (325 mg to 1g/day): Low intensity pain/fever
High Dose (5-8 grams/day): Chronic inflammatory disease/ rheumatoid arthritis
Side Effects Associated with all Non-Selective NSAIDs
- GI irritation
- Inhibition of platelet aggregation/ bleeding
- Decrease in RBF in patients dependent on vasodilatory PGs
- Hypersensitivity
Propionic Derivatives
- Ibuprofen
- Naproxen
Indomethacin
Function:
Administration:
Therapeutic Uses:
Side Effects:
Function: Reversible inhibition of COX1 and COX2
Administration: Both oral and IV
Therapeutic Uses: Gout; preterm labor; close PDA
Side Effects: Severe frontal headache
- Better tolerated if given at night
Ketorolac
Function:
Administration:
Therapeutic Uses:
Side Effects:
Function: Reversible inhibitor of COX1 and COX2
Administration: Oral, IV, and IM administration
Therapeutic Uses: Used as alternative for opioid analgesics in the treatment of post-operative pain
Side Effects: Possibility of serious adverse GI, renal, bleeding, and hypersensitivity
Piroxicam
Metabolism:
Administration (per day):
Therapeutic Uses:
Metabolism: Metabolized by CYP2C9 (extremetly long t½)
Administration (per day): Oral administration/ once a day
Therapeutic Uses: Symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis
Nabumetone (pro-drug)
Administration (per day):
Function:
Therapeutic Use:
Administration (per day): Oral administration/ once a day
Function: Active metabolite that may be more COX2 specific
Therapeutic Use: Management of osteoarthritis and rheumatoid arthritis
Sulfasalazine - Mechanism of Action
- Effect is independent of COX inhibition
- Inhibition of cytokine production
- Inhibition of lipoxygenase
- Free radical scavenger
Sulfasalazine
Pharmacokinetics:
Pharmacological effects:
Adverse effects:
Therapeutic Uses:
Pharmacokinetics: Azo bond prevents absorption in upper GI tract
Pharmacological effects: Local effect in GI to inhibit inflammation
Adverse effects: Occur in high % of patients (sulfa moiety)
Therapeutic Uses: Ulcerative colitis; Rheumatoid arthritis
Benefit of developing COX2 specific inhibitors
If only block COX2, can treat inflammation without risk of GI side effects
What does Celecoxib (Celebrex) inhibit?
COX-2 selectively
Celecoxib mechanism of action
- Binds tightly to a distinct hydrophilic side pocket region of COX-2
- Close proximity to COX2 binding site
- COX 2 specific because this site is not present in COX1
Celecoxib
Administration:
Absorption:
Metabolism:
Administration: Oral administration
Absorption: Highly bound to plasma proteins
Metabolism: Metabolized via CYP2C9 to inactive metabolites
Celecoxib
Major adverse effects:
Major Contraindications:
Major adverse effects: Increase risk of GI irritation, ulceration, bleeding
Major Contraindications: History of GI bleeding; deficiency of CYP2C9
Celecoxib Therapeutic Uses
- Signs/symptoms of rheumatoid arthritis and osetoarthritis
- Primary dysmenorrhea
- Acute pain
- Colorectal polyps
Acetaminophen Mechanism of Action
Not fully understood
No affinity for active site of COX (may be selective for brain COX)
May prevent reduction of COX to peroxidase form
- inhibition by acetaminophen would be more effective under reducing conditions of low peroxide concentration
- High levels of peroxide (inflammatory sites) are resistant to the action of acetaminophen
Acetaminophen
Administration:
Metabolism:
Excretion:
Administration: Oral administration
Metabolism: Partially by liver microsomal system
- CYP2E1, CYP1A2, CYP3A4 - half life is 2 hours
- Mainly undergoes glucoronidation and sulfation
Excretion: Renal excretion
Acetaminophen: Toxicity
- Well tolerated at normal doses
- Little to no GI issues
- Most serious is hepatic toxicity
Hepatic Toxicity with Acetaminophen
Symptoms?
Management?
- Symptoms
- Liver injury - elevated liver enzymes
- Severe cases: liver failure; death
- Management
- N-Acetylcysteine (replenishes gluathione stores)
- Earlier is better < 36 hours
- N-Acetylcysteine (replenishes gluathione stores)
Role of alcohol in acetaminophen toxicity
- Alcohol induces the P450 involved in production of toxic metabolite
- Alcohol depletes glutathione
Therapeutic use of Acetaminophen
- Acute pain and fever
- No anti inflammatory effects
