COX-1 Function
Contributes to homeostasis |
Ongoing constitutive physiologic "house keeping", vascular homeostasis, maintenance of renal, myocardial and GI blood flow, platelet function, intestinal mucosal proliferation, antithrombogenesis |
COX-1 Inhibition
Decreases mucosal defense |
Increase GI acid, and decreases GI mucus |
Decreases HCO2 secretion |
Decreases mucosal blood flow |
Special Consideration for NSAIDs
1. Both ibuprofen and naproxen may reduce the effects of furosemide (diuretic) and may reduct the effectiveness of several antihypertensive agents |
2. Indomethacin is the NSAID most likely to cause nephrotoxicity |
COX 2 Inhibitors
Due to sometimes severe GI adverse effects associated with long-term NSAID therapy, selective cox 2 inhibitors are used |
Inhibition of the chemical mediators responsible for inflammation while maintaining the cytoprotective effects of the products of COX-1 activity |
Meloxicam |
Inhibition of COX-2 may generate some problems in wound healing, angiogenesis and the resolution of inflammation |
Lower GI and renal problems |
Cox 2 may induce hypertension, renal failure and cardiac failure |
Naproxen has some cardioprotective properties |
Contraindication for NSAIDs
Reye's Syndone |
For patients under 18 years old |
Pregnancy |
Compromised Renal Function |
NSAIDs reduce renal blood flow and therefore may further reduce renal function which may have an impact on the effects of concurrent meds and elimination of the NSAID and other meds and toxins |
Compromised Liver Function |
Most NSAIDs are metabolised in liver |
Hypersensitivity |
Happens more in asthmatics |
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COX 2 Function
Works at the site of pain and inflammation |
Source of prostacyclin- platelet stability/dilate blood vessels |
COX 2 Inhibition
Decrease pain and inflammation |
Increases CV risk as it shifts the balance between platelet production TxA2 and PGI2, predisposing to platelet aggregation, thrombus formation and vasoconstriction |
Salicylates
Includes Aspirin which acts in an irreversible manner by acetylating the active site serine residue in both COX-1 and COX-2 |
Daily low dose aspirin is used as an anti-thrombogenic agent for prophylaxis and post event management of MI and stroke |
Aspirin is antithrombogenic because of its irreversible inhibition of COX, which prevents platelets from biosynthesizing TxA2 |
Within an hour of aspirin, the effects of COX-1 activity on newly formed platelets is irreversibly destroyed (acetylated) therefore TXA2 cannot be produced |
A single administration of aspirin decreases for several days the amount of thromboxane that can be generated, shifting the vascular TxA2-PGI2 balance toward PGI2 mediated vasodilation, platelet inhibition, and antithrombogenesis |
Long term use of aspirin can lead to GI ulceration and hemorrhage, nephrotoxicity and hepatic injury |
Two unique toxicities of aspirin: induced airway hyperactivity in asthmatics and reye's syndrome |
NSAID Drug to Drug Interaction
Wendy's LAMP |
mnemonic for remembering drug interactions |
Warfarin |
May increase risk of bleeding- Monitor PT and INR |
Lithium |
May increase lithium plasma levels and decrease its clearance renally- need to monitor |
ACE Inhibitors |
may decrease antihypertensiuve effects so need to monitor BP and CV function |
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NSAIDs increase BP and decrease affects of diuretics, ACE inhibitors and ARB which all relax blood vessels as NSAIDs inhibit cox-2 in kidneys which decreases sodium excretion due to a decrease in prostaglandins |
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NSAIDs may increase fluid retention and decrease blood flow to the kidneys as they block prostaglandins which dilate blood vessels and allow O2 to reach kidneys |
Methotrexate |
May lead to an increase in methotrexate toxicity- don't administer within 10 days of high dose methotrexate |
Probenecid |
May lead to reversal or uricosuric effects |
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Non-Selective COX 1 and COX 2 Inhibition
GI irritation due to decreased protection of gastric mucosa.- N&V, GI ulcer, diarrhea |
Skin reactions - mild rash, hives, photosensitivity |
Inhibition of platelet function- increase risk of bleeding |
Decreased renal blood flow- decreases GFR can cause renal ischemia- look out for pts w/ renal disease |
CVD risk |
Respiratory- bronchospasm- look out for asthmatic pts |
Risk Factors for GI complications
Over 60 in age |
history of peptic ulcer |
use of anti coagulants or corticosteroids |
History of pylori infection |
High NSAID dose or use of two NSAIDs |
Severe illness |
Reducing GI risks
Misoprostol |
Synthetic prostaglandin- Protects gastric mucosa from irritation |
Protein Pump Inhibitors |
Long lasting reduction of gastric acid production |
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Drugs end in -"prazole" |
H2 Receptor Antagonists |
Blocks the action of histamine on parietal cells in the stomach decreasing the production of acid by these cells |
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Drugs end in -"dine" |
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Not enough evidence that these alone will work in reducing GI issues |
COX-2 Inhibitor |
Allow continued protective COX-1 function |
Acetaminophen
Not an NSAID |
Has analgesic and antipyretic effects similar to aspirin |
anti-inflammatory effects are insignificant because of its weak inhibition of COX |
May be a third functional COX isoform (COX-3) |
MOA believed to involve the prostaglandin pathways within the CNS with little influence on peripheral prostaglandin synthesis |
Adverse effect= hepatotoxicity as it is metabolized by hepatic cytochrome p450 enyzmes which produces a reactive molecule which is normally detoxified by conjugation with glutathione. An overdose of acetaminophen can overwhelm glutathione stores, leading to cellular and oxidative damage and in severe cases to acute hepatic necrosis |
4000mg daily limit for adults. For those who are alcoholics or multiple medication patients and patients with liver disorders, even doses within the therapeutic range may be hepatotoxic |
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