ANTI-INFLAMMATORY DRUGS Flashcards
How do NSAIDS block pain
Prostaglandins sensitize afferent nerves to the action of bradykinin in inducing pain and so blocking their synthesis can reduce pain sensations
How do NSAIDS lower fever
prostaglandin E2 mediates pyrogen effects on the hypothalamus to increase body temperature and so, blocking prostaglandin synthesis can have anti-pyretic effects
Acetylsalicylate (aspirin) vs salicylate
Acetylsalicylate is responsible for the anti-platelet effects of low dose aspirin, does so before entering systemic circulation
In the systemic circulation salicylate (coverted in stomach and liver) is largely responsible for the remainder of the effects of aspirin.
Effect of aspirin at a low dose (80-160 mg)
At these concentrations acetylsalicylate acts as an irreversible inhibitor of Cox-1 via its ability to acetylate an active site serine of the enzyme.
Inhibition of Cox-1 in platelets prevents the production of thromboxane A2, which promotes platelet activation and aggregation during clotting.
Effect of aspirin at intermediate dose (325-1000 mg)
Salicylate reduces Cox1 and Cox2 activities but not by the same mechanism as acetylsalicylate (salicylate lacks the acetyl group needed for irreversible inhibition).
Instead, salicylate is thought to reduce Cox1 and Cox2 enzyme activities by reducing the expression of these enzymes.
Effect of aspirin at high dose (325 mg - 6g)
At higher doses salicylates begin to have more generalized anti-inflammatory activities.
Salicylates have been shown to be useful for chronic inflammatory diseases like rheumatoid arthritis at high concentrations (2-6 g daily).
Some of these effects are likely attributable to further inhibition of Cox2 activity but there also effects that are independent of inhibition of cyclooxygenase enzymes, which are likely mediated through influences on immune effector cells like neutrophils.
Toxicities associated with salicylates
- Acid/base disturbances: metabolic acidosis and respiratory alkalosis
- Tinnitus
- Nausea/vomiting, stomach ulcers/bleeding
- Combining aspirin with warfarin markedly increases bleeding risk
What is Reye syndrome
Treating children with relatively high doses of salicylates has been linked to Reye syndrome, a disorder of the liver and brain.
Reye syndrome is characterized by hypoglycemia, fatty infiltration of the liver (with associated swelling), hyperammonemia, and potentially coma.
Swelling also occurs in the brain and is associated with seizures, convulsions and loss of consciousness
What are the Propionic acid derivatives
Usually end in “-profen” except for naproxen
Main difference between ibuprofen and naproxen
A major difference between ibuprofen (found in Motrin, Advil) and naproxen (found in Aleve) is that naproxen has a longer half-life in the body and therefore a longer duration of action and so can be taken once every 12 hours rather than once every 4-6 hours.
Mechanism for ibuprofen and naproxen
Tagrte both COX-1 and COX-2 enzymes and are reversable inhibitors
Propionic acid derivatives toxicities
- The primary toxicity of ibuprofen is gastrointestinal with bleeding, ulcers, pain, and vomiting.
- All NSAIDs (especially COX-2 seelctive) carry a risk for heart effects
What are the common acetic acid derivatives
diclofenac, indomethacin
Mechanisms for diclofenac and indomethacin
They are reversible inhibitors.
Diclofenac may show a slight preference as an inhibitor of Cox-2 relative to Cox-1, which is thought to reduce its gastrointestinal side effects relative to indomethacin.
Diclofenac also appears to inhibit lipoxygenase enzymes and block leukotriene synthesis, giving it a unique mechanism of action among the NSAIDs.
Diclofenac is considerably more potent than indomethacin and aspirin.
Indomethacin readily crosses the blood brain barrier and may have unique modes of action in treating certain headaches.
Acetic acid derivatives unique toxicities
Indomethacin has significant gastrointestinal toxicity as well as an increased risk for heart attack and stroke.
In addition to these relativity common toxicities for the NSAIDs, indomethacin also has significant CNS toxicity.
Acetominophen toxicities
Hepatotoxicity - related to the effects of the toxic phase I metabolite N-acetylbenzoquinone-imine.
tacrolimus and cyclosporin mechanism
Upon entering T cells they bind to proteins called immunophilins.Tacrolimus binds an immunophilin called FKBP-12, whereas cyclosporin binds cyclophilin.
Upon interactions with tacrolimus or cyclosporin their respective immunophilins bind with a high affinity to calcineurin, and inhibit its activity as a Ca/calmodulin-dependent phosphatase.
Active calcineurin plays a major role in signaling pathways involved in T cell activation leading to the transcriptional activation of the gene producing IL-2 and other cytokines.
