Exam 3 Flashcards
Cyclosporine mechanism of action
Cyclosporine forms a complex with cyclophilin A, which bind to calcineurin to inhibit Ca2+ stimulated dephosphorylation (normally takes place via a phosphatase) of cytosolic NFAT, so NFAT can’t translocate to the nucleus.
Cyclosporine also increases the expression of transforming growth factor β (TGF-β), a potent inhibitor of IL-2 stimulated T cell proliferation and generation of cytotoxic T cells.
Tacrolimus mechanism of action
Binds to FK506 binding protein 12 (FKBP-12), which is structurally related to cyclophilin. The complex binds to calcineurin, calcium, and calmodulin to inhibit calcineurin phosphatase activity.
Rapamycin mechanism of action
Inhibits T cell activation and proliferation of downstream of IL-2R (where IL-2 binds) and other T-cell growth factor receptors. The action of rapamycin is also initiated by binding to the immunophilin, FKBP-12, but the complex does not bind to calcineurin. Instead, it binds and inhibits the kinase mammalian target of rapamycin (mTOR), which is important in T cell proliferation.
Everolimus mechanism of action
Binds to FK506 binding protein 12 (FKBP-12), which is structurally related to cyclophilin. The complex binds to calcineurin, calcium, and calmodulin to inhibit calcineurin phosphatase activity.
Azathioprine mechanism of action
In the presence of nucleophiles, azathioprine is cleaved to 6-mercaptopurine. 6-mercaptopurine is converted to 6-mercaptopurine nucleotides that inhibit DNA biosynthesis. It can also be converted to 6-thioinosine 5’-phosphate (T-IMP) that inhibits de novo purine biosynthesis. Normal cells utilize purine salvage reactions, which recycle purine bases from nucleic acids and nucleotides but lymphocytes don’t so azathioprine targets the immune system and not normal cells.
Mycophenolate mechanism of action
Selectively inhibits proliferation of lymphocytes by inhibition of IMPDH (inosine monophosphate dehydrogenase), which is the rate limiting enzyme in GMP biosynthesis. GMP is a precursor of GTP and deoxy-GTP for RNA and DNA synthesis. Mycophenolate is more selective against Type II isoform of IMPDH (which is expressed more in lymphocytes) than Type I isoform (which is expressed in most cell types).
Corticosteroids mechanism of action
HSP90 is connected to the glucocorticoid receptor in the cytosol, which has a hormone binding domain and a DNA binding domain. Cortisol binds to the hormone binding domain and HSP90 leaves so that the cortisol-glucocorticoid receptor complex can form a diner and move to the nucleus where the glucocorticoid receptor binds to the glucocorticoid response element (GRE) and triggers the expression of anti-inflammatory proteins. The glucocorticoid receptor can also bind to AP-1 responsive element, negative GRE, and NFKB responsive element, which lead to gene repression.
Corticosteroids effects
Suppression of T cells by interfering with production of cytokines. Suppression of B cells by interfering with the binding of interleukins to B cells. Suppression of neutrophils by inhibiting adhesion, chemotaxis, phagocytosis, release of toxic substances, etc. Suppression of macrophages by down-regulating the expression of Fc receptors on macrophages so macrophages are less able to phagocytose opsonized particles. Diminish production of prostaglandins and leukotrienes by inhibiting cyclooxygenase and phospholipase A2, which decreases the production of pro-inflammatory arachidonic acid metabolites.
What are eicosanoids and why are they important?
Eicosanoids are fatty acids produced by three classes of enzymes: cyclooxygenases, lipoxygenases, and cytochrome P450 epoxygenase. They are important to biological functions including inflammatory (and therefore immune) responses, pain, and fever.
Main role of phospholipase A
The release of arachadonic acid from membrane phospholipids.
PGI2 location and function
PGI2 is in endothelial cells and causes vasodilation and decreases platelet aggregation
TXA2 location and function
TXA2 is in platelets and causes vasoconstriction and platelet aggregation
PGF2 location and function
PGF2 is in the uterus and causes vasoconstriction.
PGE2 location and function
PGE2 is in most cell types and causes erythema, edema, pain, and fever
PGD2 location and function
PGD2 is located in the mast cells and in the brain and causes erythema, edema, pain, and decreased platelet aggregation.
What are the active sites in the COX binding pocket and what do they do
Arg120: interacts with the carboxylate of the fatty acid
Ser530: the residue acetylated by aspirin
Tyr385: abstracts the pro-S hydrogen to initiate the COX reaction
What COX is found throughout the body?
1
What COX is inducible?
2
What COX has the larger active site?
2
What is COX 3?
COX-3 is a controversial/proposed cyclooxygenase that has been found in the brain of dogs and may be a target of acetaminophen.
What is aspirin’s mechanism of action?
irreversibly acetylates Ser530 in the active sites of cyclooxygenase. It also alters the catalytic activity of COX-2 to make epi-lipoxins (have gastrointestinal effects and modulate vascular tome to affect regional blood flow during inflammation)
What are the complications from aspirin?
Reye’s syndrome, salicylism, aspirin hypersensitivity
What do nitrogen-containing salicylates treat?
irritable bowel syndrome
Why are the 5-p-fluorophenyl derivatives more potent than aspirin?
They’re bulky and a better competitor
Arylacetic and arylpropionic acid derivatives mechanism of action
compete with arachidonic acid at the active site of the cyclooxygenase
Arylacetic and arylpropionic acid derivatives examples
sulindac, ketorolac, tolmetin, diclofenac, etodolac
What is distinctive about the arylproprionic acid analogs?
They all have an alpha-methyl group (at the second carbon)
Does stereochemistry matter for the arylproprionic acids
The S isomer is the active form and the R isomer is inactive. The R isomer is converted to the S isomer in vivo due to metabolism
Which COX are arylpropionic acid analogs selective for?
Non-selective
What drugs are in the arylpropionic acid analogs class?
Ibuprofen and naproxen
Oxicam mechanism of action
enolic hydroxyl group that presumably interacts with Tyr385 and Ser530
What is distinctive about oxicams?
They have very long half lives
Oxicam examples
meloxicam and piroxicam
Examples of N-arylanthranilic acids
mefenamic acid, flufenamic acid, and meclofenamic acid
What happens in an acetaminophen overdose?
In acute overdose the normal pathway is saturated and a second metabolic pathway takes over to give rise to a reactive species (arylating intermediate) that reacts rapidly with and completely depletes GSH. The sulfur from GSH makes it extremely reactive and acetylcysteine is administered to react with it instead of the liver.
NSAID side effects
GI, cardiovascular, renal, hypersensitivity, neurological, hematologic
Explain the differences between NSAIDs
binding affinity, selectivity, actions on cytokines, epi-lipoxins
Mechanism for NSAID anti-inflammatory effects
block prostaglandin production that mediate inflammation
Mechanism for NSAID analgesia effects
prostaglandins sensitize nociceptive pathways and NSAIDs prevent this
Mechanism for NSAID antipyresis effects
PGE2 interacts with EP3 receptors in the hypothalamus causing signaling that results in heat generation and decrease of heat loss from the body. NSAIDs stop the production of PGE3
Mechanism for aspirin antiplatelet effects
COX-1 is in platelets and COX-2 is in the endothelial cells lining blood vessels. Platelets do not have cellular machinery and endothelial cells do so they can create more COX enzymes after aspirin acetylates them. COX-1 makes TXA2 and COX-2 makes PGI2. TXA2 causes platelet aggregation and PGI2 causes decreased platelet aggregation. PGI2 wins after the aspirin knocks the COX-1/platelets out so decreased platelet aggregation is the result.
Zileuton mechanism of action
Inhibits the 5-lipoxygenase that converts arachidonic acid to 5-HPETE, preventing formation of subsequent leuokotrienes
Zafirleukast mechanism of action
reversible and competitive inhibitor of the cysteinyl-leukotriene receptor
Montelukast mechanism of action
reversible and competitive inhibitor of the cysteinyl-leukotriene receptor
Cromolyn and Nedocromil sodium mechanism
Likely inhibits chloride channels, which may in turn inhibit calcium availability
Cromolyn and Nedocromil sodium pharmacologic result
inhibits release of mediators from several cell types involved in inflammation, can reverse increased functional activation in leukocytes obtained from the blood of the asthmatic patient, can suppress release of chemotactic peptides (chemokines), and decreases neuronal sensation related to increased reactivity airways
Lodoxamide and olopatadine ophthalmic mechanism of action
prevention of the antigen-stimulated release of histamine and other inflammatory mediators, may also prevent calcium influx into mast cells, blocks the action of histamine not the creation of it
