Pharmacology of Inflammation Flashcards
function of bradykinin
vasodilation, increase permeability of blood vessels, lower blood pressure, stimulate pain receptors
_____ are released by macrophages and mast cells in injured tissue regions to enhance the action of bradykinin
prostaglandins (PGE2)
prostaglandins:
1. derived from _______
2. belong to _____ family
3. [short/long] lived
4. [systemic/local] acting
- derived from ARACHIDONIC ACID (a fatty acid)
- belong to EICOSANOID family (including prostaglandins, thromboxanes, leukotrienes)
- short lived (action is seconds to minutes)
- locally acting
prostaglandins, thromboxanes, and leukotrienes belong to the _______ family
eicosanoid family - 20C atom molecules
collectively, prostaglandins and thromboxanes are known as _______
prostanoids (because they are structurally similar)
describe the effects of the following prostanoids:
a. PGE2
b. PGI2 (prostacyclin)
c. TXA2 (thromboxane)
a. PGE2: gastric mucus secretion, inflammation
b. PGI2 (prostacyclin): gastric mucus secretion, inhibits blood clotting, promotes vasodilation
c. TXA2 (thromboxane): promotes platelet aggregation (clotting) and vasoconstriction
which prostanoids promote gastric mucus secretion in the stomach?
PGE2 and PGI2 (prostacyclin)
which 2 prostanoids counterbalance each other to maintain cardiovascular homeostasis?
PGI2: inhibits platelet aggregation (clotting), promotes vasodilation
TXA2 (thromboxane): promotes platelet aggregation (clotting), vasoconstriction
the main prostanoid involved in inflammation is _____
what effects does it have? (5)
prostaglandin E2 (PGE2):
- vasodilation
- increase vascular permeability
- increased sensitivity of pain receptors to bradykinin
- pain neuromodulation in dorsal horn of spinal cord
- pyresis (fever)
appears at site of injury
mast cells and macrophages produce large amounts of PGE2 via what process? (name the enzyme)
catalysis of arachidonic acid by the enzyme Cyclo-OXygenase 2 (COX-2)
arachidonic acid -(COX2)-> PGE2
COX-1 vs COX-2
COX-1: produced constitutively in most cells; catalyzes arachidonic acid to biosynthesize “housekeeping” prostaglandins
COX-2: expression induced by inflammation (mast cells, macrophages) —> catalyzes arachidonic acid catalysis to PGE2
describe the steps and players of general prostaglandin synthesis (distinct from inflammatory prostaglandin synthesis)
- phospholipid in cell membrane converted to arachidonic acid via phospholipase A2
- arachidonic acid (omega 6 FA) converted to PGH2 via COX
- PGH2 converted to prostaglandins via prostaglandin synthases
describe the steps and players of inflammatory prostaglandin synthesis
- membrane phospholipid converted to arachidonic acid via phospholipase A2
- arachidonic acid (omega-6 FA) converted to prostaglandin H via COX-2
- prostaglandin H converted to prostaglandin PGE2 via PGE synthase
PGE2 produced at the site of injury
where do the processes for general vs inflammatory prostaglandin synthesis diverge
in general prostaglandin synthesis, arachidonic acid converted to PGH2 (via COX), which is then converted to prostaglandins
in inflammatory prostaglandin synthesis, arachidonic acid converted to prostaglandin H (via COX-2), which is then converted to prostaglandin PGE2 at the site of injury
NSAIDs reduce the production of ____
non-steroidal anti-inflammatory drugs
reduce production of PGE2 (inflammatory) via inhibiting COX-2
effects:
- reduce edema
- reduce bradykinin-induced pain
- reduce allodynia (skin tenderness)
- anti-pyretic (fever)
name 4 standard OTC NSAIDs
- aspirin (Bayer)
- ibuprofen (Advil)
- naproxen (Motrin, Aleve)
- diclofenac (Voltaren)
*non-steroidal
Bayer, an OTC NSAID, is generically known as
aspirin
Advil, an OTC NSAID, is generically known as
ibuprofen
Motrin and Aleve, both OTC NSAIDs, are generically known as
naproxen
describe what causes the side effects of NSAIDs
NSAIDs inhibit COX-2 to reduce PGE2 prostaglandin levels
COX-2 is similar in structure to COX-1
so non-inflammatory “housekeeping” prostaglandins produced by COX-1 are reduced…
such as PGE2 and PGI2 that are in the stomach to induce mucus secretion —> GI discomfort, bleeding caused by gastric acid
NSAIDs are contraindicated for which patients?
those with peptic ulcers, aspirin hypersensitivity, coagulation defects, congestive heart failure, others
remember that NSAIDs inhibit COX-2 (inflammatory), which is structurally similar to COX-1 (housekeeping),
so side effects develop from COX-1 inhibition —> GI discomfort, stomach bleeding (PGE2 and PGI2 in the stomach promote mucus secretion)
NSAIDs may induce asthma attacks
explain this phenomenon
after phospholipids are converted to arachidonic acid, 5-lipoxygenase may convert arachidonic acid to
5-HPETE, which becomes leukotrienes
this pathway is associated with inflammatory/immune response, allergic reactions, anaphylactic shock
*this happens in people taking too many NSAIDs - pathway is shunted
what follows if 5-lipoxygenase acts on arachiodnic acid rather than COX-1 or COX-2
arachidonic acid -(5-lipoxygenase)-> 5-HPETE —> leukotrienes
—> inflammatory/immune response, allergic reactions, anaphylactic shock
NSAIDs may induce asthma attacks (if someone is taking way too many of them)
how does aspirin (acetylsalicylic acid) work, and what is it used for?
aspirin covalently (irreversibly) binds COX-1 and COX-2 and inhibits TXA2 (thromboxane A2) production in platelets
used as anti-platelet anticoagulant drug (patients with coronary artery disease/CAD at risk of thrombosis)
lower doses (81-100mg) can be used to avoid GI problems
*do not prescribe to children because of Reye syndrome (brain swelling, liver damage)
celecoxib (Celebrex) is the only _____ still available in the US
selective COX-2 inhibitor - does not disturb housekeeping prostaglandins, so stomach bleeding/GI issues is not a side effect… however…
*selective COX-2 inhibition enhances cardiovascular risk —> due to imbalance of TXA2 over PGI2
(celeCOXib is selective for COX-2)
why are selective COX-2 inhibitors associated with cardiovascular risk?
leads to imbalance of thromboxane (TXA2 - promotes clotting/ vasoconstrictor) over PGI2 (inhibits clotting, vasodilator) —> increased risk of thrombosis
PGI2 and TXA2 counterbalance to maintain cardiovascular homeostasis
(remember that selective COX-2 inhibitors will reduce PGI2 production)
why is aspirin used to prevent myocardial infarction and stroke?
aspirin covalently (irreversibly) binds COX-1 and COX-2, and inhibits thromboxane (TXA2) production in platelets
platelets lack a nucleus, so biosynthesis of TXA2 requires new platelet cells, which takes longer
so overall effect is slight excess of PGI2 (anti-coagulation, vasodilation) over TXA2 (coagulation, vasoconstriction)
what does acetaminophen (paracetamol or APAP) do, and what does it specifically not do?
acetaminophen: anti-pyretic (reduces prostaglandin synthesis in hypothalamus), analgesic
NOT anti-inflammatory/NSAID
*short term uses has few side effects but therapeutic window is narrow
the most common cause of acute liver failure
what is the antidote
acetaminophen (paracetamol or APAP) toxicity
toxic metabolite NAPQI accumulates in liver
antidote: N-Acetylcysteine (NAC) administered IV —> increases glutathione antioxidant in liver
what enzyme is responsible for producing the minor yet toxic metabolite of acetaminophen (paracetamol or APAP)? what metabolite does it produce?
p450 (induced in alcoholics) —> produces NAPQI (toxic)
(remember that the antidote for acetaminophen toxicity is NAC, which induces glutathione - this metabolizes NAPQI to non-toxic molecules)
what is the max recommended dose per day of acetaminophen and minimum toxic single dose in healthy adults
max dose per day: 4g (8 500mg tablets)
min toxic single dose: 7.5-10g (15-20 500mg tablets)
*severe liver injury in alcoholics reported to have take <4g
what is the effect of synthetic glucocorticoids such as hydrocortisone, prednisolone, prednisone, dexamethasone, and betamethasone?
mimic action of cortisol and other endogenous glucocorticoids
steroidal anti-inflammatory drugs
—> anti-inflammatory (powerful): downregulate COX-2 production (and thereby PGE2)
—> immunosuppressive: reduced histamine production, inhibit mast cells (for treating autoimmunity and cytokine storm, but risk of infection)
glucocorticoid therapy is indicated for disorders with a ______ component
inflammatory component
ex: allergy reactions, asthma, inflammatory bowel syndrome, SLE, arthritis, bursitis, cerebral edema, atopic dermatitis
minimal effective doses preferred - can have serious metabolic complications
describe the potentially serious metabolic complications of glucocorticoid therapy
carbohydrates: stimulate gluconeogenesis and inhibit glucose uptake by cells —> hyperglycemia, weight gain, diabetes
lipids: stimulate lipolysis —> fat redistribution to face/back of neck
proteins: reduce protein synthesis —> muscle wasting, osteoporosis
