lect 11 Non-steroidal anti-inflammatory drugs Flashcards
most common NSAIDS
aspirin
two categories of NSAIDS
salicylates (aspirin) and non salicylates (ex ibuprofen, acetaminophen)
History: compound extracted from plants and its derivative
salicylic acid and acetylsalicylic acid
what does aspirin inhibit
synthesis of prostaglandins
what cleaves section of plasma membrane fatty acids and what is being released
Phospholipase A2 and release of arachidonic acid
structure of arachidonic acid and what it does
20 carbon, polyunsaturated fatty acid and acted on by enzymes to produce biologically active compounds
enzymes that produce prostaglandins and thromboxanes
cyclooxygenases
what two cyclo. produce prostaglandins
COX-1 AND COX-2
change in structure from arachidonic acid to prostaglandins
formation of a ring and adding two carbons
structure, place, role of cyclooxygenases
dimers so 2 equal active site, in the ER, converts arachidonic acid to prostaglandins
true or false? prostaglandins have autocrine and paracrine functions
True
inactivation of prostaglandins is fast or slow?
rapid fast inactivation
other functions of prostaglandins
protect stomach from hydrochloric acid and thromboxanes involved in platelet aggregation and blood clotting
true or false? Blocking prostaglandins can prevent intravascular coagulation and heart attacks
True
prostaglandins have effects on what? (7)
Renal homeostasis, sleep cycle, reproductive system, vasodilation and vasoconstriction, platelet aggregation, blood flow to organs, pain and inflammation
COX 1 activity and use
constitutively active and essential for physiological purposes like stomach protection platelet aggregation
COX-2 activity and use
inducible, essential for pathological purposes like pain and inflammation
prostaglandins act on what receptors
many different prostanoid receptor that have different subunits
NSAIDS block prostaglandins that are implicated in what three things
fever (antipyretic), pain (analgesic), inflammation (anti anflammatory)
Pain stimulus pathway
painful sensation going to spinal cord, relying in the thalamus, then the cortex, and then instantaneous reflex to withdraw from pain stimulus
periphery in sensation of pain (2)
thermoreceptors, nociception
injured cells release what
Mediators, including prostaglandins
release on mediators have effect of what
nerve endings so impulses sent to spinal cord and up the brain
involved in signaling from a variety of noxious stimuli (mediators released form injured cells and platelets)
nociceptive nerve endings
NSAIDS act predominantly where
out in the periphery at the origin of pain stimuli and inflammation (nociceptors
How does Nsaids work on periphery in relation to prostaglandins
blocks synthesis of PGs to decrease their intensity of the painful signal coming from periphery
First stage usage when pain
NSAIDS
Second stage usage when pain
OPIOiD and NSAIDS
third stage usage when pain
OPIOIDS
therapeutic usage of NSAIDS (5)
mild moderate pain like headache, inflammatory disorders, reduce fevers, prophylaxis of myocardial infarction and stroke, reduce risks of certain cancers
chemical mediators inflammation pathway
released from injured tissue to local capillary bed which induces vasodilation and fluid and cells are drawn into injured area
inflammatory mediators contribute to sensation of which nociceptors
sensitizing PGE2 or activating BK
acute inflammation
cuts, allergic reactions
chronic
cancer, arthritis, CV and neurological diseases
what is osteoarthritis
injury induced joint damage
what is Rheumatic arthritis
joints inflammed independent on the environment
racehorses NSAID
equioxx
arthritis common in excessive inbreeding
canine arthritis
ASA or acetominophen should never be given to what animal
cat
fever is induced by what
endogenous pyrogens that raise thermostatic set point in hypothalamus
which PG major player for increasing setpoint in hypothalamus for fever
PG E2
body response to pyrogens
temperature regulatying cenetr sends out impulses via ANS leading to increased heat production and decreased heat loss
side effects of nsaids to upper GI tract
dyspepsia, erosions, ulcers, GI bleeding
side effects of nsaids to renal
renal dysfunction, renal failure, blood pressure, heart failure
why can NSAIDS cause blood loss
because of its anti platelet effect
what lines the membrane layer of stomach and is protected by prostaglandins
gastric mucosa
generic name for acetylsalicylic acid
aspirin
how does aspirin inactivate COX (antithrombotic)
acetyl group of acetylsalicylic acid binds to serine residue in COX
what is thromboxane A2
made in platelets which causes vasoconstriction and thrombosis (blood clots)
does aspirin block thromboxane A2
yes
true or false? Asprin can lower risks of colon cancer
true
asprin half life and also at higher doses
3 hrs and 15 hrs
aspirin (acetylsalicylic acid) is metabolized to what
salicylic acid
enzymes that break down aspririn in lover
P450
pharmacokinetics of NSAids in liver
P450 enzymes producing metabolites and glucoronyl transferases conjugating the metabolites to make water soluble glucuronide to be excreted by kidney
pharmacokinetics of NSAids in liver
salicylic acid is an acid so reabsorbed by kidneys if tubules are acidic. for overdose, alkalinize urine so that weak acid wont be in unionized lipid soluble form and not be reabsorbed
what do we call aspirin toxicity
salicylism
sense of ringing in the ear
tinnitus
neurological syndrom when children take aspirin
Reye’s syndrome
what can we give children instead of aspirin
acetaminophen
aspirin binds reversibly or irreversibly
irreversiblly
ibuprofen binds reversibly or irreversibly
reversibly
types of ibuprofen
motrin, advil
ibuprofen blocks what
both COX 1 AND 2
cox 2 have constituitive effects on what
blood flow and kidney
cox 2 is important for what
platelet inhibition and vasodilation
which cox enxyme has a larger channel for arachidonic acid
cox 2
highly selective and large cox 2 inhibitor drug
celecoxib
why does cardiovascular problems occur with cox 2 selective inhibitors
the balance is shifted towards a prothrombotic state cause does not block cox 1
who is prothrombotic
cox 1 because they make thromboxane
who is antithrombotic
cox 2 because make prostacyclin
asprin balance on cox enzymes
does not affect balance because acts on both cox 1 and cox 2. low doses bllocks cox 1 more and that for people with thrombosis
which cox 2 inhibitor was withdrawn
rofecoxib
cox 1 is highly concentrated where in the body and cox 2 where
gi tract and found in many places like brain, kidney…
tradename drug most used (acetaminophen)
tylenol
what is the main difference between acetaminophen and other nsaids
it is not anti inflammatory
half life of acetaminophen
2-3 hours
emzymes that break it down to a toxic metabolite
CYP450
break down in liver of acetaminophen
breakon down to a toxic intermediate that is quickly conjugated
what congugates acetaminphen
glutathione
what is cellular necrosis
reaction with hepatocytes to kill liver cells if toxic intermediate of acetaminphen is not quickly conjugated
overdose of acetaminophen?
enzymes that conjugate saturated so more toxic compound
who are vulnerable to the toxicity of acetaminophen and why
alcoholics because chronic use of ethanol induces P450 enzymes that make the toxic metabolites
effects at 0-24 hour stage of acetaminophen poisining
anorexia, nausea, vomiting
effects at 24-72 hour stage of acetaminophen poisining
abdominal pain, elevated serum enzymes
effects at 72-96 hour stage of acetaminophen poisining
synptoms of liver and renal failure and pancreatitis
antidote of acetaminophenoverdose
glutathione precursor (N acetylcysteine) so that congugation can happen
