18. NSAIDs Flashcards
the overall role of NSAIDs is what?
combined anti-inflammatory, analgesic, and antipyretic properties - not curative but suppress the signs and sxs of inflammation (same manner as steroids, but are not steroids)
eicosanoids?
large family of compounds derived from lipid membranes
-arachidonic acid (AA) = dominant precursor (20-carbon fatty acid)
NSAIDS are structurally divergent weak organic acids that inhibit what?
prostaglandin (PG) and leukotriene (LT) synthesis
what are the predominant anti-inflammatory drug categories?
salicylates, propionic and acetic acid derivatives, oxicams, and COX-2 inhibitors
aspirin does what to the serine-520 of COX to inhibit its activity and exclude arachidonate from its active site?
uniquely and irreversibly acetylates
thromboxane (TXA2), prostacyclin (PGI2), and the prostaglandins (PGD2, PGE2, and PGF2a) are all what?
prostanoids
the prostanoids are synthesized from _____ and bind to receptors on _____. (hint: one word fills both blanks)
membranes
which COX is present in most tissues as the housekeeper enzyme? Which COX is inducible by inflammation and is not present at baseline (except in the brain)?
COX-1; COX-2
which has higher affinity to convert arachidonic acid to prostaglandin, COX-1 or COX-2?
both are the same
why is the excessive inhibition of COX-1 undesirable? What about COX-2 inhibition?
COX-1 maintains normal gastric mucosa and influences kidney function and platelet aggregation - so excessive inhibition is undesirable
inhibiiton of COX-2 is desirable
explain the COX-2 to COX-1 ratio?
mechanism to assess the balance of inhibition of the inducible COX-2….lower the ratio, the lower the COX-1 inhibition and the lower the overall side effect profile
each prostanoid is synthesized from what? (hint: looking for the intermediate, not arachidonic acid)
PGH2 - the short lived intermediate
the terminal synthetic enzymes that determine which prostanoid is produced is specific to what?
the cell
which prostanoid has multiple receptors?
PGE2 (has EP1-EP4)
COX-1 and COX-2 are also called what?
prostaglandin-H synthase 1&2
what reaction do COX-1/COX-2 facilitate?
Arachidonic acid to PGH2
which COX is the constitutive enzyme (but induced in the brain) and the only form of COX in platelets/
COX-1
which COX is the inducible enzyme (but constitutive in the brain)? It is upregulated by cytokines, and shear stress, GFs, and own products (Feed forward).
COX-2
peripheral _____ can gain access to the CNS and stimulate more PGE2.
PGE2
productino of PGE2 is tightly related to the upregulation of what?
COX-2
OTC NSAIDS are used acutely for what? chronically?
acute:
- fever
- sprains, strains, and lower back pains
- headaches
- dysmenorria
chronic:
- cardiovascular protection
Rx NSAIDs are used acutely for what? chronically?
acute:
- injury
- migraine
- surgery
- patent ductus arteriosis
- premature labor
chronic:
- RA
- osteoarthritis
- AS
adverse effects of NSAIDs on blood? COX enzyme effected? PG affected?
- prolonged bleeding time, GI blood loss
- COX-1
- inhibition of TXA2 synthesis
adverse effects of NSAIDs on GI? COX enzyme effected? PG affected?
- erosive gastritis; peptic ulceration exacerbation
- COX-1
- inhibition of PGI leading to decrease in gastric mucosal secretion
adverse effects of NSAIDs on pulmonary? COX enzyme effected? PG affected?
- bronchospasm, urticaria, rhinitis, nasal polyposis
- ?
- inhibition of COX allows lipoxygenase path to dominate
adverse effects of NSAIDs on renal? COX enzyme effected? PG affected?
- fluid retention, NA excretion azotemia, hyperkalemia, oliguria, anuria
- COX-1/COX-2
- inhibition of PG involved in regulation of renal blood flow, glomerular filtration, and renal Na and water excretion, mediates renin release
adverse effects of NSAIDs on uterine? COX enzyme effected? PG affected?
- delayed parturition, dystocia (difficult birth)
- COX-2
- loss of contractile effects of PGE2 and F2a on uterine muscle
what are the propionic acid derivatives?
ibuprofen, naproxen
what are the indole derivatives?
indomethacin
what are the oxicams?
piroxicam, meloxicam
what are the COX-2 selective inhibitors?
celecoxib
does ASA inhibit COX-1 or COX-2?
both covalently - low doses inhibit preferentially, but not exclusively, platelet COX-1, and higher doses inhibit both systemic COXs
only COX-1 is found in platelets and it predominantly makes TXA2
inhibition of COX by ASA is irreversible - what does this mean?
so the effect on platelets lasts 8-10 days (life of the platelet)
the effects on other cell types are shorter due to new synthesis of COX
what is the drug of choice for acute rheumatic fever (ARF)?
ASA - alters clinical manifestations but does not change the ultimate course of ARF
- suppresses exudative inflamm in joints
- contraindicated where cardiac enlargement of severe mitral valve disease with fluid retention might occur
Salicylates and other NSAIDs are contraindicated in who?
- children under 16 w/viral infections because of the potential development of Reye’s syndrome (hepatic encephalitis0
- asthmatics where ASA-induced airway hypersensitivity occurs in 10%
- when surgery or dental work will occur within a week
- during pregnancy (esp early on)
- patients w/ulcers or other GI disturbances
- pts w/severe hepatic damage
- pts w/hypoprothombinopenia
- pts w/vit K defic
- pts w/hemophilia
salicylism
(mild intoxication) starts as buzzing in the ear after repeated large doses or in susceptible individuals at subchronic antipyretic-analgesic doses. This leads to tinnitus (ringing), drowsiness, GI upset, hyperventilation, dizziness, nausea and vomiting (see Fig. 3) but all symptoms cease upon drug withdrawal.
Reye’s syndrome
rare illness characterized by hepatic encephalopahty and steatosis that develops from a virus-host reaction in a susceptible patient possibly as a result of exposure to ASA and other NSAIDs but not acetaminophen
ibuprofin (motrin, advil)
relatively non-toxic
- GI upset in some (less than that of ASA)
- discontinue before surgery
- little interaction w/anticoagulants and other drugs
- consider when using this and other drugs as anti-inflamm: expensive and takes 1-2 weeks to act because enters synovium slowly
naproxen (aleve)
- side effects incidence low
- therapeutic effect may start in 24 hours but may be delayed 1-2 weeks
- longer T1/2 than ibuprofin
indomethacin (indocin)
- anti-inflamm w/analgesic/antipyretic activity
- closing a patent ductus arteriosis
- delays premature labor
- used clinically, not OTC because super strong
- high incidence of side-effects (50%): GI, CNS
- contra-indicated w/GI diseases
ketorlac (toradol)
phenyl acetic acid derivative
- mild anti-inflamm but potent pain relief, oral, or IM/IV equiv to codeine
- post op
- anti-inflamm used in eye drops
(only water soluble NSAID and may release endogenous opioids)
tolmentin
phenyl acetic acid derivative
- used for arthritis pain
- GI side effects
dicofenac (voltaren)
phenyl acetic acid derivative
- post-op and post-trauma pain
- acute migraines
- dysmenorria, pain assoc w/endometriosus
piroxicam (feldene)
oxicam
- used to be considered dangerous but recently shown similar risks to other NSAIDs
- rx for OA mostly
tenoxicam
oxicam
- ok for chronic pain, like arthritis, not for acute postop pain
meloxicam
oxicam
- COX-2 selective (10:1) at loewr doses
- long acting
celecoxib (celebrex)
- inhibits p450 enzymes
- interacts w/ACE inhibitors
- monitor pt!
- all other cox-2 spec inhibitors were withdrawn because uninhibitied COX-1 causes thrombosis
meloxicam (MOBIC)
- selective COX-2
- OA and RA use
what keeps ductus arteriosis open?
misoprostal (Me-PGE1)
SCARS
severe cutaneous adverse reactions
- SCARs may cause permanent sequalae such as disfigurement, blindness and death - rxns occur w/out warning
but overally risks of SCARs assoc w/NSAIDs is super low and highest incidence reported with celecoxib at 6 cases per 1 million person-years
stevens-johnson syndrome
life threatening skin condition similar to TEN (toxic epidermal necrolysis) both under category of SCAR
- cell death causes the epidermis to separate from dermis
- common sites of lesions are in mucosal membranes
- meds = only known cause
NSAIDs are spontaneous Ab
- diclofenac, celecoxib, naproxen, ibuprofin, refecoxib
- no dose response effect
TXA2 acts on what?
platelets - induces platelet aggregation, vasoconstrictor
PGI2 acts on what?
vascular endothelium, inhibits platelet aggregation, vasodilator
PGF2a acts on what?
smooth muscle and corpus luteum - contracts uterus
PGE2 acts on what?
brain - induces fever
PGDS acts on what?
brain - neuromodulator involved in non-REM sleep
all of the prostanoid receptors are what type of receptors?
7 TM GPCRs so make Ca++ and cAMP (EP3 is special though…)
why can’t we antagonize prostanoid receptors?
cross-talk, splice variants
The 4 EP receptors?
- EP1 is usually linked ultimately to changes in intracellular calcium
- EP2-4 are associated with increased cAMP productive via activation of protein kinase A.
- EP2 and EP4 are closely related and differ mostly in their affinity for PGE2 or various agonists.
- EP3 on the other hand comes in many splice variants and may either inhibit or stimulate cAMP and may alter intracellular calcium as well.
prostanoid analogs - which prostanoid?: misoprostol dinoprostone dinoprost carboprost epoprostenol latanoprost, travoprost
misoprostol - PGE1 dinoprostone - PGE2 dinoprost - PGF2a carboprost - PGF2a epoprostenol - PGI2 latanoprost, travoprost - PGF2a
misoprostol use
prevents NSAID induced gastric ulcers, combo w/diclofenac
labor induction (miscarriage, abortifacient but not to be confused w/mifepristone a PR antagonist that ends pregnancy
dinoprostone use
cervical ripening
carboprost use
post-partum hemorrhage - Me-PGF2a analog that contracts uterine smooth muscle
latanoprost use
glaucoma
