AntiInflammatory, Antipyretic and Analgesic Agents Flashcards
what is inflammation?
A normal body response
inflammation occurs in response to
- infection
- physical trauma
- noxious chemicals
Goals of inflammation (3)
- prevent damage from invading organisms
- set stage for tissue repair
- remove toxins
what released blood clotting proteins at wound sites
platelets
what secretes factors that mediate vasodilation and vasoconstriction
mast cells
what secretes factors that kill and degrade pathogens
neutrophils
what removes pathogens by phagocytosis? (2)
neutrophils and macrophages
what secretes hormones called cytokines that attract immune system cells to the site and activate cells
macrophages
the inflammatory response continues until the foreign material is ____ and the wound is ______
eliminated, repaired
the inflammatory response is ____
complex
name 4 inflammatory agents
- prostaglandins
- bradykinin
- histamine
- chemotactic factors
when healing is complete the inflammatory response usually _____
subsides
what is produced from almost all cells in the body
prostaglandin
what is derived from unsaturated fatty acids present in membranes
prostaglandins
prostaglandins work as ____ hormones
local
True or False: Prostaglandins produce locally and act locally
TRUE
what makes prostaglandins different from endocrine hormones?
prostaglandins produce locally and act locally, endocrine glands produce locally but act distantly
what acid are prostaglandins derived from?
arachidonic acid
arachidonic acid is a component of the ____ ______ _____ and is also ______
cell membrane phospholipid, proinflammatory
what separates arachidonic acid from plasma lipids in response to inflammatory stimuli
phospholipase A2
what is the starting point for inflammation?
phospholipase A2
phospholipase A2 is inhibited by _____ to reduce inflammation
steroids
once arachidonic acid is freed from the cell membrane can follow 1 of 2 pathways, what are they?
- Lipoxygenase
- cycloxygenase
lipoxygenase pathway includes
leukotrienes
cyclooxygenase
prostaglandins, thromboxanes, prostacyclines
thromboxanes are
procoagulant
prostacyclines are
anticoagulant
how many isoforms of cyclooxygenase exist?
2
what are the 2 isoforms of cyclooxygenase?
COX 1 and COX 2
COX 1 has two main functions, name them
Gastric protection, platlet function
COX 2 has 3 main functions, name them
pain, bone formation, fever
Do COX 1/2 have the same or different binding sites?
different
why is it important that COX 1/2 have different binding sites?
to allow for selective targeting
5 total functions of COX1
GI protection, platlet function, vascular homeostasis, reproductive and kidney functions, pain/fever/inflammation
4 total functions of COX2
pain/fever/inflammation, bone formation
vascular homeostasis is a function of
COX1
vascular homeostasis requires the production of (2)
Prostaclycin (PG12) and Thromboxane A2 (TX A2)
Prostacyclin (PG12) in vascular homeostasis is responsible for
producing vascular endothelium and works as an anticoagulant
Thromboxane A2 (TX A2) in vascular homeostasis is responsible for
Platelet production and pro-coagulation
3 primary functions of prostacyclin in vascular homeostasis
- keep platelets inactive
- prevent platelet aggregation
- promote vasodilation
3 primary functions of thromboxane A2 in vascular homeostasis
- activate platelets
- recruits platelets to site of injury
- promotes vasoconstriction
prostacyclin (PG12) inhibits _____ _____ secretion
gastric acid
PG2 and PGF2a stimulate
production of protective mucus in small intestine and stomach
what prostaglandin production is Cox-2 responsible for?
Prostaglandin E2
Prostaglandin E2 is responsible for (5)
- temp regulation
- pain
- inflammation
- bone healing
- vasodilation
COX-1 and COX-2 both impact (3)
- pain
- fever
- inflammation
COX-1 ONLY impacts
- GI protection
- platelet production
- vascular homeostasis
what are NSAIDs?
non-steroidal anti-inflammatory drugs
what are NSAIDs NOT?
steroids
true or false: steroids have powerful anti-inflammatory actions
TRUE
are NSAIDs stronger or weaker than steroids?
weaker
what are 2 pros to NSAIDs rather than steroids?
- long term therapy
- less toxic side effects
what is a toxic side effect from steroids?
hyperglycemia
what is the mechanism of action for NSAIDs
Competitive Cyclooxygenase inhibitors
what medication is the one exception in NSAIDs that are not competitve COX inhibitors?
aspirin
how do competitive COX inhibitors work?
by blocking the hydrophobic channel by which the substrate arachidonic acid accesses the active enzyme site
3 primary therapuetic effects of a competitive COX inhibitor?
- anti-inflammatory
- Analgesia
- Anti-pyrexia
What does COX inhibition do during its anti-inflammatory property?
COX inhibition decreases prostaglandin formation
do NSAIDs alone fix the underlying process or cause of the inflammation?
NO
if you wanted to treat chronic inflammation what should you do with your NSAID doseage?
increase it
NSAID dose increase =
more adverse side effects
what is thought to be responsible for analgesia?
COX2 inhibition
what are the most important prostaglandins involved in pain?
PGE2 and PG12
how does PGE2 work?
sensitizes nerve endings to actions of chemomediators released by inflammatory process
what is pain production by PGE2 and PG12 inhibited by
NSAIDs
True or False: NSAIDs have relatively equivalent efficacy
TRUE
NSAIDs are best for which pain?
muscular, bone, vascular
what type of pain are NSAIDs not good for?
visceral (abdomen/organs)
PGE2 synthesis leads to an elevated
set-point of anterior hypothalamus thermoregulatory center (cause of fever)
do NSAIDs inhibit or promote or inhibit PGE2 synthesis and release?
INHIBIT
do NSAIDs have an effect on normal body temperature?
no
how are NSAIDs absorbed
near complete GI absorption. absorbed rapidly
does food reduce the rate of absorption of NSAIDs
yes
does food reduce the extent of absorption
no
where are most NSAIDs metabolized?
liver
NSAIDs with a short halflife
Diclofenac, ketoprofen, ibuprofen, indomethacin
NSAIDs with a long halflife
Naproxen, sulindac, nabumetone, piroxicam
most NSAIDs peak in
1-2 hours
What are 7 adverse effects to NSAIDs
- Nausea
- Vomiting
- GI distress
- Peptic Ulceration
- Bleeding
- HA & Dizziness
- Elevated LFT
what medication might prevent adverse NSAID effects?
concomitant use of H2 receptor blockers or PPIs
what is a way to decrease adverse NSAID effects
taking NSAIDs with food or milk
How could NSAIDs cause possible bleeding?
stops platelets from sticking together
the inhibition of vasodilation prostaglandins. Could decrease renal blood flow and GFR leading to tissue injury
Nephrotoxicity
Nephrotoxicity leads to retention of
sodium and water
what does sodium/water retention lead to
edema, HTN, increased creatinine, hyperkalemia
What is an adverse effect with NSAIDs specifically for asthmatics?
hypersensitive reactions (rash, bronchospasm)
How are COX-2 inhibitors unique?
in their selectivity
how are COX-2 inhibitors unique in their selectivity?
they inhibit COX2 while leaving COX1 unaffected
Pros of using a COX2 inhibitor
less GI bleeding, less dyspepsia, no effect on platelet function
what are adverse effects to COX2 inhibitors
increase risk of cardiovascular thrombotic events (MI & Stroke)
what medication is contraindicated in a patient with a sulfa allergy?
celecoxib
indications for COX2 inhibitors
rheumatoid arthritis, osteoarthritis, acute pain
COX2 agents
Celecoxib, Meloxicam
what are two medications that were removed from market due to their double incidence of MI and CVA
Rofecoxib and valdecoxib
what is aspirin?
irreversible inhibitor of COX1 at low doses
reversible COX inhibitors include
NSAIDs
how does aspirin work?
by decreasing thromboxane A2
when is aspirin considered anti-inflammatory?
high doses
why is aspirin anti-inflammatory only at high doses?
it lacks significant COX-2 effect
is aspirin a better anti platelet or a better anti-inflammatory?
anti platelet
Aspirin has a higher relative specificity for COX-1 meaning that there is a higher risk
GI events
Adverse GI effects are common due to (especially in high doses)
decreased mucus secretions
More adverse effects to aspirin
Nausea, heartburn, dose-related GI bleeding, ulcer bleeding, gastric perforation
How do you decrease GI side effects with aspirin?
co-administering aspirin with a PPI (prilosec, nexium, prevacid) OR enteric coated ASA
cons of enteric coated ASA
may decrease antiplatelet function
how long do you hold aspirin prior to surgery?
1 week
is aspirin reversible or irreversible?
irreversible effect for life of plaetlet
why do we use caution when combining ASA and NSAIDs
NSAIDs have a greater affinity for COX-1, it could antagonize the protective effects (anti-platelet) of ASA
bronchospasms as a result of hypersensitivity from ASA are more common in patients with (3)
- asthma
- nasal polyps
- recurrent rhinitis
in addition to bronchospasms in ASA hypersensitivity, what else could you see in a patient affected by this?
rash, rhinitis, edema, anaphylaxis & shock`
aspirin is contraindicated in
children
letting a child take aspirin could increase their risk of
Reye’s Syndrome
Reye’s syndrome is (rapid/slow) progressing
rapid
What are effects of Reye’s Syndrome
Liver Failure, Cerebral Edema, Death
what is the mortality rate for Reye’s Syndrome
35%
Is ASA given more a secondary or primary prevention?
Secondary
A Secondary Prevention medication is something that
reduces the risk of that illness recurring immediately after (ex. MI and ASA)
Primary prevention in medication
a preventative measure for people who meet the criteria to be at risk for the disease
Tertiary prevention is
long term
a constellation of symptoms associated to a mild form of toxicity
Salicyilism
When can Salicyilism occur?
pts with chronic use of large doses of ASA
earliest signs of Salicylism toxicity
N/V, diaphoresis, sensorineural hearing loss, tinnitus
later symptoms of Salicylism toxicity
vertigo, hyperventilation, tachycardia, hyperactivity
what type of kinetics do you want with ASA?
first order
first order kinetics
rate of elimination is proportional to dose
if you increase ASA doses, the metabolism becomes saturated and you begin following
zero order kinetics, causes increase of halflife
zero order kinetics
fixed amount of drug metabolized per unit of time
salicylic acid is a (weak/strong) acid
weak
Salicylic acid exists in a (charged/uncharged) form
both
uncharged molecules can move easily across
cellular barriers
Hallmarks of Acute Salicylate overdose
Hyperpnea, tachypnea, metabolic acidosis, tachycardia
severe salicylate intoxication can cause
AMS, coma, death, hyperthermia
what are the goals of treatment in acute salicylate poisoning
correct fluid and electrolyte balance and enhance excretion
what do you administer to increase the systemic pH in acute salicylate poisoning?
Sodium Bicarbonate
how does sodium bicarbonate work?
Alkalinization - it traps salicylate anions in the blood and within the renal tubule which limits diffusion to the CNA and facilitate excretion
Acetaminophen is considered a (strong/weak) inhibitor of prostaglandin synthesis
weak
what does Acetaminophen inhibit
prostaglandin synthesis in CNS
what are the main effects of acetaminphen?
- analgesia (block pain impulse)
- antipyresis (inhibit hypothalamic heat regulation)
what does acetaminophen not do?
anti-inflammatory and antiplatelet effect
functions of analgesia and antipyresis start how long after taking tylenol?
analgesia - 5-10 min
antipyresis - 30 min
how long does tylenol last
4-6 hours
IV acetaminophen is how much more expensive than oral
at least 10x
adverse effects of acetominophen
- hepatotoxicity
- rash
hepatoxicity can cause
hepatic necrosis and is high risk in pt with underlying disease
does acetominophen have an adverse effect on the GI system?
NO
where is acetaminophen primarily absorbed?
small intestine
what is the primary metabolism for acetaminophen?
hepatic metabolism
where is most of acetaminophen conjugated?
the liver to inactive glucronidated or sulfated metabolite
a small portion of acetaminopehn is hydroxylated to form
NAPQI
NAPQI is a
highly reactive metabolite - can react with sulfhydryl groups and lead to liver damage
maximum dose of tylenol
no more than 1 gram every 4 hours and no more than 4 grams every 24 hours
what is the leading cause of drug-induced liver failure in the US?
acetaminophen
Phase 1 (0-24 hours) of acetaminophen toxicity
N/V, general malaise, ASYMPTOMATIC
Phase 2 (24-72 hours) of acetaminophen toxicity
RUQ pain, elevated liver enzymes, pronlonged PT
Phase 3 (72-96 hours) of acetaminophen toxicity
hepatic necrosis, encephalopathy, coagulopathy, renal failure
Phase 4 (4 days-2wks) of acetaminophen toxicity
complete resolution of hepatic dysfunction
what graph is used for acetaminophen overdose?
Rumack-matthew nomogram
treatment for acetaminophen overdose
N-acetylcysteine (NAC)
how does NAC work?
maintains or restores glutathione levels and acts as a substrate for conjugation of NAPQI
NAC reduces the extent of ____ injury
liver
when is NAC most effective
when given early (within 8 hours)
is all inflammation temporary?
NO
are all causes of inflammation the same?
NO
a collection of disorders where the body is being damaged by its own immune system
autoimmune diseases
autoimmune disorders require a combination of _____ and _____
anti-inflammatory and immunosuppressive agents
a group of medicines used in combination with anti-inflammatory medications to treat autoimmune diseases
Disease-modifying anti-rheumatic drugs (DMARDs)
goals of DMARDs
- slow disease progression
- prevent further tissue damage
- induce remission
traditional DMARDs (5)
- Methotrexate
- Hydroxychloroquine
- Leflunomide
- Sulfasalazine
- glucocorticoids
Biologic DMARDs (7)
- adalimumab
- etanercept
- rituximab
- certolizumab
- golimumab
- infliximab
- abatacept
methotrexate is a ____
folate acid antagonist
how does methotrexate work?
inhibits cytokine production and purine nucleotide biosynthesis
True or False: methotrexate is a immunosuppressive and anti-inflammatory
true
can methotrexate be combined with other agents
yes
side effects of methotrexate (4)
- mucosal ulceration
- nausea
- cytopenia
- liver function test elevation
methotrexate is contraindicated in
pregnancy
