Week 6: Anti-Inflammatories Flashcards
Prototype Drugs for the Anti Inflammatory Category
- aspirin (Aspirin)
2. acetaminophen(Tylenol)
3. indomethacin (Indocin)
4. ibuprofen (Motrin, Advil, etc.)
5. celecoxib (Celebrex)
6. ketorolac (Toradol)
7. etanercept (Enbrel)
8. hydroxychloroquine (Plaquenil)
9. azathioprine (Imuran)
10. allopurinol (Zyloprim)
11. colchicine (Colcrys)
Prostaglandins
Modulate important components of inflammation: Body Temp increases, Pain Increases, Platelet Aggregation Increases
They are converted from arachidonic acid by cyclooxygenase (COX) enzyme
Chronic Inflammation = ???
More prone to blood clotting
COX 1
The first kind of COX enzyme that converts arachidonic acid to prostaglandins
HAS PROTECTIVE EFFECTS
Found in all tissues
Decreases stomach acid and increases gastric mucus = protects the stomach
Increases platelet aggregation = may prevent bleeding
COX 2
Second kind of COX
A major mediator of bad effects - we want to stop this one
Found mainly in INJURED tissues
increases inflammation
increases pain
causes fever
NSAIDS
Non steroidal anti inflammatory
many NSAIDS inhibit prostaglandin synthesis and many do so by targeting both COX 1 and 2
How do NSAIDS cause many adverse effects we see?
it blocks COX 1 (the protective effects/good stuff)
Salicylates
Class of anti inflammatories - active form
is so irritating it can only be used externally - so it includes Acetylsalicylic acid (Aspirin, ASA)
Prototype drugs for Salicylates
Aspirin (Metabolizes into the active metabolite of salicylic acid)
Aspirin is a ___ drug
ancient
Aspirin is used for what effects
Analgesic
Antipyretic
Anti Inflammatory
Anti Platelet
What is unique about aspirin
IRREVERSIBLY INHIBITS COX - good blocking COX 2 but blocks COX 1 which is also bad
What is important to know about clotting after taking aspirin
As long as ASA is still lingering it will effect COX thus impacting the life of the platelet as well
Every platelet of any age is effected by ASA, so once a platelet is effected it cannot clot well for the rest of its lifespan
Side effects from ASA are mostly due to what
inhibition of COX 1 enzyme
Since salicylic acids can only be sued externally what reason are they commonly used for
acne products
Actions of Aspirin
- Analgesia
- Antipyretic
- Anti Inflammatory
- Gastrointestinal
- Anticoagulation
What is the analgesia action of aspirin
- Effects PERIPHERAL more, not central, by preventing sensitization of pain receptors by inhibiting prostaglandin synthesis !!! - This is the main way ASA works, periphery
- Works somewhat centrally on the hypothalamus by modifying pain perception, but the action here is little and also the antipyretic effect takes place here
What is the antipyretic action of Aspirin
believed to act directly on heat regulating center in the hypothalamus
decreases fever but not below the set point
What is the anti inflammatory action of aspiring
inhibits prostaglandin synthesis (by irreversibly impacting Platelets and COX 1 and 2)
What is the GI action of aspirin
local irritation and also stimulation of the vomiting center in brain - since it blocks COX 1 it increases stomach acid and it will cause less mucus so there is a greater irritation risk
Also* if a stomach ulcer occurs you will bleed more from the anticoagulant effect and the acid will irritate flesh
What is the Anticoagulation effect of Aspirin
IRREVERSIBLY inhibits platelet aggregation, weakly inhibits prothrombin synthesis, and prolongs bleeding time
MORE LIKELY TO BLEED
Uses for Aspirin
- Effective in pain from inflammation (due to prostaglandin increases), BUT NOT sharp pain due to sensory nerve stimulation
- Anti pyretic effects - peripheral and central inhibition of prostaglandin (pyretic) activity
- Anti inflammatory - inhibits prostaglandin activity
- Anti platelet - antithrombotic effect by inhibiting thromboxane A2, a prostaglandin that induces platelet aggregation
What is the main reason we use ASA nowadays
Its Anti Platelet Effect
It blocks Thromboxane A2 which is a prostaglandin that induces platelet aggregation!
People are less likely to develop blood clots - daily ASA to prevent clots that cause MI/DVT - inhibits TXA-2 to stop platelets
It is important to know what about the excretion of ASA
IT IS EFFECTED BY URINE PH - if someone overdosed on it we could modify their urine pH to increase secretion
What are the ADRs of ASA like
widespread- many different effects - most are GI
What are the various ADRs of Aspirin
- Most are GI* - NOT an allergy but could be a SE - epigastric distress, NV, ulceration
- Respiratory - respiratory stimulation, due to increased O2 consumption - resp stimulation NOT usually a problem only seen taking too much
- CV - large doses cause peripheral vasodilation - NOT common due to low doses
- Allergic - low, but can cause asthma, angioedema, and urticaria
- Blood - Anemia, Thrombocytopenia, Coagulation Effects - iron deficiency with bleeding, low platelets and bone marrow depression (effects platelet fxn more than numbers), increases cap. permeability and increases bleeding time
- CNS - tremors, HA, vertigo, tinnitus, diplopia, agitation, can be ototoxic
- Metabolism effects
What is rare but can occur with too much aspiring
hepatic and renal toxicity
Why do we never give children with flu like illnesses aspirin?
Risk for Reyes Syndrome - potentially fatal swelling in brain and liver along with hypoglycemia
If there is a flu like viral illness, ASA weill leave them prone to Reyes Syndrome
What does it mean that ASA can be ototoxic
impacts 8th cranial nerve and too much is toxic to the ears
What is typical dosage for ASA in adults?
81 mg daily or 325 PO once
What is an important prototype drug that is non-antiflammatory analgesic, non opioid that is grouped with anti inflammatories and NSAIDS
acetaminophen (Tylenol, Tempra)
acetaminophen (Tylenol, Tempra)
a non anti inflammatory and non opioid analgesic - it can be used for its ANTIPYRETIC and ANALGESIC effects (same as Aspirin but without the anti inflammation)
acetaminophen is similar in use to ___ but what sets them apart
it is similar to NSAIDS but has NO anti inflammatory effects and NO effect on platelet aggregation
So it is good for bringing down mild to moderate pain and bringing fever down without bleeding
What is the action of acetaminophen
uncertain but it has both central and peripheral action - the central action is more important in this case compared to peripheral because it acts centrally more on perception of pain as compared to ASA
ADRs of Acetaminophen
Surprisingly free of ADRs at therapeutic doses (less or equal to 4g/day)
Large doses are extremely toxic to the liver - gets press because of liver failure
Chronic use can cause kidney damage (every day)
Many drugs have acetaminophen in it so keep that in mind when taking drugs to prevent overdose
____ is often used in similar instances with aspiring, but has fewer SE and now has an IV formulation (Ofirmev)
acetaminophen
What is the antidote to acetaminophen
acetylcysteine (Mucomyst)
sulforous compound that is a liquid and smells like rotten eggs- needs to be given cont. in precise intervals
Given with 8 hours of ingestion - 3 bags first over 1 hour, second over 4 hours, and third over 16 hours
What is important to know about Tylenol no 1-4
This is the brand name a company uses to show combinations of tylenol with codeine
Combination drugs containing acetaminophen have what suffix
-CET
ex: Percocet, Roxicet, etc
acetaminophen can be toxic to both ___ and ___
liver and kidneys
Other than ASA, what are other important NSAID prototype drugs to know
indomethacin (Indocin)
Ibuprofen (motrin, advil)
celecoxib (Celebrex)
ketorolac
What is the prototype NSAID that is an indole analog
indomethacin (Indocin)
What is the action for indomethacin (Indocin)
potent inhibitor of prostaglandin synthesis
ADRs of Indomethacin (Indocin)
GI (like most NSAIDS) - anorexia, NV, peptic ulcer, and hemorrhage
Headache
Dizziness
Tinnitus
Skin rash
Edema
Rarely - Bone marrow depression
Aggravates psych disturbances, parkinsons, and epilepsy
OCULAR CHANGES (retinal and corneal)
What is the unique side effect of indomethacin as compared to other NSAIDS
the headache - it is a distinct frontal headache (can be severe)
When is indomethacin given instead of ASA or a different NSAID
only in specific inflammatory conditions - not given for HA, pain, fever as a replacement to ASA or acetaminophen - but shares some mechanisms with the 2
What is important to know about what NSAIDs can hide
Can mask signs and symptoms of infection by decreasing fever redness and swelling
___ to ___ of indomethacin patients have a SE, and __% will have to discontinue the drug due to the headache or a rash
1/2-1/3; 20%
Indomethacin must be given with….
food milk or an antacid to slow absorption and decrease SE
What is a unique use for indomethacin that is not as an NSAID
it can be given IV to close patent ductus arteriosus in preterm infants
What is the prototype drug for NSAIDs that is a propionic derivative
ibuprofen (Motrin, Advil, etc)
Action of ibuprofen
exact mode is unknown
Does inhibit synthesis and/or release of prostaglandin
ibuprofen absorption has to be done
orally
ADRs of Ibuprofen
NV, Diarrhea, Constipation, Heartburn - GI effects
Skin eruptions, pruritis, dizziness, blurred vision, fluid retention
NSAIDS have an effect on blood flow to the kidneys so…
even one dose of an NSAID can decrease blood to kidney which leads to fluid retention and increased BP and then a HA potentially
Ibuprofen can be toxic to …
the kidneys
___ NSAIDS should be considered before oral NSAIDs and why?
Topical NSAIDS - they cause less ADRs and dont take as long as oral NSAIDs
Give what with NSAIDs like ibuprofen to decrease GI symptoms
Food
ALL NSAIDS except ___ and ___ can interfere with platelet function and prolong bleeding time - this effect is reversible in nearly every NSAID (except ___)
Salycylates and celecoxib; Aspirin
When is ibuprofen contraindicated
in patients with a hx of ASA induced bronchospasm, or those with symptoms of asthma, rhinitis, nasal polyps, angioedema, urticaria
If visual difficulties with ibuprofen occur…
stop the drug and have a complete eye exam done
Caldolor
a new IV form of ibuprofen rarely used
What is the class effect for NSAIDs
potential increased risk for cardiovascular events - increases thrombotic events, MI, CVAs, and heart failure
What is a 2nd generation NSAID
a COX 2 inhibitor - it is an NSID that only blocks COX 2 rather than both COX 1 and 2
It is great for chronic pain and arthritis conditions
Prototype COX-2 Inhibitor; 2nd Generation NSAID
celecoxib (Celebrex)
Action of celecoxib
selectively inhibits COX-2 (an isoform of cyclooxygenase)
ADRs of celecoxib
abdominal pain, diarrhea, dyspepsia -LOT LESS GI EFFECTS
renal toxicity, fluid retention, edema
- STILL has kidney, HTN, and fluid volume concerns like other NSAIDs
What is nice about using a COX-2 Inhibitor like celecoxib rather than a 1st generation NSAID
Since it only impacts the bad COX, there is less bleeding since no interference with platelet function and less GI effects since it doesnt inhibit acid inhibition
When is celecoxib contraindicated
in persons allergic to sulfonamides (contains a sulfur molecule) - not a common issue
Why is celecoxib the preferred 2nd generation NSAID over the first ever one, rofecoxib (Vioxx)
Vioxx was the first COX2 inhibitor made, but there is a higher incidence of cardiac issues and MI, and the company his this fact from the FDA
celecoxib has similar cardiac concerns but is used carefully and did not hide this fact
What did the investigation into vioxx reveal
that ALL NSAIDs, except ASA, have risk for clots and MI concerns
What is a prototype NSAID that is basically a parenteral form of ibuprofen
ketorolac (formerly known as Toradol)
Action of ketorolac
inhibits prostaglandin synthesis !!! (inhibits cyclooxygenase, which decreases prost. synthesis and activity)
May also inhibit effects of other substances that sensitize pain receptors
ADRs of ketorolac
CNS - drowsiness, sedation, dizziness, HA, sweating
CV - edema, HTN, dysrhythmias !!!!!!!
GI - nausea, GI pain, diarrhea, peptic ulceration
Other - decreased platelet adhesion, hyperkalemia, pain at injection site
NO KIDNEY PROBLEMS WITH THIS NSAID SINCE ITS ONLY USED IN SHORT TERM PAIN NOT LONGER TERM (long term could cause renal issues though)
ketorolac is used for short term management of pain which is about how many days ?
up to 5 days
*this means rather than in rheumatoid conditions it is better in post operative and musculoskeletal conditions - so it can be given instead of morphine
What can be used post op equivalent to morphine but without narcotic effects
ketorolac
___ is a short term parenteral NSAID
ketorolac (not used orally)
etanercept (Enbrel)
anti inflammatory
TNF (tumor necrosis factor) block
Anti Rheumatic
Biologic (meaning it looks at bio mechanisms not compounds adding or taking away)
Why does entanercept (Enbrel) count as an anti inflammatory
it is a TNF blocker and TNF causes inflammation so blocking it will help lower inflammation
Action of etanercept (Enbrel)
Suppresses inflammation by neutralizing TNF
Binds with TNF and prevents interactions with its normal receptors
In a long term inflammatory conditions this will decrease in drastically - before this it was symptom treatment but this can target the reason behind the inflammation
How is absorption of etanercept done (route)
subcutaneous injection
ADRs of etanercept (Enbrel)
injection site rxns - common - SIGNIFICANT concern regarding increased risk of infection (whole body drug –> systemic effects on immune system –> increased infection)
RARE: CNS disorders like mult. sclerosis, some hematologic disorders
What is a big problem for using etanercept
very expensive - 1 year is 15000
but is v worth it to young people in chronic pain
Why must CXR and TB skin tests and assessment for infection done before giving entanercept
people need skin tests and CXR because TB can lurk and blossom once immune system issues occur from taking this TNF blocker - we have to stop if infections develop
What is important to know about “Me 2 Drugs”
they are drug copies that try to block inflammation in various ways, but can be helpful if one drug doesnt work since another might
ex: enteracept - copies: humira, cimzia, orencia, actemra (all work in different ways)
hydroxychloroquin (Plaquenil)
An ANTIMALARIAL DRUG but ALSO used for inflammatory conditions
Action of hydroxycloroquine (Plaquenil)
unknown for its anti inflammatory effect. May involve suppression of antigen responsible for hypersensitivity rxns causing malaria symptom development (interaction with DNA for malaria)
ADRs of hyroxycloroquine (Plaquenil)
GI Upset (especially nausea)
Mild and transient HA
bone marrow depression
dermatitis, rashl, pruritus
alopecia
OCULAR ISSUES (retinal toxicity, photophobia, blurry vision, abnormal distant and peripheral visual fields)
What is the biggest ADR concern when taking hydroxychloroquine (Plaquenil)
Ocular issues –> IT IS IRREVERSIBVLE
Progression will stop if drug is stopped but eye damage isnt as big of an issue as people originally thought but remember eye damage is irreversible still
How does dose vary for hydroxychloroquine
it varies whether it is being given as an antimalarial or antirheumatic
When taking hydrochloroquine it is important to do what yearly if at high risk or every 5 years if low risk
an eye exam
hydroxychloroquine is not an effective treatment for what
COVID-19
What is a prototype drug that is an immunosuppressive but also an anti inflammatory
azathioprine (Imuran)
azathioprine (Imuran)
super strong immunosuppressant - sometimes used for inflammation, but ADR risk is high so it is not a common anti inflammatory anymore
Action of azathioprine (Imuran)
inhibits cell proliferation by interfering with synthesis of DNA and RNA
can act as an anti inflammatory because it inhibits responses of cells like lymphocytes or macrophages as a result of immunosuppression
affects purine metabolism - less important
ADRs of azathioprine (Imuran)
bone marrow depression
GI - NV, anorexia, jaundice
alopecia
hemorrhagic
cystitis
increased incidence of infection
neoplasm risk
VERY SERIOUS CONDITIONS CAN OCCUR - even high incidence of cancer due to immunosuppression
What must be carefully considered before using azathioprine (Imuran)? What is an important use of azathioprine still used nowadays?
severity of adverse effects should be considered carefully - smaller doses can be given if used with allopurinol
Often still used with organ transplants to decrease rejection nowadays!
The historical use of azathioprine is what
historical use for inflammatory prevention because of being a powerful immunosuppressant
Gout
a distinct inflammatory condition in the same family as other forms of arthritis
often characterized by increases of uric acid in bloodstream which can precipitate in the joints
very common still - young middle aged men
a form of arthritis
Most common area for gout
the great toe
2 Important Anti Gout Medications
allopurinol
colchicine
alopurinol (Zyloprim, Lopurin)
anti gout medication
inhibits production of uric acid
“prevents inflammation from gout”
Action of allopurinol (Zyloprim, Lopurin)
interrupts process of purine degradation BEFORE URIC ACID IS FORMED
interrupted before uric acid production is complete by inhibiting xanthine oxidase
ADRs of allopurinol
most common - DRUG RASHES
bone marrow depression, reversible hepatotoxicity, drowsiness
DOES have some liver effects though
can have serious impacts but many can take this med for years before having problems
What is important to consider if taking allopurinol with an anticoagulant
allopurinol has effects on the liver and interferes with clotting factors - risk for bleeding
What is important to think about when taking allopurinol?
- use with care with anticoagulants
- high fluid intake necessary
What is febuxostat (Uloric) in reference to allopurinol
It is a new drug and first selective xanthine oxidase inhibitor that is NOT a purine analog
more potent than allopurinol BUT still inhibits the production of uric acid likle allopurinol
colchicine (Colcrys)
specifically an anti gout anti inflammatory for gout
colchicine has nothing to do with…
URIC ACID
Action of colchicine
decreases inflammation in response to uric acid deposition into joints - very specific to gout but there is some interest in heart disease
Can colchicine be used as a general anti inflammatory
NO it does not work on other inflammatory conditions since it is specific to uric acid deposition related inflammation
ADRs of Colchicine
prolonged use = bone marrow depression, agranulocytosis, peripheral neuritis, aplastic anemia, acute poisoning
rare = cell depression - often only in short term use
given too quickly = acute poisoning –> bleeding and loss of fluids
Is colchicine a first line treatment for gout
not it is a second line treatment for gout attack - we use NSAIDs and Steroids first nowadays
Even __ doses of colchicine may prevent gout attacks
low
what is the take home message about colchicine
it is specific to the inflammation caused by gout but does not effect the uric acid it just prevent deposition
can be used for chronic gout management and some heart disease use
What is the big difference between allopurinol and colchicine
allopurinol = decreases uric acid
colchicine = does not impact uric acid, prevents deposition and inflammation
probenecid
drug that increases uric acid excretion - sometimes used instead of allopurinol
