L3: Cyclooxygenase Inhibitors and Acetaminophen

NSAID

1. anti inflammatory actions wo being a steroid

2. aspirin is the prototype

   1. the one we compare the others in the class to

3. does not include COX2 specific or selective agents nor acetaminophen

prototype

1. the one we compare the others in the class to

traditional NSAID

1. aspirin

2. ibuprofen

3. naproxen

4. naproxen sodium

5. indomethacin

6. ketorolac

risk of heart attack and stroke

COX 2 agents

1. celecoxib

2. meloxicam

risk of heart attack and stroke

the other one

acetaminophen

in between is risky

aspirin chemical class

salicylic acid derivative

arachidonic acid cascade - inflammation and pain

1. arachdonic acid

   1. releases cytokines

2. cyclooxygenase 1 and 2 (COX)

3. prostaglandins

   1. supports renal fxn (vasodilation) and platelet fxn = platelets aggregate

   2. supports gastric mucosa = from mouth to anus

   3. INDUCIBLE — produces pain and inflammation

= patient takes ibuprofen, naproxen, etc

when do kids become a pharmacological adult

12

ibuprofen

1. traditional NSAID

2. decreases the synthesis of pain and inflammation

3. inflammation-promoting prostaglandins via nonselective inhibition of COX-1 and COX-2

NSAID fxn (outcome of inh the various enzymes (cox 1/2))

1. decrease:

   1. fever (antipyretic)

   2. pain (analgesic)

   3. inflammation (anti-inflammatory)

COX 1 inhibition

1. stomach problems (mouth to anus)

2. vasoconstriction in the kidneys

3. inhibition of platelets

4. all the BAD == more side effects

asprin = _______ inh of platelets

irreversible

cardiac protective drug

a dose kills 50%

other NSAIDs = __________ inh of platelets

reversible

can you separate cox 1/2

no

reversible vs irreversible inh of platelets

1. irreversible = half dead and half fine

2. reversible = chaos

cox 2 inh

1. therapeutic GOOD —> only benefit is a slight decrease in GI tox, no inh of platelets

2. decrease in pain and inflammation

what COX2 agents were pulled off the market bc they showed an increase in CV thrombotic events

1. Valdecoxib (Bextra) and rofecoxib (vioxx)

inh of which enzyme gives side effects

COX 1

cox 2 agents side effects?

1. no side effects

cox 2 specific inhibitor

celecoxib (Celebrax)

more Cox 2 than Cox 1 inh

cox 2 selective inhibitor

meloxicam (mobic)

parents of celebrex and mobic

1. Bextra and Vioxx showed an inc in CV thrombotic events in clinical data

   1. parents are serial killers so maybe the kids are bad

cox 2 agents are only used for

pain

Celebrax and mobic

max dose of ibuprofen

800 mg every 6 hours = 3,200 mg

min mg amount for anti—inflammatory effects of NSAID

1,200 mg

for any itis

ketorolac

1. outlier

2. max of 5 days

   1. longer duration = inc risk of serious renal effects and bleeding

3. very common parenteral NSAID

4. this is what you took for those kidney stones

adult ibuprofen age

12 years and older

otc dose of ibuprofen

200

rx doses of ibuprofen

400, 600, 800

infant ibuprofen (advil, motrin) should not be used in children less than

>/ 6 mo

babies less than 6 mo old should take what

acetaminophen

babies greater or equal to 6 mo can take

acetaminophen and or ibuprofen

infant iburpofen general

1. >/ 6 mo to 23 mo

2. use weight when possible for dosing, and age when weight is not possible

childrens ibuprofen

1. 2-11 years old

2. use weight when possible for dosing, and age when weight is not possible

effects on platelets (adverse drug reactions)

1. aspirin causes irreversible inh of platelets; NSAIDs are reversible

   1. BLOOD THINNERS

   2. platelet life span is 7-10 days

2. see prolonged bleeding time

   1. discontinue 1 week prior to surgery (aspirin) and 3ish days (NSAIDs)

3. in general, aspirin, NSAID, and COX2 agents are to be discontinued a minimum of 7 days prior to a procedure

what is the minimum amount of time necessary to discontinue aspirin, COX1, COX2 prior to sx

7 days

what is the minimum amount of time necessary to discontinue traditional NSAID

3 days

renal effects - NSAIDs and COX2 specific

1. prostaglandin needed to maintain vasodilation and blood flow to the kidneys; other wise VASOCONSTRICTION occurs

hypersensitivity rxns

1. if someone is allergic to aspirin then they are probably allergic to NSAIDs and Cox 2 agents

   1. can cause bronchoconstriction, nasal polyps

celecoxib has what cross sensitivity

1. sulfa

2. chance is slim bc celecoxib is a non antibiotic sulfa drug

CNS side effects

1. salicylates - aspirin is the prototype

   1. aspirin is a salicylate

2. aspirin is most likely to cause CNS issues = tinnitus = ringing in ears

Reye syndrome

1. what happens if we give aspirin to kids less than or equal to 14 years old when they have a viral infection:

   1. influenza

   2. varicella (chicken pox)

2. reye syndrome can cause hepatitis and cerebral edema - so we avoid aspirin

3. kids are given acetaminophen or ibuprofen

GI issues

1. 15% of pt treated chronically w NSAIDs will go on to develop major GI event

2. take w food —> helps w GI issues

Acetaminophen (tylenol)

1. non NSAID analgesic

2. APAP

3. prostaglandins are not impacted

4. only an antipyretic and analgesic —> NOT an anti inflammatory drug

5. •non-NSAID analgesic: believed to exert its effects via CNS COX inhibition and activation of central serotonergic pathways

max daily does for acetaminophen

3000 mg (or 4000 mg for a couple of days)

ADR w acetaminophen

1. hepatic injury

   1. more likely to occur in chronic alcohol users

   2. many OTC and Rx products contain acetaminophen

   3. hepatically metabolized to sulfate and glucuronide conjugates

   4. small amount is metabolized by CYP450 into a hepatotoxic metabolite (NAPQI)

      1. more regullary a person drinks = shift towards more hepatotoxic metabolites

      2. NAPQI normally binds to glutathione

      3. if glutathione stores are depeleted = NAPQI is not detoxified = hepatotoxicity

2. kidney issues too

antidote for tylenol toxicity (acetaminophen overdose)

1. NAC

2. TIME SENSITIVE = must be given wi 8 hours of ingestion of acetaminophen

fever drugs: birth to 6 mo are given

acetaminophen

fever drugs: 6 mo to adult are given

acetaminophen and or ibuprofen

aspirin mech of action

1. irreversible acetylation of enzyme cyclooxygenase = inhibition of the synthesis of thromboxane A2

   1. Irreversibly inhibits platelet aggregation

   2. primarily given to prevent arteriolar lots

      1. anticoagulants are given to prevent venous clots

low dose aspirin (LD ASA) is ___ mg

81

men 45 - 79 to prevent heart attack

women 55- 79 to prevent stroke

men/women > 80 - recommended only if they have high CV risk and no additional GI bleeding risk

• take them off it bc now risk for GI bleed is higher

should aspirin and other NSAID be taken w food

yes, w largest meal of day

thienopyridine derivatives

1. clopidogrel (plavix)

   1. mech of action

      1. irreversibly inhibit ADP

      2. NOT effecting prostaglandin

2. ticagrelor (brilinta)

   1. mech of action

      1. only ADP inh that binds reversibly to platelets

         1. so it has a shorter duration of effect than clopidogrel or prasugrel

            1. might have to take 2 doses a day bc of this

3. prasugrel (effient)

   1. mech of action

      1. irreversible inhibits ADP receptor

as we go down the list the potency increases

whats more potent as an antiplatelet med aspirin or thienopyiridine derivs

thienopyridine derivs

dosing of clopidogrel (plavix)

1. can be taken alone or w aspirin

   1. duration of antiplatelet effect is 7-10 days = that is the lifespan of a platelet

adverse effect of clopidogrel (plavix)

thrombocytopenia

• low platelet amount

min amount of time to discontinue clopidogrel (plavix), ticagrelor (brilinta) before a sx

5 days

dosing of ticagrelor (brilinta)

MUST BE TAKEN W LOW DOSE ASPIRIN

if a pt takes more than 100 mg of aspirin it will impair ticagrelor (brilinta) MECH OF ACTION

ADRs of ticagrelor (brilinta)

1. dyspnea - shortness of breath

2. bradycardia

3. bleeding

dosing of prasugrel (effient)

must be taken w aspirin as well

any dose works

prasugrel (effient) ADR

bleeding BLACK BOX WARNING

most potent of the 3

prasugrel (effient) durg interactions

other drugs that increase bleeding risk

warfarin

NSAIDS

how long before a sx should you stop prasugrel (effient)

7 days

Just because the bleeding risk is higher

glycoprotein 2b/3a inh

1. given parenterally

2. no oral ones available

3. most potent

anti platelet potencies ranked

1. most —> GP 2b/3a inhibitors

2. thienopyridine derivs

   1. effient

   2. brillinta

   3. plavix

3. aspirin

what are the anticoagulants

1. warfarin (coumadin) - introduced as coumadin in 1950

   1. MOA

      1. inhibits vit K dependent liver coagulation factors: 2, 7, 9, 10, and protein C and S

sometimes a pregnant women needs an anticoagulant, what do we use for that

heparin

NOT WARFARIN

whats the half life of warfarin

40-72 hours

what do we use to adjust the dose of warfarin

INR - international normalized ratio

• used to check their PT - but that has variability

how do we monitor warfarin

monitor INR weekly for the first few weeks

then every 2 weeks

eventually every month

how long do we hold warfarin before a procedure

5 days

what INR do we want w Warfarin

2-3 = ideally 2.5

what must we maintain w warfarin

a consistent amount of vit K in kiet

• avoid sporadic ingestion of foods high in vit K = beef liver, pork liver, green tea, green leafy vegs

does Warfarin interact w a lot of drugs

yes - we need to watch this

adverse rxn for warfarin

bleeding

warnings/precautions w warfarin

1. use w vitamin K may decrease the anticoagulant effects

   1. vit K could be an antidote

2. use w NSAIDs and aspirins

   1. NSAIDS = NO

   2. aspirin - may be intentional

   3. USE ACETAMINOPHEN TYLENOL FOR PAIN/FEVER

miscellaneous PO anticoagulants

1. dabigatran (pradaxa)

   1. MOA

      1. direct thrombin inh

   2. first oral anticoagulant approved in US in over 50 years

   3. for reducing stroke risk and systemic embolism in pt w non valvular atrial fibrillation

      1. used in place of warfarin

      2. does not require monitoring of INR

2. rivaroxaban (xarelto)

3. apixaban (eliquis)

   1. MOA for both

      1. factor Xa inhibitor

1. dabigatran (pradaxa)

1. MOA

   1. direct thrombin inh

2. first oral anticoagulant approved in US in over 50 years

3. for reducing stroke risk and systemic embolism in pt w non valvular atrial fibrillation

   1. used in place of warfarin

   2. does not require monitoring of INR

1. dabigatran (pradaxa) ADR

1. bleeding

2. dyspepsia - heart burn

   1. contains cream of tartar to help w absorption = this is what causes heart burn

precautions w dabigatran (pradaxa)

compliance is key

if a dose is missed the effectiveness starts to wane wi 15 mins of the missed dose

what do rivaroxaban (xarelto) and apixaban (eliquis) replace

warfarin or low molecular weight heparin

what are ADRs of rivaroxaban (xarelto) and apixaban (eliquis)

bleeding

eliquis might be worse for this

heparin types

1. traditional heparin therapy = unfractionated heparin

   1. SC or IC

   2. LARGE STRUCTURE

   3. from pig and cow sources = more of a chance for allergies

2. low molecular weight heparin (LMWH)

   1. enoxaparin (lovenox)

   2. can be given every 12 - 24 hours

   3. used for pregnancy

MOA for traditional/UFA heparin

inactivates thrombin and factor Xa

compare the half lives of traditional/UFA heparin and LMWH

traditional has shorter half life

how do we monitor UFA/traditional heparin efficacy

aPTT

ADR of UFA/traditional heparin and LMWH

bleeding

ADR of UFA/traditional heparin

1. allergic rxn - bc from animal source

   1. HIT - heparin induced thrombocytopenia

      1. all the platelets stick together in clumps (hypercoagulable) so it looks like theres a decrease in platelets

2. with long term use:

   1. alopecia

   2. cataracts

   3. osteoporosis

LMWH MOA

only inhibit factor Xa

• so they have a longer half life