NSAIDs inhibit these prostoglandin synthase enzymes. the synthesis takes place by converting arachadonic acid

inhibition of COX2 is thought to be responsible for antipyretic, analgesic, and antinflammatory effects achieved by NSAIDs

inhibition of COX1 is thought to be linked to unwanted side effects of the GI tract.  COX1 is the dominant prostanoid producer and synthesizes housekeeping molecules

vasculature, airways, and gastrointestinal and reproductive tracts; platelets and monocytes; kidneys; the central nervous system, autonomic presynap-tic nerve terminals, and sensory nerve endings; endocrine organs; adi-pose tissue; and the eye (the effects on the eye may involve smooth muscle). 

they are the metabolized product of arachadonic acid by lipxoygenase, speccifically 5-LOX, and they play an important role in proloning the inflammatory response

lipoxygenases cannot be inhibited by NSAIDs

• most are organic acids (except nabumetone)
• most are racemic
• most absorb rapidly and completely in GI
• fast acting, not very affected by food
• often extensively plasma protein bound (usually albumin)
• they can accumulate in synovial fluid with repeated dosing
• heavily hepatically metabolized and renally excreted (therefore, not recommended for patients with impairments of either of these)

aspirin binds irreversably to allosteric site on COX1 and 2 by acetylating a serine (mostly 1)

all other NSAIDs are reversible and can exhibit selectivity

prostoglandins are responsible for maintaining the DA which would usually close when breathing initiates

intravenous injections of NSAIDs (i.e. indomethacin and ibuprogen) facilitate closure

small to large ulcers, usually caused by COX-1 inhibition, a systemic effect

patients with infections with helicobacter pylori, mucosal injury, excess alcohol use, or anticoagulent or glucocorticoid use are most suseptible

mech is that COX-1 inhib leads to down reg of PGI2 and PGE3 muscosal cytoprotectives, decreased bicarbonate production, increased acid production

tNSAIDs are associated with increased risk of MI and stroke, especially selective COX2 inhibs like celecoxib, diclofenac, and meoxicam

thromboxin (Tx) causes vasoconstriction and platelet aggregation  and is a product of COX-1.  It is inhibited by PGI2

PGI2 is produced by COX2.  Stop COX2, like many tNSAIDs do, and you stop that inhibition, and promote platelet aggregation, vasoconstriction

HOWEVER, aspirin is mostly specific to COX1, which will cut off this pathway at the production of Tx, therefore, it can have CV protective features while other tSAIDs increase risks for MIs and ischemia

------------------------------------

salicylates also carry adverse CV effects bc they instigate retention of water and salt and decreased renal fxn.  the result is increased circulating plasma volume

the medulla and cortex produce prostanoids which help modulate BP and salt excretion

COX2 prostoglandins typically increase blood flow and inhibit sodium reabsorption

COX 1 prostoglandins increase water excretion, salt excretion

the kidney also releases thromboxin and prostoglandins also increase renin (which will result in raising BP)

messing with COX messes with all these things and in an impaired individual, this is risky

if the patient has aspirin hypersensitivity, do not give any other nSAIDs

cross-sensitivity has been linked to life threatening conditions

it's been associated with broncial constriction

besides AV closure, NSAIDs can prolong pregancy bc they inhibit prostoglandins which facilitate contractions

oligohydramnios (too little amino fluid)

NSAIDs can be detected in breast milk

some herbal drugs lke motherwort and gink biloba, garil and hawthorn can decrease coagulation

displacement of previously plasma bound anticoagulants by aspirin is a concern.  do not want to release methotrexate (bone marrow suppression, GI toxicity, renal toxicity), warfarin

through glucuronidation and by CYP3A, CYP2C families

Selective serotonin receptor inhibitors= seretonin stimulates platelet aggregation and vasodialation, inhibitors can cause bleeding (somehow this includes NSAIDs)

NSAIDs can increase the reabsorption of Lithium, which is dangerous bc it has such a narrow therapeutic index

it is saturatable , therefore, there comes a point when a small increase in the conc of salicylate can lead to toxicity

salicylate metalism occures primarily in the hepatic ER and mitochondria by glucouronide conjugation. this metabolism is what is saturable

15(R)-HETE which can be metabolized by 5-LOX to yield 15-epilipoxin A4

this has potent anti-inflammatory properties through the inhibition of leukocyte activation

the effects achieved depend on the dose given.

effects from pain and fever reduction -> anti-inflamation -> anti-inflammation caused by rheumatic disease requires increasing doses

a disease of children with acute vasculitis

since aspirin can reduce inflammation and can help neutralize circulating myelin Abs which can downregulate proinflmmatory cytokines, it is considered a viable therapy

it prevents the leases of PGD from the skin

PGD release is caused by naicin sensitivity

they are capable of uncoupling Ox Phos which will cause an increase in CO2 production and a need to deeper, more frequent breathing

-liver and muscle glycogen can be depleted, excessive heat generation

-primary respiratory alkalosis can ensure of the partial pressure of CO2 falls too low due to increased respiratory rate and depth

asthma, rhinitis, and nasal polyps.  if a patient has these things, 10-25% of them will have aspirin hypersensitivity leading to production of leukotrienes

aso, laryngeal edema, angioedema, urticaria, and hypotension

nausea, vomiting, diaphoresis, tinnitus

vertigo, hyperventilation, tachycardia, hyperactivity

delirium, hallucinations, convulsions, stupor

oral, rectal, IV, rapid onset, low plasma binding, almost totally metabolized in liver by CYP ox,

slight use for anti-inflam but not considered one,

does not affect platelets

MOA: inhibits COX in CNS

reduced-glutathione sequesters a metabolite form of acetam., NAPQI which is reactive and needs to be neutralized, but this takes it out of circulation.  this contributes to the hepato-toxicity

also, chronic abuse is associated with renal papillary necrosis

there is not a large effect of acetaminophen on the anticoagulation effects of warfarin.

unless there is a better alternative, acetaminophen is the anti-inflammatory analgesic drug of choice for patients who are taking warfarin

warfarin is usually heavily protein bound and some NSAIDs

Meloxicam, Diclofenac, and Etodolac. 

indomethacin

and

ibuprofen

acetic acid derivative

20x more potent than aspirin, therefore, too strong for analgesic effects, better for fever if nothing else works

sometimes severe side effects, many of which are CNS

acetic acid derivative

potent analgesic/poor anti-inflammatory

not for use if there is an ASPIRIN ALLERGY

good for topical allergy conjunctivitis

potentially dangerous GI, renal, and bleeding complications

acetic acid deriviative

COX-2 selective (however, still some GI side-effects)

available in many forms (oral, dermal, rectal)

hepatic transaminase levels MUST be monitored because they are elevated

black box warning for CV side effects

NOT for the pregnant or nursing

naproxen and ibuprofen

naproxen is aleve.  it is popular because it has a relatively long half life

ibuprofen is an effective anaglesic, is injectable, can close the ductus arteriosus

effects of both are similar to aspirin, but generally better tolerated

why are COX2 selective drugs selective?

name one

celecoxib (celebrex) all COX-2 selectives end with "coxib"

• it has a sulfamide group, therefore, people with sulfa allergies cannot take
• the elderly develop a higher peak conc. therefore cannot give yound and old same dose

the coxibs have a hydrophobic AA side chain that fits into the allosteric site of COX-2 which is bigger than the site on COX-1, therefore, it cannot fit in COX1's

not proven to be more effacious than other NSAIDs, but fewer GI problems

what is the goal of enolic acid derivates?

name one

to try and decrease GI side effects

to have a longer half life so they are one-a-days

meloxicam

The CNS triggers hyperventilation

hyperventilation will decrease the partial pressure of CO₂ leading to an increase in bicarbonate conc and increased pH

along with this is metabolic acidosis caused by interference with the kreb cycle and increases in lactic acid

these effects of hyperventiliation are the most common acid/base distuburbances seen in ill pts.

due to an uncoupling of the ETC (causing non-shivering thermogenesis)

there will be deceased CO2 production, increased O2 consumption, depletion of liver glycogen

fever is often a PREMORBID sign

  *Frequent misdiagnosed is the elderly

it is a lower than normal amount of potassium in the blood and this can be a complication in patients whose ASA toxicity is being treated with alkalation of the urine if enough potassium is not provided

this lack of potassium will cause the tubules to reabsorb it in exchange for H+ ions.  this prevents the excretion of alkaline urine

a single bolus of sodium carbonate with a steady infusion of KCl is recommended

methyl salicylic acid.  it can be highly toxic too.  one tablespoon could kill a small child.

usually used topically, much safer this way

after 6 hours.

despite the early onset of effects, peak plasma conc may not be seen for 18-24 hours.

all the therapeutic effects of salicylates take place under first order kinetics, but it turn to zero-order kinetics once it is in toxic range

no more than 650/4hrs, except initially dose can be up to 1000

goal is to reach 15-30 mg/dl

assumes the drug conc is based on a single high dose, not chronic use

monitoring of toxicity must take place >6 hrs. after ingestion

above 50 mg/dl is mild tox, >110 is severe

the test is NOT the gold standard, has many flaw, but may serve use

time-release drugs can throw off the conc readings

when the acidosis is refractory

when the there is severe manifestation of toxicity

Phase 1 of acute acetaminophen toxicity begins within 30 minutes of ingestion and may last for 12-24 hours.

obtain serum level 4 hours after ingestion

7.5 gm is toxic dose in adults

150 mg/kg is toxic dose in kids

serum levels above 150 ug/ml is toxic range

no need to keep repeating levels after initial

liver damage in hepatic zone III

it works as a GSH substitute and increases the GSH supply

does not affect NAPQI production however

use w/n first 24 hours