• systemic and topical steroids (glucocorticioids)

• non-steroidal anti-inflammatory (aspirin) 

• histamine H1-receptor antagonists

• disease modifying agents (immunosuppressant and biologic agents)

• acetaminophen
• aspirin
• celexocib
• diflunisal
• ibuprofen
• indomethacin
• meloxicam
• naproxen
• sulfasalazine

what properties do most NSAIDS share in terms of effect?

• analgesics
• anti-inflammatory
• anti-pyretics

what is unique about aspirin's mechanism of action?

aspirin uniquely and irreversibly acetylates the serine-520 of COX to inhibit its activity and to exclude arachidonate acid from COX active site

aspirin is non-selective (COX-1 and COX-2)

other NSAIDs act via non-covalent means with some enzyme selectivity

where is COX-1 isoform localized in body?  is it constitutive or inducible?

• blood vessels
• stomach
• kidney
• platelets

COX1 = constitutive

where is COX-2 isoform localized in body?  is it constitutive or inducible?

COX-2 = inducible

• sites of inflammation
• CNS (thermoregulation)
• endometrium
  

COX-2 selective, so does not block cardioprotective actions of COX-1

what related molecule is thromboxane A2 in cardiovascular homestasis with?

prostacyclin (PG I2)

PGI2 prevents formation of the platelet plug involved in blood clot formation

it is also an effective vasodilator

• thromboxane A2: platelet formation
• prostacyclins (PG I2): antithrombotic; gastroprotective
• prostaglandin E2: renal function

COX 1 is constitutively active

• proteases
• prostaglandins
• inflammatory mediators

COX 2 is stimulated by inflammatory stimuli (heat, mechanical, chemical); it is therefore INDUCIBLE and leads to inflammation!

• anti-inflammatory effect for:
  • arthritides (RA, OA, AS)
  • systemic lupus erythematosis (SLE)
  • dysmenorrhea
• pain/analgesia
• fever/antipyresis via suppression of PGE2 in the brain (lowering sweating, body temp)

• DMARDs
• salicylates & other NSAIDs
• gold
• steroids
• anti-malarials

(in order of importance)

what drugs are indicated for ankylosing spondylitis (AS), psoriatic arthritis, Reiter's syndrome?

• ibuprofen
• indomethacin
• salicylates

what drugs are indicated for OA (degenerative joint disease)?

• acetaminophen
• salicylates
• other NSAIDs (ibuprofen, indomethacin)

• ibuprofen
• naproxen

what drugs are indicated for systemic lupus erythematosus?

• salicylates
• anti-malarials
• steroids

"patient can't see, can't pee, and can't bend the knee"

autoimmune reactive arthritis that depends in response to infection in another part of the body; characterized by:

• inflammatory arthritis in large joints
• urethritis
• inflammation of the eyes (conjunctivitis or uveitis)

chronic, inflammatory, auto-immune arthritis that affects sacroilium of the pelvic bone and joints of the spine; eventually causes fusion of the spine.

complete fusion of the spine results in rigidity, a condition known as "bamboo spine"

strong family predisposition

what are the major adverse effects of NSAIDs and what are the implicated PGs?

• increased bleeding time: decrease in TXA2
• gastritis and ulcer: decrease in PGE2, PGI2
• bronchospasm, urticaria, nasal polyps, rhinitis: increase in LTC4, D4, E4
• renal fluid retention, Na+excretion: decrease PGE2, PGI2
• delayed parturition, dystocia: decrease PGE2, PGF2

• gastric secretion
• uterine contraction

what do salicylates do and what are their limitations?

• reduce joint swelling and fever in a dose-dependent manner

but, DO NOT affect the ultimate course of RA

anti-inflammatory

one of the NSAIDs, but LACKS anti-pyrogenic property

• NOT with ASA (due to gastropathies that develop with chronic use)
• newer NSAIDs and COX-2 inhibitors are indicated
  • symptomatic relief but do NOT alter disease course
  • require concomitant use of:
    • DMARDs (anti-malarials, gold)
    • immunosuppressants (methotrexate, leflunomide, azathioprine)
    • anti-TNFa drugs (enteracept, infliximab)

what are the main contraindications for use of salicylates and other NSAIDs?

• children with viral infections <16 years due to risk of Reye's Syndrome (hepatic encephalitis and steatosis)
• asthmatics: risk of ASA induced airway hypersensitivity in 10%
• surgery/dental work: w/in 1 week of procedure
• pregnancy: esp early on
• patients with ulcers or GI disturbances
• hyperuricemia pts or those taking organic acids

what are potential drug interactions with salicylates and other NSAIDs?

• anticoagulants
• oral antidiabetic drugs
• anticonvulsants
• some antihypertensive drugs

other drugs that alter liver metabolism (antacids and alcohol can affect NSAID activity)

in what patients should ASA be completely avoided?

• hemophiliacs
• pts with severe liver damage
• hypoprothrombinopenia
• vitamin K deficiency

what are the damaging ASA effects on GI system and what causes them?

• decrease in mucus layer due to lower PG levels (E2 and I2)
• decreased platelet aggregation (lower TBX levels)
• increase H+
• end result:
  • GI irritation
  • blood loss
  • exacerbation of ulcers
• PG I2/E2 via COX-1 usually inhibits vol and pepsin content of gastric acid secretion, promotes mucus secretion (glycoprotein protectant), and inhibits platelet aggregation

• inhibition of TXA2 synthesis in platelets IRREVERSIBLY
• ADP/5-HT release inhibited
• INCREASE in bleeding time
• dose-dependent hypoprothrombinopenia in AT RISK pops at low doses

in endothelial walls, PROSTACYCLIN (PG I2) is fleetingly inhibited

• acid-base imbalance
• uncoupling of oxidative phosphorylation
• electrolyte imbalance
• dehydration at high doses of ASA leads to toxic pyresis caused by dissipation of energy normally used to convert ADP-->ATP
• methylsalicylate will cause toxic pyresis in as little of 1 tsp

what form of ASA leads to fastest absorption and why?

alkaseltzer>warm water>buffered>regular

(in order of fastest to slowest)

alkaseltzer is fastest bc drug already dissolved when hits stomach and in form ready to be absorbed

• MFO (mixed function oxidase, in liver) breaks ASA and other salicylates down into glycine conjugate (salicyluric acid)

how does urine chemistry to maximize salicylate acid excretion?

urine alkalinization to pH 8.5 enables the concentration of salicylate in the urine to rise from 10% to 85%, whereas acidifying the urine decreases it to only 5%

what are the major consequences of salicylate intoxication due to?

uncoupling of oxidative phosphorylation is at root of toxic symptoms, which include:

• increased O2 consumption
• increased CO2 production
• acceleration of glycolytic and lipolytic pathways
• depletion of hepatic glycogen
• hyperpyrexia

why does bronchospasm occur in some takers of ASA?

if COX is blocked, then the synthetic pathway is shifted towards LTC4, D4, E4 production (all bronchoconstrictors) via LOX

what are symptoms of salicylism (mild intoxication)?

• hyperventilation
• tinnitus (>25mg/dL)
• GI upset (nausea, vomiting)
• dizziness

*all sxs stop upon drug withdrawal*

• rare illness characterized by hepatic encephalopathy and steatosis (fat vacuole accumulation in the liver)
• develops from a virus-host reaction in susceptible patient
  
• possibly as result of NSAID/ASA exposure (NOT ACETAMINOPHEN)
• usually children <16 yr

severe metabolic ketolactic acidoses

salicylates directly stimulate medulla respiratory center (increase RR over depth), leading to alkalosis as CO2 is rapidly lost

the uncoupled OP in skeletal muscle indirectly increases O2 uptake and CO2 production --> stimulating respiratory depth -->respiratory alkalosis -->renal excretion of HCO3-, Na+, K+-->compensated respiratory alkalosis

metabolic AND respiratory acidosis

• salicylic acid dissosicates in blood, displacing HCO3-
• carb metabolism thrown off, leading to accumulation of lactic, pyruvic, and acetoacetic acids
• central vasomotor impairment leads to renal dysfunction--> retention of acids

respiratory acidosis results from depression of central respiratory centers leading to inability to blow off CO2

• block further absorption
• increase elimination
• correct A/B imbalance, and electrolyte disturbances

how would you treat ASA-intoxication induced acidosis?

• hydration
• electrolytes
• HCO3-
• cooling
• vitamin K (if clotting time lengthened)
• activated charcoal

how would you treat ASA-intoxication induced alkalosis?

• hydration
• electrolytes
• rebreathing
• HCO3-

what type of inhibitor is ibuprofen and what are its ADRs?

non specific COX inhibitor

little GI upset

relatively non toxic

should discontinue before surgery

proprionic acid derivative

what type of NSAID is indomethacin and for what conditions is it primarily used?

indole acetic acid derivative

non specific COX inhibition

used for long-term inflammatory conditions like AS, OA, gouty and psoriatic arthritis, and to lesser extent RA

besides treating chronic inflammatory arthritides, what other condition is indomethacin useful for?

closing patient ductus arteriosus

it is far more potent than ASA as an anti-inflammatory agent and as a COX-inhibitor; but its general use is limited by its toxicity

while it is un-uniquely a mild anti-inflammatory, anti-pyretic, and a relatively potent analgesic, ketorolac is the ONLY WATER SOLUBLE NSAID and may also release endogenous opioids

it is a phenyl acetic acid derivative

non selective, used for RA and OA

once a day dosage is convenient, but HIGH hepatotoxicity

the drug is DANGEROUS with 30% patients on LTT experiencing side effects

must be closely monitored

COX 2 inhibitor

used for: RA, OA

fewer GI side effects than other NSAIDS because of its selectivity

depends on P450 for metabolism, and so other drugs may interfere, increasing its blood level

interacts with ACE INHIBITORS

ALL OTHER COX 2 inhibitors were withdrawn from market 2005-6

Meloxicam is a less selective COX2-INH