PGE2 and PGI2 dilate afferent glomerular arterioles.
PGI2 antagonizes effect of angiotensin II on mesangial cells and thereby increases GFR. It also antagonizes vasoconstrictive effect of angiotensin II on the efferent glomerular arterioles and thereby decreases filtration fraction and the forces driving reabsorption.
PGE2 dilates medullary blood vessels—the vasa recta—which decreases medullary hypertonicity and hence the driving force for water reabsorption
PGE2 decreases reabsorption of Na+, K+ and Cl- in thick ascending limb.
PGE2 produced by macula densa cells stimulates renin release by the granular cells. Helps maintain systemic BP to maintain blood flow to kidney.
PGE2 antagonizes action of antidiuretic hormone in the medullary collecting duct.
Important: Net effect is preservation of kidney function by a local effect in the face of systemic increases in levels of vasoconstrictors.
NSAIDs can cause acute renal failure in some patients. By blocking renal prostaglandin synthesis, NSAIDs remove the last line of defense.
3) REYE’S SYNDROME –**only seen in use of salicylates like aspirin but not the other NSAIDs
This involves severe hepatic and brain damage (encephalopathy) and can occur when aspirin and other salicylates are taken by children infected with influenza or chicken pox (varicella).
This was because they produce mitochondrial damage in the liver (mitochondria makes urea from ammonia). When your liver cant make urea from ammonia it leads to ammonia in the circulation which causes hepatic encephalopathy
Mechanism is unknown and an association with other NSAIDs has not been demonstrated. In 1980, 1207 cases were reported in the U.S. Due to warnings, this has fallen to < 36 per year since 1987.
Salicylates are not normally recommended for use in children. Ibuprofen and acetaminophen are approved for use in children.
4) URIC ACID SECRETION
Low doses (1 - 2 g/day) of salicylates decrease uric acid excretion by blocking its active tubular secretion in the kidney. May produce hyperuricemia.
High doses (> 5 g/day) stimulate uric acid excretion by blocking its proximal tubule reabsorption.
Intermediate doses (2 - 3 g/day) no net effect is observed.
All doses block the effect of probenecid, which is used in treatment of gout to increase uric acid secretion.
5) CLOSING OF THE DUCTUS ARTERIOSUS
In the fetus, the d.a. connects the pulmonary artery and the aorta and is kept open by PGE2, closes soon after birth
Review: INDOMETHACIN (an NSAID) is used to close a patentductus arteriosus in neonates
Review: Also remember ALPROSTADIL (PGE1, Prostin VR Pediatric®, 1981) is used to keep the d.a. open in neonates with heart defects
Observed in about 1% of general population, but in about 20% of those with nasal polyps or asthma .
Symptoms: NSAID/aspirin induced Bronchoconstriction and shock.
Cause: Arachadonic acid can get converted into PG’s which produce bronchodilation (like PGE2 and PGI2) or arachadonic acid can enter into LT synthesis. Because NSAIDS block PG synthesis you get in PGE2 and PGI2 and the arachadonic acid is shifted into the LT synthesis and you get increased LT synthesis.
IMPORTANT: Individuals hypersensitive sensitive to aspirin are usually also sensitive to other NSAIDs, however they are less sensitive to non-acetylated salicylates and not sensitive to acetaminophen.
TOXIC EFFECTS of SALICYLATES
Due to widespread availability, accidental and intentional overdose of aspirin is not uncommon. The toxic effects of salicylic acid are correlated with the concentration of salicylate in the blood stream.
Analgesic doses usually yield blood levels of 0.06-0.1 mg/ml, while anti-inflammatory doses yield 0.15-0.35 mg/ml and levels greater than 1.6 mg/ml can be lethalIngestion of 10-30g has caused death. 4mL of methyl-salicylate (derivative of salicylic acid found in things like bengay—topical preparations for muscles) can be fatal in children.
EARLY STAGE TOXICITY (“SALICYLISM”, 0.35 - 0.5 mg/ml)
These effects can be seen at maximum therapeutic doses and the early stages of intoxication. Metabolic pathways for salicylate conjugation saturate, therefore free levels rise and t1/2 increases.
CNS Effects (most obvious)
Tinnitus—first one that you see when someone is OD. KEY INDICATOR
Emesis (CTZ) FLUID LOSS
Respiratory alkalosis is compensated by increased NaHCO3 excretion
Salicylic acid has a delocalized charge and this allow the charged form to cross lipid membranes so if you can get the protonated and the charged form to cross lipid membranes that means this drug can transport protons across membranes. Uncoupling of mitochondrial oxidative phosphorylation which makes ATP (dependent on the H+ pump, which is driven by the electron transport chain and respiration—so the whole process really depends on the membrane being impermeable to protons so these drugs can screw this up) loss of ATP as heat Body works harder and oxidizes more substrates through the TCA cycle leads to elevated CO2 production increased respiration breathing out water FLUID LOSS
NET EFFECT = FLUID LOSS, BUT NOT SERIOUS
MILD - MODERATE TOXICITY (0.5 - 0.8 mg/ml)
Stimulation of respiratory center hyperventilation (CO2 loss) Fluid loss (breathing out water)
TREATMENT of SALICYLATE POISONING—treat the symptoms
GENERAL GOALS of treating the poisoned patient are 1) to maintain respiration and circulation. 2) To reduce and keep the concentration of poison as low as possible, by minimizing absorption and maximizing elimination. 3) To minimize the pharmacological and toxicological effects.
Higher incidence of GI toxicity.---only used short term
PROPIONIC ACID DERIVATIVES—lower incidence of adverse GI effects as compared to other NSAIDS
These drugs have a similar risk of GI toxicity as aspirin and are all available as over the counter (OTC) preparations. Useful for treatment of pain, fever, menstrual pain (dysmenorrhea) and inflammation.
IBUPROFEN (Motrin®, Advil®, 1974, Caldolor®)
Half-life 1 - 2 hr
For analgesia 200 mg which is about equal to 650 mg aspirin, but for anti-inflammation 2.4 g which is about equal to 4 g aspirin.
Caldolor® (2009) first formulation for IV administration (injectable)
NAPROXEN (Naprosyn®; Aleve®, 1976, 1994)
Longer half-life (t1/2 = 14 h) than ibuprofen so less frequent dosing.
KETOPROFEN (Orudis®, 1986, 1995)
Half-life 1 - 3 hr
NSAIDS WITH VERY LONG HALF LIVES
Allow once per day dosing but take 7-12 days to reach steady state plasma concentration and both have a higher incidence of adverse GI effects than aspirin
PIROXICAM (Feldene®, 1982)
Half-life = 50 hr (very long)
OXAPROZIN (Daypro®, 1992)
Half-life = 50 hr (very long)
NSAIDS WITH RELATIVELY LOW COX-1 ACTIVITY
Selective for COX-2 over COX-1 (5-10-fold), hence lower incidence of GI problems, but not sufficient difference for FDA to allow the drugs to be promoted on this basis.
Used primarily as anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis.
NABUMETONE (Relafen®, 1991)
Long half life ~23 hr
Prodrug converted to the active form in the liver
Methoxy-naphthyl-acetic acid (compare with naproxen)
Reduces exposure of stomach to active drug
Lower incidence of ulcers (#2 NSAID in ’97; #7 in ’10)
ETODOLAC (Lodine®, 1991)
Selective (~ 10x) for COX-2 versus COX-1
Low incidence of GI symptoms (similar to placebo) #8 NSAID in ’10
MELOXICAM (Mobic®, 2000) (#2 most frequently prescribed NSAID IN 2010)
Structurally related to piroxicam, long t1/2but…
Selective (~ 10x) for COX-2 versus COX-1
Lower incidence of GI symptoms (17%, placebo, 20% meloxicam, 28% diclofenac)
CYCLO-OXYGENASE-2 (COX2) SELECTIVE INHIBITORS
Three drugs that are several hundred fold more selective for COX-2 over COX-1 were approved by the FDA. In treatment of arthritis, these drugs appear to cause less GI damage without loss of analgesic or anti-inflammatory activity.
Toxic epidermal necrolysis have been reported, watch out for skin rash developing in 1st two weeks
Contraindicated for the treatment of postoperative pain following CABG surgery due to increased risk of CV thrombosis, death due to MI, stroke, DVT, PE , in addition to risks similar to those associated with rofecoxib
It was the 62nd most frequently prescribed drug in the U.S. in 2004, but because of above problems was removed from the market April 2005
ALL NSAIDS CARRY A WARNING THAT THEY MAY CARDIOVASCULAR RISKS (except aspirin) AS WELL AS GI RISKS
Why do we still have Celebrex (CELECOXIB) still on the market? Celebrex effects COX and also inhibits calcium uptake by the SM (either by inhibitory effect on Ca channels or activating effect on K channel which regulate the Ca channel) vasodilatory effect CV risks
IMPORTANT Acetaminophen is NOT AN NSAID, it only shares the antipyretic and analgesic properties of NSAIDs. IT DOES NOT POSSESS CLINICALLY USEFUL ANTI-INFLAMMATORY PROPERTIES.
Acetaminophen is a unique drug; however, due to the fact that it has analgesic and antipyretic properties similar to aspirin and other NSAIDs, it is useful to compare their properties.
PROPERTIES - SIMILAR to ASPIRIN
Analgesic – the combination drug hydrocodone + acetaminophen (Vicodin®) is the most frequently prescribed drug in the US
Note: Often prescribed in combination with opioids, e.g. acetaminophen + hydrocodone = Vicodin®
Antipyretic ( fever)
No tolerance or physical or psychological dependence develops
PROPERTIES that DIFFER from ASPIRIN
Very little anti-inflammatory effect
No CNS effects
No association with Reye’s syndrome
No cardiovascular or respiratory effect
No gastric irritation (as compard to NSAID)
No effect on platelets (does not block platelet aggregation)
No effect on uric acid secretion The reasons for these similarities and differences have not been well established.
Peak plasma concentration achieved in about 1 hr. Half-life approximately 2 hr. These are similar to the properties of aspirin
TOXICITY of ACETAMINOPHEN OVERDOSE
Although acetaminophen has very few adverse side effects and is generally regarded as a “safe drug”, overdoses are not uncommon and can cause severe hepatic damage. Toxicity is expected at doses exceeding 7.5 g (adult) and doses of 20-25 g can cause death. In contrast to the toxic effects of aspirin, these effects are directly related to the metabolism of acetaminophen.
Low doses (< 150 mg/kg) have few side effects
Therapeutic doses (3g/day max) normally have no adverse effects
Single dose 7.5 - 15 g hepatotoxicity (necrosis)
Packaging now says severe liver damage may occur if take > 4g in 24 hours
The parent acetaminophen molecule gets metabolized by conjugation w/ glucuronic acid (glucuronidation (60%)), 35% gets conjugated with sulfate group. Both of these products are harmless and inactive. CYPP450 system can metabolize it into a quinone structure which acts as an electrophil (likes electrons) and so this reacts with glutathione (glutathione reacts with electrophils—it is an antioxidant) to produce the glucuronidated harmless product. But when these conjugation enzymes get saturated (with drug) you get more drug going through the CYPP450 oxidation which consequently will deplete the levels of glutathione reactive molecule now can react with proteins that have SH groups (mitochondria for ex have proteins that transport phosphate and these have SH groups and it can react with these and inhibit them) Death of cells in the liver if you kill enough of them you can get liver damage and death