Drugs and pregnancy



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Vascular Effects

  • 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 


  • Tubular Effects

    • 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

    • NSAIDS can cause premature closing of the d.a. when used in the last weeks of pregnancy

    • Review: INDOMETHACIN (an NSAID) is used to close a patent ductus 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

  • 6) HYPERSENSITIVITY

    • 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.

    • Treatment: Epinephrine.

    • 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 lethalIngestion 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

        • Hearing loss

        • Vertigo

        • Emesis (CTZ)  FLUID LOSS

      • Kidney

        • Respiratory alkalosis is compensated by increased NaHCO3 excretion

      • Metabolic Effects


        • 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)

      • CNS Effects

        • Stimulation of respiratory center  hyperventilation (CO2 loss)  Fluid loss (breathing out water)

          • Hyperventilation  respiratory alkalosis (CO2 loss)

          • Hyperventilation  NaHCO3 excretion by kidney  FLUID LOSS

      • Metabolic Effects

        • Heat production by uncoupled mitochondria  hyperthermia (excessive heat production)  sweating  FLUID LOSS

          • Remember these drugs can be used to lower body temperature (not in hyperthermic conditions) and here they are causing hyperthermia

        • Glycolysis stimulated to make ATP (Glycogen glucose pyruvate and lactate) b/c mitochondria cant make ATP  glycogen depleted   in blood glucose hypoglycemia

        • Levels of CO2, lactate, pyruvate (lactate and pyruvate are from glycolysis) acetoacetate (from FA’s) rise = metabolic acidosis

    • SEVERE TOXICITY (1.1 - 1.6 mg/ml)

      • CNS EFFECTS

        • Depression of Respiration  diminished CO2 loss  respiratory acidosis (HCO3- depleted)

      • Fall in plasma pH increases salicylic acid entry into the brain and decreases its excretion by the kidneys

      • Coma

    • LETHAL TOXICITY (> 1.6 mg/ml)

      • METABOLIC EFFECTS
 Hyperthermia and associated dehydration  Death

      • CNS EFFECTS
 Respiratory Failure  Death

      • KIDNEY
 Dehydration, hypernatremia, hypovolemia, PG synthesis blocked  Renal Failure  Death


  • 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.

    • TREAT SYMPTOMS - IMPORTANT

      • Reduce Hyperthermia


        • Tepid water or alcohol sponging

      • Do Blood Analysis

        • salicylate concentration

        • pH

        • electrolyte studies

        • glucose

      • Treat Dehydration and electrolyte and pH imbalances

        • IV fluids - maintain kidney function

    • MINIMIZATION OF ABSORPTION

    • ENHANCEMENT OF ELIMINATION - IMPORTANT

      • Since salicylic acid is a water soluble weak acid, excretion can be enhanced by alkalinization of the urine with IV infusion of NaHCO3 (“Alkalinize Urine”)

      • Hemodialysis currently recommended if plasma salicylate is above 1 mg/ml, but...

        • More than half of ~ 23 deaths/yr attributed to aspirin occur when salicylate conc. <100 mg/dL

        • Invasive procedure and  risk of blood clots

      • No methods exist to stimulate biotransformation (cf. acetaminophen).


    UNIQUE FEATURES of SELECTED NSAIDS

    • SALICYLATES

      • All the salicylates except DIFLUNISAL are hydrolyzed to salicylic acid.

      • SALICYLIC ACID AND SALICYLATE

        • The acid is keratolytic and used topically in treatment of warts, corns, psoriasis

        • Choline salts (Trilisate®) and Mg2+ salts (Doan’s) are available.

        • Other salicylates include SALSALATE and DIFLUNISAL

        • Compared with aspirin, salicylate has lower incidence of GI effects, hypersensitivity and no clinical effect on platelet function.

      • ASPIRIN (Bayer®, 1899, 1939)

        • Acetylates active site of cyclo-oxygenase (COX)  irreversible inhibition.

        • Potent anti-platelet drug for preventing MI and ischemic strokes.

      • METHYL-SALICYLATE
(Oil of Wintergreen, Ben-Gay®, Aspercreme®)

        • Absorbed through skin, commonly used as a topical NSAID

        • Very toxic if taken orally

        • Used as a flavoring

    • ACETIC ACID DERIVATIVES AND RELATED DRUGS

      • INDOMETHACIN (Indocin®, 1965)

        • Potent inhibitor of cyclooxygenase-1

        • Higher incidence of GI side effects than aspirin-- Toxicity > aspirin

        • Special short term uses only, closure of ductus arteriosus in premature infants, tocolysis, acute gouty arthritis

      • SULINDAC (Clinoril®, 1978)

        • Prodrug converted to active drug (sulfoxide sulfide) in the liver.

        • Undergoes enterohepatic cycling, prolonging action to 16 h

        • Lower incidence of GI toxicity than aspirin.

      • DICLOFENAC (Voltaren®, 1988; Arthrotec®, 1997)

        • Useful for osteoarthritis and rheumatoid arthritis.

        • GI toxicity risk similar to aspirin.

        • Multiple formulations

          • Rapid release for acute pain (Cataflam ® K salt),

          • Extended release for arthritis (RA)

          • Ophthalmic solution (Voltaren ®)

          • Topical solution

          • Buffered powder for oral solution (Cambia®, 2009 for migraine) are available.

          • Also Arthrotec® combines DICLOFENAC and MISOPROSTOL (to minimize side effects in the GI tract)

      • KETOROLAC (Toradol®; Acular®, 1989)

        • Used parenterally IV or IM for the short-term treatment of mild to moderate 
post-operative pain.

        • Use for < or equal to 5 days

        • 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 t1/2 but…

        • 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.

      • CELECOXIB (Celebrex®, 1998),
ROFECOXIB (Vioxx®, 99-04) VALDECOXIB (Bextra®, 01-05)

        • Currently CELECOXIB is approved for treatment of

          • Rheumatoid arthritis and osteoarthritis

          • Acute pain and menstrual pain

          • Reduction in number of polyps in familial adenomatous polyposis –THIS INDICATION WAS REMOVED IN 2011

        • Selective for COX-2 over COX-1 (300-400 fold)

        • No effect on platelet aggregation

        • Claim to have minimal adverse GI side effects, and no effect on platelets while maintaining efficacy similar to naproxen, diclofenac and ibuprofen on pain

          • Original clinical trials: Ulcers observed endoscopically:

            • celecoxib 3-7%

            • naproxen 16-35%*

            • ibuprofen 23%*

            • diclofenac 10% and 15%*

          • FDA ruled, however, that they needed to demonstrate a decreased frequency of clinically serious GI events compared to other NSAIDs in well-controlled studies

          • Result: complicated and symptomatic ulcer rates at 9 months for all patients, and those over 65 y.o celecoxib alone 0.78%, 1.4%; celecoxib +ASA 2.19%, 3.06%

          • Warning of GI toxicity is still included on label

        • Risk of adverse GI toxicity has been shown for rofecoxib to be significantly less than for naproxen (see VIGOR study below)

        • Renal effects appear to be similar to other NSAIDs, remember COX-2 is found constitutively in the kidney macula densa and TAL of the loop of Henle

      • CELECOXIB (Celebrex®, 1998)

        • Celecoxib is a sulfonamide and should not be taken by patients who are 
allergic to this class of drugs

        • Metabolized by CYP 2C9, which is inhibited by many drugs including cimetidine, zafirlukast, omeprazole, sulfonamides and ketoconazole. Also it inhibits CYP 2D6. Hence, potential for drug interactions

        • Half-life 11.2 hours and can be administered once per day for osteoarthritis

        • It was the 27th most frequently prescribed drug in the U.S. in 2004 and the 90th in 2010

      • ROFECOXIB (Vioxx®, 1999-2004)

        • It is not a sulfonamide

        • Safety compared with naproxen “VIGOR” STUDY

          • Rofecoxib 50 mg vs Naproxen 1000mg /day for nine months, 8076 patients with RA, mean age 58 yr, patients requiring low-dose aspirin were excluded

          • GI SAFETY: Incidence of ulcers, gastric perforation, upper GI bleeding, etc

            • Naproxen 121/4029

            • Rofecoxib 56/4047

            • Relative risk of symptomatic adverse GI effects = 0.46

          • Cardiovascular safety: Incidence of sudden death, MI, UA, ischemic 
stroke, TIAs, peripheral venous or arterial thrombosis

            • All end points

              • Naproxen 19/4049 Rofecoxib 45/4047

            • Non-fatal MI

              • Naproxen 4/4049 Rofecoxib 18/4047

            • There is a higher incidence of serious cardiovascular thrombotic events in patients taking rofecoxib versus those taking naproxen or as it turns out placebo – removed from market by Merck 2004

        • Rofecoxib was the 56th most frequently prescribed drug in the U.S. in 2004

      • VALDECOXIB (Bextra®, 2001-2005)

        • Note that like celecoxib, valdecoxib is a sulfonamide and should not be taken by patients who are allergic to this class of drugs

        • PROBLEMS

          • Potentially fatal skin reaction which are unpredictable

            • Fatalities due to Stevens-Johnson syndrome

            • 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

    • ACETAMINOPHEN

      • 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.

      • PHARMACOKINETICS

        • Taken orally

        • Absorbed rapidly

        • 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

          • Single dose 20 - 25 g  potentially fatal


    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

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