Med-Chem/Pharm 3: NSAIDs & Acetaminophen (EXAM 4)

Which of the following prostaglandins are responsible for the effects seen in dysmenorrhea (↑contraction of uterus, ↑cramping & ↑pain)?

-PGE₂ -PGF₂a

Which of the following prostaglandins contribute to an increase in uterine contraction during pregnancy?

-PGE₂ -PGF₂a

Match the following symptoms of acetaminophen toxicity & their onset. 1. Nausea, vomiting, ↑abdominal pain, liver enzymes in plasma 2. Progressive increase in liver enzymes in plasma, accumulation of waste products in brain, renal tubular necrosis, coma & death

1. Day 1-2 3. Day 3 10%-20% of poisoned patients may die of hepatic failure despite intensive treatment*

1. Which of the following is a synthetic *PGE2*? 2. Which of the following is a synthetic *PGE1*?

1. Dinoprostone 2. Misoprostol

Oral formulations of NSAIDs have a/an ___1____ gastric acid damage effect whereas parenteral, transdermal & some oral formulations have a/an ____2____ gastric acid damage effect.

1. Direct (primary insult) 2. Indirect (secondary insult)

Match the following: 1. Analgesic 2. Antipyretic 3. Anti-inflammatory

1. Effect is CNS & peripheral 2. Effect is CNS 3. Effects are due to PG inhibition

1. Which Acetaminophen pathway is MAJOR in adults? 2. Which Acetaminophen pathway is MAJOR in children?

1. Glucuronidation 2. Sulfonation

NSAIDs can cause gastric mucosa ulceration via 2 ways:

1. PGE₂ & PGI₂ mediated inhibition of acid secretion & cytoprotective effect. 2. PGI₂ induced inhibition of LTB₄ mediated endothelial adhesion & activation of neutrophils which results in increased leukocyte endothelial interactions AND: -Capillary obstruction -Ischemic cell injury -Proteases + oxygen radicals -Endo/Epithelial cell injury

PGI₂ (prostacyclin) and TXA₂ (thromboxane A2) have opposing roles. 1. Which one is responsible for *vasodilation* & inhibits platelet aggregation? 2. Which one is responsible for *vasoconstriction*, platelet activation & platelet aggregation?

1. PGI₂ 2. TXA₂

*study guide* 1. Which structure is a TOXIC SAR of Acetaminophen? 2. Which structure SAR of acetaminophen is associated with more side effects? *see reverse*

1. TOXIC = A (replacement of -OH with -NH2) 2. MORE SIDE EFFECTS = B (replacement of -OH with alkoxy groups) C = If R is other than methyl group = decreased therapeutic activity*

Pain is subjective and is considered the ______ vital sign per the Joint Commission.

5th NOTE: choice of drug, dose, frequency depends on multiple factors not just the pain scale*

Which of the following are physicochemical properties of NSAIDs?

A. Acidic (pKa of 3-5) B. Rapidly absorbed following oral administration C. Poor aqueous solubility D. Incomplete dissolution at higher doses & less than proportional increase in plasma AUC when dose is increased

NSAIDs have:

A. An acidic center B. An aromatic or heteroaromatic ring C. An additional center of lipophillicity in the form of either an alkyl chain or an additional aromatic ring

What are the 3 MAJOR properties of NSAIDs?

A. Analgesic B. Antipyretic C. Anti-inflammatory Several NSAIDs possess uricosuric effects*

Common symptoms of GI effects caused by NSAIDs include:

A. Anorexia B. Nausea C. Dyspepsia D. Abdominal pain E. Diarrhea *May be related with induction of gastric or intestinal ulcers*

Which of the following NSAIDs are commonly used in dysmenorrhea?

A. Aspirin B. Ibuprofen C. Naproxen D. Celebrex E. Ketoprofen NSAIDs inhibit the synthesis of prostaglandins from arachidonic acid by inhibiting COX-1/COX-2*

*KNOW* Counseling points for NSAIDs include:

A. Can cause ulcers & bleeding in GI tract B. Take with food C. Can increase chance of heart attack D. Can increase blood pressure

*study guide* Which of the following is TRUE regarding the effects of NSAIDs on kidneys?

A. Can increase water & sodium retention B. Can oppose the effects of diuretics & antihypertensives C. Can exacerbate renal problems & hypertensive complications D. Can worsen congestive heart failure (CHF) E. Chronic use of high doses can cause analgesic nephropathy (slowly progressive renal failure) *NSAIDs reduce GFR*

Replacement of (-COOH) with (-CONH₂) in Aspirin results in?

A. Decreased acidity B. Loss of anti-inflammatory activity C. ↓ GI side effects

Properties of Acetaminophen include:

A. Excellent analgesic & antipyretic activity B. Almost NO anti-inflammatory activity C. NO gastric, platelet or cardiac side effects (like NSAIDs) *NOTE: acetaminophen is the most commonly used non-narcotic analgesic-antipyretic agent*

Which of the following is TRUE regarding prostaglandins in fever?

A. Fever results due to altered hypothalamic thermoregulatory mechanisms B. Pyrogens stimulate the production of cytokines by leukocytes which increase PG synthesis in the hypothalamus C. PGs are responsible for the increase in body temp D. Other temp-rising mechanisms are activated such as reduction in heat loss via cutaneous vasodilation Pyrogens = bacterial toxins* basal temp is unaffected by NSAIDs*

Common AE's of NSAIDs include:

A. Gastritis & peptic ulceration with bleeding B. Acute renal failure in susceptible patients C. Sodium & water retention AND edema (CV risks) D. Analgesic nephropathy E. Prolongation of gestation & inhibition of labor F. PG inhibition-mediated hypersensitivity G. Platelet dysfunction MOST common AE? Gastritis & peptic ulceration with bleeding*

*KNOW; study guide* What are the 3 SAFE pathways to metabolize acetaminophen?

A. Glucuronidation B. Sulfonation C. GSH conjugation

Which of the following are released in response to local tissue damage resulting in direct stimulation of nociceptors?

A. Histamine B. Serotonin C. Bradykinin

NSAIDs during late pregnancy or to induce labor cause premature closure of the ductus arteriosus leading to what?

A. Impaired fetal circulation B. Cardiopulmonary issues

*TXA₂ is produced by activated *platelets* via *COX-1* enzyme. This results in *detrimental effects* to the heart due to:

A. Increased platelet aggregation B. Vasoconstriction

*study guide* Which of the following NSAIDs can be used to treat PDA in neonates?

A. Indomethacin injection B. Ibuprofen injection

Uses of NSAIDs include:

A. Inflammation (swelling, pain, fever) B. Rheumatoid arthritis, osteoarthritis, gout C. Dysmenorrhea D. Prophylaxis of MI/Stroke E. Alzheimer's F. Prophylaxis of colon cancer Prophylaxis of MI/stoke is only with aspirin*

NSAIDs cause gastric damage (ulceration) by:

A. Inhibiting prostaglandin synthesis B. Blocking COX-1 enzyme in the GI

Which of the following is TRUE regarding aspirin?

A. Inhibits platelet aggregation B. Used to prevent & treat arterial thromboembolic disorders C. Cardioprotective D. Low-dose has shown a higher reduction in myocardial infarction compared to naproxen

Which of the following is TRUE regarding rheumatoid arthritis (RA)?

A. Its a chronic disease that results in the body's immune cells attacking the body B. The resulting inflammation of the joints causes pain & affects joint motion C. Can start by affecting several joints D. Its caused by genetic predisposition or environmental factors or BOTH

*KNOW* What is misoprostol?

A. Its a synthetic PGE1 B. It induces uterine contractions C. It replaces gastro protective prostaglandins inhibited by NSAIDs

Which of the following is TRUE regarding osteoarthritis (OA)?

A. Its caused by damage of joint cartilage which causes wear & tear of the joints B. The joint bones rub against one another resulting in very severe pain C. Starts by affecting a single joint and may spread to other joints

Factors that contribute to the reception of pain include:

A. Mechanical stimulation from the sharp object B. Potassium released from the insides of the damaged cells C. Prostaglandins, histamines & bradykinin from immune cells that invade the area during inflammation D. Substance P from nearby nerve fibers

Salicylates can be used for:

A. Mild-to-moderate pain B. Headache C. Myalgia D. Arthralgia Examples of salicylates: aspirin, sodium salicylate, salsalate, choline salicylate, magnesium salicylate*

Which of the following types of pain are targeted by NSAIDs? NSAIDs are most useful for what kind of pain?*

A. Nociceptive pain B. Inflammatory pain NOTE: Nociceptive pain is pain from physical damage or potential damage to the body* NSAIDs are most useful for nociceptive pain*

Gastric damage can occur with _______ administration of NSAIDs.

A. Oral B. Parenteral C. Transdermal

Which of the following are considered inflammatory mediators?

A. PGH2 B. PGD2 C. PGE2 D. PGF2a E. PGI2 F. TXA2 Prostaglandin H2 is a type of Prostaglandin which is derived from arachidonic acid and is a precursor for many other prostaglandins* prostanoids = PGs & TXA2*

study guide* PG's DECREASE the threshold to stimulation of pain receptors by:

A. Peripheral sensitization of nociceptors B. Central sensitization of nociceptors

At birth, failure of ductus arteriosus to close results in PDA (patent ductus arteriosus) which can lead to?

A. Pulmonary hypertension B. Congestive heart failure C. Cardiac arrhythmias

Acetaminophen can become toxic due to:

A. Saturation of normal metabolism (i.e: toxic dose, repeated supra-therapeutic concentration) B. Alcoholism C. Induction of CYPs D. GSH depletion (due to alcohol, malnutrition, fasting) E. Drug Interactions

Traditional NSAIDs are NOT thought to afford cardioprotection due to?

A. Short half-life B. Reversibility of binding with COX enzymes *Naproxen is an exception*

*KNOW* Common side effects of NSAIDs include:

A. Stomach upset, ulcers, bleeding B. Kidney damage C. Liver damage D. Ringing in the ears (tinnitus) *tinnitus is common in people who take high doses of aspirin; it goes away once dose is reduced* *use of NSAIDs even for a short time can harm the kidneys*

Which of the following NSAIDs via clinical research have shown a reduction in colon polyps?

A. Sulindac B. Celecoxib C. Rofecoxib

*KNOW* What is misoprostol used for?

A. Termination of intrauterine pregnancy B. Off label use of early pregnancy loss, incomplete abortion treatment & labor induction (cervical ripening) C. Prevention of NSAID-induced gastric ulcers *PGE1--has 1 added role of gastroprotection* *can be formulated as diclofenac & misoprostol = more useful in elderly*

Use of dinoprostone (PGE2 synthetic) results in?

A. Termination of intrauterine pregnancy (abortifacient) B. Relaxation of the smooth muscle in the cervix allowing dilation & passage of the fetus through the birth canal (labor induction/cervical ripening)

Which of the following are advantages of prostaglandins (PGE₂ & PGI₂)?

A. They are gastroprotective B. They enhance mucosal blood flow C. They confer physical protection by forming mucosal gel D. They inhibit gastric acid secretion E. They promote NaHCO₃ production

Which of the following contribute to the presence of fever?

A. Tissue damage, inflammation, infection B. Release of cytokines, interferons, TNF-a C. Increased production of PGE₂

*KNOW* Modifications to Acetaminophen SAR results in:

A. Toxicity B. Compounds with decreased activity C. Compounds with more side effects

Which of the following is TRUE regarding acetaminophen toxicity?

A. well-tolerated at recommended doses B. Rash & allergic reaction may occur C. Possible cross-allergic reaction in patients with salicylate hypersensitivity D. Serious adverse effects occur with overdose (10-15 g acute ingestion)

What is the role of PGE₂ in the kidneys?

A. ↑ Arteriole dilation B. ↑ Filtration C. ↑ Perfusion D. ↑ Urinary output

What is the role of PGI₂ in the kidneys?

A. ↓ Na⁺ reabsorption B. ↑ Urinary output

What are the effects of using Acetaminophen (anti-pyretic analgesic)?

A. ↓ pyrogen action in thermoregulatory center in CNS B. ↓ hypothalamic set point C. Central COX inhibition (prefer COX-2) D. ↓ PGE₂ in brain E. COX-3 inhibition in the brain

What is the ONLY anti-pyretic analgesic in the market?

Acetaminophen (Tylenol)

The following characteristics below best suits what? -May delay (NOT reduce) absorption -Bound to basic plasma proteins (albumin) -Extensively bound (95-99%) to plasma proteins -High potential to displace other drugs -Antacids commonly prescribed

Acidic

_______________ essential to tumor growth requires COX-2.

Angiogenesis *NOTE: increased expression of COX-2 is seen in some cancer cells*

*KNOW* Which of the following NSAIDs is MOST effective at reducing the risk of colon cancer (50% reduction)?

Aspirin most effect in colon cancer. Other drugs are not approved yet*

*QUESTION* All of the following can be regarded as endogenous pathways related with APAP EXCEPT: A. Glucuronidation B. Sulfate conjugation C. N-acetylcysteine conjugation D. GSH conjugation E. Conjugation with hepatic protein

C

*PGI₂* is produced by *endothelial cells* via *COX-1 & COX-2* enzyme. This results in *protective effects* to the heart due to:

C. Vasodilation D. Decreased platelet aggregation

*study guide* Which of the following NSAID is truly selective for COX-2?

Celecoxib *Etodolac & Meloxicam are considered to be non-selective for COX but also have some selectivity for COX-2*

How does aspirin bind with COX enzyme (type of bond)?

Covalent bonds

Regular use of NSAIDs has been shown to ______ the risk of developing colorectal cancer.

Decrease this is especially so with a COX-2 selective NSAID*

study guide* Name one anti-depressant drug useful for chronic pain like in osteoarthritis.

Duloxetine

Acetaminophen is excreted MAINLY as?

Glucuronide conjugates

Presence of halogens on the ring results in?

Increase in anti-inflammatory activity

Unlike other NSAIDs, aspirin ________ inhibits COX-1 that catalyzes an early step in the TXA₂ synthesis.

Irreversibly *One dose of 81mg aspirin lasts for 24hrs because it binds specifically to one area*

What is the role of activated charcoal in acetaminophen toxicity?

It removes drug from the stomach NOT the blood & is ONLY useful in binding drug that has not been digested yet.

*study guide* What is NAPQI?

Its a toxic byproduct produced during the metabolism of acetaminophen

Aspirin at *__________* dose is MORE selective for COX-1

LOW

Aromatic ring of NSAIDs binds to the __________ area of the receptor.

Lipophilic

*study guide* What is the antidote for acetaminophen overdose?

N-acetylcysteine (Mucomyst, Acetadote) *MOA: it increases GSH stores & increases renal excretion*

__________________ of COX-2 leads to increased expression of vascular endothelial growth factor (VEGF).

Overexpression

Which of the following prostaglandins is present in the regulation of body temperature (raises the temperature set point)?

PGE₂

What is the significance of acetyl group at 2-OH in Aspirin?

Results in irreversible covalent binding of aspirin to COX enzyme

Which of the following contributes to the analgesic activity of NSAIDs?

Reversal of both peripheral & central sensitization of pain receptors

*KNOW; study guide* Which of the following pathway is considered the "toxic pathway" of acetaminophen metabolism?

SH-hepatic proteins *results in hepatic necrosis & renal failure* *This pathway is used when all 3 safe pathways are compromised (i.e: too much drug in the system)*

Low doses of aspirin selectively inhibit the synthesis of _______ without affecting prostacyclin (PGI₂).

TXA₂ *higher doses inhibit the synthesis of both*

*study guide* What is the main use of diclofenac and misoprostol combination. In other words this combo is great for whom?

The elderly

All NSAIDs relieve fever by inhibiting PG synthesis in the hypothalamus, but are not capable of reducing body temperature below normal (hypothermia). A. True B. False

True

Au bon pain is defined as physical suffering or distress. A. True B. False

True

COX is the major player forming TXA₂ and PGI₂ from PGH₂. A. True B. False

True

NSAIDs can prolong labor by inhibiting PGs. A. True B. False

True

The hypothalamus regulates temperature set point and maintains body temperature. A. True B. False

True

*study guide* Long term use of NSAIDs can lead to ___________.

analgesic nephropathy

NSAIDs target the enzyme COX (Cyclooxygenase) responsible for conversion of _______________ to prostaglandin (resulting in inflammation).

arachidonic acid

NSAIDs are a diverse group of chemicals BUT they all inhibit ________________.

cyclooxygenase NOTE: the inhibition of PG synthesis is largely responsible for their therapeutic effects*

*KNOW* The patency of the ________________ is maintained by PGE₂?

ductus arteriosus -required for fetal circulation which connects the aorta and the pulmonary artery & allows blood from the right ventricle to bypass the non-functioning lungs*

COX-2 is mostly expressed during ___________________.

inflammation

COX-1 is primarily inhibited in the __________ by NSAIDs resulting in AE's.

kidneys *adverse effects are more common in elderly & patients with renal insufficiency*

Accumulation of NSAIDs in stomach lining results in ________ damage.

local *enteric coated formulations help with intestinal absorption of NSAIDs*

Excessive levels of PGs/hormones cause _________________.

menstrual cramps

COX-mediated inflammatory mechanisms contribute to _________________________ associated with Alzheimer's and recent studies have shown that NSAIDs can delay or slow the progress of the AD.

neurodegeneration

COX-1 is the main isoform in ________________.

platelets

NSAIDs are NOT recommended in late pregnancy because they may increase risk of what?

postpartum hemorrhage

Use of NSAIDs during early ________________ increases risk of miscarriage.

pregnancy

Use of NSAIDs can result in loss of cardio protection due to inhibition of COX enzymes resulting in what?

reduced production of PGI₂

*study guide* Dinoprostone can increase what?

uterine contractions