Lecture XI-XII

Question 1

COX-1

Answer 1

• Constitutively expressed
• Ubiquitous
• Protects gastric mucosa, helps platelet agreggation

Question 2

COX-2

Answer 2

*Inducible in cell types with pro-inflammatory signals

• Induciblely expressed in: macrophages, monocytes, osteoblasts
• Constitutively expressed in : brain, kidney, endothelium

*Pro inflammatory response: Recruits inflammatory cells, sensitizes skin pain receptors, regulates hypothalamic temperature

synthesises prostaglandins that promote: INFLAMMATION, PAIN, FEVER

Question 3

Periphery Prostaglandin effect on Pain

Answer 3

Primary Afferent Neurons- decreases activation threshold for pain so causes pain sensitization

Question 4

Central prostaglandin effect on pain

Answer 4

Dorsal Horn Neurons- enhances depolarization of secondary sensory neurons causing CNS pain sensitization

Question 5

COX-1 action on GI tract

Answer 5

• Decrease gastric acid secretion
• Decrease bicarb production
• Increase mucous production

NSAIDs decrease PG, which decreases protection= GASTRIC TOXICITY

Treatment:

• Misprostol- a PGE1 analog (Note: Caution in women/Abortifacient)
• Omeprazole- proton pump inhibitor (inhibits gastric acid production)

Question 6

COX-1 action on CV system

Answer 6

Platelets: Only COX-1 (TXA2: vasoconstriction, platelet aggregation)

Endothelial Cells: COX-1 &2 (PGI2: vasodilator, inhibits platelet aggregation

If there is an imbalance between TXA2 and PGI2 it can cause either excessive bleeding or thrombosis.

Question 7

TXA2

Answer 7

Vasoconstriction

Platelet Aggregation

Question 8

PGI2

Answer 8

vasodilation

Inhibits platelet aggregation

Question 9

COX-1 action on the Kidney

Answer 9

COX-1 &2 always present

PG’s increase vasodilation preventing ischemia
Increase the GFR and increase the Na+/water excretion

Help prevent vasoconstriction of renal vessels in disease.

NSAIDs decrease PG, decreasing the vasodilation= RENAL TOXICITY

Usually reversible with stop of NSAID

Question 10

COX-1 on female repro

Answer 10

PG stimulate uterine contractions in child birth

Question 11

COX-1 & Ductus Arteriosus

Answer 11

Blood from pulmonary artery to aorta to bypass the lungs

Ductus is kept open by PG’s

NSAIDs
During pregnancy- premature closure
After pregnancy- induce closure to help

Question 12

Aspirin

Answer 12

Uses: Treatment of moderate pain, Inflammatory Diseases (decreases inflammation), Fever reduction, Prevention of cardiovascular events @ low doses, Cancer chemoprevention

Question 13

Aspirin Doses

Answer 13

• 81 mg/day: Antiplatelet Activity NEED TO RULE OUT HEMORRHAGIC STROKE RISK
• ~2400 mg/day: Analgesic/Anti-pyretic
• 4,600-6,00 mg/day: Anti- Inflammatory

Question 14

Aspirin Treatment of CV disease

Answer 14

Preminantly inhibits COX-1 activity in the platelets throughout the whole life span since they have no nucleus and can’t regenerate COX-1 so reduces the TXA2 (vasoconstriction, increases platelet aggregation).

Endothelial cells can regenerate COX-1 & have COX-2, low level aspirin does not affect the production of PGI2 (inhibitor of platelet aggregation & vasodilator)

Inhibiting TXA2 and not disturbing PGI2 production, provides an anti-thrombogenic anvironment

• At higher concentrations (anti-inflammatory ones), you increase the inhibition of PGI2 as well.
• Other NSAIDs inhibit COX-1 in platelets but are reversible so less effective.

Question 15

Salsalate

Answer 15

Salicylate NSAID, less potent than aspirin but better for people at risk for GI toxicity or at risk for increased bleeding.

Highly protein bound so increased drug interactions with warfarin

Question 16

Difulsinal

Answer 16

Does not cross the BBB so ineffective anti-pyretic

Less potent than aspirin but better for patients with increased risk of GI toxicity or increased risk of bleeding

Highly protein bound so increased drug interactions with warfarin

Question 17

Salicylate Toxicity

Answer 17

*At low doses metabolized in liver, eliminated in first order but at high doses, eliminated by zero order kinetics since the enzymes are saturated

Intoxication: Metabolic acidosis, hypoglycemia, confusion, tremors, seizures, delerium, respiratory depression.

Treatment: Alkalization of the urine with Sodium Bicarb. Prevents reabsorption of drug in the renal tubule

Question 18

Ibuprofen

Answer 18

Traditional NSAID

Rapid onset of action (15-30 min)
Ideal for treatment of fever or acute pain

Question 19

Naproxen

Answer 19

Traditional NSAID

Rapid onset of action- 60 min.
Ideal for anti-pyretic use
LONG SERUM HALF LIFE- 14 hours so only need dose 2x per day

Question 20

Indomethacin

Answer 20

Traditional NSAID

10x more potent than aspirin as an anti-inflammatory

Not tolerated as well as ibuprofen
~50% experience side effects

USED TO PROMOTE CLOSURE OF DUCTUS ARTERIOSUS

Question 21

Diclofenac

Answer 21

Traditional NSAID

Relatively selective for COX-2
Increased Heart/stroke risk similar to Coxibs

Question 22

Keterolac

Answer 22

Traditional NSAID

USED AS IV ANALGESIC for post surgery pain
Can replace opioid analgesics (i.e. morphine)

Question 23

Oxaprozin

Answer 23

Traditional NSAID

Long serum half life 50-60 hours, once daily dosing
More useful for gout

Question 24

Meloxican

Answer 24

Traditional NSAID

Question 25

Treatment of Gout

Answer 25

Traditional NSAIDs but not Aspirin/Salicylates

Question 26

NSAID Hypersensitivity

Answer 26

Any patient sensitive to aspirin will be sensitive to other drugs.

Build up of Arachinoic Acid which leads to the production of leukotrienes that is responsible for asthma attacks.

Question 27

Reye’s Syndrome

Answer 27

Fatal- liver degenerative disease associated with encephalitis

Young children/adolescents who have febrile viral infection

Use NSAID or acetaminophen instead of aspirin

Question 28

Aspirin & Gout

Answer 28

Aspirin blocks the ability of uric acid to be excreted by inhibiting renal transporters. You get an increase in serum uric acid that increases the gouty attack- it’s very painful. Patients with prior history of gout would never take Aspirin.

Question 29

Celecoxib

Answer 29

Competitive inhibitor of COX-2
Anti-inflammatory, anti-pyretic and analgesic properties

Mainly for rheumatoid arthritis & osteoarthritis
*Can be indicated for patients with risk of GI toxicity or increased bleeding

Risks: Associated with risk of CV diseases at higher doses. Not first choice NSAID because of this especially in patients who have previous CVD

Question 30

COX-2 inhibitor and increased CVD Risk

Answer 30

It would block the production of PGI2 which is a vasodilator/anti-platelet drug which would then alter the specturm and cause an increase in stroke/MI risk

Question 31

NSAID Contraindications

Answer 31

GI Ulcers

Renal Disorders

Bleeding disorders or on anti-coagulants (Decreases platelet aggregation, drug interaction with warfarin, discontinue prior to surgery)

Patients with history of CVD (especially for celecoxib)

Pregnancy (Delayed onset of labor, premature closure of ductus, post-partum hemorrhage risk)

ASPIRIN:

Patients with history of gout (Decreases Uric acid excretion)

Children with febrile viral infection (Risk of Reye’s Syndrome)

Question 32

Aspirin and NSAID Interaction

Answer 32

Antagonize beneficial effects of low-dose aspirin

Question 33

Oral Anti-coagulants and NSAID Interaction

Answer 33

NSAIDs displace warfarin from albumin and inhibit COX-1. Causes increased risk of bleeding due. (Partially due to more available active warfarin)

NOT CELECOXIB

Question 34

Anti-Hypertensives and NSAID Interaction

Answer 34

NSAIDs block prostaglandins that help vasodilation so they would promote vasoconstriction

Question 35

Oral Hypoglycemics (SALICYLATES) and NSAID Interaction

Answer 35

Displace protein bound medications and enhance glucose utilization

Question 36

Lithium and NSAID Interaction

Answer 36

NSAIDS impair renal function so decrease clearance

Question 37

Methotrexate and NSAID Interaction

Answer 37

Impair clearance of NTX and displace MTX from serum proteins

Question 38

Aminoglycosides and NSAID Interaction

Answer 38

Impair renal clearance of aminoglycosides

Question 39

NSAIDs for simple fever

Answer 39

Aspirin, Ibuprofen, Naproxen

Question 40

Long-term pain managment

Answer 40

Sulindac, Naproxen, Oxaprozin

Question 41

Acetaminophen

Answer 41

Fever and Pain Activity

NO- Anti-inflammation (doesn’t inhibit peripheral COX-2)
NO- Anti-platelet activity (doesn’t inhibit COX-1 in platelets)

MOA: weak inhibitor of COX-1 & 2 in PERIPHERAL TISSUES (no anti-inflammatory or platelet but reduces adverse effects) but inhibits COX-1 & 2 in the CNS (Decreases pain and fever)

Selectively metabolized in the brain to AM404- can inhibit COX-2 in th ebrain and acts on teh cannabinoid system to decrease Pain/Fever

Question 42

When to use Aceptaminophen?

Answer 42

Pain and Fever for:

Children with febrile viral infections (Avoids Reye’s Syndrome)

Patients with peptic ulcers (No GI toxicity)

Patients with hemophilia (No action on platelets)

Patients with hypersensitivity to Aspirin or other NSAIDs

Question 43

Acetaminophen Toxicity

Answer 43

At high concentrations metabolic enzymes are overwhelmed leading to a buildup of NAPQI that depletes hepatic glutathione and causes hepatic toxicity (happens with alcohol intake)

Antidote: N- acetyl Cysteine because it replenishes glutathione levels.