Lecture XI-XII Flashcards
COX-1
- Constitutively expressed
- Ubiquitous
- Protects gastric mucosa, helps platelet agreggation
COX-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
Periphery Prostaglandin effect on Pain
Primary Afferent Neurons- decreases activation threshold for pain so causes pain sensitization
Central prostaglandin effect on pain
Dorsal Horn Neurons- enhances depolarization of secondary sensory neurons causing CNS pain sensitization
COX-1 action on GI tract
- 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)
COX-1 action on CV system
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.
TXA2
Vasoconstriction
Platelet Aggregation
PGI2
vasodilation
Inhibits platelet aggregation
COX-1 action on the Kidney
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
COX-1 on female repro
PG stimulate uterine contractions in child birth
COX-1 & Ductus Arteriosus
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
Aspirin
Uses: Treatment of moderate pain, Inflammatory Diseases (decreases inflammation), Fever reduction, Prevention of cardiovascular events @ low doses, Cancer chemoprevention
Aspirin Doses
- 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
Aspirin Treatment of CV disease
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.
Salsalate
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
Difulsinal
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
Salicylate Toxicity
*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
Ibuprofen
Traditional NSAID
Rapid onset of action (15-30 min)
Ideal for treatment of fever or acute pain
Naproxen
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
Indomethacin
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
Diclofenac
Traditional NSAID
Relatively selective for COX-2
Increased Heart/stroke risk similar to Coxibs
Keterolac
Traditional NSAID
USED AS IV ANALGESIC for post surgery pain
Can replace opioid analgesics (i.e. morphine)
Oxaprozin
Traditional NSAID
Long serum half life 50-60 hours, once daily dosing
More useful for gout
Meloxican
Traditional NSAID
Treatment of Gout
Traditional NSAIDs but not Aspirin/Salicylates
NSAID Hypersensitivity
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.
Reye’s Syndrome
Fatal- liver degenerative disease associated with encephalitis
Young children/adolescents who have febrile viral infection
Use NSAID or acetaminophen instead of aspirin
Aspirin & Gout
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.
Celecoxib
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
COX-2 inhibitor and increased CVD Risk
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
NSAID Contraindications
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)
Aspirin and NSAID Interaction
Antagonize beneficial effects of low-dose aspirin
Oral Anti-coagulants and NSAID Interaction
NSAIDs displace warfarin from albumin and inhibit COX-1. Causes increased risk of bleeding due. (Partially due to more available active warfarin)
NOT CELECOXIB
Anti-Hypertensives and NSAID Interaction
NSAIDs block prostaglandins that help vasodilation so they would promote vasoconstriction
Oral Hypoglycemics (SALICYLATES) and NSAID Interaction
Displace protein bound medications and enhance glucose utilization
Lithium and NSAID Interaction
NSAIDS impair renal function so decrease clearance
Methotrexate and NSAID Interaction
Impair clearance of NTX and displace MTX from serum proteins
Aminoglycosides and NSAID Interaction
Impair renal clearance of aminoglycosides
NSAIDs for simple fever
Aspirin, Ibuprofen, Naproxen
Long-term pain managment
Sulindac, Naproxen, Oxaprozin
Acetaminophen
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
When to use Aceptaminophen?
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
Acetaminophen Toxicity
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.
