NSAIDs II Flashcards
Describe the functional interaction of prostacyclin and thromboxane A2 with relation to physiologic effects on vascular smooth muscle and platelets
- Thromboxane effects**:
- –Vascular smooth muscle: vasoconstriction (mainly in platelets).
- –Platelets: aggregation.
- Prostacyclin effects** (exactly opposite to thromboxane):
- –Vascular smooth muscle: vasodilation (mainly in endothelial cells).
- –Platelets: disaggregation.
effects of aspirin on the cyclooxygenase enzymes 1 and 2 as the relation to therapeutic uses and adverse reactions
Irreversibly inactivates COX-1 and COX-2.
effects of NSAIDs selective inhibitors on the cyclooxygenase enzymes 1 and 2 as the relation to therapeutic uses and adverse reactions
- Reversibly inhibit COX-1 and COX-2.
- Side effects:
- –Ulceration and bleeding in the GI tract, nausea. Due to inhibition of protective COX-1 effect.
- –Decrease in tissue clotting (thus increased bleeding time). Due to inhibition of thromboxane production.
- –Can reduce uterine contractions, leading to problematic delivery. Due to inhibition of prostaglandins.
effects of acetaminophen and COX-2 selective inhibitors on the cyclooxygenase enzymes 1 and 2 as the relation to therapeutic uses and adverse reactions
is NOT an NSAID. Has no anti-inflammatory effects (anti-pyretic and mild analgesic effects only) since it does not have a substantial effect on COX-1 or COX-2.
effects of COX-2 selective inhibitors on the cyclooxygenase enzymes 1 and 2 as the relation to therapeutic uses and adverse reactions
As the name implies, inhibits only COX-2 activity. Indicated for people with GI ulcers or for chronic alcoholics. But note that apparently these are being taken off the market due to increased rates of thrombosis
Describe the mechanism whereby low-dose, but not high-dose, aspirin is able to exert an anti-thrombotic / cardioprotective effect. Relate this effect to potential cardiovascular toxicity associated with use of COX-2 selective agents
- The active form of aspirin (ASA) tends to concentrate in the hepatic portal vein (inactivated in the liver). What this means is that you have a concentration differential of aspirin between the endothelial surfaces and the platelets in the bloodstream; the larger concentration in the bloodstream means that COX-1 on the platelets (pro-thrombotic) is preferentially inactivated relative to the COX-2 (anti-thrombotic) on the endothelial cells. This results in a net anti-thrombotic effect.
- –Also, recall that aspirin irreversibly inactivates the COXs– and platelets, unlike endothelial cells, can’t make new enzymes (no nucleus).
- At higher doses, the concentrations are more or less equal between the bloodstream and the endothelial surfaces– thus antithrombotic effects are negated.
Relate the low-dose, but not high-dose, aspirin is able to exert an anti-thrombotic / cardioprotective effect to potential cardiovascular toxicity associated with use of COX-2 selective agents
In endothelia, COX-2 (anti-clotting) is constitutively expressed to prevent intravascular clotting; by blocking COX-2 action there, the unopposed pro-aggregation effects of COX-1 in the endothelium leads to increased thrombus formation.
For aspirin describe: 1) Therapeutic uses 2) Metabolism and excretion 3) Common side effects at therapeutic doses
(1) Therapeutic uses: Result from irreversible inhibition of COX-1 and COX-2. Low dose aspirin given to inhibit thrombus formation.
(2) Metabolism and excretion: Recall that aspirin, beyond low-dose, is a zero-order kinetic drug. This means that adding more aspirin past a certain (easily reached) point has no effect on COXs– but it can certainly cause toxic side effects. Doesn’t, as such, have a half-life. Rapidly metabolized by esterases in blood and tissues.
(3) Side effects: increased bleeding time, GI pain and nausea. Sometimes people can have aspirin hypersensitivities (as well as to other NSAIDs).
For acetaminophen, describe: 1) Therapeutic uses 2) Metabolism and excretion 3) Common side effects at therapeutic doses
(1) Therapeutic uses: mild-moderate analgesic, antipyretic. No significant anti-inflammatory effects. Considered safe at all stages of pregnancy for short-term use; weak to no effect on clotting; no GU upset; safe to give virally infected infants.
(2) Metabolism and excretion: See ‘overdose,’ below.
(3) Side effects: mild CNS effects; mild hepatic enzyme inducer.
For ibuprofen / naproxen / ketorolac, describe: 1) Therapeutic uses 2) Metabolism and excretion 3) Common side effects at therapeutic doses
(1) Therapeutic uses: Anti-inflammatory, antipyretic, analgesic. Sometimes used for arthritis. Some transient anti-clotting activity.
(2) Metabolism and excretion: rapid, complete absorption; excreted by kidney. Ketorolac is taken IV/IM; the rest can be taken po.
(3) Side effects: Less GI irritation than aspirin. Ibuprofen is the least-GI-irritating NSAID.
For celicoxib, describe: 1) Therapeutic uses 2) Metabolism and excretion 3) Common side effects at therapeutic doses
(1) Therapeutic uses: Marketed as a COX-2 specific inhibitor. Anti-inflammatory, antipyretic, analgesic. Used for arthritis, menstrual pains, acute pain. No anticlotting effect per se.
(2) Metabolism and excretion: po admin. Metabolized by the liver, excreted by the kidney.
(3) Side effects: Some renal side effects; increased risk of adverse cardiovascular events (mainly emboli), as noted above.
For aspirin describe: 4) Overdose toxicities and their treatment 5) Contraindications to use 6) Drug-drug interactions
(4) Overdose: Causes tinnitis (ringing in the ears) at high concentrations. At very high concentrations, get uncoupling of oxidative phosphorylation– metabolic acidosis, respiratory alkalosis.
(5) Contraindications: No one with gastric ulcers, no chronic alcoholics. Notice that aspirin (not other NSAIDs) shouldn’t be used in infants with viral infections (liver damage-Reyes syndrome). Avoid use in pregnant patients.
(6) Drug-drug interactions: Low-dose aspirin has no effect if it’s taken after taking ibuprofen. Ibuprofen preferentially binds to the COXs, making aspirin incapable of binding it. If you take aspirin first, and wait three or four hours, you can take ibuprofen again with pretty close to full effect (the COXs that aspirin are going to target have been targeted).
For acetaminophen, describe: 4) Overdose toxicities and their treatment 5) Contraindications to use 6) Drug-drug interactions
(4) Overdose: recall that acetaminophen is metabolized by conjugation through easily overloaded mechanisms. It has an unconjugated, reactive intermediate form that builds up quickly in overdose situations and is extremely toxic (will destroy liver and kidney tubules). Rapid infusion of intermediate-binding molecules are needed to prevent organ failure and death. Note alcohol induces the enzyme that forms the toxic intermediate (if you’ve been drinking all night, don’t take a bunch of Tylenol to ward off the headache you’re going to have the next day).
(5) Contraindications: as above.
(6) Drug-drug interactions: none noted.
For ibuprofen / naproxen / ketorolac, describe: 4) Overdose toxicities and their treatment 5) Contraindications to use 6) Drug-drug interactions
(4) Overdose: none noted.
(5) Contraindications: Not for use in pregnant women (safety not established– seriously, after this long?).
(6) Drug-drug interactions: None noted.
For celicoxib, describe: 4) Overdose toxicities and their treatment 5) Contraindications to use 6) Drug-drug interactions
(4) Overdose: No notes.
(5) Contraindications: Not to be used in pregnant women (blocks uterine contractions). Note that celecoxib is a sulfonamide (sulfa drug) so watch out for allergic reactions.
(6) Drug-drug interactions: When taken with warfarin, potential for increased bleeding.
