NSAIDs Flashcards
Describe the biosynthetic pathways for production of prostaglandins, prostacyclin, thromboxane, and leukotrienes, including the source of the precursor arachidonic acid and the specific enzymes involved.
- PM phospholipid is converted by PLA2 to make AA
- AA is converted by COX1/2 to make PGG2 (cyclic int)
- PGG2 is converted to prostaglandins (via endoperoxide isomerase), prostacyclin, and thromboxane
Leukotriene:
• AA is converted by 5-lipoxygenase to leukotriene A4 (LTA4); this is further enzymatically converted to LTB4 (chemotaxis & phagocyte activation) OR LTC C4/D4/E4 (which do bronchi constriction)
Compare and contrast the biochemistry and physiology of cyclooxygenase-1 and cyclooxygenase-2 with regards to expression, tissue locations, physiologic role, inducers, and inhibitors.
- COX-1. Constitutively expressed for “housekeeping” functions, i.e., baseline levels of activity present at all times. Located ubiquitously
- COX-2. Induced (by cytokines [IL-1, IL-2, IFN-γ, plus lipopolysaccharide], shear stress, and growth factors) or up-regulated on as needed basis or for specialized functions. Located in inflamed or activated tissues including:
List the effects of prostaglandins on vascular smooth muscle, platelets, GI tract smooth muscle and secretory cells, kidney cells, uterus, and inflammatory cells and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.
COX-1:
• GI tract [PGE2 / PGI2 / PGF2]: Secretions: ↓ acid / pepsin secretion, ↑ mucous / bicarbonate production (cytoprotective effects); Smooth muscle [PGE2 / PGF2]: ↑ contractions
• Platelets [TXA2]: Pro-aggregatory effect
• Kidneys [PGE2 / PGI2]: ↑ Renal blood flow, promotion of diuresis
• Vascular smooth muscle: PGI2 / PGE2: vasodilation; TXA2: vasoconstriction
• Bone [PGE2]: Stimulates bone formation and resorption
INHIBITION CAUSES: GI ulceration - prolonged bleeding time - acute renal failure
COX-2:
• Areas of pain / inflammation [PGE2 / PGI2]: Enhance edema formation and leukocyte infiltration via vasodilation; potentiation of bradykinin pain-producing activity
• Hypothalamus / Fever [PGE2]: Increase in heat generation and decrease in heat loss
• Kidneys [PGE2 / PGI2]: Renal adaptation to stresses via maintenance of renal blood flow; most critical in elderly and when renal function deteriorates [thought to be present constitutively]
• Endothelial cells (upregulated by blood flow shear stress) [PGI2]: Vasodilation and anti-aggregatory platelet effects
• Uterine smooth muscle [PGE2 / PGF2]: Contributes to labor contractions near parturition
• Ductus arteriosus [PGE2]: Maintenance of patent ductus arteriosus via vasodilatory effects
INHIBITION CAUSES:
• Therapeutic actions: relief of pain - reduction of fever - reduction of inflammation
• Potential side effects: acute renal failure - thrombotic events (COX-2 selective agents) - prolonged gestation
Describe the effects of leukotrienes on inflammatory cell function and pulmonary / vascular smooth muscle.
- LTB4: Neutrophil chemotaxis, aggregation, and transmigration through endothelium
- LTC4 / LTD4 / LTE4: Increased vascular permeability, bronchoconstriction, vasoconstriction. (key role in asthma, psoriasis, and various arthritic / allergic / hypersensitivity processes)
Anti-Leukotriene Agents: good for asthma, some good in allergies
• Synthesis Inhibitor: Zileuton is an inhibitor of 5-lipoxygenase
• Antagonists of CysLT1 Receptors: Zafirlukast (Accolate®), Montelukast (Singular®)
Describe the functional interaction of prostacyclin and thromboxane A2 with relation to physiologic effects on vascular smooth muscle and platelets.
Prostacyclin (PGI2): vasodilation and dis-aggregation
Think: CYCLIST who needs good blood flow
Thromboxane (TXA2): vasoconstriction and aggregation
Think: BOXER who needs to stop the bleeding
Compare and contrast the effects of aspirin, acetaminophen, NSAIDs, and COX-2 selective inhibitors on the cyclooxygenase enzymes 1 and 2 as the relation to therapeutic uses and adverse reactions.
Which COX? Ow Fe Inf A-P Aspirin 1&2 - IRREV! Y Y Y Y NSAID 1&2 - REV Y Y Y N Celeco 2 - REV Y Y Y N Aceta CNS 2 Y Y N N
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.
- Inhibition of platelet aggregation (secondary to inhibiting platelet TXA2 synthesis). Low-dose aspirin is essentially platelet COX-1 selective via two mechanisms:
- Platelets cannot synthesize new COX-1 enzyme, thus TXA2 synthesis is inhibited for life of platelet (> 8 days); COX-2 prostacyclin synthesis in endothelial cells recovers faster.
- Largest concentration of ACETYLsalicylic acid is presystemic in portal vein (prior to hepatic metabolism by esterases), thus greater effect on circulating platelet COX-1 (TXA2 synthesis) relative to tissue endothelial cell COX-2 (prostacyclin synthesis) resulting in a decreased tendency for clotting.
Aspirin
Therapeutic uses: Result from irreversible inhibition of COX-1 and COX-2. Low dose aspirin given to inhibit thrombus formation.
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.
Side effects: increased bleeding time, GI pain and nausea. Sometimes people can have aspirin hypersensitivities (as well as to other NSAIDs).
Overdose: Causes tinnitis (ringing in the ears) at high concentrations. At very high concentrations, get uncoupling of oxidative phosphorylation– metabolic acidosis, respiratory alkalosis.
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.
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).
Acetaminophen:
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.
Metabolism and excretion: See ‘overdose,’ below.
Side effects: mild CNS effects; mild hepatic enzyme inducer.
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).
Contraindications: as above.
Drug-drug interactions: none noted.
NSAID
Therapeutic uses: Anti-inflammatory, antipyretic, analgesic. Sometimes used for arthritis. Some transient anti-clotting activity.
Metabolism and excretion: rapid, complete absorption; excreted by kidney. Ketorolac is taken IV/IM; the rest can be taken po.
Side effects: Less GI irritation than aspirin. Ibuprofen is the least-GI-irritating NSAID.
Overdose: none noted.
Contraindications: Not for use in pregnant women (safety not established– seriously, after this long?).
Drug-drug interactions: None noted.
Celicoxib
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.
Metabolism and excretion: po admin. Metabolized by the liver, excreted by the kidney.
Side effects: Some renal side effects; increased risk of adverse cardiovascular events (mainly emboli), as noted above.
Overdose: No notes.
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.
Drug-drug interactions: When taken with warfarin, potential for increased bleeding.
