NSAIDs and CV risk Flashcards
(11 cards)
Outline the origins of NSAID drugs as treatment options
Historical Origin: Aspirin derived from salicylic acid, originally extracted from willow bark.
Development: Felix Hoffmann synthesized acetylsalicylic acid (aspirin) in 1897 to improve gastrointestinal tolerance.
Describe the mechanism of action, and potential adverse effects of aspirin
Mechanism: Irreversible inhibition of COX-1, leading to decreased thromboxane A2 (TXA2) – reduces platelet aggregation.
Adverse Effects:
○ Gastropathy (gastric ulceration/bleeding) due to COX-1 inhibition.
○ Hypersensitivity reactions, including anaphylaxis, asthma, and skin eruptions.
○ Aspirin resistance in some patients due to pharmacokinetic and pharmacodynamic variations.
Explain why “low dose” aspirin is such an effective antithrombotic agent
Platelets can’t make new COX-1
○ Platelets are annucleate (they have no nucleus), so they cannot synthesise new proteins
○ Inhibition lasts for the lide of the platelet even though aspirin itself is quickly cleared from the body
○ Result: a small daily dose is enough to maintain a consistent antiplatelet effect
Selective effect on platelets, not endothelial cells
○ At low doses, aspirin is absorbed in the portal circulation (from the gut to the liver) and inhibits platelet COX-1 before entering the systemic circulation
○ This spares endothelial cells, which make prostacyclin (PGI2) a compound that inhibits platelet aggregation and dilates blood vessels
○ Higher doses of aspirin inhibit both TXA2 and PGI2 which could counteract its benefits
○ Low dose aspirin preserves the balance in favour of anti-clotting effects
Describe what aspirin hypersensitivity means and the underlying mechanisms involved are
○ Aspirin blocks COX-1
○ COX-1 helps make a substance called PGE2, whih protects the airways by
§ Relaxing smooth muscle
§ Reducing inflammation
§ Stopping allergy cells from releasing histamine and other chemicals
○ In asipirin hypersensitive people
§ Blocking COX-1 leads to less PGE2
§ Removes the brake on inflammation
§ 5-lipoxygenase (5-LO) becomes overactive
§ Leading to the overproduction of leukotrienes (LTD4 and LTE4)
§ These leukotrienes cause inflammation, narrowin of airways, and allergy like symptoms
Describe what aspirin tolerance means and the underlying mechanisms involved are
○ Pharmacokinetic
§ Insufficient concentration of aspirin in the blood resulkting in incomplete inhibition of thromboxane production and platelet aggregation
○ Pharmacodynamic
§ Occurs even when there is a sufficient concentration of aspirin in the blood
§ Due to polymorphisms wiuthin the PTGS1 gene (which encodes the COX-1 enzyme) or changes within the structure of the platelets themselves, aspirin is unable to inhibit COX-1 and subsequently platelet aggregation
What is the rationale behind design and marketing of new NSAIDs
COX-2 expression is induced at sites of inflammation
○ This discovery led to the concept of selective COX-2 inhibitors being seen as successors to non-selective NSAIDs (which were, in turn, successors to aspirin).
○ The primary rationale behind the design and marketing of these “safer” new NSAIDs was to inhibit prostaglandin production specifically at sites of inflammation (where COX-2 is induced) and thereby avoid the issues associated with gastropathy.
This suggests that non-selective NSAIDs caused gastropathy by inhibiting COX-1, which is crucial for producing protective prostaglandins in the stomach.
What is the MoA of new NSAIDs
○ NSAIDs generally exert their effects by inhibiting Cyclooxygenase (COX) enzymes.
○ Earlier NSAIDs like aspirin (at doses used for pain/inflammation), ibuprofen, naproxen, and diclofenac are considered non-selective inhibitors of both COX-1 and COX-2, or have some selectivity towards COX-1. Low-dose aspirin’s anti-platelet effect comes from its irreversible inhibition of COX-1 in platelets.
○ The “new” NSAIDs discussed in this context, such as Celecoxib and Rofecoxib, were designed to be selective COX-2 inhibitors.
○ Prostaglandins produced at sites of inflammation by COX-2 are stated to exacerbate nociception in somatosensory neurons, promoting electrical excitability and neurogenic inflammation. Inhibiting COX-2 was intended to reduce these pain and inflammation signals.
What are the adverse effects of new NSAIDs
○ While designed to avoid gastropathy, selective COX-2 inhibitors, and NSAIDs more generally, became associated with significant cardiovascular adverse effects.
○ Rofecoxib was withdrawn from the market in 2004 because a clinical trial showed a doubling of the myocardial infarction rate on Rofecoxib compared to placebo.
○ An observational study suggested that taking ibuprofen (and other NSAIDs) during a cold or flu infection increases the risk of heart attack. The risk was noted as 3.3 times higher for high dose and 3 times for low-dose preparations
Describe the evidence that “proves” prostacyclin is produced by endothelial COX1 and not COX2 as widely believed
- It is a widely held view that endothelial COX-2 expression and activity are significantly greater than COX-1, and that COX-2 is the major driver of vascular prostacyclin.
- This conventional thinking around COX-1/-2 expression, location, and function is questioned in the sources.
- Studies using laminar shear stress (LSS) have shown that it can significantly up-regulate cyclooxygenase-2 in endothelial cells.
○ This evidence has often been interpreted as pointing to COX-2 being responsible for endothelium-derived prostacyclin (PGI2). - Furthermore, studies in human volunteers using a urinary prostacyclin marker suggested that COX-2 is central to the systemic biosynthesis of prostacyclin in healthy humans.
- However, the sources present data that challenges this view.
○ Specifically, it is stated that COX-1, and not COX-2, is expressed in human aortic endothelial cells grown in culture under static conditions. - The sources also critique the basis for the conventional view.
○ The conclusion that shear stress regulates COX-2 expression is based upon studies using short periods of shear stress.
○ It is suggested that these short periods of shear stress may be perceived by cells as an inflammatory insult that resolves with time, rather than a purely physiological response. - Additionally, the sources question whether endothelial cells grown under static conditions, which often quickly lose phenotypic markers, might rapidly lose COX-2 expression that is then rescued by applying shear stress
What are the established mechanisms that relate COX inhibition to increased CV risk
- COX Enzymes and Prostanoid Roles:
1. COX-1 (platelets): Produces thromboxane A₂ (TXA₂) → promotes vasoconstriction and platelet aggregation
2. COX-2 (endothelium): Produces prostacyclin (PGI₂) → promotes vasodilation and inhibits platelet aggregation - Selective COX-2 Inhibition:
1. Suppresses prostacyclin (PGI₂) production
2. Leaves TXA₂ production (via platelet COX-1) unaffected
3. Result: A shift toward a pro-thrombotic state, increasing risk of thrombosis, heart attack, and stroke - Debate and Emerging Data:
1. Some evidence suggests COX-1 may also contribute to prostacyclin production in human endothelium under static (non-inflammatory) conditions
2. Despite this debate, the prostanoid imbalance hypothesis remains foundational
What is a novel mechanic that can relate COX inhibition to increased CV risk
Novel Mechanisms: ADMA–NO Axis & Renal COX-2 Inhibition
These are newer hypotheses exploring indirect systemic effects of COX-2 inhibition, especially involving the kidney and nitric oxide (NO) pathways.
- Central Idea:
○ Inhibition of renal COX-2 alters systemic regulators of vascular tone and inflammation, particularly through ADMA accumulation and renal dysfunction. - Key Components:
- ADMA (Asymmetrical Dimethylarginine) Hypothesis:
- NSAID-induced inhibition of kidney COX-2 increases ADMA in the bloodstream
- ADMA (and L-NMMA) inhibit eNOS → less nitric oxide (NO) is produced
- Reduced NO leads to vasoconstriction, endothelial dysfunction, and pro-thrombotic states - Impact on Blood Pressure and Atherosclerosis:
- Less NO → higher vascular tone, oxidative stress, and inflammation
- Long-term: increases risk of hypertension, atherosclerosis, and CV events - Additional Renal Effects of COX-2 Inhibition:
- Decreased renal perfusion and glomerular filtration
- Activation of renin-angiotensin-aldosterone system (RAAS)
- Sodium and fluid retention, hypertension, and oxidative stress
- These amplify cardiovascular dysfunction
