Pharmacology of Anti-inflammatory Agents

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Questions and Answers

What is a key difference between COX-1 and COX-2 enzymes in terms of their physiological roles?

COX-1 produces prostaglandins involved in homeostasis. (correct)

COX-2 is constitutively expressed in most tissues.

COX-2 is primarily responsible for platelet aggregation.

COX-1 is exclusively involved in inflammatory responses.

Which condition is a potential risk associated with the long-term use of non-selective NSAIDs?

Severe respiratory depression

Hyperglycemia-induced insulin resistance

Chronic liver failure

Increased cardiovascular events (correct)

What is the primary mechanism of action of paracetamol in alleviating pain?

Inhibition of leukotriene synthesis

Blocking the effects of pro-inflammatory cytokines

Inhibition of COX-1 and COX-2 in peripheral tissues

Action on the central nervous system to reduce pain perception (correct)

Which of the following treatments would be most appropriate for a patient with asthma who requires anti-inflammatory therapy?

Leukotriene receptor antagonists Signup and view all the answers

In terms of steroidal anti-inflammatory agents, which of the following is a common indication for their use?

Management of autoimmune disorders Signup and view all the answers

What is the primary difference in action between COX-1 and COX-2 enzymes?

COX-1 is constantly expressed, while COX-2 is expressed only during inflammation. Signup and view all the answers

What is a significant cardiovascular risk associated with the long-term use of non-selective NSAIDs?

Increased risk of myocardial infarction due to fluid retention. Signup and view all the answers

What is the main mechanism of action for paracetamol (acetaminophen)?

Inhibition of prostaglandin synthesis through peripheral actions. Signup and view all the answers

In which therapy does leukotriene inhibition play a significant role?

Treatment of asthma and allergic rhinitis. Signup and view all the answers

What distinguishes the treatment approaches for acute versus chronic inflammation?

Acute inflammation often resolves without treatment, while chronic requires ongoing therapy. Signup and view all the answers

What is a primary distinction between steroidal and non-steroidal anti-inflammatory drugs?

Steroids are immunosuppressive, while NSAIDs specifically target inflammation. Signup and view all the answers

Which populations are most commonly indicated for anti-inflammatory steroid treatments?

People with chronic inflammatory diseases like lupus and asthma. Signup and view all the answers

What is a limitation of using selective COX inhibitors compared to non-selective ones?

Selective inhibitors can be costly and may not be available for all inflammatory conditions. Signup and view all the answers

Which of the following NSAIDs is associated with the least cardiovascular risk?

Naproxen Signup and view all the answers

Which statement regarding the risks of NSAID use is accurate?

NSAID use should be avoided in patients at high risk for cardiovascular events. Signup and view all the answers

What is a plausible mechanism of action for paracetamol?

Activation of TRPA1 receptors in the spinal cord Signup and view all the answers

Which anti-leukotriene drug is NOT used for the inhibition of leukotriene synthesis?

Adalimumab Signup and view all the answers

What best describes the primary action of zileuton?

It inhibits leukotriene synthesis. Signup and view all the answers

In the context of inflammation, which treatment is more likely to target chronic inflammation?

Corticosteroids Signup and view all the answers

Which of the following accurately distinguishes between steroidal and non-steroidal anti-inflammatory approaches?

Steroidal medications offer more prolonged effects. Signup and view all the answers

Which of the following describes the action of COX-2 inhibitors in contrast to COX-1 inhibitors?

COX-2 inhibitors primarily reduce gastrointestinal side effects. Signup and view all the answers

What is a significant limitation of using selective COX inhibitors like celecoxib?

They can still carry cardiovascular risks. Signup and view all the answers

Which of the following cytokine signaling inhibitors is used specifically to prevent organ rejection?

Basiliximab Signup and view all the answers

What distinguishes COX-1 from COX-2 in terms of expression in the body?

COX-1 is expressed under normal physiological conditions while COX-2 is induced by factors like shear stress. Signup and view all the answers

Which of the following is true regarding the cardiovascular risks associated with selective COX-2 inhibitors?

Rofecoxib was withdrawn from the market due to increased risk of myocardial infarction. Signup and view all the answers

What mechanism describes how aspirin achieves its effects on COX enzymes?

Aspirin modifies COX covalently, permanently inhibiting its activity. Signup and view all the answers

In the context of asthma treatment, how do leukotrienes function?

They are involved in bronchoconstriction and contribute to inflammatory responses. Signup and view all the answers

What difference exists between treating acute and chronic inflammation with non-steroidal anti-inflammatory drugs (NSAIDs)?

Chronic inflammation may require adjunct therapies alongside NSAIDs for effectiveness. Signup and view all the answers

Which of the following accurately contrasts steroidal and non-steroidal anti-inflammatory approaches?

Steroidal drugs usually provide quicker relief than NSAIDs for acute conditions. Signup and view all the answers

What is a significant action of anti-inflammatory steroids?

They inhibit the synthesis of cytokines involved in inflammation. Signup and view all the answers

Comparing COX-1 and COX-2 inhibitors, what is a limitation unique to selective COX-2 inhibitors?

They may increase cardiovascular risks compared to non-selective inhibitors. Signup and view all the answers

What is a common misconception about the function of NSAIDs?

All NSAIDs have the same mechanism of action regardless of type. Signup and view all the answers

Study Notes

Course Information

Course: BMF (Biomedical Sciences)
Year: 1
Title: Immunopharmacology of anti-inflammatory agents
Lecturer: Prof Will Ford, 337
Date: November 2024
Location: RCSI Royal College of Surgeons in Ireland

Learning Outcomes

Appreciate drug treatment approaches for acute vs chronic inflammation
Differentiate between steroidal and non-steroidal anti-inflammatory approaches
Outline anti-inflammatory steroid actions and their patient populations
Compare COX1 and COX2 actions
Detail selective vs non-selective COX inhibitor uses and limitations

Recap: Acute Inflammation

Triggered by bacteria, cytokines, chemokines
Leads to vascular response (vasodilation, increased permeability) causing redness, heat, and swelling
Inflammatory cells migrate into tissue, releasing mediators causing pain
Key immune cells are neutrophils (PMNs)
Many pro-inflammatory mediators are involved

Local and Acute Systemic Effects of Acute Inflammation

Heat ("calor"): Increased blood flow
Redness ("rubor"): Leakage of fluid
Swelling ("tumor"): Leakage of fluid, proteins, increased blood flow, mediators
Pain ("dolor"): Chemical mediators, exudates pressing on pain receptors
Loss of function ("function laesa"): Disrupted tissue structure
Systemic effects also include fever caused by IL-1, TNFα, IL-6 release locally (often by macrophages), which act on the hypothalamus (esp. IL-1) and the liver (esp. IL-6), leading to synthesis of acute phase proteins (e.g., C-reactive protein).

Inflammation, Pain, and Local Mediators

Local mediators
- Prostaglandins and leukotrienes
- Platelet-activating factor (PAF)
- Histamine
- 5-hydroxytryptamine
- Neuropeptides
- Nitric oxide
- Bradykinin
- Adenosine and purines
- Complement
- Cytokines
Pain & Inflammation: These mediators are secreted by immune cells and responsible for inflammation symptoms (e.g., vasodilation). Pain occurs when inflammation is near a nerve fiber.

Recap: Inflammatory Pain

Inflammatory mediators (PGs, 5-HT, bradykinin) sensitize pain fibers
Sensitization rather than causing pain itself makes fibers more responsive to stimuli

Recap: Chronic Inflammation

Triggered by persistent or unresolved conditions (infections, chemicals, autoantigens)
Key players include macrophages, lymphocytes, and plasma cells
Active inflammation, tissue response, and tissue repair (including fibrosis) can all be part of chronic inflammation
Examples include rheumatoid arthritis, atherosclerosis, heart disease, COPD, Crohn's disease, asthma, lupus, psoriasis, cancer, and type II diabetes

Acute vs Chronic Inflammation

Acute: Inflammation is usually a response to an insult (infection, damage, etc.)
Chronic: Inflammation itself becomes the problem

The Good, the Bad, and the Ugly

Acute inflammation: response to infection or trauma, allows immune cell access, initiates healing
Termination is crucial, achieved by resolvins
Failure to terminate leads to chronic inflammation

Anti-inflammatory Drugs

Provide symptomatic relief (reduce inflammation causing pain and fever)
Best used temporarily while underlying issue is corrected
Acute: typically treated with NSAIDs or steroids
Chronic: often treated with combinations of NSAIDs and steroids.

Steroids vs Non-Steroidals

Steroids are immunosuppressive
NSAIDs are anti-inflammatory
Steroid examples include cortisol, cortisone, prednisone, prednisolone, and dexamethasone
Steroids are indicated for lupus, asthma, COPD, inflammatory bowel disease, and other chronic inflammatory conditions, however, they are contraindicated in active infection, depression, alcohol dependence, high blood pressure, diabetes, and heart failure.

Steroid Hormones

Glucocorticoids (e.g., cortisol): Affect carbohydrate and protein metabolism
Mineralocorticoids (e.g., aldosterone): Regulate salt retension
Androgens: Male sex hormones
Estrogens: Female sex hormones

Corticosteroids and the HPA Axis

Axis involves: hypothalamus, pituitary, adrenal glands
Cortisol is a product of this cascade
Receptors for corticosteroids are located in multiple cells and tissues

Corticosteroid Mechanism of Action

Affect gene expression (upregulate or downregulate production of inflammatory or anti-inflammatory mediators like COX-2, iNOS, and IL-10)
Act on the nucleus by regulating gene expression

Glucocorticoids

Inhibit phospholipase A2, increase annexin A-1 production
Reduce IL-1, IL-2, interferon, prostaglandins, leukotriene production
Decrease basophils, eosinophils, monocytes but increase neutrophils
Reduce circulating lymphocyte number (T > B lymphocytes, CD4+ > CD8+)
Adverse effects on carbohydrate metabolism

Use of Glucocorticoids

Replacement therapy for Addison's disease
Anti-inflammatory treatment (allergies, eczema, psoriasis, asthma, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease)
- Inhaled
- Topical
- Oral
Adverse effects include Cushing syndrome, osteoporosis, and poor wound healing

Non-steroidal anti-inflammatory drugs (NSAIDs)

Used to treat inflammation
Inhibit cyclooxygenases, thus reducing prostaglandin production
Are anti-inflammatory, analgesic and anti-pyretic
Examples: aspirin (irreversible), ibuprofen, indomethacin, diclofenac

NSAIDs and the Arachidonic Pathway

NSAIDs disrupt the arachidonic pathway, impacting prostaglandin synthesis
Affect the conversion/synthesis of prostaglandins and thromboxane A2

Cyclooxygenases (COX)

COX-1: Constitutively expressed
COX-2: Induced by factors (shear stress, growth factors, cytokines)
COX enzymes are homodimers, and inhibition of one site in the dimer can render it inactive

NSAID Range of Selectivity

Initial expectations that selective COX-2 inhibitors would have fewer side effects than non-selective inhibitors were not entirely borne out. For example, rofecoxib was withdrawn from the market in 2004 due to increased risk of cardiovascular events.

Manipulating Aspirin Dosage

Low-dose aspirin (75mg): Inhibits prostaglandin synthesis by 10-20%, platelets are affected longer than other cells (inhibited for their lifespan) and cumulative effect leads to a lasting block on platelet COX.
High dose (325mg): Inhibits total prostaglandin synthesis in the body, most cells recover their COX synthesis within 4-8 hours. Administration must be repeated for persistent inhibition of non-platelet COX.

Effectiveness of Aspirin

Reduces death following myocardial infarction (MI) by 25%
Has additive effects with heparin, thrombolytic drugs (tPA or streptokinase)
Primary prevention in those at high risk of future vascular events.

Side Effects of Aspirin

Excessive bleeding (reduced platelet function)
Gastrointestinal (GI) damage (increased acid production)
Reye's syndrome in children (liver protein acetylation)
Aspirin is the only potent, irreversible antiplatelet NSAID, other options are reversibly inhibited.

Two COX Iso-enzymes

COX-1 and COX-2 are quite similar at the molecular level. There is also a splice variant COX-3
COX-1: Constitutively expressed
COX-2: Induced
Small difference in amino acid sequence allows for selective drug targeting of COX-2 (e.g., coxibs or COX-2 inhibitors).

Coxibs

COX-2 selective inhibitors (e.g., celecoxib, rofecoxib)
Initially designed to reduce side effects like gastric ulcers.
Subsequent studies show coxibs to be associated with increased cardiovascular events (MI, stroke).

VIGOR - Clinical Trial

Clinical trial assessing the cardiovascular effects of rofecoxib vs naproxen.
Rofecoxib showed increased risk of cardiovascular events in comparison to naproxen

COX-2 and Cardiovascular Disease

Selective COX-2 inhibition reduces prostaglandin I2 (PGI2/prostacyclin) production by vascular endothelium.
Little to no effect on platelet thromboxane A2 production, which can lead to prothrombotic effects.

NSAIDs and Cardiovascular Disease

All NSAIDs increase cardiovascular risk (Naproxen the least risk).
Increased risk depends on dosage
Avoid NSAIDs in patients at high risk of cardiovascular events
Limited exposure is best approach when using NSAIDs.

Paracetamol/Acetaminophen

Not an NSAID—used for fever and pain, not inflammation.
Mechanism unclear but may involve COX-3 or AM404 activation of TRPA1.
Still has some cardiovascular, GI, and renal risks.

NSAIDs - What Happens to AA

NSAIDs block the conversion of arachidonic acid to prostaglandins
This excess arachidonic acid is diverted to lipoxygenase pathway
Lipoxygenase produces leukotrienes, leading to bronchoconstriction.

Leukotrienes

Released by leukocytes (such as mast cells).
Proinflammatory molecules
Contribute to various processes like vasodilation, mucus production, and bronchoconstriction

Anti-leukotrienes

Inhibit leukotriene synthesis or receptors (e.g., zileuton, zafirlukast, montelukast)
Used for asthma (less effective than inhaled steroids)
Veliflapon (FLAP inhibitor) in clinical trials.

Anti-leukotriene Drugs

Zileuton and zafirlukast are used in asthma treatment.
Not first-line treatment for asthma.
Don't reverse bronchoconstriction.
Often used as 'preventers' not 'relievers'.

Targeting Cytokine Signaling

Inhibitors target signalling molecules for certain cytokines, such as targeting cytokine IL-2 signalling with basiliximab (Simulect)

Perspectives

Immune responses are complex
Protective inflammation can become destructive
No single perfect approach to managing inflammation pharmacologically

What We Have Learned

Drug approaches for acute vs chronic inflammation
Steroidal vs non-steroidal anti-inflammatory approaches
Anti-inflammatory steroid actions, indicated populations
Comparison of COX1 and COX2
Uses and limitations of selective vs non-selective COX inhibitors

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Description

This quiz explores essential concepts in pharmacology related to anti-inflammatory agents, including the differences between COX-1 and COX-2 enzymes, risks of non-selective NSAIDs, and the mechanism of action of paracetamol. It also addresses appropriate treatments for asthma and indications for steroidal anti-inflammatory agents.