Inflammation

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Questions and Answers

What characterizes the inflammatory response?

Heat, pain, and immunologic memory.

Eicosanoid production and chronic infection.

Classic signs of redness, heat, swelling, pain, and loss of function. (correct)

Only swelling and redness.

Which of the following is NOT a trigger of inflammation?

Nutritional deficiency (correct)

Ischemia

Exposure to a foreign substance

Trauma

What mechanism helps to resolve inflammation?

Feedback mechanisms like lipoxins and certain eicosanoids. (correct)

A cytokine cascade leading to chronic infection.

The same inflammatory mediators causing further damage.

Continuous production of pro-inflammatory mediators.

What role do eicosanoids play in inflammation?

They facilitate the production of pro-inflammatory mediators. Signup and view all the answers

How is arachidonic acid primarily derived?

From the essential fatty acid precursor linoleic acid. Signup and view all the answers

What is a potential consequence of prolonged inflammation?

Chronic injury and long-term inappropriate response. Signup and view all the answers

Which cytokines are primarily involved in initiating the inflammatory response?

Interleukins and Tumor Necrosis Factor (TNF). Signup and view all the answers

What purpose does inflammation serve in the body?

To eliminate inciting stimuli and initiate repair. Signup and view all the answers

What is a major distinction between first and second generation H1-antihistamines?

First generation antihistamines cause more CNS adverse effects. Signup and view all the answers

Which of the following is NOT a major clinical use of H1-antihistamines?

Increasing capillary permeability in allergic conditions. Signup and view all the answers

What action do antihistamines primarily take at the H1 receptor?

They act as inverse agonists. Signup and view all the answers

Why are antihistamines not suitable as monotherapy for asthma?

Other mediators like leukotrienes also play a significant role. Signup and view all the answers

Which of the following first-generation H1-antihistamines is primarily used for treating nausea and motion sickness?

Promethazine Signup and view all the answers

What enzyme is responsible for releasing arachidonic acid from membrane phospholipids?

Phospholipase A2 Signup and view all the answers

What effect does PGE2 have in the body?

Vasodilation and bronchoconstriction Signup and view all the answers

Which of the following is NOT a product of the COX pathway?

LTB4 Signup and view all the answers

What role do lipoxins play in inflammation?

Counter-regulate leukotriene actions Signup and view all the answers

Which omega-3 fatty acid is known as Eicosapentaenoic Acid?

EPA Signup and view all the answers

What is the primary effect of TXA2 in the body?

Platelet activation Signup and view all the answers

Cysteinyl leukotrienes (LTC4, LTD4) are primarily responsible for which of these effects?

Bronchoconstriction and increased vascular permeability Signup and view all the answers

Which of the following diseases is associated with inflammation?

Asthma Signup and view all the answers

What is the primary function of PGI2 in the cardiovascular system?

Inhibits platelet aggregation Signup and view all the answers

Rheumatoid arthritis is classified under which type of disorders?

Autoimmune diseases Signup and view all the answers

What is the primary mechanism by which glucocorticoids reduce inflammation?

Lower lymphocyte and macrophage activity Signup and view all the answers

Which statement correctly describes the action of NSAIDs?

They inhibit both COX-1 and COX-2 enzymes. Signup and view all the answers

What is the role of montelukast in asthma treatment?

It antagonizes the CysLT1 receptor. Signup and view all the answers

Which cytokines are known to enhance the production of prostaglandins?

TNF-α and IL-1 Signup and view all the answers

What is a key adverse effect associated with the use of cytokine inhibitors, specifically IL-1 antagonists like Anakinra?

Increased risk of serious infections Signup and view all the answers

What is the mechanism of action of zileuton?

5-LOX inhibition via chelation of iron. Signup and view all the answers

Which type of drug is classified as a DMARD in the treatment of rheumatoid arthritis?

Methotrexate Signup and view all the answers

Which of the following is a TNF-α antagonist used to treat autoimmune diseases?

Infliximab Signup and view all the answers

Which pharmacologic class has not yet demonstrated clinical utility?

Thromboxane antagonists Signup and view all the answers

What is the role of histamine in the body besides mediating immune and inflammatory processes?

Regulation of gastric acid secretion Signup and view all the answers

Which of the following is NOT a drug class used in the treatment of rheumatoid arthritis?

Antibiotics Signup and view all the answers

How do COX-2 inhibitors primarily function to reduce pain and inflammation?

By blocking the synthesis of prostaglandins Signup and view all the answers

Which histamine receptor primarily mediates inflammatory and allergic reactions?

H1 receptors Signup and view all the answers

What happens to the levels of COX-2 when pro-inflammatory cytokines like TNF-α are present?

COX-2 synthesis is upregulated. Signup and view all the answers

What is a possible trigger for anaphylactic shock?

Insect bites Signup and view all the answers

Which of the following is true regarding leukotriene inhibitors?

They help in the management of asthma by blocking certain leukotriene receptors. Signup and view all the answers

Which cytokine inhibitor modulates T-cell activity in rheumatoid arthritis treatment?

Abatacept Signup and view all the answers

Which biological agent is known as a B-cell cytotoxic agent in rheumatoid arthritis treatment?

Rituximab Signup and view all the answers

Which statement about glucocorticoids in managing inflammatory diseases is true?

They have immunosuppressive effects. Signup and view all the answers

Which of the following conditions is NOT mentioned as part of the inflammatory diseases impacted by cytokines?

Diabetes Signup and view all the answers

Study Notes

Introduction to Inflammation

Inflammation is a complex response to tissue injury and infection, marked by redness, heat, swelling, pain, and loss of function.
The immune system, including cells and soluble factors (like antibodies and complement proteins), mediates this response.
Inflammatory cells and factors aim to eliminate the initial stimulus and initiate an immunological response.

Objectives of the Presentation

Briefly review the inflammatory process.
Examine pharmacologic strategies for managing inflammation.
Explain how anti-inflammatory agents work, particularly on eicosanoids and histamine.
Detail features of some anti-inflammatory agents.

Triggers of Inflammation

Inflammation is triggered by various stimuli, such as:
- Trauma
- Exposure to foreign substances
- Infectious agents
- Ischemia
- Immune reactions

Benefits of Inflammation

Combats foreign invaders.
Removes inciting stimuli and resolves tissue damage.

Chronic Inflammation

Sometimes, inflammation can persist for too long, leading to chronic damage.
This persistence can be due to a sustained inappropriate response (e.g., allergies) or failure to remove the offending agent (e.g., chronic infection).

Mediators of Inflammation

An initial insult triggers a cascade of cytokines (like interleukins and tumor necrosis factor).
These cytokines stimulate enzymes (like COX-2 and LOX).
The enzymes promote the production of pro-inflammatory mediators (e.g., prostaglandins and leukotrienes).
The inflammatory mediators attract inflammatory cells.

Arachidonic Acid Pathways - Overview

Arachidonic acid is a precursor to most eicosanoids.
It’s derived from essential fatty acid linoleic acid.
Alpha-linolenic acid, EPA, and DHA are omega-3 fatty acids.

Arachidonic Acid - Cellular Level

In the cell, arachidonic acid is stored in membrane phospholipids.
The enzyme phospholipase A2 releases arachidonic acid.
This is the rate-limiting step in forming eicosanoids.

Products of the COX pathway

PGE2: Acts on mast cells and macrophages; responsible for pain responses, vasodilation, bronchoconstriction, fever, and inflammatory cell activation; contributes to mucus production.
PGF2alpha: Affects bronchial smooth, uterine, and blood vessel smooth muscle; roles in vascular tone, bronchoconstriction and abortion.
PGD2: Influences neurons and mast cells; involved in bronchoconstriction (asthma), sleep control, and Alzheimer's disease.
PG12: Affects endothelial cells; inhibits platelet aggregation and causes vasodilation.
TXA2: Acts on platelets and causes vasoconstriction and platelet activation.

Products of the LOX Pathway

LTB4: Activating neutrophils, and thus, their migration, degranulation , superoxide generation, and eicosanoid synthesis. Also promotes natural killer cell activity.
LTC4, LTD4: Bind to CysLT1 receptors; responsible for vasoconstriction, bronchospasm, and increased vascular permeability.

Lipoxins

Lipoxins are products of LOX pathway; have anti-inflammatory and pro-resolving roles that counter the action of leukotrienes.
LXA4 and LXB4 are two of the lipoxins.

Some Inflammatory Diseases

Includes Asthma, Rheumatoid arthritis, Inflammatory bowel disease, Glomerulonephritis, cardiovascular and cancerous conditions

Pharmacologic Anti-inflammatory Strategies

Two main approaches exist, These include targeting inflammation and immune system components, and altering the root cause.

Pharmacologic Classes of Anti-inflammatory Agents

Glucocorticoids
COX inhibitors
Leukotriene inhibitors
Thromboxane antagonists
Cytokine inhibitors
Lipoxins/protectins/maresins

Glucocorticoids

Lower and inhibit lymphocytes and macrophages.
Indirectly inhibit phospholipase A2 by raising lipocortin levels, and thereby block the release of arachidonic acid (a precursor of prostaglandins and leukotrienes).
Reduce COX-2 synthesis.
Interfere with mast cell degranulation which lowers histamine release.

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

Inhibit cyclooxygenase enzymes, crucial for prostaglandin production.
COX-1 and COX-2 contribute to prostaglandin production.
Most NSAIDs are reversible and competitive inhibitors.
Aspirin is an exception, with irreversible effects.

Leukotriene Inhibitors (CysLT1 antagonists)

Montelukast and Zafirlukast are two CysLT1 antagonists
They block CysLT1 receptors, thereby opposing leukotriene effects.
Zileuton inhibits 5-lipoxygenase.

Leukotriene Inhibitors (5-LOX inhibitor)

Zileuton inhibits 5-lipoxygenase.
A less common approach to combating leukotrienes.

Cytokine Inhibitors (Targeting TNF-α)

Infliximab: A humanized mouse monoclonal antibody directed at TNF-α; used for rheumatoid arthritis, inflammatory bowel disease, and autoimmune conditions.
Adalimumab is another TNF-α blocking agent.

Cytokine Inhibitors (Targeting IL-1)

Anakinra is the IL-1 receptor antagonist.
Applicable for use in patients with rheumatoid arthritis.

Interplay of Inflammatory Cells and Mediators

The complexity of inflammation stems from the numerous mediators at play
Successful management necessitates targeting the various components and mechanisms.

Drugs used in Rheumatoid Arthritis

NSAIDs
Glucocorticoids
Disease-modifying antirheumatic drugs (DMARDs )
- Examples: Methotrexate, azathioprine, cyclosporine
Biologics
- Examples: abatacept, rituximab, tocilizumab, adalimumab, infliximab

Histamine

Histamine is an autocoid, a crucial mediator in immune, allergic, and inflammatory processes.
Histamine plays a part in gastric acid regulation, neurotransmission, and immune modulation.

Histamine and Anaphylaxis

Systemic mast cell degranulation can trigger anaphylaxis, a life-threatening condition.
Triggers often include hypersensitivity to insect bites, antibiotics like penicillin, or food allergens, such as peanuts.

Histamine Receptors

H1 receptors - Predominantly on vascular endothelial and smooth muscle cells. Influence inflammatory and allergic events, causing edema and bronchoconstriction, and activating primary afferent nerves.

Strategies of Histamine Inhibition

Administering antihistamines.
Stopping the degranulation of mast cells.
Counteracting histamine effects directly.

Antihistamines

Are inverse agonists for H1 receptors.
Bind to the inactive state of the receptor, shifting the equilibrium towards a non-active state.
- Types of antihistamines include first and second generations.
  - First generation antihistamines (e.g., diphenhydramine, promethazine): are less selective, can cross the blood-brain barrier, have more side effects (e.g., drowsiness, dry mouth). They're beneficial in cases of nausea and motion sickness.
  - Second-generation antihistamines (e.g., loratadine, fexofenadine, olopatadine): are more specific for H1, have fewer CNS side effects, and are useful in allergic conditions.

Clinical Uses of H1-antihistamines

Allergy relief (e.g., rhinitis, conjunctivitis, urticaria, and pruritus) particularly for prophylactic use.
Treatment of generalized itching.
Nausea and motion sickness.
Insomnia.

Limitations of Antihistamines

Not a monotherapy choice for conditions where leukotrienes have significant impact (i.e., asthma).
Ineffective for anaphylaxis.

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Description

This quiz delves into the characteristics of the inflammatory response, its triggers, and the role of eicosanoids. It also explores H1-antihistamines and their clinical uses. Test your understanding of inflammation and its resolution mechanisms with a set of targeted questions.