Pharmacology: Inflammation, Eicosanoids, and Histamine

How does inflammation occur

In 4 phases

What are the 4 phases of inflammation?

1. Vascular response to local stimuli to recruit immune cells; local vasodilation

2. Migration of circulating immune cells to the site and activation of innate/active immune responses

3. Repair and resolution

4. Chronic inflammatory responses

What does Phase 3 usually include?

Either restoration of homeostasis or fibrosis (excessive accumulation of ECM, which is produced by stimulated fibroblasts)

What are the 5 classical signs of inflammation?

Redness, heat, swelling, pain, loss of function

What is acute inflammation?

(Injury response) Resolution occurs after removal of inflammatory stimulus

What is chronic inflammation?

(persistent pathological immune response even in the absence of injury); Arises due to inappropriate responses to stimuli (e.g. allergies) or constant presence of the inflammatory stimulus (e.g. chronic infection, transplantation, autoimmunity)

What does chronic inflammation lead to?

Fibrosis which impact organ function

What is fibrosis mediated by?

The macrophages that are recruited to sites of inflammation?

What percentage of all deaths can be traced to this pathological tissue remodeling?

45%

What do therapeutic strategies against inflammation involve?

Short-circuiting such activation through several means

What are pharmacologic strategies to mitigate inflammation involve?

Modifying signal mediators of inflammation (cells and/or chemical mediators) and modifying/eliminating the pathophysiologic stimulus

Where are eicosanoids primarily derived from?

Arachidonic acid and exhibit fast-acting local but brief effects

What is the rate limiting step of eicosanoid production?

Phospholipase A2

How is arachidonic acid metabolized?

Along multiple pathways involving cyclooxygenase, lipooxygenase, epoxygenase, and isoprostane to generate effector molecules of eicosanoid

signaling.

What does eicosanoids play a role in?

The physiology and pathophysiology of cardiovascular disease, inflammation, and cancer

What are examples of eicosanoid inhibition?

• COX-1/2 inhibition (NSAIDs) 

• Thromboxane antagonists

• Lipooxygenase inhibitors/leukotriene receptor antagonists

• Cytokine inhibitors

• Epoxygenase and isoprostane inhibitors

Thromboxane antagonists

Still under development and have yet to demonstrate clinical applications

Lipoxygenase inhibitors

Find some uses in the treatment of asthma

Leukotriene receptor antagonists

Useful for the treatment of asthma

Cytokine inhibitors

(Cytokines induce COX-2 expression and stimulate inflammation) like TNF-a antagonists addressed previously

Epoxygenase and isoprostane inhibitors

Pre-clinical only

What is the cyclooxyrgenase pathway of AA metabolism mediated by?

Two cyclooxyrgenase isoforms (COX 1 and COX 2) and leads to the formation of prostaglandins, prostacyclin, and thromboxjnes

What leads to the differential functions of COX-1 and COX 2?

Differences in sub cellular localization, expression parameter, and substrates

COX 1

Constitutive expression, affects vascular homeostasis, renal/GI blood flow, and platelet activity

COX 2

Inducible expression, affects inflammation, fever, and pain

What are prostaglandins?

Potent vasodilators, mediate inflammation derived from AA

What does vascular endothelial cells express?

Both COX 1 and COX 2

What do platelet cells only express?

COX 1

What does COX 1 produce?

Thromboxane A2, which stimulates platelet aggregation, vasoconstriction, vascular remodeling, and cardiac remodeling

What is PGE2 primarily produced by?

COX1 in Gi. and kidneys to promote blood flow and mucus production

What does COX 2 produce?

PGI2 in endothelial cells to inhibit platelet aggregation via prostacyclin production

What are NSAIDs?

• One of the most commonly prescribed medications for pain/inflammation

• Account for 5-10% of all prescription annually

• Actions via inhibition of COX 1 and/or COX2

How are NSAIDs classified?

Non-selective (inhibits both COX 1 and COX 2) or COX 2 selective (-coxibs)

Where are NSAIDS absorbed?

In the GI and have high bioavailability 

What do some NSAIDS have?

First-pass metabolism and decreased bioavailability

What are other NSAIDs like?

Are prodrugs requiring hepatic activation

PK for NSAIDs?

• Highly bound to plasma proteins

• Excreted in urine

• Half-life varies from 15 minutes (aspirin0 to 45-50 hours (piroxicam)

Half-life of naproxen

14 hrs

How are NSAIDs classified?

• Chemical structure

• Selectivity for COX 1 or COX 2 

• Half-life

Why is acetaminophen not a true NSAID?

Because it lacks anti-inflammatory properties (anti-pyretic)

Why were rofecoxib and valdecoxib removed from the market?

Due to adverse cardiovascular events

What do all NSAIDS have risk of?

• Cardiovascular toxicity (even with short term <7 day use)

• GI bleeding (15-30% of chronic users; 16,500 deaths per year in the US)

• Renal insufficiency

Risk of GI bleeding for non-selective?

• Known Gi toxicity (take with food)

• Trends suggest shortest acting have lowest GI risk (ibuprofen)

Risk of GI bleeding for COX-2 inhibitors?

• Variable evidence to support a decreased risk of GI toxicity

• Trends favor GI safety with celecoxib

Who should avoid NSAIDs?

Patients with cardiovascular disease, hepatic disease, GI disorders, and the elderly

What are NASAIDs as a class have?

Ceiling effect, dose-dependent, individual response rates

What are PGE2?

Strong protective effect on GI mucosa

What does does NSAID inhibition of PGE2 synthesis result in?

Gi side effects

What are solutions to this?

1. Formulate NSAID + gastroprotective agent

2. COX-2 selective inhibitor

3. Non-NSAID pharmacologic therapy

What are examples of gastroprotective agents?

• Misoprostol

• PPI

• Histamine 2 receptor antagonists

Misoprostol

A synthetic PGE1 analog which can inhibit gastric acid secretion (not well tolerated at therapeutic doses)

PPI

Decrease gastric acid secretion

Histamine 2 receptor antagonists 

High dose; inhibits gastric acid secretion (famotidine; reduces risk of duodenal and gastric ulcers)

What is sulfasalazine?

A prodrug that is metabolized to sulfapyridine and 5-ASA by gut microbiome, less renal toxicity, and therefore may be more appropriate for patients with impaired renal function

What does 5-ASA act as?

Cox inhibitor (Same MOA as ASA)

What is sulfasalazine used for?

Ulcerative colitis

ADRs of sulfasalazine?

GI toxicity, rash, itching, bone marrow toxicity 

Propionic derivatives

• Ibuprofen/naproxen

• Ibuprofen half life 2 hrs

• Naproxen half life 12-17 hrs

• 20x greater potency than aspirin

Acetic acid derivatives

• Diclofenac

• Half-life 2 hrs

• More potent than naproxen

• Used to treat severe pain (kidney stones; RA)

Aspirin (acetylsalicylic acid; ASA)

• Half life 20 minutes but long term effect on platelets (7 days) due to irreversible COX inhibition 

• Used for moderate pain

• Antithrombogenic

Celecoxib

• COX 2 selective agent

• Half life 12 hours

• Used to treat RA

• Reduced GI ADRs vs non-selective COV inhibitors

• Increased risk of cardiotoxicity (increased thrombogenicity)

Acetaminophen

• Not a true NSAID (weak inhibition of COX)

• Analgesic/antipyretic effects

• Use instead of aspirin for at-risk patients (e.g.children)

• Half-life 2-3hrs

• Hepatotoxicity risk

What are two examples of leukotriene modifiers?

• Zileuton

• Montelukast

Zileuton

5-lipoxygenase inhibition, decrease LT-C4 production

Montelukast

Direct Leukotriene receptor (CysLT1) antagonism; dec. receptor activation to prevent bronchoconstriction

What is histamine?

A major mediator of allergic reactions and inflammation

What are the additional roles of histamine?

• Neurotransmission

• Immune modulaiton

• Regulation of gastric acid secretion

Where is histamine synthesized?

In mast cells and basophils of the immune system, enterochromaffin-like cells (ECL) in the gastric mucosa, and some neurons

How can histamine synthesis/storage be divided into?

Two pools: 

1. A slowly replicating pool in mast cells and basophils

2. A rapidly replicating pool in ECL cells and CNS neurons

What is ImAA?

Metabolite can be measured in the urine as indicator of systemic H release

What are the physiological functions of histamine?

1. Bronchoconstriction (people with asthma/RAD are ~1,000x more sensitive to histamine effect)

2. Vasodilation of the post-capillary venule bed: dilation in response to infection/injury allows immune cell access and creating erythema (swelling)

3. Contraction/separation of endothelial cells: this creates fluid release to trigger edema & localized immune responses

4. Depolarization of sensory neurons: produces itching and pain response

5. Stimulates gastric acid secretion

What are histamine actions mediated by?

Four receptor subtypes (H1, H2, H3, H4)

H1

• Vascular endothelial cells and smooth muscle cells

• Mediate inflammatory and allergic reactions (edema, erythema, bronchoconstriction, nerve sensitization; also within CNS)

H2 

Parietal cells in gastric mucosa; gastric acid secretion in stomach (also within CNS)

H3

Presynaptic neurons in CNS

Wakefulness

Appetite

Memory

H4

Mast cells, eosinophils, dendritic cells, and basophils; mediate inflammatory responses, pain, and itch.

What does histamine play a major role in?

IgE-mediated type 1 hypersensitivity reactions

What happens upon allergen exposure?

• Leads to B cell production of IgE

• IgE binds to Fc receptors on mast cells

• Re-exposure to allergen triggers IgE/Fc receptor cross-linking leads to mast cell degranulation and release of histamine

Histamine-induced allergic responses

Runny nose, itchy eyes, sneezing, and skin irritation

What does histamine response trigger?

Triggers capillary endothelial breakdown

What can also occur?

Mast cell degranulation can also occur in reprise to local injury (increases access of immune cells to site of injury

What can occur with systemic exposure to a hypersensitive allergen?

Anaphylaxis

What does anaphylaxis trigger?

Massive histamine release throughout the body

What can be life threatening

Resultant bronchoconstriction and hypotension

What can lead to blockade of histamine action?

• Anti-histamines

• Inhibition of mast cell degranulation

• Histamine counter-effectors 

Antihistamines

Inverse agonists or competitive inhibitors, selective for individual histamine receptor subtypes.

Inhibition of mast cell degranulation

Following antigen binding to the IgE/Fc receptor complex, Cl- influx through the membrane triggers degranulation; can be blocked pharmacologically (e.g. cromolyn)

Histamine counter-effectors

Agents that counteract the physiological effects of histamine (e.g. bronchoconstriction, vasodilation, hypotension). AKA why Epi used to treat anaphylaxis.

Which receptors have approved therapeutics?

Only H1 and H2 histamine receptors

How to H1 receptors exist?

In 2 conformational states in equilibrium with each other; the unoccupied receptor leans toward the active state (constitutive activity)

What does histamine act as?

An agonist for the active conformation and shifts the equilibrium further toward the active state

What do antihistamines bind preferentially to?

The receptor in the inactive conformation, shifting the equilibrium toward the inactive state and thereby acting as inverse agonists

How can H1 anti-histamines be categorized?

As first generation or second generation based on structure

What is the general structure of antihistamines?

Substituted ethylamine backbone with 2 terminal aromatic rings (compare to ethylamine sidechain of histamine). Further divided into 6 subgroups based on the substituted side-chains

Charactieristics of antihistamines?

Lipophilic and non-ionized at physiological pH

Readily cross BBB (resulting in sedation/drowsiness ADR)

What is the use of H1 anti-histamines like?

Limited use in treating asthma and anaphylaxis

What are H1 antihistamines inhibitor of?

All CYP inhibitors (risk for DDIs; dose changes in patients with liver disease)

ADRs of antihistamines?

• Cardiac toxicity (prolonged QT interval)

• Produce anti-cholinergic effects (dry mouth, pupil dilation)

What are antihistamines not recommended for?

For children <2 years of age as ADRs are more pronounced

What is diphenhydramine?

• allergic rhinitis (sneezing, runny nose); anti-itch; anti- emetic (inhibits histamine signaling from vestibular nucleus to emetic center in medulla); motion sickness and nausea.

• Can also be used for insomnia due to CNS depressant effects (associated with next-day sedation);

• fast acting (30 min),

• short duration (4-6 hrs)