Block 2_3 - Pharmacology of Inflammation Flashcards
4 signs of inflammation
heat (calor)
swelling (tumor)
redness (rubor)
pain (dolor)
Loss of function
Define Inflammation (modern day definition)
- the reaction of vascularized living tissue to local injury
- protective response to noxious stimuli
Physiological responses to ACUTE inflammation
- Vasodilation (contributes to heat+redness)
- Increase in vascular permeability (contributes to swelling)
- accumulation of inflammatory cells (recruitment of neutrophils)
Potential Harmful Effects of Inflammation
- inflammatory cells release lysosomal enzymes that may digest normal tissues
- edema/swelling that can obstruct airways or the cranial cavity = death
Define: Mediator Theory
signs and symptoms of inflammation are caused by the release of chemicals
Name Chemical Mediators
Histamine
Bradykinin
Complement
C-Reactive Protein
Cytokine
Adenosine
Cell Adhesion Molecule
Prostaglandin
Leukotriene
Glucocorticoid
Cyclooxygenase
Histamine
- Cellular Source
- Physiological Response
- Mechanism
- Pharmacology
biogenic amine - pro inflammatory
- mast cells, basophils
2.
a. vasodilation
b. increased vascular permeability
c. pain
3. Activation of GPCR
4. antihistamines (H1 antagonists) - diphenhydramine
Bradykinin
- Cellular Source
- Physiological Response
- Mechanism
- Pharmacology
peptide
- endothelial cells
2.
a. vasodilation
b. increased microvessel permeability
c. pain
3.
- Activation of GPCRs
- B2 receptor
- BK receptor antagonists (Icatibant) being tested - inhibits Bradykinin binding at B2 receptor
* treatment of acute attacks of hereditary angioedema (HAE)
Complement System
- Cellular Source
- Physiological Response
- Mechanism
- Pharmacology
plasma proteins C3a, C5b, C3b ….
- synthesized by liver, circulate in blood
2.
a. Chemotaxis - recruitment of inflammatory cells to site of injury
b. promote release of mediators from neutrophil
c. increase vascular permeability
d. excessive activation may contribute to tissue injury
3.
- protein complexes cause osmotic lysis
- specific complement receptors on some cells causes mast cell degranulation
- activation of GPCRs
- some drugs are used clinically; pre-clinical trials with a number of different complement inhibitors
Define: Acute Phase Reaction
An acute phase protein is one whose plasma concentration changes from baseline by at least 25% during inflammation
In response to injury, local inflammatory cells secrete cytokines that cause the liver to increase or decrease production of various proteins.
C-Reactive Protein
- Cellular Source
- Physiological Response
- Mechanism
- Pharmacology
pentameric shaped plasma protein
- produced in liver and adipocytes
- protein that could bind to the “C” polysaccharide of bacterial cell wall
– Acute phase reactant
– activates complement cascade
– Mediates phagocytosis
– Marker of inflammation
– Binds to phospholipids in bacteria and damaged cells
– Calcium dependent binding
- elevated CRP associated with ↑ risk of diabetes, HTN, and CV disease
- No CRP inhibitors have been developed
- statins (cholesterol lowering drugs) may reduce CRP levels
Cytokines
- Cellular Source
- Physiological Response
- Mechanism
- Pharmacology
secreted proteins - particularly pro-inflammatory Tumor necrosis factor (TNF-α) and Interleukin-1 (IL-α and IL-ß)
- nearly all inflammatory cells
- multiple effects
- TNF-α: acute phase reaction, fever, sepsis
- IL-1: acute phase reaction, fibroblast and lymphocyte proliferation, fever
- – Interaction with specific receptors to induce gene expression of number of proteins through activation of transcription factors, such as NF-κB and AP-1
- Increase cyclooxygenase (fever) and lipoxygenases
- Increase adhesion molecule expression
- Induce collagenase (fibrosis)
- TNF-α blockers
Etanercept
Infliximab
Adenosine
- Cellular Source
- Physiological Response
- Mechanism
- Pharmacology
Purine nucleoside formed from breakdown of ATP
- All cells
- increased extracelularly during injury
- anti-inflammatory effect to inhibit cytokine action
- activation of GPCRs
- Adenosine A2 agonists
- Methotrexate (releases adenosine)
- Adenosine A3
Cell Adhesion Molecules
- Cellular Source
- Physiological Response
- Mechanism
- Pharmacology
family of proteins including Ig-like CAMs, integrins, selectins, cadherins
- endothelial cells, platelets, leukocytes
– Leukocyte adhesion to endothelium is integral to repair process
– Endothelial adhesion molecules contribute to recruitment of activated platelets
3.
- Glycoproteins expressed on cell surface and mediate contact between two cells or between cells and extracellular matrix
- “contact Molecules”
- Calcium dependent
4.
- Abciximab - anti-platelet therapy in heart disease
- platelet integrin receptor antagonist
Oxygen-Derived Free Radicals
- Source
- Physiological Response
- Mechanisms
- Pharmacology
superoxide, hydroxy radicals
- all cells
- intracellular killing of bacteria by neutrophils
- a. Protein oxidation - inactivate enzymes; alter 3D structure and increase degradation
b. lipid peroxidation
- damage to phospholipids leading to cell membrane degradation
- formation of reactive products that damage proteins and DNA
c. DNA mutations - Antioxidants like Vitamin C and E (but with limited success in clinical trials)
Lipid Mediators - Prostaglandins
- Source
- Physiological Response
- Mechanisms
- Pharmacology
eicosanoids, steroids
Pro-inflammatory
- Virtually all cells
- a. vasodilation
b. pain
c. fever
d. platelet aggregation - activation of specific GPCRs
4.
NSAIDs
COX-2 inhibitors
Steroids
Lipid Mediators - Leukotrienes
- Source
- Physiological Response
- Mechanisms
- Pharmacology
- macrophages, neutrophils
- increase vascular permeability (LTC4, LTD4, LTE4)bronchoconstriction
- activation of GPCRs
- Zileuton: 5-lipoxygenase inhibitor
- Zafirlukast: Leukotriene receptor antagonist
Lipid Mediators - Glucocorticoids
- Source
- Physiological Response
- Mechanisms
- Pharmacology
- adrenal cortex
- inhibition of cytokines
- inhibition of Phospholipase A2 (via annexin, a lipocortin)
- inhibition of cyclooxygenase-2 (COX-2 only)
- inhibition of cell adhesion molecules
- activation of nuclear receptors and steroid-responsive elements to induce/repress transcription
-
steroids
- most potent and effective agents for controlling chronic inflammatory diseases
Anti-Inflammatory Drugs - Steroids
- Mechanism of Action
- bind to cytoplasmic receptors
- activated receptor-steroid complex: localizes to nucleus/binds DNA (GRE - glucocorticoid response elements)
- induce/repress transcription of target genes
- increase anti-inflammatory genes
- decrease pro-inflammatory genes
Anti-Inflammatory Drugs - Non Steroidal Anti-Inflammatory Drugs (NSAIDs)
Mechanism of Action
inhibition of cyclooxygenase reduces production of inflammatory prostanoids
Other Anti-Inflammatory Drugs
- Leukotriene Antagonists
- Inflammatory cytokine inhibitors
- Leukotriene Antagonists
- zafirlukast - competitive antagonist of leukotriene receptors
- zileuton - inhibits the synthesis of leukotrienes
- Inflammatory cytokine inhibitors
- etanercept - receptor analog
- infliximab - monocloncal antibody
Common Points about cytokine inhibitors
• NOT orally available drugs
– IV, Subq
• Adverse effects
– Risk of infection
• Therapeutic uses
– Rheumatoid arthritis
How to treat acute inflammation? (e.g. acute gout attack)
Symptomatic relief
- NSAID
- Steroid
How to treat chronic inflammation? (e.g. rheumatoid arthritis)
NSAID
steroid
etanercept
