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MCW - Pharmacology > Block 2_3 - Pharmacology of Inflammation > Flashcards

Block 2_3 - Pharmacology of Inflammation Flashcards

1
Q

4 signs of inflammation

A

heat (calor)

swelling (tumor)

redness (rubor)

pain (dolor)

Loss of function

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2
Q

Define Inflammation (modern day definition)

A
  1. the reaction of vascularized living tissue to local injury
  2. protective response to noxious stimuli
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3
Q

Physiological responses to ACUTE inflammation

A
  • Vasodilation (contributes to heat+redness)
  • Increase in vascular permeability (contributes to swelling)
  • accumulation of inflammatory cells (recruitment of neutrophils)
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4
Q

Potential Harmful Effects of Inflammation

A
  1. inflammatory cells release lysosomal enzymes that may digest normal tissues
  2. edema/swelling that can obstruct airways or the cranial cavity = death
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5
Q

Define: Mediator Theory

A

signs and symptoms of inflammation are caused by the release of chemicals

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6
Q

Name Chemical Mediators

A

Histamine

Bradykinin

Complement

C-Reactive Protein

Cytokine

Adenosine

Cell Adhesion Molecule

Prostaglandin

Leukotriene

Glucocorticoid

Cyclooxygenase

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7
Q

Histamine

  1. Cellular Source
  2. Physiological Response
  3. Mechanism
  4. Pharmacology
A

biogenic amine - pro inflammatory

  1. mast cells, basophils

2.

a. vasodilation
b. increased vascular permeability
c. pain
3. Activation of GPCR
4. antihistamines (H1 antagonists) - diphenhydramine

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8
Q

Bradykinin

  1. Cellular Source
  2. Physiological Response
  3. Mechanism
  4. Pharmacology
A

peptide

  1. endothelial cells

2.

a. vasodilation
b. increased microvessel permeability
c. pain

3.

  • Activation of GPCRs
  • B2 receptor
  1. BK receptor antagonists (Icatibant) being tested - inhibits Bradykinin binding at B2 receptor
    * treatment of acute attacks of hereditary angioedema (HAE)
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9
Q

Complement System

  1. Cellular Source
  2. Physiological Response
  3. Mechanism
  4. Pharmacology
A

plasma proteins C3a, C5b, C3b ….

  1. 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
  1. some drugs are used clinically; pre-clinical trials with a number of different complement inhibitors
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10
Q

Define: Acute Phase Reaction

A

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.

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11
Q

C-Reactive Protein

  1. Cellular Source
  2. Physiological Response
  3. Mechanism
  4. Pharmacology
A

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
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12
Q

Cytokines

  1. Cellular Source
  2. Physiological Response
  3. Mechanism
  4. Pharmacology
A

secreted proteins - particularly pro-inflammatory Tumor necrosis factor (TNF-α) and Interleukin-1 (IL-α and IL-ß)

  1. nearly all inflammatory cells
  2. multiple effects
  • TNF-α: acute phase reaction, fever, sepsis
  • IL-1: acute phase reaction, fibroblast and lymphocyte proliferation, fever
  1. –  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)
  1. TNF-α blockers

Etanercept

Infliximab

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13
Q

Adenosine

  1. Cellular Source
  2. Physiological Response
  3. Mechanism
  4. Pharmacology
A

Purine nucleoside formed from breakdown of ATP

  1. All cells
  • increased extracelularly during injury
  • anti-inflammatory effect to inhibit cytokine action
  1. activation of GPCRs
  • Adenosine A2 agonists
  • Methotrexate (releases adenosine)
  • Adenosine A3
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14
Q

Cell Adhesion Molecules

  1. Cellular Source
  2. Physiological Response
  3. Mechanism
  4. Pharmacology
A

family of proteins including Ig-like CAMs, integrins, selectins, cadherins

  1. 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
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15
Q

Oxygen-Derived Free Radicals

  1. Source
  2. Physiological Response
  3. Mechanisms
  4. Pharmacology
A

superoxide, hydroxy radicals

  1. all cells
  2. intracellular killing of bacteria by neutrophils
  3. 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
  4. Antioxidants like Vitamin C and E (but with limited success in clinical trials)
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16
Q

Lipid Mediators - Prostaglandins

  1. Source
  2. Physiological Response
  3. Mechanisms
  4. Pharmacology
A

eicosanoids, steroids

Pro-inflammatory

  1. Virtually all cells
  2. a. vasodilation
    b. pain
    c. fever
    d. platelet aggregation
  3. activation of specific GPCRs

4.

NSAIDs

COX-2 inhibitors

Steroids

17
Q

Lipid Mediators - Leukotrienes

  1. Source
  2. Physiological Response
  3. Mechanisms
  4. Pharmacology
A
  1. macrophages, neutrophils
  2. increase vascular permeability (LTC4, LTD4, LTE4)bronchoconstriction
  3. activation of GPCRs
    • Zileuton: 5-lipoxygenase inhibitor
    • Zafirlukast: Leukotriene receptor antagonist
18
Q

Lipid Mediators - Glucocorticoids

  1. Source
  2. Physiological Response
  3. Mechanisms
  4. Pharmacology
A
  1. 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
  1. activation of nuclear receptors and steroid-responsive elements to induce/repress transcription
  2. steroids
    - most potent and effective agents for controlling chronic inflammatory diseases
19
Q

Anti-Inflammatory Drugs - Steroids

  1. Mechanism of Action
A
  1. 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
20
Q

Anti-Inflammatory Drugs - Non Steroidal Anti-Inflammatory Drugs (NSAIDs)

Mechanism of Action

A

inhibition of cyclooxygenase reduces production of inflammatory prostanoids

21
Q

Other Anti-Inflammatory Drugs

  1. Leukotriene Antagonists
  2. Inflammatory cytokine inhibitors
A
  1. Leukotriene Antagonists
  • zafirlukast - competitive antagonist of leukotriene receptors
  • zileuton - inhibits the synthesis of leukotrienes
  1. Inflammatory cytokine inhibitors
  • etanercept - receptor analog
  • infliximab - monocloncal antibody
22
Q

Common Points about cytokine inhibitors

A

•  NOT orally available drugs
– IV, Subq

•  Adverse effects
– Risk of infection

•  Therapeutic uses
– Rheumatoid arthritis

23
Q

How to treat acute inflammation? (e.g. acute gout attack)

A

Symptomatic relief

  • NSAID
  • Steroid
24
Q

How to treat chronic inflammation? (e.g. rheumatoid arthritis)

A

NSAID

steroid

etanercept

25
Q

Is inflammation inevitable?

A

KEY POINT: under normal circumstances, the body is able to moderate the inflammatory response. So in some cases inflammation is not seen at all and in other cases, inflammation is never resolved

Multiple Controls of Inflammation/ How do you effectively treat inflammation?

MCW - Pharmacology (8 decks)

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