Pharmacology of inflammation Flashcards
what is inflammation and why is it important to use drugs to treat inflammation
- inflammation is the bodys mechanism for handling agent that could damage it
- its a protective response to rid the body of the cause of cell injury and the resultant dead cells that cell injury causes
- processes of acute and chronic inflammation can be damaging to the body and need to be controlled
little inflammation restores homeostatic balance, fights disease, and drives wound healing responses
too much=pathalogy (asthma, rheumatoid arthritis, IBS, gout, artherosclerosis, cancer)
immune system and inflammation
pathogens and foreign proteins into the human body can stimulate immune recognition–> inflammatory and allergic responses
innate immunity- host defense mechanisms that are immediately available on exposure to pathogen- takes hours to start
adaptive immunity- aka acquired- Ag specific and immuno memory, mediated by B and T cells following exposure to pathogens. Needs prior Ag processing and recognition- takes days to develop
acute inflammation signs
cardinal signs of acute inflammation: Rubor (red discoloration), Calor (heat), dolor (pain), tumor (mass effect), and loss of function
Vasodilation, increased vascular permeability, recruitment of neutrophils
ex: sore throat, skin reaction, acute gout
causes: microbes, physical agents, irritants, tissue necrosis
Chronic inflammation
prolonged duration- weeks months etc
participation by lymphocytes, plasma cells, macrophages, fibroblasts, and angioblasts
ex: TB, rheumatoid arthritis, ulcerative colitis, chrons asthma, gout
causes: persistent of irritant, endogenous Ag or factor
inflammation at the signaling level
initially sensed by pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and or damage associated molecular patterns (DAMPs)
Upon binding, PRRs activate signal-dependent transcription factors such as NFKB and AP-1
Induce the expression of genes that initiate the inflammatory response, exert anti microbial functions and recruit additional immune cells
Sets into motion both innate and adaptive immune responses. nearly all components are redundant. there are cytokine mediated feed forward loops that amplify the initial inflammatory response
mediator theory
signs and symptoms of inflammation are caused by the release of chemicals
receptors or sensors expressed on specialized cells
histamine
Class- cell source- physiological response- mechanism- Pharmacology-
Class- biogenic amine
cell source- mast cells + basophils
physiological response- vasodilation, vascular permeability and pain
mechanism- Activation of GPCR
Pharmacology- antihistamines (H1 antagonists)
Bradykinin Class- cell source- physiological response- mechanism- Pharmacology-
Class- peptides
cell source- endothelial cells
physiological response- vasodilation, increased microvessel permeability, pain
mechanism- activation of GPCRs
Pharmacology- BK receptor antagonists being tested
Complement system Class- cell source- physiological response- mechanism-
Class- plasma proteins
cell source- synthesized by liver, circulate in blood
physiological response-
Chemotaxis (recruitment of inflammatory cells to site of injury), promote release of mediators from neutrophils, increase vascular permeability, excessive activation may contribute to tissue injury
mechanism- complement protein complexes cause osmotic lysis and activation of GPCRs
Pharmacology-
C-reactive protein Class- cell source- physiological response- mechanism- Pharmacology-
Class- plasma protein
cell source- produced in liver in response to cytokines and adipocytes
physiological response- acute phase reactant, activates complement cascade, mediates phagocytosis, marker of inflammation
mechanism- binds to phospholipids in bacteria and damaged, cells may be specific receptors in macrophages
Pharmacology- elevated CRP=increased risk of diabetes, HTN, and CV disease. Statins may be effective in patients with elevated CRP
Cytokines Class- cell source- physiological response- mechanism- Pharmacology-
Class- secreted proteins, esp pro-inflammatory cytokines: IL1, IL6, and TNF a
cell source- nearly all inflammatory cells
physiological response- TNF a for acute phase reaction, fever, sepsis. IL1 for acute phase reaction, fibroblast, and lymphocyte proliferation, and fever. IL6 for acute phase reaction, fever, T and B cell differentiation, vascular proliferation, vascular permeability
mechanism- binds to receptor, activates NKFB and AP-1 and causes expression of proteins (COX-fever, lipoxygenase, increase adhesion molecule expression, induces collagenase-fibrosis)
Pharmacology- Etanercept, Infliximab target cytokines
Adenosine Class- cell source- physiological response- mechanism-
Class- purine nucleoside formed by breakdown of ATP
cell source- all cells
physiological response- increased adenosine conc extracellularly during injury anti inflammation, inhibits cytokine action
mechanism- activation of GPCR
cell adhesion molecules Class- cell source- physiological response- mechanism-
Class- proteins
cell source- endothelial cells, platelets, leukocytes
physiological response- leukocyte adhesion to endothelium is a pivotal event in host defense and tissue repair. Endothelial adhesion molecules contribute to recruitment of activated platelets
mechanism- contact molecules, Ca dependent
Pharmacology-
prostaglandins Class- cell source- physiological response- mechanism- Pharmacology-
Class- lipid eicosanoids, steroids
cell source- virtually all cells
physiological response- vasodilation, pain, fever, platelet aggregation (via TBX)
mechanism- activatation of GPCR
Pharmacology- NSAIDs
leukotrienes Class- cell source- physiological response- mechanism- Pharmacology-
Class- lipid, eicosanoids, steroids
cell source- macrophages, neutrophils
physiological response- increase vascular permeability, bronchoconstriction
mechanism- activation of GPCRs
Pharmacology- 5-lipoxygenase inhibitors (Zileuton); cys-leukotriene receptor antagonist (Zafirlukast)
