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124 Cards in this Set
- Front
- Back
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Types of injury to produce an inflammatory response
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mechanical, heat, chemical, bacterial, viral , antigen-antibody
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4 things about the mediators of inflammation
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-endogenous
-stored or rapidly synthesized -suppose to act only at site of injury -redundancy (many things can cause the symptoms of inflammation) |
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description of acute inflammation
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-arteriolar dilation
-venules become leaky -endothelium contracts -pavement and infiltration of leukocytes |
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What could signal acute inflammation?
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histamine, prostaglandins, leukotrienes, kinins, PAF, etc
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What does cause acute inflammation?
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-varies with situation
-mediators are a function of nature, dose and route |
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inflammatory activities
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-redness and heat
-swelling -pain -chemotaxis -airway constriction -hypotension -fever |
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Histamine characteristics
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-vasodilation
-increased vascular permeability -cause airway constriction -NOT chemotaxis |
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Difference between prostaglandins and thromboxane
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-thromboxane causes platelet aggregation and prostaglandins oppose platelet aggregation
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Leukotrienes chemotactic molecule, and what does it do?
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LTB4
reduces pain threshold |
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characteristics of leukotrienes
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airway constriction
increased vascular permeability chemotaxis |
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Big characteristic of Kinins
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-hypotension
-not a chemotactic agent |
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Causes Redness (Vasodilation)
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Histamine
PGE, PGI Kinins |
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Causes swelling (increased permeability)
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Histamine
Peptido-leukotrienes (LTC4, LTD4, LTE4) Kinins |
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Causes pain
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PGE, PGI
LTB4 Kinins |
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Chemotaxis
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LTB4 (neutrophils, etc)
Peptido leukotrienes (eosinophils) |
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Fever
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PGEs induce fever
-remember aspirin stops fever by stopping production of prostaglandins |
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Bronchoconstriction
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Histamine
Peptido-leukotrienes (LTC4, LTD4, LTE4) Kinins PGD2 |
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hypotension
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Kinins
Histamine |
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Where does histamine come from?
Where is histamine found |
the aminoacid Histadine
-all over in the granules of mast cells and -also outside of mast cells in CNS, epidermis, those undergoing growth and repair cells |
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What are the function of enzymes that act on histamine?
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They are there to inactivate histamine, no pharmacological activity
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What happens if you eat histamine?
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-nothing
-inactivated in the intestinal wall |
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What happens if you inject histamine into your skin?
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Triple response:
1) redness (arteriolar dilation) 2) flare (slow, extended redness, nerves dilating more arterioles) 3) wheal (edema from increased permeability) |
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What happens if you put histamine up your nose? (Hay fever)
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-itching
-sneezing -hypersecretion -nasal blockage from nasal dilation, edema and increase in secretion |
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Intravenous injection of histamine
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-major hypotension
-tachycardia (to raise BP) -bronchoconstriction -dilation of face, head -wheal and flare (hives) -GI secretions |
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Non-cytolytic release of histamine:
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Morphine
neuromuscular blockers kinins complement |
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cytolytic release of histamine
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-mechanical or thermal damage to cell
-venom that causes cells to lyse |
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Clinical use of histamine
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-asthma testing
-integrity of sensory neurons |
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Clasify histamines as a type of drug...
What are they historically referred to as? |
-inverse agonists: bind to the inactive receptor and stabilizes it in this state, REDUCE ACTIVITY BELOW BASAL LEVEL
-competitive antagonists |
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competitive antagonist characteristics
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-shifts dose response curve to the right, REDUCTION IN ACTIVITY BELOW BASAL LEVEL.
-Still reaches the same maximum with enough ligand |
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histamine will stimule which receptors?
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H1, 2, 3, and 4
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H1 stimulates
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-Bronchoconstriction
-Contraction of GI smooth muscle -Increased capillary permeability (wheal) -Pruritis (itch) -Release of catecholamines from the adrenal medulla |
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H2 stimulates.....
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-GASTRIC ACID SECRETION
-FEEDBACK CONTROL OFF ITS OWN RELEASE -inhibits T-lymphocyte mediated cytotoxicity |
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H1 and H2 mediated responses
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-cardiac responses (H1 and 2)
-vasodilation (H1 and 2) -nasal (H1) -dilation and edema of nasal (H1 and 2) -mucus in the nose (H2) |
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Difference in SE between old and new antihistamines?
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OLD: CNS, sedating, muscarinic effects, GI disturbances, dry mouth
NEW: non-sedating, drying or muscarinic effects |
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Why does the 1st generation of antihistamines have the CNS effects?
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-they are not recognized by the P-glycoprotein efflux pump which pumps them out
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Acute poisoning of 1st generation of antihistamines resembles _____?
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atropine poisoning
-dilated pupils, flush face, fever, dry mouth |
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Which antihistamine do you use for sedation as an additional usage?
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DIphenhydramine
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Which antihistamine has less anticholinergic effects but more GI side effects?
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Tripelennamine
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Which antihistamine would be used primarily during the day?
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Chlorpheniramine
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What are the 1st generation antihistamines?
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Diphenhydramine
Tripelennamine Chlorpheniramine |
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Why are newer antihistamines better?
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-minimal anticholinergic properties (sedation and drying)
-pumped out of CNS by P-glycoprotein |
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Non-sedating antihistamines?
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Cetirizine
Fexofenadine Loratadine |
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What was a problem with the earlier 2nd generation antihistamines?
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cardiotoxicity
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How will the dose response curve of bronchococnstriction and acetylcholine shift with new H1 antihistamines? with old?
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-the dose response will not shift with the new ones
-it will shift (but not as much as atropine) for the old ones bc they have anticholinergic effects. |
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How will the dose response curve of bronchococnstriction and histamine shift with new H1 antihistamines? with old?
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-they both will shift the curve because they act on the H1 site
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Which antihistamines would you use for motion sickness?
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-diphenhydramine and promethazine
-the anticholinergic properties |
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What effects, if any, do the antihistamines have on the common cold?
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-drying secretions by anticholinergic properties
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This is responsible for removing the second phospholipid of the glycerol backbone to release what is commonly arachidonic acid.
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phospholipase A2
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What can arachidonic acid go to?
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prostaglandin synthesis or leukotriene synthesis depending on the cell
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What is the control step of the cyclooxygenase pathway?
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availability of arachidonic acid by phospholipase A2
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What does COX do?
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-arachidonic acid to PGG2 to PGH2
-from there other enzymes from different cells can turn it into different products |
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COX-1 is constutively expressed in ____ cells and especially ______.
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most cells
platelets |
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COX-2 is constitutively expressed in _____ cells and especially for _____
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brain and kidney, not platelets
prostaglandin and thromboxane production in inflammation |
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Prostaglandin Production:
Platelets make _____ Endothelium _____ Mast Cells _____ |
Thromboxane (vasoconstriction)
Prostacyclin - PGI (vasodilator) PGD2 (bronchoconstrictor) |
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Difference between receptors of Prostacyclin and Thromboxane and their effects on platelet aggreagation and smooth muscle tone?
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Prostacyclin inhibits platelet aggregation and smooth muscle tone.
Thromboxane stimulates platelet aggregation and smooth muscle tone |
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Inflammatory effects of prostaglandins
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-PGE induces fever
-PGE and PGI induce vasodilation -PGE and PGI increase permeability -PGE causes pain -PGE and PGI lower threshold of pain |
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What is the mechanism of the drugs that intervene with prostaglandins?
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-stop their synthesis
-inhibiting COX 1 and 2 |
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Effects of drugs that inhibit cyclooxygenase, NSAIDS?
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-inhibit COX 1 and 2
-cause analgesia, anti-inflammatory, antipyretic |
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antipyretic mechanism of NSAIDs?
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cytokines act on prostaglandins to produce PGE2, acts on hyopthalamus
-inhibit production |
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Which drug irreversibly acetylate COX?
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aspirin
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What are the NSAIDs?
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-inhibit COX 1 and 2
acetylsalicylate (aspirin) ibuprofen naproxen diflunisal indomethacin sulindac ketoprofen piroxicam |
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Mechanism of selective COX inhibitors? Drug?
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COX 2 inhibition
-celecoxib |
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Acetominophen use?
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-not for antiinflammatory
-is antipyretic and analgesic |
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Gastric ulceration is related to ____ and ______ in the GI tract.
Reduced with ____ inhibitors. |
COX1 and PG synthesis
COX 2 |
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____ ____ ____ can occur with any NSAID causing kidney problems
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analgesic abuse nephropathy
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adverse effects of NSAIDs (6)
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Gastric or intestinal ulceration
Prolongation of gestation Renal function Hepatitis Increased bleeding time Aspirin hypersensitivity |
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mechanism of aspirin hypersensitivity
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-shifts production to leukotiene production, instead of prostaglandins
-or a decrease in PGE2 eliminates a blocking of leukotriene production -COX 2 are safe |
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How are COX 2 inhibitors better?
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no platelet inhibition, GI ulcereations, or aspirin hypersensitivity
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What are two bad things about aspirin toxicity?
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-associated with Reye Syndrome
-anti-inflammatory doses are close to toxic doses -aspirin irreversibly inactivates platelet COX |
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5 lipoxygenase
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-first two steps in the conversion of arachidonic acid
-they form labile intermediates that have short half lives and will break down if not used |
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What is the limiting step in the leukotriene pathway?
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Phospholipase A2 to make arachodonic acid
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FLAP
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5 lipoxygenase activating protein
-take 5 lipoxygenase from the cytosol and puts it in the membrane -future drug target |
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peptidoleukotriene formation?
(A4 --> C4) |
-done by glutathione S transferase (endothelilal or SM cell)
-or LTC4 synthase (mast or basophil) -adds to leukotriene A4 |
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Which leukotriene is a potent chemotaxic agent?
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B4
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Which leukptrienes cause airway constriction? What is the name for these?
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C4, D4, E4
peptidoleukptrienes |
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Formation of leuko B4?
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-done by LTA hydrolase
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How do you go from C4 to D4 to E4?
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lose an AA from the glutathione from C4
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Source of 5-lipoxygenase?
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myelomonocytic cells
PMN, eosinophils, basophils, monocytes, macrophages, mast cells |
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*PRIORITY SLIDE*
What are three fates of LTA4? What are the enzymes that do these? |
1) LTB4 formation (LTA4 hydrolase)
2) LTC4 formation (LTC4 synthase or glutathione S transferse) 3) travel to other cells where it can be converted to LTC4 (endothelial, SM) or LTB4 (platelet, RBC) |
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LTD4 receptor
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Cys LTR1
-acted on by LTD4 mostly -airway constriction |
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LTC4 receptor
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Cys LTR2
-acted on by LTC4 and LTD4 -cell activation |
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LTB4 receptor
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-chemotaxis
-leukocyte adhesion -protease release -ROS production -hyperalgesia |
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What is found in the synovial fluid of patients with rheumatoid arthritis and gout?
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LTB4
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What are the drug targets for asthma?
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-prevent LTC4 and LTD4 formation
-5 lipoxygenase inhibitors -Cys LTR1 (LTD4) antagonists |
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Zileuton
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-maintenance of asthma, not acute
-5-lipoxygenase inhibitor -Cyt P450 (drug interactions) |
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Zafirlukast
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-maintenance of asthma, not acute
-LTR1/LTD4 receptor antagonist -oral -Cyt P450 |
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Montelukast
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-maintenance of asthma, not acute
-LTR1/LTD4 receptor antagonist -oral |
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What's the difference between Zafirlukast and Montelukast?
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Zafirlukast is metabolized by Cyt P450
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HAE
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Hereditary angioedema
-edema in skin, GI, or larynx -C1 Inh Deficiency so you can't control kallikrein and you produce excessive kinins -use kinin inhibitors or steroids to increase C1 inhibitor production |
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What do the Kinins cause?
What do they control What are the two big ones? |
-Hypotension, Pain, inc capillary permeability, and edema
-Blood pressure and inflammation -Bradykinin and kallidin |
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What 4 enzymes are interrelated so that affecting one pathway may perturb the other pathways?
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Hageman factor
Kallikrein Plasmin (fibrolytic) C1 esterase |
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How is Kallidin produced?
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By tissue kallikrein acting on a LMW kininogen
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How is Bradykinin produced?
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By plasma kallikrein or tissue kallikrein acting on a HMW kininogen
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Degradation of Bradykinin:
What are the two enzymes? |
Carboxypeptidase N (Kinase I)
Angiotension Converting Enzyme (ACE - Kinase II) |
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Aminopeptidase P
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-removes N terminal AA
-turns Kallidan to Bradykinin |
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Kininase I
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Carboxypeptidase N
-removes arginine from C - terminal -part of compliment pathway |
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Kininase II
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ACE
-removes dipeptide from C terminal -INACTIVATION -involved in hypertension by converting angiotension I --> II for vasoconstriction |
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What receptor do Bradykinin and Kallidin act on?
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B2 -hypotension
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What receptor so des arg Bradykinin and des arg Kallidan act on?
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B1 - after trauma, long term effects (chronic inflammation)
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How do ACE inihibitors work?
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They stop the vasoconstriction of angiotension II and also cause vasodilation through bradykinin and kallidin production
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When are immunosuppressive drugs used?
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transplantation
autoimmune disease hypersensitivities |
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What are the risks of immunosuppresive drugs?
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increased risk of cancer
increased risk of all infections |
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Two classes of adrenal steroids
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corticosteroids (stop inflammation)
androgens (body building) |
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Two groups of corticosteroids
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mineralocorticoids (elelctrolyte)
glucocorticoids (carbohydrares metabolism) |
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endogenous cortisol (hydrocortisone) function
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-produced by the adrenal cortex to turn off the immune system by negative feedback
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mineralcorticoid receptor
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causes sodium retention
(want to minimize drug action on this) -aldosterone acts on it |
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glucocorticoid receptor
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causes liver glycogen deposition and anti-inflammatory
-cortisol acts on this |
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Synthetic steroids
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-betamethasone
-dexamethasone -methylpredisone -prednisone |
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Benefits of intranasal steroid
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-lower nose
-direct action on respiratory (hay fever) -comoplete hepatic first pass inactivation |
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how does the receptor for the glucorticoid receptor work?
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-the steroid has to bind with a protein to enter the cell.
-then it binds to its intracelluler receptor and enters the nucleus to act on DNA -Lag time of about a day |
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steroid affect on immune system
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-neutrophils stay in circulation
-lymphocytes are moved to extrvascular compartments -monocytes and eosinophils are decreased in peripheral blood -reduce expression of COX2 -everything else |
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What is the down side of steroids?
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-life threatening with long term use in the system
-does not cure underlying disease -can't discontinue abruptly bc your body has to have time to make cortisol or hypotension and shock can result |
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Calcineurin Inhibitors
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Cyclosporine
Tacrolimus |
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How are T-cell activated intracellularly
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Cyclophin or FKBP bind activate calcineurin to activate transcription factors to release IL-2
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Mechanism of cyclosporine
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-binds to cyclophin and inhibits calcineurin activity
-kidney toxicity |
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Mechanism of tacrolimus
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-binds to FKBP and inhibits calcineuron activity
-100 times more potent -kidney toxicity |
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Antiproliferative and antimetabolic drugs of B and T lymphocytes
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Sirolimus
Mycophenolate mofetil |
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Sirolimus (rapamycin)
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-binds to FKBP as well but does something different
-inhibits cell cycle proliferation from the IL-2 receptor -nephrotoxicity and drug interactions |
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Mycophenolate mofetil
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-selelctively inhibits guanine nucleotide biosynthesis in B and T cells
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anti-thymocyte globulin
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-eliminates lymphocytes
-lymphopenia -nephritis |
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muromonab-CD3
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CD3 - T-cell receptor complex is the target
-binds to CD3 to inactivate it -cytokine release syndrome |
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Daclizumab
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IL2 receptor antibodiy
-possible anaphylactic shock |
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Basiliximab
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IL2 receptor antibody
-possible anaphylactic shock |
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cytokine release syndrome
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-initial activation of cell releases cytokines
-flu-like symptoms/shock |
