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31 Cards in this Set
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what triggers the production of arachidonic acid and what enzyme is involved.
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AA is normally esterified in membrane. Various physical, chemical, inflammatory, and mitogenic stimuli stimulate the enzyme Phospholipase A2, involved in liberating AA from membrane lipids
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Identify the functions of the COX and 5-LOX enzymes.
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Cyclooxygenase (COX) converts arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to PGH2, precursor of prostanoids. COX1 found in all tissues (housekeeping), COX2 is inducible, early-response to shear stress, cytokines, growth factors, etc. (inflammation, cancer)
5-Lypoxygenase (5-LOX), with activating protein FLAP, converts arachidonic acid to hydroperoxyeicosatetraenoic acids (HPETEs), which rapidly convert to hydroxy derivatives (HETEs) and leukotrienes. 5-LOX present in leukocytes, hence name of products (leukotrienes). Pathway associated with asthma, anaphylaxis, cardiovascular disease. |
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Identify the classes of eicosanoids formed by the COX and 5-LOX pathways.
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COX: Prostanoids (Prostaglandins, Prostacyclin, Thromboxane)
5-LOX: HETEs, Leukotrienes, Lipoxins |
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Identify some important members of each class of eicosanoids.
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COX: Thromboxane (powerful vasoconstrictor and platelet agonist), Alprostadil (PGE1, smooth muscle relaxant to maintain ductus arteriosus in neonates), Misoprostol (PGE1 derivative, cytoprotective prostaglandin to prevent peptic ulcer, terminate early preg), PGE2 and PGF2 can induce labor, Prostacyclin (PGI2, epoprostenol, by vascular endothelium to vasodilate and block platelet aggregation)
LOX: Leukotrienes: LTC4 and LTD4 potent bronchoconstrictors and primary components of slow reacting substance of anaphylaxis (SRS-A) secreted in asthma/anaphylaxis. Lipoxins: anti-inflammatory but endogenous role unclear. epoxygenase products: EETs can cause vasodilation due to SM hyperpolarization reducing BP. isoeicosanoids: isoprostanes (prostaglandin stereoisomers) stored in membrane, cleaved, and circulate. Potent vasoconstrictors. may also enhance platelet and leukocyte adhesion and angiogenesis? |
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Identify some drugs that inhibit various enzymes or receptors in these pathways.
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COX1-2 inhibited by ibuprofen (reversible) and aspirin (covalent, irreversible).
Antileukotrienes: 5-LOX inhibitors (Zieluton), 5 LTC4 synthase inhibitor? (Zafirlukast), leukotriene receptor antagonists (Montelukast, LTD4), FLAP inhibitors, phospholipase A2 inhibitors |
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what are the 4 separate pathways Arachidonic acid can take?
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cyclooxygenase (COX), lipoxygenase (LOX), P450 epoxygenase, and isoeiconasoid pathways.
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What type of hormone are eicosanoids?
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Paracrine and autocrine, NOT endocrine due to short half-life (don't circulate). Act at site of synthesis on same cell (autocrine) or neighbor cell (paracrine).
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What type of tissue are prostaglandins most active on?
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SMOOTH MUSCLE. In vasculature, airways, GI, reproductive system. Remember contraction is from influx of intracellular Ca++ and relaxation from increase in intracellular cAMP.
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Understand the synthesis, storage, release, and degradation of histamine.
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Synthesis: Decarboxylation of Histidine, catalyzed by histidine decarboxylase.
Storage: Release: IgE antibodies triggered on cell surface leading to explosive histamine granule release.(mediate type I allergic reactions - hay fever, acute urticaria). Degradation: |
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Identify the major cell type(s) that store and release histamine.
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Mast cells, basophils, smooth muscle, endothelium, nerve endings
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Identify the four subtypes of histamine receptors, their distribution and effects (physiological functions).
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H1: Smooth muscle, endothelium, brain (postsynaptic). Activation causes phosphoinositol hydrolysis, increasing IP3 and intracellular Ca++. Physiologically causes itching (nerve endings), appetite and satiety, smooth muscle contraction, bronchoconstriction.
H2: Gastric mucosa, cardiac muscle, mast cells, brain (postsynaptic). Activation increases cAMP via Gs (can also couple to Gq). Physiologically causes smooth muscle relaxation, increased contractility and rate of heart, gastric acid secretion H3: Presynaptic autoreceptors and heteroreceptors, myenteric plexus, brain. Agonism may be important to obesity tx (knockouts eat more and are obese) H4: eosinophils, neutrophils, CD4 T cells. Very chemotactic. |
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Review the differences among the generations of histamine subtype 1 selective antagonists.
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Treatment for allergic conditions.
First generation H1 antagonists: strongly sedative. More likely to block autonomic receptors. Due to rapid access to CNS. Prevent nausea and motion sickness. Antiparkinsonism, anticholinergic actions, antiadrenergic actions (promethazine), serotonin blocking (cyproheptadine) Second generation: less sedative due to lower distribution to brain. Fewer autonomic side effects. |
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What are major actions of released histamine?
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local vasodilation, leakage of plasma-containing mediators of acute inflammation (complement, C-reactive protein), antibodies, and chemoattracts inflammatory cells. Inhibits release of lysosome contents and several T and B cell functions.
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What is the histamine triple response? What cells are involved?
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Intradermal injection causes red spot, edema, and flare. 3 cell types involved: smooth muscle in microcirculation (dilation = redness), sensory nerve endings, flare from axon reflex?
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Name the types of histamine antagonists
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Physiologic antagonist: epinephrine, act at different receptor to reverse effects of histamine, life saving in anaphylaxis.
Release inhibitor: reduce degranulation of mast cells when triggered by IgE. Cromolyn and nedocromil. Beta 2 agonists also may do this. Mechanism not understood. Receptor antagonists: antagonize histamine receptors. |
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synthesis, storage, release and
metabolism of histamine |
synthesis: from histidine, by histamine decarboxylase
storage: intracellular vesicles release: upon stimulation of histamine receptors (GPCRs? mechanism?) or by cell injury and degranulation Metabolism: RAPIDLY metabolized to inactive metabolites |
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What are the 1st generation antihistamine drugs?
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Chlorpheniramine, Diphenhydramine (Benadryl), dimenhydrinate (Dramamine), promethazine, hydroxyzine, Meclizine, cyproheptadine, doxepin
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What are the 2nd generation antihistamine drugs?
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Loratadine (claritin), Terfenadine, Cetirizine, Ketotifen
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distribution of histamine receptor
subtypes (H 1 , H 2 , H 3 , and H 4 ) and effects associated with each |
H1 - Bronchial SM (contraction), vascular endothelium (NO release, vasorelaxation), GI SM (contraction), CNS neurons (wakefulness, appetite decrease)
H2 - Bronchial SM (weak relaxation), cardiac muscle (generalized stimulation), vascular SM (relaxation), gastric mucosa (secretion), mast cells H3 - Lung (antagonize H1 induced bronchoconstriction), GI tract (antagonize H1 induce contraction), CNS (sedation) autoreceptors and heteroreceptors H4 - Bone marrow (mast cell chemotaxis) |
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H 1 and H 2 subtype specific antagonists
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H1: Most all drugs, the 1-3 generations.
H2: Cimetidine, Ranitidine |
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Understand the generations of H 1 antagonists (i.e., 1 st , 2 nd and [3 rd ])
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1st: prominent CNS and sedative effects, may have effects at other receptors
2nd and 3rd: much less sedating |
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What are the 3rd generation antihistamine drugs?
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Desloratadine (Clarinex), Fexofenadine (Allegra), Levocetirizine (Xycal). All derivatives of 2nd generations.
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What are the histamine release inhibitors (mast cell stabilizers)?
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Nedocromil, Cromolyn
They cram "crom" histamine into cells |
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Biologic functions of histamine? Effects of histamine
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-Modulation of allergic and inflammatory reactions.
-stimulation of gastric acid secretion. -neurotransmission and neuromodulator in CNS, GI -Role in WBC chemotaxis Effects: -gastric secretion via H2 -contraction of NON-VASCULAR SM -Vasodilation (low doses H1, high doses H2) -Cardiac stimulation: reflex incr HR, incr H2 receptors -increase vascular permeability -stimulate nerve ending -> pain and itch -CNS effects: wakefulness, decreased appetite |
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Where is histamine synthesized and stored?
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Mast cells, basophils, CNS neurons, enterochromaffin-like cells of stomach. Most by mast cells.
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What are the decongestants? What class of pharmaceutical are they?
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Alpha agonists:
Phenylephrine, pseudoephedrine, oxymetazoline Anticholinergic: Ipratropium |
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What are examples of expectorants?
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Guaifenesin (Robitussin, mucinex) - reduce viscosity of mucus
Acetylcysteine (Mucomyst) |
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Cough suppressants?
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OPIOIDS (Codeine, hydrocodone, morphine, dextromethorphan)
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Intranasal glucocorticoids? what used for?
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Budesonide, Ciclesonide, Flucitcasone (Flonase). Antiinflammatory control of nasal congestion and swelling in cases where expectoration and antihistamine therapy don't work.
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what is the major target of many antifungal agents?
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Ergosterol in cell membrane (different from human cholesterol).
key exception is Pneumocystis jiroveci, agent causing PCP in AIDS patients. |
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What do the echinocandin antifungal drugs target? Examples?
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Target is beta-glucan synthesis. Beta-glucan is a component of fungal cell walls.
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