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54 Cards in this Set
- Front
- Back
Eicosanoids
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- Prostaglandins and related compounds are synthesized from arachidonic acids (membrane phospholipids)
- Specific effects on target cells close to formation. - Prostaglandins, prostacyclins, thromboxane, leukotriene |
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Eicosanoids: Physiological effects
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Profound physiological effects at low concentrations:
- Inflammatory response (rheumatoid arthritis). - Production of pain and fever. - Regulation of blood pressure. - Induction of blood clotting. - Control of several reproductive functions such as the induction of labor. - Regulation of the sleep / wake cycle. |
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Eicosanoids: Pathway
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Eicosanoids: Cox-1 isoform
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- COX-1: constitutively expressed- "housekeeping" processes, homeostatic regulation.
- COX-1 catalyzes the synthesis of PGE2 and PGI 2 that have cytoprotective actions and play an important role in maintaining the integrity of the gastroduodenal mucosa. - COX-1 maintains renal function (vasomotor tone) |
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Eicosanoids: Cox-2 isoform
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- COX-2 levels increase in inflammatory diseases (arthritis).
- Inflammation is associated with up-regulation of COX-2 & increased amounts of particular prostaglandins. - COX-2 expression is increased in some cancer cells. - Angiogenesis (blood vessel development), which is essential to tumor growth, requires COX-2. |
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Eicosanoids: Cox-2 isoform cont...
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- COX-2, is an inducible isoform that is found mainly in inflammatory and immune cells (neutrophils, macrophages, mast cells, etc).
- Pro-inflammatory cytokines and growth factors induce COX-2. - At the site of inflammation, COX-2 is responsible for the generation of the hyperalgesic and pro-inflammatory prostaglandins. |
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Eicosanoids: Cox-1/Cox-2 Flowchart
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Eicosanoids: Lipoxygenase pathway
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- Lipoxygenase synthesizes Leukotriene B4, C4, D4 and E4.
- Occurs predominantly in leukocytes, in response to a variety of immunological stimuli. - The primary target of LTB4 is the leukocyte where it elicits chemotaxis, adherence, and aggregation. |
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Eicosanoids: Lipoxygenase B4
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- Causes neutrophils to adhere to vascular endothelial cells and enhances the rate of migration of neutrophils into extra-vascular tissues.
- Activates phospholipases, the production of diacylglycerols and phosphoinositides, and the release of either anti- or pro-inflammatory agents. |
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Eicosanoids: Lipoxygenase C4
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- Leukotriene C4, together with LTD4 and LTE4, cause contraction of the bronchial smooth muscle in asthma and play a role in bronchospasm.
- Leukotriene antagonists play a potential therapeutic role in asthma. |
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Eicosanoids: Thromboxane
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- Synthesized primarily in platelets.
- Potent inducer of platelet aggregation - Causes vasoconstriction. - Indicated in the pathophysiology of thrombotic events, myocardial infarction and ischemia. - What Aspirin targets. |
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Pain Neurochemistry
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Central/Peripheral sensation of Pain
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Injured Cell Pain pathway
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Eicosanoids: Antagonists - Corticosteroids
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Corticosteroids:
- Potent anti-inflammatory agents. - Inhibit phospholipase A2 - Inhibit cyclooxygenase 2 - Indicated in treatment of rheumatoid arthiritis, gout, asthma, eczema, - Available as oral, inhaled and topical agents. - Long-term use has profound adverse effects |
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Eicosanoids: Antagonists - Non-Steroidal Anti-Inflammatory Drugs:
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Non-Steroidal Anti-Inflammatory Drugs:
- Inhibition of cyclooxygenase enzymes. - Inhibition of prostaglandins involved in fever, pain and inflammation. - Blockade of thromboxane formation platelets inhibits clotting. - Indicated for inflammatory conditions, pyresis and analgesia. - Generally targets both Cox-1 & Cox-2 |
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Eicosanoids: Antagonists- Aspirin
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Thromboxane A2 stimulates blood platelet aggregation, essential to the role of platelets in blood clotting.
Aspirin’s anti-clotting effect, attributed to inhibition of thromboxane formation in blood platelets. ↓ Prophylaxis for MI and prevention of recurrence of MI, embolism and stroke. Aspirin forms a covalent bond making it effective at low doses. At high doses it works as an anti-inflammatory, but causes the worst GI side-effects at high dose. |
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Role of antagonists Chart:
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Eicosanoids: Prostaglandin Analogs
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- Alprostadil (PGE1): Treatment of erectile dysfunction
- Misoprostol (Cytotec): Prevention of peptic ulcers in patients on high dose of NSAID’S - Epoprostenol: Severe pulmonary hypertension |
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Histamine
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- Formed from the amino acid histidine
- Stored in high concentrations in vesicles in mast cells and basophils - Metabolized by -- Monoamine oxidase and diamine oxidase |
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Histamine causes:
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- Stimulation of gastric secretion H2
- Smooth muscle contraction (bronchioles) H1 - Cardiovascular (vasodilation) H1 - Pruritis - Urticaria - Mucosal Congestion H1 |
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Histamine: H1 receptors
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- Bronchoconstriction and vasodilation (via the release of nitric oxide and EDRF)
- Local edema is caused by capillary endothelial cells releasing EDRF and contracting, opening gaps in the permeability barrier-vasodilation - Manifested in allergic reactions and mastocytosis |
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Histamine: H2 receptors
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- G-coupled receptor that mediates gastric acid secretion by the parietal cells in the stomach
- Actions are mediated by activation of adenyl cyclase, which increases intracellular cAMP. - Excessive gastric acid production: -- Gastroesophageal reflux disease (GERD) -- Peptic ulcer -- Zollinger Ellison Syndrome |
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Histamine: Typical Release
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- Released from mast cells in response to IgE-mediated (immediate) allergic reactions
- Histamine blockade plays an important role in treatment of seasonal rhinitis, urticaria, and angioneurootic edema - Histamine receptors in gastric parietal cells control gastric acid secretion. |
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Histamine: Distribution
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Histamine: MOA of release
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Histamine: Allergen mediated release
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Pollen
Dust mites Mold Latex Drugs Insect Venom |
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Histamine: Drug Mediated Relsease
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Penicillin
Cepahalosporin Vancomycin Tubocurarine Succinylcholine Radiocontrast media Aspirin & NSAID’s Insulin |
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Histamine: Effect on vascular smooth muscle
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Histamine: Anaphylaxis
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- Most acute and potentially severe allergic reaction.
- Symptoms include hypotension, vasodilation, myocardial depression, dysrhythmia, urticaria, angioedema and bronchospasm. - Drug of choice is epinephrine (produces bronchodilation and increases blood pressure) |
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Histamine: Anaphylaxis triple response
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Triple Response:
- This denotes the response to intradermal administration of histamine a. Localized red spot forms around the side of injection -- Histamine - induced vasodilatory effect b. Brighter red flush or " flare" extending beyond original red spot. -- histamine- induced axon reflexes cause vasodilation indirectly c. Wheal (lump) is discernible in 1-2 min occupying the original red spot. -- caused by increased capillary permeability - reflects edema. |
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Histamine: characteristics of histamine receptor activation
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Histamine: Agents overview
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Histamine: H1 Antagonists, 1st Gen
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- Indicated for the treatment of allergies, rhinitis, inflammation and nausea associated with motion sickness.
- Interaction with muscarinic, cholinergic and adrenergic receptors (low specificity) - Produce strong sedative effects |
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Histamine: H1 Antagonists, 1st Gen: Examples
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Hydroxyzine (Vistaril)
Cyclizine (Marezene) Diphenhydramine (Benadryl) Dimenhydrinate (Dramamine) Clemastine (Tavist) Carbinoxamine (Histex) Promethazine (Phenergan) Azelastine (Optiva) Meclizine (Antivert) |
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Histamine: H1 Antagonists, 1st Gen: Hydroxyzine
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Hydroxyzine is a long-acting drug that is widely used for skin allergies, also used as a mild anxiolytic
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Histamine: H1 Antagonists, 1st Gen:
Cyclizine |
Cyclizine and meclizine are indicated for motion sickness.
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Histamine: H1 Antagonists, 1st Gen:
Promethazine |
Promethazine indicated for allergic reactions and prophylaxis and treatment of motion sickness & postoperative pain (adjunct to analgesics)
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Histamine: H1 Antagonists, 1st Gen:
Azelastine |
- Inhibits release of histamine and other mediators and intranasally, reduces hyper-reactivity of the airways and increase the motility of bronchial cilia.
- Azelastine may be administered as a nasal spray and ophthalmic agent. - Metabolized to desmethylazelastine (active metabolite) - Commonly used as a nasal spray and has an active metabolite |
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Histamine H1 Antagonists:
Adverse Effects
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- Sedation.
- GI distress - Nausea - Vomiting - Extrapyramidal reactions. |
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Histamine H1 Antagonists:
Second-Generation
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- Far less lipid soluble than the first generation
- Almost free of sedation and autonomic effects - Developed for use in chronic conditions - Most are extensively metabolized in the liver - Half-life of 12-24 hours |
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Histamine H1 Antagonists:
Second-Generation Examples
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- Fexofenadine (Allegra)
- Loratadine (Claritin) - Cetrizine (Zyrtec) |
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Histamine H1 Antagonists:
Second-Generation Indications
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- Allergic Reactions (allergic rhinitis, urticaria, dermatitis, hay fever)
- Motion Sickness and Vestibular Disturbances - Nausea and Vomiting - Sedation |
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Histamine H1 Antagonists: receptor diagram
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Histamine H1 Antagonists:
Interactions
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- Potentiation of effects of CNS depressants and alcohol
- Contraindicated with monoamine oxidase inhibitors. |
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Histamine H2 Antagonists: 4 on the market
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Classification and prototype:
Four H2 receptor blocking agents are currently available on the market: - Cimetidine (Tagamet) - Ranitidine (Zantac®) - Famotidine (Pepcid®), - Nizatidine (Axid®) |
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Histamine H2 Antagonists:
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- Structurally different from the H1 receptor blocking agents
- Typical half-life of 1-3 hours - Relatively nontoxic - Can be given in large doses - Extend the duration of action to 12-24 hours via multiple dosing |
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Histamine H2 Antagonists: MOA
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- Produce a surmountable pharmacologic blockade of histamine H2 receptors
- Relatively selective and have no actions on H1 receptors or autonomic receptors |
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Histamine H2 Antagonists:
Clinical Uses
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- Duodenal ulcer
- Gastric ulcer - Zollinger Ellison Syndrome - GERD - Reflux esophagitis |
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Histamine H2 Antagonists:
Clinical Uses
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Acid-peptic disorders:
- Specifically duodenal ulcer - Reduce symptoms, accelerate healing, and prevent recurrences - Acute ulcers are usually treated with 2 or more doses per day - Recurring ulcers can be treated with a bedtime dose - H2-blocking agents are also effective in accelerating the healing and prevention of recurrence of gastric peptic ulcers |
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Which one of the follwoing anti-histamines would be indicated for treatement of zollinger-ellison sydndrome?
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Nizatidine
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Histamine H2 Antagonists
Clinical Uses: Zollinger-Ellison syndrome
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Zollinger-Ellison syndrome:
- Characterized by acid hypersecretion, severe recurrent peptic ulceration, GI bleeding, and diarrhea - H2-blockers may be helpful but large doses are required. - Not as effective as proton pump inhibitors. (PPI’s) |
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Histamine H2 Antagonists:
Toxicity
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Cimetidine is an inhibitor of CYP-450 isoenzyme system in the liver (causes number of drug interactions)
- May also reduce hepatic blood flow - Also has significant antiandrogen effects (at high doses) |
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Drug Interactions (very important)
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