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asthma/gout
UVa med pharmacology block 2
| Question | Answer |
|---|---|
| Colchicine | Anit-inflamm - binds tubulin, inhibs polymerization/MT function - decr granulocyte migration, decr neutrophil exocytosis pain relief from gout attack T1/2 long in tissue >1week excr liver. Side fx narrow window, GI, BM, vascular fx, myopathy, CNS para |
| Allopurinol | xanthine oxidase inhib - decr uric acid synthesis gout attack t1/2 2-3hrs met'd b XO sidefx: can precipitate gout attacks |
| Alloxanthine | active metabolite of allopurinol non competitive inhib of XO T1/2 18-20hrs excr kidney sidefx: urosouric drugs incr alloxanthine elimination |
| Probenecid | Uricosuric agent incr uric acid excretion no anti-inflamm action sidefx: usually well tolerated |
| Sulfinpyrazone | Uricosuric agent incr UA excretion oral admin t1/2 4hrs excr kidney sidefx: irritates GI mucosa, decr hematopoiesis, decr platelet function |
| Albuterol | SHORT-acting Selective β2 agonist, incr cAMP & K+ conducatnace->membrane hyperpol muscle relaxation, decr mast cell degran, decr TNF release T1/2 30mins-several hours. sidefx beta activation in other tissues |
| Metaproteronol | SHORT-acting Selective β2 agonist, incr cAMP & K+ conducatnace->membrane hyperpol muscle relaxation, decr mast cell degran, decr TNF release T1/2 30mins-several hours. sidefx beta activation in other tissues |
| Pirbuterol | SHORT-acting Selective β2 agonist, incr cAMP & K+ conducatnace->membrane hyperpol muscle relaxation, decr mast cell degran, decr TNF release T1/2 30mins-several hours. sidefx beta activation in other tissues |
| Terbutaline | SHORT-acting Selective β2 agonist, incr cAMP & K+ conducatnace->membrane hyperpol muscle relaxation, decr mast cell degran, decr TNF release T1/2 30mins-several hours. sidefx beta activation in other tissues |
| Salmeterol | LONG-acting β2 agonist prevention of nightime attacks (not widely used)incr cAMP & K+ conducatnace->membrane hyperpol muscle relaxation, decr mast cell degran, decr TNF release T1/2 12hrs slow onset. sidefx beta activation in other tissues |
| Ephedrine | mixed acting a/b agonist found in OTC preps not widely used clinically Sidefx: CNS effects |
| Cromolyn sodium | Mast cell stabilizer prophylaxis prevents asthma attacks, inhibs mast cell degran slow onset of action (2-4wks) not for acute attacks sidefx cough, dry mouth, wheezing |
| Nedocromil sodium | Mast cell stabilizer prophylaxis prevents asthma attacks, inhibs mast cell degran slow onset of action (2-4wks) not for acute attacks sidefx cough, dry mouth, wheezing |
| Beclomethasone | glucocorticoid - anti-inflamm agent prophylaxis asthma tx, incr lipocortin synth decr PGs, LTs, Cox, decr immune cell activation max improvement after several wks tx |
| Fluticasone | glucocorticoid - anti-inflamm agent prophylaxis asthma tx, incr lipocortin synth decr PGs, LTs, Cox, decr immune cell activation max improvement after several wks tx |
| Flunisolide | glucocorticoid - anti-inflamm agent prophylaxis asthma tx, incr lipocortin synth decr PGs, LTs, Cox, decr immune cell activation max improvement after several wks tx |
| Prednisone | glucocorticoid - anti-inflamm agent severe exacerbation & asthma refractory to other tx, incr lipocortin synth decr PGs, LTs, Cox, decr immune cell activation max improvement after several wks tx sidefx: severe w/oral admin |
| Zileuton | LT synthesis inhib, inhibs 5-lipoxy antigen/exercise induced bronchospasm, relaxes airway T1/2 2.5hrs sidefx: decr warfarin/theophylline clearence |
| Montelukast | selective LT receptor atagonist (LTRA) antag of LTC4/D4 at cys-LT1 receptor maintenance asthma tx T1/2 3-5hrs excr bile sidefx: rare eosinophilia/vasculitis |
| Zafirlukast | selective LT receptor atagonist (LTRA) antag of LTC4/D4 at cys-LT1 receptor maintenance asthma tx T1/2 8-16hrs excr bile sidefx: rare eosinophilia/vasculitis |
| Theophylline | non-selective PDE inhibitor adenosine receptor antag 2nd line tx w/steroids met'd liver CYP450 sidefx: CNS fx, CV (ino/chromo), weak diuretic, incr muscle contraction |
| Aminophylline | Theophyllin complex non-selective PDE inhibitor adenosine receptor antag 2nd line tx w/steroids met'd liver CYP450 sidefx: CNS fx, CV (ino/chromo), weak diuretic, incr muscle contraction |
| Ipatropium bromoide | non-selective musc receptor antag decr SM contraction, mucus secretion (M3 effects) T1/2 2hrs, max effect @30mins No CNS fx |
| Omalizumab | recomb humanized IgG1k monoclonal IgE Ab - asthma tx inhibs IgE binding to FceRI (IgE receptor), SC admin T1/2 approx 26days sidefx: may interfere w/parasite immunity, cancer immune responses |
| What are the two main methods of decreasing Plasma Uric Acid in Gout patients? | - Inhibit synthesis of Uric Acid - Increase Excretion of Uric Acid |
| What are the theraputic objectives in treating Gout? | - Reduce Pain and Inflammation in Acute attack - Prevent future attacks (Decrease Plasma Uric Acid) |
| What are side effects of Colchicine? | - Nausea, Vomiting, Diarrhea (All due to inhibition of Mitosis. Affects rapidly dividing GI cells). - Bone Marrow Suppression (Inhibition of Mitosis) Rare, Dangerous side effects: - Ascending CNS Paralysis - Respiratory Depression |
| What are the NSAIDs of choice to treat Gout? Why? | Naproxen Indomethacin They do not block excretion of Uric Acid or effects of Uricosuric drugs. |
| What is the pathogenesis of Gout? | 1. Elevated Plasma Uric Acid 2. Precipitation of Uric Acid/Sodium Urate Crystals in Joints/Tissues 3. Crystals Phagocytosed by Leukocytes + more Phagocytes 4. Inflammation + Toxins in Synovial Fluid. |
| What agents are used to fight the Pain/Inflammation of Gout? | NSAIDs Colchicine |
| How effective is Colchicine? | Provides dramatic pain relief in Acute Gout attack. However, it has a narrow theraputic window, and is a 2nd line therapy. |
| How do Probenecid and Sulfinpyrazone increase Uric Acid excretion? | They block secretion (counter-intuitive), but they also block Reabsorption. The net effect is increased elimination. |
| What is the drug of choice for inhibiting Uric Acid Synthesis? | Allopurinol |
| What agents are used to increase Uric Acid excretion in Gout? | Uricosuric Agents: - Probenecid - Sulfinpyrazone |
| What is the use for Probenecid and Sulfinpyrzaone in Gout? | They increase Uric Acid excretion |
| What is the major drug interaction between Allopurinol and Probenecid? | Allopurinol delays the elimination of Probenecid. |
| What are side effects of Uricosuric agents? | Probenecid is well tolerated. Sulfinpyrazone can irritate Gastric Mucosa, and depress Hematopoiesis/Platelet function. |
| How does Allopurinol decrease Uric Acid synthesis? | Inhibition of Xanthine Oxidase *Uric Acid is end product of Purine Metabolism. Xanthine Oxidase catalyzes reaction of Hypoxanthine --> Xanthine --> Uric Acid. |
| What are the side effects of using Allopurinol? | Generally well-tolerated. However, it can precipitate a gout attack for unknown reasons. |
| How does colchicine act as an Anti-Inflammatory agent in Gout? | Decreases migration of Granulocytes into inflamed joints Decreases exocytosis of urate-ladened Neutrophils *Mechanism is by inhibition of Microtubule-mediated processes (Cytokinesis, Exocytosis, Mitosis) |
| What are the side effects of using Chromolyn and Nedocromil Sodium?00 | Almost no systemic effects. May cause Cough, Dry mouth, Wheezing (none serious, or frequent). |
| What are side effects of oral Glucocorticoids in treatment of Asthma? | - Mood disturbance - Increased Appetite - Insulin Resistance - Immune Suppression - HPA axis suppression - Growth Retardation in children |
| Why are Muscarinic Antagonists limited in their effectiveness in treating Asthma? | They only treat Ach-mediated contraction. Thus, Histamine, PGD2, LTC4, LTD4 are left untouched. |
| Why is Ipratropium Bromide used over other Muscarinic Antagonists in the treatment of Asthma? | It's structure greatly decreases its access to the CNS. Very few side effects. |
| What is the preferred class of drug for reversing Bronchial Constriction in an acute Asthma attack? | Beta-2 Adrenergic Agonist. |
| Why aren't Adrenergic Agonists such as Epinephrine, Isoproterenol, and Ephedrine used more for Asthma treatment? | They are Mixed-Acting. The most beneficial effects for asthma comes from the B2 receptor. Ephedrine is still found in some OTC Asthma preparations. |
| What is the mechanism of action for Theophylline? | Inhibition of Adenosine Receptors (A1). A1 is linked to Gi, thus blocking A1 receptors may increase cAMP --> Relax Bronchial Smooth muscle. *Mechanism unproven |
| How effective are drugs that antagonize LTC4 and LTD4 and the cys-LT1 receptor (responsible for bronchioconstrictor effects of Leukotrienes)? | They are effective at reducing Late Phase inflammatory response and Hyperresponsivity, but LESS effective than Glucocorticoids. |
| What is the most commonly used Muscarinic Antagonist in Asthma treatment? | Ipratropium Bromide |
| What is the theraputic regimen for "Severe" Asthma? | High dose Corticosteroid, long-acting B2 (Salmeterol), AND Leukotriene Modifier. |
| What is the theraputic regimen for "Mild Intermittent" Asthma? | B2 Agonist by MDI (Albuterol, Metaproterenol, Terbutaline) |
| How do Chromolyn Sodium, and Nedocromil Sodium work to treat Asthma? | Inhibit Mast Cell degranulation. They are used prophylactically to prevent attacks. *They do NOT produce bronchial dilation, and are of no use in reversing an attack that is already occurring |
| Why would a Muscarinic Antagonist be helpful in treating Asthma? | - Promote relaxation (not as effective as B2 Agonist) - Synergistic with B2 agonist in acute attacks. - Particularly effective in psychogenic exacerbations. |
| How do Glucocorticoids help in treatment of Asthma? | - Decrease inflammation responsible for Hypersensitivity (Unclear Mech) Possible Mechs: - Inhibition of Phospholipase A2 (Reduces synthesis of Leukotrienes --> Less Spasm, Less Leukocyte attraction. Reduces synthesis of PGE2, PGI2 --> Less Vasodilation |
| Why is the B2 Agonist Salmeterol not used in an acute attack? | Onset is too slow, but could be used to prevent nighttime attacks. |
| How long does it take to see clnical effects of Chromolyn and Nedocromil Sodium? | 2-4 weeks. |
| Why are Nebulizers or Metered-Dose Inhalers used for drug delivery in Asthma? | Delivers dose to Respiratory Tree/Lungs, and limits systemic side effects. Oral doses reserved for severe side effects, or drugs unable to be delivered by the above methods. |
| What is the theraputic use of Theophylline in Asthma? How does it mediate its effects? | It is used as a last resort in Asthma. - It produces Bronchial Dilation (not as effective as B2 agonist) - High doses inhibits Mast Cell degranulation. Formerly the drug of choice, but it has a narrow theraputic window. |
| Why are Chromolyn and Nedocromil Sodium used before Glucocorticoids in prevention of Asthma? | They have less side effects, especially in children. |
| Why would Inhibition of the Lipoxygenase pathway help Asthma? | Prevents formation of Leukotrienes, which are potent bronchioconstrictors, and LTB4 is a chemoattractant. |
| What is unique about the drug Omalizumab (Xolair)? | It is an IgG monoclonal antibody that selectively binds IgE. This inhibits IgE from binding to Mast Cells and Basophils. |
| What are the side effects of Theophylline? | Stimulates CNS --> Mild arousal, increased alertness, convulsions. Tremors/Nervousness - Increased Inotropic/Chronotropic effects by blockade of A1 receptors - Weak diuretic - Increase Skeletal Muscle contraction. other drugs affect metab |
| What are the side effects of using B-2 Agonists in Asthma? | Systemic effects are usually minimal when inhaled. Regular use --> Tachyphylaxis (Decreasing response to drug) If Oral: Tachycardia Decreased TPR |
| What is the theraputic regimen for "Mild Persistent" Asthma? | Cromolyn or Nedocromil If ineffective, Corticosteroid. B2 Agonist for acute attack. |
| How do Beta-2 Agonists exert their effect in Asthma? | Bind B2 receptor on Smooth Muscle --> Increase cAMP --> Muscle Relaxation. Increased cAMP in Mast Cells also inhibits degranulation. |
| What is the effectiveness of Omalizumab (Xolair)? | The effectiveness is unclear. It could have side effects, as IgE is natural defense against parasites. IgE also plays important role in recognition of cancer, thus blocking IgE might have unforseen problems. |
| What is the theraputic regimen for "Moderate Persistent" Asthma? | Corticosteroid, sometimes with long acting B2 agonist (Salmeterol) OR a Leukotriene modifier. Last resort: Theophylline |
| In the Early Phase of an Asthma attack, what molecules are released by Mast Cells? | Histamine LTB4 LTC4 LTD4 PAF (Platelet Activating Factor). *These promote Bronchioconstriction/Recruitment of Leukocytes. |
| What are the side effects of Zileuton (Lipoxygenase pathway inhibitor)? | Almost none. Can decrease clearance of Warfarin and Theophylline. |
| What molecules are usually acting on the Late Phase of an Asthma attack? | "Spasmogens" Activated T-Cells (Release Cytokines) Eosinophils (Release proteins that damage Epithelium) Neutrophils *There is Vasodilation, Edema, Mucus. Also, airway remodeling due to collagen deposition into basement membrane. |
| Why is Omalizumab (Xolair) still in limited use? | It is VERY expensive (~$1000/month) |
Created by:
sam.mrosenfeld
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