Jan 30, 2007

Jan. 30, 2007  Sample questions have been posted  When go into eCollege, go to week 4 o Lecture o Test o Self-check o 5 or 6 question to direct you on what you need to know for the test o The ones people notoriously forget to look over  each lecturer makes questions on their section  questions for Dr. Laic’s section are straight from the notes  Adverse Drug Effect Reporting website o From Health Canada o End of second lecture o Address opens up small powerpoint presentation  One test question will come from here o Log onto main page for health Canada o Table of contents on Left hand side o Click on ‘Reporting Adverse Effects’ o New page that comes up will be a huge text article on all things you can report o Within text will find ‘Medeffects’ and click on that o Will be within first or second paragraph o Table of contents on right hand side of screen o Click on ‘Learning Centre’  Questions o Were put on doc sharing, but will be changed to eSnips o Presented groups – please post your questions on eSnips and your softcopy of your presentations  Cases o Will be handed back prior to being handed out the second round of cases o Drugs acting on the Respiratory System (This section is not on the exam this Thursday)  Objectives o Brief review on how we will look at drugs for the rest of the year  The Respiratory System (not in note package) o Tracheobronchial tree bathes in mucus-containing fluid o Composed of : mucoproteins, proteins, fat, mucopolysaccharides o Function: warm/moisten inspired air and trap foreign airborne particles o Normal mucus secretions are 95% water (to maintain this need regular proper hydration and regular maintained humidity of inspired air) o Ca++ ions contribute to viscosity of sputum  Seen in cystic fibrosis o Yellow/green discolouration due to infection/stagnation of secretions

Infection can be part of copper, pulled out from immune system response  DNA strands from broken down phagocytes o Mucous produced from 3 sources  Goblet cells, bronchial glands, serous transudate from mucosal vasculature • See in bronchitis – a large about of goblet cells and a large amount of mucous o Drug therapy wants to stimulate a greater volume of secretion (more watery and less viscus) o If going to take a drug that increases the amount of secretion, need to stimulate the coughing reflex or mechanically suck out the mucous o Body makes approx 100ml/day  Classification of Drugs used for Respiratory Tract disorder o Anti-inflammatories  Glucocorticoids • Most commonly used o Bronchiodilators  Comparing the two drugs w.r.t their benefit and costs o Anti-tussives  Used to stop coughing  A lot of controversy with Dextromethorphan o Expectorants  Most common overthecounter medication is guaifenesin  Drugs affecting Respiratory Tract Fluid o Anti-mucokinetic agents  Atropine • Parasympathetolitic o Mucokinetic agents  Increase the amout of mucous we are producing and increasing the productiveness of cough  Guaifenesin • Works by stimulating the vagus nerve  Menthol/camphor/lemon oil - mostly used as steam/vapour inhalation  Ipechacuanha • Used with the vomiting centre • Used in gastric reflux via vagus nerve • Also controls cough reflex  KI • Water saline aerosols 

o Important regulatory agents to stimulate expectoration o Mucolytic agents  Help break down/liquefy the mucous  Given in aerosol form  Agents that help cleave disulfide bond  The Cough Reflex o Receptors detect changes in tension and sends afferent signals to cough centre (medulla) and cough centre sends efferent signals to diaphragm and respiratory muscles to produce cough o Anti-tussives anesthetize the afferent signal o Some directly work in the medulla  The 2 functions of coughing o Gets rid of accumulated fluid and accumulated cells from the airway o Clears and protects from microorganism proliferation o Abnormal cough  Suppress cough o Narcotic Drugs  Opiates most effective in suppressing cough  Out of the opiates, codeine is the most effective anti-tussive compared to its analgesic effect  The drugs are primarily pain killers  For it’s coughing anti-tussive effects need only a fraction of what’s given in analgesic effect  Less risk of side-effects less risk of toxicity  The exact mechanism isn’t known  Greatest risk factor • Respiratory depression • Tolerance and dependence  Dextromoethorphan • Considered to be the most widely used anti-tussive agent • Not necessarily the strongest o Non-Narcotic Drugs  Diphenhydramine • Benadryl • Anti-tussive b/c works directly with anti-cough centre  Guraifenesin • Used to make things less sticky • Sinusitis – b/c of protyolitic/disulfide bond cleaving capability  Rhinitis o Allergic rhinitis  Can be seasonal/non-seasonal

 Treated with some sort of anti-histamine or glucocorticoid o Viral rhinitis  From cold/flu  Have general malaise/discomfort  Drugs used to treat Rhinitis o Anti-histamines  Especially with allergic rhinitis  Diphenhydramine o Coriticosteroids  To treat inflammation in the nose  Most effect anti-inflammatory drugs for rhinitis  Can be given in burst therapy (high dosage for short amount of time) o Alpha-adrenergic agonists  Help decrease fluid loss from arterioles, so constrict them  Less fluid leaking out, less resistance in the area  Aerosol  Oral • Takes longer for action to happen and get longer action • If take orally risking systemic effects o Cromolyn  Can be used prophylactically before allergy season  Usually gluco-corticoids are first used, but if can’t handle them use Cromolyn o Ipratropium  Anticholenergic  Atrovent  Rhinorrhea aspect of rhinitis  Usually used for asthma  Asthma Development o Diagram  Top left corner IgE flags  Allergen comes in  Flaged by IgE  IgE sends signal to the cell for mediators to be released  Also releases lipid mediators • AA • Prostoglandins • And other immune system mediators o Diagram  Flow chart of AA production and prostaglandin production  Inflammation within the airway  Asthma Pathology

 Diagram o Hallmark for Asthma is Bronchial hyperactivity to endogenous and exogenous stimuli o Hyperactivity is amplified by the fact that there is chronic inflammation o Two big problems  Chronic inflammation  Hyperactivity  Diagram o Variety of different factors that can trigger degranulation and histamine release o B-adrenergic agents – will come up again o Even after mast cell degranulation person can still experience asthma attacks  Asthma Pathology o It’s shortness of breath happens two times  Early/immediate • Major concern is sudden immediate bronchoconstriction • Will respond very well to bronchodilators  Late/prolonged • Sustained bronchoconstriction • Not mediated by the same factors as early phase – cytokines • Increasing the hypereactivity of the bronchi • Starts with too many eosinophils  Asthma Facts o Expiratory wheeze – hallmark expiratory measure o Nearly 70% of asthma-related deaths occur at night  Parasympathetic mode  No one answer – controversial  Asthma Population o Treatment always same – improving quality of life by decreasing the amount of acute attacks  Drug treatment of Asthma (not in note package) o Short-term RELIEVERS (bronchodilators) o Long-Term CONTROLLERS (anti-inflammatory agents) o Studies indicate that asthmatic bronchospasm may be effectively treated by drugs with different modes of action, including:  Inhaled Drug Delivery Methods o Drug in solution  In very small, air-suspended solution o Inhaler  Problem • Aerosol propellant used is a CFC

o Increase risk of hypoxemia and arrhythmia o Now slowly being replaced with safer HFA (hydrofluoroalkanes) o Turbuhaler  Don’t need propellant  More complicated o Nebuliser  Can put other drugs in there, so used in hospitals  Anti-inflammatory drugs o Glucocorticoids  Serious drugs, so used for serious situations  Have greatest potential to cause adverse reactions  Limited to inhaled use  Beclomethasone, Budesomide, Fluticasone, Triamcinolone • Children can get spacer that will help propel deeper in respiratory tract, if stays in mouth get risk of thrush • Fluticasone – preferred for children b/c only needed bid • Used for preventing  Burst • Short duration, so no access to pituitary-adrenal o Mast Cell Stabilizers  Cromolyn Sodium • Autocoids – leukotrienes and prostaglandins • Used in prevention treatment of asthma • Pharmacokinetics o Oral bioavailability 1%  Means you have to take more to get a therapeutic level in the body  The amount of drug you take orally only 1% will get into blood to have an effect  Less drug is getting into the body to cause an effect • Considered nontoxic b/c of pharmacokinetic factors • Most of the side-effects are local – within respiratory tract o Leukotriene Inhibitors  Montelukasts • Used for mild to moderate treatment of asthma • Considered an alternate choice for treatment • Can take orally • Highly plasma protein bound o Watch out for interactions!!!! o Short half-life so studies haven’t showed any drug interactions

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Highly Metabolized by CYT P450 o Uh Oh!!! Watch out for interactions again!!!! Cascade effects in the body last longer, so only need one dose of the drug Don’t need as much of a dose of a bronchodilator

•  Bronchodilators o B2-Adrenergic Receptor Agonists  IV magnesium was used prior to this, to relax the smooth muscle  So for asthma patients, Mg may be something you want to consider  Sympathomimetic agents  Increase in cAMP • cAMP is the pivotal molecule here • causes a cascade of reactions • lowers intracellular Ca++ and muscle relaxes  Selective B2 Receptor Agonists • Select specifically to lower respiratory tract • So NO muscle relaxation in cardiac muscle (B1 receptor) • Used in acute attacks • Albuterol (Ventaline) • Salmeterol (Cerevent) o Muscarinic receptor antagonist  Ipratropium (adravent) • Stops Ca++ from pbeing released via IP3 system, and minimizes the amount of bronchoconstriction seen in late stage asthma • Primarily used in COPD o More effective than B2-agonists • Combination therapy o Not used as primary therapy but as cocktail of drugs o Theophylline  Falls into same category as caffeine  Similar reaction as you would see with coffee  Cascade of many different reactions and actions  More cAMP more relaxation of the muscle  Not as prominent in its therapeutic dosage as it should be • Only 10-20% of this inhibition occurs from the free drug in the body • What is the other 90% of the drug doing? o Produces block in adenosine receptors o Influences Ca++ receptors  PK • Phosphodiesterase enzyme inhibition

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Less used now Little first pass effect o Bioavailablity is higher • Has very narrow therapeutic index o Toxicity is very close to therapeutic index  Nausea, vomiting  Interactions • With some antibiotics  Naturopathic Considerations • Diet influenced theophylline as well • o Ipratropium o Theophylline