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Antitussive Med chem Lecture

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Lecture Notes for Med Chem/ CNS drugs/ B pharmacy of Purbanchal University, Nepal

Lecture Notes for Med Chem/ CNS drugs/ B pharmacy of Purbanchal University, Nepal

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  • The mechanism of ACE inhibitor-induced cough remains unresolved, but likely involves the protussive mediators bradykinin and substance P, agents that are degraded by ACE and therefore accumulate in the upper respiratory tract or lung when the enzyme is inhibited, and prostaglandins, the production of which may be stimulated by bradykinin.http://www.ncbi.nlm.nih.gov/pubmed/16428706Generation of NO, a proinflammatory substance on bronchial epithelial cells, is increased by ACEI. Iron, an inhibitor of NO synthase, thus decreases NO generation and hassuccessfully decreased ACEI-induced cough.http://hyper.ahajournals.org/content/38/2/166.short
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131005/
  • Gating mechanism and holon
  • 2nd generation Cause less drowsiness, dry mouth, and dry eyes
  • Transcript

    • 1. Antitussive (Drugs for Dry cough)
    • 2. • Cough is a normal physiological reflex action to irritation in larynx, trachea or in bronchi • It functions to expel irritating materials or mucus secretions from the respiratory tract • Cough is useful but frequent, severe and nonproductive cough can be irritating, painful or disturb sleep and needs to be controlled • Cough is not a disease but a symptom of underlying diseases
    • 3. larynx, trachea and bronchi
    • 4. Causes of different coughs Dry cough Productive cough •Bronchospasm. •Smoking, Tobacco •Allergies •Nasal Discharge •ACE inhibitors •GERD •Asthma •COPD •Exposure to dust, fumes, and chemicals •pneumonia, bronchitis, sinusitis, or tuberculosis •Dry cough needs to be suppressed •Productive cough needs to be promoted
    • 5. There are three types of antitussives • Centrally acting : Codiene, Noscapine, Dextromorphan • Antihistamines : Chlorpheniramine • Bronchodilators : Salbutamol
    • 6. Centrally acting (CNS acting) • The cough center of the brain located in the medulla oblongata area of the brain is a region of the brain which controls coughing. • Drugs that act this way need to have good penetration into the brain ie they are very liphophillic
    • 7. Codiene • It is a weak opiod agonist that shows activity by action on cough centre in the brain • Weak opiod activity limits its addiction potential but it has sedative effects and it is metabolized into morphine • Thus addicts take the OCT formulation of codeine in higher amounts to counter withdrawal effects of heroin • It’s safer alternative is pholcodeine since among it’s 7 different metabolites in human, morphine only occurs in trace amounts • http://www.ncbi.nlm.nih.gov/pubmed/2383296
    • 8. Noscapine • It is a benzylisoquinoline alkaloid from plants of the Papaveraceae family • It is found in street heroin as a contaminant • Noscapine is non-addictive and has a low side- effect incidence • This agent is primarily used for its antitussive effects • It is under study for possible cancer cure
    • 9. Dextromethorphan(DXM) • It is a morphinan type opiod anonist that has less sedation potential than codiene • DXM is also used recreationally. When exceeding label-specified maximum dosages, dextromethorphan acts as a dissociative hallucinogen • Primary metabolite is a NMDA receptor antagonist ie has a CNS depressant effect • Used in an OTC antitussive medication and
    • 10. Antihistamines • The antitussive activity of antihistamines are established from clinical trials (not enough research to establish MOA) • Following effect has been linked to antitussive action of Antihistamines but no research is conclusive enough – Sedative (study shows non-sedating Antihistamines are not antitussive) – Anticholinergic (no rank based action) – histamine H1 receptor binding strength (no rank based action) Ref: Older-Generation Antihistamines and Cough Due to Upper Airway Cough Syndrome (UACS): Efficacy and Mechanism. Lung 2008
    • 11. Chlorpheniramine • It is a first-generation alkylamine antihistamine used in the prevention of the symptoms of allergic conditions such as rhinitis and urticaria(skin rash). • Its sedative effects are relatively weak compared to other first-generation antihistamines.(this is an advantage) • Combined with opiods for OTC cough preparations • The antihistamine is helpful in cases where allergy is the reason for the cough
    • 12. Bronchodilators: Salbutamol • It is short-acting β2-adrenergic receptor agonist. • Constriction of bronchioles caused by allergen, asthma or exercise induced leads to cough • Salbutamol dilates bronchioles thus providing relief • It is absorbed through the lungs and administered by an inhaler. • (R)/Levo-salbutamol has a 100-fold greater binding affinity than (S)/Dextro-salbutamol for the β2-adrenergic receptor.
    • 13. THANK YOU
    • 14. Spot the difference! Target site- lungs Targetsite - Brain Look at the two molecules. Based on the differences in their site of action and in structure what GENERAL difference in Their design can you conclude?
    • 15. Review of Antitussives Topics covered • Current and future of centrally acting antitussives Ref: Respir Physiol Neurobiol. 2006 July 28; 152(3): 349–355 • Antitussive effect of 2nd generation antihistamines Ref: Br J Clin Pharmacol, 2003, 56, 501–504
    • 16. Current and future of centrally acting antitussives • The efficacy of codeine and dextromethorphan in humans has recently been questioned • They are less effective on cough induced by upper airway disorders than conditions involving the lower airways in humans. • The reasons are not clear.
    • 17. • Codeine was effective against cough in patients with lower airway disease (Sevelius and Colmore, 1966; Sevelius et al., 1971) • Codeine was found to be ineffective in patients with cough due to upper airway disorders (Aylward et al., 1984)
    • 18. Is there no future scope for centrally acting antitussives??? • peripherally acting antitussives have worked in animal models and are proposed as a safer alternative • there is no rationale that would support greater efficacy i those that act peripherally acting ones
    • 19. New directions i) There is an urge to cough. The more we cough, more we want to do it again ii) Also we can sometimes voluntarily block cough These two observation indicate novel mechanism of cough control that are different from the old cough centre theory Thus Drugs designed to act on these novel mechanism are hypothized to be better centrally acting antitussives
    • 20. 2nd generation Antihistamines • First-generation antihistamines block both histaminic and muscarinic receptors as well as passing the blood-brain barrier. • Second-generation antihistamines mainly block histaminic receptors and do not pass the blood-brain barrier.
    • 21. 2nd gen antihistamines are useless in cough • Fexofenadine demonstrated no antitussive activity against capsaicin-induced cough in 12 healthy volunteers and 12 patients with Upper respiratory tract infection.
    • 22. 2nd gen antihistamines are useless in stopping sneezing Loratadine, failed to suppress sneezing in rhinovirus induced cold in 66 adults Ref: Clin Infect Dis., 2001, 33 (9), 1483-1488