Medicines for Cough and Cold: PDF Lecture by Gavin Dawe

MD1140 2024-2025 Medicines for Cough and Cold Antihistamines, mucoregulators, mast cell stabilisers, decongestants, antitussives, expectorants & mucoactive agents A/Prof Gavin S. Dawe, Dept. of Pharmacology [email protected]  Aims To intro...

MD1140 2024-2025 Medicines for Cough and Cold Antihistamines, mucoregulators, mast cell stabilisers, decongestants, antitussives, expectorants & mucoactive agents A/Prof Gavin S. Dawe, Dept. of Pharmacology [email protected]  Aims To introduce the mechanisms of action and adverse effects of some important cough & cold medications. Lecture at a Glance  Do not use antibiotics for viral common cold symptoms. Does not help and increases risk of antibiotic resistance. e.g., clearing foreign material from airways < 6 Active < 6 metabolite Acetylcysteine < 2 Efficacy and Cautions: Cysteine derivatives Moderate evidence of efficacy for symptoms of common cold in adult (UpToDate) Caution: CYP2D6 ultra-rapid metabolisers Codeine Potent antitussive but Caution/not recommended for children < 18 potential for addiction less than N years old (MIMS) Narcotic Analgesics are not < 12 covered in this lecture Most potent non- Dextromethorphan opioid antitussive Cholinergic antagonism: dry mouth, urinary < 12 Caution in elderly (MIMS) < 18 retention, sinus tachycardia Both antihistamine α-adrenergic antagonism: hypotension, dizziness, Diphenhydramine and antitussive reflex tachycardia COX 5-HT receptor antagonism:  appetite inhibitors CNS Frequently in oral crosses BBB cough & cold medicine Paracetamol and NSAIDs are formulations not covered in this lecture H1 antihistamine in CNS: sedation, impaired cognitive & psychomotor, increased appetite New/Third-generation Cetirizine < 2 Loratadine Metabolite (descarboethoxyloratidine) Fexofenadine nasal & throat irritation, dry mouth, cough, unpleasant/bitter taste < 2 dry mouth, urinary retention in elderly, unpleasant taste < 12 “Rose water” odour Typical route: < 4 oral capsule/tablet Phenylephrine oral soluble granules/tablet hypertension, < 12 oral syrup intranasal tachycardia Frequently in oral inhalation (nebulized) restlessness, tremors, Pseudoephedrine cough & cold medicine inhalation formulations irritability, anxiety & insomnia  Learning Objectives To be able to: Explain the mechanisms of action and adverse effects of commonly used – Antihistamines – Antitussives – Mucoregulators – Expectorants – Mast cell stabilisers – Mucoactive agents – Decongestants Discuss which of these drugs is appropriate for – Cough versus rhinorrhoea/nasal congestion – Productive cough versus non-productive cough Discuss the cautions over use of cough and cold medications in – Paediatric patients – Geriatric patients  Common Cold Upper Respiratory Tract Infection (URTI) by viruses like rhinovirus, coronavirus (e.g., types 229E, NL63, OC43, and HKU1) and respiratory syncytial virus Runny nose / Sneezing Sore throat Headache Fever Intranasal ipratropium Analgesic Analgesic Antipyretic Intranasal/inhaled cromoglicic acid Paracetamol or NSAIDs (e.g., ibuprofen) H1-Antihistamines Refer to Antihistamines & NSAIDs lectures Intranasal corticosteroid Cough Blocked nose Cough suppressants Nasal decongestants Expectorants Mucoactive agents  Common Cold Viral infection of upper respiratory tract Usually resolve within 3 to 7 days Cough and cold medications for symptomatic relief only Inflammation Excess mucus production Histamine Post-nasal Sneeze drip Nasal congestion Cough Sore Rhinorrhoea throat Adapted from Adams et al. Pharmacology for Nurses: A Pathophysiologic Approach  Cold Rhinorrhoea/ Nasal congestion/ Cough Post-nasal drip Cough not beneficial Cough beneficial e.g. deprive sleep or e.g. clear foreign Antihistamines Decongestants comfort matter or mucus More severe Non-productive Productive Do not (“dry”) (“wet”) medicate Mucoregulators / Mast cell stabilisers Antitussive Expectorant Mucoactive  Nasal Congestion https://www.wikiwand.com/en/Rhinitis https://www.dischem.co.za/articles/post/blocked-nose Nasal congestion is associated with:  sympathetic vasoconstriction of submucosal blood vessels  parasympathetic stimulation of mucus secretion  Mucoregulator: Ipratropium Mucoregulators: Used to control severe cold symptoms Decrease mucus hypersecretion from goblet cells and submucosal glands Mechanisms of Action: Short-acting muscarinic receptor antagonist (SAMA) Blocks inflammation-induced parasympathetic cholinergic receptor (M3) activation of submucosal glands/goblet cells ↓ stimulated mucus output and sputum volume DO NOT dry basal secretion DO NOT increase normal viscosity See also Cholinergics & Anti-cholinergics lecture Side Effects: Few side effects as little enters systemic circulation via intranasal route Unpleasant taste Dry mouth Urinary retention in the elderly  Mast Cell Stabiliser: Cromoglicic acid Uses: Intranasal or inhaled for severe cold symptoms Mechanisms of Action Cromoglicic acid (cromolyn) is a mast cell stabiliser Controls chloride (Cl-) channels to inhibit cellular activation ↓ mast cell degranulation induced by IgE-mediated FcεRI crosslinking ↓ secretion of inflammatory mediators from eosinophils, neutrophils and macrophages ↑ secretion of annexin A1 – Annexin A1 inhibits prostaglandin and leukotriene production Side Effects: Throat and nasal irritation, mouth dryness, cough Unpleasant/Bitter taste  Antihistamines Cholinergic antagonism: dry mouth, urinary retention, sinus tachycardia Both antihistamine and antitussive α-adrenergic antagonism: hypotension, dizziness, reflex tachycardia 5-HT receptor antagonism:  appetite Frequently in oral cough & crosses BBB cold medicine formulations Duration of action H1 antihistamine in CNS: 4 to 6 hours sedation, impaired cognitive & psychomotor, increased appetite Rhinorrhoea Post-nasal drip Nasal congestion Mast cell Less CNS penetration: Less Degranulation lipophilic and high affinity interaction with P‐glycoprotein efflux pump Urticaria (hives) Duration of action More selective for New/Third-generation 12 to 24 hours H1 histamine receptor Metabolite (descarboethoxyloratidine) See the Histamine and Antihistamines lecture Do NOT drink fruit juices from 4h before to 1-2h after dosing  Decongestants Sympathomimetic agents e.g., phenylephrine, oxymetazoline, naphazoline, pseudoephedrine, ephedrine Oral or intranasal See also Adrenergics & Antiadrenergics Mechanism of Action: Direct alpha adrenoceptor agonists Alpha-1 selective: Phenylephrine (oral or intranasal) Non-selective: Oxymetazoline (intranasal) / naphazoline (intranasal) Indirect increase in release of adrenaline/noradrenaline Pseudoephedrine (oral) / Ephedrine (intranasal) Vasoconstriction of nasal blood vessels See also Reduce inflammation and secretion of mucus Corticosteroids lectures Nasal glucocorticoid e.g., fluticasone, mometasone Intranasal Some people report that intranasal fluticasone has a “rose water” Mechanism of Action: odour that they cannot tolerate Anti-inflammatory ↓ inflammation → ↓ congestion & mucus secretions  Decongestants – Adverse Effects Sympathomimetic Agents Rebound congestion Occurs with prolonged (> few days) use of topical intranasal decongestants CNS stimulation More likely with oral decongestants Restlessness, tremors, irritability, anxiety and insomnia Cardiovascular More likely with oral decongestants Hypertension due to vasoconstriction Tachycardia (indirect sympathomimetics e.g., pseudoephedrine) Glucocorticoids Systemic side effects limited by intranasal delivery Local mucosal dryness and irritation  Administration of Nasal Drops and Sprays Nasal spray and drop formulations of Sympathomimetics Phenylephrine Oxymetazoline, naphazoline Ephedrine Glucocorticoids e.g., fluticasone, mometasone IMPORTANT: Educate patients on the correct procedure for nasal administration to avoid accidental ingestion Antihistamine-Decongestant Combinations paracetamol paracetamol paracetamol paracetamol IMPORTANT: Avoid combining drugs in the same class: Know what over-the-counter cough and cold formulations your patient is using before prescribing. If prescribing cough and cold forumulations, know what drug classes they contain.  Cough Protussive stimuli Cigarette smoke Acid or alkaline Bradykinin Neurokinin PGE2 LTD4 Histamine TNF-α Substance P Calcitonin gene-related peptide (CGRP) Mechanical stress Chung KF (2008) Lancet 371:1364-1374 Heat or cold Cough: A defense reflex mechanism to clear the upper airways  Prevalence: 9-33% of the populationWorld market: > 4 billion per year  Acute cough (< 3 weeks) :: Sub-acute cough (3-8 weeks) :: Chronic cough (>8 weeks)  Causes: unknown, cigarette smoke, asthma/COPD/IPF, pollutants (PM10), URTI (common cold), GERD, rhinosinusitis, drug-induced (ACE inhibitor), and lung cancer  Management: elimination of precipitating factor (e.g. cigarette smoke) and treatment of underlying cause such as asthma, COPD, GERD, etc.  Cough Pathophysiology Peripheral Sensitization Central Sensitization Chung KF (2008) Lancet 371:1364-1374 NTS: Nucleus Tractus Solitarius; RAR: Rapid Adapting Receptor; SAR: Slow Adapting Receptor  Antitussives Opioid Antitussives Nonopioid Antitussives Codeine Dextromethorphan Diphenhydramine Most effective Less risk of addiction No risk of addiction Disadvantages Advantages antitussive Most effective non- opioid antitussive Potential for abuse Drowsiness, dizziness Sedation Sedation Gastrointestinal adverse Anticholinergic Respiratory effects adverse effects depression on Potential for abuse at overdose high doses  Opioid Antitussives Codeine Most effective cough suppressant Mechanism of Action: Typical Adult Dose of Codeine: Acts in CNS to suppress cough 15 to 30 mg every 3 to 4 times a day Adverse Effects: CNS – sedation Weak opioid but still has abuse potential at high dose Respiratory depression CAUTION: Should not occur at normal clinical doses CYP2D6 ultra- rapid metabolisers Risk on overdose Risk in patients with severe respiratory insufficiency Do not combine with other CNS depressants CAUTION over use in children. More sensitive to opioid-induced respiratory depression as respiratory centres and livers are not fully developed. Not recommended as antitussive < 18 years old. Addicted to cough mixture  Non-Opioid Antitussives Dextromethorphan Dextromethorphan is the Most effective non-opioid antitussive active ingredient in many over- Used for non-productive cough the-counter cough medicines Typical Adult Dose: Mechanism of Action: 10 to 30 mg every 4 to 8 hours Acts in CNS to suppress cough Not recommended < 4 years old Adverse Effects: Limited evidence for efficacy in cold CNS – drowsiness, dizziness, confusion, insomnia, excitement, nervousness Opiate but NOT an opioid. GIT – nausea, vomiting, stomach pain Multiple actions: nonselective serotonin reuptake inhibitor, Abuse potential at high dose sigma-1 receptor agonist & (at high-dose) NMDA (dissociative anaesthetic-like effect) receptor block Diphenhydramine Mechanism of Action: Antihistamine; Mechanism of antitussive action unknown Adverse Effects: Sedative, anticholinergic  Expectorants Dosage forms: Guaifenesin Oral solution or tablet Component in many cough mixture formulations Mechanism of action: Increases production of respiratory tract fluids to help liquefy and reduce viscosity of tenacious secretions Adverse Effects: Caution < 6 years old Gastrointestinal disturbance, nausea Not indicated < 2 years old Advise patients NOT for persistent cough associated with asthma or smoking Take adequate fluid to make secretions less viscous and protect renal function (nephrolithiasis reported on overdose)  Mucoactive Agents - Mucolytics Dosage forms: Acetylcysteine, carbocisteine Inhalation Effervescent tablets Smells and tastes Oral granules, syrups strongly of sulphur. Mechanism of action: Free sulfhydryl group opens disulphide bonds in mucoproteins Lowers mucous viscosity Adverse Effects: Bronchospasm Anaphylactoid reactions – rash, hypotension, dyspnea, wheezing Gastrointestinal disturbance (carbocisteine contraindicated in patients with active peptic ulcer) Caution: Elderly or debilitated patients with severe respiratory insufficiency Patients with asthma  Mucoactive Agents - Mucokinetics Bromhexine and its active metabolite ambroxol: Mucokinetic: promotes mucus clearance Increase ciliary beat frequency  adherence of mucus to cilia Stimulate surfactant production: surfactant is an anti-glue factor to prevent mucus from sticking to alveolar and bronchial walls Antioxidant as free radical scavenger Anti-inflammatory by decreasing cytokines Suppresses influenza virus multiplication Local anesthetic by blocking voltage-gated Na+ channel Potential Side Effects: Allergic reactions Cutaneous adverse effects Avoid in patients with history of asthma and peptic ulcer disease Caution < 6 years old Not indicated < 2 years old  Cough and Cold Medication Safe for Paediatric Use? CATEGORY UNDER 6 MONTHS 6 MONTHS TO 2 YEARS 2 YEARS AND ABOVE Promethazine Contraindicated Not recommended Use with caution Antihistamines Use only when benefits (e.g., chlorpheniramine, Not recommended have been assessed to Use with caution diphenhydramine) outweigh risks. Cough suppressants Use only when benefits (Codeine, Not recommended have been assessed to Use with caution dextromethorphan, outweigh risks. diphenhydramine) Cold and flu products Use only when benefits (Pseudoephedrine, Not recommended have been assessed to Use with caution ephedrine, guaifenesin, outweigh risks. phenylephrine)  Cough and Cold Medication Safe for Geriatric Use? CATEGORY CONSIDERATIONS Antihistamines Elderly more prone to sedation and confusion (e.g., promethazine, Anticholinergic effects can precipitate dementia chlorpheniramine, Contraindicated in narrow-angle glaucoma diphenhydramine) Decongestants (e.g., pseudoephedrine, Increased risk of hypertension and cardiovascular adverse events phenylephrine) Cough suppressant Not recommended. Elderly more susceptible to sedation and confusion (codeine) (opioid effects). Cough suppressant Not recommended. Elderly more susceptible to sedation and confusion (dextromethorphan) (dissociative anaesthetic-like effects). Elderly more prone to sedation and confusion Cough suppressant Anticholinergic effects can precipitate dementia (diphenhydramine) Contraindicated in narrow-angle glaucoma Expectorant Likely no significant increase in risk in elderly (Guaifenesin) Mucolytic Caution in elderly with severe respiratory insufficiency (Acetylcysteine)  Now you should be able to: Explain the mechanisms of action and adverse effects of commonly used – Antihistamines – Antitussives – Mucoregulators – Expectorants – Mast cell stabilisers – Mucoactive agents – Decongestants Discuss which of these drugs is appropriate for – Cough versus rhinorrhoea/nasal congestion – Productive cough versus non-productive cough Discuss the cautions over use of cough and cold medications in – Paediatric patients – Geriatric patients  MD1140 2024-2025 Medicines for Cough and Cold Antihistamines, mucoregulators, mast cell stabilisers, decongestants, antitussives, expectorants & mucoactive agents A/Prof Gavin S. Dawe, Dept. of Pharmacology [email protected]  Aims To discuss application of the mechanisms of action and adverse effects of some important cough & cold medications. Lecture at a Glance  Do not use antibiotics for viral common cold symptoms. Does not help and increases risk of antibiotic resistance. e.g., clearing foreign material from airways < 6 Active < 6 metabolite Acetylcysteine < 2 Efficacy and Cautions: Cysteine derivatives Moderate evidence of efficacy for symptoms of common cold in adult (UpToDate) Caution: CYP2D6 ultra-rapid metabolisers Codeine Potent antitussive but Caution/not recommended for children < 18 potential for addiction less than N years old (MIMS) Narcotic Analgesics are not < 12 covered in this lecture Most potent non- Dextromethorphan opioid antitussive Cholinergic antagonism: dry mouth, urinary < 12 Caution in elderly (MIMS) < 18 retention, sinus tachycardia Both antihistamine α-adrenergic antagonism: hypotension, dizziness, Diphenhydramine and antitussive reflex tachycardia COX 5-HT receptor antagonism:  appetite inhibitors CNS Frequently in oral crosses BBB cough & cold medicine Paracetamol and NSAIDs are formulations not covered in this lecture H1 antihistamine in CNS: sedation, impaired cognitive & psychomotor, increased appetite Medicines for New/Third-generation Cough and Cold Cetirizine < 2 Loratadine Metabolite (descarboethoxyloratidine) Fexofenadine nasal & throat irritation, dry mouth, cough, unpleasant/bitter taste < 2 dry mouth, urinary retention in elderly, unpleasant taste < 12 “Rose water” odour Typical route: < 4 oral capsule/tablet Phenylephrine oral soluble granules/tablet hypertension, < 12 oral syrup intranasal tachycardia Frequently in oral inhalation (nebulized) restlessness, tremors, Pseudoephedrine cough & cold medicine inhalation formulations irritability, anxiety & insomnia  Learning Objectives To be able to: Apply the mechanisms of action and adverse effects of commonly used antihistamines, mucoregulators, mast cell stabilisers, decongestants, antitussives, expectorants & mucoactive agents Evaluate which of these drugs is appropriate for cough versus cold and for productive cough versus non-productive cough Categorize the use of cough and cold medications in paediatric and geriatric patients What medicines do you expect your doctor to prescribe for you when you have a bad cough and cold? 6  If you have a common cold with cough and runny nose, what is the best way to cure the cold? 8  Common Cold Viral infection of upper respiratory tract Usually resolve within 3 to 7 days Cough and cold medications for symptomatic relief only Inflammation Excess mucus production Histamine Post-nasal Sneeze drip Nasal congestion Cough Sore Rhinorrhoea throat Adapted from Adams et al. A 20-year-old woman presented complaining of a dry cough that is preventing her from sleeping at night. After taking her history and performing a physical examination, her doctor suspects a cough caused by a common cold. Which of the following drugs would be MOST APPROPRIATE for this patient? 11 A 20-year-old woman presented complaining of a dry cough that is preventing her from sleeping at night. After taking her history and performing a physical examination, her doctor suspects a cough caused by a common cold. Rank the following drugs in order of their potency as antitussives (highest potency at the top to lowest potency at the bottom) 13 A 20-year-old woman presented complaining of a dry cough that is preventing her from sleeping at night. After taking her history and performing a physical examination, her doctor suspects a cough caused by a common cold. Rank the following drugs in order of their potential for addiction and abuse (highest at the top to lowest at the bottom) 15 A 34-year-old factory robotics engineer presents complaining of a runny nose (rhinorrhoea) and nasal congestion. He is unwilling to take MC as he is paid hourly for on-call maintenance and repairs. He is prescribed an oral antihistamine and an intranasal decongestant. Name ONE antihistamine that is APPROPRIATE for this patient? Why did you select this antihistamine? 17 A 34-year-old factory robotics engineer presents complaining of a runny nose (rhinorrhoea) and nasal congestion. He is unwilling to take MC as he is paid hourly for on-call maintenance and repairs. He is prescribed an oral antihistamine and an intranasal decongestant. Name ONE nasal decongestant that is APPROPRIATE for this patient? Briefly explain the clinical mechanisms of action of this nasal decongestant. 19 A 34-year-old factory robotics engineer presents complaining of a runny nose (rhinorrhoea) and nasal congestion. He is unwilling to take MC as he is paid hourly for on-call maintenance and repairs. He is prescribed an oral antihistamine and an intranasal decongestant. How would you advise this patient to administer the intranasal decongestant? 21 A mother administered cough and cold medicine that she had obtained for herself from the pharmacy to her 18-month-old daughter. The infant was initial highly excitable and then became drowsy with shallow breathing and blue lips. The mother rushed her daughter to the hospital emergency medicine department. 23 An 82-year-old man with mild cognitive impairment complains of a non-productive cough. The cough did not prevent him from sleeping last night. His GP, Dr Full Zeren, prescribes nothing. He then “doctor shops” to Dr Zero Zeren, who prescribes him antibiotics, an expectorant and a mucolytic. 25 An 82-year-old man with mild cognitive impairment complains of a non-productive cough. The cough did not prevent him from sleeping last night. His GP, Dr Full Zeren, prescribes nothing. He then “doctor shops” to Dr Zero Zeren, who prescribes him antibiotics, an expectorant and a mucolytic. 27  An 82-year-old man with mild cognitive impairment complains of a non-productive cough. He “doctor shops” to obtain a prescription for antibiotics, an expectorant (guaifenesin), and a mucolytic (acetylcysteine). Which of the following is the MOST LIKELY an adverse effect of overdose of guaifenesin? 29  An 82-year-old man with mild cognitive impairment complains of a non-productive cough. He “doctor shops” to obtain a prescription for antibiotics, an expectorant (guaifenesin), and a mucolytic (acetylcysteine). Which of the following is the MOST APPROPRIATE advice on taking guaifenesin? 31  An 82-year-old man with mild cognitive impairment complains of a non-productive cough. He “doctor shops” to obtain a prescription for antibiotics, an expectorant (guaifenesin), and a mucolytic (acetylcysteine). What advice would you give on taking acetylcysteine? 33 An 82-year-old man with mild cognitive impairment complains of a non-productive cough. He “doctor shops” to obtain a prescription for antibiotics, an expectorant (guaifenesin), and a mucolytic (acetylcysteine). He is not happy with the prescription provided by the doctor and “borrows” the following medicines from his son and daughter-in-law. 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56  Now you should be able to: Apply the mechanisms of action and adverse effects of commonly used antihistamines, mucoregulators, mast cell stabilisers, decongestants, antitussives, expectorants & mucoactive agents Evaluate which of these drugs is appropriate for cough versus cold and for productive cough versus non-productive cough Categorize the use of cough and cold medications in paediatric and geriatric patients  Competency-based spaced repetition Flashcards https://www.brainscape.com/p/36MB5-LH-D6LHJ PharmaNUS FAQs Answers to frequently asked questions and updates on pharmacology topics will be posted at: http://blog.nus.edu.sg/phcdgs Learning through creating your own questions and practicing through a peer-generated question bank https://peerwise.cs.auckland.ac.nz/at/?nus_sg MD1140 (2024-2025) Course ID: 27523 For your edutainment… Drugdle is a word game to help you actively recall and learn to spell the names of commonly prescribed drugs. https://www.drugdle.com/ PharMatch is a word card-matching game to you actively recall and learn the drug class definitions for drug name stems. https://pharmatch.app/ +Word is a crossword puzzle game to help you actively recall and learn commonly prescribed drugs. https://pharmxword.com/ PharMan is a hangman word game to help you actively recall and learn to spell commonly prescribed drugs. https://pharman.app/