common cold
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common cold
- 1. Pharmacological Treatment of Cough, Cold, & Flu Man B Paudyal
- 2. Common Cold Facts • On average, people have 3-12 colds per year • The common cold and related conditions annually result in: – 250 million restricted activity days – 30 million lost work or school days – one of the most expensive illnesses in the U.S. • More prevalent in children
- 3. Common Cold Etiology • Viruses – rhinoviruses (40-50% of cases) – influenza viruses – parainfluenza viruses – respiratory syncytial viruses – coronaviruses – adenoviruses – coxsackieviruses – enteric cytopathic human orphan (ECHO) viruses
- 4. Transmission of the Common Cold • Direct virus spread – touching infected object (inoculum of virus) – self-inoculation (touching own mucous membranes- eyes or nose, etc.) – commonly transmitted by children • Indirect droplet spread – sneezing and coughing – secondary method of transmission
- 5. What this means!!! • Most colds are transmitted via hand to mucosal tissue contact. • ….Cause is directly related to lack of washing hands!!!
- 6. Clinical Presentation: Common Cold • Sore or scratchy throat • Sneezing • Rhinorrhea (clear or purulent) • Nasal congestion • Fever may occur in children • Adults may experience malaise • Non-productive cough that may become productive as the cold progresses
- 7. Common Cold • Median duration of symptoms – 7-13 days • Seasonal variation – peak occurrence: • September (back to school surge) • October • early spring
- 8. Clinical Presentation: Influenza • Headache, sore throat, cough, runny nose, and sneezing • Non-productive cough • Disabling impact • Sudden fever, sweating, and chills • Malaise and mylagia – may last up to 2 weeks • Backache • Sensitivity to light
- 9. Common Cold and Influenza Symptom Common Cold Influenza Fever Rare Sudden Onset Temp 102-104° F Headache Rare Prominent Myalgia Slight Prominent Fatigue Mild Extreme Rhinitis Common Less Common Congestion Common Less Common Sneezing Common Less Common Sore Throat Common Less Common Cough Mild, Hacking Common, Often Severe Complications Sinusitis Bronchitis, Pneumonia
- 10. Common Cold Prevention and Treatment • Prevention: – patient education – hand washing • Treatment goal: – relieve symptoms – minimize adverse effects – improve patient quality of life
- 11. Natural Products
- 12. Zinc • Mechanism of action is unknown. – Hypothesized to inhibit viral shedding but unproven. • Clinical studies are limited and controversial. • Lozenges generally have 23 mg Zn and should be taken q2h while awake! • Adverse effects are not uncommon but are not life-threatening. Adverse Effect Incidence(%) Nausea 20.4 Mouth Irritation 24.5 Bad Taste 79.6 Dry mouth 10.2
- 13. Vitamin C • Anecdotal evidence only! • Correlational data suggest vitamin C may participate in immune function – Enhance WBC function and activity – Increases interferon levels – Improves antibody levels and responses – Increases secretion of thymic hormones
- 14. Echinacea • Chemical analysis has revealed numerous constituents with pharmacological activity. • Appears to be most effective in patients with compromised immune systems.
- 15. “Cough Medicine” Expectorants and Cough Suppressants
- 16. Expectorants • Irritation of the bronchioles produces an increase in mucoprotein content and a concomitant increase in mucus viscosity. • Most expectorants act by reducing the surface tension of secretions. • Remember the adage, water is good for what ails you? – Water is indeed the best expectorant available
- 17. Expectorants (continued) • Other expectorants include guiafenesin, although efficacy is not proven. • Herbal remedies used as expectorants include licorice, horehound, thyme, and eucalyptus. – The last three act by stimulating bronchial glands.
- 18. Cough Suppresants/Antitussives • First question should be, “Do we want to suppress this cough?!?” • Antitussives act at one of two sites – Centrally on the medullary cough center – Locally at the site of irritation • Local actions – Increase formation and secretion of saliva which produces more frequent swallowing, thereby diminishing the cough reflex – Some have local anesthetic properties on the lung and throat, which suppresses the cough
- 19. Dextromethorphan • Antitussive – d-isomer of a codeine analog – central acting agent – low addiction potential – no analgesic properties • Some drug interactions • May not work as well as opiates
- 20. Codeine • Use – narcotic analgesic – anti-tussive-direct central action in the medulla • High abuse potential – Schedule V • Consider drug interactions – CNS depressant
- 21. Codeine • Adverse Effects: – >10%: • Drowsiness, Constipation – 1-10: • CNS: dizziness, confusion, euphoria, malaise, headache, restlessness, CNS stimulation • Respiratory: SOB, dyspnea (use with caution in patients with respiratory disorders) • Skin: rash, urticaria • GI: xerostomia, anorexia, N/V • GU: decreased urination, ureteral spasm
- 22. Lozenges • Lozenges or compressed tablets: – 5-10 mg menthol • MOA: – local anesthetic effect on nerve receptors with the respiratory tract • Directions: – 2 YOA and older: Place one lozenge in the mouth and allow to dissolve slowly over several minutes Q1H PRN or AD
- 23. Camphor and Menthol • Found in Vicks VapoRub® and MenthoRub® – Rubbed on throat and/or chest or used in humidifiers • Menthol is also found in some cough syrups • Both menthol and camphor have local anesthetic properties on the throat and lungs
- 24. Combination Preparations • Many cough medicines (syrup, capsule, or tablet) contain compounds for relief of other symptoms. – Decongestants (esp pseudoephrine & PPA) – Antihistamines • Promethazine acts as antihistamine and as local anesthetic in throat thereby suppressing cough
- 25. Decongestants • Mechanism of action: – Activate α and β-adrenergic receptors. • Effect as decongestant: – directly stimulate alpha-adrenergic receptors of respiratory mucosa causing vasoconstriction – shrinks swollen mucosa and improves ventilation – directly stimulates beta-adrenergic receptors causing bronchial relaxation • Other effects (adverse effects) – Vasoconstriction – Tachycardia – Increase glycogenolysis and gluconeogenesis – CNS stimulation Can result in angina, HTN, and worsening of CV disease
- 26. Topical Decongestants • Available in nasal drops or sprays • Local action – minimizes systemic absorption • Available OTC • Side Effects: – rhinitis medicamentosa (rebound vasodilation) – burning, stinging, sneezing, nasal dryness • Limit use to 3-5 days
- 27. Nasal Saline or Drops • MOA: – soothes irritated nasal tissues – moisturizes nasal mucosa • Dosage Forms: – commercial: sprays, drops – homemade solution: 1 tsp. salt / 7 oz. warm water • Dosage: – 2-6 drops per nostril QID PRN nasal dryness or discomfort
- 28. Topical Decongestants Topical Agent: Duration of Action: Phenylephrine HCl Up to 4 hours Naphazoline HCl 4-6 hours Tetrahydralazine HCl 4-6 hours Oxymetazoline HCl Up to 12 hours Xylometazoline HCl Up to 12 hours
- 29. Systemic Decongestants • Include – Pseudoephedrine • duration is 4-6 hours – Phenylpropanolamine (PPA) • duration is 4-6 hours – Some natural products contain Ephedra (epinephrine) • duration is 6-8 hours • Effects on blood pressure, heart rate – PPA>Ephedrine>Pseudoephedrine
- 30. Systemic Decongestants • Compared to topical decongestants: – longer onset of action (no immediate relief) – longer duration of effect – no rebound vasodilation – no local irritation • Risks: – increases heart rate, contractility – can significantly increase BP – can worsen angina
- 31. Systemic Decongestants • Overview of Side Effects: – >10% • CV: tachycardia, palpitations, arrhythmias • CNS: nervousness, transient stimulation, insomnia, excitability, dizziness, drowsiness • neuromuscular: tremor – 1-10% • CNS: HA • GI: xerostomia, nausea • other: weakness, diaphoresis – <1% • respiratory: SOB, dyspnea
- 32. Antihistamines
- 33. Histamine Receptor Subtypes Receptor Subtype Distribution Postreceptor Mechanism H1 Smooth muscle, endothelium, brain ↑ IP3, DAG H2 Gastric mucosa, cardiac muscle, mast cells, brain ↑ cAMP H3 Pre-synaptic Inhibit histamine release
- 34. Histamine • Found in almost all tissues of the body – Stored in mast cells • Actions – Potent vasodilator of arterioles – Increases microvascular permeability – Bronchoconstriction – Contraction of GI smooth muscle – Increase gastric secretion • Triple response (AKA “wheal and flare” – Immediate development of red spot around injection site due to microvascular dilation. – Larger reddened area due to axon-mediated vasodilatory reflex response. – Appearance of a wheal due to increased capillary permeability.
- 35. Antihistamines • Alkylamines • Ethanolamines • Ethylenediamines • Phenothiazines • Piperidines • Piperazines • Second Generation Agents
- 36. Mechanism of Action • Bind to and inhibit histamine-induced activation of H1 receptors • Some agents appear to block the release of inflammatory mediators from mast cells and basophils (H2 action) – azatadine, terfenadine, cetirizine, and loratadine • Antagonize histamine actions ⇑ capillary permeability – “triple response” – itching – nasal, salivary, and lacrimal hypersecretion • Some are known to bind and inhibit muscarinic, alpha, and serotonergic receptors • Block sodium channels in excitable membranes – provide local anesthesia similar to lidocaine – diphenhydramine and promethazine are very potent
- 37. H1 Receptor Antagonists • Side effects – Sedation • Antimuscarinic effect: must cross BBB – Anticholinergic side effects (esp. ethanolamine & ethylenediamine subgroups) • dry mouth, urine retention, constipation – GI side effects • anorexia, nausea, vomiting, epigastric pain • some decrease N&V and motion sickness – Orthostatic hypotension (esp. phenothiazine subgroup) • binds to and inhibit alpha receptors • Drug interactions – cardiac drugs, CNS depressants, antibiotics
- 38. H-1 vs Ach Antagonism • Pharmacophore H-1 • Pharmacophore Ach • Bulky Groups Aromatic and Cycloalkyl • Amine=Tertiary • Bulky Groups Aromatic • Amine Tertiary or Quarternary Bulky Bulky H-Bond ChainC Amine Bulky Bulky ChainC Amine
- 40. H1 Receptor Antagonists- Role in Therapy • First line treatment – perennial and seasonal allergic rhinitis • Symptom control – allergic rhinitis – allergic conjunctivitis • Contraindications – BPH, bladder neck obstruction – narrow-angle glaucoma – acute asthma attacks – stenosing peptic ulcer, pyloroduodenal obstruction – neonates and newborn infants
- 41. H1 Receptor Antagonist Selection • Side Effects – sedation – anticholinergic side effects – GI side effects • Duration of action – dosing schedule – compliance • Risk of drug interactions • Costs • Other patient characteristics
- 42. Controlling Sedation with the H1 Antagonists • Slow dose titration – institute therapy using slow dosage titration • SR dosage forms – administer evening doses of long acting (QD) products or sustained release dosage forms of shorter acting products • Second generation – select a second generation relatively non-sedating product • Add a decongestant – increased CNS stimulation often offsets sedation • Chronic administration
- 43. H1 Receptor Antagonist Titration Schedule Start with a small dose QHS only and continue this dose for at least 3 days or until the patient has minimal AM sedation Add a small dose in the morning and continue this regimen for another 3 days Continue increasing the dose in this manner, adding to the HS dose alternately with the AM dose, until symptom control is achieved Do not D/C medication once symptoms improve; It is important to maintain the routine in order to avoid symptoms and sedation
- 45. First Generation H1 Antagonists • General Class Side Effects: – >10% • CNS: mild to moderate sedation • Respiratory: thickening of bronchial secretions – 1-10% • CNS: HA, fatigue, nervousness, dizziness • GI: ⇑ appetite, weight gain, nausea, diarrhea, GI pain, xerostomia • neuromuscular: arthralgia, weakness • respiratory: pharyngitis – <1% • hepatic: hepatitis • respiratory: bronchospasm
- 46. First Generation Antihistamine Comparison Drug Sedation Antichol Activity GI Alkylamine Class 1 ++ +++ - Ethanolamine Class 2 ++++ ++++ + Ethylenediamine Class 3 +++ + +++ Phenothiazine Class 4 ++++ ++++ - Piperazine Class +++ ++ - Piperidine Class +++ +++ - 1 Brompheniramine least sedating of class 2 Diphenhydramine most sedating of class 3 Pyrilamine least sedating of class 4 Promethazine most sedating of class
- 47. Alkylamines “-pheneramines” Anti- histamine Dosing Interval Anti-ACh Activiy Anti-H1 Acticity Sedation Brom- 4-6 +++ ++++ + Chlor- 4-6 +++ +++ + Dexchlor- 4-6 +++ ++++ + Tripolodine ++ ++ ++
- 48. Ethanolamines Anti-histamine D.I. (hr) Anti- ACh Activiy Anti- H1 Acticit y Anti- 5HT Activity Na+ Channel Blockade Sedation Carboxyamine 6-12 ++++ ++ -/+ -/+ ++ Clemastine 12 ++++ ++ + - +++ Diphenhydramine 6-8 ++++ ++ + +++ ++++ Dimehydrinate 4-8 +++ + ++ -/+ ++++ Doxylamine 1 +++ + ++ - ++++
- 49. Ethylenediamines Anti-histamine D.I. (hr) Anti- ACh Activiy Anti-H1 Acticity Sedation Pyrilamine 6-8 -/+ + + Tripelennamine 4-6 -/+ ++ ++
- 50. Phenothiazines • Several class indications: – antihistamine – antiemetic, motion sickness – sedation – neuroleptic • Antihistamine: – block H1 receptors • Antiemetic: – blocks postsynaptic mesolimbic DA receptors – partially blocks CTZ center – blocks acetylcholine receptors in the vestibular center
- 51. Phenothiazines • Antiemetic (continued) – halogenation of the R1 side chain of the phenothiazines • increases antiemetic activity and frequency of EPS side effects • decreases sedation and hypotension – thiethylperazine (Torecan® ) – prochlorperazine (Compazine ® ) • Other – alpha blockade • orthostatic hypotension
- 52. Phenothiazines • Caution in elderly (> 60 YOA): – most likely to develop side effects • hypotension, syncope, confusion, EPS side effects, agranulocytosis, photosensitivity, akathisia, and dystonia during phenothiazine therapy – increased risk with prolonged therapy
- 53. Piperidines Anti-histamine D.I. (hr) Anti-ACh Activiy Anti-H1 Acticity Anti-5HT Activity Sedation Azatidine 12 ++ ++ + ++ Cyproheptadine 8 ++ ++ ++ + Phenindamine 4-6 ++ ++ + +/-
- 54. Piperazines Anti-histamine D.I. (hr) Anti-ACh Activiy Anti-H1 Acticity Sedation Cyclizine 4-6 ++ ++ + Dimenhydrinate 4-6 +++ ++ ++++ Hydoxyzine 6-8 ++ +++ ++++ Meclizine 24 ++ ++ +
- 55. Second Generation Agents Peripherally Selective Non-Sedating
- 56. Second Generation Agents- Relatively Non-Sedating • Less lipophilic – decreased distribution across BBB into CNS – decreased centrally mediated sedation • Drug interactions – do not interact with ethanol or CNS depressants to intensify sedation or inebriation
- 57. Patient Selection for Second Generation Agents • Expensive • H1 treatment failure – poor response – non-compliance – significant side effects • Evaluate – drug interactions
- 58. Second Generation Antihistamine Comparison Drug Sedation Antichol Activity GI Terfenadine + + - Astemizole + + + Cetirizine + + + Fexofenadine + + ± Loratadine + + + Terfenadine and Astemizole removed from market
- 59. Azelastine • “Third” generation antihistamine • Products: – Astelin® • Mechanism of Action – antagonizes histamine at H1 receptors – may also have anti-inflammatory activity
- 60. Azelastine • Pharmacokinetics – 40% of dose reaches systemic circulation – metabolized in liver by CyP450 – active metabolite • Adverse Effects – 5-12% somnolence – 9-32% bitter taste – nasal burning, epistaxis, sore throat, dry mouth • Contraindicated in pregnancy
Editor's Notes
- Some rhinitis sufferers also have congestion. Topical and systemic decongestants are used to treat this symptom. Due to the high prevalence of concomitant rhinitis and congestion, many combination products with antihistamines and decongestants are marketed. There are two classes of decongestants that are used: phenylamines and imidazolines.
- As covered in previous lectures, the nasal tissue is erectile tissue and is highly innervated by the sympathetic and parasympathetic nervous sytems. Sympathetic stimulation of the tissue results in vasoconstriction, decreased blood flow, and corresponding decreases in tissue size and airway widening. Parasympathetic stimulation results in vasodilation, increased blood flow, tissue engorgement, and subsequent airway constriction. Mast cells which contain histamine and other immunological mediators line the upper airways and are involved in the immunological response to foreign antigens and in the regulation of nasal patency. Decongestants provide sympathetic stimulation and therefore, results in vasoconstriction of the vessels in the nose, decreased blood flow to the area, and a corresponding decrease in tissue size and thus an airway widening. They also directly stimulate beta cells on the airways resulting in bronchodilation and improved air flow. However, this also results in cardiac stimulation and increased heart rate, contractility, and blood pressure. This can be problematic in patients with cardiac disease.
- Topical nasal decongestants are available in nasal drops and sprays. The topical application minimizes systemic absorption. Side effects include rhinitis medicamentosa which is rebound vasodilation (once the agents are discontinued) associated with prolonged use of topical agents. This can be very serious. Due to the risk of rhinitis medicamentosa, the use of topical decongestant products should be limited to 3-5 days. Other side effects include burning, stinging, sneezing, and nasal dryness.
- Normal saline irrigation can soothe irritated nasal tissues and moisturize the nasal mucosa. Commercial saline nasal sprays are available, such as Afrin Saline Mist, Ayr Nasal Mist, and Ocean Nasal Spray. Two sprays in each nostril four times a day or as needed for nasal dryness is the typical dosage. For children under the age of six, the nasal drops may be easier to administer and the dosage is 2-6 drops per nostril QID PRN nasal dryness or discomfort. A homemade solution can be made using 1 teaspoon salt to every 7 ounces of warm water. A bulb syringe can be used to administer this solution to the nose.
- Again, note that phenylephrine has the shortest duration of action and oxymetazoline and xylometazoline have the longest.
- Systemic decongestants are often used for congestion symptoms. They have a delayed onset of action, but they also have a longer duration of effect with no risk of rebound vasodilation and local irritation. However, these agents do have an increased side effects profile, including an increased heart rate and contractility, increased BP, and worsened angina.
- As a class, the side effects of these agents include tachycardia, palpitations, arrhythmias, nervousness, transient stimulation, insomnia, excitability, dizziness, tremor, and possibly drowsiness (unpredictable). When used in combination products, these effects often offset the sedative side effects of the antihistamines.
- However, in many patients avoidance is not enough and we have to utilize pharmacotherapy in order to control their symptoms. First, let’s discuss control of rhinitis symptoms. The first line therapy for the control of rhinitis symptoms in both perennial and seasonal allergic rhinitis and conjunctivitis is the use of a systemic first generation antihistamines. There are several classes of antihistamines including alkylamines, ethanolamines, ethylenediamines, phenothiazines, piperidines, piperazines, “second generation”, and “third generation” agents. We will often discuss class effects of these agents, but it is important to know which medications are included in each of these classes. Also, many of these medications have multiple uses. For instance, promethazine (Phenergan) is an antihistamine which is often used clinically for the management of nausea and vomiting. When there is another use of these agents which you will often see in practice, I will try to point it out.
- All of the antihistamines have a common mechanism of action. They act by competitively antagonizing histamine by directly and reversibly blocking H1 receptors (binding to these receptors without activating them). One second generation agent, astemizole, has a very high affinity for H1 receptors and the effects of this medication are not readily reversible after discontinuation of the drug. As we discussed in the immunology lecture, there are three subtypes of histamine receptors- H1, H2, and H3, and the H1 receptors are located throughout the respiratory tract, on blood vessels, and on smooth muscle. When H1 receptors are stimulated it results in increased capillary permeability, smooth muscle contraction, pulmonary vasoconstriction, increased cGMP levels in cells, enhanced mucus secretion, leukocyte chemokinesis, and prostaglandin production in lungs. This results in the clinical presentation of rhinitis- nasal, salivary, and lacrimal hypersecretion; itching; and wheal-and-flare formation. By blocking the receptor, these physiological effects of histamine are prevented. In addition to this MOA, some agents such as azatadine, terfenadine, cetirizine, and loratadine also block the release of histamine from the mast cells and basophils and therefore, have two sites of action. However, the clinical significance of this observation has not been determined.
- Antihistamines are available in a number of dosage forms including oral (tablets, capsules, liquids), opthalmic, and nasal. Overall, the class side effects include sedation, anticholinergic side effects (dry mouth, urine retention, constipation, and cardiovascular effects), and gastrointestinal effects (anorexia, nausea, vomiting, and epigastric pain). These side effects vary between chemical classes and generations. There are several clinically significant drug interactions with these agents including cardiac drugs, CNS depressants, and antibiotics. In fact two of the second generation agents (terfenadine (Seldane) and astemizole (Hismanal)) have been withdrawn from the market because of the life threatening arrhythmias (torsade de pointes) associated with drug interactions between these agents and commonly prescribed medications such as erythromycin, azithromycin, ketoconazole, fluconazole, metronidazole, and cimetidine. These agents should be used with caution in the elderly because these patients have an increased sensitivity to anticholinergic side effects. Geriatric patients have an increased risk of side effects including dizziness, excessive sedation, syncope, toxic confusional states, and hypotension. These agents are contraindicated in narrow-angle glaucoma, bladder neck obstruction, and symptomatic prostatic hypertrophy due to anticholinergic side effects.
- If you evaluate the chemical structures of antihistamines, you will notice a lot of similarities in the structural activity relationship between anticholinergic and antihistamine compounds. This is why most first generation compounds possess significant anticholinergic effects, resulting in dry mouth, constipation, and some GI effects. Although the anticholinergic effects include antisecretory actions on the nasal mucousa, and this is beneficial in allergic rhinitis- the other effects are not. Look at the similarities in the general structures above. The amine in the case of antihistamines is tertiary and in the antimuscarinics tertiary or quarternary. The chain is of variable length in both antagonists and both have bulky groups at the branch point. In the ACh antagonists there is often a group that is capable of forming a hydrogen bond. This may or may not be present in the antihistamines.
- Systemic first generation antihistamines are first line agents for both perennial and seasonal allergic rhintis. They are used for symptom relief in allergic rhinitis and conjunctivitis. Due to the high anticholinergic side effects, they are contraindicated in patients with symptomatic BPH and bladder neck obstruction (these patients are already experiencing urinary retention and hesitancy which would be worsened by the anticholinergic side effects) and narrow angle glaucoma (which is also worsened by anticholinergic side effects which increases intraocular pressure by blocking aqueous humor outflow). They need to be used with caution in patients with asthma. For years there has been concern about antihistamines drying the mucus in asthma patients and resulting in mucus plugging. However, more recent studies have indicated that antihistamines can be beneficial in patients with an atopic etiology of their asthma. Antihistamines also need to be used with caution in patients with a stenosing peptic ulcer and in newborns and neonates.
- When choosing a first line antihistamine for a patient, a number of considerations must be included in the decision. First, the side effect profile of the agent should be examined. What is the incidence of sedation, anticholinergic side effects, and GI side effects associated with these agents? Does the patient have any concomitant conditions or life circumstances which would be effected by this side effect profile? For instance, a geriatric patient may be very sensitive to the sedative and anticholinergic side effects of the first generation agents. Also, a pharmacy student may not be able to tolerate the sedative side effects of these agents. You all might go to sleep while listening to my lecture, and we wouldn’t want that would we? Next, we need to screen the patient’s medication profile to identify any possible drug interactions that would influence our decision. Next, the duration of action of the agent should be considered. Agents with longer durations of action are dosed less frequently and this should improve compliance. For instance, if a patient has trouble remembering to take their medications, then an agent that is dosed less frequently would be a better choice. Finally, the costs and outcomes of the agents should be considered and the most cost-effective therapy should be selected.
- Sedation is a common side effect with the first generation antihistamines. These agents cross the blood brain barrier and inhibit histamine-mediated pathways that control wakefulness and sleep. There are a few methods to decrease the sedative side effects of the first generation antihistamines. The first method is to start low and go slow, by slowly titrating the dose of the medication and using chronic administration, not intermittent (PRN) dosing. It is always a good idea to initiate therapy on a day when the patient is not busy and will not be effected by the sedative side effects. For instance, start on a weekend or holiday, and then titrate the dose on the weekends until you get an effective dose for symptom control. Another alternative is to administer an evening dose of a long acting (long half life) or sustained release dosage form of a medication. With this method, the sedative side effects will be concentrated during the evening hours when these effects will be beneficial. The extended duration of action will provide daytime effect. A third option is to change to a second generation, relatively non-sedating agent. A fourth option is to add a decongestant to the regimen if the patient is experiencing nasal congestion. The decongestant’s side effect profile (nervousness, insomnia, agitation, excitability, etc.) may offset the sedative properties of the antihistamines
- This is an example of a titration schedule for first generation antihistamines designed to decrease the adverse effect profile of these agents. Start with a small dose QHS, and continue this dose for 3-7 days or until the patient is experiencing minimal morning sedation. Then add a small dose in the morning. Continue this regimen for another three days. Continue increasing this dose in this manner, adding to the QHS dose alternating with the AM dose until symptom control is achieved. It is very important that you counsel your patients not to D/C the medication once their symptoms improve. Chronic administration is necessary to avoid sedation (and to control symptoms).
- Now let’s discuss the first generation agents.
- All agents in this class have a high incidence of sedation, anticholinergic side effects (urinary retention, constipation, dry mouth, dry eyes, blurred vision, etc.), and GI side effects (nausea, diarrhea, and GI pain). These are the most common causes of non-compliance among these agents. The incidence of these side effects vary between chemical classes and agents, and I provide a summary table later in the lecture that demonstrates the class differences.
- This chart provides a comparative summary of the side effect profiles of the first generation antihistamines. The ethanolamines and the phenothiazines are the most sedating of all, with diphenhydramine (++++) and promethazine (++++) being the agents with the highest sedation in these classes. Remember that diphenhydramine, promethazine, and hydroxyzine are often used for sedation in the clinical setting. Brompheniramine (++) is the least sedating alkylamine, but all alkylamines are relatively low. Pyrilamine (++), methidilazine (++), and cyproheptadine(++) are agents in other classes with low sedative properties. The ethanolamines and phenothiazines also have very high anticholinergic side effects (++++), so they should be used with caution in elderly patients. Phenothiazines have the additional risks of EPS side effects and orhthostatic hypotension. The ethylenediamines have the lowest anticholinergic side effects (+), but hydroxyzine is pretty good too (++). The ethylenediamines have the highest GI side effects (+++).
- As a class, phenothiazines are used for a number of indications including antihistamine actions, antiemetic, motion sickness, sedation, and as a neuroleptic (which you will be learining more about with the next module- psychiatric module). The antihistamine action is due to the competitive blockade of histamine at H1 receptors which blocks the physiological effect of histamine (as discussed earlier). The antiemetic action is due to multiple actions including the blockade of postsynaptic mesolimbic dopamine receptors, partial blockade of the CTZ center, and the blockade of acetylcholine receptors in the vestibular center (anticholinergic activity).
- Halogenation of the R1 side chain of the phenothiazines results in increased antiemetic activity and increases the frequency of EPS side effects. This is because halogenation increases dopaminergic antagonism (as with the phenothiazines that are used as neuroleptics) and although dopamine is blocked in the mesolimbic regions- which results in the therapeutic effects of these agents as neuroleptics- it also blocks DA in the substantia nigra which upsets the normal DA to Ach balance and produces a drug induces parkinson’s syndrome (EPS side effects). DA is low and Ach is high. This imbalance is somewhat compensated because these agents also block Ach, and therefore, both are lowered. This means that EPS is not as bad as it would be otherwise, since the balance of DA and Ach is what is important. There is also a decreas in sedation and hypotension. Examples of agents with halogenation at this site, and therefore, good antiemetic activity include thiethylperazine (Torecan) and prochlorperazine (Compazine).
- Due to these effects, these agents should be used very cautiously in the elderly (patients over 60 YOA), because these patients are the most likely to develop side effects. Geriatric patients are more likely to experience hypotension, syncope, and EPS side effects during therapy and their risks increase with prolonged therapy.
- Now, let’s discuss the second generation agents which are relatively non-sedating when compared to the first generation agents.
- The second generation agents have decreased sedative properties due to modifications in the chemical structures of the compounds that make them less lipophilic, therefore, they do not cross the BBB and do not block histamine receptors in the CNS. Therefore, they have less centrally mediated CNS sedative side effects. A few references indicate that in addition to the decreased lipophilicity, that these agents also have a receptor selectivity for peripheral receptors when compared to central receptors. This has not been supported by further study, and the primary mechanism is the decreased lipophilicity. Second generation agents do not interact with ethanol or CNS depressants to intensify sedation or inebriation.
- The second generation agents are more expensive, and are not indicated for every patient. If patients have a poor response to an H1 agent, if they are non-compliant with an H1 agent (especially if this was due to side effects), or if they are not able to tolerate the side effects of H1 agents, then a second generation agent should be considered. There are more clinically relevant drug interactions with the second generation agents and the patients medication profile must be screened for possible drug interactions before initiating therapy.
- This table provides a comparative summary of the second generation agents. When compared to the first generation agents, all three of these agents have favorable sedation and anticholinergic profiles.
- There is one newer agent that is sometimes referred to as a “third generation” antihistamine- azelastine (Astelin). It is the first nasal antihistamine and it has some anti-inflammatory activity also. It comes as a 0.1% nasal spray. It is approved for use in patients &gt;12 YOA and the dose is 2 sprays per nostril BID.
- The most common side effects are somnolence and a bitter taste in the mouth which often passes. It has also caused nasal burning, nose bleeds, sore throat, and dry mouth. It is contraindicated in pregnancy.