Antiallergic Drugs and Allergic Rhinitis 2024-2025 PDF

Antiallergic drugs and allergic rhinitis Dr Michele Chahoud, Assistant Professor Pharm.D, MCP, PhD 1 Objectives H1 Antihistamines ➔mechanism of action, ➔therapeutic uses, ➔pharmacokinetics, ➔adverse effects Drugs used to treat aller...

Antiallergic drugs and allergic rhinitis Dr Michele Chahoud, Assistant Professor Pharm.D, MCP, PhD 1 Objectives H1 Antihistamines ➔mechanism of action, ➔therapeutic uses, ➔pharmacokinetics, ➔adverse effects Drugs used to treat allergic rhinitis ➔H1 Antihistamines ➔ Corticosteroids quick review, ➔ Alpha adrenergic agonists, ➔ Other agents 2  Review: Histamine Histamine is formed by the tissues on which it acts and, therefore, function as local hormones ➔ Location: Histamine is present in practically all tissues, with significant amounts in the lungs, skin, blood vessels, and gastrointestinal (GI) tract. It is found in high [C] in mast cells and basophils. 3  Review: Histamine ➔ Release of histamine: Most often, histamine is just one of several chemical mediators released in response to stimuli such as : ✓toxins from organisms, ✓venoms from insects and spiders, ✓and trauma. 4  Review: Histamine Mechanism of action H1 receptors’ activation in the brain cause ➔ Wakefulness ➔ Appetite suppression Histamine H1 receptors mediate many pathological processes, including allergic rhinitis, atopic dermatitis, conjunctivitis, urticaria, bronchoconstriction, asthma, and anaphylaxis (potentially life-threatening allergic reaction that can occur rapidly after exposure to an allergen) 5  Review: Histamine ➔Role in allergy and anaphylaxis The symptoms resulting from IV injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. These include: ✓contraction of airway smooth muscle, ✓stimulation of secretions, ✓dilation and increased permeability of the capillaries, ✓and stimulation of sensory nerve endings. 6  H1 Antihistamines or H1 blockers The older first-generation drugs are still widely used because they are effective and inexpensive. They treat: allergic reactions such as urticaria and allergic rhinitis However, most of these drugs penetrate the CNS (high lipid solubility) and cause sedation ➔ they can be used as a short term for sleeping disturbances. However, they tend to interact with other receptors, producing a variety of unwanted adverse effects. 7 8  H1 Antihistamines or H1 blockers The second-generation agents are specific for peripheral H1 receptors. They are made polar (less lipid soluble)➔ these agents do not penetrate the blood brain barrier and cause less CNS depression than do the first-generation drugs. ➔ To treat allergic reactions 9 10  H1 Antihistamines or H1 blockers A. Actions H1 blockers ➔ reversibly block H1 receptors➔ they block the receptor- mediated response of a target tissue. They are much more effective in preventing symptoms than reversing them once they have occurred. However, most of these agents have additional effects unrelated to their ability to block H1 receptors. These effects reflect binding of the H1-receptor antagonists to ✓cholinergic, ✓adrenergic, ✓or serotonin receptors 11  H1 Antihistamines or H1 blockers A. Actions 12  H1 Antihistamines or H1 blockers B. Therapeutic uses 1. Allergic and inflammatory conditions: H1-receptor blockers are useful in treating and preventing allergic reactions caused by antigens acting on immunoglobulin E antibody. 13  H1 Antihistamines or H1 blockers B. Therapeutic uses 1. Allergic and inflammatory conditions: ✓Oral antihistamines are the drugs of choice in controlling the symptoms of allergic rhinitis and urticaria because histamine is the principal mediator released by mast cells. ✓Ophthalmic antihistamines, such as ketotifen, and others, are useful for the treatment of allergic conjunctivitis. ✓However, the H1-receptor blockers are not indicated in treating bronchial asthma, because histamine is only one of several mediators that are responsible for causing bronchial reactions. 14  H1 Antihistamines or H1 blockers B. Therapeutic uses 2. Motion sickness and nausea: Along with the antimuscarinic agent scopolamine, certain H1-receptor blockers, such as diphenhydramine and promethazine, are the most effective agents for prevention of the symptoms of motion sickness. 1- Suppression of the Chemoreceptor Trigger Zone (CTZ): ➔By blocking histamine and modulating neurotransmitter activity in the CTZ, promethazine helps suppress the emetic (vomiting) reflex. 2- Antimuscarinic effects: The antimuscarinic effects contribute to the antiemetic action by reducing cholinergic stimulation in the vomiting center in the brain, making it less responsive to stimuli that trigger nausea and vomiting. 3- The vestibular system in the inner ear plays a crucial role in balance and spatial orientation. Motion sickness often involves conflicting signals between the visual and vestibular systems. By inhibiting H1 receptors in the vestibular system, promethazine can help alleviate symptoms associated with motion sickness, such as nausea and vomiting. They are usually not effective if symptoms are already present and, thus, should be15taken prior to expected travel.  The vomiting center receives input from the CTZ and other sources (vestibular system, gastrointestinal tract).It triggers the act of vomiting The CTZ, acts as a primary detector of toxins, drugs etc… The CTZ releases neurotransmitters like dopamine, serotonin, and acetylcholine to signal the vomiting center. 16  H1 Antihistamines or H1 blockers B. Therapeutic uses 3. Insomnia Although they are not the medications of choice, many first-generation antihistamines, such as diphenhydramine, have strong sedative properties and are used in the treatment of insomnia. The use of first-generation H1 antihistamines is contraindicated in the treatment of individuals working in jobs in which wakefulness is critical. The second-generation antihistamines have no value as somnifacients. 17  H1 Antihistamines or H1 blockers C. Pharmacokinetics H1-receptor blockers are well absorbed after oral administration The average plasma half-life is 4 to 6 hours, but the second-generation agents is 12 to 24 hours, allowing for once daily dosing. First-generation H1-receptor blockers are distributed in all tissues, including the CNS. 18  H1 Antihistamines or H1 blockers D. Adverse effects: First-generation H1-receptor blockers have a low specificity, interacting not only with histamine receptors but also with: ✓Muscarinic cholinergic receptors, ✓α-adrenergic receptors, ✓and serotonin receptors 19  H1 Antihistamines or H1 blockers D. Adverse effects: 2d generation 20  H1 Antihistamines or H1 blockers D. Adverse effects Sedation: First-generation H1 antihistamines, such as chlorpheniramine, diphenhydramine, hydroxyzine, and promethazine, bind to H1 receptors and block the neurotransmitter effect of histamine in the CNS. ➔The most frequently observed adverse reaction is sedation ➔Other central actions include fatigue, dizziness, lack of coordination. Elderly patients are more sensitive to these effects. Sedation is less common with the second-generation drugs, since they do not readily enter the CNS. Second-generation H1 antihistamines are specific for peripheral H1 receptors. 21  H1 Antihistamines or H1 blockers D. Adverse effects 3. Drug interactions: Interaction of H1-receptor blockers with other drugs can cause serious consequences, such as potentiation of effects of other CNS depressants, including alcohol. In addition, the first-generation antihistamines (diphenhydramine and others) with anticholinergic (antimuscarinic) actions may decrease the effectiveness of cholinesterase inhibitors (donepezil, rivastigmine, and galantamine ➔ INDIRECT-ACTING CHOLINERGIC AGONISTS) in the treatment of Alzheimer where we have a deficiency of cholinergic neurons and therefore lower levels of ACh in the CNS. 22  H1 Antihistamines or H1 blockers 4. Overdoses: Although the margin of safety of H1-receptor blockers is relatively high and chronic toxicity is rare, acute poisoning is relatively common, especially in young children. The most common and dangerous effects of acute poisoning are those on the CNS, including hallucinations and convulsions. If untreated, the patient may experience a deepening coma and collapse of the cardiorespiratory system. 23 Drugs used to treat allergic rhinitis 24  Review: Rhinitis Rhinitis Nose Inflammation ➔inflammation of the mucous membranes of the nose ➔characterized by: ❖ sneezing, ❖itchy nose/eyes, ❖watery rhinorrhea, ❖nasal congestion, ❖and sometimes a nonproductive cough 25 Review: Rhinitis inhalation of an allergen Rhinitis attack ➔ Type 1 hypersensitivity reaction Allergic rhinitis ➔ hay fever Caused by: -Hay -Dust -Pollen -Animal hair 26  Therapeutic treatment 1- Antihistamines are preferred therapies for 2- Corticosteroids (intranasal) allergic rhinitis 3- α-Adrenergic agonists 4- Other agents !!Avoid triggering allergens!! 27  Antihistamines Oral anti-histamine ➔ fast onset of action ➔useful for the management of symptoms of allergic rhinitis caused by histamine release, such as sneezing, watery rhinorrhea, and itchy eyes/nose. ➔they are more effective for prevention of symptoms, rather than treatment once symptoms have begun. 28  Antihistamines Oral anti-histamine 1rst or 2d generation? 1rst generation ➔ such as diphenhydramine and chlorpheniramine, are usually not preferred due to adverse effects, such as sedation, cognitive and psychomotor impairment, and other anticholinergic effects 2d generation➔ such as loratadine, desloratadine, cetirizine… are generally better tolerated 29  Antihistamines Ophthalmic and nasal antihistamine delivery devices are available for targeted, topical tissue delivery. Examples of topical intranasal antihistamines include olopatadine and azelastine (both second generation) Intranasal antihistamines provide increased delivery of the drug with fewer adverse effects. Combinations of antihistamines with decongestants are effective: ➔when congestion is a feature of rhinitis, ➔or when patients have no response or incomplete control of symptoms with intranasal corticosteroids. 30  Corticosteroids *Glucocorticoids are a group of steroid hormones, which are secreted by the two adrenal glands present on top of each kidney. The most important glucocorticoid in humans is cortisol, and it’s generally released during times of stress, like during an illness or starvation. Cortisol helps to regulate both the immune response as well as cellular metabolism like gluconeogenesis. With regard to the immune response, cortisol promotes an overall anti- inflammatory state by inhibiting the two main products of inflammation - prostaglandins and leukotrienes - as well as inhibiting interleukin-2 production by white blood cells. 31  Corticosteroids *Since the discovery of glucocorticoids in the 1940s and the recognition of their anti-inflammatory effects, they have been amongst the most widely used and effective treatments to control inflammatory and autoimmune diseases. Synthetic glucocorticoids in our body produce the same effect as endogenous cortisol. The main therapeutic effects of glucocorticoids are : 1- Anti-inflammatory effect 2- Immunosuppression 32  Corticosteroids MA*: Inhibition of phospholipase A2 Activity ➔ This prevents the release of arachidonic acid from cellular phospholipids. Corticosteroids suppress the inflammation by ✓activating anti-inflammatory genes, ✓switching off inflammatory gene expression, ✓and inhibiting inflammatory cells 33 Corticosteroids 34  Corticosteroids !!Intranasally!! ➔Intranasal corticosteroids, such as beclomethasone, budesonide, fluticasone (Rinisona®) mometasone (Nasonex®), and triamcinolone (Nasacort®), are the most effective medications for treatment of allergic rhinitis. ➔With an onset of action that ranges from 3 to 36 hours after first dose, intranasal corticosteroids improve sneezing, itching, rhinorrhea, and nasal congestion 35  Corticosteroids ➔Systemic absorption is minimal, and adverse effects of treatment are localized. ➔These include nasal irritation and, rarely, candidiasis. ➔To minimize systemic absorption, patients should be instructed to avoid deep inhalation during administration into the nose, because the target tissue is the nose, not the lungs or the throat. ➔For patients with chronic rhinitis, improvement may not be seen until 1 to 2 weeks after starting therapy. 36  α-Adrenergic agonists Short-acting α-adrenergic agonists ("nasal decongestants"), such as phenylephrine, Xylometazoline (Otrivine®) ➔constrict dilated arterioles in the nasal mucosa When administered intranasally, these drugs have a rapid onset of action and show few systemic effects. 37  α-Adrenergic agonists However, intranasal formulations of α-adrenergic agonists (xylometazoline Otrivine®) should be used for no longer than 3 days due to the risk of rebound nasal congestion (rhinitis medicamentosa)➔ inflammation of the nasal mucosa caused by the overuse of topical nasal decongestants. For this reason, the α-adrenergic agents are not used in the long-term treatment of allergic rhinitis. Administration of oral α-adrenergic agonists results in a longer duration of action but also increased systemic effects, such as increased blood pressure and heart rate. 38  Other agents ➔Intranasal cromolyn may be useful in allergic rhinitis, particularly when administered before contact with an allergen ➔ inhibits the degranulation of mast cells➔ inhibits the release of histamine and leukotrienes from the mast cells. ➔To optimize the therapeutic effect, dosing should begin at least 1 to 2 weeks prior to allergen exposure Side effects ➔ headache, feeling irritable 39 Practice questions A 25-year-old man suffering from hay fever started treatment with an over-the-counter antihistamine preparation. Which of the following statements best explains the molecular mechanism of action of the prescribed drug to treat this patient’s hay fever? A. Reversible binding to H2 receptors B. Reversible binding to H1 receptors C. Irreversible binding to H1 receptors D. Irreversible binding to H2 receptors 40  Practice questions A 43-year-old heavy machine operator complains of seasonal allergies. Which medication is most appropriate for management of his allergy symptoms? A. Diphenhydramine B. Promethazine C. Hydroxyzine D. Fexofenadine 41  Practice questions Which histamine receptor antagonist is known to enter the central nervous system readily and cause sedation? A. Hydroxyzine B. Cetirizine C. Desloratadine D. Loratadine 42