Basic Pharmacology Mod 4: Anti-Allergy Drugs PDF

BASIC PHARMACOLOGY 09/01/2024. MOD 4: ANTI-ALLERGY DRUGS Micah Muriel E. Oliv...

BASIC PHARMACOLOGY 09/01/2024. MOD 4: ANTI-ALLERGY DRUGS Micah Muriel E. Oliver, MD, DPCP Trans Group/s: 9B, 10B I. INTRODUCTION Corticosteroids have a role in the management of A. IMPORTANCE OF STUDYING ANTI-ALLERGY allergic diseases. MEDICATIONS Mast cell stabilizers are usually used for the treatment of asthma. 1. INCREASE IN BURDEN OF ALLERGIC DISEASES Other medications are used as adjuncts or treatment for allergy. Such as allergic rhinitis, dermatitis, asthma, and severe cases of anaphylaxis II. HISTAMINE A hydrophilic molecule consisting of an imidazole ring 2. INCREASE IN DRUG OVERUSE and an amino group. It is connected by an ethylene group. Most of the anti-allergy medications are Synthesized from histidine via decarboxylation over-the-counter drugs, hence there is an increase in Acts through 4 classes of receptors: drug overuse. ○ H1 ○ H2 3. IMPROVEMENT OF CLINICAL DECISION MAKING OF ○ H3 HEALTH CARE PROVIDERS ○ H4 As physicians, we need to know by heart the The four histamine receptors are all G protein-coupled management for common allergic diseases, and the receptors (GPCRs). most commonly anticipated adverse reactions or side ○ They can be differentially activated by analogues effects. of histamine, and inhibited by specific antagonists. Knowledge on this will help us improve our clinical Plays an important role in gastric acid secretion decision in managing common allergic diseases. Functions as a neurotransmitter and neuromodulator of both CNS and PNS Also plays a role in immune function or in immediate B. SUMMARY OF ANTI-ALLERGY MEDICATIONS allergic response and chemotaxis of WBCs ANTI-ALLERGY MEDICATIONS A. DISTRIBUTION AND BIOSYNTHESIS Generally very low concentration in plasma and other 1st Generation body fluids ○ But significant in human CSF Diphenhydramine High concentration in tissues containing large numbers Chlorpheniramine of mast cells such as skin, bronchial mucosa, and Hydroxyzine intestinal mucosa Promethazine ○ Mast cells are specifically numerous at sites of Meclizine potential tissue injury such as nose, mouth, feet, H1 Receptors internal body surfaces, and blood vessels 2nd Generation (particularly at pressure points and bifurcation) Cetirizine B. SYNTHESIS, STORAGE, AND METABOLISM Levocetirizine Fexofenadine 1. FORMATION Loratadine Formed by decarboxylation of L-Histidine (an amino Desloratadine acid) a reaction catalyzed in mammalian tissues by enzyme, L-Histidine decarboxylase Beclomethasone Once formed, it is either stored or rapidly inactivated Budesonide (metabolized) Corticosteroids Very little are excreted and unchanged Fluticasone Triamcinolone 2. SYNTHESIS Mast Cell Cromolyn sodium Synthesized in either a mast cell or non-mast cell site: Stabilizers Nedocromil MAST CELL NON-MAST CELL SITE Ipratropium SITE Leukotriene inhibitors Decongestants Others Mast cells Epidermis (Pseudoephedrine) Basophils Neurons in CNS Epinephrine (for anaphylactic ○ Histamine functions as shock) neurotransmitter [6:12] in Pharmacology - Mod # Topic Title 1 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  regenerating or rapidly mechanism mediated by H2 growing tissues receptors. Enterochromaffin-like cells Mast cells and basophils in (ECL) of gastric fundus skin show negative feedback (mucosa) mechanisms wherein mast ○ 2nd important non-neuronal cells in lungs or the site of histamine storage and respiratory bronchioles do release not. ○ Release histamine to activate Hence, histamine can limit the the acid-producing parietal intensity of the allergic reaction cells of the mucosa. in the skin and blood. ○ Turnover is rapid due to the continuous release of Chemotaxis Histamine has an active histamine, rather than it being chemotactic attraction to stored. inflammatory cells such as neutrophils, eosinophils, basophils, monocytes, and 3. STORAGE lymphocytes. After being synthesized by mast cells and basophils, it is stored in secretory granules. ○ Most tissue histamine is sequestered and bound in Histamine inhibits the release of lysosome contents in granules or vesicles in the mast cells or basophils. several T and B lymphocytes. Most of these reactions The bound form of histamine is biologically inactive, are mediated by H2 or H4 receptors. but many stimuli can trigger the release of mast cell Release of the peptides from nerves in the response to histamine, allowing the free amine to exert its action inflammation is probably modulated by the histamine to the surrounding tissues. acting on the presynaptic H3 receptors. The histamine content of many tissues is directly related to their mast cell content. 4.2 Chemical and Mechanical Release The turnover rate of histamine’s secretory granule is slow, usually taking days to weeks. Types of release that do not require energy. NOT ASSOCIATED with mast cell injury or explosive 4. RELEASE degranulation. Causes the granulation and histamine release. The release of histamine is by two mechanisms: ○ Immunologic Release ○ Chemical/Mechanical Release III. PHARMACODYNAMICS OF HISTAMINE All histamine receptors are G-protein Coupled 4.1 Immunologic Release Receptors (GPCRs). These receptors recognize a wide variety of signals Most important pathophysiologic mechanism of ranging from photons to ions. proteins, histamine release. neurotransmitters, and hormones which are important Has an effector phase. for signal transduction PROCESS RECEPTOR DESCRIPTION Starts in the mast cells and basophils. The two H1 Bronchoconstriction 1 cells are sensitive by IgE antibodies causing the Contraction of gut granulation. *Vascular dilation both H1, H2 Granulation happens when mast cells and H2 Acid secretion by gastric parietal basophils are exposed to appropriate antigen, cells 2 leading to simultaneous release of histamine, ATP, Edema and stimulation of nerve and other mediators stored in the granules. ending It then triggers the exocytosis of the contents of H3 Auto-receptors on histaminergic the secretory granules that in addition to histamine, neurons → inhibits histamine 3 includes serotonin, proteases, lysosomal enzymes, release cytokines, and proteoglycans. Heteroreceptors on non-histaminergic neurons → As a result, it causes the mast cells to granulate modulates the release of other 4 and thereby, lead to histamine release. neurotransmitters H4 Blood SOME CHARACTERISTICS OF HISTAMINE Eosinophils Dendritic Cells Negative It can modulate its own Mast Cells Feedback Control release and that of other Monocytes Mechanism mediators from synthesized Basophils mast cells in some tissues by T Cells a negative feedback control Chemotaxis Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 2 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  GI Tract characteristic phenomenon Dermal Fibroblast known as “the triple response of CNS Lewis” consists of : Primary sensory afferent neurons Local reddening around the injection site for a few seconds and maximal at 1 RECEPTOR LOCATION AND CLINICAL minute. The initial red APPLICATIONS spots result from the direct vasodilating effect of the H1 H1 and H2 are distributed widely in histamine or H1 the periphery (PNS) and in your receptor-mediated nitric central nervous system (CNS) oxide production. Their activation by histamine can exert A clear or a red flush local or widespread effect extending about 1 cm Majority of your H1 receptor agents beyond the original red are used for treatment of allergy spot and developing more slowly and the flare is due to H2 H2 receptors are mainly expressed in histamine-induced the CNS, especially the basal stimulation of axonal reflexes ganglia, hippocampus, and cortex that causes vasodilation H2-mediated cyclic AMP signalling indirectly. is a crucial step in acid secretion by Wheal or swelling that is gastric parietal cells discernible in 1-2 minutes at the injection site will reflect H3 Auto-receptors on histaminergic histamine’s capacity to neurons → inhibits histamine release increase capillary Heteroreceptors on permeability or edema non-histaminergic neurons → formation. modulates the release of other Lowers Systemic Blood Pressure neurotransmitters (SBP) ○ It causes depression of SBP. Histamine’s effect on the cardiac H4 Because of the unique localization and contractility and electrical function of H4 receptors, H4 events indirectly. antagonists are promising candidates ○ The direct cardiac effects of to treat inflammatory conditions and histamine given intravenously possibly pruritus and neuropathic pain are overshadowed by baroreceptor reflexes stimulated Stimulation of H2 receptors increases cAMP and by reduced blood pressure. leads to feedback inhibition of histamine release from ○ Histamine can also cause shock. mast cells and basophils, whereas activation of H3 and If given in large doses for release H4 receptors has opposite effects by decreasing during systemic anaphylaxis, can cellular cAMP. cause a profound progressive fall in blood pressure. EFFECTS OF HISTAMINE IN THE ORGAN SYSTEMS Smooth Contractions Muscle ○ Histamine directly contracts or ORGAN DESCRIPTION more rarely relaxes SYSTEM extravascular smooth muscles. ○ Contraction is due to activation CVS Dilates resistance vessels of H1 receptors in smooth ○ The activation of H2 receptors muscle to increase intracellular on the vascular smooth muscle calcium. stimulates the cyclic AMP-PKA ○ Relaxations are mainly due to pathway. This causes dilation that activation of H2 receptors. develops more slowly and more Although the plasmogenic influence of sustainably. H1 receptors is dominant in human Increases capillary permeability bronchial smooth muscles, H2 ○ Increased capillary permeability is receptors with dilator function are the histamine’s effect on the small also present. vessel that results in the efflux of Thus, histamine induced the plasma protein and fluid bronchospasm is potentiated slightly into the extracellular spaces by H2 blocking. and increase in lymph flow Patients with bronchial asthma and causing edema. certain pulmonary diseases are ○ The H1 receptor activation on much more sensitive to the the endothelial cells is the major bronchoconstrictor effects of mediator of this response. histamine. ○ If histamine is injected intradermally, it elicits a Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 3 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  It inhibits the more rapid vasodilator effects mediated Peripheral Histamine stimulate various nerve by activation of the H1 receptors on endothelial cells, Nerve endings causing sensory defects: which cause the synthesis, release of the nitric oxide, endings ○ Epidermis → causes itch and other mediators at a lower dose of histamine. ○ Dermis → evokes pain and It inhibits the venous constriction seen in some sometimes accompanied by vascular beds. itching It suppresses the action of the histamine on the nerve endings, including the flare component of the triple Stimulant actions on the nerve response and the itching caused by intradermal endings, including autonomic afferent injection. and efferent, contribute to the flare component of triple response and to the indirect effects to the bronchi and other organs. CNS Neuronal histamine has stimulatory and inhibitory functions in the CNS. Stimulatory: promote wakefulness, cognition, locomotion, energy metabolism, nociception. Inhibitory: suppress appetite, convulsions, stress-induced excitation, and denervation-induced supersensitivity. Immune Activation of H4 receptors has been System associated with induction of cellular Effects of H1 Receptor Antagonists. shape change, chemotaxis, secretion of cytokines and upregulation of B. EFFECTS OF H1 RECEPTOR ANTAGONIST IN THE adhesion molecules. ORGANS It does not suppress gastric acid secretion. ○ Gastric acid secretion is the function of the H2 IV. ANTI-ALLERGY MEDICATIONS receptor. ○ However, the antimuscarinic properties of many H1 antagonists may contribute to the lessened secretion in cholinergically innervated glands, which can reduce ongoing secretion in the respiratory tree. During hypersensitivity reactions, histamine is one of many potent autacoids released, and its relative contribution on the ensuing symptoms varies widely with species and tissue. The protection accorded by H1 antagonists vary accordingly. In humans, edema formation and H are effectively suppressed. Anti-allergy Medications. It is ineffective in blocking bronchoconstriction due to asthma. H1-receptor has both agonist and antagonist receptors. Many 2nd generation H1 antagonists, such as The goal of allergy treatment is to suppress or inhibit cetirizine, desloratadine, fexofenadine, olopatadine, cholinergic effects of inflammatory response. ketotifen and others exhibit mast cell stabilizing effects H1 receptor antagonist acts as an inverse agonist. resulting in a reduced release of mast cells mediator ○ An inverse agonist is a drug that binds on the during an allergic response. same receptor as your agonist, it induces a ○ These agents also have anti-inflammatory pharmacological response opposite to that of the properties, which can induce reduced cytokine agonist but the effects of both can be blocked by secretion, decrease adhesion molecules the antagonist. expression, and inhibition of eosinophil infiltration. ○ An agonist increases the activity of the receptor above its basal level, whereas inverse agonist, it decreases the activity below the basal level. A. EFFECTS OF H1 RECEPTOR ANTAGONIST It inhibits all the effects of histamine on the cardiovascular, smooth muscle, nerve endings, and immune system. In the cardiovascular system, vasodilation, increase in capillary permeability, and hypotension is prevented. It inhibits most of the effects of histamine on smooth muscle, especially in the constriction of the respiratory smooth muscle. Effects of H1 Receptor Antagonists in the Organs. Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 4 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  The 1st generation H1 antagonist can both stimulate activity and few are and depress the CNS. more potent than STIMULATION Procaine — ○ Stimulation is occasionally encountered in patients Promethazine is given conventional doses. The patients become especially active. restless, nervous, and unable to sleep. However the ○ Central excitation is also a striking feature of concentrations overdose, which commonly results in convulsion, required for this effect particularly in infants. are much higher than DEPRESSION those that antagonize ○ Central depression usually accompanies histamines interaction therapeutic doses of the older H1 antagonists. with its receptors. ○ Diminished alertness, slowed reaction times, and somnolence (sleepiness/drowsiness) are common manifestations. Patients vary in their susceptibility and responses to individual drugs. H1 receptor blockers are classified into 1st and 2nd generation. H1 RECEPTOR BLOCKERS 1st Generation 2nd Generation Has sedating effects Has a lesser sedative Ethanolamines (i.e., effects diphenhydramine) are Nonsedating because particularly prone to they do not cross the Effects of H1 Receptor Antagonist. cause sedation blood-brain barrier Because of its sedative This is due to their C. PHARMACOKINETICS: H1 RECEPTOR ANTAGONIST effects, 1st Generation decreased antihistamines cannot lipophilicity, and be tolerated or used because they are PHARMACOKINETICS OF H1 RECEPTOR safely by many substrates of the ANTAGONIST patients, except at P-glycoprotein, which bedtime pumps them out of the Absorption Well absorbed in the GI tract. BBB, capillary Agents are rapidly absorbed after endothelial cells, and oral administration. back to the capillary Peak blood concentration occurs in 1 lumen to 3 hours. Effects last 4 to 6 hours for 1st DRUG PROTOTYPE: DRUG PROTOTYPE: generation agents. However, some Diphenhydramine Cetirizine drugs are much longer acting. Chlorpheniramine Levocetirizine Hydroxyzine Fexofenadine Distribution Widely distributed throughout the Promethazine Loratadine body. Meclizine Desloratadine The 1st generation can enter the CNS — why it can cause sedation Tend to inhibit Have NO effect on compared to 2nd generation drugs muscarinic muscarinic receptors cholinergic Metabolism All 1st generations and most 2nd responses generation are metabolized by Can also be used to CYPs in the liver. treat motion Some are extensively metabolized sickness, as a result primarily by the microsomal system of their anti-cholinergic in the liver. properties Several of the 2nd generation Promethazine has the agents are metabolized by the strongest muscarinic CYP3A4 system, thus are subject to blocking activity among important interactions when other these agents, and is drugs (such as ketoconazole) inhibit the most effective H1 this subtype of P450 enzymes. antagonist in combating motion Excretion Histamine is excreted unchanged in sickness the urine. Most appear as metabolites. Some H1 antagonists Many H1 antagonists have active have local anesthetic metabolites, except; ○ Cetirizine and acrivastine Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 5 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  which are less than 40% ○ Leukopenia, metabolized. ○ Agranulocytosis ○ Fexofenadine, levocetirizine, ○ Hemolytic anemia and epinastine are less than 10% metabolized. Note: May be reduced by taking the drugs with meals Cetirizine, levocetirizine, and acrivastine are excreted primarily into the urine. Fexofenadine is mainly excreted in SIDE EFFECTS NOT OBSERVED WITH 2ND the feces. GENERATION H1 ANTAGONIST Epinastine is excreted in both urine (55%) and feces (30%). Other side effects owing to anti-muscarinic action of some First Generation H1 Antagonist: ○ Dryness of the mouth and respiratory D. DRUG INTERACTIONS: H1 RECEPTOR ANTAGONIST passages sometimes inducing cough H1 receptor antagonists can cause some drug ○ Urinary tension or frequency interactions. ○ Dysuria Plasma levels of H1 antagonists may be reduced The mentioned drugs under the H1 receptors antagonist REDUCED ELEVATED usually have a CNS adverse effect such as sedation and anti-inflammatory effect. when co-administered with When co-administered that One particular H1 antagonist has notable side effects in drugs that induce CYP compete with or inhibit satiety (e.g., cyproheptadine can cause weight gain as Synthesis CYP isoform it increases appetite). (Benzodiazepines) (Erythromycin, Ketoconazole, Anti- depressants) TERATOGENIC NON-TERATOGENIC Azelastine Chlorpheniramine Lethal Ventricular Arrhythmias occur in several Hydroxyzine Diphenhydramine patients taking either of the early 2nd Generation agents Fexofenadine Cetirizine such as Terfenadine and Astemizole, in combination Loratadine with Ketoconazole, Itraconazole or Macrolide antibiotics such as Erythromycin. Combination of H1 Receptor Antagonist: Doxylamine + These antimicrobial drugs inhibit the metabolism of Vitamin B6 (Pyridoxine) many drugs by CYP3A4 and cause significant increase ○ Treats nausea and vomiting for pregnancy in blood concentration of the anti-histamines. ○ Related to teratogenic effects as antihistamine can The mechanism of the toxicity involves blocking of the be secreted in small amounts in breast milk potassium channel in the heart, the result is the ○ First generation antihistamines taken by lactating prolongation and a change in shape of the action mothers can cause symptoms such as irritability, potential, and these changes lead to arrhythmia. drowsiness, or respiratory depression in the nursing infant E. ADVERSE EFFECTS: H1 RECEPTOR ANTAGONIST There are specific populations to consider when using H1 receptor antagonists ADVERSE EFFECTS OF H1 RECEPTOR ANTAGONIST ○ Pregnant patients Antihistamine crosses the placenta Sedation: most Blurred-vision Caution is advised for women who are or may become pregnant frequent side effect Diplopia Acute poisoning with first generation H1 antagonist Dizziness Euphoria poses the greatest danger due to central excitatory Tinnitus Nervousness effects (syndrome resemble atropine poisoning): Flaccitude Insomnia ○ Hallucinations Incoordination Tremors ○ Excitement Fatigue ○ Ataxia ○ Incoordination ○ Athetosis ADDITIONAL POTENTIAL SIDE EFFECTS ○ Convulsions ○ Fixed, dilated pupils with a flushed face Loss of appetite ○ Sinus tachycardia Nausea and vomiting ○ Urinary Retention Epigastric distress ○ Dry mouth Constipation ○ Fever Diarrhea Allergic dermatitis Other hypersensitivity reactions: SUITABLE H1 RECEPTOR ANTAGONIST FOR ○ Drug fever DIFFERENT AGE GROUPS ○ Photosensitization Hematological complications: (Very rare) ELDERLY CHILDREN Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 6 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Drug under class Phenothiazine (Promethazine) is the H1 receptor antagonist H1 receptor antagonist preferred therapy for motion sickness and can cause 2nd generation 2nd generation marked sedation. Greater than 65 years 2nd generation drug Cyproheptadine is the only first-generation H1 receptor old, especially with has been approved by antagonist that has a serotonin activity and is used for impaired cognition FDA for use in children adjunctive treatment of patients with loss of appetite. function and are available in 2nd generation H1 receptor antagonists are not These population lack appropriate lower lipophilic and cannot cross the blood-brain barrier. sedative and dose formulation Hence, they have less sedative effects but have equal anti-cholinergic such as chewables, effectiveness in the treatment for allergy. effects for the first rapidly dissolving generation drug tablets or syrup G. DRUG CLASSES The use of over-the-counter cough and cold 1. CLASS DIBENZOXAZEPINE medications containing mixtures of Doxepin Has activity both on H1 and H2 antihistamine, receptors decongestants, Adjunct treatment for depression antitussive, and Best given in younger age groups expectorants in Causes drowsiness and sedation children has been associated with Olopatadine Used for allergic rhinitis and serious side effects allergic conjunctivitis and even death. 2nd Gen H1 receptor Antagonist First generation Topical H1 Antagonist antihistamines are (+) Mast cell stabilizing and NOT recommended for anti-inflammatory effects use in children because their sedative 2. CLASS ETHANOLAMINE effects can impair learning and school performance. Diphenhydramine 1st Gen H1 Receptor Antagonist Prototype drug F. CLINICAL USE +++ Antimuscarinic Activity GI side effects are low (+) effective drug for mild sedation 3. CLASS ETHYLENEDIAMINE Pyrilamine 1st Gen H1 Receptor Antagonist Same sedative effects (+) GI effects 4. CLASS ALKYLAMINE Chlorphenamine 1st Gen H1Antagonist ++ Most potent H1 Antagonist Some H1 antihistaminic drugs in clinical use. S/E: CNS Stimulation Less drowsiness effect Drugs under class Ethanolamines (Carbinoxamine, Suitable for daytime use Dimenhydrinate, Diphenhydramine) are mainly used for mild sedation and anti-motion sickness. Acrivastine 2nd Gen H1 Receptor ○ They also exhibit significant anticholinergic Antagonist effects. Higher incidence of mild ○ Anticholinergic drugs work by blocking the action sedation of acetylcholine, thereby blocking its neurotransmission, inhibiting involuntary muscle 4. CLASS PIPERAZINE movements and bodily functions. Drugs under class Piperazine derivatives Hydroxyzine 1st Gen H1 Receptor Antagonist (Hydroxyzine, Cyclizine, Meclizine) are usually used for Has long-acting effect motion sickness. Used for skin allergies ○ It has none to some anticholinergic activity. Similar sedative effects Drugs under class Alkylamines (Chlorpheniramine) are Can be used as adjunct treatment usually a component of common “colds” medications. for anxiety (anti-anxiety drug) ○ Has a slight sedative effect and some anticholinergic activity. Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 7 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  enzymes, receptors, and proteins that have been Cyclizine and 1st Gen H1 Receptor Antagonists activated during acute or chronic inflammatory Meclizine Used for motion sickness processes. Less likely to cause sedation Corticosteroids have widespread effects on the gene compared to hydroxyzine transcription. It increases the transcription of anti-inflammatory genes and it can also suppress Cetirizine Has minimal anticholinergic transcription of many inflammatory genes. effect Steroids have many inhibitory effects on many Higher incidence of drowsiness inflammatory and structural cells that are activated in compared to other 2nd Gen drugs asthma and prevent the recruitment of inflammatory Has mast-cell and cells into the airway. anti-inflammatory activity In cases like asthma, which is an inflammatory-mediated condition, oral, inhalational, and Levocetirizine Active enantiomer intravenous route can be used. 2nd Gen H1 Receptor Antagonist Has slightly greater potency A. MODE OF ACTION: CORTICOSTEROIDS May be used at half the dose with During asthma, the inflammatory stimuli (e.g., IL-1β and less resultant sedation TNF-α) activate IKK-β leading to activation of the transcription factor NF-kB 5. CLASS PHENOTHIAZINE Binding of this protein leads to activation of HAT (Histone Acetyltransferase), which is important in gene transcription and expression. Promethazine 1st Gen H1 Receptor Antagonist Corticosteroid, as it enters the cell and binds to Has sedative effects and some cytosolic GR (Glucocorticoid Receptor) proteins, it cholinergic effects forms receptor-ligand complexes with HAT and CRBP Preferred drug for motion binding protein causing suppression of the gene sickness transcription This eventually leads to suppressed activated 6. CLASS PIPERIDINE inflammatory chain production. Cyproheptadine 1st Gen H1 Receptor Antagonist Used as an appetite stimulant for patients with poor appetite Notable side effect: weight gain ONLY drug with both antihistamine and anti-serotonin activity Can cause drowsiness Has some anticholinergic effects Loratadine 2nd Gen H1 Receptor Antagonist Anti-inflammatory action of Corticosteroids in Asthma Mainly used for allergic rhinitis Intracellularly. but is also used for other several allergic diseases At the cellular level, both inflammatory cells and Has mast cell-stabilizing and structural cells (specifically of the bronchial airways) anti-inflammatory properties are affected by corticosteroids. Desloratadine 2nd Gen H1 Receptor Antagonist Active metabolite of Loratadine Has similar effect to Loratadine but lacks significant anticholinergic actions and penetrate poorly into the CNS Has mast cell-stabilizing and anti-inflammatory properties Fexofenadine 2nd Gen H1 Receptor Antagonist Non-sedating Has mast cell-stabilizing and Corticosteroids affect both inflammatory and structural cells. anti-inflammatory properties Corticosteroids decrease the number of circulating eosinophils thereby decreasing modulation of V. CORTICOSTEROIDS inflammatory responses. The predominant effect of corticosteroids is to switch As a result, there will be a decrease of your off multiple inflammatory genes encoding cytokines, T-helper lymphocytes → decrease in effective chemokines, adhesion molecules, inflammatory Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 8 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  They should be started in any patient who needs to use cytokines, a chemoattractant → decrease in other Beta-Agonist inhaler for symptom control more than inflammatory cells such as mast cells, twice weekly macrophages, and dendritic cells. Effective in and among: During asthma, there are structural changes causing ○ Mild, moderate, and severe asthma hyperresponsiveness of the respiratory airway. ○ Children and adults Symptoms of this are coughing, increased Should be used twice daily bronchial secretions, and bronchospasm. ○ A regimen that improves adherence once control Therefore, corticosteroids decrease inflammatory asthma has been achieved which may require mediators, prevent and reverse the increase of 4-time daily dosing initially or a course of oral vascular permeability due to inflammatory steroid, if symptoms are severe. mediators, and therefore lead to resolution of airway For systemic steroids, we have oral and intravenous edema. routes. However, corticosteroids have no direct effect on ○ Intravenous steroids are indicated in asthma if the the contractile responses of airway smooth lung function is less than 30% predicted and in muscles. patients who show no significant improvement with Improvement in lung function after you inhaled nebulized beta 2 agonists. corticosteroids is presumably due to an effect of the ○ Hydrocortisone is the steroid of choice because it chronic inflammation edema airway responsiveness. has the most rapid onset. It is about 5-6 hours after Lastly, the decrease of mucus secretion is partly administration compared with 8 hour prednisolone. due to the resolution of respiratory edema brought ○ It is common to give hydrocortisone 4 mg/kg about by an inflammatory process. initially followed by a maintenance dose of 3 mg/kg every 6 hours. It is important in decreasing effective circulating ○ Methylprednisolone is also available for inflammatory cells leading to ineffective intravenous use. chemoattraction. Intravenous therapy is usually given until a satisfactory It prevents further structural damage leading to response is obtained. Then oral prednisolone may be enhanced inflammatory recruitment of cells at the substituted. site of inflammation. The net effect of corticosteroid use is suppression of INHALED CORTICOSTEROIDS multi-level inflammatory response. Beclomethasone ICS should be given twice B. PHARMACOKINETICS: CORTICOSTEROIDS IN Budesonide daily. ASTHMA Fluticasone Triamcinolone Once daily: Budesonide, PHARMACOKINETICS: CORTICOSTEROIDS IN Mometasone, Ciclesonide, ASTHMA Fluticasone Absorption Inhalational; Absorbed from the airway All ICS are equally effective in asthma. and alveolar surfaces Distribution Systemic INHALED CORTICOSTEROIDS A portion of an inhaled dose reaches the systemic circulation Inhaled corticosteroids (ICS) are all equally The fraction of an inhaled steroid effective as anti asthma drugs but there are that is deposited in the differences in their pharmacokinetics. oropharynx is swallowed and absorbed from the gut Budesonide Lower oral bioavailability than Fluticasone inhaled beclomethasone (BDP) Metabolism Liver Mometasone because they are subject to a The absorbed fraction may be Ciclesonide greater first pass hepatic metabolized in the liver and metabolism which results in undergo first pass metabolism reduced systemic absorption from before reaching into the systemic the fraction of inhaled drug that is circulation followed and thus reduce adverse effect Excretion Kidney; Bile, Feces Most corticosteroids are conjugated Ciclesonide is a pro-drug that is with sulfates or glucuronides to converted to the active metabolite increase their solubility in water and by esterases in the lungs giving it a they are readily excreted via urine, low bioavailability and a high bile, or feces. therapeutic index Budesonide Fewer systemic effects than C. ROUTE OF ADMINISTRATION: CORTICOSTEROIDS IN Fluticasone inhaled beclomethasone and ASTHMA propionate triamcinolone and they are preferred in patients who need high doses of 1.INHALED CORTICOSTEROIDS inhaled corticosteroid and in The route recommended as first line therapy in case children of acute exacerbation of asthma Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 9 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  However, its use has declined due to more Fluticasone Longest duration of action and is widespread use of more effective inhaled furoate suitable for once daily dosing corticosteroids, particularly in children ○ Cromones are no longer recommended for Usually combined with long-acting asthma therapy beta-agonist (LABA) Vilanterol ○ Interest continues in this compound as it causes down regulation of mast cell activity Nedocromil Sodium ADVERSE EFFECTS ○ Structurally related drug ○ Similar pharmacological profile to Cromolyn LOCAL SIDE EFFECTS SYSTEMIC SIDE ○ Subsequently developed EFFECTS VI. OTHER ANTI-ALLERGIC MEDICATIONS Dysphonia or Adrenal suppression hoarseness of voice and insufficiency 1. IPRATROPIUM Oropharyngeal Growth suppression Ipratropium bromide is an anticholinergic drug. candidiasis Bruising Action: prevents cholinergic-induced Cough Osteoporosis bronchoconstriction and decreases mucus Cataracts secretions. Glaucoma Side effects: dry mouth (most common), tachycardia, Metabolic glaucoma, and urinary retention. abnormalities This drug is usually in combination with Albuterol in (glucose, insulin, acute asthma therapy. triglycerides) Psychiatric 2. LEUKOTRIENES INHIBITORS disturbances (euphoria, Action: blocks cys-LT1-receptors and provides depression) modest clinical benefit in asthma. Pneumonia There is considerable evidence that cys-LTs or Cysteinyl Leukotrienes are produced in asthma and that they have potent effects in airway function. Inducing: 2. SYSTEMIC CORTICOSTEROIDS ○ Bronchoconstriction ○ Airway Hyperresponsiveness Very effective to reduce inflammatory processes ○ Plasma exudation however it is related to several adverse effects ○ Mucus secretion especially with longer use and sudden withdrawal of the ○ Eosinophilic inflammation drug They inhibit the inhaled cys-LTs but they are less Side effects of long-term corticosteroids therapy effective than inhaled corticosteroids in controlling ○ Fluid retention asthma and preventing exacerbations. ○ Increased appetite Administered orally and relatively well tolerated. ○ Weight gain Side effects: headache, eosinophilic granulomatosis ○ Skin and Capillary fragility with polyangiitis (EGPA), neuropsychiatric events ○ Hypertension Drug prototype: Monteleukast ○ Peptic ulcerations ○ Have been associated with increased serious ○ Diabetes neuropsychiatric events in children and adults ○ Psychosis including suicidal thoughts. ○ Dermal thinning The frequency tends to increase with age Oropharyngeal candidiasis occurs in about 5% of the patients especially those who use Metered dose spacers for inhaled corticosteroids ○ May have local side effects due to the deposition of corticosteroid within the oropharynx ○ Causes hoarseness and weakness of the voice (dysphonia) due to the atrophy of the vocal cords following laryngeal deposition of the steroids ○ Dermal thinning, skin and capillary fragility are common side effects for the elderly due to inhaled corticosteroids ○ Uncommon side effects for oral steroids: cataracts and osteoporosis 3. MAST CELL STABILIZERS Main action: blocking triggered induced asthma such as exercise induced asthma Effects of Cysteinyl Leukotrienes. Cromolyn Sodium ○ “Disodium cromoglycate” EFFECTS OF CYSTEINYL LEUKOTRIENES ○ Derivative of a khellin, an Egyptian herbal remedy ○ Was found to protect against allergen challenge Factors Aspirin, exercise, allergen, cold air, without any bronchodilator effect Platelet activating factor (PAF), and ○ Popular in the past due to its good safety profile Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 10 of 12 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  sulfur dioxide can trigger activation of Other Choices mast cell and eosinophils A. H1 Receptor: mainly use for anti-allergy medication C. H3 Receptor: acts as autoreceptors for important Mast cells Once activated, they trigger neurotransmitter signaling and transduction and it is and arachidonic acid which is involved in mainly expressed in the CNS eosinophils important biological functions such as D. H4 Receptor: found mainly in the blood growth development and it is a precursor Involved in some inflammatory processes of numerous mediators. Is also involved in neuropathic pain and pruritus Leukotrienes Products of 5-Lipoxygenase, a 2. Which among anti-allergy medication is the best pathway of arachidonic acid metabolism, treatment in cases of anaphylaxis secondary to are often involved in airway bee sting? inflammation. A. Corticosteroids B. Epinephrine Cysteinyl Promote allergic inflammation by C. Pseudoephedrine Leukotrienes enhancing immune responses that D. Leukotriene Inhibitors increases adhesion, migration, and survival of inflammatory cells. Answer: B. Epinephrine All of the mentioned choices are used as anti-allergy Sum of Proceeds to plasma exudation, mucus medications. However in cases of anaphylaxis or pathways secretion, bronchoconstriction, and shock, Epinephrine can immediately reverse eosinophil recruitment. inflammatory effects specifically reversing possible immediate bronchoconstriction secondary to a severe allergic response. Therefore, anti-leukotrienes block this mentioned pathway. Other Choices A. Corticosteroids: are a good candidate for 3. PSEUDOEPHEDRINE anaphylaxis, however compared to epinephrine, the Used for temporary relief of stuffy nose and sinus effects of corticosteroids