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 CONTENT ADDITIONAL INFO RESOURCES 3. IMPROVEMENT OF CLINICAL DECISION MAKING OF ★ → HEALTH CARE PROVIDERS OUTLINE As physicians, we need to know by heart the management for common allergic diseases, and the most commonly anticipated adverse reactions or side I. Introduction effects. A. Importance of Studying Anti-Allergy Medications Knowledge on this will help us improve our clinical B. Summary of Anti-Allergy Medications decision in managing common allergic diseases. II. Histamine A. Distribution and Biosynthesis B. SUMMARY OF ANTI-ALLERGY MEDICATIONS B. Synthesis, Storage, and Metabolism III. Pharmacodynamics of Histamine IV. Anti-Allergy Medications ANTI-ALLERGY MEDICATIONS A. Effects of H1 Receptor Antagonist B. Effects of H1 Receptor Antagonist in the Organs 1st Generation C. Pharmacokinetics: H1 Receptor Antagonist D. Drug Interactions: H1 Receptor Antagonist Diphenhydramine E. Adverse Effects: H1 Receptor Antagonist Chlorpheniramine F. Clinical Use Hydroxyzine G. Drug Classes Promethazine V. Corticosteroids Meclizine A. Mode of Action: Corticosteroids H1 Receptors B. Pharmacokinetics: Corticosteroids in Asthma 2nd Generation C. Route of Administration: Corticosteroids in Asthma Cetirizine VI. Other Anti-Allergic Medications Levocetirizine VII. Clinical Application Fexofenadine Loratadine References Desloratadine Beclomethasone LEARNING OBJECTIVES Budesonide To determine the main classes of Anti-Allergy Corticosteroids Fluticasone medications. Triamcinolone To know the drug prototype for each drug classification To understand the pharmacokinetics and Mast Cell Cromolyn sodium pharmacodynamics of anti-allergy medications. Stabilizers Nedocromil To know the drug indication and contraindications of anti-allergy medic Ipratropium To differentiate classes of H1 receptor antagonists Leukotriene inhibitors To enhance clinical decision making in terms of Decongestants diagnosis and management of most common allergic Others (Pseudoephedrine) diseases/illnesses. Epinephrine (for anaphylactic shock) I. INTRODUCTION A. IMPORTANCE OF STUDYING ANTI-ALLERGY Corticosteroids have a role in the management of MEDICATIONS allergic diseases. Mast cell stabilizers are usually used for the treatment of 1. INCREASE IN BURDEN OF ALLERGIC DISEASES asthma. Other medications are used as adjuncts or treatment Such as allergic rhinitis, dermatitis, asthma, and severe for allergy. cases of anaphylaxis II. HISTAMINE 2. INCREASE IN DRUG OVERUSE A hydrophilic molecule consisting of an imidazole ring and an amino group. Most of the anti-allergy medications are over-the-counter It is connected by an ethylene group. drugs, hence there is an increase in drug overuse. synthesized from histidine via decarboxylation Acts through 4 classes of receptors: ○ H1 ○ H2 Pharmacology - Mod # Topic Title 1 of 13 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.  ○ H3 The turnover rate of histamine’s secretory granule is ○ H4 slow, usually taking days to weeks. The four histamine receptors are all G protein-coupled receptors (GPCRs). 4. RELEASE ○ They can be differentially activated by analogues The release of histamine is by two mechanisms: of histamine, and inhibited by specific antagonists. ○ Immunologic Release Plays an important role in gastric acid secretion ○ Chemical/Mechanical Release Functions as a neurotransmitter and neuromodulator of both CNS and PNS 4.1 Immunologic Release Also plays a role in immune function or in immediate allergic response and chemotaxis of WBCs Most important pathophysiologic mechanism of histamine release. A. DISTRIBUTION AND BIOSYNTHESIS Has an effector phase. Generally very low concentration in plasma and other body fluids PROCESS ○ But significant in human CSF High concentration in tissues containing large numbers Starts in the mast cells and basophils. The two cells of mast cells such as skin, bronchial mucosa, and 1 are sensitive by IgE antibodies causing the intestinal mucosa granulation. ○ Mast cells are specifically numerous at sites of potential tissue injury such as nose, mouth, feet, Granulation happens when mast cells and basophils internal body surfaces, and blood vessels are exposed to appropriate antigen, leading to (particularly at pressure points and bifurcation) 2 simultaneous release of histamine, ATP, and other mediators stored in the granules. B. SYNTHESIS, STORAGE, AND METABOLISM It then triggers the exocytosis of the contents of the 1. FORMATION secretory granules that in addition to histamine, Formed by decarboxylation of L-Histidine (an amino 3 includes serotonin, proteases, lysosomal enzymes, acid) a reaction catalyzed in mammalian tissues by cytokines, and proteoglycans. enzyme, L-Histidine decarboxylase Once formed, it is either stored or rapidly inactivated As a result, it causes the mast cells to granulate and (metabolized) 4 thereby, lead to histamine release. Very little are excreted and unchanged 2. SYNTHESIS SOME CHARACTERISTICS OF HISTAMINE Synthesized in either a mast cell or non-mast cell site: Negative It can modulate its own release MAST CELL SITE NON-MAST CELL SITE Feedback Control and that of other mediators Mechanism from synthesized mast cells in Mast cells Epidermis some tissues by a negative Basophils Neurons in CNS feedback control mechanism ○ Histamine functions as mediated by H2 receptors. neurotransmitter [6:12] in Mast cells and basophils in regenerating or rapidly skin show negative feedback growing tissues mechanisms unlike the mast Enterochromaffin-like cells (ECL) cells in lungs or the respiratory of gastric fundus (mucosa) bronchioles do not. ○ 2nd important non-neuronal Hence, histamine can limit the site of histamine storage and intensity of the allergic reaction release in the skin and blood. ○ Release histamine to activate the acid-producing parietal Chemotaxis Histamine has an active cells of the mucosa. chemotactic attraction to ○ Turnover is rapid due to the inflammatory cells such as continuous release of neutrophils, eosinophils, histamine, rather than it being basophils, monocytes, and stored. lymphocytes. 3. STORAGE Histamine inhibits the release of lysosome contents in After being synthesized by mast cells and basophils, it is several T and B lymphocytes. Most of these reactions stored in secretory granules. are mediated by H2 or H4 receptors. ○ Most tissue histamine is sequestered and bound in Release of the peptides from nerves in the response to granules or vesicles in the mast cells or basophils. inflammation is probably modulated by the histamine The bound form of histamine is biologically inactive, acting on the presynaptic H3 receptors. but many stimuli can trigger the release of mast cell histamine, allowing the free amine to exert its action to 4.2 Chemical and Mechanical Release the surrounding tissues. Types of release that do not require energy. The histamine content of many tissues is directly ○ NOT ASSOCIATED with mast cell injury or related to their mast cell content. explosive degranulation. Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 2 of 13 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.  ○ Causes the granulation and histamine release. to treat inflammatory conditions and possibly pruritus and neuropathic pain III. PHARMACODYNAMICS OF HISTAMINE All histamine receptors are G-protein Coupled Receptors (GPCRs). Professor’s Notes: These receptors recognize a wide variety of signals Stimulation of H2 receptors increases cyclic AMP and ranging from photons to ions. proteins, leads to feedback inhibition of histamine release from mast neurotransmitters, and hormones which are important cells and basophils, whereas activation of H3 and H4 for signal transduction receptors has opposite effects by decreasing cellular cyclic AMP. RECEPTOR DESCRIPTION EFFECTS OF HISTAMINE IN THE ORGAN SYSTEMS H1 Bronchoconstriction Contraction of gut ORGAN DESCRIPTION *Vascular dilation both H1, H2 SYSTEM H2 Acid secretion by gastric parietal cells CVS Dilates resistance vessels Edema and stimulation of nerve ○ The activation of H2 receptors on ending the vascular smooth muscle stimulates the cyclic AMP-PKA H3 Auto-receptors on histaminergic pathway. This causes dilation that neurons develops more slowly and more ○ Inhibits histamine release sustained. Heteroreceptors on non-histaminergic Increases capillary permeability neurons ○ Increased capillary permeability is ○ Modulates the release of other the histamine’s effect on the small neurotransmitters vessel that results in the efflux of the plasma protein and fluid into H4 Blood the extracellular spaces and Eosinophils increase in lymph flow causing Dendritic Cells edema. Mast Cells ○ The H1 receptor activation on the Monocytes endothelial cells is the major Basophils mediator of this response. T Cells ○ If histamine is injected Chemotaxis intradermally, it elicits a 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 minute. The initial red spots RECEPTOR LOCATION AND CLINICAL APPLICATIONS result from the direct vasodilating effect of the H1 H1 and H2 are distributed widely in the histamine or H1 periphery and in your central nervous receptor-mediated nitric system (CNS) oxide production. Their activation by histamine can exert A clear or a red flush local or widespread effect extending about 1 cm beyond Majority of your H1 receptor agents the original red spot and are used for treatment of allergy developing more slowly and the flare is due to H2 H2 receptors are mainly expressed in histamine-induced the CNS, especially the basal ganglia. stimulation of axonal reflexes hippocampus, and cortex that causes vasodilation H2-mediated cyclic AMP signalling is indirectly. a crucial step in acid secretion by Wheel 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 non-histaminergic permeability or edema neurons → modulates the release of formation. other neurotransmitters Lowers Systemic Blood Pressure (SBP) H4 Because of the unique localization and ○ It causes depression of SBP. function of H4 receptors, H4 Histamine’s effect on the cardiac antagonists are promising candidates Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 3 of 13 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.  contractility and electrical events IV. ANTI-ALLERGY MEDICATIONS indirectly. ○ The direct cardiac effects of histamine given intravenously are overshadowed by baroreceptor reflexes stimulated by reduced blood pressure. ○ Histamine can also cause shock. If given in large doses for release during systemic anaphylaxis, can cause a profound progressive fall in blood pressure. Smooth Contractions Muscle ○ Histamine directly contracts or Anti-allergy Medications. Dr. Oliver’s Video Lecture on more rarely relaxes extravascular Anti-Allergy Drugs smooth muscles. ○ Contraction is due to activation of H1-receptor has both agonist and antagonist receptors. H1 receptors in smooth muscle The goal of allergy treatment is to suppress or inhibit to increase intracellular calcium cholinergic effects of inflammatory response. and relaxations mainly due to H1 receptor antagonist acts as an inverse agonist. activation of H2 receptors. ○ An inverse agonist is a drug that binds on the same Although the plasmogenic influence of receptor as your agonist, it induces a H1 receptors is dominant in human pharmacological response opposite to that of the bronchial smooth muscles, H2 agonist but the effects of both can be blocked by receptors with dilator function are also the antagonist. An agonist increases the activity of present. the receptor above its basal level, whereas inverse Thus, histamine induced agonist, it decreases the activity below the basal bronchospasm is potentiated slightly level. by H2 blocking. Patients with bronchial asthma and A. EFFECTS OF H1 RECEPTOR ANTAGONIST certain pulmonary diseases are much It inhibits all the effects of your histamine on the more sensitive to the cardiovascular, smooth muscle, nerve endings, and bronchoconstrictor effects of immune system. histamine. In the cardiovascular system, vasodilation, increase in capillary permeability, and hypotension is prevented. It inhibits most of the effects of histamine on smooth Peripheral Histamine stimulate various nerve muscle, especially in the constriction of your respiratory Nerve endings causing sensory defects: smooth muscle. endings ○ Epidermis - causes itch It inhibits the more rapid vasodilator effects mediated by ○ Dermis - evokes pain and activation of the H1 receptors on endothelial cells, which cause the synthesis, release of the nitric oxide, and sometimes accompanied by other mediators at a lower dose of histamine. itching It inhibits the venous constriction seen in some vascular Stimulant actions on the nerve beds. endings, including autonomic afferent It suppresses the action of the histamine on the nerve and efferent, contribute to the flare endings, including the flare component of the triple response and the itching caused by intradermal component of triple response and to injection. the indirect effects to the bronchi and It does not suppress gastric acid secretion. other organs ○ Gastric acid secretion is the function of th2 H2 receptor. However, the antimuscarinic properties of many H1 antagonists may contribute to the lessened secretion in cholinergically innervated CNS Neuronal histamine has stimulatory glands, which can reduce ongoing secretion in the and inhibitory functions in the CNS. respiratory tree. 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 shape change, chemotaxis, secretion of cytokines and upregulation of adhesion molecules Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 4 of 13 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.  DEPRESSION ○ Central depression usually accompanies therapeutic doses of the older H1 antagonists. ○ 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 Effects of H1 Receptor Antagonists. Dr. Oliver’s Video diphenhydramine) are Nonsedating because Lecture on Anti-Allergy Drugs particularly prone to they do not cross the cause sedation blood-brain barrier B. EFFECTS OF H1 RECEPTOR ANTAGONIST IN THE Because of its sedative This is due to their ORGANS effects, 1st Generation decreased lipophilicity, It does not suppress gastric acid secretion. antihistamines cannot and because they are ○ Gastric acid secretion is the function of the H2 be tolerated or used substrates of the receptor. However, the antimuscarinic properties of safely by many P-glycoprotein, which many H1 antagonists may contribute to the patients, except at pumps them out of the lessened secretion in cholinergically innervated bedtime BBB, capillary glands, which can reduce ongoing secretion in the endothelial cells, and respiratory tree. back to the capillary During hypersensitivity reactions, histamine is one of lumen many potent autacoids released, and its relative contribution on the ensuing symptoms varies widely with DRUG PROTOTYPE: DRUG PROTOTYPE: species and tissue. The protection accorded by H1 Diphenhydramine Cetirizine antagonists vary accordingly. Chlorpheniramine Levocetirizine In humans, edema formation and H are effectively Hydroxyzine Fexofenadine suppressed. Promethazine Loratadine It is ineffective in blocking bronchoconstriction due to Meclizine Desloratadine asthma. Many 2nd generation H1 antagonist, such as cetirizine, Tend to inhibit Have no effect on desloratadine, fexofenadine, olopatadine, ketotifen muscarinic cholinergic muscarinic receptors and others exhibit mast cell stabilizing effects resulting responses in a reduced release of mast cells mediator during an Can also be used to allergic response. These agents also have treat motion sickness, anti-inflammatory properties, which can induce reduce as a result of their cytokine secretion, decrease adhesion molecules anti-cholinergic expression, and inhibition of eosinophil infiltration. properties Promethazine has the strongest muscarinic blocking activity among these agents, and is the most effective H1 antagonist in combating motion sickness Effects of H1 Receptor Antagonists in the Organs. Dr. Oliver’s Video Lecture on Anti-Allergy Drugs The 1st generation H1 antagonist can both stimulate and depress the CNS. STIMULATION ○ Stimulation is occasionally encountered in patients given conventional doses. The patients become restless, nervous, and unable to sleep. ○ Central excitation is also a striking feature of overdose, which commonly results in convulsion, particularly in infants. Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 5 of 13 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.  when co-administered with When co- administered Effects of H1 Receptor Antagonist. Anti- Allergy Medications- drugs that induce CYP that compete with or inhibit Video Lecture Synthesis CYP isoform (Benzodiazepines) (Erythromycin, Some H1 antagonists have local anesthetic activity and Ketoconazole, Anti- few are more potent than Procaine-Promethazine is especially active. However the concentrations required depressants) for this effect are much higher than those that antagonize histamines interaction with its receptors. Lethal Ventricular Arrhythmias occur in several patients taking either of the early 2nd Generation agents such as C. PHARMACOKINETICS: H1 RECEPTOR ANTAGONIST Terfenadine and Astemizole, in combination with Ketoconazole, Itraconazole or Macrolide antibiotics such PHARMACOKINETICS OF H1 RECEPTOR as Erythromycin. ANTAGONIST These antimicrobial drugs inhibit the metabolism of many drugs by CYP3A4 and cause significant increase Absorption Well absorbed in the GI tract. in blood concentration of the anti histamines. Agents are rapidly absorbed after The mechanism of the toxicity involves blocking of the oral administration. potassium channel in the heart, the result is the Peak blood concentration occurs in 1 prolongation and a change in shape of the action to 3 hours. potential, and these changes lead to arrhythmia. Effects last 4 to 6 hours for 1st generation agents. However, some E. ADVERSE EFFECTS: H1 RECEPTOR ANTAGONIST drugs are much longer acting Adverse Effects of H1 Receptor Antagonist Distribution Widely distributed throughout the body. Sedation - most Blurred-vision The 1st generation can enter the CNS- it is why it can cause sedation frequent side effect Diplopia compared to 2nd generation drugs Dizziness Euphoria Tinnitus Nervousness Metabolism All 1st generations and most 2nd Flaccitude Insomnia generation are metabolized by CYPs Incoordination Tremors in the liver. Fatigue Some are extensively metabolized primarily by the microsomal system in the liver. Additional Potential Side Effects: Several of the 2nd generation agents Loss of appetite are metabolized by the CYP3A4 Nausea and vomiting system, thus are subject to important Epigastric distress interactions when other drugs (such Constipation as ketoconazole) inhibit this subtype Diarrhea of P450 enzymes. Note: May be reduced by taking the drugs with meals Excretion Histamine is excreted unchanged in the urine. Most appear as H1 Antagonist such as Cyproheptadine, may increase metabolites. appetite and may cause weight gain Many H1 antagonists have active Other side effects owing to anti-muscarinic action of metabolites, except; some First Generation H1 Antagonist: ○ Cetirizine and acrivastine which ○ Dryness of the mouth and respiratory passages are less than 40% metabolized. sometimes inducing cough ○ Fexofenadine, levocetirizine, ○ Urinary tension or frequency and epinastine are less than ○ Dysuria 10% metabolized. ○ Allergic dermatitis Cetirizine, levocetirizine, and ○ Other hypersensitivity reactions: acrivastine are excreted primarily into Drug fever the urine. Fexofenadine is mainly excreted in Photosensitization the feces. ○ Hematological complications: (Very rare) Epinastine is excreted in both urine Leukopenia, (55%) feces (30%). Agranulocytosis Hemolytic anemia D. DRUG INTERACTIONS: H1 RECEPTOR ANTAGONIST H1 receptor antagonists can cause some drug Professor’s/Editor’s Notes: interactions. The mentioned drugs under H1 receptor antagonists Plasma levels of H1 antagonists may be reduced usually have CNS adverse effects such as sedation and anti-inflammatory effect. REDUCED ELEVATED Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 6 of 13 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.  Dryness of the mouth and respiratory passages sometimes Sedative effects of first generation inducing cough, urinary retention or frequency, and dysuria antihistamine can impair learning and school are not observed with 2nd Generation H1 antagonists. performance First generation antihistamines are not recommended for use in children because their One particular H1 antagonist has notable side effects in sedative effects can impair learning and school satiety. performance. ○ Ex: Cyproheptadine can cause weight gain F. CLINICAL USE Teratogenic Non-teratogenic Antihistamines Antihistamines Azelastine Chlorpheniramine Hydroxyzine Diphenhydramine Fexofenadine Cetirizine Loratadine Combination of H1 Receptor Antagonist: Doxylamine + Vitamin B6 (Pyridoxine) ○ Treats nausea and vomiting for pregnancy ○ Related to teratogenic effects as antihistamine can be secreted in small amounts in breast milk ○ First generation antihistamines taken by lactating mothers can cause symptoms such as irritability, Some H1 antihistaminic drugs in clinical use. Anti-Allergy drowsiness, or respiratory depression in the nursing Medications Video Lecture. infant There are specific populations to consider when using Drugs under class Ethanolamines (Carbinoxamine, H1 receptor antagonists Dimenhydrinate, Diphenhydramine) are mainly used for ○ Pregnant patients mild sedation and anti-motion sickness. Antihistamine crosses the placenta ○ They also exhibit significant anticholinergic effects. Caution is advised for women who are or may ○ Anticholinergic drugs work by blocking the action of become pregnant acetylcholine, thereby blocking its Acute poisoning with first generation H1 antagonist neurotransmission, inhibiting involuntary muscle poses the greatest danger due to central excitatory movements and bodily functions. effects (syndrome resemble atropine poisoning): Drugs under class Piperazine derivatives ○ Hallucinations (Hydroxyzine, Cyclizine, Meclizine) are usually used for ○ Excitement motion sickness. ○ Ataxia ○ It has none to some anticholinergic activity. ○ Incoordination Drugs under class Alkylamines (Chlorpheniramine) are ○ Athetosis usually a component of common “colds” medications. ○ Convulsions ○ Has a slight sedative effect and some ○ Fixed, dilated pupils with a flushed face anticholinergic activity. ○ Sinus tachycardia Drug under class Phenothiazine (Promethazine) is the ○ Urinary Retention preferred therapy for motion sickness and can cause ○ Dry mouth marked sedation. ○ Fever Cyproheptadine is the only first-generation H1 receptor Suitable H1 Receptor Antagonist for Different Age antagonist that has a serotonin activity and used for Groups adjunctive treatment of patients with loss of appetite. ○ Elderly → H1 Receptor Antagonist Second 2nd generation H1 receptor antagonists are not Generation lipophilic and cannot cross the blood-brain barrier. Greater than 65 years old, especially with Hence, they have less sedative effects but have equal impaired cognition function effectivity in the treatment for allergy. these population lack sedative and anti-cholinergic effects for the first generation G. DRUG CLASSES drug ○ Children → H1 Receptor Antagonist Second 1. CLASS DIBENZOXAZEPINE Generation Second generation drug has been approved by Doxepin has activity both on H1 and H2 FDA for use in children and are available in receptors appropriate lower dose formulation such as Adjunct treatment for depression chewables, rapidly dissolving tablets or syrup Best given in younger age groups The use of over-the-counter cough and cold Causes drowsiness and sedation medications containing mixtures of antihistamine, decongestants, antitussive, and Olopatadine Used for allergic rhinitis and allergic expectorants in children has been associated conjunctivitis with serious side effects and even death. 2nd Gen H1 receptor Antagonist Topical H1 Antagonist Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 7 of 13 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.  (+) Mast cell stabilizing and Preferred drug for motion sickness anti-inflammatory effects 6. CLASS PIPERIDINE 2. CLASS ETHANOLAMINE Cyproheptadine 1st Gen H1 Receptor Antagonist Diphenhydramine 1st Gen H1 Receptor Used as an appetite stimulant Antagonist for patients with poor appetite Prototype drug Notable side effect: weight gain +++ Antimuscarinic Activity Only drug with both GI side effects are low antihistamine and anti-serotonin (+) effective drug for mild activity sedation Can cause drowsiness Has some anticholinergic effects 3. CLASS ETHYLENEDIAMINE Loratadine 2nd Gen H1 Receptor Antagonist Pyrilamine 1st Gen H1 Receptor Mainly used for allergic rhinitis Antagonist but is also used for other Same sedative effects (+) GI several allergic diseases effects Has mast cell-stabilizing and anti-inflammatory properties 4. CLASS ALKYLAMINE Desloratadine 2nd Gen H1 Receptor Antagonist Chlorphenamine 1st Gen H1Antagonist Active metabolite of Loratadine ++ Most potent H1 Antagonist Has similar effect to Loratadine S/E: CNS Stimulation but lacks significant Less drowsiness effect anticholinergic actions and Suitable for daytime use penetrate poorly into the CNS Has mast cell-stabilizing and Acrivastine 2nd Gen H1 Receptor anti-inflammatory properties Antagonist Higher incidence of mild Fexofenadine 2nd Gen H1 Receptor sedation Antagonist Non-sedating Has mast cell-stabilizing and 4. CLASS PIPERAZINE anti-inflammatory properties Hydroxyzine 1st Gen H1 Receptor Antagonist V. CORTICOSTEROIDS Has long-acting effect The predominant effect of corticosteroids is to switch off Used for skin allergies multiple inflammatory genes encoding cytokines, Similar sedative effects chemokines, adhesion molecules, inflammatory Can be used as adjunct treatment enzymes, receptors, and proteins that have been for anxiety (anti-anxiety drug) activated during acute or chronic inflammatory processes. Cyclizine and 1st Gen H1 Receptor Antagonists Corticosteroids have widespread effects on the gene Meclizine Used for motion sickness transcription. It increases the transcription of Less likely to cause sedation anti-inflammatory genes and it can also suppress compared to hydroxyzine transcription of many inflammatory genes. Steroids have many inhibitory effects on many Cetirizine Has minimal anticholinergic effect inflammatory and structural cells that are activated in Higher incidence of drowsiness asthma and prevent the recruitment of inflammatory compared to other 2nd Gen drugs cells into the airway. Has mast-cell and In cases like asthma, which is an inflammatory-mediated anti-inflammatory activity condition, oral, inhalational, and intravenous route can be used. Levocetirizine Active enantiomer 2nd Gen H1 Receptor Antagonist A. MODE OF ACTION: CORTICOSTEROIDS Has slightly greater potency During asthma, the inflammatory stimuli (e.g., IL-1β and May be used at half the dose with TNF-α) activate IKK-β leading to activation of the less resultant sedation transcription factor NF-kB Binding of this protein leads to activation of HAT 5. CLASS PHENOTHIAZINE (Histone Acetyltransferase), which is important in gene transcription and expression. Corticosteroid, as it enters the cell and binds to cytosolic Promethazine 1st Gen H1 Receptor Antagonist GR (Glucocorticoid Receptor) proteins, it forms Has sedative effects and some receptor-ligand complexes with HAT and CRBP binding cholinergic effects protein causing suppression of the gene transcription Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 8 of 13 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.  This eventually leads to suppressed activated ○ Lastly, the decrease of mucus secretion is partly inflammatory chain production. due to the resolution of respiratory edema brought about by an inflammatory process. B. PHARMACOKINETICS: CORTICOSTEROIDS IN ASTHMA PHARMACOKINETICS: CORTICOSTEROIDS IN ASTHMA Absorption Inhalational; Absorbed from the airway and alveolar surfaces Distribution Systemic A portion of an inhaled dose reaches the systemic circulation Anti-inflammatory action of Corticosteroids in Asthma The fraction of an inhaled steroid Intracellularly. Anti- Allergy Medications- Video Lecture that is deposited in the oropharynx is swallowed and absorbed from the At the cellular level, both inflammatory cells and gut structural cells (specifically of the bronchial airways) are affected by corticosteroids. Metabolism Liver The absorbed fraction may be metabolized in the liver and undergo first pass metabolism before reaching into the systemic circulation Excretion Kidney; Bile, Feces Most corticosteroids are conjugated with sulfates or glucuronides to increase their solubility in water and they are readily excreted via urine, bile, or feces. Corticosteroids affect both inflammatory and structural cells. C. ROUTE OF ADMINISTRATION: CORTICOSTEROIDS IN Anti- Allergy Medications- Video Lecture ASTHMA It is important in decreasing effective circulating 1.INHALED CORTICOSTEROIDS inflammatory cells leading to ineffective chemoattraction. It prevents further structural damage leading to The route recommended as first line therapy in case enhanced inflammatory recruitment of cells at the site of of acute exacerbation of asthma inflammation. They should be started in any patient who needs to use The net effect of corticosteroid use is suppression of Beta-Agonist inhaler for symptom control more than multi-level inflammatory response. twice weekly Explaining the diagram above, Effective in and among: ○ Corticosteroids decrease the number of circulating ○ Mild, moderate, and severe asthma eosinophils thereby decreasing modulation of ○ Children and adults inflammatory responses. Should be used twice daily ○ As a result, there will be a decrease of your ○ a regimen that improves adherence once control T-helper lymphocytes —> decrease in effective asthma has been achieved which may require cytokines, a chemoattractant —> decrease in other 4-time daily dosing initially or a course of oral inflammatory cells such as mast cells, steroid, if symptoms are severe. macrophages, and dendritic cells. For systemic steroids, we have oral and intravenous ○ During asthma, there are structural changes routes. causing hyperresponsiveness of the respiratory ○ Intravenous steroids are indicated in asthma if the airway. Symptoms of this are coughing, increased lung function is less than 30% predicted and in bronchial secretions, and bronchospasm. patients who show no significant improvement with ○ Therefore, corticosteroids decrease inflammatory nebulized beta 2 agonists. mediators, prevent and reverse the increase of ○ Hydrocortisone is the steroid of choice because it vascular permeability due to inflammatory has the most rapid onset. It is about 5-6 hours after mediators, and therefore lead to resolution of airway administration compared with 8 hour prednisolone. edema. ○ It is common to give hydrocortisone 4 mg/kg initially ○ However, corticosteroids have no direct effect on followed by a maintenance dose of 3 mg/kg every 6 the contractile responses of airway smooth muscles hours. and improvement in lung function after you inhaled ○ Methylprednisolone is also available for intravenous corticosteroids is presumably due to an effect of the use. chronic inflammation edema airway Intravenous therapy is usually given until a satisfactory responsiveness. response is obtained. Then oral prednisolone may be substituted. Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 9 of 13 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.  Inhaled corticosteroids are all equally effective as anti asthma drugs but there are differences in their Metabolic pharmacokinetics. abnormalities ○ Budesonide, fluticasone, mometasone and (glucose, insulin, ciclesonide have a lower oral bioavailability than triglycerides) your BDT. Psychiatric disturbances (euphoria, INHALED CORTICOSTEROIDS depression) Pneumonia Beclomethasone ICS should be given twice Budesonide daily. 2. SYSTEMIC CORTICOSTEROIDS Fluticasone Triamcinolone Once daily: Budesonide, Very effective to reduce inflammatory processes Mometasone, Ciclesonide, however it is related to several adverse effects Fluticasone especially with longer use and sudden withdrawal of the drug Side effects of long-term corticosteroids therapy All ICS are equally effective in Asthma ○ Fluid retention ○ Increased appetite INHALED CORTICOSTEROIDS ○ Weight gain ○ Skin and Capillary fragility Budesonide Lower oral Bioavailability ○ Hypertension Fluticasone than inhaled ○ Peptic ulcerations Mometasone beclomethasone (BDP) ○ Diabetes Ciclesonide because they are subject to ○ Psychosis a greater first pass hepatic ○ Dermal thinning metabolism which results in The frequency tends to increase with age reduced systemic Oropharyngeal candidiasis occurs in about 5% of the absorption from the fraction patients especially those who use Metered Dose of inhaled drug that is spacers for inhaled corticosteroids followed and thus reduce ○ May have local Side effects due to the deposition of adverse effect corticosteroid within the Oro-pharynx ○ Causes hoarseness and weakness of the voice Ciclesonide is a pro-drug (dysphonia) due to the atrophy of the vocal cords that is converted to the following laryngeal deposition of the steroids active metabolite by ○ Dermal thinning, skin and capillary fragility are esterases in the lungs common side effects for the elderly due to inhaled giving it a low bioavailability corticosteroids and a high therapeutic ○ Uncommon side effects for oral steroids: Cataracts index and osteoporosis Budesonide Fewer systemic effects 3. MAST CELL STABILIZERS Fluticasone propionate than inhaled Main action: Blocking triggered induced asthma such as beclomethasone and exercise induced asthma triamcinolone and they are Cromolyn Sodium preferred in patients who ○ “Disodium cromoglycate” need high doses of your ○ Derivative of a khellin, an Egyptian herbal remedy inhaled corticosteroid and ○ Was found to protect against allergen challenge in children without any bronchodilator effect ○ Popular in the past due to its good safety profile Fluticasone furoate Longest duration of However, its use has declined due to more action and is suitable for widespread use of more effective inhaled once daily dosing corticosteroids, particularly in children ○ Cromones are no longer recommended for asthma Usually combined with therapy long-acting beta-agonist ○ Interest continues in this compound as it causes (LABA) Vilanterol down regulation of your mast cell activity Nedocromil Sodium ○ Structurally related drug ADVERSE EFFECTS ○ Similar pharmacological profile to Cromolyn ○ Subsequently developed Local Side Effects Systemic Side Effects Dysphonia or Adrenal suppression VI. OTHER ANTI-ALLERGIC MEDICATIONS hoarseness of voice and insufficiency Oropharyngeal Growth suppression 1. IPRATROPIUM candidiasis Bruising Ipratropium bromide is an anticholinergic drug. Cough Osteoporosis Action: Prevents cholinergic-induced Cataracts bronchoconstriction and decreases mucus secretions. Glaucoma Pharmacology - Mod 4 🏠 Anti-Allergy Drugs 10 of 13 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.  Side effects: Dry mouth (most common), Tachycardia, Glaucoma, and Urinary retention. Sum of Proceeds to Plasma exudation, mucus This drug is usually in combination with Albuterol in pathways secretion, bronchoconstriction, and acute asthma therapy. eosinophil recruitment. 2. LEUKOTRIENES INHIBITORS Therefore, anti-leukotrienes block this mentioned Action: Blocks cys-LT1-receptors and provides modest pathway. clinical benefit in asthma. There is considerable evidence that cys-LTs or Cysteinyl 3. PSEUDOEPHEDRINE Leukotrienes are produced in asthma and that they have Used for temporary relief of stuffy nose and sinus pain potent effects in airway function. Inducing: and pressure caused by infection or other allergic ○ Bronchoconstriction conditions ○ Airway Hyperresponsiveness A sympathomimetic drug (mixed-acting adrenergic ○ Plasma exudation agonist) used primarily as a bronchodilator and nasal ○ Mucus secretion decongestant ○ Eosinophilic inflammation Acts like ephedrine but has similar pharmacological They inhibit the inhaled cys-LTs but they are less properties to epinephrine but has a longer lasting effect effective than inhaled corticosteroids in controlling and has a seamless stimulation asthma and preventing exacerbations. Administered orally and relatively well tolerated. 4. EPINEPHRINE Side effects: Headache, Eosinophilic Granulomatosis with Polyangiitis (EGPA), Neuropsychiatric events Drug prototype: Monteleukast MECHANISM OF ACTION IN ALLERGIES ○ have been associated with increased in serious neuropsychiatric events in children and adults Bronchodilation In cases of anaphylactic shock, including suicidal thoughts. for Anaphylaxis induces rapid bronchodilation acting at the B2 Receptors Anti-Inflammatory inhibits antigen-induced releases of