Pharma Immune System PDF

Immunopharmacology...

Immunopharmacology Charles C. Monsada, MD I. IMMUNOSUPPRESSIVE AGENTS Drugs that suppress the immune response A. GLUCOCORTICOIDS B. IMMUNOSUPPRESSIVE ANTIBODIES Majority are immunomodulating pharmaceuticals, cytotoxic drugs originally applied in cancer therapy 1. IMMUNE GLOBULIN INTRAVENOUS (IGIV) Most are used as an effective treatment for autoimmune and 1 Hydrocortisone inflammatory diseases Prepared from pooled plasma of thousands of healthy donors, and These agents block lymphocyte activation and proliferation 2 Prednisone no single specific antigen is the target of the antibody. Reduce acute transplant rejection by suppressing cellular immunity Predominantly contains monomeric IgG, with limited amounts of (used as prophylaxis) 3 Triamcinolone dimers. Frequently combined to achieve greater efficacy with decreased toxicity 4 Provides intact and functional IgG molecules, which can provide the Betamethasone patient with broad spectrum antibodies and anti-idiotypes that Chronic suppression increases risk of infection 5 contain different immunomodulatory and not neutralizing antibodies. Dexamethasone The pool of different antibodies will have a normalizing effect on the Reduces inflammation via suppressive effects on the concentration, distribution, and function of peripheral leukocytes, inflammatory patient’s immune network. cytokines, and chemokines. Mainstay in the treatment of inflammatory diseases such as SLE (systemic lupus erythematosus) and Bronchial Asthma. Mechanism of Action ○ Associated with many side effects and toxicities Reduction of T helper cells 1. MECHANISM OF ACTION 2. EFFECT OF STEROIDS Increase of regulatory T cells ○ Suppress the immune response Inhibition of Phospholipase A2 The adverse effects of steroids are directly linked to the general effect of Decreased spontaneous immunoglobulin production ○ Part of the arachidonic acid pathway which is most steroids. Fc receptor blockade primarily involved in the process of inflammation Increasing serum glucose, a steroid effect, may be translated to developing ○ Fc - fragment crystallizable region Suppression of inflammatory cytokine production (IL-1, IL- hyperglycemia in patients. Increased antibody catabolism 2, TNF-a, IFN-v) Steroids may also increase fat deposition → weight gain, buffalo hump, and Anti–idiotypic activity or inhibition of cytokine synthesis/action Down regulation of destructive enzymes, collagenase moon facies, which is a characteristic of Cushing syndrome. production Steroids may also cause catabolism in the lymphoid, connective muscle, Clinical Use Summary of the actions of the different immunosuppressants. peripheral fat, and skin → muscle wasting, thinning of skin, impaired wound Usually varies, but it can be utilized primarily in: First Aid for the USMLE Step 1, 2015 edition healing, osteoporosis, and growth suppression. ○ Immunoglobulin deficiencies It may also reduce manifestations of inflammation, which is the preferred ○ Autoimmune diseases Calcineurin inhibitors, cyclosporine and tacrolimus, will bind with effect primarily in the context of immunopharmacology. Reduced ○ Bone marrow transplantation manifestations of inflammation → immunosuppression, and patients will cyclophilin. Once they bind with cyclophilin, they will then be able to actually be more at risk of different infections. 2. HYPERIMMUNE GLOBULINS block the T cell activation by preventing IL 2 transcription. Some patients may also have behavioral changes when taking steroids → insomnia, euphoria, or depression. IGIV preparations made from pools of selected human or animal Corticosteroids suppress both B and T cell function by decreasing Steroids are directly related to mineralocorticoids (e.g. aldosterone) → donors with high titers of antibodies from a particular virus or toxin transcription of many cytokines via alteration of the glucocorticoid hypertension, hypokalemia, and edema when these steroids stimulate IV administration reduces risk of severity of infection response element (GRE). mineralocorticoid receptors. ○ GRE is specifically present on the regulatory region of the gene In the long term effect of steroids, it may cause adrenal suppression. Clinical Use and regulates the transcription by RNA polymerase II and associated transcription factors. GLUCOCORTICOIDS Respiratory syncytial virus General Effects Adverse Effects Cytomegalovirus Sirolimus (Rapamycin) and everolimus are proliferation signal Increase serum glucose Hyperglycemia, Diabetes Mellitus Varicella zoster inhibitors. Specifically, they inhibit your mTOR (Molecular Target of Human herpes virus 3 Rapamycin). Weight gain, buffalo hump, moon Hepatitis B virus Net increase fat deposition ○ mTOR is a key component of a complex in the cellular signaling facies Rabies pathway involved in different cellular responses. Tetanus Muscle wasting, thinning of skin, Digoxin overdose ○ Blockade of mTOR will then lead to inhibition of interleukin driven Catabolism in lymphoid, connective Molecular level mechanism of action of corticosteroids. impaired wound healing, T-cell proliferation. muscle, peripheral fat, and skin Katzung's Basic & Clinical Pharmacology, 16th edition osteoporosis, growth suppression Azathioprine, an antimetabolite, is a precursor of the 6- Reduce manifestations of Immunosuppression, Peptic Ulcer mercaptopurine and will inhibit lymphocyte proliferation by blocking inflammation Disease the nucleotide synthesis. Behavioral changes Insomnia, euphoria → depression May stimulate mineralocorticoid Hypertension, hypokalemia, receptors edema May induce adrenal suppression C. CALCINEURIN INHIBITORS E. CYTOTOXIC AGENTS F. MONOCLONAL ANTIBODIES Humanized and chimeric monoclonal antibodies directed against a wide array of therapeutic targets 1. CYCLOSPORINE 1. AZATHIOPRINE Chimeric antibodies typically contain antigen-binding murine variable regions and human constant regions Most have a suffix -mab Differ with tacrolimus primarily on their binding site Prodrug of mercaptopurine Most are given primarily for cancer therapy Inactivated by Xanthine Oxidase ○ Other uses: utilized primarily for autoimmune disease therapy Mechanism of Action ○ Patients receiving Allopurinol for hyperuricemia should have the dose of Azathioprine reduced Binds to cyclophilin to act as a calcineurin inhibitor to 1/4 or 1/3 the usual amount to prevent toxicity MONOCLONAL ANTIBODIES FOR CANCER THERAPY Inhibits gene transcription of IL-2, IL-3, and IFN- Agent Target Clinical Use Regarding the binding site of distrons, they block specifically the T Mechanism of Action cell activation Alemtuzumab CD52 CLL, MS Produce Immunosuppression by interfering with purine nucleic acid metabolism at steps that are ○ Hence, inhibit gene transcription required for the wave of lymphoid cell proliferation after antigenic stimulation Clinical Use Metastatic colorectal cancer, Renal Clinical Use Adverse Effect Bevacizumab VEGF cell carcinoma, non-squamous non- Given orally or via IV, for tissue transplantation small cell lung cancer Rheumatoid arthritis Bone marrow suppression (causes Used in combination with methotrexate Crohn's disease pancytopenia) ○ standard prophylactic regimen to prevent graft versus host Multiple sclerosis Head and neck cancer; KRAS Skin rashes disease Prednisone-resistant antibody-mediated Fever Cetuximab EGFR negative, EGFR positive metastatic Autoimmune disorders idiopathic thrombocytopenic purpura Nausea and vomiting colorectal cancer ○ uveitis, rheumatoid arthritis, psoriasis Autoimmune hemolytic anemia Gastrointestinal symptoms (higher dosage) Hepatic dysfunction (high serum alkaline B cell non-Hodgkin lymphoma CLL, Adverse Effect phosphatase Rituximab CD20 rheumatoid arthritis, ITP Nephrotoxicity ○ one of the limiting factors for the use of the drug 2. CYCLOPHOSPHAMIDE Trastuzumab Her2/neu Breast cancer, gastric cancer ○ most important and limiting adverse effect Hypertension Alkylating agent Note: Dr. Monsada made a table but make sure to read the books also. Liver dysfunction Destroys proliferating lymphoid cells but also alkylate some resting cells Monoclonal antibodies also have other applications that are not specific to autoimmune diseases Hyperkalemia Altered mental status Clinical Use Adverse Effect MONOCLONAL ANTIBODIES FOR AUTOIMMUNE DISEASE THERAPY Seizure Agent Target Clinical Use Hirsutism In Smaller doses: Hematologic, gastrointestinal and Gingival hyperplasia Autoimmune disorder (SLE) mucocutaneous toxicity are common Antiplatelet agent for prevention of Acquired factor XIII antibodies Hemorrhagic Cystitis Platelet ischemic complications in patients Autoimmune hemolytic anemia ○ Most notable adverse effect of Abciximab 2. TACROLIMUS glycoproteins IIb/IIa undergoing percutaneous coronary Antibody-induced pure red cell aplasia Cyclophosphamide - Antidote MESNA intervention Wegener granulomatosis Cardiac toxicity Mechanism of Action Electrolyte disturbance Osteoporosis; inhibits osteoclast Mechanisms of action: Binds to the FK506 binding protein (FKBP) maturation (mimics Denosumab RANKL blocks T-cell activation (similar to cyclosporin) by preventing IL-2 Professor’s Notes: osteoprotegerin) transcription In the exam if you are asked what is the antidote of Cyclophosphamide you need to answer MESNA 10 to 100 times more potent than cyclosporine in inhibiting immune Omalizumab IgE Refractory allergic asthma response Ointment used in therapy for atopic dermatitis and psoriasis 3. PYRIMIDINE SYNTHESIS INHIBITORS RSV prophylaxis for high-risk Palivizumab RSV F protein infants Adverse Effect Leflunomide, Teriflunomide ○ Leflunomide – prodrug Similar to cyclosporine but it may also cause hypoglycemia and Ranibizumab, Bevacizumab Once metabolized in the body, the principal active metabolite will be Teriflunomide VEGF Neovascular … neurotoxicity (Avastin) In contrast with cyclosporin, it does NOT have gingival hyperplasia or hirsutism Mechanism of Action Both are notorious for their nephrotoxic effect OTHER APPLICATIONS OF MONOCLONAL ANTIBODIES Reversibly inhibit mitochondrial enzyme dihydroorotate dehydrogenase (involved in pyrimidine Agent Target Clinical Use D. PROLIFERATION SIGNAL INHIBITORS synthesis) → decreased lymphocyte activation Clinical Use Adalimumab, Certolizumab, IBD, rheumatoid arthritis, 1. SIROLIMUS, EVEROLIMUS Soluble TNF-alpha Golimumab, Infliximab ankylosing spondylitis, psoriasis Mechanism of Action Leflunomide Teriflunomide mTOR inhibitor. Approved for rheumatoid arthritis For relapsing remitting multiple sclerosis CD25 Daclizumab Relapsing multiple sclerosis Binds FKPB Should be started with loading dose Does not require a loading dose. (part of IL-2 receptor) Blocks T-cell activation and B-cell differentiation by preventing response to IL-2 Complement Paroxysmal nocturnal Adverse Effects Eculizumab Clinical Use protein C5 hemoglobinuria Kidney transplant rejection prophylaxis ADVERSE EFFECTS OF PYRIMIDINE SYNTHESIS INHIBITORS Use as prophylaxis for steroid-refractory acute and chronic GVH Natalizumab α4-integrin Multiple sclerosis, Crohn disease disease in hematopoetic stem cell transplant recipients Elevation of liver enzymes Leukopenia Renal impairment Thrombocytopenia Ustekinumab IL-12/IL-23 Psoriasis, psoriatic arthritis Adverse Effects Teratogenic Myelosuppression (especially thrombocytopenia) ★ should not be given primarily to pregnant patients. Hepatotoxicity Diarrhea Hypertriglyceridemia Pneumonitis Renal Toxicity is less common with proliferation signal inhibitors  II. IMMUNOSTIMULANT AGENTS PRACTICE QUESTIONS Drugs that increase the immune responsiveness of patients who have either selective or generalized immunodeficiency Reminder: each individual is assigned to make two (2) practice questions each, with respective rationales. Major potential uses include immunodeficiency disorders, chronic DISCLAIMER: Practice questions WERE NOT fact-checked and DID NOT undergo proofreading. Please be advised. You may comment on the specific question if you have any corrections. infectious diseases, and cancer A. CYTOKINES TITLE OF THE TOPIC A large and heterogenous group of proteins with diverse functions Immunoregulatory proteins synthesized by leukocytes and play numerous roles in the function of the immune system QUESTION RATIONALE ANSWER Able to mediate their effect to receptors of relevant cells, appear to act similarly to hormones Which among the following are pyrimidine synthesis inhibitors? E In other instances, cytokines may have antiproliferative, antimicrobial, and antitumor effects A. Leflunomide B. Teriflunomide CLINICAL USE C. Alemtuzumab Hairy cell leukemia, D. All of the above E. Only two among the choices Chronic myelogenous leukemia, INF α Malignant melanoma, Which among the following monoclonal antibodies targets Her2/neu Trastuzumab targets Her2/neu and is used primarily in patients with C Kaposi sarcoma and is commonly used in breast cancer therapy? breast cancer. INF B Relapsing-type multiple sclerosis A. Rituximab Reference: Video Lecture INF γ Chronic granulomatous disease B. Eculizumab IL-2 Metastatic renal carcinoma and malignant melanoma C. Trastuzumab D. Alemtuzumab TOXICITIES TRUE or FALSE: Aside from being mediators of immune function, Cytokines may also have antiproliferative, antimicrobial, and A Fever cytokines may also have antimicrobial effects antitumor effects. Malaise Myalgias A. TRUE Reference: Video Lecture Myelosuppression B. FALSE REFERENCES Katzung B, Vanderah T. Basic and Clinical Pharmacology. 15th Edition. McGraw-hIll Lange. 2021 Brunton L, Hilal-Dandan R, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 13th Edition, McGraw-H  Anti-allergy drugs Micah Muriel E. Oliver, MD, DPCP I. INTRODUCTION II. HISTAMINE A hydrophilic molecule consisting of an imidazole B. SYNTHESIS, STORAGE, AND METABOLISM A. IMPORTANCE OF STUDYING ANTI-ALLERGY MEDICATIONS ring and an amino group. It is connected by an ethylene group. 1. FORMATION 4. RELEASE 1. INCREASE IN BURDEN OF ALLERGIC DISEASES synthesized from histidine via decarboxylation Formed by decarboxylation of L-Histidine (an amino acid) a reaction The release of histamine is by two mechanisms: Acts through 4 classes of receptors: catalyzed in mammalian tissues by enzyme, L-Histidine ○ Immunologic Release Such as allergic rhinitis, dermatitis, asthma, and severe cases of ○ H1 anaphylaxis decarboxylase ○ Chemical/Mechanical Release ○ H2 Once formed, it is either stored or rapidly inactivated (metabolized) ○ H3 Very little are excreted and unchanged Immunologic Release 2. INCREASE IN DRUG OVERUSE ○ H4 Most of the anti-allergy medications are over-the-counter drugs, The four histamine receptors are all G protein-coupled 2. SYNTHESIS Most important pathophysiologic mechanism of histamine release. hence there is an increase in drug overuse. receptors (GPCRs). Synthesized in either a mast cell or non-mast cell site: Has an effector phase. ○ They can be differentially activated by analogues 3. IMPROVEMENT OF CLINICAL DECISION MAKING OF HEALTH PROCESS of histamine, and inhibited by specific antagonists. MAST CELL SITE NON-MAST CELL SITE CARE PROVIDERS Plays an important role in gastric acid secretion Functions as a neurotransmitter and neuromodulator Starts in the mast cells and basophils. The two cells are sensitive As physicians, we need to know by heart the management for Mast cells Epidermis 1 of both CNS and PNS by IgE antibodies causing the granulation. common allergic diseases, and the most commonly anticipated Basophils Neurons in CNS Also plays a role in immune function or in immediate adverse reactions or side effects. ○ Histamine functions as allergic response and chemotaxis of WBCs Knowledge on this will help us improve our clinical decision in neurotransmitter [6:12] in regenerating Granulation happens when mast cells and basophils are exposed managing common allergic diseases. or rapidly growing tissues 2 to appropriate antigen, leading to simultaneous release of A. DISTRIBUTION AND BIOSYNTHESIS Enterochromaffin-like cells (ECL) of histamine, ATP, and other mediators stored in the granules. B. SUMMARY OF ANTI-ALLERGY MEDICATIONS Generally, very low concentration in plasma and gastric fundus (mucosa) other body fluids ○ 2nd important non-neuronal site of It then triggers the exocytosis of the contents of the secretory ○ But significant in human CSF histamine storage and release 3 granules that in addition to histamine, includes serotonin, ANTI-ALLERGY MEDICATIONS High concentration in tissues containing large ○ Release histamine to activate the acid- proteases, lysosomal enzymes, cytokines, and proteoglycans. numbers of mast cells such as skin, bronchial producing parietal cells of the mucosa. 1st Generation mucosa, and intestinal mucosa ○ Turnover is rapid due to the continuous ○ Mast cells are specifically numerous at sites of As a result, it causes the mast cells to granulate and thereby, release of histamine, rather than it 4 potential tissue injury such as nose, mouth, feet, lead to histamine release. Diphenhydramine being stored. internal body surfaces, and blood vessels Chlorpheniramine (particularly at pressure points and bifurcation) Hydroxyzine 3. STORAGE SOME CHARACTERISTICS OF HISTAMINE Promethazine After being synthesized by mast cells and basophils, it is stored in Meclizine secretory granules. Negative Feedback It can modulate its own release and that of H1 Receptors ○ Most tissue histamine is sequestered and bound in granules or other mediators from synthesized mast Control Mechanism 2nd Generation vesicles in the mast cells or basophils. cells in some tissues by a negative The bound form of histamine is biologically inactive, but many stimuli feedback control mechanism mediated by Cetirizine can trigger the release of mast cell histamine, allowing the free amine to H2 receptors. exert its action to the surrounding tissues. Mast cells and basophils in skin show Levocetirizine The histamine content of many tissues is directly related to their mast negative feedback mechanisms unlike the Fexofenadine cell content. mast cells in lungs or the respiratory Loratadine The turnover rate of histamine’s secretory granule is slow, usually taking bronchioles do not. Desloratadine days to weeks. Hence, histamine can limit the intensity of the allergic reaction in the skin and blood. Beclomethasone Budesonide Chemotaxis Histamine has an active chemotactic Corticosteroids Fluticasone Triamcinolone attraction to inflammatory cells such as neutrophils, eosinophils, basophils, monocytes, and lymphocytes. Mast Cell Cromolyn sodium Stabilizers Nedocromil Histamine inhibits the release of lysosome contents in several T and B Ipratropium lymphocytes. Most of these reactions are mediated by: Leukotriene inhibitors ○ H2 or H4 receptors. Others Decongestants (Pseudoephedrine) Epinephrine (for anaphylactic shock) Release of the peptides from nerves in the response to inflammation is probably modulated by the histamine acting on the presynaptic H3 Corticosteroids have a role in the management of allergic diseases. receptors. Mast cell stabilizers are usually used for the treatment of asthma. Other medications are used as adjuncts or treatment for allergy Chemical and Mechanical Release Types of release that do not require energy. ○ NOT ASSOCIATED with mast cell injury or explosive degranulation. ○ Causes the granulation and histamine release.  III. PHARMACODYNAMICS OF HISTAMINE All histamine receptors are G-protein Coupled Receptors (GPCRs). These receptors recognize a wide variety of signals ranging from photons to ions. proteins, neurotransmitters, and hormones which are important for signal transduction EFFECTS OF HISTAMINE IN THE ORGAN SYSTEMS Smooth Contractions Muscle ○ Histamine directly contracts or more rarely relaxes RECEPTOR DESCRIPTION, LOCATION, AND CLINICAL APPLICATIONS extravascular smooth muscles. CVS Dilates resistance vessels ○ Contraction is due to activation of H1 receptors in smooth ○ The activation of H2 receptors on the vascular smooth muscle Bronchoconstriction muscle to increase intracellular calcium and relaxations stimulates the cyclic AMP-PKA pathway. This causes dilation Contraction of gut that develops more slowly and more sustained. mainly due to activation of H2 receptors. *Vascular dilation both H1, H2 Although the plasmogenic influence of H1 receptors is dominant in Increases capillary permeability human bronchial smooth muscles, H2 receptors with dilator H1 H1 and H2 are distributed widely in the periphery and in your central ○ Increased capillary permeability is the histamine’s effect on the function are also present. nervous system (CNS) small vessel that results in the efflux of the plasma protein and Thus, histamine induced bronchospasm is potentiated slightly by Their activation by histamine can exert local or widespread effect fluid into the extracellular spaces and increase in lymph flow H2 blocking. Majority of your H1 receptor agents are used for treatment of allergy causing edema. Patients with bronchial asthma and certain pulmonary diseases are ○ The H1 receptor activation on the endothelial cells is the major much more sensitive to the bronchoconstrictor effects of histamine. mediator of this response. *Vascular dilation both H1, H2 ○ If histamine is injected intradermally, it elicits a characteristic Edema and stimulation of nerve ending Peripheral Histamine stimulates various nerve endings causing sensory phenomenon known as “the triple response of Lewis” consists Nerve defects: of: H2 H2 receptors are mainly expressed in the CNS, especially the basal endings ○ Epidermis - causes itch Local reddening around the injection site for a few seconds ganglia. hippocampus, and cortex ○ Dermis - evokes pain and sometimes accompanied by itching and maximal at 1 minute. The initial red spots result from H2-mediated cyclic AMP signalling is a crucial step in acid secretion Stimulant actions on the nerve endings, including autonomic the direct vasodilating effect of the histamine or H1 by gastric parietal cells afferent and efferent, contribute to the flare component of triple receptor-mediated nitric oxide production. response and to the indirect effects to the bronchi and other organs Auto-receptors on histaminergic neurons A clear or a red flush extending about 1 cm beyond the ○ Inhibits histamine release original red spot and developing more slowly and the flare CNS Stimulatory: H3 is due to histamine-induced stimulation of axonal reflexes promote wakefulness, cognition, locomotion, energy metabolism, Heteroreceptors on non-histaminergic neurons that causes vasodilation indirectly. nociception. ○ Modulates the release of other neurotransmitters Inhibitory: Wheel or swelling that is discernible in 1-2 minutes at the suppress appetite, convulsions, stress-induced excitation, and Blood injection site will reflect histamine’s capacity to increase denervation-induced super sensitivity. Eosinophils capillary permeability or edema formation. Dendritic Cells Immune Activation of H4 receptors has been associated with induction of Mast Cells cellular shape change, chemotaxis, secretion of cytokines and Lowers Systemic Blood Pressure (SBP) System Monocytes upregulation of adhesion molecules Basophils ○ It causes depression of SBP. Histamine’s effect on the cardiac T Cells contractility and electrical events indirectly. Chemotaxis H4 GI Tract ○ The direct cardiac effects of histamine given intravenously are Dermal Fibroblast overshadowed by baroreceptor reflexes stimulated by reduced CNS blood pressure. Primary sensory afferent neurons Because of the unique localization and function of H4 receptors, H4 ○ Histamine can also cause shock. If given in large doses for antagonists are promising candidates to treat inflammatory conditions release during systemic anaphylaxis, can cause a profound progressive fall in blood pressure. and possibly pruritus and neuropathic pain Professor’s Notes: Stimulation of H2 receptors increases cyclic AMP and leads to feedback inhibition of histamine release from mast cells and basophils, whereas activation of H3 and H4 receptors has opposite effects by decreasing cellular cyclic AMP.  IV. ANTI-ALLERGY MEDICATIONS B. EFFECTS OF H1 RECEPTOR ANTAGONIST IN THE ORGANS C. PHARMACOKINETICS: H1 RECEPTOR ANTAGONIST It DOES NOT SUPPRESS gastric acid secretion. PHARMACOKINETICS OF H1 RECEPTOR ANTAGONIST ○ Gastric acid secretion is the function of the H2 receptor. H1 RECEPTOR BLOCKERS However, the antimuscarinic properties of many H1 Absorption Well absorbed in the GI tract. antagonists may contribute to the lessened secretion in 1st Generation 2nd Generation Agents are rapidly absorbed after oral cholinergically innervated glands, which can reduce ongoing administration. secretion in the respiratory tree. Has sedating effects Has a lesser sedative effect Peak blood concentration occurs in 1 to 3 hours. During hypersensitivity reactions, histamine is one of many potent Ethanolamines (i.e., Nonsedating because they Effects last 4 to 6 hours for 1st generation agents. autacoids released, and its relative contribution on the ensuing diphenhydramine) are do not cross the blood- However, some drugs are much longer acting symptoms varies widely with species and tissue. The protection particularly prone to cause brain barrier accorded by H1 antagonists vary accordingly. sedation This is due to their Distribution Widely distributed throughout the body. In humans, edema formation and H are effectively suppressed. Because of its sedative decreased lipophilicity, and The 1st generation can enter the CNS- it is why it Anti-allergy Medications. It is ineffective in blocking bronchoconstriction due to asthma. effects, 1st Generation because they are can cause sedation compared to 2nd generation Many 2nd generation H1 antagonist, such as cetirizine, antihistamines cannot be substrates of the P- drugs H1-receptor has both agonist and antagonist receptors. tolerated or used safely by glycoprotein, which pumps desloratadine, fexofenadine, olopatadine, ketotifen and The goal of allergy treatment is to suppress or inhibit cholinergic many patients, except at them out of the BBB, effects of inflammatory response. others exhibit mast cell stabilizing effects resulting in a reduced Metabolism All 1st generations and most 2nd generation are release of mast cells mediator during an allergic response. These bedtime capillary endothelial cells, metabolized by CYPs in the liver. H1 receptor antagonist acts as an inverse agonist. and back to the capillary agents also have anti-inflammatory properties, which can induce Some are extensively metabolized primarily by ○ An inverse agonist is a drug that binds on the same receptor as reduce cytokine secretion, decrease adhesion molecules lumen the microsomal system in the liver. your agonist, it induces a pharmacological response opposite to expression, and inhibition of eosinophil infiltration. Several of the 2nd generation agents are that of the agonist but the effects of both can be blocked by the DRUG PROTOTYPE: DRUG PROTOTYPE: metabolized by the CYP3A4 system, thus are antagonist. An agonist increases the activity of the receptor Diphenhydramine Cetirizine subject to important interactions when other drugs above its basal level, whereas inverse agonist, it decreases the Chlorpheniramine Levocetirizine (such as ketoconazole) inhibit this subtype of activity below the basal level. Hydroxyzine Fexofenadine Promethazine Loratadine P450 enzymes. A. EFFECTS OF H1 RECEPTOR ANTAGONIST Meclizine Desloratadine It inhibits all the effects of your histamine on the cardiovascular, Excretion Histamine is excreted unchanged in the urine. smooth muscle, nerve endings, and immune system. Tend to inhibit muscarinic Have no effect on Most appear as metabolites. cholinergic responses muscarinic receptors Many H1 antagonists have active metabolites, Can also be used to treat except; In the cardiovascular system, vasodilation, increase in capillary motion sickness, as a result ○ Cetirizine and acrivastine which are less than permeability, and hypotension is prevented. of their anti-cholinergic 40% metabolized. properties ○ Fexofenadine, levocetirizine, and epinastine It inhibits most of the effects of histamine on smooth muscle, Effects of H1 Receptor Antagonists in the Organs. Promethazine has the are less than 10% metabolized. especially in the constriction of your respiratory smooth muscle. strongest muscarinic Cetirizine, levocetirizine, and acrivastine are The 1st generation H1 antagonist can both stimulate and blocking activity among excreted primarily into the urine. It inhibits the more rapid vasodilator effects mediated by activation depress the CNS. these agents, and is the Fexofenadine is mainly excreted in the feces. of the H1 receptors on endothelial cells, which cause the synthesis, STIMULATION most effective H1 Epinastine is excreted in both urine (55%) feces release of the nitric oxide, and other mediators at a lower dose of ○ Stimulation is occasionally encountered in patients given antagonist in combating (30%). histamine. conventional doses. The patients become restless, nervous, and unable to sleep. motion sickness It inhibits the venous constriction seen in some vascular beds. ○ Central excitation is also a striking feature of overdose, D. DRUG INTERACTIONS: H1 RECEPTOR ANTAGONIST which commonly results in convulsion, particularly in H1 receptor antagonists can cause some drug interactions. It suppresses the action of the histamine on the nerve endings, infants. Plasma levels of H1 antagonists may be reduced DEPRESSION including the flare component of the triple response and the itching ○ Central depression usually accompanies therapeutic REDUCED ELEVATED caused by intradermal injection. doses of the older H1 antagonists. ○ Diminished alertness, slowed reaction times, and when co-administered with drugs When co- administered that somnolence (sleepiness/drowsiness) are common manifestations. that induce CYP Synthesis compete with or inhibit CYP Patients vary in their susceptibility and responses to individual (Benzodiazepines) isoform (Erythromycin, drugs. Ketoconazole, Anti- H1 receptor blockers are classified into 1st and 2nd generation. depressants) Lethal Ventricular Arrhythmias occur in several patients taking either of the early 2nd Generation agents such as Terfenadine and Astemizole, in combination with Ketoconazole, Effects of H1 Receptor Antagonist. Itraconazole or Macrolide antibiotics such as Erythromycin. These antimicrobial drugs inhibit the metabolism of many drugs Some H1 antagonists have local anesthetic activity and few are more potent than Procaine-Promethazine is especially active. by CYP3A4 and cause significant increase in blood concentration However the concentrations required for this effect are much of the anti-histamines. higher than those that antagonize histamines interaction with its receptors. The mechanism of the toxicity involves blocking of the potassium channel in the heart, the result is the prolongation and a change Effects of H1 Receptor Antagonists. in shape of the action potential, and these changes lead to arrhythmia. E. ADVERSE EFFECTS: H1 RECEPTOR ANTAGONIST G. DRUG CLASSES 1. CLASS DIBENZOXAZEPINE 6. CLASS PHENOTHIAZINE Adverse Effects of H1 Receptor Antagonist Teratogenic Antihistamines Non-teratogenic Antihistamines Doxepin has activity both on H1 and H2 Promethazine 1st Gen H1 Receptor Antagonist Sedation - most frequent Blurred-vision Azelastine Chlorpheniramine Diphenhydramine receptors Has sedative effects and some side effect Diplopia Hydroxyzine Cetirizine Adjunct treatment for depression cholinergic effects Euphoria Fexofenadine Dizziness Loratadine Best given in younger age groups Preferred drug for motion sickness Nervousness Tinnitus Causes drowsiness and sedation Insomnia Flaccitude Tremors Combination of 7. CLASS PIPERIDINE Incoordination Olopatadine Used for allergic rhinitis and allergic Fatigue H1 Receptor Antagonist: Doxylamine + Vitamin B6 (Pyridoxine) conjunctivitis ○ Treats nausea and vomiting for pregnancy Cyproheptadine 1st Gen H1 Receptor Antagonist 2nd Gen H1 receptor Antagonist Additional Potential Side Effects: ○ Related to teratogenic effects as antihistamine can be secreted in Used as an appetite stimulant for Topical H1 Antagonist Loss of appetite small amounts in breast milk patients with poor appetite ○ First generation antihistamines taken by lactating mothers can cause (+) Mast cell stabilizing and anti- Nausea and vomiting inflammatory effects Notable side effect: weight gain Epigastric distress symptoms such as irritability, drowsiness, or respiratory depression in Only drug with both antihistamine and Constipation the nursing infant There are specific populations to consider when using H1 receptor anti-serotonin activity Diarrhea 2. CLASS ETHANOLAMINE Can cause drowsiness antagonists ○ Pregnant patients Has some anticholinergic effects Note: May be reduced by taking the drugs with meals Antihistamine crosses the placenta Diphenhydramine 1st Gen H1 Receptor Antagonist Caution is advised for women who are or may become pregnant Prototype drug Loratadine 2nd Gen H1 Receptor Antagonist H1 Antagonist such as Cyproheptadine, may increase Acute poisoning with first generation H1 antagonist poses the greatest +++ Antimuscarinic Activity Mainly used for allergic rhinitis but is appetite and may cause weight gain danger due to central excitatory effects (syndrome resemble atropine also used for other several allergic GI side effects are low Other side effects owing to anti-muscarinic action of some poisoning): diseases (+) effective drug for mild sedation ○ Hallucinations First Generation H1 Antagonist: Has mast cell-stabilizing and anti- ○ Excitement ○ Dryness of the mouth and respiratory passages ○ Ataxia inflammatory properties sometimes inducing cough ○ Incoordination 3. CLASS ETHYLENEDIAMINE ○ Urinary tension or frequency ○ Athetosis Desloratadine 2nd Gen H1 Receptor Antagonist ○ Dysuria ○ Convulsions Pyrilamine 1st Gen H1 Receptor Antagonist Active metabolite of Loratadine ○ Fixed, dilated pupils with a flushed face Has similar effect to Loratadine but lacks Same sedative effects (+) GI effects ○ Sinus tachycardia significant anticholinergic actions and Side Effects Not Observed with 2nd Generation H1 ○ Urinary Retention penetrate poorly into the CNS Antagonist ○ Dry mouth ○ Fever Has mast cell-stabilizing and anti- 4. CLASS ALKYLAMINE Suitable H1 Receptor Antagonist for Different Age Groups