Adobe Systems Department of Pharmacology Antihistaminines Adobe Systems Histamine - autacoid (local hormone) - endogenous amine (hydrophilic) - in tissues is formed from histidine Location: in granules in mast cells, basophiles (histaminocytes) → bound to heparan sulphate and acidic protein in almost all tissues, highest levels in lungs, GIT, skin Main roles in the body: neurotransmitter – CNS mediator of allergic/inflammatory reactions – mast cells, basophilles regulation of gastric acid release (↑) - stomach [USEMAP] Adobe Systems Histamine is released from mast cells granules by exocytosis (activation of phospholipase C a ↑ Ca2+) Stimuli: imunological: antigen + IgE physical, chemical or mechanical cell damage drugs [USEMAP] Adobe Systems doi:10.1038/nrd2465 [USEMAP] Adobe Systems Histamine metabolism L-histidine histidinde karboxylase imidazole-N- methyltransferase Histamine metylhistamine diamine oxidase MAO metylhimidazole acetaldehyde imidazole acetaldehyde aldehyde dehydrogenase methylimidazole acid imidazeacetic acid [USEMAP] Adobe Systems Histamine receptors 4 subtypes (H1 – H4) G protein-coupled receptors their stimulation results in increase in cellular concentration of Ca2+ ions [USEMAP] Adobe Systems H1 receptors postsynaptic, Gq-protein ↑ phospholipase C → ↑ IP3 and DAG → ↑ Ca2+ Location: endothel, smooth muscles (vessels, bronchi, uterus, GIT), peripheral neuron ending, CNS (!!!) Effects: smooth muscle contraction (bronchi, uterus, ileum) vasodilatation of minor vessels (↓BP, reddening of skin) increase in vessel permeability (swelling) irritation of peripheral neuron endings (itching, even pain) excitation of CNS [USEMAP] Adobe Systems H2 receptors postsynaptic, Gs-protein ↑ activity of adenylate cyclase → cAMP Location: stomach mucosa, heart, vessels, immune system Effect: in stomach: gastric acid, pepsine, intrinsic factor secretion slower and longer vasodilatation + inotropic, + chronotropic effect [USEMAP] Adobe Systems H3 receptors presynaptic, Gi protein → inhibition of N-type Ca2+ channels → ↓ cellular Ca2+ feedback inhibition of histamine release heteroreceptors, ↓ release of other neurotransmitters Location: mainly in CNS (but in PNS tissues as well) Effects: sedation negative chronotropic effect bronchoconstriction [USEMAP] Adobe Systems H4 receptors possibly isoform of H3 Location: eosinophiles, basophiles, bone marrow, thymus, intestine, spleen Effects: influencing activity of immune system important for chemotaxis [USEMAP] Adobe Systems Histamine in clinical practise limited use (ineffective when given orally) diagnostics in allergology histamine analogue → betahistine [USEMAP] Adobe Systems Lewis reaction typical response to intradermal histamine administration: skin reddening (vasodilatation of arterioles) wheal (capillary permeability) flare (redness in the surrounding area due to arteriolar dilatation mediated by axon reflex) used in allergy testing – positive control it is used to evaluate the potential antiallergic effect of H1 antihistamines [USEMAP] Adobe Systems How to antagonize effects of histamine? Treat the symptom vasoconstrictiors, sedatives, antacides, tocolytics etc. Treat the cause inhibition of synthesis (glucocorticoids) inhibition of release (cromoglycate, nedokromil, β2-SM, glucocorticoids) receptor antagonism: - non-specifically, indirectly (epinephrine) - specifically, directly (H1, H2, H3 - antihistaminines) [USEMAP] Adobe Systems Allergy has a high incidence, 10-30% (and growing) genetic factors various theories about its origin Mechanism of alergic reaction: early contact with allergen allergen binds to IgE antibody degranulation of cells containing histamine activation of phospholipase C → mobilization of intracellular Ca2+ → mediators are released: HIS, PG, LT, PAF, cytokines [USEMAP] Adobe Systems Stephan C. Bischoff. Nature Reviews Immunology 7, 93-104, February 2007 [USEMAP] Adobe Systems Allergy treatment always as an addition to taking enviromental control measures and avoiding allergen H1- antihistamines glucocorticoids mast cells stabilizers immunotherapy epinephrine (anaphylactic shock) [USEMAP] Adobe Systems H1 antihistamines MoA: antagonization of H1 receptor they antagonize the allergy symptomes caused by histamine high selectivity to H1 rp. → low affinity to H2 rp. 3 generations AE: antimuskaric, antiserotonergic a antiadrenergic effects of older drugs of this group (sedation, fluctuating blood presure,...) block of Na+ channels → locally anaesthetic and antipruritic effect [USEMAP] Adobe Systems H1 antihistamines pharmacokinetics Dosage forms: oral, topical, parenteral (i.m., infusion) easy and quickly absorbed from GIT distributed evenly in the body metabolized in liver (some in form of prodrug) excreted in urine, stool drugs of I. generation cross the blood-brain barrier → central effects (sedation) cross the placenta and are distributed into milk! [USEMAP] Adobe Systems H1 antihistamines - I. generation relatively old drugs in general lower selectivity to H1 receptors they cross the blood-brain barrier effect lasts approx. 4 - 6 h rather common adverse effects dimetinden (Fenistil®) promethazine bisulepin (Dithiaden®) moxastine – for motion sickness (Kinedryl®) cyproheptadine – treatment of serotonin syndrome ketotifen [USEMAP] Adobe Systems H1 antihistamines AE of I. generation sedative, even hypnotic eff.– driving, heavy mashinery operation (!) paradoxical reaction (children, elderly) = excitation (sleeplessness, nervousness, tachycardia, tremor, ...) indigestion (nausea, vomiting, diarrhea x constipation) skin symptoms → phototoxicity anticholinergic effects increas in appetite (antiserotoninergic effect) ortostatic hypotension (weak block of α-adrenergic rp.) [USEMAP] Adobe Systems H1 antihistamines II. and III. generation -low distribution to CNS – minimal sedative effect - -better properties – higher selectivity towards rp., less AE - - effect lasts for 12 – 24 hours, given 1 - 2 times a day II. generation •cetirizine •loratadine •fexofenadine •azelastine •levocabastine III. generation •levocetirizine •desloratadine •bilastine •rupatadine [USEMAP] Adobe Systems Novel H1 antihistamines III. generation bilastine high selectivity towards H1-receptors, antiinflammatory properties not metabolized by liver or intestinal wall, low potential for drug-drug interaction rupatadine long-term effect dual effect (H1 antagonist + blocks PAF receptors) [USEMAP] Adobe Systems H1 antihistamines AE of II. generation arrythmogenic→ QT interval prolongation (some drugs even withdrawn) possible sedation when overdosed (cetirizine) Interactions: are metabolised by CYP3A4 → be cautious of inhibitors of this isoform (macrolide ATB, azole antifungals, verapamil, grapefruit juice...) [USEMAP] Adobe Systems H1 antihistamines Indications I treatment of symptoms of allergic diseases - allergic rhinitis - urticaria, drug and food allergy add-on treatment of anafylactic reactions pruritus of various ethiology (e.g. itching in allergic and non-allergic dermatitis + insect bites) tinitus, Meniére‘s disease [USEMAP] Adobe Systems H1 antihistamines Indications II migraine nausea a vomiting movement sickness (moxastine, embramine) vertigo prophylactic premedication before some drugs (e.g. monoclonal antibodies) sleeplessness, when hypnotics are not tolerated anxiety (hydroxyzine → mild anxiolytic effect) [USEMAP] Adobe Systems H1 antihistamines Contraindications - alcohol dependency - hypersensitiveness to that substance - serious hypotension - simultaneous administration of sedative drugs (I.generation) - activities which require full attention (I.generation) - patients with history of arrythmias (II. generation) [USEMAP] Adobe Systems H3 antihistamines betahistine MoA: H3 antagonist, H1 agonist analogue of histamine improves microcirculation of the inner ear by vasodilatating capillaries indications: tinitus, vertigo, Menière‘s disease [USEMAP] Adobe Systems Department of Pharmacology Drugs used in diseases characterized by bronchial obstruction [USEMAP] Adobe Systems Bronchial asthma chronic inflammatory disease of airways affecting 300 million people all across the globe prevalence in CZ: 8 %, in children over 10 % Characteristics: bronchial hyper-reactivity obstruction (often reversible) inflammation Symptoms: shortness of breath (bronchoconstriction, mucous plug, oedema, airway remodeling due to the inflammation) difficult and prolonged expiration → wheezing, whistling cough (especially at night or in early morning) [USEMAP] Adobe Systems Bronchial asthma ALERGIC ASTHMA NON-ALERGIC ASTHMA •allergy not present •excercire-induced, aspirin-sesitive, infectious, work-related, endogenous [USEMAP] Adobe Systems https://www.canstockphoto.com/anatomy-of-asthma-6231875.html [USEMAP] Adobe Systems Diagnose Anamnesis – personal, familiar Clinical examinations - auscultation, signs of atopy, eosinophilia, PEF – Peak Expiratory Flow FEV 1 – Forced Expired Volume Laboratory tests- eosinophilia, IgE Allergy testing [USEMAP] Adobe Systems Classification with regard to seriousness Intermittent – sign up to once a week, night symptoms up to twice a month, pulmonary function normal Mild persistent– signs no more than once daily, night symptoms up to twice a month, PEF at least 80 % Moderate persistent– signs once a day and are not permanent, night sign no more than once a week, PEF 60-80 % Severe persistent– permanent signs, daily, obstruction, PEF ≤ 60 % [USEMAP] Adobe Systems Managment of asthma the disease itself cannot be fully treated, the goal is to keep asthma under control Goals: minimalize both acute and chronic symptoms reduction of exacerbations (lessen SABA administration) improvement of the quality of life (physical activity) avoid adverse effects of the treatment [USEMAP] Adobe Systems Chronic obstructive pulmonary disease (COPD) affecting 600 million people all across the globe prevalence: 8 % risk factors: smoking, polluted air, dust and chemical vapors at workplace, genetic predisposition Characteristics: chronic inflammation caused and maintained by long-term exposure to harmful agents (irritating gases and particles) poorly reversible, progressing bronchial obstruction production of mucus Symptoms: cough (usually whole day, hardly ever only during night) expectoration shortness of breath [USEMAP] Adobe Systems Managment of COPD we can only slow the progression reduction of risk factors is necessary (mainly top quit smoking) Goals: symptom reduction improvement in physical condition and overall health state prevention of complications and exacerbations [USEMAP] Adobe Systems Administration oral, parenteral (injections, infusions) inhalation - local administration, high drug concentration at the site of action - fast onset of the effect - - minimal penetration to systemic circulation → ↓ risk of side effects [USEMAP] Adobe Systems - β2 sympathomimetics - parasympatholytics - glucocorticoids - methylxanthines - roflumilast (COPD only) - antileukotrienes - imunoprofhylactics - monoclonal antibodies - noselective sympathomimetics (epinephrine, life-saving medication) - adjuvant medication (antitussics, drugs facilitating expectoration) BRONCHODILATATORS asthma only Drugs used in diseases characterized by bronchial obstruction [USEMAP] Adobe Systems β2 sympathomimetics MoA: selective β2 stimulants - inhibition of mediator release from mast cells + stimulation of ciliary beat frequency - diagnostics – post-bronchodilator test (salbutamol) - mostly inhaled, may be also given orally (mainly in kids) - not completely selective in their binding to β receptors long-term use = down-regulation of receptors [USEMAP] Adobe Systems β2 sympathomimetics Indication: asthma, COPD AE: nervousness, tremor, cephalgia, palpitation, hypokalemia (mainly when given orally) CI: hypertension, dysrhythmia, pregnancy [USEMAP] Adobe Systems β2 sympatomimetics Short-acting = SABA (also rapid-acting = RABA) fast onset of effect, which lasts 4 – 6 hours, inhalation salbutamol fenoterol Long-acting = LABA effect lasts for up to 12 hours, inhaled or administered orally salmeterol clenbuterol formoterol (RABA) indakaterol (U-LABA) vilanterol (U-LABA) [USEMAP] Adobe Systems Parasympatholytics MoA: competitive antagonism of M receptors - in a form of inhalation - can be combined with β2-sympathomimetics or glucocorticoids Indication: COPD, asthma AE: if entering the systemic circulation (low risk, they contain quaternary nitrogen in their structure) – anticholinergic effects CI: glaucoma, prostate hypertrophy, pregnancy [USEMAP] Adobe Systems Parasympatholytics ipratropium - used in asthma as well – in patients resistent to β2 sympathomimetic treatment (approx. 1/6 of patients) short acting (SAMA) aclidinium (LAMA) tiotropium (U-LAMA) glykopyrronium-bromide (U-LAMA) umeclidinium (U-LAMA) COPD only [USEMAP] Adobe Systems Glucocorticoids MoA: inhibition of phospholipase A2 by lipocortin Effects I: ↓ cytokine, PG a LT secretion ↓ lipolytic and proteolytic enzyme secretion ↓ endothelial permeability block of cell migration ↓ bronchial hyperreactivity, [USEMAP] Adobe Systems 45 Glucocorticoids Effects II: reduction of edema prevention of chronic irreversible changes (hypertrophy and hyperplasia of bronchial smooth muscles, subendothelial fibrosis and thickening of mucous basal membrane) increase in sensitivity of β2 adrenergic receptors to β2-SM [USEMAP] Adobe Systems MoA at the cellular level glucocorticoid + cytoplasma receptor production of specific mRNA production of some proteins (lipocortins) [USEMAP] Adobe Systems MoA at the cellular level After entering the cell they bind to specific receptors in cytoplasm causing change of conformation = activation of receptors Complexes of corticoid + receptor are transported to cell nucleus and bind to DNA elements. The result is increased transcription of genes either inducing or inhibiting synthesis of other proteins GLC receptors are present in all tissues!!! Proteins called lipocortins are able to suppress phospholipase A Slide3 [USEMAP] Adobe Systems Antiinflammatory effect of GC AA cascade inhibition membrane phospholipids lipocortin glucocorticoids phospholipase A2 arachidonic acid Inh. 5-LOX lipooxygenase A-A NSAIDs LEUKOTRIENS cyclooxygenase PROSTAGLANDINE PROSTACYCLINES TROMBOXANES inflammation Mobilization of fagocytosis Changes in vessels permeability Inflammation [USEMAP] Adobe Systems Glucocorticoids given by inhalation lower risk of systemic adverse effects AE: affected vocal cords – croaky voice, oral candidiasis (thrush) beclomethasone budesonide fluticasone ciclesonide mometasone systemic administration orally, via injection – acute conditions, doses are gradually decreased, in severe persistent asthma – if nothing else is effective prednisone triamcinolone hydrocortisone (injection) [USEMAP] Adobe Systems Methylxanthines MoA: phosphodiesterase 1 – 4 inhibitors adenosine receptors antagonists sustained-release drug forms Effects: – bronchodilatation – cardiostimulation (+chrono, +inotropic eff. ) – diuretic eff. – CNS and respiratory center stimulation – stimulation of hydrochloric acid secretion [USEMAP] Adobe Systems Methylxanthines Effects: - substrates of CYP450 – be cautious if patient is a smoker! CI: pregnancy, epilepsy, cardiovascular disease AE: tachycardia, palpitations, sleeplessness [USEMAP] Adobe Systems Methylxanthines theophylline - combination therapy with β2 SM is convenient - becoming obsolent, therapeutic drug monitoring needed - variable pharmacokinetics, low therapeutic index aminophylline - a complex of theophylline and ethylendiamine (better solubility) - COPD, emphysema [USEMAP] Adobe Systems roflumilast selective long-acting inhibitor of phosphodiesterase 4 reduces the inflammation in bronchi in COPD [USEMAP] Adobe Systems Antileukotrienes MoA: antagonism of LT-receptors / inhibition of lipoxygenase LT receptor antagonists: treatment of persisting asthma, allows lowering of glucocorticoid dose 1-2x a day, orally montelukast Inhibitors of LOX: need for frequent application not registered in CZ (zileuton – USA) [USEMAP] Adobe Systems Imunoprophylactics (mast cells stabilizers) MoA: stabilisation of mast cell membrane → ↓ Ca2+ influx → ↓ degranulation of mast cells and thereby ↓ histamine release influence on lymphocyte function prevention of asthma attack, they do not affect already present bronchospasm Use: as preventive, long-term, maintenance therapy – mild and moderate asthma when combined with other antiasthmatics, they allow lowering of their dose CI: pregancy (1. trimester) nedokromil, ketotifen (H1 antihistamine), cromoglycate [USEMAP] Adobe Systems Monoclonal antibodies Anti-IgE omalizumab antibodies against a part of IgE, which binds to mast cells Indication: severe persistent allergic asthma, which cannot be otherwise controlled administered subcutaneously in specialized centers only [USEMAP] Adobe Systems http://www.remedia.cz/Okruhy-temat/Respiracni-onemocneni/Omalizumab-terapeuticka-perspektiva-v-lecb e-tezkeho-bronchialniho-astmatu/8-1o-gD.magarticle.aspx vtextu20060906032727 Anti-IgE omalizumab [USEMAP] Adobe Systems Monoclonal antibodies Anti-IL-5 mepolizumab, reslizumab add-on treatment for severe refractory eosinophilic asthma in adult patients [USEMAP] Adobe Systems Other options Bronchial thermoplasty •bronchoskopic procedure, during which a therapeutic radiofrequency energy is delivered to the airway wall, resulting in reduction of smooth mucle cells Allergen immunotherapy •induces tolerance to the triggering allergen • • [USEMAP] Adobe Systems Devices for inhaled medications MDI = metered dose inhalers drugs as solutions, propellants BAI = breath-actuated inhalers DPI = dry powder inhalers spinhaler, diskhaler, turbohaler nebulizers (liquid → aerosol) [USEMAP] Adobe Systems Devices for inhaled medications spacers for children and elderly patient must be educated how to use their inhaler → up to 41 % of patients use incorrect technique inhalers often combine two drugs (bronchodilator + glucocorticoid or two bronchodilators) [USEMAP] Adobe Systems 200905280912_meshcare_4 article_images main Adobe Systems Adjuvant medication in diseases characterized by bronchial obstruction and another drugs affecting respiratory system antitussives drugs facilitating expectoration H1 antihistamines (mainly II. a III. generation) [USEMAP]