Adobe Systems Department of Pharmacology 1 Antihistaminines Adobe Systems 2 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 Adobe Systems 3 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 Adobe Systems 4 doi:10.1038/nrd2465 Adobe Systems 5 Histamine metabolism L-histidine histidinde karboxylase imidazole-N- methyltransferase Histamine metylhistamine diamine oxidase MAO metylhimidazole acetaldehyde imidazole acetaldehyde aldehyde dehydrogenase methylimidazole acid imidazeacetic acid Adobe Systems 6 Histamine receptors 4 subtypes (H1 – H4) G protein-coupled receptors their stimulation results in increase in cellular concentration of Ca2+ ions Adobe Systems 7 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 Adobe Systems 8 PL C Alberts et al., The molecular Biology of the Cell, 2002 Adobe Systems 9 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 Adobe Systems 10 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 Adobe Systems 11 H4 receptors possibly isoform of H3 Location: eosinophiles, basophiles, bone marrow, thymus, intestine, spleen Effects: influencing activity of immune system important for chemotaxis Adobe Systems 12 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) Adobe Systems 13 Histamine in clinical practise limited use (ineffective when given orally) diagnostics in allergology histamine analogue → betahistine Adobe Systems 14 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 Adobe Systems 15 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 Adobe Systems 16 Stephan C. Bischoff. Nature Reviews Immunology 7, 93-104, February 2007 Adobe Systems 17 Allergy treatment always as an addition to taking enviromental control measures and avoiding allergen H1- antihistamines glucocorticoids mast cells stabilizers immunotherapy epinephrine (anaphylactic shock) Adobe Systems 18 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 Adobe Systems 19 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! Adobe Systems 20 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 Adobe Systems 21 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.) Adobe Systems 22 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 Adobe Systems 23 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) Adobe Systems 24 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...) Adobe Systems 25 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 Adobe Systems 26 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) Adobe Systems 27 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) Adobe Systems 28 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