Antihistamines 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 • Histamin receptors •4 subtypes (H1 – H4) •G protein-coupled receptors •their stimulation results in increase in cellular concentration of Ca2+ ions • H1 receptors •postsynaptic, Gq-protein ↑ phospholipase C → ↑ IP3 and DAG → ↑ Ca2+ •Location: ‒endothel, smooth muscles (vessels, bronchi, uterus, GIT), peripheral neuron ending, CNS (!!!) •Effect: ‒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 – • • 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 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) •Effect: ‒sedation ‒negative chronotropic effect ‒bronchoconstriction • H4 receptors •possibly isoform of H3 •Location: •eosinophiles, basophiles, bone marrow, thymus, intestine, spleen •Effect: –influencing activity of immune system –important for chemotaxis • 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) – Histamine in clinical practise •limited use (ineffective when given orally) •diagnostics in alergology •histamine analogue → betahistin 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 •is used to evaluate the potential antialergic effect of H1 antihistamines Allergy treatment •always as an addition to taking enviromental control measures and avoiding allergen •H1- antihistamines •glucocorticoids •mast cells stabilizers •immunotherapy •epinephrine (anaphylactic shock) H1 antihistaminines •MoA: reversible competitive antagonism •they antagonize the allergy symptomes caused by histamine •high selectivity to H1 rp. → low affinity to H2 rp. •3 generations • •AE: –antimuscaric, antiserotonergic a antiadrenergic effects of older drugs of this group (sedation, fluctuating blood presure,...) – –block of Na+ channels → locally anaesthetic and antipruritic effect 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! 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 •promethazine •bisulepin •moxastine – for motion sickness •ketotifen • •sedative, even hypnotic eff.– driving, heavy mashinery operation (!) •paradoxical reaction (children, elderly) = excitation (sleeplessness, nervousness, tachycardia, tremor, ...) •indigestion (nauzea, vomiting, diarrhoea x constipation) •skin symptoms → phototoxicity •anticholinergic effects •increasment in appetite (antiserotoninergic effect) •ortostatic hypotension (weak block of α-adrenergic rp.) H1 antihistamines AE of I. generation •low distribution to CNS – minimal sedative effect •better properties – higher selectivity towards rp., less adverse effects •effect lasts for 12 – 24 hours, given 1 - 2 times a day • H1 antihistamines II. a III. generation II. generation •cetirizine •loratadine •fexofenadine III. generation •levocetirizine •desloratadine •bilastine •rupatadine 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) •arrythmogenic→ QT interval prolongation (some drugs even withdrawn) •possible sedation when overdosed (cetirizine) •Interaction: – are metabolised by CYP3A4 → be cautious of inhibitors of this isoform (macrolide ATB, azole antifungals, verapamil, grapefruit juice...) H1 antihistamines AE of II. generation •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 •migraine •nausea a vomiting –movement sickness (moxastine, embramine) –vertigo •prophylactic premedication before some drugs (e.g. monoclonal antibodies) – I. generation •sleeplessness, when hypnotics are not tolerated •anxiety (hydroxyzine → mild anxiolytic effect) H1 antihistamines Indication •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) • H1 antihistamines Contraindications 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