H1 ANTIHISTAMINES Histamine, histamin receptors, H1 antihistamines PharmDr. Ondřej Zendulka, Ph.D. • biogenic amine, autacoid • in plants and animals as well • human – 3 functions • allergy mediator •HCl prosuction • neurotransmitter • • stored in mast cells • impulses for histamin release: 1.antigen + IgE 2.physical influence 3.drugs 4. HISTAMINE HISTAMIN- metabolismus histidindecarboxylase imidazol-N- methyltransferase diaminooxydase Histamine L-histidine methylhistamine methylimidazolacetic acid imidazolacetic acid imidazola cetaldehyde methylhimidazol acetaldehyde MAO aldehyddehydrogenase •subtypes H1-H4 •G protein coupled •stimulation = changes in intracelullar Ca2+ concentration H1 - endotel, smooth muscles of GIT, uterus and bronchi - capillary permeability increase, smooth muscles contractions, nervous system – CNS allertnes, PNS sensitive neurons stimulation H2 - gastric mucosa, imune system, vessels - HCl secretion, + ino a chronotropic effect - vasodilation HISTAMINE - receptors H3 - CNS and PNS - negative feedback of histamine liberation - sedation, negative chronotropic action, bronchoconstriction H4 - basophils, bone marrow, thymus, intestine, spleen - infleance on immune system activity - essential for chemotaxis HISTAMINE - receptors 1. CVS •vazodilation - H1 a H2 receptors •↓ BP, ↑ capillary permeability •+ chronotroic and inotropic effect H2 Rc Neurons •itching, pain H1 Rc CNS •regulation of vigilance GIT •HCl secretion H2 Rc •smooth muscle contraction H1 Rc HISTAMINE - effects 1. Erection •H2 receptors • Uterus •contraction • Skin •Lewis reaction (triple response) •capillary smooth muscle – red colour •capillary endothelium - swelling •sensory nerves –itching/pain • HISTAMINE - effects 1. Antagonism of histamine effects Symptomatic •vasoconstring. agents, sedatives, antacids, tocolytics atc. Causal •synthesis inhibition - glucocorticoids •release inhibition– cromoglycate, nedocromil, betablockers, glucocorticoids •receptor blockade - indirect – epinephrine - selective H1 H2 antihistamines HISTAMINE - effects Alergie •inappropriate immune system reaction to harmless environmental substances • •frequent illness 10-30% • •increasing incidence • •hereditary • Antihistamines - allergy Allergens • nonparasitic antigens causes I. type of hypersensitivity •herbal, animal, synthetic • Antihistamines - allergy Allergic reaction •acute response – reaction on antigen, histamine release, production of IL 4 and IgE • •late-phase response – with 4 and more hours of onset - migration of leukocytes into site of reaction and development of inflammation Antihistamines - allergy Allergic reaction symptoms •allergic rinitis • •allergic conjunctivitis • •allergic skin reaction • •allergic eczema • •allergic asthma • •anaphylactic reakce Antihistamines - allergy Diagnostic tools •case history •intradermal or prick tests •set of allergens is tested •principle – local allergic reaction is evoked • • •http://www.youtube.com/watch?v=5i5ni8E0spc •http://www.youtube.com/watch?v=4-tyrYDgTQw&feature=related •http://www.youtube.com/watch?v=CvUp6eqdG88&feature=related Antihistamines - allergy •after histamine intradermal injection Lewis reaction lichturtikaria1 Therapy •prevention •Immunotherapy •hyposensitisation + sublingual immunotherapy (SIT) •Omalizumab – anti IgE • •Pharmacotherapy •epinephrine – anaphylactic reaction •corticoids •H1 antihistamines Antihistamines - allergy •H1 receptors competetive antagonists •high specificity against H1 subtype •II. gen. – irreversible bound to Rc •all administration routes •classification into 2 generations • Indications: pharmacotherapy of allergic reactions adjuvans in therapy of anaphylaxis pruritus insect bite or sting nausea, vomitus insomnia loc. anaesthesia H1 Antihistamines Effects •smooth muscles – block of bronchoconstriction and decrease of GIT smooth muscle tone • •vessels - vasodilation block (partially via – H2 Rc) - ↓ capillary permeability •nervous system - CNS inhibition - sedation - local anaesthetic effect - block of sensitive nerves irritation H1 Antihistamines I. generation •less selective to H1 •cross BBB •action lasts for 4-6h •higher incidence of side effects AE: sedation antimuscarinic (atropine) activity allergy paradox stimulation abdominal dyscomfort antiserotonine and antiadrenergic effect H1 Antihistamines I. generation •clemastine (Tavegyl) •dimetindene (Fenistil, Vibrocil) •promethazine (Coldrex, Prothazin) •bisulepine (Dithiaden) •cyproheptadine (Peritol) •antazoline (Spersallerg, Sanorin-Analergin) •diphenhydramine (Psilo-Balsam) •ketotifene (Zaditen, Ketotifen) •chlorphenamine (Grippostad, Humex, Trigrip) •azelastine (Alergodil) • •embramine (Medrin) • moxastine (Kinedryl) H1 Antihistamines II. generation •higher selectivity against H1 •do not cross BBB = sedative activity not present •lower incidence of adverse effects •long biol. halftime 12-24h • Adverse effects: arythmias (terfenadinue and astemizole) sedation after overdosing inhibition of P450 H1 Antihistamines II. generation •cetirizine (Analergin, Zyrtec, Zodac) •levocetirizine (Sintir, Xyzal) •loratadine (Claritine, Flonidan, Roletra) •desloratadine (Aerius, Azomyr, Neoclarityn) •fexofenadine (Afexil, Ewofex, Telfast) •rupatadine (Tamalis) •acrivastine •ebastine •terfenadine •mizolastine H1 Antihistamines