Antihistamines Histamine •chemical messenger that mediates many celular responses • –inflammation –allergic reaction – H1 –gastric acid secretion - H2 –neurotransmission – H3 – Release of histamine •stimuli causing histamine release • –„storage“ cell destruction •injury • –action of histamine deliberators •foreign proteins •drugs – curare, morphin •allergy, anaphylaxis Mechanism of action •binding to specific receptors on the cell surface •variety of responses •H1-H2 – important ligands •H3-H4 – no usefull ligands •metabotropic type • – Actions of histamine – H1 •exocrine secretion –increase of nasal and bronchial mucus production • ® respiratory symptoms of allergic reaction •bronchial smooth muscle –bronchoconstriction ® symptoms of asthma •intestinal smooth muscle –constriction ® cramps and diarrhoea •sensory nerve endings ® itching Actions of histamine – H1+2 •cardiovascular system –lowers blood pressure reducing peripheral resistance –positive chronotropism – •skin –rapid dilation and increased permeability of capilars •itching, swelling, pain, bladders Actions of histamine – H2 •stomach –stimulation of hydrochloric acid secretion • •direct vasodilatation –slower but persistent for a longer time Actions of histamine – H3 •CNS –inhibition of histamine release from histaminergic neurons – autoreceptors – –probably play an important role in satiety regulation Histaminergic drugs used in therapy •histamine – for diagnosis • •betahistine (analog) in Menier´s disease • H1 partial agonist/H3 antagonist • •betazol – H2 agonist (increases gastric secretion) Treatment possibilities •histamine – no clinical importance •mast cells stabilize agents •sodium cromoglycate, nedocromil •H1 antihistamines •1st gen. - diphenhydramine, promethazine, fenistil •2nd gen. - cetirizine, loratadine •3rd gen. - levocetirizine, desloratadine •H2 antihistamines •cimetidine, ranitidine, famotidine H1 Pharmacodynamics •Competitive antagonism - H1 •No efect on H2 – limited influence on blood vessels •Older compounds have anticholinergic, anti-5-HT and antiadreneric effects • •Block the allergy symptoms: –partially bronchoconstriction –rapid dilatation of blood vessels –increased membrane permeability –itching 1st generation •Pass BBB – sedative effect •diphenhydramine (hypnotic) (Psilo-Balsam) •moxastine (Kinedryl tbl) •clemastine (Tavegyl tbl) •dimetinden (Fenistil roll on) •promethazine (Prothazin tbl) – originally antipsychotic drug •bisulepine (Dithiaden tbl) •azelastine (Allergodil nas spr) 2nd generation •Do not pass BBB •Cetirizine •Loratadine –Both suitable for long-term therapy and small children (from 1 year) 3rd generation •Do not pass BBB; less/no effect on QTc • •Levocetirizine – Xyzal •Desloratadine – Aerius •Fexofenadine - Ewofex Use •non-complicated allergical symptoms •local treatment – insect sting •allergic itching •allergic rhinitis •motion sickness and nausea •sedatives •anaphylactic shock – i.v. • Adverse effects •sedation •inhibition of other receptors – cholinergic type M •atropin-like effect –dry mouth