Antihistamines This study material is recommended specifically for practical courses from Pharmacology II for students of general medicine and stomatology. These brief notes could be used to prepare for the lesson and as a base for own notes during courses. Addititonal explanations and information are given in single lessons.

HISTAMINE CATEGORIZATION, CLASSIFICATION

HISTAMINE occurence: basic roles in the human body impulses for histamine release:

HISTAMINE- metabolism histidine decarboxylase imidazol-N- methyltransferase Histamine diaminooxidase MAO aldehyd dehydrogenase methylimidazolacetic acid imidazolacetic acid

endothel, smooth muslces Histamine receptors subtypes H1-H4 G protein coupled H1-receptors H2-receptors H3-receptors H4-receptors endothel, smooth muslces (vessels, bronchi, uterus, GIT), peripheral nerves, CNS gastric mucosa, heart, immune system, vessels, CNS CNS, PNS presynaptic neurons) H3 isoform (T-lymph., eosinoph., basoph., intestine, spleen, thymus)

HISTAMINE - receptors H1 H2

HISTAMINE - receptors H3 H4

HISTAMINE - effects Histamine effects antagonization Symptomatic Causal synthesis inhibition - glucocorticoids release inhibition– cromoglycate, nedocromil, β-sympatomimetics, glucocorticoids receptor antagonists - nonspecific, indirect– epinephrine - selective H1 H2 H3 antihistamines

Histamine therapeutic use negligible CI: allergic reactions, AB, pregnancy, HT, glucocorticoids,… dg. in allergology oraly not active Histamine analogue betahistine synthetic orogin, weak H1-agonist, strong H3 antagonist on presynaptic rcp.→ increase histamine turnover I: Menier‘s disease, vertigo, tinnitus, weak internal ear perfusion

Antihistamines – allergic reactions Hypersensitivity incidence development theories

Mechanism of allergic reaction

Signs of allergic reactions senzory nerves irritation vessel permeability increase smooth muscle contraction glandular hypersecretion

H1 - antihistamines ethanolamines alkylamines phenothiazines piperazines piperidines others R1 X – C – C - N R2

H1 – antihistamines: mode of action reversible competetive antagonism on H1 receptors

H1 – antihistamines: effects antagonize allergic symptomes induced by histamine: older agents penetrate BBB and gets into CNS

H1 – antihistamines- pharmacokinetics easy and fast GIT absorption equally sistributed in the body CNS penetration– presence of central symptoms: - „classic“ antihistamines get to CNS, do have suppressive and other effects on CNS - modern drugs of 2nd generation does not!! intensive metabolisation in liver with microsomal enzymes duration of effect: short acting 4 – 6hrs: most of classical H1 antihistamines long acting 12 – 24hrs: most of 2nd generation drugs routes of administration:

H1 – antihistamines: indications symptomatic treatment of hypersensitivity allergic rhinitis urticaria, drug and food allergies adjuvans in the treatment of anaphylaxis pruritus of different ethiology e.g.. allergic and non allergic itching dermatoses insect bites tinnitus, Menier‘s disease migraine nausea and vomitus kinetosis (moxastine, embramine) vertigo insomnia - when intolerance to hypnotics is present anxiety (hydroxyzine) - weak anxiolytic effect

H1 - antihistamines 1st generation older drugs generally lower selectivity to H1 subtype cross BBB effect app 4-6 hrs higher incidence of AE

H1 - antihistamines 1st generation clemastine dimetindene promethazine bisulepine cyproheptadine antazoline diphenhydramine ketotifen chlorphenamine azelastine embramine theoclate (=mebrofenhydrinate) moxastine theoclate (=mefenhydrinate) diphenhydramine theoclate (=difenhydrinate)

H1 anitihistamines Adverse effects CNS – sedation up to hypnotic effect paradoxical stimulation CI: GIT nausea, vomiting, diarhhoex constipation

H1 – antihistamines 2nd generation minimal penetration to CNS – minimal sedation more favorable – higher H1 selectivity, stroger binding to receptors administered once or twice a day

H1 – antihistamines 2nd generation Adverse effects arhytmogenic effect QT interval prolongation less in fexofenadin astemizole – withdrawn from market sedation after overdosing (cetirizine) Interactions: CYP3A4 inhibitors

H1 - antihistamines II. generation cetirizine levocetirizine loratadine desloratadin e terfenadine fexofenadine acrivastine ebastine rupatadine mizolastine

KONTRAINDIKACE H1 ANTIHISTAMINIK