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Antiallergic drugs

Sumy State University. Antiallergic drugs. Lecture on pharmacology for 3-rd year students of medical institute Gluschenko N.V. Allergy. represents a sensitivity to a specific substance , called an allergen , that is contacted through the skin , inhaled into the lungs or injected.

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Antiallergic drugs

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  1. Sumy State University Antiallergicdrugs Lecture on pharmacology for 3-rd year students of medical institute Gluschenko N.V.

  2. Allergy • represents a sensitivityto a specificsubstance, calledanallergen, thatiscontactedthroughtheskin, inhaledintothelungsorinjected.

  3. The prevalence of allergic diseases and asthma is escalating. • Approximately 30 to 40 percent of the world’s population suffers from allergic diseases. • An estimated 300 million individuals worldwide have asthma, and this is likely to increase to 400 million by the year 2025.* • Allergic rhinitis, a risk factor for asthma, affects 400 million people annually, and food allergies affect 200 to 250 million. • The number of avoidable deaths from asthma occurring every year is estimated at 250,000.* *World Health Organization (WHO)

  4. Types of allergic reactions • (according to Gell and Cumbs): • I type reactions (anaphylactic) are a severe whole-body allergic reactions that occur within minutes ofexposure, progresses rapidly and can lead to anaphylactic shock and death. • Examples: • -anaphylactic shock; • -bronchial asthma. • II type reactions (humoral cytotoxic immune reactions) • Examples: • -transfusion reactions; • -Rh incompatibility

  5. Types of allergic reactions(according to Gell and Cumbs): • III type reactions (autosensibilization) Examples: -arthus reactions; -serum sickness. • IV type reactions Examples: -rejection of transplanted tissues; -contact dermatitis.

  6. Classification of allergic reactions in clinic: • 1.reactions of immediate type • (I, II, III after Cumbs) • 2. reactions of delayed type (IV type after Cumbs)

  7. Allergy - Diagnosis Skin test • Several allergens are introduced to the skin • The test is positive if the skin shows a reaction

  8. General principles of prevention and treatment of allergic reactions: 1) Avoiding contact with the allergen. 2) Performing specific desensitization by repeated introduction of small doses of specific antigen. 3) Performing nonspecific desensitization through administration of drugs which depress immune reactions (immune depressants). 4) Using antiallergic drugs which are able to prevent releasing the mediators of allergic reactions through stabilization of mast sells’ membranesor to block receptors with which these mediators interact in tissues. 5) Symptomatic treatment of allergic reactions manifestations which have already developed.

  9. Directions of therapy of hypersensitivity reactions of immediate type • 1)Antiallergic drugs : • а) drugs which stabilize membranes of mast cells and basophiles and slow down releasing of mediators of hypersensitivity reactions; • b) antihistamine drugs – block receptors with which histamine binds in the tissues. • 2) Drugs which decrease damage of the tissues: • Glucocorticosteroids. • 3) Drugs of symptomatic treatment: • Adrenalin; • euphyllin.

  10. Antihistamine drugs R1 CH3 CH2-CH2-N R1 CH3 Structure of nucleus of Н1histamine-receptors antagonists (H1histamine-blockers)

  11. Allergy - Histamine • Histamine: • Endogenousbioactiveamine: synthesized, storedandreleasedin • mastcells, whichareabundantintheskin, GI, andtherespiratorytract; • basophilsintheblood; • neuronsinthe CNS andPNS. • Physiologicalactions: • Primarystimulantforgastricacidandpepsinsecretion. • (acidsecretionisfurtherenhancedbygastrinandvagalstimulation) • Neurotransmitter(bothinthe CNS andperipheralsites). • Pathophysiologicalactions: • Mediatorofimmediatehypersensitivityreactionsandacuteinflammatoryresponses. • Anaphylaxis. • Duodenalulcer.

  12. Allergy - Histamine Receptors: • partofthesuperfamilyofG-proteincoupledreceptors H1-Receptors: • GqcoupledtoPhospholipase C. • CNS, smoothmusclecellsofairways, GI tract, cardiovascularsystem, endothelialcellsandlymphocytes => Vasodilation, bronchoconstriction, seperationofendothelialcells, painanditching, allergicrhinitis, motionsickness. H2-Receptors: • GscoupledtoAdenylylCyclase. • Parietalcellsof stomach; vascularsmoothmusclecells => mediatehistamineinducedgastricacidsecretion; vasodilation.

  13. Allergy - Histamine H3-Receptors: • Gi/o coupled to AC, also to N-type voltage gated Ca channels and reduce Ca influx. • CNS => Presynaptic, feedback inhibition of histamine synthesis and release; alsocontrols release of other neurotransmitters. H4-Receptors: • coupled to Gi/o in mast cells, can trigger calcium mobilization. • found primarily in bone marrow and immune cells => mast cell chemotaxis.

  14. Allergy - HistamineEffects ActionsofHistamine: Vascular: • H1 - vasodilationmediatedby NO andPGs (viaendothelialcells); • H2 - vasodilationmediatedbycAMP (vascularsmoothmusclecells); • H1 - coronaryvasoconstriction; • H1 - increasedpermeabilityofpostcapillaryvenules => edema. Heart: • H1 - decreased AV conduction; • H2 - increasedchronotropy; • H2 - increasedinotropy. Lung: • H1– bronchoconstriction; • H1 - increasedmucusviscosity; • H1 - stimulationofvagalsensorynerveendings: coughandbronchospasm. GastrointestinalSystem: • H2 - acid, fluidandpepsinsecretion; • H1 - increasedintestinalmotilityandsecretions. CutaneousNerveEndings: • H1 - painanditching.

  15. Symptomsrangefrommildallergicsymptomstoanaphylacticshock: Mild/cutaneous: erythema, urticaria, and/or itching. Moderate: skin reactions, tachycardia, dysrhythmias, moderatehypotension, mild respiratory distress. Severe/anaphylactic: severe hypotension, ventricular fibrillations, cardiac arrest,bronchospasm, respiratory arrest.

  16. Allergy - DrugsTargetingHistamine H1 Receptor Antagonists – H1-histamine blockers. They are antiallergic drugs. H2 Receptor Antagonists– H2-histamine blockers. This drugs decreas secretion of HCl, use for the treatment of stomach ulcer. Mast Cell Stabilizers

  17. Mechanism of action of“Antihistamines” drugs block histamine H1-receptors, reducing or eliminating the effects of histamine: spasm of the bronchial tubes, intestines, uterus, lower blood pressure, increased vascular permeability, itching, swelling, redness. block histamine receptors available. Drugs not displace molecules mediator, are connected to receptors. This is because the affinity of histamine for H1 receptors significantly higher.

  18. H1-Antagonists (“Antihistamines” drugs) Firstgenerationdrugs (Sedating): • Ethylenediamines: 1st antihistamines => obsolete • Ethanolamines: • Diphenhydramine (Dimedrol, Benadryl) • Doxylamine • Clemastine • Alkylamines:Chlorpheniramine (Suprasytine) • Piperazines: Diprasine, Meclizine, Hydroxyzine • Ather drugs: • Fenkarol • Diasoline

  19. PharmacologicalcharacterizationofantihistaminedrugsofthefirstgenerationPharmacologicalcharacterizationofantihistaminedrugsofthefirstgeneration • Peripheralanti-muscariniceffects: (alsoblockM-receptors). Cased by drymouth, blurredvision, constipation, urinaryretention. • Antyserotoninactivity (increaseof appetiteandincrease of bodyweight). • Potentiate CNS depressants (opioids, sedatives, generalanasthetics, alcochol). • Thereareaninjectableformsofreleasesousedforthetreatmentofacuteallergicconditions.

  20. PharmacologicalcharacterizationofantihistaminedrugsofthefirstgenerationPharmacologicalcharacterizationofantihistaminedrugsofthefirstgeneration • Effect occurs within 15-20 min. after administration. • Penetrate through blood/brain barrier (lipophilicity) and block H1-receptors of CNS, and as a result, cause sedation and reduce coordination of attention(contraindicated in occupations related to concentration). • Have short duration of action, as prescribed 3-4 times per day. • Prolonged use develops tachyphylaxis (reduced therapeutic efficiency). Therefore is necessary to replace one drug of another drug from this group every 7-10 days.

  21. Indicationsforuseofantihistaminedrugsofthefirstgeneration • Anaphylactic reactions. • Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis). • Sedative/sleep aid. • Prevention of motion sickness. • Premedication. • For potention of CNS depressants (opioids and nonopoid analgesics, sedatives drugs).

  22. Side effects of Н1-histamine receptors blockers of 1st generation 1) Depression of CNS (disorders of coordination, increased tiredness, dizziness,diplopia, tremor, euphoria, nervousness, insomnia). 2) Disturbance of GI functioning : increase of appetite, nausea, vomiting, pain in epigastria, constipation or diarrhea. 3) As a result of M-cholinoblocking activity – dryness of mucous membranes, eye disorders - blurred vision, impotence, ischuria, tachycardia, headache, psychosis. 4) In case of repeated administration – tachyphylaxis.

  23. H1-Antagonists drugs of the second generetion (non-sedating) • Terfenadine(Lamisil) • Astemisole(Hismanal) • Loratadine(Klaritin) • Akrivastine • Cetirisine(Zirtec) • Levakarbastine • Azelastine

  24. PharmacologicalcharacterizationofantihistaminedrugsofthesecondgenerationPharmacologicalcharacterizationofantihistaminedrugsofthesecondgeneration • High specificity and affinity to Н1-receptors. • Non penetrable through blood/brainbarrierin therapeutic doses (have not sedative action). • Absence of blockade of other types of receptors ( M-cholino-, Serotonin-receptors). • Thatwaydon’tincreaseof appetiteandbodyweight, don’t cased by drymouth, blurredvision, constipation, urinaryretention.

  25. PharmacologicalcharacterizationofantihistaminedrugsofthesecondgenerationPharmacologicalcharacterizationofantihistaminedrugsofthesecondgeneration • Have long duration of action (over 24 hours). Prescribe 1 time per day. • Absence of tachyphylaxis. Can be administered for a long time (up to 1 year). • After withdrawal of the drugs – have efficiency during the 1 week.

  26. Side effects of Н1-histamine receptors blockers of the second generation • Drugs are metabolized by CYP- 450 enzymes (Terfenadine and Astemisole) . • In patients with liver diseases, in case of higher daily doses, with administration of drugs that also are metabolized by CYP- 450 enzymes can cause ventricular tachycardia. • Examples of such drugs: • Macrolides (erythromycin, clarithromycin) • Antifungal drugs (intraconazole, ketaconazole). • Drugs are contraindicated during pregnancy and lactation.

  27. PharmacologicalcharacterizationofantihistaminedrugsofthethirdgenerationPharmacologicalcharacterizationofantihistaminedrugsofthethirdgeneration Drugs are pharmacologically active metabolites of antihistamine drugs of the second generation. Have been created to eliminate cardio-toxicity and enhance the effect.

  28. H1-Antagonists drugs of the third generetion (non-sedating) • Active metabolite of Terfenadine – is Fexofenadine (Allegra, Telfast, Fastofen, Tilfur,  Vifas, Telfexo, Allerfexo)

  29. H1-Antagonists drugs of the third generetion (non-sedating) • Active metabolite of Loratadine – is Dezloratadine • NeoClarityn,  • Claramax,  • Clarinex,Larinex,  • Aerius, Dazit,  • Azomyr,  • Deselex.

  30. H1-Antagonists drugs of the third generetion (non-sedating) Active metabolite of Cetirizine – is Levocetirizine (Xyzal)

  31. PharmacologicalcharacterizationofantihistaminedrugsofthethirdgenerationPharmacologicalcharacterizationofantihistaminedrugsofthethirdgeneration Have 3 mechanismsofaction: antihistaminic — blockingof Н1-histamine receptors; antiallergic — suppressionofleukotrieneandproinflammatorycytokineproduction; anti-inflammatoryeffect — decreaseinproductionofgranulocyticmacrophagefactor. Actionbeginin 15–30 minutesaftertheintakeandlastsmorethan 24 hours. Prescribe 1 time/day.

  32. PharmacologicalcharacterizationofantihistaminedrugsofthethirdgenerationPharmacologicalcharacterizationofantihistaminedrugsofthethirdgeneration • They are not linked to cytochrome Р450 system, and thus it does not overload hepatocytes in relation to detoxification function. Have not cardiotoxic action. • This medicinal drugsare excreted by liver and kidneys in unchanged state. Owing to such peculiarities, can be taken concomitantly with other preparations. •  Antibiotics • Antimycotics • Antidepressants • H2-histamine receptor blockers • Ethanol

  33. Indications for use of H1-Antagonists drugs of 2- and 3- generetions allergicrhinitisandpollinosis; allergicconjunctivitis, pharyngitis; acuteurticaria; atopicdermatitis; bronchialasthmaofallergicetiology; medicamentousallergy, whichismanifestedbyskinsymptomatic — theremaydevelopQuincke'sedema, Lyell'ssyndrome, andStevens-Johnsonsyndrome.

  34. Contrindications for use of H1-antagonistsdrugs of 2- and 3 generetions • Shouldnotbeusedincasesof: • Pregnancy. • Lactation. • Hypersensitivitytoanycomponentsofthepreparation. • Thepreparationshouldbeusedwithcautionin: • Severliverfailure. • Youngagepriorto 2 years.

  35. Mast Cell Stabilizers • Sodium Cromoglycate (Intal, Nasalcrom) • Nedocromil (Tilade)

  36. Mechanism of action • They block a calcium channel essential for mast cell degranulation, • stabilizing the cell and thereby preventing the release of histamine and related mediators. • One suspected pharmacodynamic mechanism is the blocking of IgE-regulated calcium channels. • Without intracellular calcium, the histamine vesicles cannot fuse to the cell membrane and degranulate.

  37. Indications for use: • Treatment of bronchial asthma ( As inhalers to prevent asthma attack). • Allergic rhinitis (as nasal sprays). • Allergic conjunctivitis (as eye drops). • Drugs only help prevent them - and they work best if and only if you use their regularly, and if you start using it well before (like 2-4 weeks before) the beginning of the season for your particular allergens.

  38. Allergy - Leukotrienes • Leukotrienes: • Generated by 5-Lipoxygenase: • Converts AA into 5-HPETE, which in turn is converted into • – LTB4: potent mediator of inflammation • and • – Cysteinyl-LTs (LTC4, LTD4, LTE4 = SRS-A): mediate asthmatic responses

  39. Physiological actions: LTB4: Cys-LTs: • Mediated by specific LTB4 receptor. • Adherence, chemotaxis and activation of macrophages. • Stimulates cytokine and chemokine production. • Present in inflammatory exsudates (RA, ulcerative colititis, psoriasis). • Mediated by shared receptor for LTC4, LTD4 and LTE4. • Contraction of bronchial muscles (longer lasting than histamine). • Peripheral vasodilation, coronary vasoconstriction. • Found in sputum of chronic bronchitis, asthmatic lung; lavage of allergic rhinitis.

  40. Classification • Leukotriene Esterase Inhibitors: (5-Lipoxygenase inhibitor) • Zileuton (Zyflo) 2. Cys-LTs-R antagonists: Montelukast (Singulair ) Zafirlukast (Accolate)

  41. Zileuton Mechanism of action: specific inhibitor of 5-lipoxygenase and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. Pharmacological effects: contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients.

  42. Montelukast and Zafirlukast • Mechanism of action • blocker Cys-LTs-R and prevent effects of cysteinyl -leukotrienes (LTC4, LTD4, LTE4) • Pharmacological effects: • Decrease airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. • In allergic rhinitis, decrease symptoms of nasal obstruction.

  43. Cys-LTs-R antagonists:

  44. Indications for use: • for the prophylaxis and chronic treatment of moderate and severe bronchial asthma in adults and children 12 years of age and older; • for the relief of symptoms of allergic rhinitis (seasonal allergic rhinitis in adults and pediatric patients 12 years of age and older); • aspirin-induced asthma.

  45. Side effects • Erythromycin reduces the absorption of zafirlukast, potentially reducing the effects of zafirlukast. • Hepatotoxicity. • Indicated in age only 12 and over. • Contraindicated during pregnancy and breast-feeding. • Expensive ($ 273 per month for zileuton).

  46. GLUCOCORTICOIDS Ant allergic and anti-inflammatory drugs

  47. Important agents • Injactable • Betamethasone • Prednisolone • Hydrocortisone • Dexamethasone • Methylprednisolone • Triamcinolone • Inhalation • Beclamethasone • Flunisalide • Budesonide

  48. Important agents Oral Topical • Betamethasone • Prednisolone • Methylprednisolone • Fludricortisone • Betamethasone • Flucinolone • Clobetasol • Mometasone

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