ANTIHISTAMINES

1. ANTIHISTAMINES MODIFIED BY Israa

2. Histamine • Is an endogenous substance synthesized, stored and released in (a) mast cells, which are abundant in the skin, GI, and the respiratory tract, (b) basophils in the blood, (c) some neurons in the CNS andperipheral NS

3. IgE - Antibody Induced Release (food, penicillin, venoms, etc) ANTIGEN Y Y IgE Non-immune Releasers (opioids, tubocurarine, vancomycin etc) H H Inhibitors of Release (Cromolyn Albuterol) H H H H H ACUTE INFLAMMATORY RESPONSE IMMEDIATE HYPERSENSITIVITY REACTION

4. Effects of Histamine • ↑production of nasal & mucus secretion (H1) • Bronchial smooth muscle (H1) → bronchoconstriction. • Sensory nerve endings (H1) →cause itching & pain. • Stomach (H2) →↑gastric acid secretion. • Heart (H1& H2) →↑rate & force of contraction. • Arterioles (H1& H2) →vasodilatation. • Capillaries (H1)→ vasodilatation &↑ permeability result in redness

5. The pathological role of histamine • Cellular mediator of immediate hypersensitivity reaction and acute inflammatory response • Anaphylaxis • Seasonal allergies • Duodenal ulcers • Gastrinoma (Zollinger-Ellison Syndrome) • Systemic mastocytosis

6. Receptors of histamine It acts on specific receptors • H1-receptors occurs at postsynaptic sites-Smooth muscle ,Exocrine glands, Brain and Endothelium • H2-receptors occurs at postsynaptic sites-Gastric mucosa ,Heartand Mast cells • H3-receptors occurs at presynaptic sites-Nerve endings & Brain, inhibit the release of neurotransmitters. • H4- Highly expressed in bone morrow and white blood cells. Mediate mast cell chemotaxis.

7. Classification of antihistamines • They are classified into H1-blockers & H2-blockers. • No currently available antagonist for H3 orH4 Receptors

8. H1-blockers • They block the histamine action on H1 receptors • Best work if given before histamine release (prophylactically ) because they only bind to the free receptors • Can be divided in to • First Generation: Sedating • Second Generation: Non-sedating

9. First Generation Agents • Ethanolamines: DIPHENHYDRAMINE • Ethylenediamine: TRIPELENNAMINE • Alkylamine: CHLORPHENIRAMINE • Phenothiazine: PROMETHAZINE (Phenergan) • Piperazines: HYDROXYZINE

10. First Generation Agents uses • In anaphylaxis and other cases where histamine release can occur (epinephrine must also be used) Anti-allergy (allergic rhinitis, allergic dermatoses, contact dermatitis) • Sedative/sleep aid • To prevent motion sickness • Antiemetic: prophylactic for motion sickness • Antivertigo • Local anesthetic • Antitussive

11. Pharmacokinetics for the first generation • Are absorbed from the GIT. • Can also be given parenterally & topically. • Most of them appear widely distributed throughout the body, but some do not penetrate the BBB, • Are most effective when used prophylactically. • Most of the them are metabolized extensively in the liver.

12. additional effects of the first generation • Block H1 receptors CNS→ sedation, dizziness & fatigue. • Anticholinergic effect → dry mouth, urinary retention, tachycardia • α- blocking effect →postural hypotension, reflex tachycardia. • Antiserotonin effect → ↑appetite

14. Adverse Effectsof the first generation • Sedation (Paradoxical Excitation in children) • Dizziness • Fatigue • Tachydysrhythmias in overdose - rare • Peripheral antimuscarinic effects • dry Mouth • blurred Vision • constipation • urinary Retention

15. Adverse effects observed with first generation antihistamines

16. The use of first generation H1 antihistamines is contraindicated in treatment of individuals working in jobs where wakefulness is critical

17. Second generation H1-blockers • Examples for this group: loratadine,fexofinadine, cetirizine, astemazole • Are specific for H1 receptors. • Do not penetrate the BBB so they show less CNS toxicity.

18. Pharmacokinetics for the second generation • Cetirizine (C), loratadine (L), fexofenadine (F) • well absorbed and are excreted mainly unmetabolizedform. • C and L are primarily excreted in the urine • F is primarily excreted in the feces • They induce Cyt P450 liver enzymes

19. Adverse Effects of the second generation • in general, these agents have a much lower incidence of adverse effects than the first generation agents. • terfenadineand astemizolewere removed from the market due to effects on cardiac K+ channels - prolong QT interval (potentially fatal arrhythmia “torsades de pointes”)

20. H2-blockers These drugs produce their action by blocking histamine H2 receptors→↓ gastric acid secretion. Example: Cimetidine, ranitidine Will be discussed in GIT lectures

21. Treatment of cough Modified By :ISRAA

22. cough • Cough is a useful physiological mechanism that serves to clear the respiratory passages of foreign material and excess secretions. • It should not be suppressed indiscriminately. • There are, however, many situations in which cough does not serve any useful purpose but may, instead only annoy the patient or prevent rest and sleep.

23. Cough • Chronic cough can contribute to fatigue, especially in elderly patients, in such situations the physicians should use a drug that will reduce the frequency or intensity of the coughing. • Cough reflex is complex, involving the central and peripheral nervous systems as well as the smooth muscle of the bronchial tree.

24. Cough • It has been suggested that irritation of the bronchial mucosa causes bronchoconstriction, which in turn, stimulates cough receptors ( which probably represent a specialized type of stretch receptor) located in the tracheobronchial passages.

25. Types of cough • Acute cough =lasting<3 weeks • Chronic cough =lasing >8 weeks Cough may be i) Un productive (dry) cough OR ii) Productive cough (sputum)

26. Most common causes of cough • Common cold, • Upper/lower respiratory tract infection • Allergic rhinitis • Smoking • Chronic bronchitis • Pulmonary tuberculosis • Asthma • Gastroesophageal reflux • Pneumonia • Congestive heart failure • Bronchiectasis • Use of drugs (e.g., Angiotensin-converting enzyme inhibitors)

27. Treatment of Cough • Antitussives (cough center suppressants) • Expectorants • Mucolytics • Antihistamines • Pharyngeal Demulcents

28. 1) Antitussive • Antitussive drugs act by ill defined effect in the brain stem , depressing an even more poorly defined “cough center”. • All opioid narcotic analgesic have antitussive narcotic analgesic in doses lower than those required for pain relief • They have minimum analgesic and addictive properties • Newer agent that only act peripherally on sensory nerves in bronchi are being assessed

29. i)CODIENE • It is the gold standard treatment for cough suppression • It decreases the sensitivity of cough center in the CNS to peripheral stimuli, decrease the mucosal secretion which thicken the sputum, and inhibit ciliary activity • These therapeutic effect occur at doses lower than those required for analgesia but still incur common side effect like constipation, dysphoria, and fatigue, in addition to addiction potential

30. ii) DEXTROMETHORPHAN • Is a synthetic derivative of morphine that suppresses the response of the central cough center • It has no analgesic effect, has low addictive profile, but may cause dysphoria at higher doses • Has significantly better side effect profile than codeine and has been demonstrated to be equally effective for cough suppression

31. 2) Expectorants (Mucokinetics) • Act peripherally • Increase bronchial secretion OR • Decrease its viscosity and facilitates its removal by coughing • Loose cough ►less tiring & more productive

32. Classification of Expectorants Classified into a) Directly acting E.g., Guaifenesin (glycerylguaiacolate), Na+ & K+ citrate or acetate, b) Reflexly acting E.g., Ammonium salt

33. Directly acting expectorants i) Sodium & potassium citrate or Acetate • They increase bronchial secretion by salt action ii) Guaifenesin • Expectorant drug usually taken by mouth • Available as single & also in combination • MOA=Increase the volume & reduce the viscosity of secretion in trachea & bronchi

34. Reflexly acting expectorants • Ammonium salts • Gastric irritants = reflex increase in bronchial secretions + sweating

35. 3) Mucolytics • Help in expectoration by liquefy the viscous tracheobronchial secretions • E.g., Bromhexine, Acetyl cysteine, i) Bromhexine • Synthetic derivative of vasicine MOA of Bromhexine • a) Thinning & fragmentation of mucopolysaccaride fibers • b) ↑ volume & ↓ viscosity of sputum

36. 3) Mucolytics ii) Acetylcysteine • Given directly into respiratory tract • MOA of acetylcysteine: Opens disulfide bond in mucoproteins of sputum =↓ viscosity • Uses: • Cystic fibrosis Onset of action quick---used 2-8 hourly • Adverse effects: • Nausea, vomiting, bronchospasm in bronchial asthma

37. 4) Antihistamines • Added to antitussives/expectorant formulation • Due to sedative anticholinergic actions produce relief from cough but lack selectivity for cough center • No expectorant action =▼secretions (anticholinergic effect) • Suitable for allergic cough • E.g., Chlorpheniramineand diphenhydramine

38. 5) Pharyngeal demulcents • Soothe the throat (directly & also by promoting salivation • Reduces afferent impulses from inflamed/irritated pharyngeal mucosa • Provide symptomatic relief in dry cough arising from throat • E.g. lozenges, cough drops, glycerine, liquorice, honey

39. Good luck