1. Nathan P. Samsa, Pharm.D., R.Ph.
Antihistamines
Nathan P. Samsa, Pharm.D., R.Ph.

2. My Objectives Answer the objectives they refuse to teach us
Design this lecture in a logical manor to facilitate understanding

3. Histamine Brief overview: Derived from amino acid histidine
“Antihistamine” is old terminology
Politically correct term: “H1-Receptor Antagonist” N H O 3 +
Histidine
decarboxylase
Histamine

4. Objectives
930
931
2937
2938
2939
2943
2946
2947

5. Antihistamines: 2937
Objective 2937: List three important sites where histamine is stored in the body, and describe/identify the types of cells which store histamine at these sites

6. Antihistamines: 2937 cont. Storage sites: Cellular production:
Gastrointestinal mucosa
Epidermis
Bronchial mucosa
Cerebrospinal fluid
Cellular production:
Mast cells-tissues (predominant)
Basophils-blood

7. Antihistamines: 2938
Objective 2938: Based on analog binding and resulting physiological changes distinguish among histamine receptor subtypes H1, H2, and H3

8. Antihistamines: 2938 cont. H1
Couples to Gq–protein to activate phospholipase C
Found throughout the CNS and densely concentrated in hypothalamus
Stimulates wakefulness

9. Antihistamines: 2938 cont. H2
Couples to Gs-protein to activate adenylyl cyclase
Found predominatly in the GI tract
Increases secretion of gastric acid from parietal cells in the stomach
Antagonists block acid secretion
Cimetadine (Tagamet®)
Famotidine (Pepcid®)
Nizatidine (Axid®)
Ranitadine (Zantac®

10. Antihistamines: 2938 cont. H3
Couples with Gi-protein to inhibit adenylyl cyclase
Proposed as a neural presynaptic auto-receptor serving to modulate histamine synthesis and release in the CNS, as well as neurotransmitters (e.g. acetylcholine, dopamine, GABA, norepinephrine, serotonin)
Peripheral tissue, including the gastric mucosa, where it may negatively control gastric acid secretion

11. Antihistamines: 2938 cont. H4
Couples with Gi-protein to inhibit adenylyl cyclase
Just recently discovered
The H4 receptor is highly expressed in peripheral blood leukocytes and intestinal tissue, making this receptor a potentially interesting target in allergic and inflammatory diseases

12. Antihistamines: 2943
Objective 2943: Describe the effects of histamine on:
Bronchiolar smooth muscle
The cardiovascular system
Nerve endings
Secretory tissues

13. Antihistamines: 2943 cont. Bronchiolar smooth muscle:
Contraction due to H1 activation
Dilitation due to H2 activation
Humans have less bronchoconstriction from histamine than other species
Leukotrienes and platelet activating factor are the major contributors of bronchoconstriction

14. Antihistamines: 2943 cont. The cardiovascular system:
“Triple Response”
Localized red spot-maximum diameter
Due to direct vasodilator effect of histamine
Brighter red flush (flare) extending around original spot
Due to indirect histamine stimulation of axons that cause vasodilation
Wheal that occupies original localized red spot
Due to direct vasoconstriction and edema formation

15. Antihistamines: 2943 cont. The cardiovascular system cont.:
Vasodilation:
H1 response is relatively rapid and short lived
On endothelial cells-secrete local vasodilatory substances which eventually stimulate NO production
H2 response is slower and more sustained
On vascular smooth muscle cells
Therefore H1 antagonists effectively counter small dilator responses to low concentrations of histamine, but only blunt the initial phase

16. Antihistamines: 2943 cont. The cardiovascular system cont.:
Vasoconstriction:
H1 stimulation causes postcapillary venules to contract, separating the cells, exposing freely permeable basement membranes
Edema
Permits passage of mast cells recruited to tissues

17. Antihistamines: 2943 cont.
The cardiovascular system cont.:

18. Antihistamines: 2943 cont. The cardiovascular system cont.: Heart:
H1 effects:
Acts directly to slow AV conduction
H2 effects:
Promotes influx of Ca2+
Increases heart rate by hastening diastolic depolarization in the SA node
Baroreceptor reflexes typically stimulate to counteract the decreased heart rate

19. Antihistamines: 2943 cont. Nerve endings:
Histamine stimulates various nerve endings
Epidermis: Itch
Dermis: Pain
Thought to be associated with the “flare” component of the triple response
Typically H1 receptor mediated

20. Antihistamines: 2943 cont. Secretory tissues:
Exocrine glands: potent stimulator of gastric secretion (HCl & pepsin)
Enhances salivary and lacrimal gland secretion (minimal unless large doses are given)
Stimulates chromaffin cells in adrenal medulla to secrete catecholamines

21. Antihistamines: 2939
Objective 2939: Explain how histamine may limit the intensity of allergic reactions in skin and blood

22. Antihistamines: 2939 cont.
In allergic response, IgE is generated and binds to mast cells and basophils
IgE binding causes eventual release of histamine from vesicles
The vasoconstrictive properties of histamine help to prevent spread of mediators from the immediate areas

23. Antihistamines: 2947
Objective 2947: Explain how first generation antihistamines produce sedation, urinary retention and even blurred vision

24. Antihistamines: 2947 cont.
Antihistamines exhibit effects other than H1-mediated
M1: Antimuscarinic activity
Atropine-like properties/“anti-SLUD”
Anti-parkisonism
Ethanolamines, ethylenediamines
α1: Alpha antagonism
Orthostatic hypotension
Phenothiazines

25. Antihistamines: 2947 cont. 5-HT2 IKr Anti-emetic Antivertigo
Relaxes gastric smooth muscle
Cyproheptadine, azatadine, phenothiazines
IKr
Prolong phase 3 of action potential by inhibiting potassium rectifier channels
Ethanolamines, piperidines
Anti-emetic
Medullary chemoreceptor trigger zone
Antivertigo
Diminishes vestibular stimulation

26. Antihistamines: 2947 cont. First generation antihistamines:
All have properties beyond peripheral H1 antagonism
Knowing the intricacies of the side effects help to tailor the drug to the patient
Many side effects are marketed a
Diphenhydramine
As Anti-allergy: Benadryl®
As Sleep aid: Unisom®

27. Antihistamines: 2947 cont. Second generation antihistamines:
Astemizole (off-market)
Desloratidine
Loratidine
Fexofenidine
Terfenadine (off-market)

28. Antihistamines: 2947 cont. Second generation antihistamines:
Second generation antihistamines do not cross the blood brain barrier well, thus they do not inhibit hypothalamic wakefulness
They bind much more selectively to peripheral H1 receptors and have a lower binding affinity for the cholinergic and alpha-adrenergic receptor sites than other antihistamines

29. Antihistamines: 2947 cont. First-&-a-half generation antihistamines:
Cetirizine
Still has higher incidence of drowsiness than true second generation agents
FDA does not allow cetirizine to be marketed as a second generation
Summary statement between generations:
1st generations bind non-selectively to central and peripheral H1-receptors while 2nd generations bind H1-receptors selectively

30. Antihistamines: 2946
Objective 2946: Describe the mechanism of potential drug-drug interactions which may lead to lethal ventricular arrhythmias in patients taking terfenadine and antibiotics such as erythromycin

31. Antihistamines: 2946 cont.
Erythromycin blocks the metabolism of either drug by inhibiting CYP3A4
Increased astemizole and terfenadine concentrations inhibit the potassium rectifier currents (IKr) in cardiac myocytes, therefore slowing repolarization

32. Antihistamines: 2946 cont.
Clinically manifested as prolongation of the QT interval, possibly leading to torsade de pointes
Ethanolamines and loratidine possibly

33. Antihistamines: 931
Objective 931: Discuss the pharmacology (mechanisms of action, pharmacodynamics, indications, and contra-indications) of the following antihistamines:
Ethanolamines: Dimenhydrinate, Diphenhydramine
Ethylaminediamines: Pyrilamine
Piperazine derivatives: Hydoxyzine, Cyclizine, Meclizine
Alkylamines: Brompheniramine, Chlorpheniramine
Phenothiazine derivatives: Promethazine
Piperidines: Fexofenadine
Others: Loratadine, Cetirizine

34. Antihistamines: 931 cont. Ethanolamines: Carbinoxamine (Cardec®)
Clemastine (Tavist®)
Dimenhydrinate (Dramamine®)
Diphenhydramine (Benadryl®)
Doxylamine (Unisom®)

35. Antihistamines: 931 cont. Ethanolamines: Highly anticholinergic
Structure mimics anti-muscarinics
Highly sedative
Crosses blood brain barrier readily
Low incidence of GI side effects
Diphenhydramine is metabolized into dimenhydrinate

36. Antihistamines: 931 cont. Ethylaminediamines (Ethylenediamines):
Pyrilamine (Triaminic®)
Tripelennamine (PBZ®)

37. Antihistamines: 931 cont. Ethylaminediamines (Ethylenediamines):
Very specific for H1 receptors
Moderate incidence of somnolence
Common GI side effects
Lower incidence of anticholinergic and anti-emetic properties than other classes

38. Antihistamines: 931 cont. Piperazines (Cylizines): :
Cetirizine (Zyrtec®)
Cyclizine (Marezine®)
Hydoxyzine (Atarax®, Vistaril®)
Meclizine (Antivert®)

39. Antihistamines: 931 cont. Piperazines (Cylizines):
Moderately potent antihistaminics with a lower incidence of drowsiness
Slow onset and long duration of action
Some piperazines exhibited a strong teratogenic potential, inducing a numberof malformations in rats
Cetirizine is a metabolite of hydroxyzine
Does not cross the blood brain barrier as well as hydroxyzine

40. Antihistamines: 931 cont. Alkylamines: Brompheniramine (Dimatapp®)
Chlorpheniramine (Chlor-Trimeton®)
Dexchlorpheniramine (Polaramine®)
Pheniramine (Poly-Histine®)
Tripolidine (Actidil®)
Pyrrolidines:
Acrivastine (Semprex-D®)

41. Antihistamines: 931 cont. Alkylamines: Most potent H1 antagonists
Generally regarded as one of the better daytime-use 1st generation H1 antagonists
Only moderate incidence of somnolence
Has some anticholinergic activity
CNS stimulation more common than other classe
Acrivastine does not display significant anticholinergic activity at therapeutic concentrations, and does not cross the blood brain barrier readily

42. Antihistamines: 931 cont. Phenothiazines: Methdilazine (Tacaryl®)
Promethazine (Phenergan®)
Trimeprazine (Temaril ®)

43. Antihistamines: 931 cont. Phenothiazines:
Have relatively high anticholinerc effects
Has some 5-H2 antagonistic effect
Major use is for anti-emetic properties

44. Antihistamines: 931 cont. Piperidines: Dibenzocycloheptenes/heptanes:
Azatadine (Optimine®)
Cyproheptadine (Periactin®)
Phenindamine (Nolahist®)
Second generationn piperidines:
Astemizole (Hismanal®)
Desloratidine (Clarinex®)
Fexofenadine (Allegra®)
Loratidine (Claritin®)
Terfenadine (Seldane®)

45. Antihistamines: 931 cont. Piperidines:
Highly selective for peripheral H1
Have no significant anticholinergic effects
Well tolerated
Astemazole and terfenadine were pulled from the U.S. market due to drug interactions
Desloratidine is a metabolite of loratidine
Fexofenadine is a metabolite of terfenadine
The heptanes have 5-HT2 & H1 antagonism

46. Antihistamines: 931 cont. Others: Loratadine, Cetirizine
If they researched better, they’d know these drugs fit in the classes already listed
Phthalazinones:
Azelastine (Astelin®)
Selective antagonism of H1-receptors versus other neurotransmitter receptors (low antimuscarinic activity)

47. Antihistamines: 930
Objective 930: explain why H1-antihistamines are clinically useful in treatment of allergic rhinitis and urticaria but not in management of bronchial asthma

48. Antihistamines: 930 cont.
Allergic bronchoconstriction is caused primarily by leukotrienes and platelet activating factor
This is why leukotriene receptor antagonists are a treatment in asthma management
In other animals, histamine causes allergic bronchoconstriction

49. References Basic & Clinical Pharmacology-Katzung
Goodman & Gilman’s The Pharmacological Basis of Therapeutics-Hardman
Principles of Medicinal Chemistry-Foye