Antihistamines

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Antihistamines

• Nathan P. Samsa, Pharm.D., R.Ph.

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My Objectives

• Answer the objectives they refuse to teach us
• Design this lecture in a logical manor to
  facilitate understanding

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Histamine

• Brief overview
• Derived from amino acid histidine
• Antihistamine is old terminology
• Politically correct term H1-Receptor Antagonist

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Objectives

• 930
• 931
• 2937
• 2938
• 2939
• 2943
• 2946
• 2947

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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

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Antihistamines 2937 cont.

• Storage sites
• Gastrointestinal mucosa
• Epidermis
• Bronchial mucosa
• Cerebrospinal fluid
• Cellular production
• Mast cells-tissues (predominant)
• Basophils-blood

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Antihistamines 2938

• Objective 2938 Based on analog binding and
  resulting physiological changes distinguish among
  histamine receptor subtypes H1, H2, and H3

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Antihistamines 2938 cont.

• H1
• Couples to Gqprotein to activate phospholipase C
• Found throughout the CNS and densely concentrated
  in hypothalamus
• Stimulates wakefulness

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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

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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

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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

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Antihistamines 2943

• Objective 2943 Describe the effects of histamine
  on
• Bronchiolar smooth muscle
• The cardiovascular system
• Nerve endings
• Secretory tissues

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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

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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

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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

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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

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Antihistamines 2943 cont.

• The cardiovascular system cont.

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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

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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

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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

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Antihistamines 2939

• Objective 2939 Explain how histamine may limit
  the intensity of allergic reactions in skin and
  blood

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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

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Antihistamines 2947

• Objective 2947 Explain how first generation
  antihistamines produce sedation, urinary
  retention and even blurred vision

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Antihistamines 2947 cont.

• Antihistamines exhibit effects other than
  H1-mediated
• M1 Antimuscarinic activity
• Atropine-like properties/anti-SLUD
• Anti-parkisonism
• Ethanolamines, ethylenediamines
• a1 Alpha antagonism
• Orthostatic hypotension
• Phenothiazines

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Antihistamines 2947 cont.

• 5-HT2
• 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

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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

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Antihistamines 2947 cont.

• Second generation antihistamines
• Astemizole (off-market)
• Desloratidine
• Loratidine
• Fexofenidine
• Terfenadine (off-market)

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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

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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

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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

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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

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Antihistamines 2946 cont.

• Clinically manifested as prolongation of the QT
  interval, possibly leading to torsade de pointes
• Ethanolamines and loratidine possibly

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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

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Antihistamines 931 cont.

• Ethanolamines
• Carbinoxamine (Cardec)
• Clemastine (Tavist)
• Dimenhydrinate (Dramamine)
• Diphenhydramine (Benadryl)
• Doxylamine (Unisom)

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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

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Antihistamines 931 cont.

• Ethylaminediamines (Ethylenediamines)
• Pyrilamine (Triaminic)
• Tripelennamine (PBZ)

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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

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Antihistamines 931 cont.

• Piperazines (Cylizines)
• Cetirizine (Zyrtec)
• Cyclizine (Marezine)
• Hydoxyzine (Atarax, Vistaril)
• Meclizine (Antivert)

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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

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Antihistamines 931 cont.

• Alkylamines
• Brompheniramine (Dimatapp)
• Chlorpheniramine (Chlor-Trimeton)
• Dexchlorpheniramine (Polaramine)
• Pheniramine (Poly-Histine)
• Tripolidine (Actidil)
• Pyrrolidines
• Acrivastine (Semprex-D)

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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

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Antihistamines 931 cont.

• Phenothiazines
• Methdilazine (Tacaryl)
• Promethazine (Phenergan)
• Trimeprazine (Temaril )

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Antihistamines 931 cont.

• Phenothiazines
• Have relatively high anticholinerc effects
• Has some 5-H2 antagonistic effect
• Major use is for anti-emetic properties

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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)

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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

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Antihistamines 931 cont.

• Others Loratadine, Cetirizine
• If they researched better, theyd know these
  drugs fit in the classes already listed
• Phthalazinones
• Azelastine (Astelin)
• Selective antagonism of H1-receptors versus other
  neurotransmitter receptors (low antimuscarinic
  activity)

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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

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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

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References

• Basic Clinical Pharmacology-Katzung
• Goodman Gilmans The Pharmacological Basis of
  Therapeutics-Hardman
• Principles of Medicinal Chemistry-Foye
• http//web6.duc.auburn.edu/deruija/hist_antihis.p
  df
• http//www.courses.vcu.edu/ptxed/m2/powerpoint/dow
  nload/Lichtman20Antihistamine.PDF
• http//www.duc.auburn.edu/deruija/hist_intro.pdf
  
• http//www.sigmaaldrich.com/sigma/rbi-handbook/sg_
  ls_cs_rbibook_histamine.pdf