Transcript Respiratory Pharmacology Objectives

Antihistamines
Nathan P. Samsa, Pharm.D., R.Ph.
My Objectives
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Answer the objectives they refuse to
teach us
Design this lecture in a logical manor to
facilitate understanding
Histamine
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Brief overview:
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Derived from amino acid histidine
O
H
N
+
NH 3
N
Histidine
O
O
H
Histidine
N
decarboxylase
O
N
Histamine
“Antihistamine” is old terminology
 Politically correct term: “H1-Receptor
Antagonist”
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Objectives
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930
931
2937
2938
2939
2943
2946
2947
Antihistamines: 2937
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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
Antihistamines: 2937 cont.
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Storage sites:
Gastrointestinal mucosa
 Epidermis
 Bronchial mucosa
 Cerebrospinal fluid
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Cellular production:
Mast cells-tissues (predominant)
 Basophils-blood
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Antihistamines: 2938
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Objective 2938: Based on analog binding
and resulting physiological changes
distinguish among histamine receptor
subtypes H1, H2, and H3
Antihistamines: 2938 cont.
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H1
Couples to Gq–protein to activate
phospholipase C
 Found throughout the CNS and densely
concentrated in hypothalamus
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Stimulates wakefulness
Antihistamines: 2938 cont.
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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
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Cimetadine (Tagamet®)
 Famotidine (Pepcid®)
 Nizatidine (Axid®)
 Ranitadine (Zantac®
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Antihistamines: 2938 cont.
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H3
Couples with Gi-protein to inhibit adenylyl
cyclase
 Proposed as a neural presynaptic autoreceptor 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.
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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
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Objective 2943: Describe the effects
of histamine on:
1. Bronchiolar smooth muscle
2.The cardiovascular system
3.Nerve endings
4.Secretory tissues
Antihistamines: 2943 cont.
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Bronchiolar smooth muscle:
Contraction due to H1 activation
 Dilitation due to H2 activation
 Humans have less bronchoconstriction from
histamine than other species
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Leukotrienes and platelet activating factor are
the major contributors of bronchoconstriction
Antihistamines: 2943 cont.
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The cardiovascular system:
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“Triple Response”
1.
Localized red spot-maximum diameter
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2.
Brighter red flush (flare) extending around
original spot
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3.
Due to direct vasodilator effect of histamine
Due to indirect histamine stimulation of axons that
cause vasodilation
Wheal that occupies original localized red spot
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Due to direct vasoconstriction and edema formation
Antihistamines: 2943 cont.
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The cardiovascular system cont.:
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Vasodilation:
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H1 response is relatively rapid and short lived
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H2 response is slower and more sustained
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On endothelial cells-secrete local vasodilatory
substances which eventually stimulate NO production
On vascular smooth muscle cells
Therefore H1 antagonists effectively counter
small dilator responses to low concentrations of
histamine, but only blunt the initial phase
Antihistamines: 2943 cont.
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The cardiovascular system cont.:
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Vasoconstriction:
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H1 stimulation causes postcapillary venules to
contract, separating the cells, exposing freely
permeable basement membranes
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Edema
Permits passage of mast cells recruited to tissues
Antihistamines: 2943 cont.
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The cardiovascular system cont.:
Antihistamines: 2943 cont.
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The cardiovascular system cont.:
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Heart:
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H1 effects:
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H2 effects:
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Acts directly to slow AV conduction
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
Antihistamines: 2943 cont.
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Nerve endings:
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Histamine stimulates various nerve endings
Epidermis: Itch
 Dermis: Pain
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Thought to be associated with the “flare”
component of the triple response
 Typically H1 receptor mediated
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Antihistamines: 2943 cont.
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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
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Objective 2939: Explain how histamine
may limit the intensity of allergic
reactions in skin and blood
Antihistamines: 2939 cont.
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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
Antihistamines: 2947
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Objective 2947: Explain how first
generation antihistamines produce
sedation, urinary retention and even
blurred vision
Antihistamines: 2947 cont.
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Antihistamines exhibit effects other
than H1-mediated
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M1: Antimuscarinic activity
Atropine-like properties/“anti-SLUD”
 Anti-parkisonism
 Ethanolamines, ethylenediamines
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α1: Alpha antagonism
Orthostatic hypotension
 Phenothiazines
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Antihistamines: 2947 cont.
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5-HT2
Relaxes gastric smooth muscle
 Cyproheptadine, azatadine, phenothiazines
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IKr
Prolong phase 3 of action potential by inhibiting
potassium rectifier channels
 Ethanolamines, piperidines
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Anti-emetic
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Medullary chemoreceptor trigger zone
Antivertigo
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Diminishes vestibular stimulation
Antihistamines: 2947 cont.
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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
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Diphenhydramine
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As Anti-allergy: Benadryl®
As Sleep aid: Unisom®
Antihistamines: 2947 cont.
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Second generation antihistamines:
Astemizole (off-market)
 Desloratidine
 Loratidine
 Fexofenidine
 Terfenadine (off-market)
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Antihistamines: 2947 cont.
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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.
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First-&-a-half generation antihistamines:
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Cetirizine
Still has higher incidence of drowsiness than true
second generation agents
 FDA does not allow cetirizine to be marketed as a
second generation
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Summary statement between generations:
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1st generations bind non-selectively to central
and peripheral H1-receptors while 2nd
generations bind H1-receptors selectively
Antihistamines: 2946
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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
Antihistamines: 2946 cont.
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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
III
Antihistamines: 2946 cont.
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Clinically manifested as prolongation of
the QT interval, possibly leading to
torsade de pointes
Ethanolamines and loratidine possibly
Antihistamines: 931
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Objective 931: Discuss the pharmacology
(mechanisms of action, pharmacodynamics,
indications, and contra-indications) of the
following antihistamines:
1. Ethanolamines: Dimenhydrinate, Diphenhydramine
2. Ethylaminediamines: Pyrilamine
3. Piperazine derivatives: Hydoxyzine, Cyclizine, Meclizine
4. Alkylamines: Brompheniramine, Chlorpheniramine
5. Phenothiazine derivatives: Promethazine
6. Piperidines: Fexofenadine
7. Others: Loratadine, Cetirizine
Antihistamines: 931 cont.
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Ethanolamines:
Carbinoxamine (Cardec®)
 Clemastine (Tavist®)
 Dimenhydrinate (Dramamine®)
 Diphenhydramine (Benadryl®)
 Doxylamine (Unisom®)
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Antihistamines: 931 cont.
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Ethanolamines:
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Highly anticholinergic
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Structure mimics anti-muscarinics
Highly sedative
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Crosses blood brain barrier readily
Low incidence of GI side effects
 Diphenhydramine is metabolized into
dimenhydrinate
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Antihistamines: 931 cont.
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Ethylaminediamines (Ethylenediamines):
Pyrilamine (Triaminic®)
 Tripelennamine (PBZ®)
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Antihistamines: 931 cont.
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Ethylaminediamines (Ethylenediamines):
Very specific for H1 receptors
 Moderate incidence of somnolence
 Common GI side effects
 Lower incidence of anticholinergic and antiemetic properties than other classes
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Antihistamines: 931 cont.
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Piperazines (Cylizines): :
Cetirizine (Zyrtec®)
 Cyclizine (Marezine®)
 Hydoxyzine (Atarax®, Vistaril®)
 Meclizine (Antivert®)
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Antihistamines: 931 cont.
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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
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Does not cross the blood brain barrier as well as
hydroxyzine
Antihistamines: 931 cont.
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Alkylamines:
Brompheniramine (Dimatapp®)
 Chlorpheniramine (Chlor-Trimeton®)
 Dexchlorpheniramine (Polaramine®)
 Pheniramine (Poly-Histine®)
 Tripolidine (Actidil®)
 Pyrrolidines:
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Acrivastine (Semprex-D®)
Antihistamines: 931 cont.
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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.
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Phenothiazines:
Methdilazine (Tacaryl®)
 Promethazine (Phenergan®)
 Trimeprazine (Temaril ®)
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Antihistamines: 931 cont.
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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.
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Piperidines:
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Dibenzocycloheptenes/heptanes:
Azatadine (Optimine®)
 Cyproheptadine (Periactin®)
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Phenindamine (Nolahist®)
 Second generationn piperidines:
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Astemizole (Hismanal®)
 Desloratidine (Clarinex®)
 Fexofenadine (Allegra®)
 Loratidine (Claritin®)
 Terfenadine (Seldane®)
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Antihistamines: 931 cont.
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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.
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Others: Loratadine, Cetirizine
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If they researched better, they’d know these
drugs fit in the classes already listed
Phthalazinones:
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Azelastine (Astelin®)
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Selective antagonism of H1-receptors versus
other neurotransmitter receptors (low
antimuscarinic activity)
Antihistamines: 930
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Objective 930: explain why H1antihistamines are clinically useful in
treatment of allergic rhinitis and
urticaria but not in management of
bronchial asthma
Antihistamines: 930 cont.
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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
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Basic & Clinical Pharmacology-Katzung
Goodman & Gilman’s The Pharmacological Basis of
Therapeutics-Hardman
Principles of Medicinal Chemistry-Foye
http://web6.duc.auburn.edu/~deruija/hist_antihis.pdf
http://www.courses.vcu.edu/ptxed/m2/powerpoint/do
wnload/Lichtman%20Antihistamine.PDF
http://www.duc.auburn.edu/~deruija/hist_intro.pdf
http://www.sigmaaldrich.com/sigma/rbihandbook/sg_ls_cs_rbibook_histamine.pdf