Antihistamines Nathan P. Samsa, Pharm.D., R.Ph.. My Objectives Answer the objectives they refuse to teach us Answer the objectives they refuse to teach

AntihistaminesAntihistamines

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

My ObjectivesMy Objectives

Answer the objectives they refuse to Answer the objectives they refuse to teach usteach us

Design this lecture in a logical manor Design this lecture in a logical manor to facilitate understandingto facilitate understanding

HistamineHistamine

Brief overview:Brief overview: Derived from amino acid histidineDerived from amino acid histidine

““Antihistamine” is old terminologyAntihistamine” is old terminology Politically correct term: “HPolitically correct term: “H11-Receptor -Receptor

Antagonist”Antagonist”

NH

N

O

NH3

+

O

NH

N

O

O

Histidinedecarboxylase

Histidine Histamine

ObjectivesObjectives

930930 931931 29372937 29382938 29392939 29432943 29462946 29472947

Antihistamines: 2937Antihistamines: 2937

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

Antihistamines: 2937 Antihistamines: 2937 cont.cont.

Storage sites:Storage sites: Gastrointestinal mucosaGastrointestinal mucosa EpidermisEpidermis Bronchial mucosaBronchial mucosa Cerebrospinal fluidCerebrospinal fluid

Cellular production:Cellular production: Mast cells-tissues (predominant)Mast cells-tissues (predominant) Basophils-bloodBasophils-blood


Objective 2938: Based on analog Objective 2938: Based on analog binding and resulting physiological binding and resulting physiological changes distinguish among changes distinguish among histamine receptor subtypes Hhistamine receptor subtypes H11, H, H22, , and Hand H33


HH11

Couples to GCouples to Gqq–protein to activate –protein to activate phospholipase Cphospholipase C

Found throughout the CNS and densely Found throughout the CNS and densely concentrated in hypothalamusconcentrated in hypothalamus Stimulates wakefulnessStimulates wakefulness


HH22

Couples to GCouples to Gss-protein to activate -protein to activate adenylyl cyclaseadenylyl cyclase

Found predominatly in the GI tractFound predominatly in the GI tract Increases secretion of gastric acid from Increases secretion of gastric acid from

parietal cells in the stomachparietal cells in the stomach Antagonists block acid secretionAntagonists block acid secretion

Cimetadine (TagametCimetadine (Tagamet®®)) Famotidine (PepcidFamotidine (Pepcid®®)) Nizatidine (AxidNizatidine (Axid®®)) Ranitadine (ZantacRanitadine (Zantac®®


HH33

Couples with GCouples with Gii-protein to inhibit adenylyl -protein to inhibit adenylyl cyclase cyclase

Proposed as a neural presynaptic auto-Proposed as a neural presynaptic auto-receptor serving to modulate histamine receptor serving to modulate histamine synthesis and release in the CNS, as well synthesis and release in the CNS, as well as neurotransmitters (e.g. acetylcholine, as neurotransmitters (e.g. acetylcholine, dopamine, GABA, norepinephrine, dopamine, GABA, norepinephrine, serotonin)serotonin)

Peripheral tissue, including the gastric Peripheral tissue, including the gastric mucosa, where it may negatively control mucosa, where it may negatively control gastric acid secretiongastric acid secretion


HH44

Couples with GCouples with Gii-protein to inhibit -protein to inhibit adenylyl cyclaseadenylyl cyclase

Just recently discoveredJust recently discovered The HThe H4 4 receptor is highly expressed in receptor is highly expressed in

peripheral blood leukocytes and peripheral blood leukocytes and intestinal tissue, making this receptor a intestinal tissue, making this receptor a potentially interesting target in allergic potentially interesting target in allergic and inflammatory diseasesand inflammatory diseases


Objective 2943: Describe the effects Objective 2943: Describe the effects of histamine on: of histamine on: 1.1. Bronchiolar smooth muscle Bronchiolar smooth muscle

2.2. The cardiovascular system The cardiovascular system

3.3. Nerve endings Nerve endings

4.4. Secretory tissuesSecretory tissues


Bronchiolar smooth muscle:Bronchiolar smooth muscle: Contraction due to HContraction due to H11 activation activation

Dilitation due to HDilitation due to H22 activation activation Humans have less bronchoconstriction Humans have less bronchoconstriction

from histamine than other speciesfrom histamine than other species Leukotrienes and platelet activating factor Leukotrienes and platelet activating factor

are the major contributors of are the major contributors of bronchoconstriction bronchoconstriction


The cardiovascular system:The cardiovascular system: ““Triple Response”Triple Response”

1.1. Localized red spot-maximum diameterLocalized red spot-maximum diameter Due to direct vasodilator effect of histamineDue to direct vasodilator effect of histamine

2.2. Brighter red flush (flare) extending around Brighter red flush (flare) extending around original spotoriginal spot Due to indirect histamine stimulation of axons that Due to indirect histamine stimulation of axons that

cause vasodilationcause vasodilation

3.3. Wheal that occupies original localized red spotWheal that occupies original localized red spot Due to direct vasoconstriction and edema formation Due to direct vasoconstriction and edema formation


The cardiovascular system cont.:The cardiovascular system cont.: Vasodilation:Vasodilation:

HH11 response is relatively rapid and short lived response is relatively rapid and short lived On endothelial cells-secrete local vasodilatory On endothelial cells-secrete local vasodilatory

substances which eventually stimulate NO substances which eventually stimulate NO productionproduction

HH22 response is slower and more sustained response is slower and more sustained On vascular smooth muscle cellsOn vascular smooth muscle cells

Therefore HTherefore H11 antagonists effectively counter antagonists effectively counter small dilator responses to low concentrations small dilator responses to low concentrations of histamine, but only blunt the initial phaseof histamine, but only blunt the initial phase


The cardiovascular system cont.:The cardiovascular system cont.: Vasoconstriction:Vasoconstriction:

HH11 stimulation causes postcapillary venules stimulation causes postcapillary venules to contract, separating the cells, exposing to contract, separating the cells, exposing freely permeable basement membranesfreely permeable basement membranes

EdemaEdema Permits passage of mast cells recruited to tissuesPermits passage of mast cells recruited to tissues


The cardiovascular system cont.:The cardiovascular system cont.:


The cardiovascular system cont.:The cardiovascular system cont.: Heart:Heart:

HH11 effects: effects: Acts directly to slow AV conductionActs directly to slow AV conduction

HH22 effects: effects: Promotes influx of CaPromotes influx of Ca2+2+

Increases heart rate by hastening diastolic Increases heart rate by hastening diastolic depolarization in the SA nodedepolarization in the SA node

Baroreceptor reflexes typically stimulate to Baroreceptor reflexes typically stimulate to counteract the decreased heart ratecounteract the decreased heart rate


Nerve endings:Nerve endings: Histamine stimulates various nerve Histamine stimulates various nerve

endingsendings Epidermis: ItchEpidermis: Itch Dermis: PainDermis: Pain

Thought to be associated with the Thought to be associated with the “flare” component of the triple response“flare” component of the triple response

Typically HTypically H11 receptor mediated receptor mediated


Secretory tissues:Secretory tissues: Exocrine glands: potent stimulator of Exocrine glands: potent stimulator of

gastric secretion (HCl & pepsin)gastric secretion (HCl & pepsin) Enhances salivary and lacrimal gland Enhances salivary and lacrimal gland

secretion (minimal unless large doses secretion (minimal unless large doses are given)are given)

Stimulates chromaffin cells in adrenal Stimulates chromaffin cells in adrenal medulla to secrete catecholaminesmedulla to secrete catecholamines


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


In allergic response, IgE is generated In allergic response, IgE is generated and binds to mast cells and basophilsand binds to mast cells and basophils

IgE binding causes eventual release IgE binding causes eventual release of histamine from vesiclesof histamine from vesicles

The vasoconstrictive properties of The vasoconstrictive properties of histamine help to prevent spread of histamine help to prevent spread of mediators from the immediate areasmediators from the immediate areas


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


Antihistamines exhibit effects other Antihistamines exhibit effects other than Hthan H11-mediated-mediated MM11: Antimuscarinic activity: Antimuscarinic activity

Atropine-like properties/“anti-SLUD”Atropine-like properties/“anti-SLUD” Anti-parkisonismAnti-parkisonism Ethanolamines, ethylenediaminesEthanolamines, ethylenediamines

αα11: Alpha antagonism: Alpha antagonism Orthostatic hypotensionOrthostatic hypotension PhenothiazinesPhenothiazines


5-HT5-HT22 Relaxes gastric smooth muscleRelaxes gastric smooth muscle Cyproheptadine, azatadine, phenothiazinesCyproheptadine, azatadine, phenothiazines

IIKrKr Prolong phase 3 of action potential by Prolong phase 3 of action potential by

inhibiting potassium rectifier channelsinhibiting potassium rectifier channels Ethanolamines, piperidinesEthanolamines, piperidines

Anti-emetic Anti-emetic Medullary chemoreceptor trigger zoneMedullary chemoreceptor trigger zone

AntivertigoAntivertigo Diminishes vestibular stimulationDiminishes vestibular stimulation


First generation antihistamines:First generation antihistamines: All have properties beyond peripheral HAll have properties beyond peripheral H11

antagonismantagonism Knowing the intricacies of the side Knowing the intricacies of the side

effects help to tailor the drug to the effects help to tailor the drug to the patientpatient

Many side effects are marketed aMany side effects are marketed a DiphenhydramineDiphenhydramine

As Anti-allergy: BenadrylAs Anti-allergy: Benadryl®®

As Sleep aid: UnisomAs Sleep aid: Unisom®®


Second generation antihistamines:Second generation antihistamines: Astemizole (off-market)Astemizole (off-market) DesloratidineDesloratidine LoratidineLoratidine FexofenidineFexofenidine Terfenadine (off-market)Terfenadine (off-market)


Second generation antihistamines:Second generation antihistamines: Second generation antihistamines do Second generation antihistamines do

not cross the blood brain barrier well, not cross the blood brain barrier well, thus they do not inhibit hypothalamic thus they do not inhibit hypothalamic wakefulness wakefulness

They bind much more selectively to They bind much more selectively to peripheral Hperipheral H1 1 receptors and have a lower receptors and have a lower binding affinity for the cholinergic and binding affinity for the cholinergic and alpha-adrenergic receptor sites than alpha-adrenergic receptor sites than other antihistamines other antihistamines


First-&-a-half generation antihistamines:First-&-a-half generation antihistamines: CetirizineCetirizine

Still has higher incidence of drowsiness than true Still has higher incidence of drowsiness than true second generation agentssecond generation agents

FDA does not allow cetirizine to be marketed as a FDA does not allow cetirizine to be marketed as a second generationsecond generation

Summary statement between Summary statement between generations:generations: 11stst generations bind non-selectively to generations bind non-selectively to

central and peripheral Hcentral and peripheral H11-receptors while 2-receptors while 2ndnd generations bind Hgenerations bind H11-receptors selectively-receptors selectively


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


Erythromycin blocks the metabolism of Erythromycin blocks the metabolism of either drug by inhibiting CYP3A4 either drug by inhibiting CYP3A4

Increased astemizole and terfenadine Increased astemizole and terfenadine concentrations inhibit the potassium concentrations inhibit the potassium rectifier currents (Irectifier currents (IKrKr) in cardiac myocytes, ) in cardiac myocytes, therefore slowing repolarizationtherefore slowing repolarization

II I


Clinically manifested as prolongation Clinically manifested as prolongation of the QT interval, possibly leading to of the QT interval, possibly leading to torsade de pointestorsade de pointes

Ethanolamines and loratidine Ethanolamines and loratidine possiblypossibly


Objective 931: Discuss the pharmacology Objective 931: Discuss the pharmacology (mechanisms of action, (mechanisms of action, pharmacodynamics, indications, and pharmacodynamics, indications, and contra-indications) of the following contra-indications) of the following antihistamines: antihistamines: 1.1. Ethanolamines: Dimenhydrinate, DiphenhydramineEthanolamines: Dimenhydrinate, Diphenhydramine2.2. Ethylaminediamines: PyrilamineEthylaminediamines: Pyrilamine3.3. Piperazine derivatives: Hydoxyzine, Cyclizine, Meclizine Piperazine derivatives: Hydoxyzine, Cyclizine, Meclizine 4.4. Alkylamines: Brompheniramine, ChlorpheniramineAlkylamines: Brompheniramine, Chlorpheniramine5.5. Phenothiazine derivatives: Promethazine Phenothiazine derivatives: Promethazine 6.6. Piperidines: Fexofenadine Piperidines: Fexofenadine 7.7. Others: Loratadine, CetirizineOthers: Loratadine, Cetirizine


Ethanolamines: Ethanolamines: Carbinoxamine (CardecCarbinoxamine (Cardec®®)) Clemastine (TavistClemastine (Tavist®®)) Dimenhydrinate (DramamineDimenhydrinate (Dramamine®®)) Diphenhydramine (BenadrylDiphenhydramine (Benadryl®®)) Doxylamine (UnisomDoxylamine (Unisom®®))


Ethanolamines: Ethanolamines: Highly anticholinergicHighly anticholinergic

Structure mimics anti-muscarinics Structure mimics anti-muscarinics Highly sedativeHighly sedative

Crosses blood brain barrier readily Crosses blood brain barrier readily Low incidence of GI side effectsLow incidence of GI side effects Diphenhydramine is metabolized into Diphenhydramine is metabolized into

dimenhydrinatedimenhydrinate

Antihistamines: 931 Antihistamines: 931 cont. cont.

EthylaminediaminesEthylaminediamines (Ethylenediamines):(Ethylenediamines): Pyrilamine (TriaminicPyrilamine (Triaminic®®)) Tripelennamine (PBZTripelennamine (PBZ®®))

Antihistamines: 931 Antihistamines: 931 cont. cont.

Ethylaminediamines Ethylaminediamines (Ethylenediamines):(Ethylenediamines): Very specific for HVery specific for H11 receptors receptors Moderate incidence of somnolenceModerate incidence of somnolence Common GI side effectsCommon GI side effects Lower incidence of anticholinergic and Lower incidence of anticholinergic and

anti-emetic properties than other anti-emetic properties than other classesclasses


Piperazines (Cylizines): : Piperazines (Cylizines): : Cetirizine (ZyrtecCetirizine (Zyrtec®®)) Cyclizine (MarezineCyclizine (Marezine®®)) Hydoxyzine (AtaraxHydoxyzine (Atarax®®, Vistaril, Vistaril®®)) Meclizine (AntivertMeclizine (Antivert®®))


Piperazines (Cylizines):Piperazines (Cylizines): Moderately potent antihistaminics with a Moderately potent antihistaminics with a

lower incidence of drowsinesslower incidence of drowsiness Slow onset and long duration of actionSlow onset and long duration of action Some piperazines exhibited a strong Some piperazines exhibited a strong

teratogenic potential, inducing a teratogenic potential, inducing a numberof malformations in rats numberof malformations in rats

Cetirizine is a metabolite of hydroxyzineCetirizine is a metabolite of hydroxyzine Does not cross the blood brain barrier as Does not cross the blood brain barrier as

well as hydroxyzinewell as hydroxyzine


Alkylamines: Alkylamines: Brompheniramine (DimatappBrompheniramine (Dimatapp®®)) Chlorpheniramine (Chlor-TrimetonChlorpheniramine (Chlor-Trimeton®®)) Dexchlorpheniramine (PolaramineDexchlorpheniramine (Polaramine®®)) Pheniramine (Pheniramine (Poly-HistinePoly-Histine®®)) Tripolidine (Tripolidine (ActidilActidil®®)) Pyrrolidines:Pyrrolidines:

Acrivastine (Semprex-DAcrivastine (Semprex-D®®))


Alkylamines:Alkylamines: Most potent HMost potent H11 antagonists antagonists Generally regarded as one of the better Generally regarded as one of the better

daytime-use 1daytime-use 1stst generation H generation H11 antagonists antagonists Only moderate incidence of somnolenceOnly moderate incidence of somnolence

Has some anticholinergic activityHas some anticholinergic activity CNS stimulation more common than other CNS stimulation more common than other

classeclasse Acrivastine does not display significant Acrivastine does not display significant

anticholinergic activity at therapeutic anticholinergic activity at therapeutic concentrations, and does not cross the concentrations, and does not cross the blood brain barrier readilyblood brain barrier readily


Phenothiazines: Phenothiazines: Methdilazine (TacarylMethdilazine (Tacaryl®®)) Promethazine (PhenerganPromethazine (Phenergan®®)) Trimeprazine (Temaril Trimeprazine (Temaril ®®) )


Phenothiazines:Phenothiazines: Have relatively high anticholinerc effectsHave relatively high anticholinerc effects Has some 5-HHas some 5-H22 antagonistic effect antagonistic effect Major use is for anti-emetic propertiesMajor use is for anti-emetic properties


Piperidines: Piperidines: Dibenzocycloheptenes/heptanes:Dibenzocycloheptenes/heptanes:

Azatadine (OptimineAzatadine (Optimine®®)) Cyproheptadine (PeriactinCyproheptadine (Periactin®®))

Phenindamine (NolahistPhenindamine (Nolahist®®)) Second generationn piperidines:Second generationn piperidines:

Astemizole (HismanalAstemizole (Hismanal®®)) Desloratidine (ClarinexDesloratidine (Clarinex®®)) Fexofenadine (AllegraFexofenadine (Allegra®®)) Loratidine (ClaritinLoratidine (Claritin®®)) Terfenadine (SeldaneTerfenadine (Seldane®®))


Piperidines:Piperidines: Highly selective for peripheral HHighly selective for peripheral H11

Have no significant anticholinergic effectsHave no significant anticholinergic effects Well toleratedWell tolerated Astemazole and terfenadine were pulled Astemazole and terfenadine were pulled

from the U.S. market due to drug interactionsfrom the U.S. market due to drug interactions Desloratidine is a metabolite of loratidineDesloratidine is a metabolite of loratidine Fexofenadine is a metabolite of terfenadineFexofenadine is a metabolite of terfenadine The heptanes have 5-HTThe heptanes have 5-HT22 & H & H11 antagonism antagonism


Others: Loratadine, CetirizineOthers: Loratadine, Cetirizine If they researched better, they’d know these If they researched better, they’d know these

drugs fit in the classes already listeddrugs fit in the classes already listed

Phthalazinones:Phthalazinones: Azelastine (AstelinAzelastine (Astelin®®))

Selective antagonism of HSelective antagonism of H11-receptors versus -receptors versus other neurotransmitter receptors (low other neurotransmitter receptors (low antimuscarinic activity)antimuscarinic activity)


Objective 930: explain why HObjective 930: explain why H11--antihistamines are clinically useful in antihistamines are clinically useful in treatment of allergic rhinitis and treatment of allergic rhinitis and urticaria but not in management of urticaria but not in management of bronchial asthmabronchial asthma


Allergic bronchoconstriction is Allergic bronchoconstriction is caused primarily by leukotrienes and caused primarily by leukotrienes and platelet activating factorplatelet activating factor This is why leukotriene receptor This is why leukotriene receptor

antagonists are a treatment in asthma antagonists are a treatment in asthma managementmanagement

In other animals, histamine causes In other animals, histamine causes allergic bronchoconstrictionallergic bronchoconstriction

ReferencesReferences Basic & Clinical PharmacologyBasic & Clinical Pharmacology-Katzung-Katzung Goodman & Gilman’sGoodman & Gilman’s The Pharmacological Basis of The Pharmacological Basis of

Therapeutics-HardmanTherapeutics-Hardman Principles of Medicinal ChemistryPrinciples of Medicinal Chemistry-Foye-Foye http://web6.duc.auburn.edu/~deruija/hist_antihis.phttp://web6.duc.auburn.edu/~deruija/hist_antihis.p

dfdf http://www.courses.vcu.edu/ptxed/m2/powerpoint/http://www.courses.vcu.edu/ptxed/m2/powerpoint/

download/Lichtman%20Antihistamine.PDFdownload/Lichtman%20Antihistamine.PDF http://www.duc.auburn.edu/~deruija/hist_intro.pdfhttp://www.duc.auburn.edu/~deruija/hist_intro.pdf http://www.sigmaaldrich.com/sigma/rbi-handbook/http://www.sigmaaldrich.com/sigma/rbi-handbook/

sg_ls_cs_rbibook_histamine.pdfsg_ls_cs_rbibook_histamine.pdf

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Antihistamines Nathan P. Samsa, Pharm.D., R.Ph.. My Objectives Answer the objectives they refuse to teach us Answer the objectives they refuse to teach