Histamine and Serotonin

ByS.Bohlooli, PhD

Ardabil University of Medical Sciences

Basic pharmacology of histamine

ChemistryPharmacokineticsPharmacodynamics

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Distribution

Histamine is widely, if unevenly, distributed throughout the animal kingdom and is present in many venoms, bacteria, and plants.

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Chemistry and pharmacokinetics

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Metabolism

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Storage and release Immunologic release

histamine plays a central role in immediate hypersensitivity and allergic responses

The release of histamine only partially explains the biological effects that ensue from immediate hypersensitivity reactions

Chemical and mechanical release Tubocurarine, succinylcholine, morphine

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Pharmacodynamics Mechanism of action Tissue and organ system effect

Nervous system Cardiovascular system Bronchial smooth muscle Gastrointestinal tract smooth muscle Other smooth muscle organs Secretary tissue Metabolic effects The triple response Other effects possibly mediated by histamine

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Receptor Subtype

DistributionPostreceptor Mechanism

Partially Selective Agonists

Partially Selective Antagonists

H1

 Smooth muscle, endothelium, brain

Gq, IP3, DAG 

HistaprodifenMepyramine, triprolidine, cetirizine

H2

 Gastric mucosa, cardiac muscle, mast cells, brain

Gs, cAMP 

AmthamineCimetidine,1 ranitidine,1 tiotidine 

H3

 Presynaptic: brain, myenteric plexus, other neurons

Gi, cAMP 

R--Methylhistamine, imetit, immepip 

Thioperamide, iodophenpropit, clobenpropit,1 tiprolisant1

 H4

 Eosinophils, neutrophils, CD4 T cells

Gi, cAMP 

Clobenpropit, imetit, clozapine

Thioperamide

Nervous system

regulation of drinking body temperature secretion of antidiuretic hormone control of blood pressure perception of pain wakefulness

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Cardiovascular System

Vasodilation Increased "Capillary" Permeability Triple Response of Lewis Heart Histamine Shock

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Extravascular Smooth Muscle

Contraction is due to activation of H1 receptors

relaxation (for the most part) is due to activation of H2 receptors

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Exocrine Glands

regulator of gastric acid secretion

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Peripheral Nerve Endings

Pain Itch

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Clinical pharmacology of histamine Clinical use

a diagnostic agent to assess nonspecific bronchial

hyperreactivity in asthmatics as a positive control injection during allergy

skin testing Toxicity and contraindications

Flushing, hypotension,tachycardia, headache wheals, brochoconstriction, gastrointestinal upset

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Histamine antagonists

H1 receptor antagonists H2 receptor antagonists

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Basic Pharmacology of H1 Receptor Antagonists

Chemistry PharmacokineticsPharmacodynamics

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Chemistry Structure-

activity Relationship reversible

competitive inhibitors

contain a substituted ethylamine moiety

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Pharmacokinetics

Absorption, distribution Metabolism:

Astemizole and Terfenadine

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Pharmacological Properties

Smooth Muscle Capillary Permeability Flare and Itch Immediate Hypersensitivity

Reactions Central Nervous System

Can both stimulate and depress the CNS

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Pharmacodynamics

Histamine receptor blockade Other actions

Sedation Antinausea and antiemetic actions Antiparkinsonism effects Antichlinoceptor effect: Promethazine Adrenoceptor blocking action Serotonin blocking action Local anesthesia: Promethazine

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Clinical pharmacology of H1 receptor antagonists

Clinical use Allergic reaction Motion sickness and vestibular disturbance Nausea and vomiting of pregnancy?

Toxicity Sedation, antimuscarninc action, Drug allergy Drug interaction Teratogenic effects

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Table 24-2. Preparations and Dosage of Representative H1-Receptor Antagonists*

CLASS AND NONPROPRIETARY NAME

TRADE NAMEDURATION OF ACTION, HOURS

PREPARATIONSa

SINGLE DOSE (ADULT)

First-Generation Agents    

Tricyclic Dibenzoxepins    

Doxepin hydrochlorideSINEQUAN6-24O, L, T10-150 mg

Ethanolamines    

Carbinoxamine maleateRONDEC,d others

3-6O, L4-8 mg

Clemastine fumarateTAVIST, others12O, L1.34-2.68 mg

Diphenhydramine HClBENADRYL; others

12O, L, I, T25-50 mg

DimenhydrinateDRAMAMINE; others

4-6O, L, I50-100 mg

Ethylenediamines    

Pyrilamine maleatePOLY-HISTINE-D d

4-6O, L, T25-50 mg

Tripelennamine HClPBZ4-6O25-50 mg, 100 mg (sustained release)

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Piperazines    

Hydroxyzine HClATARAX; others

6-24O, L, I25-100 mg

Hydroxyzine pamoateVISTARIL6-24O, L25-100 mg

Cyclizine HClMAREZINE4-6O50 mg

Cyclizine lactateMAREZINE4-6I50 mg

Meclizine HClANTIVERT; others

12-24O12.5-50 mg

Phenothiazines    

Promethazine HClPHENERGAN; others

4-6O, L, I, S12.5-50 mg

Piperidines    

Cyproheptadine HClcPERIACTIN4-6O, L4 mg

Phenindamine tartrateNOLAHIST4-6O25 mg

Second-Generation Agents    

Alkylamines    

AcrivastinebSEMPREX-Dd6-8O8 mg

Piperazines    

Cetirizine hydrochloridebZYRTEC12-24O5-10 mg

Phthalazinones    

Azelastine hydrochloridebASTELIN12-24T2 sprays per nostril

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Piperidines    

Levocabastine hydrochlorideLIVOSTIN6-12TOne drop

LoratadineCLARITIN24O, L10 mg

DesloratadineCLARINEX, AERIUS

24O5 mg

EbastineEBASTEL24O10-20 mg

MizolastineMIZOLLEN24O10 mg

FexofenadineALLEGRA, TELFAST

12-24O60 mg

HCl, hydrochloride. *For a discussion of phenothiazines, see Chapter 18. aPreparations are designated as follows: O, oral solids; L, oral liquids; I, Injection; S, suppository; T, topical. Many H1-receptor antagonists also are available in preparations that contain multiple drugs. bHas mild sedating effects. cAlso has antiserotonin properties. dTrade name drug also contains other medications.

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Application:Common Cold?

Despite persistent popular belief, H1 antagonists are without value in combating the common cold.

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Basic pharmacology of serotonin

ChemistryPharmacokineticsPharmacodynamics

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Chemistry & pharmacokinetics

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Pharmacodynamics

Mechanism of action

Tissue and organ system effect Nervous system Airways Cardiovascular

system Gastrointestinal

tract Skeletal muscle

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Clinical pharmacology of Serotonin

Serotonin agonists Serotonin antagonists

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Table 11-4. Serotonergic Drugs: Primary Actions and Clinical Uses

RECEPTORACTIONDRUG EXAMPLES

CLINICAL DISORDER

5-HT1APartial agonist

Buspirone, ipsaperone

Anxiety, depression

5-HT1DAgonistSumatriptanMigraine

5-HT2A/2CAntagonistMethysergide, trazodone, risperidone, ketanserin

Migraine, depression, schizophrenia

5-HT3AntagonistOndansetronChemotherapy-induced emesis

5-HT4AgonistCisaprideGastrointestinal disorders

5-HT transporter

InhibitorFluoxetine, sertraline

Depression, obsessive-compulsive disorder, panic disorder, social phobia, posttraumatic stress disorder

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Serotonin antagonists

Phenoxybenzamine (5HT2) Cyproheptadine (5HT2) Ketanserin (5HT1C) Odansetrone (5HT3)

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Appetite control through serotonin?

Sertonin related to sleep, emotion, sex, and appetite

Could reduce food intake Fenfluramine, dexfenfluramine

Cause serotonin release and inhibition of food uptake

Toxicity: fatal and nonfatal pulmonary hypertension Valvular lesions

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