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HISTAMINE AND SEROTONIN

By

SROTA DAWN.

M . Pharma (Pharmacology)

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AUTACOID

Definition:

The term is derived from ‘GREEK’

• Autos = self

• akos = healing substance or Remedy

or

some times called Local Hormones

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Classification of autacoids

A. Amine Autaciods:

1. Histamine

2. Serotonin or 5-HT

B. Eicosanoids (PGs; Thromboxane ; Leukotriens)

C. Peptides Autociods:

1) Kinins (bradykinin, kallidin)

2) Renin; Angiotensins etc

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HISTAMINE

• Histamine means ‘ TISSUE AMINE ’( Histos- tissue)

• Present in all animal tissues and in some plants also.

• mediators of allergic and inflammatory reactions; also involved in Gastric Acid Secretions ; and act as Neurotransmitter & Neuromodulator.

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• Histamine is presents mostly in MAST cells.

• Tissues rich is histamine are skin, gastric mucosa, intestinal mucosa, lungs, liver and placenta.

• Non mast cell histamine occurs in brain, epidermis, gastric mucosa, and growing regions.

• Histamine is also present in blood, most of body secretions, venoms, pathological fluids.

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Synthesis of histamine

Histidine

Histamine(beta imidazolylethylamine)

Decarboxylase

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Metabolism of histamine

Histamine

N-methyl transferase

n-methyl histamine

Diamine oxidase

Imidazole acetic acid

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Storage and Release:

Histamine is usually found in storage granules as complex with sulphated polysaccharides, heparin and released (locally) by:

a) Immunological Mechanism

b) Tissue injury Mast cell degranulation

c) Chemical and physical Conditions

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Histamine receptors

• Histamine binds to three types of Receptors , namely

• H1 ,

• H2 ,

• H3 (see table 1)

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Partially selective Antagonists

Partially Selecetive Agonists

Post receptor Mechanism

Distribution Receptor sub type

Mepyramine , triprolidine

2-( m-fluorophenyl)-histamine

↑IP3 , DAG Smooth muscle , endothelium , brain

H1

Ranitidine , tiotidine

Dimaprit, impromidine , amthamine

↑cAMP Gastric mucosa , Cardiac muscle , mast cells , brain.

H2

Thioperamide, iodophenpropit ,. clobenpropit

R- α-Methylhistamine, imetit , immepip

G protein –coupled

Presynaptic: brain, myentric plexus, other neurons

H3

Table no 1

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Selected Actions of Histamine in Humans

Heart

H1 - decreased AV conduction

H2 - increased chronotropy,

decreased inotropy

H1, H2 - increased automaticity

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Selected Actions of Histamine in Humans

Vascular

H1 – in vascular endothelium NO and PG release vasodilation. In coronary vessels vasoconstriction. Increased permeability of post capillary venules

H2 – in vascular cells vasodilation mediated by cAMP

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Selected Actions of Histamine in Humans

Lung

H1 – bronchoconstriction, increased mucus viscosity

H2 - slight bronchodilation, increased mucus secretion

H1 - stimulation of vagal sensory nerve endings: cough

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Selected Actions of Histamine in Humans

Gastrointestinal System

H2 - acid, fluid and pepsin secretion

H1 - increased intestinal motility and secretions

Cutaneous Nerve Endings

H3 - pain and itching

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Triple Response of Willis

Sub-dermal histamine injection causes:

1. Red spot (few mm) in seconds: direct vasodilation effect , H1 receptor mediated

2. Flare (1cm beyond site): axonal reflexes, indirect arteriolar vasodilation, and itching, H1 receptor mediated

3. Wheal (1-2 min) same area as original spot, edema due to increased capillary permeability, H1 receptor mediated

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Histamine-related Drugs

• Mast Cell Stabilizers (Cromolyn Na, Nedocromil –Tilade , Albuterol)

• H1 Receptor Antagonists (1st and 2nd generation)

• H2 Receptor Antagonists (Ranitidine, Cimetidine)

• H3 Receptor Agonist and Antagonists (potential new drugs being developed)

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Histamine H1- Antagonists

• First Generation: Sedating

• Second Generation: Non sedating

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First Generation Agents

Examples

• Ethanolamines: DIPHENHYDRAMINE (Benadryl) CLEMASTINE (Tavist)

• Alkylamine: CHLORPHENIRAMINE (Chlortrimeton)

• Phenothiazine: PROMETHAZINE (Phenergan)

• Piperazines: HYDROXYZINE (Vistaril)

CYCLIZINE (Antivert)

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Uses of 1st generation drugs:

• Adjunctive in anaphylaxis and other cases where histamine release can occur (H2 antagonist, and epinephrine must also be used in anaphylaxis)

• Anti-allergy (allergic rhinitis, allergic dermatoses, contact dermatitis)

• Sedative/sleep aid

• To prevent motion sickness (meclizine, cyclizine)

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Uses

• Antiemetic: prophylactic for motion sickness (promethazine)

• Antivertigo (meclizine)

• Local anesthetic: (diphenhydramine)

• Antitussive (diphenhydramine)

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Adverse effects of 1st generation drugs

Adverse Effects:

• Sedation (Paradoxical Excitation in children)

• Dizziness

• Fatigue

• Tachy dysrhythmias in overdose - rare

• Allergic reactions with topical use

• Peripheral anti-muscarinic effects

• dry Mouth

• blurred Vision

• constipation

• urinary Retention

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Drug interactions

Drug interactions:

• Additive with classical antimuscarinics

• Potentiate CNS depressants

• opioids

• sedatives

• general and narcotic analgesics

• alcohol

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Pharmacokinetics of 1st generation drugs

• Well absorbed from the GI-tract

• Widely distributed

• Cross BBB

• Placental transfer

• Hepatic transformation, renal elimination of the metabolites (induce hepatic microsomal enzymes)

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Examples• CETIRIZINE (Zyrtec)

• FEXOFENADINE (Allegra)

• LORATADINE (Claritin)

• DESLORATADINE (Clarinex- FDA Approved In 2002)

• LORATADINE (Claritin Hives Relief - FDA Approved In 2004)

• AZELASTIN (Intranasal Spray)

• Anti-allergy

Second Generation Agents

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Serotonin

Definition and Location:

• it is a neurotransmitter found in enterochromaffin cells in GIT (90%) , and in plateletes and in raphe nuclei of brain stem.

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Pharmacological actions of Serotonin

• CVS:

1) Blood vessels:

Potent and direct contractions on smooth muscle (via 5- HT2 ) EXCEPT : Skeletal Muscles and Heart blood

vessels.

• Note : 5- HT can give rise to triple action:

Decrease BP due to chemoreceptor response then increase BP due to Vasoconstriction (5- HT2), then decrease B.P due to skeletal muscle V.D

2) Platelet: Increase platelet aggregation via 5-HT2

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GIT:1) increase contraction of smooth muscle (via

5- HT4 stimulated the release of ACH).

2) Nausea and vomiting (via 5-HT3)

Respiration : 5-HT may produce weak bronchoconstriction.

CNS: very important.(Appetite; depression and

mania; Pain; reduce Anxiety; Schizophrenia).

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Clinical use of serotonergic agonists

1) Buspirone: 5-HT1A agonist used as anxiolytic agent.

2) Sumatriptan: 5-HT1D agonist for migraine (Treatment and prophylactic).

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3) Metoclopromide (Plasil): 5-HT4 agonist as prokinetic agent

for Rx of gastroesophagial reflex.

And also used for N/V via 5-HT3 antagonistic action.

4) Dexfenfuramine: Acts by stim. Release and inhib. Reuptake of serotonin.

Used as anorexic agent.

Clinical use of serotonergic agonists

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Clinical use of antagonists

1) Ondansetron & Granisetron: 5-HT3 antagonists Common

used for Rx of N/V induced by cytotoxic (chemotherapy) drugs.

2) Cyproheptadine: Both H1, 5-HT1,2 and cholinergic antagonist

used for Rx carcinoid tumor (significant increases in serotonin) and to increase appetite..

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Clinical use of antagonists

3) Ketanserin: 5-HT2/1c antagonist and α1-adrenergic blocker.

(used as antihypertensive agent)

4) Methysergide: This is an ergot alkaloid acts as 5-HT1,2

antagonist used for Rx of migraine.

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Reading

Goodman and Gilman11th editionChapter 24

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THANK YOU