Histamine & Antihistamines

Dr.C.Adithan

Overview of lecture Autacoids Histamine

Histamine receptorsDistribution, MOA, FunctionsAgonists: Clinical use

Antihistamines 1st Generation drugs 2nd Generation drugs Therapeutic uses Adverse effects

Autacoids

Autos = self; akos = remedy or medicinal agent Local hormones These are produced by the tissues or endothelial

cells which after being released act locally at the site or near the site of their release.

Classification Amines: histamine, serotonin (5-HT) Peptides: kinins, angiotensin Lipid derived: prostaglandins,

leukotrienes, thromboxanes, platelet activating factor (PAF).

Others: endothelium-derived relaxing factor (NO), cytokines .

Sir Henry Dale

Histamine1907: synthesised as a curiosity by Windaus and Vogt

1911: responsible for anaphylaxis by Dale and Laidlaw

Histamine Imidazole derivative, a biogenic amine is an endogenous substance synthesized, stored

and released in (a) mast cells, which are abundant in the skin, GI, and the respiratory tract, (b) basophils in the blood, and (c) some neurons in the CNS and peripheral NS

It is not a drug but is important due to its physiological and pathophysiological actions. Therefore, drugs that inhibit its release or block its receptors have therapeutic value.

‘histamine’ - Greek word for tissue (‘histos’)

Biosynthesis of histamine

Histamine metabolism

N-Methyl histamine Imidazoleacetic acid

N-Methyl imidazole acetic acid Imidazole acetic acid riboside

N-Methyl transferase Diamine oxidase

MAO-B Phosphoribosyl transferase

Histamine

Storage of histamine Mast cells Basophils Histaminocytes (stomach) Histaminergic neurons

Stored in secretory granuleshigh in skin, bronchial mucosa and intestinal mucosa

Storage ‘Slow-turnover’ histamine is stored as

heparin-histamine complex in cytoplasmic granules in mast cells (lungs, GIT) and basophils.

‘Fast-turnover’ histamine is stored in CNS neurons, skin and ECL of stomach.

ECL: Enterochromaffin like cells, a type of neuroendocrine cells found in the gastric glands

Release of ‘Slow turnover’ histamine

Allergic reaction:

Antigen combines with IgE antibodies on the surface of mast cells or basophils.

Release of histamine Immunologic release

Exposure of an antigen to a previously sensitized (exposed) subject can immediately trigger allergic reactions. If sensitized by IgE antibodies attached to their surface membranes will degranulate when exposed to the appropriate antigen and release histamine, ATP and other mediators

Chemical & mechanical release due to mast cell injury

IgE - Mediated Releasers

Food: eggs, peanuts, milk products, grains, strawberries, etc

Drugs: penicillins, sulfonamides, etc Venoms: fire ants, snake, bee, etc Foreign proteins: nonhuman insulin, serum

proteins, etc Enzymes: chymopapain

Morphine and other opioids, i.v. Aspirin and other NSAIDs in some asthmatics Vancomycin, i.v. (Red man syndrome),

polymixin B Some x-ray contrast media Succinylcholine, d-tubocurarine, 48/80 Anaphylotoxins: c3a, c5a Cold or solar urticaria

Non-immune Releasers

Diseases: histamine release Mastocytosis (too many mast cells)

Systemic : urticaria, dermographism, pruritus, headache, weakness, hypotension, flushing of face, diarrhea or peptic ulceration

Cutaneous – pigmented cutaneous lesions that sting when stroked

Gastric carcinoid tumors (geographical flush) Myelogenous leukemia (basophils -chronic

pruritus) Insect stings Venoms and some sea foods

Drugs that inhibit histamine release

Adrenaline EphedrineIsoproterenolMast cell stabilizers

Histamine receptors: H1, H2, H3 & H4, G-protein coupledCharacteristic H1 H2 H3 H4

G-protein coupling Gq/11 Gs Gi/o Gi/o

Second messenger

Ca2+, NO, cGMP cAMP cAMP cAMP ,Ca2+

Distribution Smooth muscle, endothelial cells, CNS

Gastric parietal cells, cardiac muscle, mast cells, CNS

CNS: presynaptic

Cells of hematopoietic origin

Representative antagonist

chlorpheniramine ranitidine pitolisant JNJ7777120

Gq-phospholipase C activation, Ca2+ channel opening; Gs-adenylyl cyclase activation; Gi-adenylyl cyclase inhibition ; G0- Ca2+ channel inhibition

Pharmacological Actions

Histamine- Allergic actions Immediate hypersensitivity and allergic response (IgE) Other mediators released : PLA2, PAF, LTC4 & LTD4, kinins

Mast cellsbasophils

IgE

Atopic individuals

rhinitis,asthma

atopic dermatitis

Blood vessels:Vasodilation (H1 & H2) in arteries (NO mediated)

tends to constrict large vessels (rodents)Increased capillary permeability (H1)Lowering of BPConstricts veins extravasation of fluid & edemaTriple response of Lewis: flush, flare and wheal

Heart:Force of contraction of heart heart rateSlows AV conduction (arrhythmia in high doses)

LungsH1 – bronchoconstriction, increased mucus viscosityH2 - slight bronchodilation, increased mucus secretionH1 - stimulation of vagal sensory nerve endings: cough

Gastric acid secretion: marked increase

Direct action exerted on parietal cells through H2 receptors, mediated by increased cAMP generation which activates membrane proton pump

Sensory nerve endings: Peripheral nerve endings: Itching, pain, flare

Autonomic ganglia and adrenal medulla:Stimulated and release of adrenaline, secondary rise of BP

Does not cross BBB

ICV admn causes Raise in BPCardiac stimulation hypothermiabehavioural arousalVomitingADH release

Mediated by H1 and H2 receptors

CNS

Pathophysiological roles:• Cellular mediator of immediate HSR and

acute inflammatory response• Anaphylaxis• Seasonal allergies• Duodenal ulcers• Systemic mastocytosis• Gastrinoma (Zollinger-Ellison Syndrome)

Uses: No therapeutic value

1.Diagnostic – nonspecific bronchial hyperreactivity in asthmatics

2.Positive control during allergy skin testing

Histamine-related Drugs

Mast Cell Stabilizers (sodium cromoglycate, Nedocromil )

H1 Receptor Antagonists (1st and 2nd generation)

H2 Receptor Antagonists (Ranitidine, Cimetidine)

H3 Receptor Agonist and Antagonists (potential new

drugs being developed)

Ist generation

DiphenhydramineDimenhydranatePromethazineChlorpheniramineMeclizineCyclizineCinnarazineHydroxazine

IInd generation

CetrizineLevo cetrizineFexofenidineLoratidineAzelastinemezolastine

Histamine H1- Antagonists

1st gen. antihistamines

Short to intermediate acting

Sedation

Anti muscarinic actions

2nd gen. antihistamines

Long acting

Least / No sedation

No autonomic effects

Pharmacological Actions

Pharmacological Actions

1.Antagonism of histamine: Block: bronchoconstriction, triple responseFall BP: low dose blocked, for high dose both H1 and H2 blocker needed2. Antiallergic action: type I reaction suppressed Anaphylactic fall in BP: partially blocked Asthma in man: unaffected3. CNS: variable effect: sedation, no sedation, restlessness, insomnia4. Anti-cholinergic action: more in 1st generation5. Local anaesthetic: Not used clinically6. BP: fall only with i.v., admn and not with p.o.

Therapeutic uses

Bronchial asthma: ineffective since(1) Leukotrienes and PAF are more important

(2) Histamine is high in conc. Conventional dose of antihistamine are not adequate

Anaphylactic shock and laryngeal oedema: Adjuvant value only. Adrenaline is essential

Perennial vasomotor rhinitis, atopic dermatitis, chronic urticaria: less marked effect, combine with H2 blocker

First Generation AgentsAdverse Effects: Sedation (Paradoxical Excitation in children) Dizziness Fatigue Peripheral antimuscarinic effects like

Dry MouthBlurred VisionConstipationUrinary Retention

Drug interactions: Additive with classical antimuscarinics Potentiate CNS depressants

opioidssedativesgeneral and narcotic analgesicsalcohol

First Generation Agents

H 2 antagonist

Ranitidine, cimetidine, famotidine s/e of cimetidine: antiandrogenic Uses – peptic ulcer disease.

ACh

PGE2

Histamine Gastrin

Adenyl cyclase

_ +

ATP cAMP

Protein Kinase (Activated)

Ca++

+

Ca++

Proton pump

K+ H+

Gastric acid

Parietal cellLumen of stomach

AntacidOmeprazole

Ranitidine

H2M3

Misoprostol

_

__

+

PGE receptor

+

+

Gastrinreceptor+

+

+

Thank you