Autocoids - Histamines

3.
AUTOCOIDS AND RELATED DRUGS

INTRODUCTION TO AUTOCOIDS AND CLASSIFICATION
Autacoid This term is derived from Greek: autos—self, akos—healing substance or

remedy
DEFINITION : These are diverse substances produced by a wide variety of cells in the body,
having intense biological activity, but generally act at the site of synthesis and release, also
known as ‘local hormones’.
These heterogeneous substances have widely differing structures and pharmacologic
activities.
Autacoids are biological factors which act like local hormones, have a brief duration ,act near
the site of synthesis, and are not blood borne.
CLASSIFICATION
In addition, cytokines (interleukins, TNFα, GM-CSF, etc.) and several peptides like
gastrin, somatostatin, vasoactive intestinal peptide and many others may be considered as
autacoids.
HISTAMINE. 5-HT AND THEIR ANTAGONIST
HISTAMINE
• Histamine is a chemical messenger mostly generated in mast cells.
• Histamine, meaning ‘tissue amine’ (histos—tissue) is almost ubiquitously present in
animal tissues and in certain plants.
• Histamine, via multiple receptor systems, mediates a wide range of cellular responses,
including allergic and inflammatory reactions, gastric acid secretion, and
neurotransmission in parts of the brain.
LOCATION
• Histamine is present in practically all tissues, with significant amounts in the lungs,
skin, blood vessels, and GI tract.
• It is found at high concentration in mast cells and basophils.
• Histamine functions as a neurotransmitter in the brain.
• It also occurs as a
component of venoms and in secretions from insect stings.
SYNTHESIS AND METABOLISM
• Synthesized by decarboxylation of histidine
• Metabolized by P450 system by methylation and oxidative deamination
SITE OF SYNTHESIS AND STORAGE

• Histamine is synthesized and stored in the following sites:
1. Neurons in the brain
2.Entero chromaffin cells in the gastric mucosa
3. Mast cells.
• If histamine is not stored, it is rapidly inactivated by the enzyme amine oxidase.
RELEASE OF HISTAMINE
• Destruction of cells as a result of cold, bacterial toxin, trauma.
• Dissolution of cytoplasmic granules as a result of action of radiations.
• Allergy and Anaphylaxis .
• Action of drugs, histamine liberators.
HISTAMINE RECEPTORS
• Released histamine binds with the receptors.
• Histamine receptors belongs to the family of G-Proteins coupled receptors.
• Receptors are present at the cell surface of the target tissue .
MECHANISM & PHARMACOLOGICAL ACTION

H1 RECEPTOR BINDING : Binding Of Histamine With H1 Receptors
o Stimulates intracellular activity of Phosphatidyl Inositol Triphosphate
o Increases Intracellular levels of Ca++
Actions :
1. Exocrine excretion : Increased production of nasal and bronchial mucus, resulting in
respiratory symptoms.
2. Bronchial smooth muscles : Constriction of bronchioles results in symptoms of
asthma and decreased lung capacity.
3. Intestinal smooth muscles : Constriction results in cramps and diarrhoea.
4. Sensory nerve endings : Itching and pain
H2 RECEPTOR BINDING : Binding Of Histamine With H2 Receptors
o Stimulates intracellular activity of CAMP.
Actions :
1. Stomach : Increased gastric acid secretion
BOTH H1 & H2 RECEPTORS
Actions :
1. Cardiovascular system : Lowers systemic blood pressure by reducing peripheral
resistance. Causes positive chronotropism (mediated by H2 receptors) and a positive
inotropism (mediated by both H1 and H2 receptors).
2. Skin : Dilation and increased permeability of the capillaries results in leakage of
proteins and fluids into the tissues. In the skin, this results in the classic “triple
response”.
Triple response of histamine
The triple response of histamine refers to a series of reactions that occur upon the injection of
histamine into the skin.
• Red Spot/Erythema : A red spot typically refers to a localized area of redness on the
skin due to the capillary dilation, this enhances the access of immune cell in the
damaged area to initiate repair process causing erythema or redness.
• Wheal : A wheal is a raised, swollen area of skin that often accompanies the flare
reaction. It typically appears as a rounded, pale, or reddened area with defined
borders. The wheal forms due to increased permeability of blood vessels in the skin,
allowing fluid to leak into the surrounding tissues.
• Flare : A flare refers to the spreading redness and warmth around the injection site.
This occurs due to the vasodilation in the skin, leading to increased blood flow to the
area.
PATHOPHYSIOLOGICAL ROLES
• Gastric secretion
• Allergic phenomenon
• As transmitter
• Inflammation
• Tissue growth and repair
USES
No therapeutic uses
DRUGS
Betahistine : Orally active drug used to control vertigo in meniere disease, contraindicated in
asthmatic and ulcer patient.
H1- ANTI HISTAMINES
The term antihistamine refers primarily to the classic H1-receptor blockers. These
drugs competitively antagonize actions of histamine at the H1 receptors. The H1-receptor
blockers can be divided into first- and second-generation drugs.
CLASSIFICATION
PHARMACOLOGICAL ACTION
Qualitatively all H1 antihistaminic have similar actions, but there are quantitative
differences, especially in the sedative property.
1. Antagonism of histamine : They effectively block histamine induced
bronchoconstriction, contraction of intestinal and other smooth muscle and triple
response etc
2. Antiallergic action : Many manifestations of immediate hypersensitivity (type I
reactions)
are suppressed. Urticaria, itching and angioedema are well controlled. Anaphylactic
fall in BP is only partially prevented.
3. CNS : The older antihistamines produce variable degree of CNS depression.
4. Anticholinergic action : Many H1 blockers in addition antagonize muscarinic actions
of Ach
PHARMACOKINETICS
• Oral administration
• Distributed in all tissues including CNS
• Metabolised by cytochrome P450
• Excreted in urine
USES
1. Allergic reactions
2. Motion Sickness
3. Nausea
4. Urticaria
5. Common cold
6. Cough
SIDE EFFECTS
1. Sadness
2. Fatigue
3. Tremor
4. Blurred Vision
5. Dryness of mouth
6. Sedation
7. Hypotensions
DRUG INTERACTION
• CNS depressant (potentiate the effect )
• MAO Inhibitors (exacerbate the sedative activity)
• Anticholinergics
SECOND GENERATION ANTIHISTAMINES
Second generation antihistamines have following properties than first generation
antihistamines.
• Absence of CNS depressant property.
• Higher H1 selectivity : no anticholinergic side effects.
• Additional antiallergic mechanisms apart from histamine blockade: some also inhibit
late phase allergic reaction by acting on leukotrienes or by antiplatelet activating
factor effect
• These newer drugs have the advantage of not impairing psychomotor performance
(driving etc. need not be contraindicated), produce no subjective effects, no
sleepiness, do not potentiate alcohol or benzodiazepines.
H2 RECEPTOR BLOCKERS
Ranitidine, famotidine, roxatidine, and many others have been added subsequently.
They are primarily used in peptic ulcer, gastroesophageal reflux and other gastric
hypersecretory states.
PHARMACOLOGICAL ACTION
• Blocks gastric acid secretion
• Uterine relaxation (in rat)
• Bronchial relaxation (in sheep)
• Cardiac stimulation (in isolated guinea pig heart).

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3.

AUTOCOIDS AND RELATED DRUGS

Autacoid This term is derived from Greek: autos—self, akos—healing substance or

SITE OF SYNTHESIS AND STORAGE

MECHANISM & PHARMACOLOGICAL ACTION

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