Iftekhar Ahmed, 43rd Batch

AUTACOIDS

Introduction

Greek word autos- self; akos- remedy (healing substance). These are substances produced by wide
variety of cells in the body having intense biological activity. The autacoids are also called as local
hormone. (Hormone release by the specific cells whereas act upon distant target tissue).
 Naturally occurring substances.
 Localized in tissues and normally do not circulate.
 Differ from hormones and neurotransmitters.
 Short duration of action.
 Usually involved in response to injury.
 Generally act locally at the site of synthesis & release.

Classification of Autacoids

Basis of chemical nature autacoids are classified into following group

 Decarboxylated amino acid (amine autacoids) - Histamine , Serotonin
 Polypeptides autacoids - Angiotensins, Kinins, VIP, Substance P
 Endothelium-derived autacoids - Nitric oxide (NO), Endothelins (peptide)
 Lipid derived autacoids – Prostaglandins, Leukotrines, Platelet activating factor

Release and Functions of Endogenous Histamine

Histamine has important physiological roles. After its release from storage granules as a result of
the interaction of antigen with immunoglobulin E (IgE) antibodies on the mast cell surface,
histamine plays a central role in immediate hypersensitivity and allergic responses.
The actions of histamine on bronchial smooth muscle and blood vessels account for many of
the symptoms of the allergic response.
In addition, some drugs act directly on mast cells to release histamine, causing untoward effects.
Histamine has a major role in regulating gastric acid secretion and also modulates
neurotransmitter release.
 Histamine Synthesis

Histamine is formed by the decarboxylation of the amino acid histidine by the enzyme L-histidine
decarboxylase

Synthesised in mast cells/ basophils of immune system, ECL cells of the gastric mucosa and
certain neurones

Site of histamine synthesis

1. Mast cells:

Most of the histamine produced in mast cells, mast cells are found in everywhere in the body from
nose, mouth, palm, fat, blood vessel to internal body surface.

1. Non mast cells:

a) Brain: Some parts of histamine is produced in nerve cells which is called neuron transmitter.

b) Stomach: Another important part of histamine production is the ECL cell of stomach which
is responsible for production of gastric acid.

Conditions That Release Histamine

1. Tissue injury: Any physical or chemical agent that injures tissue, skin or mucosa will cause the
immediate release of histamine from mast cells.
2. Allergic reactions: 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, mast cell will degranulate when exposed to the appropriate antigen and release
histamine, ATP and other mediators.
3. Drugs and other foreign compounds: Morphine, dextran, antimalarial drugs, dyes,
antibiotic bases, alkaloids, amides, quaternary ammonium compounds, enzymes (phospholipase C).
Penicillins, Tetracyclines, Basic drugs- amides, amidines, diamidines, Toxins, venoms, Proteolytic
enzymes, Bradykinin, Kallidin, & Substance P
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Mechanism of Histamine-Releasing Agents.

Histamine releasing substances activate the secretory responses of mast cells and basophils by
causing a rise in intracellular Ca2+. Some are ionophores and directly facilitate the entry of Ca2+ into
the cell; others, such as neurotensin, act on specific G protein–coupled receptors (GPCRs).
In contrast, the precise mechanism by which basic secretagogues (e.g., substance P, mastoparan,
kallidin, compound 48/80, and polymyxin B) release histamine still is unclear. These agents can
directly activate Gi proteins after being taken up by the cell but more recent evidence indicates the
involvement of a cell-surface GPCR. The downstream effectors appear to be βγ subunits released
from Gαi, which activate the PLCβ–IP3–Ca2+ pathway. Antigen–IgE complexes lead to mobilization
of stored Ca2+ and activation of isoforms of PLCγ.

Histamine Degradation

There are two major paths of

histamine metabolism in humans.
The more important of these involves
ring methylation to form N-
methylhistamine, catalyzed by
histamine-N-methyltransferase,
which is distributed widely. Most of
the N-methylhistamine formed is
then converted to N-
methylimidazoleacetic acid by
monoamine oxidase (MAO).

Alternatively, histamine may

undergo oxidative deamination
catalyzed mainly by the nonspecific
enzyme DAO, yielding
imidazoleacetic acid, which is
then converted to imidazoleacetic
acid riboside

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Histamine Receptor Subtypes

H1–receptors:
Stimulate PLC and increase IP3 and intracellular Ca2+. They are present in:
- Vascular endothelium of arterioles and capillaries causing vasodilatation by NO release,
increase capillary permeability causing edema and decrease blood pressure.
- Extravascular smooth muscles (bronchi, GIT, uterus, urinary bladder) causing contraction.
- Sensory nerve endings causing itching and pain sensation.
Representative agonist: 2-CH3 histamine
Representative antagonist: Chlorpheniramine

H2-receptors:
Linked to Gs protein and stimulate adenyl cyclase increasing cAMP. They are present in:
- Vascular smooth muscles of arterioles and capillaries causing vasodilatation by increasing
cAMP with calcium efflux and decrease blood pressure. The effect of histamine on blood
vessels is mediated mainly through H1–receptors and to a lesser extent H2-receptors.

- Gastric mucosa increasing volume of gastric juice, secretion of gastric acid, pepsin and
intrinsic factor.

- Heart increasing heart rate and force of contraction.

Representative agonist: Dimaprit
Representative antagonist: Ranitidine

H3-receptors:
Linked to Gi protein and inhibit adenyl cyclase decreasing cAMP. They are present in:
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 - H3 receptors are expressed mainly in the CNS, especially in the basal ganglia, hippocampus,
cortex, Presyneptic junction and myenteric plexus

- H3 receptors act as presynaptic autoreceptors on histamine-containing neurons that

mediated feedback inhibition of the release and synthesis of histamine.
Representative agonist: (R)--2-CH3 histamine
Representative antagonist: Chlobenpropit

H4-receptors:
Linked to Gi protein and inhibit adenyl cyclase decreasing cAMP. In some cell the increase Ca2+
concentration. They are present in:
 H4 receptors are on immune active cells such as eosinophils and neutrophils, as well as in the
gastrointestinal (GI) tract and CNS.
Representative agonist: (R)--2-CH3 histamine
Representative antagonist: JNJ7777120

Major Physiological Actions

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Role in Allergic Responses

The principal target cells of immediate hypersensitivity reactions are mast cells and basophils. As
part of the allergic response to an antigen, IgE antibodies are generated and bind to the surfaces of
mast cells and basophils via specific high-affinity Fc receptors.
Atopic individuals develop IgE antibodies to commonly inhaled antigens. This is a heritable trait,
conferring a predilection to rhinitis, asthma, and atopic dermatitis.
Within seconds of the intravenous injection of a histamine liberator, human subjects experience a
burning, itching sensation. This effect, most marked in the palms of the hand and in the face, scalp,
and ears, is soon followed by a feeling of intense warmth. The skin reddens, and the color rapidly
spreads over the trunk. Blood pressure falls, the heart rate accelerates, and the subject usually
complains of headache. After a few minutes, blood pressure recovers, and crops of hives usually
appear on the skin. Colic, nausea, hypersecretion of acid, and moderate bronchospasm also occur
frequently.

An Allergic Reaction

Histamine and Anaphylaxis (Life Threatening)

 Systemic mast cell degranulation as result of hypersensitivity reaction to insect bites,

antibiotic (penicillin) or ingestion of certain foods (nuts)
 Massive release of histamine throughout the body causing:
– Global vasodilation
– Hypotension: systemic pooling of fluid due to extravasation of plasma into the
interstitium
– Severe bronchoconstriction and epiglottal swelling
 Can be lethal within minutes

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The “Triple Response”

If histamine is injected intradermally, it elicits a characteristic phenomenon known as the triple

response. This consists of
(1) A localized red spot extending for a few millimeters around the site of injection that appears
within a few seconds and reaches a maximum in about a minute;
(2) A brighter red flush, or "flare," extending about 1 cm or so beyond the original red spot and
developing more slowly; and
(3) A wheal that is discernible in 1 to 2 minutes and occupies the same area as the original small red
spot at the injection.

Pharmacological Effects

 Cardiovascular System.
Histamine characteristically causes dilation of resistance vessels, an increase in capillary
permeability, and an overall fall in systemic blood pressure. In some vascular beds, histamine will
constrict veins.
 Vasodilation.
This is by far the most important vascular effect of histamine in human beings. Vasodilation involves
both H1 and H2 receptors distributed throughout the resistance vessels in most vascular beds
 Increased "Capillary" Permeability.
This effect of histamine on small vessels results in outward passage of plasma protein and fluid into
the extracellular spaces, an increase in the flow of lymph and its protein content, and edema
formation. H1 receptors on endothelial cells are the major mediators of this response.
 Constriction of Larger Vessels.
Histamine tends to constrict larger blood vessels, A net increase in total peripheral resistance and
an elevation in blood pressure can be observed. As noted earlier, H1-receptor-mediated constriction
may occur in some veins and in conduit coronary arteries

 Heart.
Histamine affects both cardiac contractility and electrical events directly. It increases the force of
contraction of both atrial and ventricular muscle by promoting the influx of Ca2+, and it speeds heart
rate by hastening diastolic depolarization in the sinoatrial (SA) node. It also acts directly to slow
atrioventricular (AV) conduction, to increase automaticity, and in high doses especially, to elicit
arrhythmias.
 Exocrine Glands.
Histamine is an important physiological regulator of gastric acid secretion. This effect is mediated
by H2 receptors.

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 Extravascular Smooth Muscle.
Histamine stimulates or, more rarely, relaxes various smooth muscles. Contraction is due to
activation of H1 receptors, and relaxation (for the most part) is due to activation of H2 receptors.
Bronchial muscle is exquisitely sensitive. The uterus of some species is contracted by histamine; in
the human uterus, gravid or not, the response is negligible. Responses of intestinal muscle also vary
with species and region, but the classical effect is contraction. Bladder, ureter, gallbladder, iris, and
many other smooth muscle preparations are affected little or inconsistently by histamine.
 Peripheral Nerve Endings: Pain, Itch, and Indirect Effects.
Histamine stimulates various nerve endings and sensory effects causing itch and pain. In the
periphery, neuronal receptors for histamine are generally of the H1 type

Betazole

Betazole is a histamine analogue. It produces the same effects as histamine, binding the H2 receptor
which is a mediator of gastric acid secretion. This agonist action thereby results in an increase in the
volume of gastric acid produced.

Adverse effects
Flushing, Burning sensations

Betahistine

Betahistine is an antivertigo drug first used for treating vertigo associated with Ménière's disease. It
is also commonly used for patients with balance disorders.
Betahistine has a very strong affinity as an antagonist for histamine H3 receptors and a weak affinity
as an agonist for histamine H1 receptors. The active ingredient is a specific histamine agonist with
virtually no H2-activity.

Side Effects
Stomach upset and headache
Contraindication
Betahistine is contraindicated in patients with Phaeochromocytoma

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H1-Receptor Antagonists

Mechanism of Action: H1 Antagonists

 Displaces histamine from the H1 receptor, which is a G-protein coupled receptor

 Histamine leads to formation of IP3 and a release of stored Ca++, followed by a cascade of other
events.

 H1 receptor blockade prevents this activity and leads to a decrease in Ca++ inside of the cell

Classification of H1 Antagonists

 2 categories:
– First generation (less specific)
 Diphenhydramine
 Chlorpheniramine

– Second generation (specific for H1)

 Fexofenadine
 Loratadine
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 Differentiated by their side effect profiles
– 1st generation – sedating
– 2nd generation – non-sedating

First Generation H1 Antagonist

 Low specificity
 Some effects may be undesirable, others of therapeutic value (anticholinergic – drying of
nasal mucosa; sedative effects - insomnia)
 Many OTC antihistamines are 1st generation

Second Generation H1 Antagonist

 E.g. Loratadine, fexofenadine, cetrizine

 Decreased CNS penetration compared with 1st generation
antagonists
– Ionised at physiological pH
– Exhibit high binding to albumin & less free to
diffuse into CNS
 Side effects:
– cardiotoxic effects at high conc.
– Ventricular arrhythmias (terfenadine:-
withdrawn)
– Metabolised by cyt P450 caution with other
drugs detoxified by P450

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1st Vs 2nd Generation Antihistamines

First generation Second generation

Short acting Long Acting

Cross the blood brain barrier Do not cross blood brain barrier

Show antimuscarinic effects Don’t show antimuscarinic effects

Show antihistamine action Show antiallergic action

Cause sedation, drowsiness, and decreased They don’t have such effects
cognitive processing
Impairs psychomotor performance Don’t impair psychomotor performance

Third Generation Antihistamines

Third-generation H1-antihistamines are second-generation antihistamines informally labeled

third-generation because the active enantiomer (levocetirizine) or metabolite(desloratadine and
fexofenadine) derivatives of second-generation drugs are intended to have increased efficacy with
fewer adverse drug reactions.
 Levocetirizine
 Desloratadine
 Fexofenadine

Therapeutic Uses of H1 Blockers

1. Allergic rhinitis, relieves rhinorrhea, sneezing, and itching of eyes and nasal mucosa.
2. Common cold: palliative, dries out the nasal mucosa. Often combined with nasal decongestant
and analgesics.
3. Allergic dermatoses: can control itching associated with insect bites.
4. Outpatient procedures for preanesthetic sedation and prevention of nausea and vomiting
(Promethazine (Phenergan)). Phenergan also inhibits salivary and bronchial secretions and can be
used as a local anesthetic.
5. Antiemetic: prevention or treatment of nausea and vomiting (Bendectin, doxylamine with
pyridoxine).
6. Hypnotics: limited value.
7. Other uses:
a. Reduction of tremors and muscle rigidity in Parkinson's disease
b. Treatment of migraine headaches

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H2 Receptor Antagonists

 Differ structurally from H1 antagonists: contain an intact 5-membered ring and an

uncharged side chain
 Competitively bind to H2 receptors on parietal cells
– Reduce gastric acid secretion (↓cAMP)
– Use: heart burn, peptic ulcer disease
 Major side effect of cimetidine involves inhibition cyt P450 mediated drug metabolism
– Can result in increased plasma levels of co-administered drugs eg warfarin
 Cimetidine, Famotidine, Nizatidine, and Ranitidine

Clinical Uses

H2-antagonists are used by clinicians in the treatment of acid-related gastrointestinal conditions,

including:
 Peptic ulcer disease (PUD)
 Gastroesophageal reflux disease (GERD/GORD)
 Dyspepsia
 Prevention of stress ulcer (a specific indication of ranitidine)

Side Effects

 Constipation.
 Diarrhea.
 Difficulty Sleeping.
 Dry Mouth.
 Dry Skin.
 Headaches.
 Sexual Dysfunction

SUMMARY OF HISTAMINE EFFECTS

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