Autacoids- Histamine, Serotonin and
Prostaglandins
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Autacoids
The term autacoids is derived from the Greek words: autos-self and akos-
healing.
They include a wide variety of substances which are locally released (in
a paracrine fashion) and act for a short distance at their sites of release. In
contrast to hormones, they are not released in the blood.
They may act as: Immunomodulators (increase or decrease the immune
response and the associated inflammation) or transmitters. Besides, they have
a role in normal physiology and pathophysiological conditions.
Autacoids are broadly classified as:
Amine Autacoids: Histamine, Serotonin (also known as 5-
Hydroxytryptamine/ 5-HT)
Lipid-derived Autacoids: Prostaglandins, Leukotrienes, etc
Peptide Autacoids: Bradykinin, Angiotensinogen
Miscellaneous: Cytokines (Interleukins, TGF-beta, TNF-alpha,
Epidermal Growth Factors, etc), gastrointestinal peptides
(bombesin, gastrin, Vasoactive intestinal peptide/VIP
Histamine
It is a tissue amine (histo-tissue), which is closely associated with allergic
reactions (Type I Hypersensitivity Reactions)
Found in: Mast cells and basophils(predominant stores of histamine), skin,
gastric mucosa, lungs, liver, placenta.
It is also found in blood, body secretions, venoms, etc.
Synthesis: It is synthesized from amino acid histidine.
Storage: In storage granules and is held by acidic proteins (Histamine itself is
positively charged)
Release: It is released by the process of exocytosis in response to allergens
which are detected by the receptors on mast cells. However, beta-agonists
inhibit release of histamine.
Action on Receptors: Histamine acts on four types of receptors, based on
specific receptor antagonists as:
H1
H2
H3- Auto-receptor with no clinical application
H4- Has found a role in inflammatory states and rhinitis, allergy
Actions on Body Systems:
Nervous System- Stimulate sensory nerve endings which transmit
pain and itch sensations
Cardiovascular System- Decrease blood pressure (systolic and
diastolic)
Respiratory System- Cause bronchoconstriction
Gastrointestinal System- Intestinal smooth muscle contraction
and peristalsis. Increased secretion of gastric acid, pepsin and
intrinsic factor (for Vit.B12 absorption)
Uterus- Uterine smooth muscle contraction and abortion
Thus, excessive release causes flushing, vasodilation, pain (typical of acute
inflammation), hypotension and tachycardia (characteristic of anaphylactic
shock) and angioedema, bronchospasm, increased wakefulness and increased
gastric acid secretion (acidity). These actions are antagonised by the specific
receptor antagonists.
Histamine Antagonists:
Depending upon their receptor action, as mentioned above, the histamine
antagonists are classified as follows:
H1 Antagonist: They are the most widely used anti-histaminics. However,
second generation anti-histaminics are preferred today over the traditional first
generation anti-histaminics since latter have marked sedative effects and CNS
actions.
First Generation Anti-Histaminics:
Being lipid soluble, they cross the blood brain barrier and enter the CNS, having
marked sedative action. They include:
Promethazine, Diphenhydramine, Dimenhydrinate-Potent and
Marked Sedation
Chlorpheniramine, Chloryclizine- Potent and Moderate Sedation
Mepyramine and Pheniramine- Less Potent and Mild Sedative
Second Generation Anti-Histaminics:
Being less lipid soluble, they do not enter the CNS and thus, have no/negligible
sedative action. They include the widely used over-the-counter medications
such as:
Cetrizine, Levocetrizine, Terfenadine, Astemizole, Ketotifen, Loratadine
Serotonin
Synthesis: It is a monoamine derivative of tryptophan amino acid, also known
as 5-Hydroxytryptamine.
Storage: Nearly 90% of serotonin is found in the entero-chromaffin like cells in
the alimentary canal (regulate intestinal movements) while 10% is found in the
nervous system in the brain (regulate mood, appetite, sexual desire, attitude,
memory and behaviour). It is synthesized in the brain, but CANNOT cross the
blood-brain barrier.
Serotonin in the blood is also stored in the platelets, which release it during
bleeding from the vessel. Serotonin causes vasoconstriction and thus, limits
blood loss.
Patho-Physiological Effects: They can be either due to an excess or
deficiency of serotonin.
High Serotonin Levels:
Obsessive Compulsive Disorder
Pulmonary Vasoconstriction leading to pulmonary hypertension
Mania and Elation
Low Serotonin Levels:
Mood lability, including depression and suicidal ideation
Unexplained tears, disturbed sleep cycle
Release: It occurs by serotoninergic neurons in the CNS in response to various
stimuli, and is also affected by normal Circadian Rhythm.
Receptors and Mechanism of Action: The action of serotonin is mediated by
serotonin receptors numbered from 5HT-1 to 5HT-7.
Except 5HT-3 (which is ligand gated receptor), all the other receptors are G-
Protein Coupled Receptors (which act via a secondary messenger signalling
pathway)
Prostaglandins
They are hormone like lipid compounds which are derived from fatty acids. They
are synthesised from essential fatty acids.
Release: They act in an autocrine and paracrine fashion to bring out their
desired effects. They are released by two main transporters: Multidrug-
Resistance Protein (MRP4) and ATP-Binding Cassette transporter (ABCC–4).
Pharmacological Actions:
Blood Pressure Regulation: PGE2 and PGI2 (Prostacyclin), result in
vasodilation and a fall in blood pressure. Thus, they are used in treatment of
pulmonary hypertension.
Inflammation: PGD2 is anti-inflammatory while PGE1 and PGE2 are pro-
inflammatory (redness, swelling, transudation of fluid and pain)
Uterus: PGE2 and PGF2-alpha cause uterine contraction. Thus, during induction
of abortion, the analogues of the above two prostaglandins are used.
Pain and Fever: PGE2 acts on thermoregulatory centre present in the
hypothalamus causing fever (pyrogen). Thus, NSAIDS, which inhibit the
prostaglandin formation such as Aspirin, Paracetamol and Ibuprofen are
used as first line drugs for management of fever.
Gastrointestinal System: Prostaglandins decrease gastric acid secretion and
are thus muco-protective and ulcero-protective. However, they increase
pancreatic secretions and increase intestinal motility.
Immune System: Prostaglandins decrease the immunological functions of B
and T lymphocytes.
Respiratory System: PGEs causes smooth muscle relaxation whereas PGFs
cause bronchoconstriction. Thus, they have antagonistic effects on the bronchi.
Renal System: PGE2 is the most abundant prostaglandin in the kidneys. They
increase GFR and thus, urine output.
Platelets: PGI2 inhibits platelet aggregation (Clopidogrel is used in
maintenance treatment of myocardial infarction as it is anti-aggregatory for
platelets). PGE2 and Thromboxane A2 promotes platelet aggregation and
thrombosis.
Eyes: They decrease the intraocular pressure and are thus used in the
treatment of glaucoma. Eg. Latanoprost, Carboprost, Travoprost.
