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.