What is Autocoids / Autocoids PDF Notes / NEET Notes / Pharmacy Pharmacology Notes
The word autocoids derive its origin from the Greek words autos meaning self and akos meaning healing element . Auto coids are chemical signals produced by different cells of the body. They act locally at the site where they are synthesised and released ( e.g., at the site of inflammation within the inflammatory pockets).
Autocoids are chemical substances that are produced within the cells and are released in response to different stimuli to cause various p hysiological actions. Mostly the action of auto coids is localised but large amounts of them can be transported through circulation to exert their eff ects at sites, other than where they are synthesised. Since auto coids act locally, they are also described as local hormones. Autocoids are biologically active compounds which act on smooth muscles of different tissues. Pathological conditions like inflammation, allergy, and hypersensitivity result from an imbalance in their synthesis or release.
Autocoids include a wide range of substances having different structure and pharmacological activities, e.g., histamine, serotonin, eicosanoids, Platelet - Activating Factor (PAF), and several polypeptides.
4.1.2. Classification
Depending on their chemical classes (amines, peptides, or lipids), autocoids are categorised as follows:
) Amines: Histamines and Serotonin (or 5-HT).
2) Polypeptides: Bradykinin and Angiotensin.
3) Lipids:
i) Eicosanoids or Arachidonic Acid Metabolites: Leukotrienes, Thromboxanes, and Prostaglandins.
ii) Platelet activating factor.
4.1.3. Histamine Histamine is a nitrogen-containing organic compound belonging to the group of amines. It is produced in almost all the animal cells during a local immune response. It regulates various physiological functions of the gut. In addition, it also play s a role in neurotra nsmission. Release of histamine is the initiating factor of any inflammatory response.
Histamine is synthesised and released on stimulation of basophils and mast cells (found in the nearby connective tissues) as a part of an immune res ponse against foreign pathogens. This causes increased vascular (capillary) permeability for WBCs and other proteins to facilitate adequate invasion of foreign bodies present within the tissues.
4.1.3.1. Biosynthesis Histamine is a hydrophilic compound containing an imidazole ring and an amino group linked by two methylene groups. It shows wide distribution in living organisms and is found in venoms, bacteria, and plants, ranging in amount fro m 1-100g/g. Histamine is synthesised by the decarboxylation of histidine (an amino acid), catalysed by the enzyme L -Histidine Decarboxylase (HDC). Histidine consumed in diet also forms a source for the synthesis of histamine by the action of the diverse microbial-flora present in the gut. The riboside of imidazole acetic acid is the end product of the cycle of histamine synthesis , which is active in negligible amounts and is excreted via urine (figure 4.1)
Histamine undergoes degradation more significantly by the N-Methyl transferase degradation pathway. Fluoromethyl histidine acts as a suicidal inhibitor for the enzyme L-histidine decarboxylase. Mast cells are the primary storage sites for histamine in almost all the tissues. However, when i n the blood, it is the circulating basophil. Mast cells exhibit histidine decarboxylase activity and show the presence of some specific granules for the storage of histamine, heparin, neutrophil chemotactic factor, eosinophil chemotactic factor, and few enzymes. Several biolog ical fluids, platelets, and leuk ocytes have been found to con tain histamine in small amounts; also cerebrospinal fluid contains a significant amount of histamine. Sites other than the mast cells for the synthesis and storage of hista mine comprises of epidermal cells, gastrointestinal mucosal cells, cells within the regenerating tissues, and the neurons. Gastric mucosa of the gastrointestinal tract has max imum concentration of histamine; and this concentration constantly decreases in t he distal part because the regular fresh synthesised histamine is
released out and not stored. On the other hand, when histamine concentration is found to be depleted in the tissues with rich am ounts of mast cells, it may take several weeks for its concentration to be restored to its normal value. 4.1.3.2. Histamine Receptor Subtypes H1, H 2, and H 3 types of histaminergic receptors mediate all the biological effects of histamine. When histamine was recognised and the anti -histamines (H1 blockers) were produced at the starting of this century , it was known that all the histamine actions cannot be blocked. The Nobel Laureate , James Black identified the H2 receptors. Recently, evidence for the existence of H 3 receptors has been discovered. In table 4.1 , the histamine receptors are differentiated:
H4 Receptors: These receptors are linked to the pathology of allergy and asthma; and regulate the changes in cellular shape, chemotaxis, and up -regulation of adhesion molecules (CD11 b/CD18 and ICAM, P -selectin). H4 receptors present on haematopoietic cells (neutrophils and eosinophils) have been recognised lately.
4.1.3.3. Mechanism of Action The action of histamine is observed when it combines with specific histamine receptors (HR 1, HR 2, HR 3, and HR 4) present within the cells. All these four receptors belong to the category of G-protein coupled receptors. Receptors mediate th e histamine action. Table 4.2 illustrates the various sub - types, location, mechanism of action, and effects of histamine receptors
4.1.3.4. Pharmacological Actions The various physiological actions exerted by histamine on different organs and tissues of the body are:
1) Nervous System: Histamine is known to be a potent stimulator of the sensory nerves. The release of histamines in epidermis results in itching , whereas its release in dermis results in pain mediated via H 1 receptors. The response to insect bites, in the form of urticaria (hives), mainly involves the sensory nerve stimulation.
2) Cardiovascular System i) Blood Vessels: Histamine causes constriction of large blood vessels and dilatation of small arterioles. In humans, the most significant action of histamines is vasodilatation (decrease in blood pressure) involving both H1 and H2 receptors. Activation of H1 receptors via Endothelium-Derived Relaxing Factor (E DRF) (NO/PGI 2) is responsible for short -lived and rapid vasodilatation
Vasodilatation caused by the activation of H 2 receptors occurs slowly and continues (associated with a decrease in BP) via the cAMP -PKA pathway. A low dose of H 1-receptor antagonists blocks the histamine response, while a high dose of the same blunts the initial phase of the response, which is seen to be quite large. A fall in the systemic blood pressure is generally complemented by reflex tachycardia.
ii) Increased Capillary Permeability: This effect is observed by stimulation of H 1 receptors that cause contraction and separation of endothelial cells. Thus, plasma proteins and fluids are allowed to enter the extracellular space, resulting in oedema (a manifestation of urticaria). iii) Lewis’s T riple Response: In 1927, Lewis observed a characteristic Triple Response (TR) on injecting histamine via intradermal route. It is marked by the following features:
a) The injection site appears to be surrounded by a localised red coloured spot within a few se conds that maximises within a minute. The vasodilatory action of histamine causes such response.
b) A bright red coloured flare or flush is seen surrounding the initial red spot by up to a centimetre. Stimulation of axon reflexes by histamine leading to an indirect vasodilatation is responsible for the same.
c) After 1 or 2 minutes, a wheal or a swelling is seen at the injection site and also surrounding it. The fluid and protein exudation from the post-capillary venules is responsible for such symptoms.
iv) Histamine Shock: Intravenous administration of histamine in large doses (as during anaphylaxis) causes an intense fall in blood pressure. This occurs as a result of the dilatation of blood vessels, which acquires more blood, thus increasing permeability, and decreasing venous return and cardiac output. v) Heart: The contractility of heart increases due to stimulation of H 2 receptors. Thus, a stimulation of cardiac automaticity as well as SA and AV nodal activities is observed.
3) Histamine and Allergic Reaction: Once antigen interacts with IgE antibody (or Fc receptor) present on the mast cell surface, the stored histamine is released. This condition is evident in atopic individuals (immediate hypersensitivity reaction is seen followed by allergy, i.e., smooth muscle relaxation and vasodilatation). Many drugs , e.g., d-tubocurarine, morphine, vancomycin, polymyxin -B, dextran, radiocontrast dyes, etc., have the property of releasing histamine from mast cells, without sensitisation, but not from non -mast cells or tissues ( e.g., gastric mucosa, epidermis, rapidly growing tissues, and CNS neurons). But these agents may cause anaphylactoid reaction (i.e., fall in blood pressure, tachycardia, headache, urticaria , bronchospasm, and red skin)
Histamine from non -mast cells plays a major role in regulating the secretion of gastric acid. It is also responsible for controlling the release of neurotransmitters (such as substance P and bradykinin ). Pathological states like myeloid leukaemia and carcinoid tumour (showing an increase in basophil count) are associated with an increase in histamine which causes pruritus and flushing, respectively. Cold urticaria, solar urticaria, cholinergic urticaria, scratching urticaria, etc., are also associated with histamine release. Release of histamines is the only cause for an allergic reaction; however, it has now been proved that sensitised mast cells also release histamine along with various other substances, such as eicosanoids, PAF, kinins, and 5-HT.
4) Histamine and Gastric Acid Secretion: Histamine is a potent gastric acid secretion mediated by the action of H 2 receptors on gastric parietal cells. If H2 receptors are blocked, the secretion of acid in response to histamine, gastrin, and vagal stimulation is eliminated. Patients suffering from peptic ulcer are treated with H2 receptor antagonists.
5) Action on Smooth Muscles: Smooth muscles contract and relax on activation of H1 and H2 receptors, respectively. The most important action of H1 receptors is to mediate constriction of bronchial muscles in asthma patients; however, this response is not so prominent among individuals not suffering from any such disease. Relaxant responses precipitated by the stimulation of H2 receptor are overshadowed by the dominant H1 action.
4.1.3.5. Pathophysiological Actions The various pathophysiological actions exerted by histamine are: 1) Gastric Secretion: HCl secretion in stomach is mediated by histamines, and it shows a high turnover rate. On being stimulated, histamine is rel eased locally from histaminocytes present near the parietal cells.
2) Allergic Phenomena: Histamine primarily mediates hypersensitivity reactions. Histamine is released from the mast cells, and an antigen-antibody reaction occurs on their surface resulting in urticaria, angioedema, bronchoconstriction, and anaphylactic shock. The hypothalamus and midbrain have non-mast cell histamine which is responsible for restlessness.
3) Inflammation: Histamines mediate vasodilatation and changes occurring during inflammation . Leukocyte adhesion to vascular endothelium is promoted by histamines by the expression of adhesion molecule , i.e., Pselectin on endothelial cell surface. This leads to the sequestration of leukocytes at the inflammation site. Histamine may also help in the regulation of microcirculation depending on the local needs.
4) Tissue Growth and Repair: Histamine has been implicated in the process of tissue growth and repair since growing and regenerating tissues contain histamine in high concentrations.
5) Headache: Histamine also plays a role in headache that is vascular in origin, although no conclusive evidence has been obtained as yet
4.1.3.6. Histamine Agonists Along with histamine, the other drugs that act as histamine agonists are:
1) Betazole: Its activity is ten times greater at H2-receptors than at H1-receptors.
2) Impromidine: It is used for investigations with about 10,000 H 2 to H 1 activity ratio.
3) Methimepip:It is a histamine agonist acting specifically against H3 receptors. Therapeutic Uses Histamine agonists are mainly used for diagnostic purposes. They are primarily employed for allergy testing , for the assessment of histamine sensitivity , and for testing the function of gastric secretion (they have been replaced with pentagastrin, which is a synthetic peptide analogue of gastrin having lesser adverse effects). Adverse Effects Histamine agonists may cause f lushing, burning sensations, hypotension, tachycardia, and bronchoconstriction.
4.1.4. Histamine Antagonists (Antihistamines) Histamine antagonists are the drugs that antagonise the histamine action. Following are the three types of histamine receptor antagonists:
1) H1-Antagonists: These are classical antihistamines which block the physiological effects of histamine and are used in allergic disorders.
2) H2-Antagonists: Cimetidine, Ranitidine , and Famotidine are the examples of H2-antagonists which reduce the gastric HCl secretion and are used in peptic ulcer.
3) H3-Antagonists: Thioperamide is an example of H3-antagonist which regulates histamine release from histaminergic neurons of CNS by presynaptic auto -regulatory mechanism. It is not recommended to be used therapeutically. The effects of histamine can be antagonised by two groups of drugs:
1) Physiological Antagonists: The classical example of this group of histamine antagonist is adrenaline. These antagonists act at different receptor sites on the same biological system but elicit opposite response; for example, histamine acts on H 1 receptors of bronchial smoo th muscles and blood vessels to elicit bronchoconstriction and vasodilatation or fall in BP, whereas adrenaline acts as 2-receptors of bronchial smooth muscles and α1-receptor of blood vessels to produce bronchodila tion and vasoconstriction or rise of BP and thereby counteracts the deleterious effects of histamine in anaphylactic shock.
2) Pharmacological or Receptor Antagonists: These antagonists are either competitive or non-competitive inhibitors of histamine at receptor sites. They block the effects of histamine by receptor occupancy
4.1.4.1. H1-Antagonists Until the discovery of H 1 receptors, no other histamine receptors had been identified. H 1 antagonists were termed as antihistamines. They cause a competitive inhi bition of only H 1 receptors. Adrenaline (a physiological antagonist of histamine ) acts via adrenergic receptors and reverses the bronchodilation and vasoconstriction effects of histamine. Histamine release from mast cells is blocked by cromolyn sodium and corticosteroids. H1 receptor antagonists are employed in the treatment of allergic disorders. Classification
1) First Generation H1-Antagonists: They cross the blood-brain barrier readily and produce drowsiness. i) Ethanolamines: Diphenhydramine hydrochloride and Dimenhydrinate.
ii) Ethylenediamines: Pyrilamine maleate and T ripelennamine hydrochloride.
iii) Alkylamines: Chlorpheniramine maleate and Brompheniramine maleate.
iv) Piperazines: Cyclizine hydrochloride and Meclizine hydrochloride.
v) Piperidines: Cyproheptadine hydrochloride.
vi) Phenothiazines: Promethazine hydrochloride.
vii) Tricyclic Dibenzoxepins: Doxepin hydrochloride.
2) Second Generation H1-Antagonists: They do not cross the blood-brain barrier readily, thus produce less drowsiness.
i) Alkylamines: Acrivastine.
ii) Piperazines: Cetirizine hydrochloride.
iii) Phthalazinones: Azelastine hydrochloride.
iv) Piperidines: Terfenadine, Astemizole, Loratadine, and Fexofenadine. Mechanism of Action The action of histamines on H 1 receptors is blocked by antihistamines (H 1 blockers) categorised in to first - and second -generations. The binding of firstgeneration antihistamines is seen on central and peripheral H 1 receptors while that of second-generation antihistamines is seen on peripheral H 1 receptors. Though the sedative effects of second -generation antihistamines are lesser as compared to those of first -generation antihistamine, still they are beneficial for the treatment of allergies. Pharmacological Actions
1) Histamine Antagonism: The histamine actions ( e.g., dilatation of capillaries, decrease in BP, urticaria, allergic reactions, itching, contraction of smooth muscles, and triple response formation) are effectively blocked by H1 antihistamines. However anaphylactic shock is only partially prevented by antihistamines. It should be remembered tha t histamine is not alwa ys the only cause of an allergy, so all allergic reactions may not be blocked by antihistamines; for example, leukotriene and PAF are more significant mediators in asthma, thus they cannot be controlled by antihistamines alone. H1 blockers also show no effect on HCl secretion.
2) Anti-Allergic Reactions: The allergic reactions like urticaria, itching, and angioedema can be controlled by the action of H 1 antagonists; however, it is not practically possible to control anaphylaxis and asth ma as they are mediated by factors other than histamine.
3) Effects on CNS: H1-antihistamines show sedative effects on CNS; however, a quantitative difference is seen depending on the capability of a compound to cross the blood-brain barrier. They are also seen to accelerate the effects of CNS depressants. Promethazine (phenargan) possesses sedative effects. Recently discovered H1 antagonists (e.g., astemizole, terfenadine, loratadine, cetirizine, and fexofenadine) do not possess sedative effects because they do not show absorption in brain.
4) Anticholinergic Actions: Diphenhydramine, promethazine, and pheniramine are the H 1-antihistamines acting as potent anticholinergic agents. They reduce lacrimal and nasal secretions while accounting for dryness of mouth. This anticholinergic action is beneficial for treating conditions like motion sickness and Parkinsonism.
5) Antiemetic and Antitussive Actions: Morning sickness (vomiting during pregnancy) and motion sickness can be effectively prevented by some H 1- antihistamines.
6) Local Anaesthetic Effect: Some antihistamines ( e.g., mepyramine and antazoline) possess local anaesthetic effects, still are not employed for this purpose.
7) Blood Pressure: Intravenous administration of most antihistamines results in a decrease in blood pressure which is not seen in case of oral administration of these agents. Therapeutic Uses
1) Allergic Disorders: H1 antihistamines provide symptomatic relief to various allergic states like urticaria, acute or chronic dermatitis, pruritus, hay fever, and a llergic rhinitis. Itching and urticaria occurring as a result of drug reactions can be treated using H1 blockers. Though they are known to prevent the occurrence of anaphylaxis , however once anaphylactic conditions result, they are not able to treat the same. For example, adrenaline is the drug of choice in treating anaphylactic conditions , while glucocorticoids are used to treat the long-lasting effects after anaphylaxis. H1 receptor blockers are ineffective to treat asthma mediated by histamine and other mediators. They are useful in the treatment of allergic reactions resulting from insect bite (bees and wasp), food, drugs, and ivy poisoning. Since an allergic reac tion may also involve other auto coids such as PAF, PGs, leukotriene, etc., antihistamines are not useful in controlling all types of allergic reactions.
2) Pre-Anaesthetic Medication: The sedative and anticholinergic action s of promethazine render it useful in children
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