Histamine and Antihistamine ppt / Histamine and Antihistamine Classification / Histamine and Antihistamine Pharmacology / Histamine and Antihistamine Notes

HISTAMINE :

                                       Histamine, meaning ‘tissue amine’ (histos—tissue) is almost ubiquitously present in animal tissues and in certain plants, e.g. stinging nettle. Its pharmacology was studied in detail by Dale in the beginning of the 20th century when close parallelism was noted between its actions and the manifestations of certain allergic reactions. Histamine was implicated as a mediator of hypersensitivity phenomena and tissue injury reactions. It is now known to play important physiological roles.

                                  Histamine is present mostly within storage granules of mast cells. Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs, liver and placenta. Nonmast cell histamine occurs in brain, epidermis, gastric mucosa and growing regions. Turnover of mast cell histamine is slow, while that of nonmast cell histamine is fast. Histamine is also present in blood, most body secretions, venoms and pathological fluids. 

Synthesis, storage and destruction :

                                                                     Histamine is β imidazolylethylamine. It is synthesized locally from the amino acid histidine and degraded rapidly by oxidation and methylation (Fig. 11.1). In mast cells, histamine (positively charged) is held by an acidic protein and heparin (negatively charged) within intracellular granules. When the granules are extruded by exocytosis, Na+ ions in e.c.f. exchange with histamine to release it free (Fig. 11.2). Increase in intracellular cAMP (caused by β adrenergic agonists and methylxanthines) inhibits histamine release. Histamine is inactive orally because liver degrades all histamine that is absorbed from the intestines.


Histamine receptors :

                                             Four types of histaminergic receptors have now been clearly delineated and cloned. Analogous to adrenergic α and β receptors, histaminergic receptors were classified by Asch and Schild (1966) into H1 and H2 :those blocked by then available antihistamines were labelled H1 . Sir James Black (1972) produced the first H2 blocker burimamide and confirmed this classification. Till now, only these two receptors are clinically relevant. A third H3 receptor, which serves primarily as an autoreceptor controlling histamine release from neurones in the brain was identified in 1983. Though some selective H3 agonists and antagonists have been produced, none has found any clinical application. Features of these 3 types of histaminergic receptors are compared in Table 11.1.

                              Molecular cloning has revealed yet another (H4 ) receptor in 2001. It has considerable homology with H3 receptor and binds many H3 ligands. 4-Methyl histamine, earlier In sensitized atopic individual, specific reaginic (IgE) antibody is produced and gets bound to Fc epsilon receptor I (FcεRI) on the surface of mast cells. On challenge, the antigen bridges IgE molecules resulting in transmembrane activation of a tyrosine-protein kinase (t-Pr-K) which phosphorylates and activates phospholipaseCγ. Phosphatidyl inositol bisphosphate (PIP2 ) is hydrolysed and inositol trisphosphate (IP3 ) is generated which triggers intracellular release of Ca2+. The Ca2+ ions induce fusion of granule membrane with plasma membrane of the mast cell resulting in exocytotic release of granule contents. In the granule, positively charged histamine (Hist+ ) is held complexed with negatively charged protein (Prot– ) and heparin (Hep– ) molecules. Cationic exchange with extracellular Na+ (and Ca2+) sets histamine free to act on the target cells.





                             considered to be a specific H2 agonist, has shown greater affinity and selectivity for the H4 receptor, and is now labelled a H4 agonist. Eosinophils, mast cells and basophils are the primary cells expressing H4 receptors. Activation of H4 receptors enhances chemotaxis of these cells. The H4 receptor may be playing a role in allergic inflammation. Some H4 antagonists are being explored as potential drugs for allergic inflammatory conditions like rhinitis and asthma. Intestines and brain are the other sites where H4 receptors have been located.



PHARMACOLOGICAL ACTIONS :

1. Blood vessels :

                                    Histamine causes marked dilatation of smaller blood vessels, including arterioles, capillaries and venules. On s.c. injection flushing, especially in the blush area, heat, increased heart rate and cardiac output, with little or no fall in BP are produced. Rapid i.v. injection causes fall in BP which has an early short lasting H1 and a slow but more persistent H2 component. With low doses only the H1 component is manifest since H1 receptors have higher affinity. Fall in BP due to large doses is completely blocked only by a combination of H1 and H2 antagonists. Dilatation of cranial vessels causes pulsatile headache.

                                  Like many other autacoids and ACh, vasodilatation caused by histamine is partly (H1 component) indirect, mediated through ‘endothelium dependent relaxing factor’ (EDRF), i.e. NO; the receptor being located on the endothelial cells. H2 receptors mediating vasodilatation are located directly on the vascular smooth muscle.
          
                                   Larger arteries and veins are constricted by histamine. This is mediated by H1 receptor on vascular smooth muscle. Histamine also causes increased capillary permeability due to separation of endothelial cells resulting in exudation of plasma. This is primarily a H1 response.

 
Injected intradermally, it elicits the triple response consisting of:

Red spot: due to intense capillary dilatation. 

Wheal: due to exudation of fluid from capillaries and venules. 

Flare: i.e. redness in the surrounding area due to arteriolar dilatation mediated by axon reflex.

2. Heart :

                     Direct effects of histamine on in situ heart are not prominent, but the isolated heart, especially of guinea pig, is stimulated—rate as well as force of contraction is increased. These are primarily H2 responses but a H1 mediated negative dromotropic (slowing of A-V conduction) effect has also been demonstrated.

3. Visceral smooth muscle :

                                                     Histamine causes bronchoconstriction; guinea pigs and patients of asthma are highly sensitive. Large doses cause abdominal cramps and colic by increasing intestinal contractions. Guineapig uterus is contracted while that of rat is relaxed; human uterus is not much affected as are most other visceral smooth muscles.

                                             Smooth muscle contraction is a H1 response. In few instances H2 mediated relaxation is also seen, e.g. bronchial muscle of sheep, human bronchi after H1 blockade when H2 response is unmarked.

4. Glands :

                          Histamine causes marked increase in gastric secretion—primarily of acid but also of pepsin (see Ch. 47). This is a direct action exerted on parietal cells through H2 receptors, and is mediated by increased cAMP generation, which in turn activates the membrane proton pump (H+ K+ ATPase).

                  Histamine can increase other secretions also, but the effect is hardly discernable.

5. Sensory nerve endings :

                                                      Itching occurs when histamine is injected i.v. or intracutaneously. Higher concentrations injected more deeply cause pain. These are reflections of the capacity of histamine to stimulate nerve endings.

6. Autonomic ganglia and adrenal medulla :

           These are stimulated and release of Adr occurs, which can cause a secondary rise in BP.

7. CNS :

                     Histamine does not penetrate bloodbrain barrier—no central effects are produced on i.v. injection. However, intracerebroventricular administration produces rise in BP, cardiac stimulation, behavioural arousal, hypothermia, vomiting and ADH release. These effects are mediated through both H1 and H2 postsynaptic receptors.


PATHOPHYSIOLOGICAL ROLES :


1. Gastric secretion :

                                           Histamine has dominant physiological role in mediating secretion of HCl in the stomach (see Fig. 47.1). Nonmast cell histamine occurs in gastric mucosa, possibly in cells called ‘histaminocytes’ situated close to the parietal cells. This histamine has high turnover rate. It is released locally under the influence of all stimuli that evoke gastric secretion (feeding, vagal stimulation, cholinergic drugs and gastrin) and activates the proton pump (H+ K+ ATPase) through H2 receptors.

                                        H2 blockers not only suppress acid secretion induced by histamine but also markedly diminish that in response to ACh and gastrin. By a mutually synergistic interaction the three secretagogues amplify responses to each other with histamine playing the dominant role. As such, antimuscarinic drugs dampen the response to histamine and gastrin as well. All three secretagogues activate the same proton pump (H+K+ATPase) in the parietal cell membrane, but through their own receptors.


2. Allergic phenomena :

                                                  Mediation of hypersensitivity reactions was the first role ascribed to histamine. It is an important, but only one of the mediators of such phenomena. Released from mast cells following AG : AB reaction on their surface (involving IgE type of reaginic antibodies; Fig. 11.2) in immediate type of hypersensitivity reactions, histamine is causative in urticaria, angioedema, bronchoconstriction and anaphylactic shock. The H1 antagonists are effective in controlling these manifestations to a considerable extent, except asthma and to a lesser extent anaphylactic fall in BP in which leukotrienes (especially LTD4 ) and PAF appear to be more important. Histamine is not involved in delayed or retarded type of allergic reactions.

3. As transmitter :

                                       Histamine is believed to be the afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings.

                                  Nonmast cell histamine occurs in brain, especially hypothalamus and midbrain. It is involved in maintaining wakefulness; H1 antihistaminics owe their sedative action to blockade of this function. In the brain H1 agonism suppresses appetite. This may explain the appetite promoting action of certain H1 antagonists. Histamine also appears to participate as a transmitter regulating body temperature, cardiovascular function, thirst, and possibly other functions, mainly through H2 (postsynaptic receptors) and H3 (presynaptic autoreceptors and heteroreceptors).


4. Inflammation :

                                     Histamine is a mediator of vasodilatation and other changes that occur during inflammation. It promotes adhesion of leukocytes to vascular endothelium by expressing adhesion molecule P-selectin on endothelial cell surface, sequestrating leukocytes at the inflammatory site. It may also regulate microcirculation according to local needs.
                                     

5. Tissue growth and repair :

                                                     Because growing and regenerating tissues contain high concentrations of histamine, it has been suggested to play an essential role in the process of growth and repair.

6. Headache :

                             Histamine has been implicated in certain vascular headaches, but there is no conclusive evidence.


USES :

                      Histamine has no therapeutic use. In the past it has been used to test acid secreting capacity of stomach, bronchial hyperreactivity in asthmatics, and for diagnosis of pheochromocytoma, but these pharmacological tests are risky and obsolete now.


Betahistine :

                             It is an orally active, somewhat H1 selective histamine analogue, which is used to control vertigo in patients of Meniéré’s disease. It possibly acts by causing vasodilatation in the internal ear. It is contraindicated in asthmatics and ulcer patients.

HISTAMINE RELEASERS :

A variety of mechanical, chemical and immunological stimuli are capable of releasing histamine from mast cells.

1. Tissue damage: trauma, stings and venoms, proteolytic enzymes, phospholipase A. 

2. Antigen: antibody reaction involving IgE antibodies. 

3. Polymers like dextran, polyvinyl pyrrolidone (PVP). 

4. Some basic drugs—tubocurarine, morphine, atropine, pentamidine, polymyxin B, vancomycin and even some antihistaminics release histamine by displacing it from the binding site, and not by an immunological reaction. This release is not exocytotic, and does not require Ca2+. 

5. Surface acting agents like Tween 80, compound 48/80 etc. The primary action of these substances is release of histamine from mast cells, therefore they are called ‘histamine liberators’. They produce an ‘anaphylactoid’ reaction—itching and burning sensation, flushing, urticaria, fall in BP, tachycardia, headache, colic and asthma. 


H1 ANTAGONISTS (Conventional antihistaminics) :


                      These drugs competitively antagonize actions of histamine at the H1 receptors. Recent evidence indicates that histamine H1 receptor exhibits some degree of constitutive activity at certain sites, and few H1 antagonists are also inverse agonists. The first H1 antagonists were introduced in the late 1930s and have subsequently proliferated into an unnecessary motley of drugs. Nevertheless, they are frequently used for a variety of purposes. More commonly employed now are the less sedating/nonsedating second generation H1 antihistamines added after 1980. Seemingly, H1 antihistaminics have diverse chemical structures, but majority have a substituted ethylamine side chain. They are classified and listed in Table 11.2. 


be continued ... next post 
Histamine and Antihistamine ppt / Histamine and Antihistamine Classification / Histamine and Antihistamine Pharmacology / Histamine and Antihistamine Notes 

1 comment:

Powered by Blogger.