Histamines, Antihistamines & Prostaglandin.pptx

Histamines, Antihistamines & Prostaglandin.pptx

• 1.
  Histamines, Antihistamines & Prostaglandin Presenter:- Dr ArunSingh 2nd Year PG Student Department of Pharmacology SMS Medical College,Jaipur
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  Histamines & Antihistamines
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  Learning Objectives • Introduction •Synthesis, storage, distribution of Histamine • Role of Histamine • Anti histamine • Its therapeutic uses • Adverse effects • Summary
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  Introduction Histamine is themost important amine autacoids. Autacoids are endogenous molecules that do not fall into traditional autonomic groups. They do not act on cholinoceptors or adrenoceptors but have powerful pharmacologic effects on smooth muscle and other tissues.
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  What are the Autocoids? Theword autacoid comes from the Greek: autos (self) & akos (medicinal agent, or remedy) They all have the common feature of being formed by the tissues on which they act; thus, they function as local hormones The autacoids also differ from circulating hormones in that they are produced by many tissues rather than in specific endocrine glands.
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  Autocoids Includes – 1.Amineautocoids: Histamine, Serotonin 2.Lipid derived: Prostaglandins and Leukotrienes 3.Peptides: Bradykinin, angiotensin 4.Others: Cytokines
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  Histamine
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  Properties Biogenic amine present in- animal and plant tissues -venoms and stinging secretions • One of the mediators involved in inflammatory & hypersensitivity reactions.
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  • Histamine ispresent in many human tissues, including skin, intestinal mucosa, heart, lung, and nerve endings in the brain. • The usual body storage sites for histamine include mast cells and basophils.
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  Synthesis, storage, distributionof Histamine Biosynthesized in mammalian tissues Decarboxylation of the amino acid L-Histidine yields Histamine Histamine is formed from the amino acid histidine and is stored in high concentrations in vesicles in mast cells, enterochromaffin cells in the gut, some neurons, and a few other cell types.
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  Histamine is metabolizedby the enzymes monoamine oxidase and diamine oxidase. Non-mast cell histamine occurs in brain, epidermis, gastric mucosa. A variety of stimuli, both immunological and nonimmunological, may trigger the release of histamine from the mast cell or basophil. During tissue stresses of growth or repair, histidine decarboxylase activity is increased; histamine synthesis is also increased, which suggests that histamine may be important in healing processes. The newly formed histamine is rapidly metabolized rather than being stored.
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  • Histamine degradedrapidly by oxidation to imidazole acetic acid Degraded rapidly by methylation to N-methyl histamine • Very little histamine is excreted unchanged. • So, excess production of histamine in the body (eg. in systemic mastocytosis) can be detected by measurement of its major metabolite, imidazole acetic acid, in the urine.
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  Receptors and Effects There arefour types of histamine receptors present in the our body. (all GPCR’s): (a)H1 receptors: It’s mediate effects on smooth muscle leading to vasodilation (relaxation of vascular smooth muscle), increased permeability & contraction of non- vascular smooth muscle. (b)H2 receptors: It’s mediate histamine stimulation of gastric acid secretion & may be involved in cardiac stimulation (c)H3 receptors: The feedback inhibition in CNS, GIT, Lungs & Heart (d)H4 receptors: Eosinophils, Neutrophils & CD4 T- cells
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  The triple response,a classic demonstration of histamine effect, is mediated mainly by H1 and H2 receptors. This response involves a small red spot at the center of an intradermal injection of histamine surrounded by an edematous wheal, which is surrounded by a red flare.
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  Recept or Mechanism Function Antagonists H1Gq, ↑ IP3 & DAG Ileum contraction, Modulate circadian cycle, Itching, Systemic vasodilatation, Bronchoconstriction Diphenhydram ine/Loratadine /Cetirizine/ Fexofenadine H2 Gs, ↑cAMP, ↑Ca2+ Speed up sinus rhythm ,Stimulation of gastric secretion ,Smooth muscle relaxation ,Inhibit antibody synthesis, T-cell proliferation & cytokine production Cimetidine/ Ranitidine/ Famotidine/ Nizatidine H3 Gi, ↓cAMP Decrease Acetylcholine, Serotonin and Norepinephrine neurotransmitter release in the CNS, Presynaptic auto- receptors ABT-239/ Ciproxifan/ Clobenpropit/T hioperamide H4 Gi, ↓cAMP Mediate mast cell chemotaxis Thioperamide/ JNJ 7777120
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  Pharmacological Action (A)Exocrine Excretion(H1):- ↑ Production of nasal + bronchial mucus (B)Bronchial Smooth Muscle(H1):- Bronchiolar constriction Asthmatic symptoms ↓ Lung capacity (C) Intestinal Smooth Muscle(H1):- Contraction Intestinal cramps & diarrhea (D)Sensory Nerve Endings(H1):- Itching & pain
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  (E)Cardiovascular System(H1&2):- ↓ Peripheralresistance ----↓Systemic BP +ve chronotropism(H2) +ve inotropism (F)Skin(H1&2):- Dilatation & ↑ permeability of the venules Leakage of fluid + proteins into the tissues Classic “triple-response”(wheal formation+ reddening due to local VD(<1-2 min) + flare(halo)
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  (G)Stomach(H2) :- ↑ GastricHCl secretion
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  Adverse Effects ofHistamines Release • Itching, Urticaria • Flushing • Hypotension • Tachycardia • Bronchospasm • Angioedema • Wakefulness • Increased acidity (Gastric acid secretion)
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  Histamine has notherapeutic use. In the post it has been used to test acid secreting capacity of stomach, bronchial hyperreactivity in asthamatics, and for diagnosis of pheochromocytoma, but these pharmacological tests are risky and obsolete now.
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  Betahistine It is anorally active, somewhat H1selective histamine analogue, which is used to control vertigo in patients of Meniere disease. It possibly acts by causing vasodilation in the internal ear. It is contraindicated in asthmatics and ulcer patients.
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  Anti-histamines
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  Overview • The effectsof histamine released in the body can be reduced in several ways • Physiologic antagonists, especially epinephrine, have smooth muscle actions opposite to those of histamine, by acting at different receptors • This is important clinically because injection of epinephrine can be lifesaving in systemic anaphylaxis/other conditions in which massive release of histamine(and other more important mediators)occurs
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  Histamine Release Inhibitors • Reduce thedegranulation of mast cells that results from immunologic triggering by antigen -IgE interaction • Cromolyn and nedocromil appear to have this effect and have been used in the treatment of asthma, although the molecular mechanism underlying their action is not fully understood • Beta2-adrenoceptor agonists also appear capable of reducing histamine release
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  H1-Antagonists(Conventional Antihistaminics) • Thesedrugs competitively antagonizes actions of histamine at the H1 receptors. • A wide variety of antihistaminic H1 blockers are available from several different chemical families. • Recent evidence indicates that histamine H1 receptor exhibits some degree of constitutive activity, and the H1 antagonists are also inverse agonists. • The first compounds of this type were introduced in the late 1930s and have subsequently proliferated into an unnecessary motley of drug.
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  Clinical Classification ofH1-Anti -Histamine DRUG DOSE ROUTE I. HIGHLY SEDATIVE Diphenhydramine 25–50 mg Capsule , Syrup Promethazine 25–50 mg Oral, i.m. (1 mg/kg) tab II. MODERATELY SEDATIVE Pheniramine 20–50 mg Oral, Tab, Syp, Injection Cyproheptadine 4 mg Oral Tab , Syp Cinnarizine 25–50 mg Tab III. MILD SEDATIVE Chlorpheniramine 2-4 mg Oral, I.M Clemastine 1-2 mg Oral, Syp
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  DRUG DOSAGE PREPARATIONS Fexofenadine120–180 mg Oral TAB Loratadine 10 mg Oral Tab, Suspension Cetirizine 10 mg Oral Tab, Syp Levocetirizine 5-10 mg Oral Tab, Syp Azelastine 4 mg Oral Nasal Spray Mizolastine 10 mg Oral Tab Ebastine 10 mg Oral Tab
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  • Two majorsubgroups or “generations” have been developed. • The older members of the first- generation agents, typified by diphenhydramine, are highly sedating agents with significant autonomic receptor-blocking effects. • A newer subgroup of first-generation agents is less sedating and has much less autonomic effect. • Chlorpheniramine and Cyclizine may be considered prototypes.
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  Classification of H1-Antihistaminics FirstGeneration Second Generation • Diphenhydramine • Cetirizine • Dimenhydrinate • Levocetirizine • Doxylamine • Fexofenadine • Promethazine • Loratidine • Hydroxyzine • Desloratidine • Pheniramine • Ebastine • Cyproheptadine • Astemizole • Meclizine •Acrivastine • Chlorpheniramine • Dexchlorpheniramine
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  • The second-generationH1 blockers, typified by cetirizine, fexofenadine, and loratadine, are far less lipid soluble than the first-generation agents and have greatly reduced sedating and autonomic effects. • All H1 blockers are active by the oral route. Several are promoted for topical use in the eye or nose. • Most are metabolized extensively in the liver. • Half-lives of the older H1 blockers vary from 4 to 12 h. • Second generation agents have half-lives of 12–24 h.
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  Mechanism and Effects:- H1blockers are competitive pharmacologic antagonists or inverse agonists at the H1 receptor; these drugs have no effect on histamine release from storage sites. They are more effective if given before histamine release occurs. Because their structure closely resembles that of muscarinic blockers and α-adrenoceptor blockers, many of the first-generation agents are potent pharmacologic antagonists at these autonomic receptors.  A few also block serotonin receptors. As noted, most older first-generation agents are sedating, and some— not all—first-generation agents have anti-motion sickness effects.
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  Many H1 blockersare potent local anesthetics. H1-blocking drugs have negligible effects at H2 receptors. Clinical Use:- H1 blockers have major applications in allergies of the immediate type (i.e. those caused by antigens acting on IgE antibody-sensitized mast cells). These conditions include hay fever and urticaria. Diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine are used as anti-motion sickness drugs. Diphenhydramine is also used for management of chemotherapy-induced vomiting. Doxylamine, in combination with pyridoxine, is promoted for the prevention of morning sickness in pregnancy.
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  Adverse effects ofthe first-generation H1 blockers:- These are sometimes exploited therapeutically (eg.in their use as hypnotics in over-the-counter sleep aids). Toxicity and Interactions :- Sedation is common, especially with diphenhydramine and promethazine and these drugs should not be consumed before operating machinery. It is much less common with second-generation agents, which do not enter the CNS readily. Antimuscarinic effects such as dry mouth and blurred vision occur with some first-generation drugs in some patients. Alpha-adrenoceptor blockade, which is significant with phenothiazine derivatives such as promethazine, may cause orthostatic hypotension.
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  Interactions:- It occur betweenolder antihistamines and other drugs with sedative effects (e.g. benzodiazepines and alcohol). Drugs that inhibit hepatic metabolism may result in dangerously high levels of certain antihistaminic drugs that are taken concurrently.  For example, azole antifungal drugs and certain other CYP3A4 inhibitors interfere with the metabolism of astemizole and terfenadine, 2 second-generation agents that have been withdrawn from the US market because high plasma concentrations of either antihistamine can precipitate lethal arrhythmias.
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  H2-Antagonists(H2-Antihistaminics) The first H2blocker Burimamide was developed by Black in 1972. Metiamide was the next, but both were not found suitable for clinical use. Cimetidine was introduced in 1977 and gained wide usage. Ranitidine, famotidine, roxatidine, and many others have been added subsequently.
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  These drugs donot resemble H1 blockers structurally. They are orally active, with half- lives of 1–3 h. Because they are all relatively nontoxic, they can be given in large doses, so that the duration of action of a single dose may be 12–24 h. All four agents are available in oral over-the counter formulations.
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  Mechanism and Effects:- H2antagonists produce a surmountable pharmacologic blockade of histamine H2 receptors. They are relatively selective and have no significant blocking actions at H1 or autonomic receptors. The only therapeutic effect of clinical importance is the reduction of gastric acid secretion, but this is a very useful action. Blockade of cardiovascular and mast cell H2-receptor-mediated effects can be demonstrated but has no clinical significance.
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  In Zollinger-Ellison syndrome,which is associated with gastrinoma and characterized by acid hypersecretion, severe recurrent peptic ulceration, gastrointestinal bleeding, and diarrhea, these drugs are helpful, but very large doses are required; proton pump inhibitors are preferred. Clinical Use:- In acid-peptic disease, especially duodenal ulcer, these drugs reduce nocturnal acid secretion, accelerate healing, and prevent recurrences. Acute ulcer is usually treated with 2 or more doses per day, whereas recurrence of duodenal ulcers can often be prevented with a single bedtime dose. H2 blockers are also effective in accelerating healing and preventing recurrences of gastric peptic ulcers. Intravenous H2 blockers are useful in preventing gastric erosions and hemorrhage that occur in stressed patients in intensive care units.
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  • Similarly, theH2 blockers have been used in gastroesophageal reflux disease (GERD), but they are not as effective as proton pump inhibitors. Toxicity:- Cimetidine is a potent inhibitor of hepatic drug-metabolizing enzymes and may also reduce hepatic blood flow. Cimetidine also has significant antiandrogen effects in patients receiving high doses. Ranitidine has a weaker inhibitory effect on hepatic drug metabolism; neither it nor the other H2 blockers appear to have any endocrine effects.
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  Prostaglandin
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  Introduction • Prostaglandins &their related compounds prostacyclins (PGI), thromboxanes (TXA), leukotrienes (LT) & lipoxins are collectively known as eicosaniods, they all contain. • In 1970s it became clear that aspirin like drugs act by inhibiting PG synthesis, and that in addition to the classical PGs (Es and Fs), thromboxane (TX), prostacyclin (PGI) and leukotrienes (LTs) were of great biological importance.
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  Structure of prostaglandin •Prostaglandins are derivatives of 20-carbon fatty acid - prostanoic acid, hence known as prostanoids. • This has a cyclopentane ring (formed by carbon atoms 8 to 12) & two side chains, with carboxyl group on one side. • Prostaglandins differ in their structure due to substituent group & double bond on cyclopentane ring. • Most important prostaglandins (PGF2 & PGF2α), prostacyclins (PGI2), thromboxanes (TXA2) & leukotrienes (LTA4).
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  Synthesis of Prostaglandin •Arachidonic acid (5,8,11,14 - eicosatetraenoic acid) is the precursor for most of the prostaglandins in humans. • It occurs in the endoplasmic reticulum. • Release of arachidonic acid from membrane bound phospholipids by phospholipase A2. • It occurs due to a specific stimuli by hormones – epinephrine or bradykinin.
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  • Oxidation &cyclization of arachidonic acid to PGG2 which is then converted to PGH2 by peroxidase. • PGH2 serves as the immediate precursor for the synthesis of a number of prostaglandins, including prostacyclins & thromboxane. • This is known as cyclic pathway of arachidonic acid.
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  Cyclooxygenase • e –a suicide enzyme. • Prostaglandin synthesis can be partly controlled by suicidal activity of the enzyme cyclooxygenase. • Enzyme is capable of undergoing self catalysed destruction to switch off PG synthesis.
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  Inhibition of ProstaglandinSynthesis • Corticosteroids (e.g. cortisol) prevent the formation of arachidonic acid by inhibiting the enzyme phospholipase A2. • Anti-inflammatory drugs inhibit the synthesis of prostaglandins, prostacyclins & thromboxane. • They block the action of cyclooxygenase. • Aspirin irreversibly inhibits cyclooxygenase.
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  Degradation of Prostaglandin Synthesis All theeicosanoids are metabolized rapidly. Degradation occur in lung & liver. Two enzymes, namely 15-α-hydroxy PG dehydrogenase & 13-PG reductase, convert hydroxyl group at C15 to keto group & then to C13 and C14 dihydroderivative.
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  Biological Actions of Prostaglandin • Prostaglandinsact as local hormones. • PGs are produced in almost all the tissues. • PGs are not stored & they are degraded to inactive products at the site of their production. • PGs are produced in very small amounts & have low half-lives.
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  • Regulation ofblood pressure: The prostaglandins (PGE, PGA & PGl2) are vasodilator in function. • This results in increased blood flow and decreased peripheral resistance to lower the blood pressure. • PGs serve as agents in the treatment of hypertension. • Inflammation
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  Inflammation: • PGEI &PGE2 induce the symptoms of inflammation (redness, swelling, edema etc.) due to arteriolar vasodilation. • PGs are natural mediators of inflammatory reactions of rheumatoid arthritis, psoriasis, conjunctivitis etc. • Corticosteroids are used to treat these inflammatory reactions, since they inhibit prostaglandin synthesis.
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  Reproduction: • PGE2 &PGF2 are used for the medical termination of pregnancy & induction of Labour. • Pain and fever: Pyrogens (fever producing agents) promote prostaglandin synthesis leading to the formation of PGE2 in hypothalamus-regulation of body temperature. • PGE2 along with histamine & bradykinin cause pain. • Migraine is also due to PGE2. • Aspirin & other non-steroidal drugs inhibit PG synthesis & thus control fever & relieve pain.
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  Regulation of gastricsecretion: • Prostaglandins (PGE) inhibit gastric secretion. • PGs are used for the treatment of gastric ulcers. • PGs stimulate pancreatic secretion & increase the motility of intestine which often causes diarrhea.
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  Influence on immunesystem: • Macrophages secrete PGE which decreases the immunological functions of B-& T-lymphocytes. Effects on respiratory function: • PGE is a bronchodilator whereas PGF acts as a constrictor of bronchial smooth muscles. • PGE & PGF oppose the actions of each other in the lungs. • PGEI & PGE2 are used in the treatment of asthma.
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  Influence on renalfunctions: • PGE increases glomerular filtration rate & promotes urine output. • Excretion of Na+ & K+ is also increased by PGE. Effects on metabolism: • Prostaglandins influence certain metabolic reactions, through the mediation of cAMP. • PGE decrease lipolysis, increases glycogen formation & promotes calcium mobilization. • Platelet aggregation
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  Platelet aggregation &thrombosis: • The prostaglandins – prostacyclins (PGI2), inhibit platelet aggregation. • Thromboxanes (TXA2) & prostaglandin E2 promote platelet aggregation & blood clotting that might lead to thrombosis.
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  Mechanism of action ofPGs • PGE increases cAMP & PGF increases cGMP.
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  Biological Applications of Prostaglandins • Theyare used in the treatment of gastric ulcers, hypertension, thrombosis, asthma etc. • Prostaglandins are also in the medical termination of pregnancy, prevention of conception, induction of labor etc.
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  Leukotrienes • Leukotrienes aresynthesized by leucocytes, mast cells, lung, heart, spleen etc., by lipoxygenase pathway of arachidonic acid. • Leukotrienes (A4, B4, C4, D4 & E4) are synthesized through the intermediate, 5- hydroperoxyeicosatetraenoic acid (5-HPETE).
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  Synthesis of Leukotrienes
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  • Leukotrienes (C4,D4 & E4) are components of slow-reacting substances of anaphylaxis (SRSA), released after immunological challenge. • SRS-A is 100 -1,000 times more potent than histamine or prostaglandins in its action as a stimulant of allergic reactions. • Leukotrienes are implicated in asthma, inflammatory reactions, hypersensitivity (allergy) and heart attacks.
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  • Leukotrienes causecontraction of smooth muscles, bronchoconstriction, vasoconstriction, adhesion of white blood cells & release of lysosomal enzymes. • Lipoxins are involved in vasoactive & immunoregulatory functions.