Antihistamine Alex-1 (1) (6).pdfetiecyiecciye iyeiec

Antihistamine Alex-1 (1) (6).pdfetiecyiecciye iyeiec

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  ANTIHISTAMINIC AND RELATED
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  2 COURSE OUTLINE: • Overview:what is histamine? • Biosynthesis, Metabolism • Receptor types and physiological effects • H1, H2, H3, H4,… • Chemistry of histamine • Classes of histamine antagonists • H1 receptor antagonists (blockers) » 1st generation antihistamines » 2nd generation antihistamines » 3rd generation antihistamines • H2 receptor antagonists (blockers)
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  WHAT IS HISTAMINE? •a chemical messenger released by cells. • widely distributed in the body • acts as a local hormone • one of the major inflammatory mediator • the highest concentrations in human tissues: Lung,stomachandskin[33μg/g tissue] 3
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  BIOSYNTHESIS Synthesized chiefly in •Mast cells : stomach, liver, L/S intestine, heart and lung • Basophilic granulocytes: blood Other sites of synthesis include: ▪ Neurons of the C N S and ▪ Epidermis of the skin 4
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  Termination of HistamineAction • Cellular uptake • Metabolism (Major) 5
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  H1 RECEPTORS ➢ Itis found in smooth muscles of intestine, bronchi, blood vessels, adrenal medulla, endothelial cell and lymphocytes. ➢ Histamine H1 receptors are G-protein linked receptors. It is sequence of 491 amino acids residue. ➢ H1 - receptors mediate smooth muscle contraction, increased vascular permeability, pruritus, prostaglandin, decreased artrio ventricular conduction time accompanied by tachycardia and activation of vagal reflexes 6
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  H2-receptors • They arelocated on the cell membrane of acid secreting cells of gastric mucosa and mediate the gastric acid secretary actions of histamine. • The physiological effects of H2-receptor ligands are mediated by a stimulatory G- protein coupled receptor. 7
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  H3 AND H4RECEPTORS H3 Receptor… Thought to be a G P C R • May play role in C N S (auto receptors) • Possible regulation of synthesis and release of Hist. • Signaling pathway unknown H4 Receptor… • G P C R • Found in intestines, spleen, T-cells and neutrophils • Suggests role in Immunity. 8
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  CHEMISTRY AND SAROF HISTAMINE  NH2 N 3  1 HN  NH2 NH 1  2 3 N 4 5  • Hydrophilic hetrocyclic molecule •Contains imidazole ring linked with alkyl amino group • pka’s 9.40 (aliphatic amine) 5.74 (imidazole N, 2o amine) There are two tautomeric forms of histamine. • 4-(β-aminoethyl) imidazole (Nτ-tautomer) and • 5-(β-aminoethyl) imidazole (N-tautomer) ➢Both forms are active physiologically.    9 Nτ-tautomer N-tautomer
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  WHAT ARE ANANTIHISTAMINES? 10 • “Compete against the receptors’ natural substrates’’ • drugs that reduce or eliminate the effects mediated by the chemical histamine • The term antihistamine only refers to H1 receptor antagonists (actually inverse agonists) • Antihistamines compete with histamine for binding sites at the receptors. And cannot remove the histamine if it is already bound
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  11 • Classes ofHistamine antagonists • H1 receptor antagonists (blockers) » 1st generation antihistamines » 2nd generation antihistamines » 3rd generation antihistamines • H2 receptor antagonists (blockers)
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  1ST GENERATION ANTIHISTAMINES SAR •2 aromatic rings, connected to a central carbon, nitrogen, or oxygen • Spacer between central atom and the amine, usually 2-3 carbons in length. (Can be linear, ring, branched, saturated or unsaturated) • The amine is substituted with small alkyl groups • Chirality at X and having the rings in different planes influences potency of the drug C H2 N X Ar Ar' R' R n General H1 Receptor Antagonist d ~ 4-6Ao 12
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  CLASSES OF FIRSTGENERATION H1 RECEPTOR ANTAGONISTS 13 • Ethanolamines • Ethylenediamines • Alkylamines (Propylamines) • Tricyclics Ar Ar' X C H2 Spacer n N R R' X n Class ofAntihistamines O 2 Ethanolamines N 2 Ethylenediamines C 2 Propylamines
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  ETHYLENEDIAMINES 14 • These werethe first group of clinically effective H1- antihistamines.They also display a relatively high frequency of central nervous system depressant (sedation) and gastrointestinal side effects. The anticholinergic and antiemetic actions of these compounds is relatively low compared to most other classical antihistamines. Mepyramine (Pyrilamine)
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  PIPERAZINES/CYCLIZINES 16 • The piperazinesor cyclizines can also be considered to be ethylenediamine derivatives or cyclic ethylenediamines (cyclizines). • The piperazines are moderately potent antihistaminics with a lower incidence of drowsiness. They are more useful as antiemetics and antinauseants and in the treatment of motion sickness • Cyclizine HCl is used primarily in the prophylaxis and treatment of motion sickness. • Lactate Injection is used for intramuscular injection because of the limited water solubility of the hydrochloride. • Chlorcyclizine HCl has an additional ring Cl substituent which reduces activity. Chlorcyclizine is indicated in the symptomatic relief of urticaria, hay fever, and certain other allergic conditions
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  • Meclizine HCland Buclizine HCl are N-benzyl substituted piperazines. • Although it is a moderately potent antihistaminic, meclizine is used primarily as an antinauseant in the prevention and treatment of motion sickness and in the treatment of nausea and vomiting associated with vertigo and radiation sickness. • Buclizine HCl is highly lipid-soluble and has central nervous system depressant, antiemetic, and antihistaminic properties 17 Buclizine Meclizine Cyclizine Chlorcyclizine
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  ETHANOLAMINES Diphenhydramine (Nytol/Benedryl) •Oldest andmost effective antihistamine on the market •In addition to antihistaminic action, diphenhydramine exhibits anticholinergic, antidyskinetic, antiemetic, antitussive, and sedative properties. •has antinauseating effect • also used in motion sickness • Drowsiness is a side effect common to the tertiary aminoalkyl ethers, presumably as a result of the ability of these compounds to penetrate and BBB and occupy central H1-receptors 18
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  The 8-chloro-theophylline saltof diphenydramine Clemastine (Tavist) DIMENHYDRINATE (DRAMAMINE) •Exhibits fewer side effects than most antihistamines • Widely used as an antiprurtic (stops itching) • Anti-emetic (anti nausea) • Also causes strong sedation • Readily crosses the BBB 19 O N Cl O Cl NH N N N N O O Cl
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  • Diphenylpyraline isstructurally related to diphenhydramine with the aminoalkyl side chain incorporated in a piperidine ring. It is a potent antihistaminic. • Clemastine is structurally related to chlorodiphenhydramine with the aminoalkyl side chain incorporated in a pyrrolidine ring, and it has an additional benzylic methyl group Diphenylpyraline 20 Clemastine
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  ALKYLAMINES (PROPYLAMINES) 21 Long acting 4xactive than ethanolamines • The halogenated pheniramines are significantly more potent (20-50 times) and have a longer duration of action than the parent pheniramine. • These drugs have fewer GI adverse effects, but a greater incidence of CNS sedation.
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  AKYLAMINES Chlorpheniramine • Originally usedto prevent allergic conditions •Shown to have antidepressant properties and inhibit the reuptake of serotonin • The first SSRI was made as a derivative of chlorpheniramine • Available over the counter •Used to treat the common cold by relieving runny nose, itchy, watery eyes and sneezing * * Two optical isomers and d form is active N N Brompheniramine (Dimetap) Br 22
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  TRIPROLIDINE • Used toalleviate the symptoms associated with allergies •Can be combined with other cold medicine to relieve “flu-like” symptoms There are Two geometrical isomers of Triprolidine, trans form is active 23
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  R A (Y)n B X C Y could beC H2 , hetro atom, or CH2-hetro atom W h e n X = O; Alkyl amino ether = N; ethylenediamine = C; propyleneamine TRICYCLICS •These drugs are structurally related to tricyclic antidepressants, which explains why they have cholinergic side effects • The general structural feature R = C H 3 - C H 3 - C H N C H 3 C H 3 24
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  PROMETHAZINE (PHENERGAN) •This drughas extremely strong anticholinergic and sedative effects •It was originally used as an antipsychotic, however now it is most commonly used as a sedative or antinausea drug (also severe motion sickness) and requires a prescription. •In addition to its antihistaminic action, it is a potent antiemetic, anticholingeric and sedating agent, and significantly potentiates the action of analgesic and sedative drugs N S N CH3 25
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  CYPROHEPTADINE •THIS DRUG BOTHAN ANTIHISTAMINE AND • AN ANTISEROTONERGIC AGENT • IT IS A 5-HT2 RECEPTOR ANTAGONISTAND ALSO BLOCKS CALCIUM CHANNELS • USED TO TREAT HAY FEVER AND ALSO TO STIMULATE APPETITE IN PEOPLE WITH ANOREXIA • IT IS ALSO RARELY USED TO TREAT SSRI INDUCED SEXUAL DYSFUNCTION AND ALSO CUSHING’S SYNDROME (HIGH LEVEL OF CORTISOL IN THE BLOOD) AND MIGRAINE HEADACHES Ketotifen N O S N •This drug is available in two forms: an ophthalmic form used to treat allergic conjunctivitis or itchy red eyes and an oral form used to prevent asthma attacks •It has several adverse side effects including drowsiness, weight gain, dry mouth, irritability and increased nosebleeds 26
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  SECOND GENERATION H1-RECEPTOR ANTAGONISTS •These are the newer drugs and they are much more selective for the peripheral H1-receptors involved in allergies as opposed to the H1- receptors in the CNS • Therefore, these drugs provide the same relief with many fewer adverse side effects and non sedating. • The structure of these drugs varies and there are no common structural features associated with them • They are bulkier and but less lipophilic than the first generation drugs, therefore they do not cross the BBB as readily. • Recent studies have also showed that these drugs also have anti- inflammatory activity and therefore, would be helpful in the management of inflammation in allergic airways disease. 27
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  SECOND GENERATION H1-RECEPTORANTAGONISTS Acrivastine (Semprex-D) •This drug relieves itchy rashes and hives •It is non-sedating because it does not cross the BBB readily • Structurally related to the ethylenediamines and the ethanolamines and thus produce significant anticholinergic effects. • Perennial and seasonal allergic and vasomotor rhinitis; relief of symptoms from colds, urticaria, angioedema, anaphylactic reactions, pruritus, allergic conjunctivitis 28 N N Cl O OH O Cetirizine (Zyrtec)
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  Loratadine (Claritin) TERFENADINE •Itis the only drug of its class available over the counter • It has long lasting effects and does not cause drowsiness because it does not cross the BBB readily •It was formerly used to treat allergic conditions •In the 1990’s it was removed from the market due to the increased risk of cardiac arrhythmias Cl O CH3 O HO N OH 29
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  AZELASTINE (ASTELIN OR OPTIVAR) 30 Levocabastine (Livostin) •It is a mast cell stablilizer •Available as a nasal spray (Astelin) or eye drops for pink eye (Optivar) •Both of these drugs are used as eye drops to treat allergic conjunctivitis Olopatadine (Patanol) N O N N Cl
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  THIRD GENERATION H1-RECEPTORANTAGONISTS 31 • These drugs are derived from second generation antihistamines • They are either the active enantiomer or metabolite of the second generation drugs designed to have increased efficacy and fewer side effects Levocetrizine (Zyzal) •This drug is the active enantiomer of cetirizine and is believed to be more effective and have fewer adverse side effects. • Also it is not metabolized and is likely to be safer than other drugs due to a lack of possible drug interactions •It does not cross the BBB and does not cause significant drowsiness •It has been shown to reduce asthma attacks by 70% in children
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  DESLORTADINE (CLARINEX) 32 Fexofenadine (Allegra) •It is the active metabolite of Lortadine •Even though it is thought to be more effective, there is no concrete evidence to prove this •It was developed as an alternative to Terfenadine •Fexofenadine was proven to be more effective and safe
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  CLINICAL USESOF ANTIHISTAMINES/H1ANTAGONISTS 33 • Allergic rhinitis (common cold) • Allergic conjunctivitis (pink eye) • Allergic dermatological conditions • Urticaria (hives) • Angioedema (swelling of the skin) • Pruritus (atopic dermatitis, insect bites) • Anaphylactic reactions (severe allergies) • Nausea and vomiting • Antiasmathic
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  H2 HISTAMINE ANTAGONISTS. Inthe beginning—ulcer therapy in 1964 ▪Ulcers are localized erosions of the mucous membranes of the stomach or duodenum. It is not known how these ulcers arise, but the presence of gastric acid aggravates the problem and delays recovery. ▪In the early 1960s, the conventional treatment was to try and neutralize gastric acid in the stomach by administering bases such as sodium bicarbonate or calcium carbonate. ▪However, the dose levels required for neutralization were large and caused unpleasant side-effects and it is not effective. A better approach would be to i n h i bit the release of gastric acid a t source. DISORDERS associated with elevated secretion of gastric acid NSAID-Associated Ulcer Zollinger-Ellison Syndrome Helicobacter Pylori (H. Pylor~) Reflux Esophagitis/GERD 34
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  Antrum Stomach Pyloric Sphincter Oesophagus Duodenum Histamine Acetylcholine Gastrin Cck2 M3 2 Parietal Cells Stomach Receptors Ion channel Proton pump + H + + cAMP + + + - H+ HCl Cl Anticholinergic drugs ╠► unwanted side effects Gastrin receptor blocker ╠► unsuccessful 35
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  Gastric receptors arepharmacologically distinct. The classic H1 antagonists don’t interact with H2 receptors. No effect on gastric acid release Developing a Lead Compound • A classic example of rational drug design • work began in 1964 • There was no lead compound to work from • Take a closer look at Histamine H2 HISTAMINE ANTAGONISTS. 36
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  BURIMAMIDE 37 • Burimamide isthe prototype H2-receptor antagonist. • highly specific competitive antagonist of histamine at H2 receptors, • 100 times more potent than Nα-guanylhistamine. • It is the 4 carbons bridged analogue with guanidine moiety of Nα- guanylhistamine is replaced with thiourea group as well as addition of an N-methyl group [provides a beneficial increase in hydrophobicity ] Burimamide HN N N H NHMe Chain extention S HN N N H NH2 NH Guanylhistamine
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  METIAMIDE • analogue ofburimamide with side-chain electron withdrawing atom (sulfur) inserted into the side-chain • an electron donating methyl group added at position 4 of the imidazole ring • increase the population of N-H tautomer which affords enhanced H2 receptor affinity. • Maintain the preferred conformation of metiamide – methyl group acts as a conformational blocker • Metiamide is ten times more active than burimamide HN N S N H NHMe S CH3 38
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  S N NHMe H Thiourea Toxic sideeffects NH N NHMe H Guanidine Drop in activity but no agonist activity! H N NHMe N CN Cyanoguanidine group Cimetidine inhibits H2 receptors and thus inhibits gastric acid release. The drug does not show the toxic side-effects observed for metiamide and has been shown to be slightly more active. • The cyanoguanidine moiety acts as a bio-isostere for the thiourea group. • Both groups are planar and of similar geometry. • Both groups are polar but essentially neutral. • Both groups have high dipole moments. • Both groups have low partition coefficients. •They are weakly basic and also weakly acidic such that they are un-ionized at pH 7.4 and hence possess enhanced antagonistic activity CIMETIDINE HN N S N H NHMe N CH3 CN 39
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  Structure of someH2 receptor blockers ANALOGUES OF CIMETIDINE terminal nitroketeneaminal + different heterocyclic ring 30 times more active than cimetidine equipotent with ranitidine 40
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  INHIBITION OF HISTAMINERELEASE (MAST CELL STABILIZERS) O NaO2C O O CH2CHCH2 O O O CO2Na OH Cromolyn sodium 41