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histamine intro and the medicinal chemistry view of antihistamines

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  1. 1. HistamineSubmitted by:Ahmad al-jifri
  2. 2. Outlines:• What is histamine ?• What is allergy ?• what is the role of histamine in allergy?• What is an antihistamine?
  3. 3. What is histamine ?• Is a physiologically active amine, C5H9N3, foundin plant and animal tissue and released frommast cells as part of an allergic reaction inhumans.-It stimulates gastric secretion and-causes dilation of capillaries,-constriction of bronchial smooth muscle, and-decreased blood pressure.Imidazolinering and amine gp
  4. 4. Synthesis of Histamine :• Formed from the amino acid Histadine in adecarboxylation reaction with the enzymehistadine decarboxylase• Occurs primarily in mast cells and basophils
  5. 5. MOA and receptors:Histamine exerts its actions by combining withspecific cellular receptors located on cells. Thefour histamine receptors that have beendiscovered are designated H1 through H4.
  6. 6. Type Location FunctionH1 Found on smooth muscles,endothelium, and centralnervous system tissueCauses vasodilation, bronchoconstrictionbronchial smooth muscle contraction, separationof endothelial cells (responsible for hives),and pain and itching due to insect stings; theprimary receptors involved in allergic rhinitissymptoms and motion sickness; sleep regulation.H2 Located on parietal cells Primarily stimulate gastric acid secretionAnd we use antiacidic drugs for this receptorH3 Found on central nervoussystem and to a lesserextent peripheral nervoussystem tissueDecreased neurotransmitter release:histamine, acetylcholine, norepinephrine,serotoninH4 Found primarily inthe basophils and inthe bone marrow. It is alsofound onthymus, smallintestine, spleen, andcolon.Plays a role in chemotaxis.
  7. 7. What is allergy ?• An allergy is an overreaction of the immunesystem to a normally harmless substance calledallergen• Common allergens :-pollen-animal dander-dust-mites-Chemicals-a variety of food
  8. 8. Common allergic reactions :• Include eczema, hives, hayfever,asthma attacks, food allergies, andreactions to the venom ofstinging insects such as wasps andbees.• Mild allergies like hay fever are highlyprevalent in the human population andcause symptoms such as allergic conjunctivitis,itchiness, and runny nose.
  9. 9. what is the role of histamine inallergy?
  10. 10. What is an antihistamine?• A drug that reduces or eliminates the effectsmediated by the chemical histamine• The term antihistamine only refers to H1receptor antagonists
  11. 11. Clinical Uses of Antihistamines :• Allergic rhinitis (common cold)• Allergic conjunctivitis (pink eye)• Allergic dermatological conditions• Urticaria (hives)• Angioedema (swelling of the skin)• Puritus (atopic dermatitis, insect bites)• Anaphylactic reactions (severe allergies)• Nausea and vomiting (first generation H1-antihistamines)• Sedation (first generation H1-antihistamines)
  12. 12. Adverse side effects:• Associated with the first generation H1-antihistamines and due to their lackof selectivity for the H1 receptor and anti-cholinergic activity. Side effects aredue to CNS depression(by crossing BBB):• Sedation• Dizziness• Tinnitus (ringing in the ear)• Blurred vision• Euphoria• Uncoordination• Anxiety• Insomnia• Tremor• Nausea/vomitting• Dry mouth/dry cough• Newer second generation H1-antihistamines are more selective for theperipheral histamine receptors and have far less side effects(doesn’t crossBBB) (drowsiness, fatigue, headache, nausea and dry mouth)
  13. 13. First antihistamine• Piperoxan• Discovered in 1933 by Jeff Forneau and DanielBovent while developing a guinea pig animalmodel of anaphylaxis• They received the Nobel Prize in 1957
  14. 14. Classes of first generation H1 receptorantagonist antihistamines• Ethylenediamines• Ethanolamines• Alkylamines• Piperazines• Tricyclics
  15. 15. Common Structural Features of classicalfirst generation antihistamines• 2 aromatic rings ESSENTIAL,connected to a centralcarbon, nitrogen, or oxygenamine gp ESSENTAIL• Spacer between central atomand the amine, usually 2-3carbons in length. (Can belinear, ring, branched,saturated or unsaturated)• The amine is substituted withsmall alkyl groups• Chirality at X and having therings in different planesincreases potency of the drug
  16. 16. Ethylenediamines• These were the first group of clinicallyeffective H1-antihistaminesMepyramine (Pyrilamine)
  17. 17. Ethanolamines• This class has significant anticholinergic side effects andsedation, however reduced the gastroinestnal side effectsDiphenhydramine (Benedryl)Benedryl : used in cough syrups• Oldest and most effective antihistamine on themarket• Available over the counter• Because it induces sedation, it’s used innonprescription sleep aids such as Tylenol PM• Also inhibits the reuptake of serotonin, which ledto the search for viable antidepressants with similarstructures (prozac)
  18. 18. EthanolaminesClemastine (Tavist)• Exhibits fewer side effects than most antihistamines• Widely used as an antiprurtic (stops itching)
  19. 19. Alkylamines• Isomerism is an important factor in this class ofdrugs, which is due to the positioning and fit ofthe molecules in the H1-receptor binding site• These drugs have fewer sedative and GI adverseeffects, but a greater incidence of CNSstimulation• These drugs lack the “spacer molecule” (which isusually a nitrogen or oxygen) between the twoaromatic rings and at least one of the rings hasnitrogen included in the aromatic system
  20. 20. Akylamines• Chlorphenamine•Halogen at p-position of phenylring,increases the activity 20 times•Originally used to prevent allergicconditions•Shown to have antidepressantproperties and inhibit thereuptake of serotoninPheniramine (Avil)•Used most often to treat hay fever orurticaria (hives)•Antihistamine component of Visine-A
  21. 21. Piperazines• Structurally related to the ethylenediamines and the ethanolamines andthus produce significant anti-cholinergic effects• Used most often to treat motion sickness, vertigo, nausea and vomitingCyclizine•Used to treat the symptoms associated withmotion sickness, vertigo and post-op followingadministration of general anaesthesia andopiods•Mechanism of inhibiting motion sickness isnot well understood, but it may act on thelabyrinthine apparatus and thechemoreceptor trigger zone (area of the brainwhich receives input and induces vomiting)
  22. 22. Piperazines• Chlorcyclizine•This drug is used to treat motion sickness
  23. 23. Tricyclics• These drugs are structurally related to tricyclicantidepressants, which explains why they have cholinergicside effectsPromethazine (Phenegran)•This drug has extremely strong anticholinergicand sedative effects•It was originally used as an antipsychotic,however now it is most commonly used as asedative or antinausea drug (also severe morningsickness) and requires a prescription
  24. 24. Tricyclics• Cyproheptadine•This drug both an antihistamine andan antiserotonergic agent•It is a 5-HT2 receptor antagonist andalso blocks calcium channels•Used to treat hay fever and also tostimulate appetite in people withanorexia•It is also rarely used to treat SSRIinduced sexual dysfunction and alsoCushing’s Syndrome (high level ofcortisol in the blood) and migraineheadaches
  25. 25. Second generation H1-receptorantagonists• called "non- sedating" because they cause less sedation than theirpredecessors• These are the newer drugs and they are much more selective forthe peripheral H1-receptors involved in allergies as opposed to theH1-receptors in the CNS• Therefore, these drugs provide the same relief with many feweradverse side effects• The structure of these drugs varies and there are no commonstructural features associated with them• They are however bulkier and less lipophilic than the firstgeneration drugs, therefore they do not cross the BBB (reason ofnon –sedating name)as readily• Recent studies have also showed that these drugs also have anti-inflammatory activity and therefore, would be helpful in themanagement of inflammation in allergic airways disease (Devaliaand Davies).
  26. 26. Second generation H1-receptorantagonistsLoratadine (Claritin)•It is the only drug of its classavailable over the counter•It has long lasting effects and doesnot cause drowsiness because it doesnot cross the BBB•Used for watery eyes, runny nose(rhinitis), itching eyes, and sneezingTerfenadine(Seldane)•It was formerly used to treat allergicconditions•In the 1990’s it was removed fromthe market due to the increased riskof cardiac arrythmias
  27. 27. Second generation H1-receptorantagonistsFexofenadine (Allegra)•It was developed as an alternativeto Terfenadine•Fexofenadine was proven to bemore effective and safe•Used for chronic urticaria (hives)Citrizine (Zyrtec)cetirizine is more sedating thanthe other non-sedatingantihistamines.available over-the-counterUsed for sneezing, itchy nose(allergic rhinitis) and itchyeyes
  28. 28. References• Dental farmacology 2005, prof.ervin erdos• Medecinal chemistry, Dr.touseef begum•••••