5/31/2017 What is histamine? - Looks simple. Made from aminoacid histidine. histamine histidine H H N N N N N H N H H H O OH pK 's = 5.7, 9.8 a pKa's = 1.9, 6.0, 9.3 How is it made – Handout. What does it do? – Four different receptors known now. All part of G protein- coupled family. H1 – immune response that causes hives, makes blood vessels leaky H2 – stimulates stomach acid secretion, H3 – found in CNS and can inhibit release of other neurotransmitters, H4 - found in bone marrow and white blood cells and regulates neutrophil release from bone marrow. It is also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea 1 © Oxford University Press, 2013 Hives also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. They may also burn or sting. Often the patches of rash move around. Hives often occur following an infection or as a result of an allergic reaction such as to medication, insect bites, food, psychological stress, cold temperature, or vibrations. In half of cases the cause remains unknown. Risk factors include having conditions such as hay fever or asthma. Diagnosis is typically based on the appearance. Patch testing may be useful to determine the allergy. Prevention is by avoiding whatever it is that causes the condition. Typically they last a few days and do not leave any long -lasting skin changes . Fewer than 5% of cases last for more than six weeks. The condition frequently recurs. Treatment is typically with antihistamines such as diphenhydramine and ranitidine. In severe cases, corticosteroids or leukotriene inhibitors may also be used. Antihistamines that block the histamine H1 receptors are the first line of therapy. About 20% of pppeople are affected. Cases of short duration occur equally in males and females while cases of long duration are more common in females. Cases of short duration are more common among children while cases of long duration are more common among those who are middle aged. Hives have been described at least since the time of Hippocrates. The term urticaria is from the Latin urtica meaning "nettle“. 2 © Oxford University Press, 2013 1 5/31/2017 Peptic ulcer disease (PUD), is a break in the lining of the stomach, first part of the small intestine, or occasionally the lower esophagus. An ulcer in the stomach is known as a gastric ulcer while that in the first part of the intestines is known as a duodenal ulcer. Common symptoms upper abdominal pain that improves with eating. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people have no symptoms. Complications may include bleeding, (15% of people) with an ulcer perforation, and blockage of the stomach. Common causes include the bacteria Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs). Other less common causes include tobacco smoking, stress due to serious illness, Crohn disease and liver cirrhosis, among others. H. pylori can be diagnosed by testing the blood for antibodies or a biopsy of the stomach. Diet does not play an important role in either causing or preventing ulcers . Treatment includes stopping smoking , stopping NSAIDs, stopping alcohol, and medications to decrease stomach acid. The medication used to decrease acid is usually either a proton pump inhibitor (PPI) or an H2 blocker . Ulcers due to H. pylori are treated with a combination of medications such as amoxicillin, clarithromycin, and a PPI. Peptic ulcers are present in around 4% of the population. They newly began in around 87.4 million persons worldwide in 2015. About 10% of people develop a peptic ulcer at some point in their life. They resulted in 267,500 deaths in 2015 down from 327,000 deaths in 1990. 3 © Oxford University Press, 2013 In the early 1960s only one class of antihistamine was known (H1 now) First generation antihistamines Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders. Sedation is a common side effect of H1-antihistamines that readily cross thbldhe blood–bibbrain barr ier; some o fhf these drugs, suc h as N O diphenhydramine and doxylamine, are therefore used to treat insomnia. H1-antihistamines can also reduce inflammation. diphenhydramine (Benadryl) 4 © Oxford University Press, 2013 2 5/31/2017 Second generation antihistamines Mepyramine crosses the blood–brain barrier to a much lower degree than the first-generation N antihistamines. Their main benefit is they N primarily affect peripheral histamine receptors (as opposed to the CNS) and therefore are less O N sedating. However, high doses can still induce the central nervous system drowsiness. The reason Mepyramine for their peripheral selectivity is that most of these compounds are zwitterionic at physiological pH (around pH 7.4). As such, they are very polar, meaning that they do not easily cross the blood– brain barrier and act mainly outside the central nervous system. Possible synthesis O O NH2 H N N N H C H O H N N O Cl N O N O Mepyramine 5 © Oxford University Press, 2013 Second generation antihistamines Ketotifen is a noncompetitive H1-antihistamine and mast cell stabilizer. It is most commonly sold ketotifen O as a salt with fumaric acid, ketotifen fumarate, and is available in two forms. In its ophthalmic form, S it is used to treat allergic conjunctivitis, or the itchy red eyes caused by allergies. In its oral form, it is used to prevent asthma attacks. Ketotifen relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies. It starts working within minutes after N administering the drops. The mean elimination half life is 12 hours. It was known that histamine stimulated stomach acid, but none of the known antihistamines inhibited acid secretion. 6 © Oxford University Press, 2013 3 5/31/2017 ANTI-ULCER AGENTS - HISTAMINE ANTAGONISTS Ulcers •Localised erosions of the mucous membranes of the stomach and duodenum •Potentially fatal if untreated •Caused by stress, infection (H. Pylori), smoking and drugs (NSAIDS) •Agrevated by gastric acid (HCl) in the stomach •Estimated 1 out of 10 people will have one sometime in their life Therapy of ulcers •Old days: antacids, bland diet (crackers, milk), surgery on stomach •New days: •Lower the levels of gastric acid a. histam ine antagon ists and b. proton pump inhibitors •Antibacterial agents vs. H. Pylori •Herbal remedies 7 © Oxford University Press, 2013 Parietal cells and gastric acid release Acetylcholine oesophagus Histamine Gastrin + M + 3 + H2 Cck2 cAMP + + + Parietal Cells - Stomach H+ Cl Stomach HCl Antrum Pyloric Receptors Sphincter Ion channel Duodenum Proton pump Notes •Release of gastric acid is promoted by acetylcholine, gastrin and histamine 8 © Oxford University Press, 2013 4 5/31/2017 sulfonated tyrosine O3SO O CO2 CO2 H Glu Glu Ala Met Phe N Pro Leu Gly Gly Trp Glu Glu Glu N Trp Asp NH3 O H CO O C CO O CO modified Glu 2 2 2 2 gastrin - peptide hormone (made by G cells) O CH3 H3N H2 CH3 C N N H H3C O C CH H 3 2 N acetyl choline histamine 9 © Oxford University Press, 2013 10 © Oxford University Press, 2013 5 5/31/2017 Biosynthesis of histamine from the amino acid histidine (with vitamine B6) H B H B H H O HO O CO2H N O N N H H NH OH H N -2 N O3PO H B H B N histidine (pKa's = 1.8, 6.1, 9.3) H N PLP - vitamine B6 (aldehyde version) H B B H B H H O O O H C O O N C N N H H NH H NH N NH N N A similar process occurs with H B many other amino acids, including synthesis of neurotransmitters serotonin and N dopamine (which forms N PLP - vitamine B6 N epinephrine and norepinephrine). (imine version) H Glutamate can react in a similar H H manner. B H O H H B Histamine is released when O N cells are damaged. It N increases the permeabililty H NH N of small blood vessels and NH allows white blood cells HN H into that area to defend H against infection. Allergic N reactions and irritation are histamine common side effects. H N PLP - vitamine B6 (aldehyde version) 11 H © Oxford University Press, 2013 Histamine - Properties Notes •A chemical messenger released by cells •Two possible tautomers •Acts as a local hormone •pKa for the -NH2 group = 9.80. •% ionisation at pH 7.4 = 99.6 •pKa for the imidazole ring = 5.74 •Imidazole ring is slightly ionized at blood pH Percent conjugate acid and conjugate base plasma pH = 7.4 H N N H N H pKa1 = 5.7 pKa2 = 9.8 N N N HN H HN H HN H H H H [B:] [B:] pH - pKa = log pH - pKa = log What could make the [HB+] [HB+] pKa go higher or lower? [B:] [B:] 7.4 - 5.7 = 1.7 = log 7.4 - 9.8 = -2.4 = log The conjugate acid is [HB+] [HB+] positive and the [B:] [B:] =101.7 =50/1=98%/2% =10-2.4 = 1 / 250 = 0.4% / 99.6% conjugate base is neutral. [HB+] [HB+] Two tautomer possibilities BH H H H N N N N N N N N H H H3N H3N H H3N H3N is closer to the side chain B H N How does the pKa of imidazole compare to pKa1 of histamine? N H (higher, lower or similar)? 12 © Oxford University Press, 2013 6 5/31/2017 Histamine Actions Histamine is released by cell damage Stimulates dilation of blood vessels with increased permeability White blood cells escape blood vessels and access area of tissue damage White blood cells combat infection BUT Histamine is also released by allergies, asthma, hay fever and insect bites 13 © Oxford University Press, 2013 Classical antihistamines Commonly used to treat symptoms such as inflammation & itching MeO NMe2 NMe2 O N N Mepyramine Diphenhydramine Benadryl •But no effect on gastric acid release •Casts doubt on histamine receptors being present on parietal cells •Histamine may promote gastric