Antihistamine introduction by Ho-Chang Kuo, MD (郭和昌醫師)
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The document summarizes the history and development of antihistamines for treating allergic rhinitis and histamine-induced wheals. It discusses the different types of histamine receptors (H1, H2, H3, H4) and their functions. It then outlines the evolution of various antihistamines from early sedating 1st generation drugs to newer 2nd and 3rd generation non-sedating drugs like levocetirizine. The optimal properties of antihistamines and pharmacokinetic profiles of select antihistamines are also compared.
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Antihistamine introduction by Ho-Chang Kuo, MD (郭和昌醫師)
- 1. Mississippi River, New Orleans, LA 抗組織胺的發展 History of Antihistamine 郭和昌 醫師 高雄長庚兒童過敏免疫風濕科 2010 Treatment of allergic rhinitis & histamine induced wheal
- 3. 台北地區學童氣喘盛行率
- 5. Pathophysiology of allergic disorders KD Yang at al. Clinical Immunology
- 7. 1937 1942 1979 1954 1996 1988 2001 口乾、眼花、拮抗 EPS 椎體外症候群 嗜睡 History of Antihistamines Anti-histaminic effect Anti-cholinergic effect 抗乙醯膽鹼 H 3 Sedative effect 鎮定作用 H 3 Staub Bovet phenbenzamine chlorpheniramine Hydroxyzine levocetirizine terfenadine fexofenadine astemizole cetirizine loratadine desloratadine
- 8. 各式各樣的抗組織胺 (1) Alkylamines Ethanolamine Ethylenediamine Chlorpheniramine Brompheniramine Tripolidine Diphenhydramine Clemastine Antazoline Tripenelamine Acrivastine CLASS OLD 1st GENERATION 2nd NEW GENERATION H 1 selective
- 9. 各式各樣的抗組織胺 (2) Piperidine Others Phenothiazine Methdilazine Promethazine Loratadine Terfenadine Ebastine Mizolastine Astemizole Ketotifen Azelastine Desloratadine Fexofenadine Tecastemizole Azatadine CLASS OLD 1st GENERATION 2nd NEW GENERATION Newer GENERATION Piperazine Levocetirizine Cetirizine Hydroxyzine
- 10. 各種抗組織胺的演變 Hydroxyzine 1954 Cetirizine 1987 Levocetirizine 2001 Terfenadine 1981 Fexofenadine 1996 Loratadine 1988 Desloratadine 2001 Ebastine 1990 Carebastine ? Parent drug Metabolite Eutomer
- 13. Holliday Inn, New Orleans, LA Which one is useful?
- 14. The Nobel Prize in Chemistry 2001 For “the development of catalytic asymmetric synthesis” William S. Knowles 1/4 of the prize St. Louis, MO, USA b. 1917 Ryoji Noyori 1/4 of the prize Nagoya University Nagoya, Japan b. 1938 得獎原因 : 鏡像異構物催化氫化反應 K. Barry Sharpless 1/2 of the prize The Scripps Research Institute La Jolla, CA, USA b. 1941 得獎原因 : 鏡像異構物催化氧化反應
- 15. 東京 - 皇居二重橋 Optimal properties of antihistamines
- 16. Allergy 2006: 61: 1086–1096 理想的抗組織胺
- 18. Levocetirizine 對於受器具有高度的選擇性 pKi 3 4 5 6 7 8 9 10 Low selectivity could lead to unwanted side effects Inflamm Res. 2003 Apr;52 Suppl 1:S49-50 H1 M2 M5 M3 M4 M1 Levocetirizine Loratadine Desloratadine Fexofenadine < 4.0 Highly selective
- 19. Levocetirizine 對於受器具有良好的親合力 Effects on the histamine (10 -4 M) induced contraction on the isolated guinea pig trachea Pharmacology . 2007;79(2):104-13. Levocetirizine inhibited completely the contractions whereas cetirizine reached only 80% inhibition of the contraction after 120 minutes. Control (DMSO 0.1%) Cetirizine 2.10 -6 M Levocetirizine 10 -6 M Dextrocetirizine 10 -6 M 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 Time (min) E max (%)
- 20. 抗組織胺 PK-PD 的比較圖 Am J Med 2002;113(9A): 38S–46S. Fundam Clin Pharmacol 2004 (18): 399–411. Levocetirizine Desloratadine Fexofenadine Cetirizine Absorption (t max; hours) 0.8 ±0.5 3.0 1.0 - 3.0 1.0 ±0.5 Plasma t ½ (hours) 7 ±1.5 27 14.4 6.5 - 10 Distribution (Vd; l/kg) 0.33 49 5.8 ± 0.7 0.56 Protein binding (%) 96 - 60 - 70 93 Excretion in urine/feces (%) 85/13 41/47 12/80 60/0 Onset of action (hours) 0.5 3 1 - 2 0.7 Duration of action (hours) > 24 > 24 24 > 24
- 21. A new trend of souvenirs collection
- 23. Allergy march
- 24. Pediatr Neonatol 2009;50(1):18−25 Prevalence of AR in Taiwan
- 25. Co-morbidity of AR Allergy 2006: 61: 656–664
- 26. Treatment of AR sneezing rhinorrhea nasal nasal eye obstruction itch symptoms H1-antihistamines oral +++ +++ 0 to + +++ ++ intranasal ++ +++ + ++ 0 intraocular 0 0 0 0 +++ Intranasal CS +++ +++ ++ ++ + Chromones intranasal + + + + 0 intraocular 0 0 0 0 ++ Decongestants intranasal 0 0 ++ 0 0 oral 0 0 + 0 0 Anti-cholinergics 0 +++ 0 0 0 Anti-leukotrienes + ++ ++ ? ++
- 31. Levocetirizine and desloratadine in EEU TM Evolution of Major Symptom Complex (MSC) score Int J Clin Pract . 2004 Feb;58(2):109-18. * * 10.0 8.0 9.0 6.0 4.0 7.0 5.0 3.0 2.0 1.0 0.0 -1.0 -2.0 -3.0 0 1 2 3 Drug intake 4 5 23 24 25 26 * † * † * † * † * † * † * † * * * * † * † * † * * * * 27 28 * † * † * † * † * † * † * † * * * * † Drug intake Desloratadine 5 mg Placebo Levocetirizine 5 mg Period I Reduction from baseline MSC Score (LS Mean) Period II Period III Hours after first drug intake * p < 0.001 vs placebo ° p < 0.05 vs placebo p < 0.05 vs desloratadine † (n=373)
- 33. Clin Ther. 2009 May;31(5):921-44. Indication of desloratadine, fenofenadine and levocetirizine
- 34. Levocetirizine for the treatment of AR and chronic idiopathic urticaria in adults and children. Clin Ther . 2009 Aug;31(8):1664-87.
- 35. Cost-effectiveness Clin Ther . 2009 Aug;31(8):1664-87.
- 36. Central Park, NY
- 37. Central park, Kaohsiung Skin wheal
- 40. Histamine H 1 -Receptors and the Wheal and Flare Response H 1 -receptors on blood vessels - local vasodilatation - local oedema (wheal) H 1 -receptors on nerves - itching (pruritus) - surrounding reddening (flare) 1 2 1 2
- 41. Step-up tx for chronic urticaria Clin Exp Allergy. 2007;37(5)631-650. 6) Add or substitute other second-line agents (ie, cyclosporin or a low-dose corticosteroid*) 5) Consider adding or substituting with second- line agent (ie, anti-leukotriene) 4) Consider sedating antihistamine at night 3) Add second non-sedating H 1 antihistamine (regular or as required) 2) Higher dose of H 1 antihistamine 1) Standard dose of non-sedating H 1 antihistamine * Low-dose daily corticosteroid (5–10 mg/day) or low-dose alternative day corticosteroid (15–20 mg alt day) could be considered. Treatment should be stepped down once control is achieved Recommendations of the British Society for Allergy and Clinical Immunology Identification of Triggers Education and Avoidance of Triggers
- 42. Wheal response during 24 hours Ann Allergy Asthma Immunol . 2002 Feb;88(2):190-7. (n=18 crossover) 1600 1400 1200 1000 800 600 400 200 0 Placebo Ebastine (10 mg) Fexofenadine (180 mg) Loratadine (10 mg) Levocetirizine (5 mg) Mizolastine (10 mg) mm 2 .h (n=18 crossover)
- 43. Flare response during 24 hours 50’000 40’000 30’000 20’000 10’000 0 Placebo Ebastine (10 mg) Fexofenadine (180 mg) Loratadine (10 mg) mm 2 .h (n=18 crossover) Ann Allergy Asthma Immunol . 2002 Feb;88(2):190-7. Levocetirizine (5 mg) Mizolastine (10 mg)
- 45. Levocetirizine in the treatment of chronic idiopathic urticaria British Journal of Dermatology 2006 154, 533–538 . Control levocetirizine
- 46. Inhibition of allergen-induced wheal and flare reactions by levocetirizine and desloratadine. Br J Clin Pharmacol . 2008 Feb;65(2):172-9.
- 48. 1/3 of acute childhood urticaria leading to patient hospitalization was related to M pneumoniae infection. Ann Allergy Asthma Immunol. 2009 Aug;103(2):134-9.
- 49. Kapellbrucke, Luzern More than anti-histamine…
- 50. Allergy, Asthma & Clinical Immunology 2009, 5 :14 levocetirizine, but not desloratadine or placebo, significantly decreased the number of eosinophils, neutrophils and IL-8 levels in nasal lavage samples during the pollen season while treatment with either antihistamine Significantly reduced IL-4 levels .
- 51. 4wks J Pharmacol Sci 2008 108, 149 – 156. IL-12Rβ1 ICAM1+ T cells helper/ inducer T cells effector helper /inducers cells
- 52. 北海道 - 函館山 - 百萬夜景 Levocetirizine (Xyzal: 驅異樂 )
- 55. Manila Bay
- 56. 逆境中生存
- 57. What is his need ? Vena Periactin Clarinase desloratadine Allergra Xyzal Or Just clothes ! Manila bay
- 58. Thanks a lot! 雅典學院 :Academy, 8000pc puzzle 不同的抗組織胺 特性、親合力、藥物動力學特性、藥效 都有很大的差異 選擇最合適的抗組織胺 !
Notas del editor
- Adhesion Molecules-Complementary cell surface molecules expressed on leukocytes, endothelial and structural cells that allow leukocyte adherence
- The history of antihistamines began in 1937 with the discovery by Anne-Marie Staub and Daniel Bovet of the first antihistaminic compound, for which Bovet was awarded the Nobel prize. This discovery opened the door for many pharmaceutical companies to develop antihistaminic drugs and soon after a number of drugs with antihistaminic properties – the first generation antihistamines - appeared on the market. While exerting good antihistaminic properties, the first generation antihistamines were plagued by important unwanted side effects of which the major ones were anti-cholinergic effects (dry mouth) and sedation due to the penetration to the CNS. Consequently, an effort was made to develop compounds free of these unwanted effects. This resulted in the development of the second generation H 1 -antagonists, most of them metabolites of the first generation antihistamines. Terfenadine was the first of these new compounds to be launched onto the market. While, indeed, sedation and anti-cholinergic side effects were no longer attributes of this compound, its use was associated with important heart problems in a limited number of patients which lead to its withdrawal from the market in most of the countries. Astemizole, the second of the second generation antihistamines had the same problems and had the same fate as terfenadine. The new antihistamines that followed: cetirizine (1988), loratadine and fexofenadine were free not only of anti-cholinergic and CNS side effects but also from cardiotoxicity. However, the research did not stop here and these second generation compounds were followed by a newer drugs of which the most recently introduced is levocetirizine (2001)
- The older antihistaminic agent terfenadine was found to metabolize into the related carboxylic acid , fexofenadine. Fexofenadine was found to retain all of the biological activity of its parent while giving fewer adverse reactions in patients, so terfenadine was replaced in the market by its metabolite . [5] Fexofenadine was originally synthesized in 1993 by Massachusetts -based biotechnology company Sepracor , which then sold the development rights to Hoechst Marion Roussel (now part of Sanofi -Aventis ), and was later approved by the Food and Drug Administration (FDA) in 1996. AMRI holds the patents to the intermediates and production of fexofenadine HCl along with Roussel. Since that time, it has achieved blockbuster drug status with global sales of $1.87B USD in 2004 (with $1.49B USD coming from the United States ). AMRI received royalty payments from Aventis that enabled the growth of AMRI. Desloratadine is a drug used to treat allergies . It is marketed under several trade names such as NeoClarityn , Claramax , Clarinex and Aerius . It is an active metabolite of loratadine , which is also on the market.
- For more than 50 years of history of antihistamines real progresses hav – and this is where it ended!! Ebastine (trade names Kestine , Evastin , Ebastel , Aleva ) is a non-sedating H1 antihistamine . It does not penetrate the blood-brain barrier and thus allows an effective block of the H1 receptor in peripheral tissue without a central side effect, i.e not causing sedation or drowsiness. The basic patent for ebasine in Europe is EP-B-134124. It is often provided in micronised form, due to poor water solubility. Chewable, non-chewable, and syrup forms of cetirizine are similarly absorbed rapidly and effectively, with absorbed food minutely affecting the absorption rate which yields a peak serum level one hour after administration; [3] in a study of healthy volunteers prescribed 10mg tablets, once daily for 10 days, a mean peak serum level of 311 ng/mL was observed. [4] The metabolic effects of cetirizine are long acting; remaining in the system for a maximum of 21 hours before being excreted, the average elimination half-life is 8 hours. [3] [4] 70% of the drug is excreted or eliminated by kidney function within 72 hours, and 10% is removed through urine or excrement; [3] [4] of which half is observed as unchanged cetirizine compound. [3] [4] Like many other antihistamine medications, cetirizine is commonly prescribed in combination with pseudoephedrine hydrochloride , a decongestant . These combinations are marketed using the same brand name as the cetirizine with a &quot;-D&quot; suffix ( Zyrtec-D , Virlix-D , etc.) Additionally, cetirizine HCl not sold in combination with pseudoephedrine, is commonly known and marketed in the United States under the brand name, &quot;Zyrtec.&quot; Formerly only available by a prescription, both Zyrtec and Zyrtec-D are currently available over the counter in the United States. In the Philippines, a leading cetirizine is Aforvir.
- Amphetamine (Benzedrine; street amphetamine is also racemic) and dextroamphetamine (Dexedrine) Bupivacaine (Marcain) and levobupivacaine (Chirocaine) Cetirizine (Zyrtec / Reactine) and levocetirizine (Xyzal) Citalopram (Celexa / Cipramil) and escitalopram (Lexapro / Cipralex) Methylphenidate (Ritalin) and dexmethylphenidate (Focalin) Modafinil (Provigil) and armodafinil (Nuvigil) Ofloxacin (Floxin) and levofloxacin (Levaquin) Omeprazole (Prilosec) and esomeprazole (Nexium) Salbutamol (Ventolin) and levalbuterol (Xopenex) Zopiclone (Imovane) and eszopiclone (Lunesta)
- (only one enantiomer can actively exert a certain function while the other one is inactive; just like the human beings who, in general, have a dominant hand either the right or the left one). As consequence, even if enantiomers are characterized by the same physical and chemical properties, they can have different biological functions. Due to the stereoselectivity of the biological systems, for many drugs existing in two enantiomeric forms only one of the enantiomers is responsible for the therapeutic activities of the respective drug while the other one is inactive. Therefore, separating the active enantiomer of a drug from the inactive one becomes important and the recommendation of FDA is that drug molecules having stereocenters should be given to patients only in the active enantiomeric form and not as a racemic mixture. Some drug molecules are chiral, and the enantiomers have different effects on biological entities. They can be sold as one enantiomer or as a racemic mixture. Examples include Thalidomide , Ibuprofen , and Salbutamol . Adderall is a mixture of several different enantiomers. A single amphetamine dose combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and D/L-amphetamine aspartate monohydrate. The prescription analgesic tramadol is also a racemate. In some cases (e.g., Ibuprofen and Thalidomide), the enantiomers are interconverted in vivo . This means that preparing a pure enantiomer for medication is largely pointless. In cases like Salbutamol and Thalidomide, the inactive isomer may be harmful. Methamphetamine is available by prescription under the brand name Desoxyn . The active component of Desoxyn is dextro-methamphetamine hydrochloride. This is the right-hand isomer of methamphetamine. The left-handed isomer of methamphetamine, levo-methamphetamine, is less centrally-acting and more peripherally-acting; therefore a racemic mixture of dextro/levo-methamphetamine is not used in current medical practice. In the past, due to different levels of restrictions on precursor chemicals and lack of knowledge by those preparing the final product, racemic methamphetamine was produced and sold on the black market. Newer techniques typically use asymmetric synthesis methods, and yield a majority of D-methamphetamine and relatively little L-methamphetamine. In the chemical name, a D/L- prefix indicates that both the levo & dextro isomers are contained in the product to some unspecified degree. Whereas a DL- prefix with no slash mark indicates that both levo & dextro isomers of the molecule are present in an equal 1:1 ratio, with 50% of each.
- Until 2001 the separation of the chiral molecules at an economical industrial level was impossible. However in 2001 scientific progress in the domains of chemistry and technology allowed UCB to go one step further in the process of drug development. In 2001 the Nobel prize in chemistry was given for new developments in the field of chiral chemistry. Due to their work, the separation of chiral molecules became possible and UCB was finally able to separate levocetirizine from dextrocetirizine and to develop Xyzal ®.
- ‘ What is expected from a good antihistamine?’ Pharmacodynamic attributes are: high affinity for the H1 receptor meaning that it’s binding is strong and persistent. high selectivity for the H1 receptor, meaning it binds to the histamine receptor, but not to other type of receptors (mainly muscarinic ones), and so it is free from side effects.
- Affinity to the H1 receptor essential in exerting the antihistaminic activity. Selectivity for the H 1 histamine receptor is also imperative in order to reduce the unwanted side effects which characterized the first generation antihistamines. In a study comparing the selectivity and the affinity of levocetirizine with that of loratadine, desloratadine, fexofenadine it was shown that levocetirizine has the higher selectivity for H1 receptor compared with any of the other antihistamine studied. Fexofenadine also showed almost the same level of affinity and selectivity for H1 receptor as levocetirizine. While desloratadine showed the highest affinity for the H 1 receptor, it also had a high affinity for all 5 types of muscarinic receptors, which suggests that its antihistaminic activity of could be accompanied by anticholinergic side effects.
- Evaluated the ability of equivalent concentrations of the three compounds to induce relaxation of the guinea pig trachea in which contraction was previously provoked by stimulation with histamine. Three increasing concentrations of histamine were used (10 -6 , 10 -5 , 10 –4 ) and the antihistaminic effect of drugs was evaluated for each histamine concentration. At high concentrations of histamine (10-4 M ) the antihistaminic effect of levocetirizine was more potent than that of cetirizine as it had the ability to inhibit completely the histamine induced contraction while cetirizine reached only 80% inhibition at 120 minute. Also at the same histamine concentration the antihistaminic effect of dextrocetirizine was very weak, matching closely the placebo response.
- When comparing other pharmacokinetic characteristics of levocetirizine with that of the major second generation antihistamines currently in use, it appears that levocetirizine has the fastest absorption from the gastrointestinalfastest & is the compound excreted unchanged in the urine in the highest proportion , has the fastest onset of action and a duration of action of at least 24 hours.
- The Mechanisms of Urticaria The title diagram illustrates that the mast cell is the primary cause of Urticaria Reference : UCB Training Manual Chapter 3 Allergy and Allergic Cascade 3.3.5 Urticaria Braunwald, Eugene; Fauci, Anthony; Kasper, Dennis; Hauser, Stephen; Longo, Dan; Jameson, Larry, ed (2001). Harrison's principles of internal medicine (15th Edition ed.). New York: McGraw-Hill. pp. 95 & 306. ISBN 0070072728 .
- The Mechanisms of Urticaria The title diagram illustrates that the mast cell is the primary cause of Urticaria Reference : UCB Xyzal Training Manual Chapter 3 Allergy and Allergic Cascade 3.3.5 Urticaria
- Histamine H1-Receptors and the Wheal and Flare Response Diagram thirteen summarises the role of histamine receptors in the skin. Number one indicates that histamine H1-receptors are on the local blood vessels which will cause local vasodilatation and local oedema. Number two indicates that histamine H1-receptors are also present on the nerves which initiate pruritus and the surrounding neurogenic flare. Reference : UCB Xyzal Training Manual
- Reference : UCB Xyzal Training Manual