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Tiotropium Bromide Binding to Muscarinic (M3) Acetylcholine

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Tiotropium Bromide Binding to Muscarinic (M3) Acetylcholine Tiotropium Bromide Binding to Muscarinic (M3) Acetylcholine Receptor Poster Team: Anna Depies, Sean Ford, Tiffany Kremmer, Micaela Pommerening, Megan Shaff, Karina Sundar, and Carolyn Van Straten Jmol Team: Paul Rosman and Jerry Sulewski Educators: Dr. Daniel Sem, PhD. and Dr. Frank Dailey, PhD. Institution: School of Pharmacy, Concordia University Wisconsin, Mequon, WI 53097 Professional Mentors: Dr. Joseph Sterzinger, PharmD, Aurora Summit Medical Center, WI; William Roland, RPh, Walgreens, North Wales, PA ABSTRACT 9 THE PROTEIN RECEPTOR 4-5, 7 THE NEXT QUESTION 8 Once the tiotropium bromide molecule encounters the receptor, it binds deep inside the core and is covered by a The HandiHaler® is the original delivery system that uses an Tiotropium bromide (Spiriva®) is a long acting, inhaled anti- tyrosine lid (Fig. 1). The tyrosine lid creates an environment where the drug can interact with the hydrophobic encapsulated dry powder dosage form. Delivery of the drug to the cholinergic agent used for maintenance of chronic obstructive regions inside the receptor. lungs requires a specific breathing pattern; complete exhalation of pulmonary disease (COPD). Tiotropium bromide acts by breath, sealing lips around the HandiHaler® mouthpiece, and one competitively and reversibly inhibiting muscarinic receptors M1, The M3 receptor (Fig. 2) has a leucine in the ECL2 portion of the binding site, unlike M2 which has a slow and deep breath that is strong enough to vibrate the powder M2, and M3. This mechanism of action causes bronchodilation phenylalanine in the ECL2 portion. The substitution creates a larger binding pocket which does not cause a A patient presents to the pharmacy with prescrifromptions the capsule for tw ando sintoepa thera lungs.te long -acting and relaxation of smooth muscle in the lungs. The tiotropium disruption of the hydrogen bond created by the thiophene ring of tiotropium bromide and the tyrosine of the The FDA recently approved a new dosage form and delivery bromide molecular structure provides higher binding specificity receptor (Fig. 3). This unique interaction accountsa fornt itsim higherusca affinityrinic andinha slowerlati ondissociation medic ofa ttiotropiumions pre scribed by his doctor for the treatment of his system of tiotropium bromide, the Respimat® Inhalation Spray. to the M3 receptor when locally administered. Our goal was to bromide from the M3 receptor and provides a 24-hour duration of action. newly diagnosed COPD. The physician prescribedThis onc systeme da isi lcomprisedy tiotropi of solutionum brom that isi dedelivered in a pre- clarify the interactions between the tiotropium molecule and its measured and slow-moving mist, activated by the press of a receptors. (Spiriva® HandiHaler®) and twice daily aclidinium bromide (Tudorza ®). He requested Receptor Location Anticholinergic Effect button. There is no difficult breathing pattern required for delivery M1 Brain Delirium, increasedthe body pha temperaturermacist fill whichever medication is covereofd the by new the formula pat iintoent the’s lungs.insurance as well as CASE STUDY M2 Heart Tachycardia the medication the pharmacist finds to be most appropriBoth tiotropiumate f orbromide the dosagepatient forms in arerega saferds and to efficacious for M3 Smooth muscle Decreased secretions/urination, constipation preventing exacerbations of COPD. The same active drug is potenial adherence. The patient states that they dodelivered not w inant the t twoo t adosageke a forms,medi providingcation selectivitythat mus fort the M3 A patient presents to the pharmacy with prescriptions for be used more than once daily but that he has also receptorheard andfrom local a delivery friend to ctheurre lungs.ntl They t atwoki ngdosage forms tiotropium bromide and aclidinium bromide (Tudorza®). Both also share the same half-life of 5 to 6 days. medications are long-acting antimuscarinic inhalation ECL2 portion of Spiriva that the medication is ineffecbindingtive site and tastes awful when they swallow the medications for COPD. Differences between the dosage forms are as follows: - Past Medical History: COPD capsules. Pertinent health information for the patient includes hisHandiHaler recent di® a gnos Respimatis for ® - Family History: cardiac disorder COPD and a family histFigureory 3 (above)of c: Theardi molecularac tstructureroubl of e; howBioavailabilityever, the pa t i e nt 19.5% him s e l f ha s not 33% tiotropium bromide showing its interactions - Patient prefers the drug to be covered by insurance, dosed Excretion (urine) 14% 18.6% experienced any heart isins theue bindings to site da of thete M3. receptor Dry mouth 14-16% 4% once daily, and for it not to have a bad taste. Figure 2 (above): All four subunits of the M3 receptor with tiotropium bromide (red) bound URI 41-43% 0% MOLECULAROptimal STORY Mus 1,c 5arinic Competitive Antagonists sDuetru toc thetu rsafetyal fe andatu efficacyres: of tiotropium bromide, there is no need to modify the molecular structure. Both forms of the drug are 1, 4-5, 7 Optimal Muscarinic Competitive Antagonists Structural Features administered once daily and only available as name brand, but THE MOLECULE are relatively affordable for patients. R1" Future studies should focus on a greater understanding of the Use & Dosing R1 and R2: Two large carbocyclic or heterocyclic metabolism of tiotropium bromide and any long-term side effects. - Long-term treatment of bronchospasms and exacerbation rings prevent a conformational change required to R2" X" (CH2)n"·N" reduction associated with COPD signal the G-coupled protein. The rings bind outside 2-3, 6, 9 SUMMARY - Tiotropium bromide is available as a once-daily regimen in the active site, allowing the drug molecule to act as R3" two an antagonist. The antagonist action of tiotropium bromide on the M1, M2, and different dosage forms: R3: Increased binding strength due to a hydroxyl X: Esters are rapidly hydrolyzed in the acidic M3 receptors creates an anti-cholinergic effect in the body. The R1 and R2: 2 different large carbocyclic or heterocyclic rings - 18 mcg inhalation powder administered via the group forming an extra hydrogen bond with M3. environment of our gastrointestinal tract (GIT). This M3 receptor drug target of COPD is located in the lungs, making HandiHaler®; and · limitsRi systemicng struc bioavailability,ture enha whilence increasings bindi ngpotency of the recinhaledeptor medicationoutside aof first the-line a therapygonis duet to quick and local - 5 mcg inhalation spray administered via via the of tiotropium bromide. Esterases in the plasma also delivery of the drug. Inhibition of the M1, M2, and M3 receptors Respimat® Inhaler prevent(Ac theet ylmoleculecholi nefrom) bibindingndi ngmuscarinic site, w receptorshich pre ventreducess the secretions conform anda tairwayiona lconstriction change inne theede lungs,d t ogiving Known ADRs and DDIs outsidesigna of thel t helungs. G protein the patient reduced COPD symptoms. - Tiotropium bromide is limited in systemic absorption (~14%) (CH2)n: Provides separation of the ester and the We clarified that tiotropium bromide has higher affinity to the M3 - Minimal crossing of the Brain Barrier (BBB) limits additional · quaternaryTwo diammoniumfferent andrings maximizes incre potency.ases potency receptor which promotes a longer duration of action and limits toxicities N: A quaternary ammonium with cationic action limits side effects. Our patient was given tiotropium bromide rather R3: Hydroxyl group - Any systemic absorption may increase risk of other off-target systemic bioavailability. It is not hydrophobic enough to than aclidinium bromide due to the highly specific inhibition of the effects such as · be absorbedHydroxyl from groupthe GIT andform will snot a npass ext thera BBB. H-bond wiM3th receptorthe re candept theor, once inc dailyrea regimen.sing the A Respimat strengt®h dosage - Dry mouth: 4% (spray); 14-16% (powder) Lack of hydrophobicity prevents tiotropium from binding form was chosen for the ease of use and reduced side effects. - Upper respiratory infection (URI): 41-43% (powder only) Figure 4 (above): Tiotropium bromide (red) sitting in the active site of otherof muscarinic binding receptors in the brain. an M3 subunit (green) · Hydroxymethyl group is the next best thing to a hydroxyl groupREFERENCES X: Ester 1. Barnes PJ. The Pharmacological Properties of Tiotropium. Chest. 2000. 2000; 117(2Suppl):63S- Important Structural Features of the Molecule and an Alternative Anticholinergic 6S. Accessed November 29, 2014. 2. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of Acute Exacerbations of COPD: · Esters increase potency and are rapidly hydrolAmericanyz Collegeed i ofn Chest the Physicians acidi andc Canadian envi Thoracicronm Societyent Guideline. of Chest. Tiotropium bromide Aclidinium bromide: 2015;147(4):894-942. - Two thiophene rings increase functional muscarinic our GI tract and by esterase in our plasma 3. Durham MC. Tiotropium (Spiriva): a once-daily inhaled anticholinergic medication for chronic - N-methyl scopolamine moiety replaced with N- obstructive pulmonary disease. Proc (Bayl Univ Med Cent). 2004:17(3):366-73. receptor selectivity N: Quaphenoxypropylternary am(-1m-azabicycloonium [2.2,2]group octane, is the resulting most potent4. Foye WO, Lemke TL, Williams DA. Foye’s Principles of Medicinal Chemistry. 7th Ed. Lippincott Williams & Wilkins, 2008. - Dithienyl derivative of N-methyl scopolamine in kinetic selectivity for M3 v M2 5. Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium
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