Curs ADO
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Transcript of Curs ADO
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ANTIDIABETICELE ORALE
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ADO disponibile
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Clase de ADO - Sediul de aciune
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Biguanidele Substane hipoglicemiante cu structur biguanidic n extractele de plante cu aciune hipoglicemiant (Galega officinalis)
Efectul hipoglicemiant al nucleului guanidinic era cunoscut nc din 1918
Biguanidele au fost introduse n practica medical n 1957
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Datorit acidozei lactice frecvente la pacienii tratai cu fenformin, biguanidele au fost interzise n SUA, Canada, Scandinavia i Germania
Metforminul i buforminul au fost utilizate n continuare n unele ri Europene (inclusiv n Romnia)
Metforminul reintrodus n SUA din 1995 (stimulat i de rezultatele extrem de favorabile n UKPDS)Biguanidele
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Metformin / Mecanism de aciune Scderea rezistentei la insulina la nivel hepatic (aciune puternic asupra hiperglicemiei bazale): Creterea sintezei de glicogen/ inhibitia glicocogenolizei Reducerea gluconeogenezei
Scaderea rezistentei la insulina la nivelul muchilor scheletici cu creterea captrii glucozei
Scaderea HbA1c cu 1-2%
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Tratamentul cu metformin / Avantaje
Evitarea creterii ponderale
Nu determin hipoglicemii
Efect favorabil asupra riscului cardiovascular (tratamentul pe termen lung scade riscul de IM)
Efect favorabil asupra profilului lipidic
Asociat insulinoterapiei duce la reducerea dozelor cu 20-30%
Evitarea suprasolicitrii excesive a celulelor beta-pancreatice
Ar putea oferi protecie mpotriva unor forme de cancer
A fost aprobat recent n tratamentul DZ tip 2 la copii i adolesceni
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Metformin / Mod de administrareIniierea: 500 mg de 1-2 ori/ziTitrare: cu 500 mg la 3-7 zileDoza optim: 2000-2500 mg/ziDoza maxim: 3000 mg/ziAdministrare dup mas (evitarea reaciilor adverse digestive)
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Metformin / Efecte secundare Tulburri digestive (dependente de doz, tranzitorii la initierea tratamentului) Anorexie Grea Balonare Diaree
Risc crescut de acidoz lactic (prin inhibitia gluconeogenezei din lactat)
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Salpeter et al. Cochrane Database Syst Rev 2010 limita superioar a incidenei reale a acidozei lactice pentru 100,000 pacieni-ani a fost de 4.3 cazuri pentru metformin i 5.4 cazuri pentru grupul cu alte ADO.
Nu exist nici o dovad din studiile prospective comparative sau din studiile observaionale de cohort c metformin ar fi asociat cu risc crescut de acidoz lactic, sau cu niveluri crescute de lactat comparativ cu alte tratamente anti-hiperglicemice.Acidoza lactica (?)
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Metformin / Contraindicatii clasice Intolerana digestiv la biguanide
Insuficiena renal moderata/severa
Afectarea hepatic sever
Toate situaiile susceptibile s asocieze creterea acidului lactic Insuficien cardiac decompensata Insuficien respiratorie Anemie severa Ischemie periferica acuta majora Pacienti critici (sepsis, colaps, oc hemoragic)
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metformin, previously contraindicated in heart failure, can now be used if the ventricular dysfunction is not severe, if patients cardiovascular status is stable ....
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Sulfoniluree / Mecanism de aciune Stimularea exocitozei granulelor secretorii insulinice prin legare de canalul KATP cu nchiderea acestuia
Stimularea insulinosecretiei independent de nivelul glicemiei
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Insulinosecreia fiziologic
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Structura diferitelor sulfoniluree
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Sulfonilureice
SULFONILUREE SCDERE MEDIE HbA1c 1-2%Produs originalcp (mg)AdmDoza maxima (mg)Clorpropamid1001/zi100Tolbutamid5003/zi1500GlibenclamidManinil, Manirom, Gliburide, Euglucon1.75, 3.5, 55551-3/zi20GliclazidDiaprel, EsquelDiaprel MR80602/zi1/zi240120GlipizidMinidiabGlucotrol XL55, 103/zi1/zi20GliquidonaGlurenorm303/zi120GlimepiridAmaryl1, 2, 3, 4, 61/zi6
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Sulfoniluree / Efecte secundare Hipoglicemii Pruden la vrstnici si alte categorii de pacienti la risc
Creterea ponderal
Suprasolicitarea cronic a celulelor beta poate duce la epuizarea mai rapid a rezervei lor funcionale
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Deficit absolut de insulin (DZ tip 1)
Insuficiena renal moderata/severa (admisa gliquidona pn n stadiul IV, glipizid, gliclazid la doze mici)
Insuficiena hepatic (sever)
Hipersensibilitatea la sulfoniluree
Tranzitor n infecii severe, traumatisme, intervenii chirurgicale, intoleran digestiv, etc.Sulfoniluree / Contraindicatii
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Meglitinide / Mecanism aciune - Farmacodinamic SUR1 are dou situsuri de legare: unul pentru gruparea sulfonilureic (de care se leaga sulfonilureele) i altul pentru gruparea benzamido (de care se leag meglitinidele)
Cresc prima faz a insulinosecreiei
Absorbie rapid i complet din tractul digestiv, cu atingerea unui maxim plasmatic dup o or
Insulinemia ncepe s creasc dup 10-15 minute
Maxim dup 30-60 minute
Durata de aciune: 4-6 ore
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Meglitinide
GLINIDE Scdere HbA1c 0,8-2%cp (mg)AdmDoza maxim (mg)NateglinidaStarlix60, 1203/zi360RepaglinidaReneos, NovoNorm0.5, 1, 23/zi12
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Tiazolidindione / Mecanism de aciune Activarea receptorilor PPAR
Efect la nivelul tesutului adipos (diferentierea precursorilor adipocitari cu formarea de adipocite tinere)
Cresterea preluarii de AGL la nivelul tesutului adipos Scderea insulinorezistenei periferice, n special muscular i hepatic Scderea esutului adipos visceral Ameliorarea steatozei hepatice non-alcoolice
Ameliorarea profilului lipidic
Scderea produciei de citokine i adipokine
Efecte antiinflamatorii
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Structura TZD
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TZD folosite curent in clinica
TIAZOLIDINDIONE Scdere HbA1c 0,8-1%cp (mg)AdmDoza maxima (mg)TroglitazonaRetras datorit efectelor secundare hepatice
PioglitazonaActos15, 30, 451/zi45RosiglitazonaRetras datorit riscului crescut de evenimente CV
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Tiazolidindione / Efecte secundare Cretere ponderal (2-5 kg n primul an de tratament)
Retenie hidrosalin (edeme la 2-3% din pacieni)
Crete riscul insuficienei cardiace
Creterea riscului de osteoporoz/fracturi
Cresterea riscului de carcinom urotelial (?)
Cresterea riscului de IM (rosiglitazona) (?)
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Tiazolidindione / Contraindicaii Insuficiena cardiaca
Osteoporoz
Afectare hepatica severa, hepatita activa
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Inhibitori de alfa-glicozidaz / Mecanism de aciune -glucozidaza este o enzim care particip la procesul de digestie a glucidelor
Mediaz scindarea polizaharidelor i a dizaharidelor pn la glucoz
Inhibarea -glucozidazei ntrzie digestia i absorbia glucidelor
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Inhibitori de alfa-glicozidaz folosii curent n clinic
Inhibitori Glucozidaz Scdere HbA1c 0.5% cp (mg)AdmDoza maxim (mg)AcarbozaGlucobay50, 1003/zi600
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Inhibitori de alfa-glicozidaz / Efecte secundare Distensie abdominal
Flatulen
Diaree
Sindrom de malabsorbie n cazul dozelor foarte mari
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Inhibitori de alfa-glicozidaz / Contraindicaii Intoleran
Boli gastrointestinale severe asociate (enterite, enterocolite, rectocolite, etc.)
Ciroza hepatica
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Efectul incretinic
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Adaptat dup Flint A, et al. J Clin Invest. 1998;101:515-520.; Adaptat dup Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adaptat dup Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adaptat dup Drucker DJ. Diabetes. 1998;47:159-169.Efectele GLP-1 la om
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Administrarea GLP-1 la om Administrarea GLP-1 la pacienii cu DZ tip 2 a dus la: Reducerea glicemiei a jeun Scderea excursiilor glicemice postprandiale Supresia eliberrii exagerate de glucagon postprandial Ameliorarea rspunsului celulelor beta la glucoz i creterea capacitii maximale de insulinosecreieAciunea dispare rapid dup ncetarea infuziei cu GLP-1, timpul de fiind de ~ 5 minuteGLP-1 nu poate fi administrat dect parenteral
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Inhibitori de Dipeptidil Peptidaza 4 Dipeptidil Peptidaza 4 (DPP4) degradeaz hormonul incretinic GLP-1
A fost dezvoltat o clasa de inhibitori specifici ai aciunii DPP4 cu scopul de a crete nivelul plasmatic de GLP-1
Inhibitorii DPP4 pot fi administrai oral
Efectul hipoglicemiant este moderat (scaderea HbA1c cu 0,6-0,8%)
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Inhibitori DPP4 - Structur chimic
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Inhibitori DPP4 pe pia
Inhibitori DPP4 Scdere HbA1c 0.6%-0.8%cp (mg)AdmDoza maxima (mg)SitagliptinJanuvia1001/zi100VildagliptinGalvus501x2/zi100SaxagliptinOnglyza51/zi5AlogliptinNesina251/zi25LinagliptinTradjenta51/zi5
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Analogi GLP-1/ Mecanism de actiuneAgenti administrati injectabil ce realizeaza nivele farmacologice de agonist GLP-1
Determina efectele GLP-1 pe tesuturile tintaStimularea secretiei de insulina si inhibarea secretiei de glucagon mediate de glucozaIntarzierea evacuarii gastriceEfect central de satietate precoce
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Analogi GLP-1
Scdere HbA1c 1-1.5%(g)(mg)AdmInj s.c.Doza maximExenatideByetta5,10 g2/zi20 g/ziExenatide LARBydureon2 mg1/sapt2 mg/sptLiraglutideVictoza0.6 mg1/zi1.8 mg/ziLixisenatideLyxumia10, 20 g1/zi20 g/zi
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SGLT2 aciune fiziologic
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Inhibitori SGLT2 / Mecanism de aciune Blocarea transportorului de glucoz de la segmentului S1 al tubilor contori proximali
Scderea reabsorbiei tubulare a glucozei
Creterea eliminrii urinare de glucoz
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Structura SGLT2i
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Inhibitori SGLT2 pe pia
Inhibitori SGLT2 Scdere HbA1c 0.5%cp (mg)AdmDoza maxima (mg)DapagliflozinForxiga101/zi10CanagliflozinInvokana1001-3/zi300
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Inhibitori SGLT2 / Efecte secundare Polakiurie
Deshidratare, hipotensiune arterial
Creterea riscului de ITU si candidoze genitale
Lombalgii
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Ghidul ADA 2015
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Va multumesc!
Choice of agents in current use
Sulphonylureas, -glucosidase inhibitors, thiazolidinediones and meglitinides, and of course metformin, are all available for use in type 2 diabetes. Metformin is located in the pivotal position given its role in reducing hyperglycaemia and excess risk of morbidity from life-threatening complications. The choice of single-agent therapy has never been so broad with at least a dozen candidate agents to select from. As a result there are a large number of potential combinations of oral antidiabetic agents.
DISCUSSIONBy decreasing -cell workload and improving -cell response, the incretin glucagon-like peptide 1 (GLP-1) is an important regulator of glucose homeostasisA thorough understanding of the five GLP-1 glucoregulatory effects is important to assess the value of GLP-1 in controlling glucose levels, particularly during the postprandial period Upon ingestion of food, GLP-1 is secreted in into the bloodstream and enhances glucose dependent insulin secretion from -cells GLP-1 suppresses inappropriately elevated glucagon secretion from alpha cells Lower levels of glucagon lead to a reduction of glucose output from the liver and indirectly reduce the -cell workloadBy slowing the gastric emptying rate, GLP-1 slows the release of nutrients into the gut allowing more time to control the postprandial increase in glucose levelsGLP-1 promotes satiety, potentially through centrally mediated mechanisms
BACKGROUNDGLP-1 is secreted from L cells of the small intestineGLP-1 decreases -cell workload, hence the demand for insulin secretion, by:Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (-cell workload)Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on -cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose outputHaving effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:159-169.Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:1546-1553.Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:515-520.DISCUSSIONWhen given to patients with type 2 diabetes, glucagon-like peptide 1 (GLP-1) is associated with improved glycaemic control, suppression of inappropriately high glucagon secretion, improved beta-cell responsiveness, reduced food intake and weight loss