Medicatia metabolica

CuprinsMedicaia antidiabetic:Insulina Antidiabeticele oraleMedicaia hipolipemiantMedicaia n hiperuricemiiMedicaia n obezitate

Tratamentul farmacologic al DZantidiabetice orale: DZ tip 2insulin: DZ tip 1, DZ tip 2 insulinonecesitant

Tipuri de insulina dupa provenientaAnimal: porcin, bovinUman:prin semisintez din insuline animaleprin inginerie geneticAnalogii de insulin: prin inginerie genetic (E. coli, Sacharomyces cerevisiae)

Tipuri de insulina dupa durata de actiuneCu aciune foarte rapid: analogii rapizi de insulin: HUMALOG, NOVORAPIDCu aciune rapid: ACTRAPID, HUMULIN R, INSUMAN RAPIDCu aciune intermediar: INSULATARD, HUMULIN N, INSUMAN BASALCu aciune lent i ultralent: LENTE, MONOTARDAnalogii de insulin cu aciune prelungit: GLARGINE, DETEMIRInsuline premixate: MIXTARD 30, HUMULIN M3, INSUMAN COMB 25, HUMAMIXT 25, NOVOMIX 30

Farmacocinetica preparatelor de insulina Preparat Debut Peak DurataLispro/Aspart 5-15 minute 1-2 ore 3-4 oreRapida (AR, HR, IR) 30-60 minute 2-4 ore 6-8 oreNPH, Insulatard 1-2 ore 4-8 ore 16-24 oreMonotard 2-4 ore Dificil de precizat 22-28 oreGlargine 1-2 ore Plat ~24 oreDetemir 1-2 ore Plat ~12 ore

Analogii de insulina Prezint diferene structurale fa de insulin, ceea ce le modific farmacocinetica (absorbia de la locul de injecie), cu consecine asupra profilului de aciune

Se cunosc peste 300 de analogi de insulina

Primul analog cu aciune rapid:Asp B10- retras datorit aciunii sale mitogenice (induce tumori mamare la roztoare)

Analogii de insulina Cu actiune Ultrarapid:Lispro (HUMALOG)- Eli LillyAspart (NOVORAPID)- Novo NordiskCu actiune Lent:Glargine (LANTUS)- AventisDetemir- Novo Nordisk

Structura analogilor cu actiune rapida: Lispro si AspartLispro (HUMALOG- Eli Lilly)Prolina din poziia B28 schimb locul cu Lizina din poziia B29

Insulina Aspart (NOVORAPID, NOVOLOG- Novo Nordisk)Prolina din poziia B28 este nlocuit cu Acidul Aspartic

Efectele Lispro si Aspart- trasaturi cliniceDebut mai rapid al aciunii: Permite administrare imediat nainte de masCombate hiperglicemia postprandial precoce !!Durata mai scurt de aciune:Hipoglicemia postprandiala tardiv rarFrecvent hiperglicemie postprandial tardivNecesit administrare concomitent de insulin bazal

400350300250200150100MealSC injection50003060Time (min)90120180210150240LisproRegular Human500450400350300250150502001000050100Time (min)150200300250AspartRegular HumanPlasma Insulin (pmol/L)Plasma Insulin (pmol/L)MealSC injectionHeinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.Analogii cu actiune rapida vs insulina umana rapida

Analogii cu actiune lenta- Glargine (Lantus)Acidul aspartic (Asp) din pozitia A21 este nlocuit cu Glicina (Gli)La Treonina (Tre) B30 se adaug dou molecule de Arginin (Arg)

Glargine vs NPH InsulinLepore, et al. Diabetes. 1999;48(suppl 1):A97.6543210010Timp (h) dup injecia SC 2030GlargineNPH Rata de utilizare a glucozei(mg/kg/h)-Glargine se absoarbe mai lent i mai egal, datorit modificrii structurale ce duce la precipitarea n esuturi dup injectare

Insulina Detemir (Novo-Nordisk)Insulin acilat cu acizi grai => absorbie ntrziata i uniform de la locul de injecieEficacitate similar cu NPHEchivalen: 2,5 uniti Detemir/unitate de insulin uman

Strategii insulinice2 injecii 3 injeciiConventionale: 4 injecii cu:-insulina rapid: 60% din total, adm. naintea meselor (3 prize)-insulina bazal: 40% din total fracionat n 1-2-(3-4) prizeIntensive: Basal Bolus Therapy

Stilou de insulin5-21

Pomp de insulin

Efectele adverse ale insulinoterapieiHipoglicemieAlergie la insulina animalInsulinorezistenLipodistrofiiAbcese localeDurere la locul injectriiTulburri de vedere reversibileEdeme insulinice

Hipoglicemia-se definete prin scderea glicemiei sub 65 mg/dl-factori favorizani: -supradozaj de insulin -cantitate sczut de glucide -ntrzierea mesei -nealimentare -injectarea insulinei ntr-un vas de snge -efort fizic prea mare -vrsturi, diaree, ingestie de alcool-manifestri clinice polimorfe: transpiraii, tremurturi, dureriepigastrice, senzaie de foame imperioas, oboseal, agitaie-poate merge pn la pierderea cunotinei i deces

Cai noi de administrare a insulineiDirect n vena porta: pompe de insulin interneSubcutan, fara injectie: cu ajutorul unor jeturi de aer cu presiune mare (jet injectors)Inhalator: sub form de aerosol lichid sau pulbere Oral: spray oral (Oralin, Oralgen), capsuleTranscutan- patch-uri

Insulina inhalatorieAdministrarea insulinei sub form de aerosoli lichizi sau solizin teste clinice de faza a IV-a: Insulina EXUBERA050100150200250300Baseline20 min1 hr2 hr3 hrTimp dupa mancareAerosol InsulinPlacebo*P < 0.05 vs placebo****Glicemie postprandial(mg/dL)

Medicatia antidiabeticaSecretagoge: stimuleaz secreia de insulinderivaii de sulfoniluree metiglinideleInsulinosensibilizatoare: scad insulinorezistenabiguanideleglitazoneleInhib absorbia glucidelor n intestininhibitorii de alfa-glucozidaz intestinal

Principalele locuri de actiune a ADOSulfonilureeMetiglinideInsulina injectat ficatglicemiaGlitazonetractul GIInhibitorii de -glucozidaz +p a n c r e a sMetforminmuchi/esut adipos()(+)()(+)()(+)4-5Absorbia de carbohidrai

Produciade glucoz

Secreia de insulin Preluarea glucozei

Secreia de insulin

DERIVATII DE SULFONILUREE (SU)Mecanism de aciune:stimuleaz secreia de insulin din celulele beta pancreatice (faza I a secreiei insulinice) prin aciune asupra canalelor de K+alte aciuni: crete nr. receptori insulin, scade producia hepatic de glucozFarmacocinetic:legare de proteinele plasmatice 75-95%metabolizare hepatic eliminare renal: sub form de metabolii sau sub form activ

DERIVATII DE SULFONILUREE (SU)Generaia I: hipoglicemiante slabe -Tolbutamida, Clorpropamida, Tolazamida

Generaia a II-a: hipoglicemiante puternice-Glibenclamid (MANINIL): cp 5 mg, 1,75 mg, 3,5 mg-Gliclazid (DIAPREL): CP 80 mg, 30 mg (forma micronizat)-Glipizid (GLUCOTROL XL): cp 5 mg, 10 mg-Gliquidon (GLURENORM): cp 30 mg

Generaia a III-a: hipoglicemiant puternic-Glimepirid (AMARYL): cp 1, 2, 3 mg

Proprietatile SUTolbutamida (I)4-25 (7)6-10 1000-2000 100Clorpropamida (I) 25-60 (35) 24-72 100-500 90-95Glibenclamida (II) 5 16 2,5-15 50Glipizida XL (II) 6 24 5-10 70Gliclazida (II) 10 (5-6) 6-12 80-240 60-70Gliquidona (II)1,5-2 5-7 15-120 5 (95 % biliar)Glimepirida (III) 9 16-24 1-8 -Denumire T1/2 (h) DA (h) Doza/zi (mg) Excreie renal (%)

SU- reactii adverseHipoglicemie:favorizat de: alcool, nealimentaie, vrst peste 70 de ani, efort, afeciuni hepatice, insuficien renaldurat lung (cteva ore, chiar zile)- necesit supraveghereDigestive: greuri, vrsturi, anorexie, alterarea probelor hepaticeHematologice (rare dar foarte severe): pancitopenie, anemie hemolitic, trombocitopenieAntalcool i antidiuretic (clorpropamida)

MetiglinideleStimuleaz secreia de insulin a celulelor beta-pancreaticeDurat de aciune scurt: controleaz glicemia imediat dup masReprezentani:Repaglinida (Novonorm): cp 0,5, 1, 2 mgdoza: 1,5-16 mg/zio mas, o doz, nici o mas, nici o doz)Nateglinida (Starlix)Reacii adverse: hipoglicemia

BiguanideleMecanism de aciune:Cresc aciunea insulinei la nivel post-receptor => scad insulinorezistenaScad absorbia glucidelor n intestinInhib gluconeogeneza hepaticMetabolizate hepatic, eliminate renalReprezentani:Fenformin- scos din uzMetformin: MEGUAN, SIOFOR, METFOGAMMA - cp 500 mg, 850 mg- doza zilnic: 1000-2500 mgBuformin: SILUBIN, DIABITEN

Biguanidele- reactii adverseDigestive: greuri, vrsturi, epigastralgii, diaree, gust metalicMetabolice: acidoza lactic, n prezena factorilor favorizani (insuficien cardiac, insuficien renal, insuficien hepatic)

Glitazonele (Thiazolidindionele)Mecanism de aciune: activeaz un receptor nuclear ce crete transcripia unor gene ce mediaz efectul insulinei (PPAR = peroxisome-proliferator-activated receptor)

Efect: crete aciunea periferic a insulinei (scade insulinorezistena) ! nu influeneaz insulinosecreia

Necesit prezena insulinei pentru a fi eficiente

Glitazonele (Thiazolidindionele)Reprezentani:Troglitazona- scoas din uzRosiglitazona (AVANDIA): cp 4 mg doz zilnic: 4-8 mgPiogliazona (ACTOS): cp 15 mgdoz zilnic: 15-30 mgReacii adverse:Insuficien hepaticRetenie hidrosalin: edeme, agravarea insuficienei cardiaceAnemie diluionalCrete LDLc

Inhibitorii de alfa-glucozidazaMecanism de aciune: inhib alfa-glucozidaza intestinal=> scade digestia glucidelor care vor fi eliminate n scaunReprezentani:Acarboza (GLUCOBAY)MiglitolReacii adverse:meteorism, flatulendiaree

Treptele combaterii hiperglicemieiPacieni cu diabet zaharat tip 2Optimizarea stilului de viaTerapie oralInsulinoterapie (monoterapie sau n combinaie cu agei orali)

Tratamentul dislipidemiilorHiperlipidemie = creterea nivelului plasmatic al:colesterolului (C)si/sautrigliceridelor (TG)

Dislipidemie= totalitatea tulburrilor cantitative i calitative ale lipidelor serice

Castelli WP. Am J Med. 1984;76:4-12, Gotto AM Jr, et al. Circulation. 1990;81:1721-173310-year CHD death rate (Deaths/1000)Serum cholesterol (mg/dL)Scderea cu 1% a CT duce la scderea cu 2% a riscului de boal coronarian(MRFIT) (n=361,662)15020025030005040302010CHD indications per 1000Fiecare cretere cu 1% a CT se asociaz cu creterea cu 2% a riscului de boal coronarianSerum cholesterol (mg/100 mL)Framingham Study (n=5209)204205-234235-264265-294295Relaia dintre creterea colesterolului i riscul de boal coronarian (studii epidemiologice)

Indicatiile dietei vs terapie medicamentoasaTb 3 on jones notes bout whether diet or drug

Dieta

Medic

Obiectiv

Fara CPI, < 2 FR

LDL > 160 mg/dL

LDL > 190 mg/dL

LDL < 160 mg/dL

Fara CPI, > 2 FR

LDL > 130 mg/dL

LDL > 160 mg/dL

LDL < 130 mg/dL

Cu CPI sau alte manifestari de ats

LDL > 100 mg/dL

LDL > 130 mg/dL

LDL < 100 mg/dL

Management1) Ne-farmacologic Diet hipolipidic, cu colesterol < 300 mg Efort fizic regulat

2) Farmacologicinhibitori de HMG-CoA reductazAcid nicotinic Rini biliareFibrai

In trepte

Mecanism de actiune:Inhib 3-hidroxi-3-metilglutaril-coenzima A (HMG-CoA) reductaza, enzima ce catalizeaz etapa limitant de vitez a biosintezei colesterolului- catabolism LDL, inhib sinteza LDL , i nr receptorilor pt. LDL .Eficien:TC 15-45%LDL 20-60%HDL 5-12%TG 10-37%Indicaii: CT, LDL or dislipidemie mixt ( LDL & moderat a TG)Inhibitorii de HMG-CoA Reductaz (Statinele)

Majore hepatotoxicitate mialgii teratogenic (probabil)Minoredispepsierash

Inhibitorii de HMG-CoA Reductaz (Statinele)- Efecte adverse

Doza (mg/zi)atorvastatin (Sortis, cp 10mg, 20mg)10-80simvastatin (Zocor, cp 10mg, 20mg)10-40pravastatin (Elisor, cp 10mg, 20mg)10-40lovastatin (Mevacor, cp 20mg)20-80fluvastatin (Lescol, caps 20mg, 40mg)20-80Inhibitorii de HMG-CoA Reductaz (Statinele)- Reprezentanti

Efectul statinelor asupra LDL-C scderea medie a LDLc in % -50-40-30-20-10Doza (mg)-6020408010FluvastatinPravastatinSimvastatin*******Lovastatin

(40 mg bid)Atorvastatin

(80 mg qd)

Mecanism de aciuneIncomplet precizat: clearance-ul VLDL prin aciunii lipoproteinlipazei producia VLDL Eficacitate:LDL + 10%HDL 10-25%TG 40-55%Indicaii: TGDislipidemii mixte (TG & HDL)Fibratii

Uzuale:litiaz biliardispepsie si dureri abdominaleRare:miozitaritmii ventriculare

Atentie la asocierea cu statineleFibratii- reactii adverse

Doza (mg/zi)bezafibrat (Regadrin 200 mg/cp) 600-1200 mg

ciprofibrat (Lipanor 100 mg/cps)100 mg

fenofibrat (Lipanthyl M 100 mg/cp)300 mg

gemfibrozil (Gevilon 600 mg/cp)600-1200 mgFibratii- reprezentanti

Locul de actiune al medicatie hipolipemiante

Medicatia in hiperuricemiiIn criza de gut (artrita acut gutoas):ColchicinaAINSIn afara crizei de gut:uricofrenatoarele: inhib sinteza acidului uricindicate n litiaz renal, colici nefretice, uricurie > 700 mg/24 huricoeliminatoarele: cresc eliminarea urinar de acid uricindicate n uricurie < 700 mg/zi i n absena litiazei renale sau a colicilor nefretice

Colchicina- cp 1 mgMecanism de aciune: inhiba degranularea leucocitar i are efect antiinflamator =>reduce inflamaia i durerea n atacul acut de gut i previne apariia unor noi atacuri

Reacii adverse:diaree, dureri abdminale, hepatitdepresie medularmoarte subit

Colchicina- cp 1 mgAdministrare:-artrita acut gutoas0,5-1 mg iniial, apoi 0,5-1 mg la 2 h (doza max. n prima zi 4-8 mg)3 mg/zi in ziua a II-a, 2 mg/zi n ziua a III-a i a IV-a1 mg/zi- 2 sptmni-tratament de fond: 1-2 spt. nainte de i 1-3 luni dup nceperea trat. hipouricemiantdoz: 0,5-1 mg/ziscop: prevenirea unor noi atacuri

Uricofrenatoarele Allopurinol (Mylurit, Zylurit) cp 100 mg, 400 mgMecanism de aciune: inhib sinteza de acid uricDoza: 200-400 mg/zi Indicaii: tratament cronic, cnd sunt contraindicate uricoeliminatoareleNu se administreaz n puseu dar, dac pacientul era tratat anterior cu Allopurinol, nu se ntrerupe

UricoeliminatoareleProbenecid (Benemid) cp 500 mgdoza:1-2 g/zi (2 prize)RA: digestiveSulfinpirazona (Anturan) cp 100 mgdoza: 200-600 mg/zi (3 prize)are i efect antiagregant plachetarBenziodaron (Amplivix)

Tratamentul farmacologic al obezitatiiAnorexigene centrale: amfetamine i derivai

Medicamente cu aciune periferic

Anorexigene centraleMecanism de aciune: inhib centrul foamei prin blocarea recaptrii neurotransmitorilor (serotonin, adrenalin)Reprezentani:Fentermina, Fenfluramina, DexfenfluraminaAmfepramona Sibutramin (REDUCTIL cp 10 mg, 15 mg)Reacii adverse:gur uscat, depresie/anxietatepe termen lung: fibroza valvular i pulmonarScoase din uz

Medicamente cu actiune periferica- Xenical (ORLISTAT)Mecanism de aciune: inhib lipaza pancreatic determin scderea absorbiei grsimilor n intestin (aprox. 30% din grsimile ingerate)Beneficii:n asociere cu dieta: scdere ponderalamelioreaz tolerana la glucozamelioreaz profilul lipidicReacii adverse: steatoree

The End

Slide 6-22INSULIN TACTICSComparison of Human Insulins and AnaloguesInsulin has been used therapeutically for more than 70 years. In general, human insulin, synthesized by genetically altered microorganisms, has a more rapid onset of action and a shorter duration of action than previous preparations derived from animal pancreas. Regular human insulin has an onset of action ranging from about 30 to 60 minutes with peak concentrations achieved at between 2 and 4 hours. The intermediate-acting insulins, NPH and lente, have gradual onset and peak effects usually between 4 and 8 hours, and a total duration of 10 to 20 hours. Human ultralente insulin is somewhat longer-acting, but still usually falls short of a 24-hour effect. Short-acting insulin analogues (lispro and aspart) have very desirable action profiles at mealtimes because they have an onset of action ranging from 5 to 15 minutes; the peak of action occurs 1 hour after injection, and the insulin effect practically vanishes 4 hours after administration. Insulin glargine is a long-acting analogue insulin that has essentially no peak. Glargine is absorbed within 1 to 2 hours and has a plasma concentration about 50% lower than that observed with NPH, but twice the duration of action.Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151-1167; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3:308-334; Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus. St Louis, Mo: Mosby-Year Book Inc; 1998:108-116; Riddle MC. Evening insulin strategy. Diabetes Care. 1990;13:676-685.Slide 6-27INSULIN TACTICSShort-acting Analogues: Lispro and AspartClinical FeaturesTwo quick-acting insulin analogues, insulin lispro and insulin aspart, have absorption profiles that more closely match normal mealtime patterns. Small alterations in their molecular structure relative to human insulin reduce their tendency to aggregate into pairs (dimers) or groups of six (hexamers) molecules, thus speeding their absorption after subcutaneous injection. Because of this property, they can be given immediately before meals. This timing is much more convenient for patients than waiting 20 to 40 minutes after the injections to begin eating. Their quick onset of action matches normal mealtime peaks of plasma insulin better than does human regular insulin. Clinical studies have shown that these properties lead to less prominent peaks of glucose after meals and less late postprandial hypoglycemia. However, rapid waning of the effects of mealtime lispro and aspart leads to greater dependency on adequate basal insulin levels between meals and overnight.Slide 6-28INSULIN TACTICSShort-acting Insulin Analogues: Lispro and Aspart Plasma Insulin ProfilesThis figure shows two separate experiments displaying the plasma insulin profiles after injection of insulin lispro and insulin aspart in comparison to that of human regular insulin. The experiment with lispro, shown on the left, included 10 patients with type 1 diabetes, and the experiment with aspart shows findings from 18 healthy subjects. Both of these analogues have very rapid onset of action, which allows them to be taken immediately before meals. Both reach a peak about 1 hour after injection, with a decline in baseline levels in 4 hours, closely matching normal insulin patterns. The delayed and extended profile of human regular insulin is seen in both studies, with significant elevations above baseline persisting well beyond 4 hours after injection.Heinemann L, Heise T, Wahl LC, et al. Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro (B29)] human insulin. Diabet Med. 1996;13:625-629; Mudaliar SR, Strange P, Lindberg FA, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin. Diabetes Care. 1999;22:1501-1506.Slide 6-34INSULIN TACTICSGlargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose ClampLepore et al conducted pharmacokinetic studies of insulin glargine in 20 type 1 diabetes patients. Patients were studied in a two-way crossover clamp design after subcutaneous injection. Onset of action was more delayed with insulin glargine (median 1.1 vs 0.7 hours, respectively) and more prolonged (median 22.8 vs 13.8 hours, respectively) compared with NPH. Glucose utilization rates shown on this slide indicate that insulin glargine has a peakless, long-acting profile that closely mimics that of nondiabetic subjects. Lepore M, Kurzhals R, Pampanelli S, Fanelli CG, Bolli GB. Pharmacokinetics and dynamics of s.c. injection of the long-acting insulin glargine (HOE1) in T1DM. Diabetes. 1999;48 (suppl 1):A97.Slide 6-35INSULIN TACTICSInsulin Glargine Summary of Completed TrialsGlucose-insulin clamp studies have compared the actions of insulin glargine with those of NPH. In general, these trials have found that insulin glargine provides a smooth, continuous release of insulin from the injection site. With an essentially flat profile, compared with other insulins, insulin glargine has a longer duration of action, providing constant levels for about 24 hours. Studies have demonstrated no variation in absorption rates at various injection sites (arm, leg, abdomen). Finally, the duration of action of insulin glargine allows for once-daily dosing. Improvements in glycemic control indicate that insulin glargine is clinically equivalent to NPH, with significantly fewer incidents of nocturnal hypoglycemia.