Adobe Systems Define footer – presentation title / Department of Pharmacology 1 ANTIDIABETICS Alena Máchalová [USEMAP] Diabetes Mellitus Chronic, metabolic, etiopathogenetically heterogeneous disease, the underlying feature is hyperglycemia: • ≤ 5.6 mmol/L • IFG 5.6 (6,1) -6.9 mmol/L • IGT 2hPG ≥7.8 <11.1 mmol/L after oGTT Due to the insufficient effect of insulin or its absolute or relative deficiency The genetic predisposition of both forms of DM [USEMAP] Statistics •In 20 years there is a 10% increase in number of patients with diabetes • •31.12.2006 there is about 750 000 of diabetics • •From this number 91,5 % is II. type, 6,7 % I.type, other forms are rare • •Absolute number of 2. type diabetics is constantly increasing • •Therapy of 2.type diabetes represents 5–10 % expenses in healthcare [USEMAP] lack of insulin Adipose tissue impaired utilisaton of Glc Muscles ¯glucose oxidation ¯ proteosyntheis proteins turnover.... AA HYPERGLYCEMIA OSMOTIC DIURESIS ¯ glucose uptake by insulin – senzitive cells lipolysis faty acids production ketogenesis acidosis ® CNS insult, coma, exitus - dehydration - hypovolemia - impaired renal functions protein catabolism AA in liver [USEMAP] •hyperglycemia • •glycosuria, osmotic dehydration • •intracelular lack of Glu ® catabolism, lipolysis • •metabolic acidosis • •deep breathing • •ketoacidotic coma Acute diabetic syndrome [USEMAP] •protein glycation, autooxidation, peroxidation of lipids, lipoproteins • •micro / macro - angiopaties • •late complications of DM •Nefropathy •Diabetic foot •Infections •Retinopathy • Chronic diabetic syndrome [USEMAP] •absolute lack of insulin peak between 13 and 15 years, high mortality if not treated A - autoimmune form with antibodies B - idiopatic form no antibodies DM I.type [USEMAP] •(cca 90 %) • •Relative lack of insulin due to •damaged production in beta cells •insulin resistance in peripheral tissues • • both conditions are mutually potentiating • • genetic and exogenous factors - obesity, stress, low physical activity • • peak between 45-65 years, 60-90 % with obesity DM II. type [USEMAP] •Insulin resistance • •Hypertension • •Hypertriglyceridaemia • •Disorders of glucose tolerance or diabetes • •Obesity type of apple (male type of obesity) Metabolic syndrome - - 1.type – more pronounced symptoms, fast onset (weeks) - polyuria, polydypsia, nycturia, loss of bodyweight when eating normally, tiredness, weakness, loss of consciousness or coma (in children) - - - 2.type – less apparent symptoms, slow onset (months, years) - - others – organ complications – itching, impairs in vision, pain or formication*, neuralgias, problems with healing wounds, skin affections, bad teeth, loss of teeth, loss of erection, low libido… Clinical symptoms * Formication is the sensation resembling that of small insects crawling on (or under) the skin when nothing is actually there [USEMAP] •(3-5 % pregnant women) → in 20 % non-obese and 60 % obese women develope DM type 2 in 15 - 20 years • •peak between 24.-28.week – anti-insulinary effects of placental hormones • •risks for foetus - diabetic foetopathy – large organs, high birth weight, hypoglycaemia after delivery, hyperbilirubinemia, hypocalcemia big ≠ developed! Gestational DM [USEMAP] OGTT 75 g of glucose in 200 ml of water 2 hours later sample collection and determination of glycemia in venous plasma Interpretation • ≤ 7.8 mmol /L DM excluded •7.8 - 11 mmol / L - Impaired glucose tolerance •˃ 11.1 mmol / L Diabetes mellitus In pregnancy is cut-off value more strict: 8,5 mmol/l after 2 hours [USEMAP] •DM accompanying •pancreatic diseases •tumors of adrenal gland •hyperthyreosis •chronic renal insuficience • •Drug induced DM - glucocorticoids, thiazide diuretics, MAb (Pd-L, PD-1L, CTLA4) • •Toxins (streptozotocin) Secondary DM [USEMAP] LADA - latent autoimunne diabetes of adults DM I. type manifesting in adults > 35 yrs, with normal weight and insulin sensitivity MODY - maturity onset diabetes of the young DM II. type, < 25 yrs, more than 5 yrs treated by OAD/non-insulin monogenous forms of diabetes (insulin transporter or insulin synthesis) Rare subtypes of diabetes [USEMAP] •Lifestyle and regimen, diet, exercise •Pharmacotherapy with insulin or GLDs •Concomitant metabolic and CV disorders HbA1c Treatment of diabetes Zobrazit zdrojový obrázek Zobrazit zdrojový obrázek Zobrazit zdrojový obrázek [USEMAP] Adobe Systems Define footer – presentation title / Department of Pharmacology 16 Insulin • History •1869 – medicine student Paul Langerhans (Berlin) discovered unknown inslets of tissue • •1889 – Minkowski – connection between panceras and diabetes in dog • Further work was interruped by the 1st world war (Paulescu – Budapest) • •1921 – Banting + Best + Marjorie, Toronto • • •Leonard Thompson – 14 ys, the 1st injection of insulin to a human patient 11.1.1922, died at 27 • •Elizabeth Hughes Gosset – the first US pacient, 14 ys, 23,5 kg; died in 1981 • •The first producer Eli Lilly and Company • • Although Paulescu discovered the principles of the treatment his saline extract could not be used on humans, and he was not mentioned in the 1923 Nobel Prize. Professor Ian Murray was particularly active in working to correct "the historical wrong" against Nicolae Paulescu. Murray was a professor of physiology at the Anderson College of Medicine in Glasgow, Scotland, the head of the department of Metabolic Diseases at a leading Glasgow hospital, vice-president of the British Association of Diabetes, and a founding member of the International Diabetes Federation. Murray wrote: Insufficient recognition has been given to Paulesco, the distinguished Roumanian scientist, who at the time when the Toronto team were commencing their research had already succeeded in extracting the antidiabetic hormone of the pancreas and proving its efficacy in reducing the hyperglycaemia in diabetic dogs. File:C. H. Best and F. G. Banting ca. 1924.png C. H. Best and F. G. Banting ca. 1924 1921 – Banting + Best + Marjorie, Toronto Best and Banting http://heritage.utoronto.ca/fedora/repository/default:11756/OBJ/FULL_SIZE.jpg Marjorie – pes, který přežil celé léto Adobe Systems Define footer – presentation title / Department of Pharmacology 20 Insulin - physiology • 1. hormonal - antagonism with glucagon in the liver, cortisol muscle tissue, aldosterone and growth hormone 2. autoregulation - glycaemia works back to secretion – Glc penetrates into B cells and opens Ca channel, signal for insulin release 3. nervous system - PS has a hypoglycemizing effect, S hyper. Insulin is produced at a dose of 20-40 IU / day - 1/2 continuous, 1/2 pulse N Insulin is rapidly metabolised by proteases and glutathione insulin transhydrogenases (plasma half-life of 3-5 min) Regulation of blood glucose [USEMAP] [USEMAP] Amplifiers of glucose-induced insulin secretion gastrin, secretin, cholecystokinin GLP1 beta-adrenergic stimulation (b2, b1) AA (Lys, Arg, Leu) Insulin secretagogues glucose glucagon fatty acids GLDs Factors decreasing insulin secretion somatostatin insulin (negative feedback) a-activation of sympathetic n. s. (adrenalin) galanin (neuropeptide) [USEMAP] Insulin receptor Lincová a kol. 2002 [USEMAP] Insulin receptor Lincová a kol. 2002 [USEMAP] lowmolecular protein, 2 chains (A 21 AA, B 30 AA), 2 S-S bonds, 5808 Da Synthesis - preproinsulin (107 AA) ® ® proinsulin (82 A + B + C-peptide)®insulin marker of endogenous secretion of insulin + signalling activity Bez názvu Insulin [USEMAP] A buňky produkují glukagon D buňky somatostatin PP buňky pankreatický polypeptid The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes. Apart from animals, insulin-like proteins are also known to exist in Fungi and Protista kingdoms. Struktura – 50tá léta, Sanger, první protein se ozřejmenou strukturou První syntetický humánní (E. coli) – 1978, na trhu 1982 – Humulin C-peptid např zde, proto že u rekombinantního inzulinu chybí, uvažuje se o různých problémech, není to uplně fyziologické Review Exp Diabesity Res . 2004 Jan-Mar;5(1):15-23. doi: 10.1080/15438600490424479. Molecular and cellular effects of C-peptide--new perspectives on an old peptide John Wahren^ ^1, Jawed Shafqat, Jan Johansson, Alexander Chibalin, Karin Ekberg, Hans Jörnvall Affiliations expand •PMID: 15198368 • PMCID: PMC2478619 • DOI: 10.1080/15438600490424479 Free PMC article Abstract New results present C-peptide as a biologically active peptide hormone in its own right. Although C-peptide is formed from proinsulin and cosecreted with insulin, it is a separate entity with biochemical and physiological characteristics that differ from those of insulin. There is direct evidence of stereospecific binding of C-peptide to a cell surface receptor, which is different from those for insulin and other related hormones. The C-peptide binding site is most likely a G-protein-coupled receptor. The association constant for C-peptide binding is approximately 3 x 10(9) M(-1). Saturation of the binding occurs already at a concentration of about 1 nM, which explains why C-peptide effects are not observed in healthy subjects. Binding of C-peptide results in activation of Ca2+ and MAPK-dependent pathways and stimulation of Na+,K(+)-ATPase and eNOS activities. The latter 2 enzymes are both deficient in several tissues in type 1 diabetes. There is some evidence that C-peptide, and insulin may interact synergistically on the insulin signaling pathway. Clinical evidence suggests that replacement of C-peptide, together with regular insulin therapy, may be beneficial in patients with type 1 diabetes and serve to retard or prevent the development of long-term complications. Pharmacokinetic parameters •A: inter- and intra-individual variability in absorption (25-50 % after s.c., i.m.) application site, vascularity, temperature, massage, sunbathing, vasodilatators •D: no binding to plasmatic proteins, Vd = EC water • •M: fast metabolisation by proteases and transhydrogenases, in diabetics also degradation in kidneys T 1/2 7-10 min. [USEMAP] Therapeutical use of insulin •must be administered in •IDDM (DM I. Type) •ketosis, ketonuria nebo ketoacidosis • •patients with serious infection/gangrene •patients younger than 30 years •DM II where blood Glc. not normalized with POAD, diet •DM II patients, corticosteroids use, liver or kidney impairment [USEMAP] a)animal insulins •from porcine or bovine pancreas •different primary structure •purified but immunogenic •monocomponent •used till the 1980s, today only AUV Insulins produced by recombinant techonology (since 1980s): b) human insulin •designation HM, identical structure c) insulin analogues •the primary structure of the protein is specifically altered to modify the pharmacokinetics Types and origin of insulin [USEMAP] Recombinant insulin is produced either in yeast (usually saccharomyces cerevisiae) or E. coli. In yeast, insulin may be engineered as a single-chain protein with a KexII endoprotease (a yeast homolog of PCI/PCII) site that separates the insulin A chain from a c-terminally truncated insulin B chain. A chemically synthesized c-terminal tail is then grafted onto insulin by reverse proteolysis using the inexpensive protease trypsin; typically the lysine on the c-terminal tail is protected with a chemical protecting group to prevent proteolysis. The ease of modular synthesis and the relative safety of modifications in that region accounts for common insulin analogs with c-terminal modifications (e.g. lispro, aspart, glulisine). The Genentech synthesis and completely chemical synthesis such as that by Bruce Merrifield are not preferred because the efficiency of recombining the two insulin chains is low, primarily due to competition with the precipitation of insulin B chain. Classification of insulins Short or rapid acting •clear solutions without adjuvants or modifications slowing absorption •possible i.v. application (the only type) Neutral aqueous solutions of HM insulins (crystalline insulin, soluble insulin) disadvantage – formation of hexameres in site of application onset 30 min. maximum 1 - 3 h lenght 4 – 6 h Insulin analogues: insuliny lispro, aspart, glulisin more rapid action disadvantage – in monotherapy is neccessary often administration onset 10 - 20 min. aspart, 15-30 lispro maximum 1 - 2 h lenght 2 – 5 hod. (according to the dose) Zobrazit zdrojový obrázek [USEMAP] Molekuly krátcepůsobícího HM inzulinu podaného v subkutánní injekci mají tendenci v místě depa tvořit hexaméry. Ty pak prodlužují nutnou disociací na diméry a monoméry možnost okamžitého vstřebávání inzulinu do krve. Doba nástupu hypoglykemizujícího účinku inzulinu se prodlužuje a glykemie po jídle příliš stoupá, aby naopak v pozdní fázi po jídle nebo před dalším jídlem kvůli přetrvávajícím hladinám inzulinu v krvi nevítaně klesala. Řada nemocných byla nucena aplikovat preprandiální dávky inzulinu i více než 45 minut před jídlem, což v běžném životě působí nemalé obtíže a nepříjemnosti. Nelze opomenout také některé nevýhody léčby krátcepůsobícími analogy inzulinu, kterými jsou: • častá nutnost podávat nejméně 2krát denně bazální inzulin (a to i u nemocných, kterým při léčbě krátcepůsobícími HM inzuliny stačila 1 dávka) • v některých případech nutnost podávat analoga i vícekrát než 3krát denně (to znamená i před přesnídávkou a odpolední svačinou). Classification of insulins Intermediate – acting insulins •modifications of physical and chemical characteristics of preparation decrease its solubility and slow absorption •only for s.c., i.m. admin onset 1 - 2,5 h maximum 4 - 8 h lenght 12 - 24 h Isophan (NPH*) – mixture insulin + protamin + zinc – cloudy solution due to crystals of protamin with insulin Semilente, Lente (mixture of semilente + ultralente** in 30:70 ratio) – cloudy zinc suspensions of insulin Disadvantages •when used on night, maximum of the effect is at 4-6 am, risk of hypoglycaemia •absorption may interindividually vary *Neutral Protamine Hagedorn **slow onset and prolonged duration, poorly soluble crystalised insulin Zobrazit zdrojový obrázek [USEMAP] Hans Christian Hagedorn (6 March 1888 – 6 October 1971) was the creator of NPH insulin and the founder of Nordisk Insulinlaboratorium, which is known today as Novo Nordisk. Biography[edit] Hagedorn and August Krogh (1874–1949) obtained the rights for insulin from Banting and Best in Toronto. In 1923 they formed Nordisk Insulinlaboratorium, and in 1926 with August Krogh he obtained a Danish Royal Charter as a non-profit foundation.^[1] In the 1930s he became interested in modifying the absorption rate of insulin. He was aware that contaminating proteins slowed the absorption of insulin into the bloodstream, but these caused irritation and side effects. Thus he searched for a protein that would not cause any irritation. He came upon protamine, a protein isolated from fish sperm. Hagedorn discovered that the addition of protamine to insulin caused the insulin to form microscopic clumps. These clumps took longer to dissolve into the bloodstream. This complex of protamine and insulin is known as NPH (neutral protamine Hagedorn) insulin. It is one of the earliest example of engineering drug delivery. Zinek upravuje pH Classification of insulins Long – acting insulins Cloudy suspensions of large zinc-insulin crystals with very slow absorption, s.c. administration ultralente - poorly soluble crystalline insulin with slow onset and prolonged duration of action onset 2 – 3 h maximum 10-18 h lenght 24 – 36 h Analogues – clear appearance, less AE, lower weight gain detemir (Levemir) = „predictable insulin“ – small interindividual variability glargin (Lantus, Abasaglar) = „peakless insulin“ - even longer effect, flat curve action/time degludec (Tresiba) = ultralong acting onset 1-2 h maximum 6 – 8 h detemir, no peak for glargin lenght up to 24 h, 42 h for degludec [USEMAP] Inzulinový analog glargin (21A-Gly-30Ba-L-Arg- 30Bb-Arg-human insulin) je prvním dlouzepůsobícím inzulinovým analogem používaným v klinické praxi. Vychází z molekuly HM inzulinu, kdy přidáním dvou pozitivně nabitých molekul argininu v B-řetězci a výměnou kyseliny aspartové na pozici 21 A-řetězce za neutrálně nabitý glycin je získán analog, který má prokazatelně bezvrcholový profil svého účinku, a je proto označován jako „peakless inzulin“ s nástupem účinku za 2–4 hodiny a trváním nejméně 24 hodin. Na rozdíl od všech HM dlouze a střednědlouze působících inzulinů, které jsou neprůhlednou suspenzí, je glargin průhledný roztok. Výsledky řady dosud publikovaných klinických studií přesvědčivě dokladují, že se u glarginu jedná o účinný a bezpečný preparát s vyrovnaným inzulinemickým profilem během 24 hodin při jeho jednorázovém podávání. Glargin lze podávat kdykoliv během dne a jeho hypoglykemizující profil je identický a potřebné dávky se nemění. Druhým (a na našem trhu již dostupným) dlouzepůsobícím inzulinovým analogem je detemir. Způsob změny jeho farmakokinetických vlastností je odlišný od krátcepůsobících inzulinových analog a analoga glargin. Nejde o záměny AK v B-řetězci inzulinu, ale prodloužení jeho účinku je dosaženo přidáním kyseliny myristové (14 uhlíkaté mastné kyseliny), která zajišťuje tvorbu hexamérů a dihexamérů s protrahovaným uvolňováním dimérů a monomérů v cirkulující krvi. Protrahovaný účinek detemiru je dále způsoben vazbou na albumin v krvi. Inzulin detemir je často označován jako střednědlouzepůsobící inzulin, protože doba trvání jeho účinku je kratší než inzulinu glargin – přibližně 20 hodin. Obdobně jako analog glargin, i detemir prokazuje v klinických studiích i ambulantních pozorováních významně nižší riziko hypoglykemických příhod s akcentací na noční hypoglykemie. Jeho podávání u diabetiků 2. typu není provázeno zvyšováním hmotnosti a jeho akční profil má výrazně nízkou intraindividuální variabilitu. Proto je detemiru přiřazován přívlastek „inzulin s předvídatelným účinkem“. A právě tato velmi malá variabilita je pozitivní vlastností detemiru, která má významný podíl na zlepšení kompenzace u nemocných diabetem léčených inzulinem NPH. Umožní nemocnému lépe odhadovat a upravovat svůj inzulinový režim i stravovací režim podle fyzické aktivity během dne. Zobrazit zdrojový obrázek [USEMAP] Insulin preparations Aqeous solutions – only short acting i.v. Suspensions of insulin, suspensions of „zinc-insulin“, suspensions „protamin-zinc-insulin“ – never i.v. Powder for inhalation stabilised mixtures of insulin in different ratios [USEMAP] Types of insulin analouges C:\vyuka\ilustrace\inzulinová analoga.jpg INZULÍN A NOVINKY V LÉČBĚ INZULÍNEM, MUDr. Pavlína Piťhová, 4 / 2006 INTERNI MEDICINA PRO PRAXI [USEMAP] Zobrazit zdrojový obrázek Zobrazit zdrojový obrázek Zobrazit zdrojový obrázek [USEMAP] NPH - neutral protamine Hagedorn (also known as Humulin N, Novolin N, Novolin NPH, NPH Iletin II, and isophane insulin) = komplex inzulin + zinek + protamin Insulin RMP labeling „PUR“ - chromatophically purified „monocomponent“ - highly purified without contaminating impurities (proinsulin, ins. fractions) - animal / human „HM“ - human Lenght of action: 1) short acting - „rapid“ 2) intermediate - acting - „Dep“ (D) - semilente 3) intermediate - acting with prolonged duration of action - „interdep“ (ID) - lente 4) long - acting - „superdep“ (SD) - ultralente [USEMAP] Delivery systems (self-administration) 1) Insulin injections - calibrated by IU 2) Insulin pens - pen-sized injectors, + blood glucose detectors 3) Insulin pumps - automated administration of insulin (s.c. / i.v.) according to glycemia 4) Nasal insulin delivery, insulin inhalations 040090 Zobrazit zdrojový obrázek Zobrazit zdrojový obrázek [USEMAP] Inhalace? Inhalační byl rok na trhu v USA ale neujal se Zobrazit zdrojový obrázek chlapik_s_dtron d-tronplus •the lowest total daily dose • •monitoring of glycaemia • •intensified regimens = more doses → lower total dose and tighter compensation • • •insulin pump Treatment strategies [USEMAP] 41 Zobrazit zdrojový obrázek Examples of physiologic insulin delivery. A) Once-daily glargine serves as a basal insulin that is typically given at bedtime. Rapidly acting insulin are used as prandial insulins. This allows patients to change meal times at will. B) Intermediate-acting NPH, given twice daily, can be used as a basal insulin, and can be combined with a rapid-acting “prandial” insulin. This regimen (shown as a 50:50 dosage ratio) is more difficult to adjust because NPH has a 2 hour delay, limited duration of action, and a time course that gives it “prandial-like” properties. Figure adapted from DeWitt & Hirsch (2003) https://tmedweb.tulane.edu/pharmwiki/doku.php/insulin_regimens [USEMAP] •hypoglycaemia •allergy •lipodystrophy •insulin resistance - spec. antibodies •weight gain Complications of insulin therapy [USEMAP] Plasma glucose under 2,8 mmol/l Causes •Insulin overdose •Vomiting, diarrhoea, delayed eating •Physical strain •Concomitant liver, heart or kidney insufficency - Symptoms – fast onset •Agitation •Tremor, sweating •Hunger •EEG changes, loss of conscousness, coma, death Therapy: •fast intake of sacharides/glucose i.v. (40% glukose 30-50 ml or more) •glucagon + following glucose Hypoglycaemia [USEMAP] Increases glycaemia, heart contractility and heart rate Decreases gastric and pancreatic secretion and smooth muscle tone Therapeutical use •Hypoglycaemia in DM (condition of glycogen reserves) – pen (s.c./i.m. or transanasal) •Diagnostics in endrocrinology AE – rare •Nausea, vomiting •Allergic reactions Glucagon Zobrazit zdrojový obrázek [USEMAP] When the glucose level comes down to the usual physiologic value, insulin release from the β-cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from islet of Langerhans alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia. Antidiabetics = GLD (glucose lowering drugs) Adobe Systems The effect of most GLDs is bound to preserved insulin secretion Most GLDs are contraindicated in pregnancy (metformin may be used) Indications: •T2DM - if not properly compensated with diet •T1DM with a high insulin resistance, when insulin does not lead to a sufficient decrease in blood glucose (Oral) antidiabetics (OAD, GLD) [USEMAP] Classical approach in type 2 DM 1.Regimen changes : diet + exercise 2. 2.GLD monotherapy 3. 3.Combined GLD or GLD + insulin 4. 4.Insulin Drugs do not replace changes in lifestyle!!! • age, weight, blood insulin level • glycemia (fasting and postprandial) • comorbidities, metabolic syndrome [USEMAP] GLDs 1.Biguanides (metformin) 2.Sulphonylurea derivatives 3.Thiazolidindiones 4.Inhibitors of intestinal glucosidases 5.Meglitinides 6.GLP1 (incretine) analoges 7.Inhibitors of DPP IV 8.SGLT2 (sodium-glucose cotransporter) inhibitors [USEMAP] metformin - buformin, fenformin MoA: • increase sensitivity of peripheral tissues to insulin • increase insulin binding to its receptor Do not affect insulin secretion, functions of B cells → no hypoglycemia They need preserved insulin secretion for their effect 1. Biguanides = metformin „euglycemic agents“ [USEMAP] Other effects: •reduce hepatic gluconeogenesis •decrease glucose absorption from GIT •decrease LDL, VLDL, FFA, TAG •increase fibrinolytic activity (inhibition PAI-1) AE lactic acidosis in renal insufficiency (excreted by the kidneys as the active compound) •nausea, GIT problems cca 20 % patients •anemia (absorption of B12) •reduction of bodyweight •disulfiram effect - [USEMAP] KI: •Kidney diseases (GF under 60 ml/min/1,73 m2) •alcoholism •liver diseases Therapeutic use •DM type 2 - 1st choice drug in obese patients •In all combinations (+ insulin, glitazones, SU, incretines…) • •Off-label – PCOS, anticancer effect (AMPK / mTOR) • [USEMAP] Type 2 DM, drug of choice (especially in obese patients) Non-obese in combinations (with insulin, glitazones, analogues, SU, incretins, gliflozines) OFF label indication: PCOS (polycystic ovary syndrome) KI: •Kidney diseases (GF under 60 ml/min/1,73 m2) •alcoholism •liver diseases Therapeutic use •DM type 2 - 1st choice drug in obese patients •In all combinations (+ insulin, glitazones, SU, incretines…) • •Off-label – PCOS, anticancer effect (AMPK / mTOR) • Type 2 DM, drug of choice (especially in obese patients) Non-obese in combinations (with insulin, glitazones, analogues, SU, incretins, gliflozines) OFF label indication: PCOS (polycystic ovary syndrome) Zápatí prezentace 53 MoA: 1) pancreatic – increase insulin release, but NOT synthesis 2) extrapancreatic •potentiation of endogenous insulin effect on the target tissue •reduction of hepatal glucose production •reduction of hepatal insulin degradation •reduction of serum glucagon levels •increase the number of insulin receptor on ERYS, adipocytes, monocytes 2. Sulfonylurea derivatives (SU) [USEMAP] Struktura tolbutamidu extrapancreatic effects on potassium channel is insignificant 220px-Sulfonamide 220px-Hydrochlorothiazide-2D-skeletal 220px-Furosemide Sulfonamide functional group Hydrochlorthiazide Furosemid 240px-Sulfonylurea_group_and_radicals Sulfonylurea [USEMAP] Adobe Systems [USEMAP] I. generation - chlorpropamid tolbutamid II. generation - glibenklamid glipizid gliklazid glikvidon III. generation - glimepirid 2nd line of treatment, only exceptionally 1st choice in thin patients 2. Sulfonylurea derivatives (SU) [USEMAP] Adverse effects •hypoglycemia •increased appetite •metal taste in mouth •headaches •nausea (5 %) •fluids retention •allergy, fotosensitivity 2. Sulfonylurea derivatives (SU) Contraindications •hypoglycemia •ketoacidosis •renal/hepatal impairment •pregnancy •age •hypersensitivity [USEMAP] 3. Thiazolidindiones (glitazones) Drugs: rosiglitazon troglitazon pioglitazon MoA •ligands of PPARg (part of the steroid and thyroid superfamily of nuclear receptors) modulate the expression of the genes involved in the metabolism of lipids and glucose increase the sensitivity of periphery to insulin [USEMAP] Struktura rosiglitazonu 3. Thiazolidindiones (glitazones) [USEMAP] Struktura rosiglitazonu •decrease glycemia by positive effect on insulin resistance, important in pre-diabetic state •better glucose utilisation in the muscle (↑ glycogen synthesis and glycolysis) •some positive metabolic effects •¯ production of FFA, TAG, peroxidation of LDL, ↑ HDL •¯ TNFa, resistin (causes IR in peripheral tissues) •¯ gluconeogenesis in liver •↑ glucose oxidation and lipogenesis in adipose tissue • • CVS AE (rosiglitazone, 2010) !!! • 3. Thiazolidindiones (glitazones) Therapeutic use •sensitizers of insulin receptors •the onset of effect in 4 weeks •not 1st line, used in combinations (metformin, SU) • Side effects •Rosiglitazone increased risk of heart attack and stroke •Troglitazone was withdrawn for hepatotoxicity •Fluid retention •Osteoporosis •Weight gain Contraindications •Hypersensitivity • •Predisposition to heart failure • •Liver damage • •Pregnancy, lactation • • 3. Thiazolidindiones (glitazones) „euglycemic drugs“ – do not act hypoglycemic on euglycemic individuals [USEMAP] 4. Inhibitors of intestinal glucosidases acarbose MoA • reduce sacharides absorption from GIT • competitive inhibition of the gut α – glucosidases (inhibits the cleavage of the polysacharides from the meal) •Suitable for monotherapy and combinations Drugs acarbose miglitol voglibose [USEMAP] •decrease postprandial glycemia •do not affect monosacharides absorption •acarbosis does not reach the systemic blood, miglitol does •„educative drugs“- consequences in bad compliance In case of hypoglycemia sucrose can not be administered orally (necessary are monosacharides - Glu, Fru) / or Glucagon 4. Inhibitors of intestinal glucosidases [USEMAP] Drugs: repaglinid nateglinid (STARLIX, TRAZEC) meglitinid MoA similar to SU-derivatives (bind to SUR, but different receptor site), fast onset •through different receptor at K+ channel •block ATP- sensitive K+ channel in membrane of beta-cells → depolarisation of membrane → activation of voltage-gated Ca2+ channel → influx Ca2+ → insulin release 5. Meglitinides [USEMAP] Pharmacokinetics: • good bioavailibility, fast effect!! – no meal, no tablet • extensive protein binding (up to 98 %) • metabolized - inactive compounds • excreted mainly in faeces 5. Meglitinides [USEMAP] Clinical use: •2nd line, often combined with metformin - esp. if patient not sufficiently compensed •alternative of the SU medication in patients with renal impairment (excreted into bile) •administration before meals - rapid onset and fading effect for 4 hours •skipping a meal = skipping a dose (risk of hypoglycaemia if taken) 5. Meglitinides [USEMAP] Contraindications: • hypersensitivity • • DM I. type • • diabetic ketoacidosis • • pregnancy, lactation AE: •hypoglycemia • •nausea • •diarrhea • •joint pain 5. Meglitinides [USEMAP] File:Incretins and DPP 4 inhibitors.svg [USEMAP] 6. GLP1 – Glucagon-like peptide 1 analogues MoA: •↑ insulin secretion (dependent on glycemia) •↓ glucagon secretion, •prolong stomach content evacuation gila_monster Heloderma suspectum, Gila Monster exenatide, liraglutide lixisenatid, semaglutide, albiglutide s.c. administration !!! GLP1 is physiologically secreted postprandially, in DM2 not sufficient levels Registered also as antiobesitics (liraglutide, semaglutide) [USEMAP] Liraglutide: used in obesity (BMI above 27) The GLP-1R is widely distributed throughout the brain [Merchenthaler et al. 1999] and densely expressed in hypothalamic nuclei involved in the regulation of appetite such as the paraventricular and arcuate nuclei [Shughrue et al. 1996]. GLP-1 has an appetite suppressant effect and the GLP-1 response to oral glucose is obtunded in obese patients [Færch et al. 2015]. The mechanism through which GLP-1 regulates appetite appears to be mediated through both peripheral and central nervous system (CNS) pathways. The action of GLP-1 on gut motility has been reviewed elsewhere [Marathe et al. 2011. An important effect is the slowing of gastric emptying which occurs as a result of GLP-1 activity [Delgado-Aros et al. 2002]. The resultant gastric stretch stimulates vagal afferent signals to the solitary nucleus of the medulla and onto the appetite centres of the hypothalamus to induce satiety or the area postrema to induce nausea. Early satiety and nausea are common side-effects of GLP-1 agonist drugs but are generally transient. Indeed, the retardation of gastric emptying by GLP-1 is subject to a rapid tachyphylaxis in experimental studies [Nauck et al. 2011]. Despite this, weight loss with GLP-1 agonists has been maintained in the absence of upper gastrointestinal side effects in clinical trials [Shyangdan et al. 2011], suggesting an alternative appetite suppressant pathway. The CNS effects of GLP-1 have also been recently reviewed [van Bloemendaal et al. 2014]. It is estimated that 10–15% of endogenous GLP-1 secreted by intestinal L cells may reach the systemic circulation [Holst et al. 2005] where it is found in concentrations of approximately 10–40 pmol/l [Orskov et al. 1996]. From there, endogenous GLP-1 may be able to cross the blood–brain barrier and directly activate GLP-1R in the CNS [Kastin et al. 2002], while more substantial evidence attests to the ability of liraglutide and other GLP-1 analogues to do so [Secher et al. 2014; Hunter and Holscher, 2012]. Liraglutide has been shown to directly stimulate POMC neurons and inhibit neuropeptide-Y and Agouti-related peptide neurons of the arcuate nucleus resulting in appetite suppression [Secher et al. 2014]. These actions may also be accompanied by effects on other areas of the brain such as the mesolimbic system resulting in diminished food-induced reward signals and hence reduced food-seeking behaviour [Dickson et al. 2012; Dossat et al. 2011]. The efficacy of GLP-1 receptor agonists in maintaining weight loss may be explained by an attenuation of the fall in the anorexigenic hormone leptin that accompanies weight loss [Iepsen et al. 2014]. It is unclear whether GLP-1 influences energy expenditure. Some rodent models have demonstrated increased thermogenesis with administration of GLP-1 [Osaka et al. 2005]. Human studies, however, have yielded conflicting results [Harder et al. 2004; Horowitz et al. 2012]. In summary, while GLP-1 may increase energy expenditure in pharmacological concentrations, its predominant influence on body weight is through suppression of energy intake through direct and indirect actions on the appetite and food-reward centres of the brain and through local gastrointestinal effects. 7. DPP-IV inhibitors = Gliptins MoA: Inhibition of degradation of incretins (GLP1) Advantages: no hypoglycemia, stops progress of illness • DPP IV GLP-1 metabolites ↑ insulin secretion ↓secr. of glucagon ↓GLC dipeptidyl peptidase 4 [USEMAP] 7. DPP-IV inhibitors = Gliptins MoA: •inhibition of degradation of incretins (GLP1) •effect lasts for 24 hod – 2-3x higher levels of GLP1 Advantages: •no hypoglycemia •stop progress of DM •protection of B-cells •better glycemic control than conventional drugs [USEMAP] 7. DPP-IV inhibitors = Gliptins Therapeutic use: •DM 2 in combinatin with other GLDs •+ metformin – 1st choice in insufficient compensation •+ sulfonylurea derivate - in KI of metformin •+ thizolidindione - in KI of metformin •+ statin AE: pancreatitis, hypoglycaemia (in combination with Insulin/SU) dipeptidyl peptidase 4 linagliptin sitagliptin vildagliptin aloglitpin [USEMAP] 8. SGLT2 inhibitors = glycosuric drugs •SGLT2 is •selectively exprimed in kidneys •responsible for reabsorption of Glc from the filtrate back to circulation (even in hyperglycaemia) • •glykosuric effect is apparent after a single dose and lasts for 24 hours • •size of glycosuric effect depends on Glc concentration and GFR, NOT levels of insulin • •glycosuria leads to •loss of energy → reduced bodyweight •mild increase of diuresis and natriuresis •Hb1Ac decrease by 0.8% sodium-glucose co-transporter [USEMAP] K účinku potřebují fční ledviny, mají mírný diuretický efekt, hypoglykemie s inzulinem nebo sekretagogy 8. SGLT2 inhibitors = glycosuric drugs Therapeutic use: •Suitable for monotherapy as well as combinations CAVE hypoglyceamia in combination with insulin / SU •Cardioprotective (AIM, stroke, renoprotective !! Convincing data from large studies CI, caveats: •over 75 years, •kidney dysfunctions, concurrent loop diuretics, •hypotension, •electrolyte dysbalance AE: •thirst •genital infections •risk of lower limb amputations (mainly of the toe) •hypoglycemia - in monotherapy the risk is minimal; in combination with insulin / der. SU risk high dapagliflozin canagliflozin empagliflozin ertugliflozin [USEMAP] K účinku potřebují fční ledviny, mají mírný diuretický efekt, hypoglykemie s inzulinem nebo sekretagogy [USEMAP] Patients with high CV risk Treatment algorithm in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, or high/very high CV risk European Heart Journal, ehz486, https://doi.org/10.1093/eurheartj/ehz486 Useful links American Diabetes Association http://www.diabetes.org/ Drugs used in gastric ulcer disease 80 Gastric ulcer disease Peptic ulcers – result of dysbalance between protective and harmfull factors 81 [USEMAP] 82 Zobrazit zdrojový obrázek [USEMAP] Main goals of the treatment •supress pain •improve healing (mucosa reparation) •prevent relapses supress harmfull factors increase mucosa resistence 83 neutralization inhibition of HCl secretion eradication of H. pylori antacids anticholinergic drugs H2 antagonists H+ pump antagonists ATBs cytoprotective drugs [USEMAP] Antacids •symptomatic therapy to reduce pain •HCl neutralisation in stomach = increase in pH → decrease in pepsin activity (pH optimum 2) • •NaHCO3 (strong, rapid relief from pain) •CaCO3 (strong, rapid relief from pain, not for chronic treatment absorption of Ca2+) •MgO / Mg(OH)2 (laxative) •Mg [AlO2(OH)] •Al2O3 (gel, long-lasting eff., constipation) •Bi(OH)2NO3 (weak eff., supress H. pylori) 84 May be used in mixture Mg(OH)2 + Al2O3 [USEMAP] Antacids Indications: •dyspepsia, hyperacidity, pyrosis •reflux oesophagitis •symptomatic treatment of GIT disorders •begining of antiulcerous therapy •rapid relief from pain 85 AE: •absorption of Ca, Mg (cardiac complications) • •Al – constipation • •Mg – laxative effect • •decreased absorption of other drugs [USEMAP] H2 antihistamines Mechanism of action: •competitive H2 receptor antagonisms •selective supression of HIS-induced secretion •inhibition of intrinsic factor secretion (B12) Indications: •ulcer disease (primary and secondary, prevention of relapse) •Zollinger-Ellison syndrome (↑gastrin) •reflux oesophagitis •prophylaxis of gastrotoxicity in NSAIDs treatment 86 ranitidine famotidine Adverse effects: •myalgia, diarrhoea, constipation •CNS - confusion, glossolalia, headache •endocrine - antiandrogenic efect (cimetidine) - impotence, gynekomastia •blood – granulocytopenia, trombocytopenia, neutropenia..aplastic anemia (ranitidine) •hepatotoxicity – ALT, AST Caution: pass placental barrier [USEMAP] Proton pump inhibitors •administered as a pro-drugs •acidic environment in the parietal cells → active metabolites •enterosolvent coating, parenteral 87 Indications: •H. pylori eradication in ulcer disease •ulcer disease •reflux oesophagitis •Zollinger-Ellison syndrome (↑gastrin) •prophylaxis of stress-induced ulcer •prophylaxis of NSAIDs- induced gastropathy •in risk groups of patients (e.g. LMWH, warfarin) omeprazole, esomeprazole pantoprazole, lansoprazole rabeprazole MoA: irreversible inhibition of PP and supression of HCl secretion regardless the origin of the stimulus (re-synthesis needed for regeneration of activity) [USEMAP] Proton pump inhibitors AE: •dyspepsia, •headache •rarely cytopenia •P450 inhibition 88 Zobrazit zdrojový obrázek Zobrazit zdrojový obrázek [USEMAP] Selective parasympatolytics Mechanism of action: •acetylcholine antagonism in M1/3 receptors •convenient is selective inhibition •supress CO2- 3 and mucus secretion •similar action as H2 antagonists 89 pirenzepine Indications: •peptic ulcer disease •dyspepsia after NSAIDs treatment •stress ulcer prevention CI: •glaucoma •prostate hypertrophy •urination disorders [USEMAP] OBSOLETE Cytoprotectives Sucralfate = octasulfate of sucrose + aluminium hydroxide •strong mucoprotective eff. •needs acidic pH!! •binds pepsin and bile acids •incr. prostaglandins synthesis 90 sucralfate bismuth salts alginic acid protective effect on the stomach mucosa AE: •not absorbed •dyspepsia, Al- constipation •decrease bioavailability of other drugs – tetracyclines, phenytoin, digoxine, cimetidine... [USEMAP] Bismuth salts = basic salts of bismuth and citric acid •chelatation of proteins on ulcer surface → protective barrier •PG secretion stimulation •antibacterial action (eradication of H. pylori) • Eicosanoids PGE1, PGI2 = main natural protective factors synthetised in gastric mucosa •increase mucus and HCO3 production, perfusion •unstable, only derrivatives administered as prevention of harmfull effects of NSAID •Misoprostol - PGE1 - abortions!!!! Cytoprotectives [USEMAP] Eradication of H. pylori •G- bacteria, over 80 % are asymptomatic • •eradication decrease frequency of relapses to 0-10 % • •complex therapy - combination of 2 antibiotics – with H+ pump inhibitors for 1 – 2 weeks 92 Tripple therapy: PPI + amoxicilin (2x 1000 mg) + claritromycin/azithromycin (2x 500 mg) or metronidazole (2x 500 mg) ev. sequential In resistant pathogen + tetracyclin or bismuth salts [USEMAP] Thank you for your attention 93 [USEMAP]