Antidiabetic drugs Department of Pharmacology MF MU [USEMAP] Adobe Systems Antidiabetic drugs ̶Insulins ̶Drugs used in T2DM [USEMAP] Diabetes mellitus chronic multifactorial endocrine and metabolic disease DM I. type (IDDM) absolute deficiency in insulin (10 - 15 %) - infections or toxic effect on pancreas - autoimmune DM II. type (INDDM) relative deficiency in insulin (85 - 90 %) [USEMAP] Clinical picture Polyuria, polydypsy, nighttime urination, weight loss in normal appetite, physical weakness, fatigue, blurred vision, coma (children) Randomly detected glycemia above 11.1 mmol / L Fasting glycaemia above 7.0 mmol / L T1DM - symptoms are more pronounced, develop quickly (weeks) T2DM - less noticeable symptoms, evolving from months to years - other - related to organ complications - itchy skin, visual disturbances, pain and tingling, neuralgia, badly healing wounds, skin affections, tooth decay, potency disorders, libido ... [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] Insulin resistance Hypertension (high blood pressure) Hypertriglyceridaemia (elevated TAG) Disorders of glucose tolerance or diabetes Obesity type of apple (male type of obesity) METABOLIC SYNDROME [USEMAP] Insulin = lowmolecular protein, 2 chains (A 21 AA, B 30 AA), 2 S-S bonds Synthesis - preproinsulin (107 AA) ® ® proinsulin (82 AA, A,B +C-peptide)®insulin marker of endogenous secretion of insulin (is not metabolized by the liver so quickly) Bez názvu [USEMAP] somatostatin insulin (negative feedback) a - activation of sympathetic n.s. (adrenalin) Factors decreasing insulin secretion [USEMAP] Insulin receptor Lincová a kol. 2002 [USEMAP] Insulin receptor Lincová a kol. 2002 [USEMAP] Adobe Systems Types of insulin ̶ ̶ ̶ A) animal insulin - from pork or beef pancreas, highly pure, monocomponent, today only AUV B) human insulin - produced biosynthetically (synthetically since the 1960s, biosynthetically from 70 years, commercially since 1982) is called HM C) insulin analogues- biosynthetically prepared, spec. Properties - length of action (short, prolonged effect) - the production of antibodies to insulin depends on the purity [USEMAP] Adobe Systems Terapeutical use of insulin -DM I. Type -ketosis, ketonuria or ketoacidosis •- patients with serious infetion/gangrene - -DM II where blood Glc. not normalized with POAD, diet -DM II patients, use corticosteroids, liver or kidney impairment [USEMAP] Adobe Systems Insulin preparations ̶ ̶ ̶ solutions/suspensions of insulin suspesions of „zinc-insulin“ suspensions „protamin-zinc-insulin“ S insulin as a mixture of mono-/di-/tetra-/hexamers + pH, stability, isotonicity adjusted [USEMAP] Adobe Systems ̶ ̶ ̶ Insulin preparations Short acting A) insulin analogues: insulin lispro, aspart, glulisine Can be administered intravenously Start of operation 0-15 min. Maximum of efficacy 30-45 min after admin. Effective for 2 - 5 hours. B) neutral aqueous solutions of insulins (Crystalline insulin, soluble insulin) Can be administered intravenously Start of action 30 min. Maximum 1 - 3 hours. Effective for 4 - 6 hours. [USEMAP] Intermediate acting NPH (Neutral Protamine Hagedorn) Protamine insulins or mixtures of amorphous and crystalline forms of insulin in a ratio of 30:70 Start of operation 1 - 2.5 hours Maximum 4 - 8 hours. Working time 12 - 24 hours. Almost no longer used – Adobe Systems ̶ ̶ ̶ Long acting Crystalline suspensions of large crystals with very slow absorption Analogs and their conjugates (glargin, detemir, degludec) Onset of effect 2 - 3 hours Maximum 10-18 h (not apparent in degludec) Effective for 24 - 36 hours. Steady state after 3 days (3 doses) Less hypoglycemia than NPH, less weight gain [USEMAP] Adobe Systems •Complications of insulin therapy • •- hypoglycaemia •- allergy •- lipodystrophy •insulin resistance - spec. antibodies •weight gain • • • [USEMAP] Adobe Systems Delivery systems (self-administration) •1) Insulin pen - cartridge with extendable needle; In the form of a fountain pen •2)Insulin pumps - continuous infusion s.c. (better compensation, less infectious risk) •3)Insulin syringes - with a sealed needle, calibrated per unit •4) Inhalation (USA) / transnasal ? [USEMAP] mista-vpichu-vektor -01 preferred acceptable Insulin administration sites 040090 spuitpen getmedia chlapik_s_dtron d-tronplus Výsledek obrázku pro medtronic 640 g Výsledek obrázku pro medtronic 640 g Hypoglycaemia - below 2.8 mmol / l Causes : - overdose with insulin - delayed food intake, vomiting, diarrhea - excessive physical load (delayed hypoglycaemia) In the elderly, liver, kidney, cardial insufficiency Rapid onset of symptoms: nervousness, tremor, palpitations restlessness, hunger, sweating, consciousness disorders, changes in EEG, coma, exitus Therapy: Saccharide / glucose delivery p.o./i.v. (40% glucose, 30-50 ml or more) Glucagon, followed by glucose [USEMAP] Antidiabetics [USEMAP] Criteria for initiation of pharmacotherapy of DM II type and suitable selection of drug • OAD do not replace regimen (diet) • age, weight, blood insulin level • glycemia (fasting and postprandial) • comorbidities, metabolic syndrome (Oral) antidiabetics The effect is linked to the ability of insulin secretion Most OAD are contraindicated in pregnancy (metformin may be used) - indication: - 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 Adobe Systems Antidiabetics ̶biguanides ̶sulfonylurea derivatives (SU) ̶thiazolidindiones ̶alpha-glucosidase inhibitors ̶meglitinides ̶GLP1 analogues ̶Inhibitors of DPP IV ̶SGLT2 (sodium-glucose cotransporter) inhibitors [USEMAP] Biguanides metformin fenformin buformin Mechanism of action • increase sensitivity of peripheral tissues to insulin • increase insulin binding to its receptor • reduce hepatic gluconeogenesis • decrease glucose absorption from GIT Do not affect insulin secretion, function of B cells → no hypoglycemia „euglycemic agents“ [USEMAP] Adobe Systems •Further benefits: •Direct stimulation of glycolysis in the periphery •Reduce hepatic gluconeogenesis •Delay Glc absorption from GIT •Decrease plasma glucagon levels •Increase the proportion of HDL Chol. → improve lipid profile •Improve rheological properties of blood •Are not metabolized, low protein binding • •Side effects •Lactic acidosis •Nausea, GIT problems about 20% of people (diarrhea) •Reduced absorption vit. B12 •Weight loose •disulfiram effect [USEMAP] sulfonylurea derivatives (SU) mechanism of action 1) pancreatic – release of I. from beta - cell 2) extrapankreatic - potentiation of endogenous I effect on the target tissue - reduction of hepatal glucose production - reduction of hepatal Insulin degradation - reduction of serum glucagon levels Tolbutamide [USEMAP] SU derivatives I. Generation - chlorpropamide tolbutamide II. Generation - glibenclamide (gliburide) glipizide gliclazide gliquidone III. Generation - glimepiride Therapeutic use: not drugs of choice, 2nd line treatment [USEMAP] Adverse effects • increased appetite • metal taste in mouth • Hypoglycemia •headaches, nausea (5 %) • fluids retention • allergy, fotosensitivity Contraindications DM Type 1 monotherapy, hypoglycemia, ketoacidosis, kidney or liver failure pregnancy, hypersensitivity [USEMAP] Thiazolidinediones rosiglitazone rosiglitazon pioglitazon troglitazon Mechanism of action • increase the sensitivity of periphery to insulin • ligands of PPARg (part of the steroid and thyroid superfamily of nuclar receptors) modulate the expression of the genes involved in the metabolism of lipids and glucose [USEMAP] Thiazolidindiones • Lowering blood glucose by the primary effect on insulin resistance - in diabetic and pre-diabetic patients • Does not cause hypoglycemia, scavengers •Increase glycogen synthesis and glycolysis in muscles •Stimulating glucose oxidation and lipogenesis in adipose tissue and reducing gluconeogenesis in the liver ... optimal metabolic effects Therapeutic use Sensitizers of insulin receptors The onset of effect in 4 weeks Side effects Hepatotoxicity Fluid retention Increase TAG Contraindications Hypersensitivity Predisposition to heart failure Liver damage Pregnancy, lactation [USEMAP] Adobe Systems Inhibitors of intestinal glucosidase acarbose Mechanism of the action • reduce sacharides absorption from GIT • competitive inhibition of the gut α - glucosidases (inhibits the cleavage of the polysacharides from the meal) acarbose miglitol voglibose [USEMAP] Adobe Systems • • decrease postprandial glycemia • do not affect monosacharides absorption • acarbosis do not rech the systemic blood, miglitol does • „educative drugs“- consequences in bad compliance In hypoglycemia and the simultaneous treatment with other POADs can not be administered sucrose (monosacharide necessary - Glu, Fru) or Glucagon Inhibitors of intestinal glucosidase [USEMAP] Meglitinides repaglinide Mechanism of the action similar to SU-derivatives: block ATP- sensitive K+ channel in membrane of beta-cells, depolarisation of membrane, activation of voltage-gated Ca2+ channel, influx Ca2+ , insulin release through different receptor at K+ channel repaglinid nateglinid meglitinid [USEMAP] Clinical use • combined with metformin - esp. if patient not suffciently compensed • alternative of the SU medication in patients with renal impariment (excreted in bile) Contraindications: • hypersensitivity • DM I. type • diabetic ketoacidosis • pregnancy, lactation AE: Hypoglycemia, nausea, diarrhea, joint pain [USEMAP] DM - Complications 1) hypoglycemia consciousness - sweet (sacharide) drink, meal unconsciousness - i.v. Glu 20-40% - u DM I. type i.v. glucagon [USEMAP] 2) allergy (hypersensitivity IgE) - corticosteroids, adrenalin i.v. 3) insulin resistance - IgG against insulin (animal insulins), change insulin preparation, POAD 4) lipodystrophy - change application sites (scheme), esthetic surgery DM - Complications [USEMAP] Diabetic nefropathy - hypertrophy, hyperfiltration; ® nefropathy, blood pressure (ACEi), microalbuminuria, insufficiency Diabetic neuropathy – gabapentin, pregabaline, carbamazepine, TCA, duloxetine Hyperlipoproteinemia - diet, statins, fibrates, probucol, nicotinic acid.. DM - Complications [USEMAP] Diabetic foot - micro- and macrovascular impairments a)neuropatic - warm, non-sensitive, dry, complicated with neuropathic ulcer oedema b) ischemic - cold, without pulsations c) neuroischemic - ulcerations, gangrene Diabetic retinopathy - protein glycation, small vessels collagenisation; microangiopathy DM - Complications [USEMAP] relapse of infections, mycosis hypertension DM - Complications [USEMAP]