Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Toxicodynamics wikipedia , lookup
Drug interaction wikipedia , lookup
Discovery and development of ACE inhibitors wikipedia , lookup
Metalloprotease inhibitor wikipedia , lookup
Discovery and development of integrase inhibitors wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Atypical antipsychotic wikipedia , lookup
Neuropharmacology wikipedia , lookup
Psychopharmacology wikipedia , lookup
Discovery and development of dipeptidyl peptidase-4 inhibitors wikipedia , lookup
ANTIDIABETIC AGENTS Jiří Slíva DIABETES MELLITUS • Multifactorial disease with genetic component • Main symptoms: hyperglycemia, metabolic disturbances • Relative or total absence of insulin → increase of the glucose blood level • Borderline DM: concentration of glucose plasma level 7.0 mmol/L – fasting and 11.1 mmol/L 2 hours after the meal TYPE l diabetes (IDDM, insulindependent diabetes mellitus) • Formerly juvenile diabetes • LADA (latent autoimmune diabetes in adults) • Total absence of insulin • Langerhans islets B-cells lesion (usually caused by autoimmune disease) → infiltration of islets with Tlymphocytes • Antibodies against islets tissue and insulin TYPE ll diabetes (NIDDM, non-insulin dependent diabetes mellitus) • Formerly senile diabetes (onset in adulthood) • Relative absence of insulin • Levels of insulin could be normal or above or below normal • Insulin-sensitive tissues show a lack of insulin-sensitivity or a reduction of insulin receptors is supposed • NIDDM patients are often obese ANTIDIABETIC AGENTS DM l. type treatment • Insulin DM ll. type treatment (PAD) • • • • • Sulphonylureas Biguanides α-glucosidase inhibitors Glitazones (thiazolidinediones) Glinides etc. INSULIN • Human insulin – low molecular protein – strong electronegative (binding to positively charged proteins in circulation and to membrane insulin receptors) – two peptide chains A (21 AAs) a B (30 AAs), linked by disulphide bridges Structure of human insulin INSULIN • Proteohormone - glucose utilization - metabolism of lipids and proteins (storage of these basal sources, „anabolic“ hormone) Lack of insulin (either absolute of relative) ►DIABETES MELLITUS INSULIN SECRETION Daily production: 20 – 40 IU • Basal secretion (cca 50 %) - independent on food intake - blocks glucose production in liver - responsible for fasting euglycaemia • Stimulated secretion (cca 50%) - stimulated by food intake - regulates postprandial glycaemia INSULIN TREAMENT INDICATIONS • DM type 1 • Some DM type 2 patients or patients with secondary diabetes • • • • • • Insulin treatment in DM type 2 patients PAD treatment failure Allergy to PAD Diabetes in pregnancy Severe renal or liver insufficiency Clinical situations with contemporary decompensated diabetes (operation, infection, etc.) INSULIN SYNTHESIS • preproinsulin → proinsulin → insulin a C-peptide (shows the endogenous insulin secretion) • Insulin release from pancreatic B-cells each 15 30 min HEALTHY DIABETIC PATIENT INSULIN RELEASE FROM B-CELLS Controlled by glucose concentration a) influx of glucose to the B-cell by GLUT-2 transporter b) metabolism of glucose by glukokinase c) increase of ATP concentration in the cell d) closure of ATP-sensitive potassium channels e) depolarization and opening of voltage-sensitive Ca2+ channels f) degranulation of B-cells and insulin release to the extra cellular space INSULIN RECEPTORS • glycoproteins (muscle, adipose tissue) • two heterodimers linked by disulphide bridges, each consists of α- and β- subunit • α-subunit – extra cellular, binding place for insulin • β-subunit – transmembrane protein with tyrosine kinase activity Figure : Insulin-receptor complexes on the cell surface cause chemical responses to occur within the cell. This figure was reproduced pending permission from the authors of Life, 6th Ed (Purves et al, 2001). INSULIN EFFECTS • The main hormone of metabolic processes in liver, muscle and adipose tissue • stimulates anabolic and inhibits catabolic processes • Facilitates gathering of glucose, aminoacids and lipids from food • Acute effect of insulin ►hypoglycemia ACUTE CONSEQUENCES OF INSULIN SHORTAGE • Lack of insulin in glucose metabolism → hyperglycemia • Osmotic diuresis → polyuria • Renal loss of water, Na+ and K+ → dehydration, thirst • Dehydration → hypovolemia • Release of fatty acids →hyperacidlipidemia INSULIN THERAPY • The daily dose as low as possible! (up to 40 IU / day) • Shorter-acting insulin → more doses daily → better compensation of DM → using lower daily dose INSULIN THERAPY • „Conventional“ therapy - insulin in one or two daily doses (good compensation just in type 2 DM patients) • „Intensified“ therapy - covers basal and prandial need of insulin (more doses, better compensation, lower daily dose) ANIMAL INSULIN SOURCES • bovine and porcine pancreas → complicated purification • Bovine insulin is different from human insulin in three amino acids, porcine in one amino acid • human insulin ADVANTAGE: less allergic reactions CLASSIFICATION OF INSULIN PREPARATIONS • According to sources and purity • According to duration of action CLASSIFICATION OF INSULIN PREPARATIONS • Sources and purity – Animal – Human – Insulin analogues • Duration of action – – – – Short-acting Intermediate-acting Long-acting Combined (mixtures) ANIMAL INSULINS • Bovine • Porcine • Mixtures According to level of purity • Chromatography purified (PUR) • Highly purified – monocomponent (MC) (significantly less contaminated) HUMANE INSULINS (HM) • emp insulin – enzyme techniques to modify porcine insulin • crb insulin – chain recombinant DNA in bacteria INSULIN ANALOGUES • short-acting (glulisine) • intermediate-acting (lispro) – chain recombinant DNA in bacteria technique – the penultimate lysine and proline residues on the Cterminal end of the B-chain are reversed • long-acting (glargine, detemir) DURATION OF ACTION • Short-acting - onset 30 minutes, peak 2-4 hours Soluble simple insulin Lispro • Intermediate- and long- acting - duration of action between 16 and 35 hours Semilente (suspension, amorphous insulin zinc) Lente (suspension, mixture,amorphous insulin zinc, insulin zinc crystals) Isophan insulin (NPH)(complex of protamine and insulin) Ultralente (suspension, poorly soluble insulin zinc crystals) • Combined - fixed mixtures (biphasic,..) Time profiles Pharmacokinetics of insulin • The speed of absorption depends on pharmaceutical properties, dosage, and tissue perfusion • Practically no plasma protein binding • • • • Degradation of insulin: kidneys (35‒40 %), liver (60 %), the opposite in exogenous insulin biologic half-life: 7‒10 minutes hydrolysis of S-S bridges between A and B chains by insulinase further degradation by proteolysis Adverse reactions: acute • hypoglycemic reaction – in insulin over dosage, inadequate caloric intake (less food), higher physical activity → sympathetic reaction (sweating, tremor, tachycardia, weakness) and → parasympathetic reaction (hunger, nausea, „clouded“ vision) • Hypoglycemic coma – i.v. glucose (20‒50 ml 40% Glu) or glucagon (i.m., s.c.), than glucose or sweet drinks p.o. Adverse reactions: long-term • Long term therapy with repeated episodes of hypoglycemia (namely in older patients) => CNS disturbances (fuzziness, incoordinated speech, bizzare behavior) Insulin application Application forms Insulin syrretes • Special plastic syrretes, volume 1 ml with sealed needle • 1 scale segment = 1 IU of insulin • Single use • Most common application form (adults) • Cheap Note: One international unit of insulin (1 IU) is defined as the "biological equivalent" of 34.7 μg of pure crystalline insulin. This corresponds to the old USP insulin unit, where one unit (U) of insulin was set equal to the amount required to reduce the concentration of blood glucose in a fasting rabbit to 45 mg/dl (2.5 mmol/L). Application forms Insulin pens • Injectors like pen • Extensible needle • Perfect for intensified insulin therapy Structure of insulin pen Application forms Insulin pumps • subcutaneous continual infusion • highly reliable, digital, miniature • advantage: exchange each 48 hours, comfortable for the patient • disadvantage: expensive, repeated measurement of glycemia during the day, higher risk of cutaneous infection (permanent needle) Inhalable insulin • currently not available • previously approved in U.S (Exubera) • effective, but no better than injected short-acting insulin • it is unlikely to be cost-effective • in 2011 announced that when applied deep into the nostrils may delay the onset of Alzheimer's disease Note: under development ‒ buccal spray, insulin pills, insulin patch, … ORAL ANTIDIABETIC DRUGS Oral Antidiabetic Drugs Classification of oral antidiabetics: • Sulphonylureas • Biguanides • Intestinal glucosidase inhibitors • Glitazones (thiazolidinediones) • Glinides • Gliptins (syn. dipeptidyl-peptidase 4 (DPP-4) • SGLT inhibitors Other antidiabetics: Incretinoenhancers Oral Antidiabetic Drugs • insulin „sensitizers“ – biguanides – glitazones (thiazolidinediones) • insulin „secretagogues“ – sulphonylureas – fast (short) insulin secretagogues (Glinides) – incretins and DPP-4 Inhibitors • Intestinal glucosidase inhibitors • SGLT inhibitors Biguanides • Mechanism of action: – peripheral insulin uptake enhancement (skeletal muscle,...) • Main drugs: – metformin • Adverse effects: – lactate acidosis Glitazones (Thiazolidinediones) • Mechanism of action: – peripheral insulin receptors sensitization – targeting peroxisome proliferator-activated receptor (PPARgamma) – improving insulin resistance • Main drugs: – Pioglitazone (Actos) – [Rosiglitazone (Avandia) – withdrawn in 2010, because of problems with cardiovascular safety)] • Adverse effects: – hepatotoxicity – congestive heart failure… Sulphonylureas • Mechanism of action : insulin secretion stimulation • Main drugs: Tolbutamide, Glibenclamide, Glipizide, Gliclazide • Adverse effects : hypoglycemia Fast (short) insulin secretagogues: glinides • Mechanism of action: – insulin secretion stimulation (glycaemia dependent) • Main drugs: – repaglinide, nateglinide • Adverse effects: – hypoglycemia, GIT disturbances x Sulphonylureas vs. glinides Sulphonylureas Glinides 1) moderate to long-lasting eff. 2) 1x or 2x daily 3) decreased FBG 4) low eff. on the early secretion of insulin 5) low influence of postprandial glycaemic oscilation 6) clinically significant risk of hypoglycaemia (mostly at night) 7) weight gain 2–4 kg 8) average decrease of HbA1c: 1.5 % 9) lower price 1) 2) 3) 4) 5) 6) 7) 8) 9) short action administration with each meal postprandial decrease of glycaemia improved postprandial secretion of insulin signif. influence of PP glycaemic oscilation low risk of hypoglycaemia lower weight gain average decrease of HbA1c is comparable in repaglinide; nateglinide: 0.8 % higher price Intestinal (Alpha) Glucosidase Inhibitors • Mechanism of action: – decrease of intestinal carbohydrate absorption • Main drugs: – acarbose – miglitol • Adverse effects: – diarrhoe Physiology of incretins Note: GLP-1 …Glucagon-like peptide 1; GIP …glucose-dependent insulinotropic polypeptide Baggio LL, 2007 Physiology of GLP-1 Drucker D, 2006 Note: Glucagon-like peptide 1 (GLP-1) Physiology of GIP Note: GIP …glucose-dependent insulinotropic polypeptide Baggio LL, 2007 Structure of GLP-1 and incretinomimetics Drucker D, 2006 Gliptins: mechanism of action • sitagliptin, vildagliptin, saxagliptin - inhibitors of dipeptidyl peptidase-4 (DPP-4) = incretin enhancers => increased level of GLP-1 & GIP GIP …glucose-dependent insulinotropic polypeptide Lauster CD, 2007 Gliptins + metformin HbA: Hemaglobin A; ITT: Intent to treat; LAF: Vildagliptin; MET: Metformin; PBO: Placebo Fonseca V, 2007 Characteristics and effects of GLP-1 receptor agonists and DPP-4 inhibitors Ahrén B, 2011 Glycosuric agents Marsenic O, 2009 Glycosuric agents • dapagliflozin – SGLT-2 inhibitor Marsenic O, 2009 Petr Potměšil • Extension of presentation about antidiabetics Possible risk of pancreatic damage after use of drugs influencing incretins Increased incidence of pancreatitis (?) actually re-assessment of safety in course by EMA, no change in recommendations for therapy available at the moment (published in Mar-2013, details: www.ema.europa.eu) • DPP-4 inhibitors (inhibitors of dipeptidylpeptidase IV) Sitagliptin Vildagliptin Saxagliptin • Analogues of GLP-1 (glucagone like peptide) • Liraglutid • Agonists of receptor for GLP-1 • Exenatid Diabetes – comparison of metabolic effects of insulin and glucagone A/ Insulin B/ Glucagone • 1) ↑ oxidation of glucose and ↓ gluconeogenesis • 1) ↑ glycogenolysis • 2) ↑ synthesis of glycogen and lipids • 3) anabolic effect • 2) hyperglycaemia Comparison of pharmacokinetic parameters of sulphonylureas and biguanides A/ Sulphonylureas B/ Biguanides • ↑ binding to plasm. • do not bind to plasm. proteins proteins • ↑ biotransformation, • no extensive biotransformation, thus contraindicated in elimination mainly by patients with severe renal excretion, thus impairment of hepatic/renal contraindicated in function patients with severe impairment of renal functions Some treatment options for diabetic neuropathic pain • Tricyclic antidepressants: low tolerability (antimuscarinic eff.) • SSRI - limited efficacy: sometimes not recommended for pain • SNRI antidepressants (AE: disturbed sleep at start) 1/ venlafaxine (Effectin): ↑ dose - possible hypertension 2/ duloxetine (Cymbalta): also approved for urinary stress incontinence and GAD (general. anxiety disorder) • Antiepileptic drugs (AE: sedation, weight gain) 1/ gabapentin (Neurontin) 2/ pregabalin (Lyrica), also for GAD, improves sleep 3/ carbamazepin – many interactions with other drugs