Drugs for Diabetes Mellitus

Drugs for Diabetes Mellitus

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  Drugs for Diabetes Mellitus Dr.Arthi II nd yr Post graduate Department of Pharmacology Rajah Muthiah Medical college
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  INSULIN • Human insulinconsists of 51 aa in two chainsconnected by 2 disulfide bridges (a single gene product cleaved into 2 chains during post-translational modification). • T1/2 ~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleavesthe disulfidelinks. • Bovine insulin differs by 3aas, pork insulin differs by 1aa. • Insulin is stored in acomplexwith Zn2+ions.
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  SYNTHESIS OF INSULIN
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  INSULIN RELEASE • Secretionismost commonly elicited by elevated glucose levels; increasedglucoselevelsin β-cellsresults inincreased ATPlevels, this results in ablock of K+channels causing membrane depolarization which opensCa2+channels. • Theinflux of Ca2+results in apulsatile secretion ofinsulin; continued Ca2+influx results in activation of transcription factors for insulin. • Oral glucoseelicits more insulin secretion than IVglucose; oral administration elicits gut hormones whichaugment the insulin response.
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  Mechanismof InsulinAction • Insulinbinds to specific high affinity membrane receptors with tyrosine kinaseactivity • Phosphorylation cascade results in translocation of Glut-4 (and some Glut-1) transport proteins into the plasmamembrane. • It induces the transcription of several genes resulting in increased glucosecatabolism and inhibits the transcription ofgenes involved in gluconeogenesis. • Insulin promotes the uptake ofK+ into cells.
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  TheGoalof InsulinTherapy Administration ofinsulins are arranged to mimic the normal basal, prandial and post-prandial secretionof insulin. Shortacting forms are usually combined with longer acting preparations to achieve this effect.
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  Conventional insulins: Short acting-regular insulin Intermediate- NPH insulin Insulin Analogs Ultra short acting-Lispro, Aspart, Glulisine Long acting- Glargine, Detemir INSULIN PREPARATIONS
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  INSULIN PREPARATIONS
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  • Lispro, aspartand glulisine forms are classified as rapid- acting insulins because of their rapid onset and short duration of action • Rapid acting insulins usually administered 15 minutes prior to a meal or immediately following a meal • These are mostly combined with basal insulin to maintain baseline level of insulin. • Onset of action is 15-30min and lasts for 3-4hrs. RAPID ACTING INSULIN PREPARATIONS
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  Regular insulin: starts within60 min and lasts for 6-8 hrs , soluble human crystalline insulin with added Zn ions It controls the post prandial hypoglycemia
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  Intermediate –actingInsulinPreparations Isophane NPHinsulin: Neutralprotamine insulin is a suspension of crystalline zinc insulin combined with protamine (a polypeptide). The conjugation with protamine delays its onset of action and prolongs it effectiveness. It is usually given in combination with regular insulin.
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  Long-actinginsulinpreparations 1.Insulin glargine: Precipitationat theinjection site extends the duration of action of thispreparation. pH has to kept acidic. 2.Detemir insulin: hasaFAsidechain complexed with insulin resulting in slowdissolution. 3.Insulin degludec: has a FA side chain which allows fomation of multi-hexamers forming a subcutaneous depot resulting in slow dissolution.
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  Various premixed combinationsof human insulins are available ◦ 70% NPH insulin plus 30% regular insulin (Humulin 70/30®) ◦ 50% NPH insulin plus 50% regular insulin ◦ 75% NPL insulin plus 25% insulin lispro (Humalog Mix®) INSULIN COMBINATIONS
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  AdverseEffectsof Insulin 1. Hypoglycemiamay occur due to insulin overdose, insufficient caloric intake (missed meal, improper meal content, delayed meal, etc.). Ethanol consumption promotes hypoglycemic response. Symptoms: ↑ HR, diaphoresis, anxiety, 2. Hypokalemia -insulin draws K+into the cell with glucose (hyperglycemia with normalK+). 3. Lipodystrophy at injectionsite 4. Weight gain 5. Inslin reistance
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   Insulin secretagogues ◦Sulfonylureas  Meglitinides-Repaglinide, Nateglinide  Insulin sensitizers ◦ Biguanides-Metformin ◦ Thiazolidinediones-Pioglitazone , Rosiglitazone  α-Glucosidase inhibitor-Acarbose, Miglitol, Voglibose  Dipeptidyl peptidase-IV inhibitors-Gliptins
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  Sulfonylureas Theseagents promote therelease of insulin from β-cells (secretogogues)The primary drugs used today are the second- generation drugs glibenclamide, glipizide, and glimepiride ; Mechanism: – Theseagents require functioning β-cells, they stimulate release by blockingATP- sensitive K+channels resulting in depolarization with Ca2+influx which promotes insulin secretion. – Theyalso reduce glucagon secretion and increase the binding of insulin to target tissues. – Theymay also increase the number of insulin receptors • Pharmacokinetics: Theseagents bind to plasma proteins, are metabolized in the liver and excreted by the liver or kidney. Glimipride has highest plasma protein binding.
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  Sulfonylureas Adverse Effects: • Theseagentstend to causeweight gain, hyperinsulinemia and hypopglycemia. • Hepatic or renal insufficiency causes accumulation of these agents promoting the risk of hypoglycemia. • There are anumber of drug-drug interactions. Elderly patients appear particularly susceptible to the toxicities of theseagents.
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  Meglitinideanalogs Theseagents repaglinide andnateglinide act as secretogogues. • Mechanism: Bind to ATPsensitive K+channels like sulfonylureas acting in asimilar fashion to promote insulin secretion however their onset and duration of action are much shorter. • When used in combination with other oral agents they produce better control than any monotherapy. • Adverse Effects: Lesshypoglycemia than sulfonylureas • Drugs that inhibit CYP3A4(ketoconozole, fluconazole, erythromycin, etc.) prolong their duration of effect. • Drugs that promote CYP3A4(barbiturates, carbamazepine and rifampin) decrease their effectiveness.
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  Insulin Sensitizers Biguanides andThiazolidinediones. Biguanides: • Metformin is classified asan insulin sensitizer, it increases glucose uptake and utilization bytarget tissues. It requires the presenceof insulin to be effective but does not promoteinsulin secretion. The risk of hypoglycemia is greatlyreduced. • Mechanism: • Inhibits hepatic gluconeogenesis. • It increases the uptake of glucose by skeletal muscles • It also reduces hyperlipidemia (↓LDL and VLDL cholesterol and ↑ HDL). • Metformin also decreases appetite. It is the onlyoral hypoglycemic shown to reduce cardiovascular mortality. Itcan be used in combination withother oral agents and insulin. • Adverse effects: Nausea, mettallic taste, anorexia, vitamin B12 deficieny
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  Thiazolidinediones (Glitazones) • MOA: Theseagents bind to PPAR-gamma receptor which is expressed in adipose tissue, skeletal muscle and liver which controls glucose and lipid metabolism. • It increases the GLUT-4 glucose transporters in skeletal muscle and adipose tissue. • Pioglitazone is given at a dose of 11-45mg dose daily • Rosiglitazone at a dose of 4-8mg daily • Adverse effects: edema and fluid retention, deposition of subcutaneous fat.
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  • Mechanism ofAction: Theseagents act through the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ).Ligandsfor PPAR-γregulate adipocyte production, secretion of fatty acidsand glucosemetabolism. Agentsbinding to PPAR-γresult in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle. Hyperglycemia, hypertriglyceridemia and elevated HbA1care all improved. HDLlevels are also elevated.Accumulation of subcutaneous fat occurs with theseagents.
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  α-GlucosidaseInhibitors Thisenzyme hydrolyses oligosaccharides to monosaccharideswhich are then absorbed. Acarbose also inhibits pancreatic amylase. The normal post-prandial glucose rise is blunted, glucoselevels rise modestly and remain slightly elevated for aprolonged period, lessof an insulin response is required and hypoglycemia is avoided; use with other agents may result in hypoglycemia. Sucraseis also inhibited by thesedrugs.
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  α-GlucosidaseInhibitors Acarbose and miglitolare two agents of thisclassused for type 2diabetes. Mechanism of action:Theseagents are oligosaccharide derivatives taken at the beginning of ameal delay carbohydrate digestion by competitively inhibiting α-glucosidase, amembrane bound enzyme of the intestinal brushborder. Pharmacokinetics: Acarbose is poorly absorbed remaining in the intestinal lumen. Migitol is absorbed and excreted by the kidney. Both agents exert their effect in the intestinal lumen. Adverse Effects: flatulence, diarrhea, cramping. Metformin bioavailability is severely decreased when usedconcomitantly. Theseagents should not be used in diabetics withintestinal pathology.
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  IncretinTherapy • • • Incretinsare naturally occurringhormonesthatthe gutreleases throughoutthe day the level of activeincretinsincreases significantlywhen foodis ingested. Endogenousincretinsare GLP-1(glucagon-likepeptide 1) and GIP (glucose-dependentinsulinotropicpeptide) GIPandGLP-1are the 2 major incretin hormonesin humans
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  Incretin Therapy sitagliptin
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  MECHANISMOFACTION: Theseincretins are releasedfrom the gut in response to ingestion of food and collectively contribute to glucosecontrol by: • Stimulating glucose-dependent insulin release from pancreaticbeta cells (GLP-1and GIP): • Decreasing glucagon production from pancreatic alpha cells (GLP-1) when glucose levels are elevated. Thecombination of increased insulin production and decreased glucagon secretion reduces hepatic glucose production when plasma glucoseis elevated.
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  The physiologic activityof incretins is limited by the enzyme dipeptidyl peptidase-4 (DPP-4), which rapidly degrades active incretins after their release. TheIncretin Effect Is Diminished in Type2 Diabetes Levels of GLP-1 are decreased. The insulinotropic response to GIP is diminished but not absent. Defective GLP-1 release and diminished response to GIP may be important factors in glycemic dysregulation in type 2 diabetes.
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    Orally activeDPP-4 inhibitors used for the treatment of patients with type 2 diabetes ◦ Sitagliptin - 100mg OD ◦ Vildagliptin -50mg ◦ saxagliptin, linagliptin, alogliptin
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  Dipeptidyl peptidase 4Inhibitors: • Orally active DPP-4 inhibitors used for the treatment of patients with type 2 diabetes ◦ Sitagliptin - 100mg OD ◦ Vildagliptin -50mg ◦ saxagliptin, linagliptin, alogliptin
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  Mechanism of action Inhibitthe enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as GLP-1 Prolonging the activity of incretin hormones results in increased insulin release in response to meals and reduction in glucagon secretion It delays the gastric emptying and supresses appetite.
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   DPP-4 inhibitorsmay be used as monotherapy or in combination with a sulfonylurea, metformin, glitazones, or insulin Adverse effects  Nasopharyngitis  Headache  Pancreatitis has occurred with sitagliptin 
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  Adverse effects  Nasopharyngitis Headache  Pancreatitis has occurred with sitagliptin
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   Dapagliflozin  Canagliflozin Mechanismof action:  SGLT2 is responsible for reabsorbing filtered glucose in the tubular lumen of the kidney  By inhibiting SGLT2, these agents decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose  Decreases reabsorption of sodium and causes osmotic diuresis reducing systolic blood pressure
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   Given oncedaily in the morning  Canagliflozin should be taken before the first meal of the day  Metabolized by glucuronidation to inactive metabolites  Should be avoided in patients with renal dysfunction
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  Adverse effects:  Femalegenital mycotic infections urinary tract infections, and urinary frequency  Hypotension 
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  Bromocriptine and colesevelamproduce modest reductions in HbA1c  The mechanism of action of glucose lowering is unknown  Indicated for type 2 diabetes  Modest efficacy, adverse effects limit their use in clinical practice
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   Used asan adjunct to mealtime insulin therapy in patients with type 1 and type 2 diabetes  Acts as amylinomimetic, delaying gastric emptying, decreasing postprandial glucagon secretion, and improving satiety  Administered SC and should be injected immediately prior to meals  When pramlintide is initiated, the dose of rapid- or short-acting insulin should be decreased by 50% prior to meals to avoid a risk of severe hypoglycemia  Pramlintide may not be mixed in the same syringe with any insulin preparation
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   Adverse effects ◦Nausea ◦ Anorexia ◦ Vomiting  Pramlintide should not be given to patients with diabetic gastroparesis, cresol hypersensitivity, or hypoglycemic unawareness
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  Dual PPAR alphaand gamma agents • Saroglitazar 2-4 mg/day • Aleglitazar 150-600microgm/d.
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  Standardvs.IntensiveTreatment Type GlucoseGoal HbA1cGoalTreatments BGMonitoring Normal 110mg/dl 6% ------------ -------------- Standard 225-275mg/dl 8-9% InsulinBID 2-3perday Intensive 150mg/dl 7% 3ormore 4-6perday Thetrade off between standard and intensive therapy is morefrequent hypoglycemic events (hypoglycemic events, seizuresand coma) for a marked delay in the onset of diabetic complications both microvascular and macrovascular. HbA1c=Hemoglobin A1cis auseful measure of glucose control over the prior 3-6 months, hyperglycemic episodesresult in the nonspecific glycosylation of variousproteins.
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