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Pharmacotherapy of diabetes mellitus
1. Pharmacotherapy of Diabetes Mellitus Dr Naser Ashraf Tadvi Associate Professor Kamineni Institute of Medical Sciences Narketpally, Nalgonda
2. Diabetes Diabetes is a group of metabolic disorders characterized by chronic hyperglycemiaassociated with disturbances of carbohydrate, fat and protein metabolism due to absolute or relative deficiency in insulin secretion and/or action Diabetes causes long term damage, dysfunction & failure of various organs
3. Diagnosis of diabetes Fasting Plasma Glucose ≥ 126 mg / dl Symptoms of DM and a random blood glucose level of ≥ 200 mg/dl Oral glucose tolerance test 2 hr after 75 gm glucose load ≥ 200 mg / dl
4. Classification of DiabetesProposed by ADA - 1997. Type I: Absolute Insulin Deficiency due to islet cell destruction Either immune mediated or idiopathic Type II: Relative insulin deficiency due to impaired -cell function Marked ↑ peripheral insulin resistance Type III: Other Specific types Type IV:Gestational Diabetes
5. Other specific types A) Genetic defects of Beta cell function B) Genetic defects in Insulin action C) Diseases of the Exocrine Pancreas D) Secondary to Endocrinopathies E) Drugs / Chemical induced F) Infections G) Uncommon form of Immune Mediated Diabetes. H) Other Genetic Syndromes associated with Diabetes MODY Syndromes Lipo atrophic Diabetes FCPD Pancreatitis Trauma Neoplasia Cystic Fibrosis Hemochromatosis Acromegaly Cushings Syndrome Pheochromocytoma Hyperthyroidism Steroids Thiazides Diazoxide Beta Blockers Thyroid Hormones Congenital Rubella CMV Anti insulin Receptor Antibodies Down’s Syndrome Turners Klinefelters
23. Bioassay of insulin 1 IU reduces the BSL to 45 mg/dl in fasting rabbits 1 mg insulin = 28 IU Can also be measured by radioimmunoassay or enzyme immunoassay
36. Carbohydrate metabolism Over all action of insulin is to ↓ glucose level in blood ↑ Transport of glucose inside the cell ↑ Peripheral utilization of glucose ↑ Glycogen synthesis ↓ Glycogenolysis ↓ Neoglucogenesis
37. Lipid metabolism ↓ Lipolysis ↑ Lipogenesis ↑ Glycerogenesis ↓ Ketogenesis ↑ Clearance of VLDL & chylomicrons from blood through enzyme Vascular Endothelial Lipoprotein Lipase
44. Insulin molecule INS Insulin Mediated Glucose Transport Insulin Receptor Complex a subunit a a Tyrosine Kinase Activation b b b subunit Metabolised Stored as Glycogen Glucose b b INS a a G Storage vesicle containing GLUT 4
45. Fate of insulin Distributed only extracellularly Must be given parenterally Addition of zinc or protein decreases its absorption & prolongs the DOA Insulin released from pancreas is in monomeric form Half life of insulin = 5 -9 minutes
46. Different types of insulin preparations Conventional preparations of insulin Produced from beef or pork pancreas 1 % of other proteins Potentially antigenic Highly purified insulin preparations Gel filtration reduces proinsulin (50-200PPM) Human insulins Newer insulin analogs
48. Highly purified insulin preparations Single peak insulins Purified by gel filtration contain 50 to 200 PPM proinsulin Actrapid: purified pork regular insulin Monotard: purified pork lente Mixtard: purified pork regular(30%) + isophane(70%) Mono component insulins After gel filtration purified by ion exchange chromatography contain 20 PPM proinsulin Actrapid MC, Monotard MC
49. Human insulins Human (Actrapid, monotard, insulatard, mixtard) Obtained by recombinant DNA technology Advantages More water soluble as well as hydrophobic More rapid SC absorption , earlier & more defined peak Less allergy Disadvantages Costly Slightly shorter DOA
50. Indications of human insulins Insulin resistance Allergy to conventional preparations Injection site lipodystrophy During pregnancy Short term use of insulin
52. Insulin Lispro Produced by Inversing proline at B28 with lysine at B29. Forms weak hexamers , dissociate rapidly Needs to be injected immediately before, during or even after meals Better control of meal time glycemia & lower incidence of PP hypoglycemia
53. Insulin aspart: Proline at B28 replaced by aspartic acid Change reduces tendency for self aggregation Insulin glulisine lysine replaces aspargine at B3 & glutamic acid replaces lysine at position B29
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56. Insulin glargine Prepared by adding 1 glycine at A21 together with 2 arginine residues at end of B chain Improved Stability Much better bioavailabilty Smooth peakless effect is obtained Fasting & interdigestive BGL effectively lowered irrespective of time of day Lower hypoglycemic episodes Cannot be mixed with other insulins
57. Insulin detemir Soluble long acting basal insulin analog with flat action profile and prolonged duration Threonine in B30 ommited & C14 fatty acid chain attached to amino acid B29 Prolonged action Strong self association Albumin binding Fatty acid side chain
68. Drug interactions of insulin Non selective beta blockers Thiazides,furosemide, corticosteroids, OCP , nifedipine↑ BSL Alcohol Precipitates hypoglycemia Salicylates, lithium, theophylline, may accenuate hypoglycemia
69. Uses of insulin Diabetes mellitus Must for type I diabetics Can be used in type II diabetics Diabetic ketoacidosis Hyperosmolar non ketotic hyperglycemic coma
70. Indications of insulin in type II DM Primary or secondary failure of oral hypoglycemics Pregnancy Perioperative period CKD Steroid therapy LADA Fasting > 300 mgms HbA1c > 10 Unintentional wt loss with or with out ketosis Type 2 with DKA ( severe beta cell dysfunction)
108. Pathogenesis of DKA (How ketoacidosis occurs) Hyperketonemia ↑ Lipolysis ↑ FFA to liver ↓ Alkali reserve ↑ Acetyl coA Acidosis ↑ AcetoacetylcoA -Hydroxy butrate Acetoacetate Acetone
109. Treatment of DKA Fluid therapy Rapid acting regular insulin Potassium Bicarbonate Phosphate Antibiotics Treatment of precipitating cause General measures
110. Fluid therapy Adequate tissue perfusion is necessary insulin action Normal saline is fluid of choice for initial rehydration 1 litre in first hour Next 1 L in next 2 hours 2 litres in next 4 hours 2 litres in next 8 hours i.e 4 to 6 litres in 24 hours When BSL reaches 300 mg% fluid should be changed to 5 % dextrose with concurrent insulin
111. Insulin in DKA Regular/ short acting insulin IV treatment of choice Loading dose = 0.1-0.2 U/kg IV bolus Then 0.1 U /kg/hr IV by continuous infusion Rate doubled if no significant fall in BSL in 2 hr 2-3 U/hr after BSL reaches 300mg% If patient becomes fully conscious encouraged to take oral food & SC insulin started
112. Potassium replacement In initial stage of treatment potassium not administered because in DKA it remains normal or ↑ In presence of insulin infusion Sr potassium ↓ hence 10 mEq/L potassium can be added with 3rd bottle of normal saline Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr
113. Bicarbonates & phosphates Bicarbonates If blood pH > 7.1 no need of sodium bicarbonate In presence of severe acidosis 50 mEq of sodium bicarbonate added to IV fluid Phosphates Non availability of ideal preparation Replacement not very essential unless < 1 mEq/L potassium phosphate 5-10 m mol/hr
114. Hyperosmolar Non Ketotic Coma Usually occurs in type II Dehydration with severe hyperglycemia without ketoacidosis, because insulin inhibits hormone sensitive lipase The general principle of T/t is same as for DKA except that pt needs more faster fluid replacement Half NS preferred 2 Lit in 2 Hrs followed by 1 Lit in next 2 hrs Low dose heparin to prevent vascular thrombosis & intravascular coagulation
115. Insulin resistance State in which normal amount of insulin produces subnormal amount of insulin response ↓ insulin receptors ↓ affinity for receptors May be acute or chronic Requirement of > 200 Units of insulin per day in absence of stress Common in type II diabetics & obese
132. Sulfonylureas I Generation Tolbutamide Chlorpropamide II Generation Glipizide Gliclazide Glibenclamide (Glyburide) Glimepiride
133. Mechanism of action Release of insulin by acting on SUR1 receptors Primarily augment phase 2 of insulin secretion Presence of at least 30% functional -cells essential for their action. Minor action: ↓ glucagon secretion Extra pancreatic action: ↑sensitivity of peripheral tissue to insulin by ↑insulin receptors
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135. Pharmacokinetics Well absorbed orally Highly bound to plasma proteins > 90% Have low volume of distribution Cross placenta C/I in pregnancy Metabolized in liver Excreted in urine
138. GLIMEPIRIDE Lesser risk of hypoglycemia Insulin sparing effect (Significant extra pancreatic effects) Relatively safe in elderly and mild renal failure Antiplatelet and antifibrinolytic activity Little or no weight gain FDA approved combination therapy with insulin Safe and effective for use in the pediatric population ↑Levels of plasma adiponectin & ↓ TNF α Stimulates GLUT4 expression
139. Why Glibenclamide is more potent and longer acting than other SU 1. May accumulate within cells and directly stimulate exocytosis of insulin granules 2. Greater/longer binding to SUR-1 receptors 3. Slower absorption and distribution 4. Inhibition of hepatic insulinase 5. Suppressionof several counter-regulatory hormones 6. More suppression of HGO 7. May stimulate insulin synthesis
140. Adverse effects Hypoglycemia: GI disturbances: Nausea, vomiting, metallic taste, diarrhoea & flatulence Weight gain Hypersensitivity Not safe in pregnancy Chlorpropamide: cholestatic jaundice, dilutionalhyponatremia, antabuse reaction
141. Contraindications Allergy to SU Renal failure: 3. Significant hepatic dysfunction 4. Severe infections, stress, trauma, major surgery, CVA, AMI 5. Pregnancy (except Glibenclamide) 6. T1DM
142. Drug interactions Drugs that ↑ SU action Salicylates, sulfonamides Cimetidine , warfarin, sulfonamides Propranolol Drugs that ↓ SU action Phenytoin, phenobarbitone , rifampicin Corticosteroids, thiazides, furosemide, OCP
151. Repaglinide Well tolerated in elderly patients in renal impairment Adverse effects: Mild headache, dyspepsia, arthralgia, headache Indicated in type II DM Dose : start 0.5mg with meals can ↑ 16mg/day
152. Nateglinide Stimulates first phase of insulin secretion More rapid acting & shorter duration than repaglinide Mainly used in post prandial hyperglycemia without producing late phase hypoglycemia Little effect on fasting BSL Adverse effects: diziness, nausea, flu like symptoms Dose: 60 to 180 mg TDS with meals
153. Biguanides Metformin & phenformin Little or no hypoglycemia Also improves the lipid profile in type II diabetic patients Metformin dose = 0.5 to 2.5 g/day in 2-3 divided doses
154. Mechanism of action Suppress hepatic & renal gluconeogenesis ↑ uptake & utilization of glucose by skeletal muscles which reduces insulin resistance Inhibit alimentary absorption of glucose Interfere with mitochondrial respiratory chain & promote peripheral glucose utilization by enhancing anaerobic glycolysis
155. Pharmacokinetics Taken orally , well absorbed through GI tract Not metabolized at all Excreted unchanged in urine
161. Thiazolidinediones (Glitazones) Rosiglitazone & pioglitazone Selective agonists of PPAR Bind to nuclear PPAR Activate insulin responsive genes - regulate carbohydrate & lipid metabolism Sensitize the peripheral tissues to insulin ↓blood glucose by Inhibit hepatic gluconeogenesis Promote lipogenesis ↑ Glucose transport into muscle & adipose tissue
162. Thiazolidinediones Hyperglycemia, hyperinsulinemia, and elevated HbA1c levels are improved. Pioglitazone has no effect on LDL levels, ↓ triglyceride & ↑ HDL Rosiglitazone has inconsistent effect on lipid profile it ↑ HDL & LDL levels The TZDs lead to a favorable redistribution of fat from visceral to subcutaneous tissues.
163. Pharmacokinetics Both Rosiglitazone & pioglitazone are completely absorbed from GIT Highly bound to plasma proteins (>95%) Rosiglitazone metabolized by CYP2C8, Pioglitazone metabolized by CYP2C8 & CYP3A4 Drug interactions less with rosiglitazone Metabolites of rosiglitazone are excreted in urine and those of pioglitazone in bile
164. Pioglitazone: 15 to 45 mg once daily orally Rosiglitazone: 4 to 8 mg once daily orally Pt who benefit most are type II DM with substantial amount of insulin resistance Also used in PCOD Monotherapy – Hypoglycemia rare Add-on Therapy – readjust dosage. Takes one month to act
165. Adverse effects Weight gain: due to fluid retention & edema ↑ Extracellular fluid volume Worsening of CHF ↑ Deposition of subcutaneous fat Mild anemia: due to hemodilution Hepatotoxicity : rare Rosiglitazone: ↑risk of fractures especially in elderly women
168. Pancreatic amylase Oligosaccharides/ Disaccharides Maltose, Isomaltose, Sucrose glucosidase enzymes (in the lining of cells of intestinal villi) Monosaccharides (Glucose, fructose) Absorbed in lower part of intestine Mechanism of action Dietary Carbohydrates (Starch) Glucosidase inhibitors X 104
169. Acarbose Complex oligosaccharide Inhibits -glucosidase as well as -amylase Reduces postprandial hyperglycemia without increasing insulin levels Regular use reduces weight In prediabetics reduces occurrence of type II DM, hypertension & cardiac disease Dose: 50 to 100 mg TDS Given just before food or along with food
170. Adverse effects Flatulence, diarrhoea, abdominal pain Do not cause hypoglycemia by themselves but may cause if used with Sulfonylureas If hypoglycemia occurs should not be treated with routine sugar (sucrose), Glucose should be used Contraindicated in inflammatory bowel disease & intestinal obstruction
179. Sitagliptin Orally active inhibitor of DPP-4 Prevents degradation of endogenous GLP-I Dose: 100mg a da Mainly used in post prandial hyperglycemia No action on weight and lipids Costly
180. Pramlintide Synthetic amylin analog Improves overall glycaemic control,↓ PPG Reduces BW : anorectic action Well tolerated Given SC before meals SE: GI disturbances/Less hypoglycemia when used alone Can be used in type I DM
181. Principles of treatment of Type 2 DM Grade Diabetes Mellitus as mild, moderate or severe NB: FBG (150 -200 ---mild ) HbA1c < 8 ( 200-250 --- Moderate) HbA1c 8 - 9 ( more than 250 severe) HbA1c 9 - 10 For severe DM start on insulin if there is wt loss & ketosis For mild & moderate DM use metformin if obese & sulfonylureas if not obese
185. If diabetes not controlled Look for SU failure Occult infection – TB – UTI Drug history and compliance Food history – hypoglycaemia and compliance
186. cardiac problem – avoid glitazones if in failure avoid metformin Renal problem – avoid metformin
187. Liver problem – avoid glitazone and metformin In general patients with complication Short acting SU or insulin
188. Be ware of other drugs - Diuretics - Corticosteroid - Other hormones - ACE inhibitors
Editor's Notes
Viz eyes , kidneys, nerves, heart and blood vessels. In nut shell diabetes can be defined as metabolic as well as vascular disorder.
Diagnosis of DM based on urine sugar is unreliable, when fasting plasma glucose is or random blood sugar is . On more than one ocassion
Marked increase in peripheral insulin resistance at receptor or post receptor level and increased hepatic glucose output GESTATIONAL DIABETES MELLITUS: FASTING > 126, PP > 140
Term origins from inselgerman word for islet/island.1869: Paul langerhans noticed clumps of cells scattered throughout the bulk of pancreas named them islets of langerhans
In spring of 1921 a canadian scientist Banting, asked JJR Macleod, professor of physiology to allow him to work in his lab , initially he was sckeptical but later on agreed alloweed him to use lab during summer vacation, supplied him with 2 10 dogs and 2 assistants but banting required only one assistant so flip of coin between charles best a medical student and clarknobel, best won it . So clark not only lost the flip but also the nobel
Biosynthesis of insulin takes place in two intermediate stages , preproinsulin and pro insulin. Synthesis of pre proinsulin takes place in endoplasmic reticulum which is cleaved by protease activity to proinsulin, Pre pro insulin is a single chain polypeptide containing 86 aminoacidsPre pro insulin -> proinsulin + insulin + c peptide The resultant pro insulin is packaged in vesicles and transported to golgii apparatus. The cleavage of pro insulin occurs in golgii apparatus to insulin and c peptide by enzymes trypsin and carboxy peptidase B like activity. After removal of c peptide insulin co precipitates with zinc as microcrystals within secretory granules. Conversion of proinsulin to insulin takes 30 to 120 min , pre pro insulin to proinsulin 10 -20 min The yielding insulin has low solubilty and co-precipitates with zinc to form microcrystals within the secretory granule , insulin is associated into diamers and presence of zinc can associate into hexamers . Zinc hexamers are then packed together to form a crystal lattice2 atoms of zinc can complex with 6 atoms of insulin, human pancreas can contain upto 8 mg of insulin = 220 units 1mg = 28 U insulin
Structure of insulin was fully worked out by sanger in 1956 Insulin is a 2 chain polypeptide having 51 aminoacids and 6000 molecular weight There are minor differences between human pork & beef insulin , pork insulin differs from human insulin in 1 amino acid only , beef insulin differs in 3 amino acids at 8, 10, 30 positionsHuman TIT , PORK TIA, BEEF AVA. C peptide: facilitates the correct folding of A & B chains of insulin and also maintains the alignment of the disulfide bridge in the insulin molecule before its removal , insulin is extracted in liver where as C peptide is not therefore plasma level of c peptide is good indicator of insulin secretion, it also has some biological actions , ameliorates autonomic neuropathy, stimulates glucose transport in muscles, induces vascular smooth muscle dilation.
Recombinant insulin synthesized by using E coli was first isolated by hebertboyer in year 1977
OTHER STIMULANTS FOR INSULIN RELEASE INCLUDE AMINO ACIDS MAINLY ARGININE AND LEUCINE, FATTY ACIDS.
Or by its potency of inducing hypoglycemic convulsions
Islets richly supplied by sympathetic & vagal nerves PRIMARY CENTRAL SITE OF REGULATION OF INSULIN SECRETION IS HYPOTHALAMUS Ventrolaterl nuclei stimulate insulin releaseVentromedial nuclei – opposite effect
Glucagon evokes release of insulin as well as somatostatinInsulin inhibits glucagon secretion Somatostatin inhibits the release of both insulin and glucagon
The over all actions of insulin are to favour storage of fuel: glucose, fats & proteins through effects on liver, muscles and adipose tissue It also influences cell growth, and metabolic function of various tissues Excess secretion of insulin leads to hypoglycemia and deficient secretion leads to hyperglycemia
Depending on type of action Liver, adipose tissue & muscle
Increased storage of fuel ↑ Transport of glucose inside the cell except in tissues where glucose is the only source of energy like brain, RBC, WBC, MEDULLARY CELLS OF KIDNEY
INSULIN
Degraded in GIT if given orally Monomeric form insulin is easily difffusible and biologically active
Other proteins like proinsulin, other polypeptides, pancreatic proteins
Conventional insulin preparations derived from pork and beef pancreas, Prompt insulin Zn suspension(Semilente)Regular insulin has to be injected 2-3 times a day, so it has been modified by zinc or protamine to yield slow absorption and longer action. The protamine zinc insulin and lenteinsulins are no longer available commercialyNPH insulin does not contain either excess of zinc or protamine hence it can be mixed with regular insulin in any proportion immediately before use.
Conventional or standard preparations of insulin contain 1 % or more of other proteins (proinsulin, other polypeptides) which are potentially antigenic. In the 1970s the improved purification techniques were applied which resulted in availability of highly purified and practically non antigenic preparations Immunogenecity of pork MC insulin equivalent to human insulins where as single peak preparations still have significant immunogenecityThese preparations are more costly but have greater stabilty, less allergic reactions, less insulin resistance & lipodystrophy.
It is unwise to transfer stabilized patient from one species of insulin to other without any good reason, though it is desirable to employ human highly purified insulin in all diabetics, in developing countries conventional insulin preparations are still used due to economic reasons
The presently available insulins tend to form hexamers when stored. After SC administration this self associated hexamers dissociate into diamers and then monomers. The monomeric form is the active form of insulin. This sequence of events takes around 30 to 40 min resulting in slow rise & fall in insulin concentration compared to insulin secreted by the beta cells in response to eating. This results in high postprandial hyperglycemia and susceptibility to hypoglycemia particularly before next meal. Further in between the meals and at night the beta cells secrete insulin at a constant rateto maintain basal conc with a flat profile. The conventional isophane and lente preparations are not able to maintain constant basal conc of insulin. Hence presently available soluble insulin or intermediate acting insulin are not able to match the natural insulin profile that occurs post prandially and in post absorptive period. This has prompted the development of designer insulins which will have physiological action profile like normal insulin
First recommended DNA analogue approved by FDA in 1996Developed with the aim of improving glycemic control at meal times. This modification did not alter receptor binding, but blocked the formation of insulin dimer and hexamer. Thisallowed larger amount of active monomeric insulin to beavailable for postprandial or after meal, injections.USING REGIMEN OF 2-3 DAILY MEAL TIME INSULIN LISPRO INJECTIONS, A SLIGHLTLY GREATER REDUCTION IN HbA1c compared to regular insulin has been reported. Fewer episodes of hypoglycemia occurred
It remains soluble at ph 4 of formulation but precipitates at neutral ph encountered on SC injection , a depot is created from which monomeric insulin dissociates slowly to enter circulation.Onset is delayed but relatively low levels of insulin are maintained for upto 24 hrs, smooth peakless effect obtained, thus it is suitable for once daily injection to provide background insulin action
Local reactions: swelling, erythema, stinging , lipodystrophy and lipoatrophy not seen with newer preparations Allergy: infrequent due to contaminating proteins : urticaria, angioedema, anaphylaxis are the manifestations Edema: some patients develop short lived dependent edema due to sodium retention
Acute intake of Alcohol Precipitates hypoglycemia by depleting hepatic glycogenSalicylates, lithium, theophylline, may accenuate hypoglycemia By enhancing insulin secretion and increasing peripheral glucose utilization.
Many type II diabetics can be treated with exercise and controlled diet only
0.4 to 0.8 U /Kg
Along with OHA –( SU / Metformin )
DKA is a complication of Type I DM very rare in NIDDM, The common precipitating factors are infection, trauma, stress, etc. Clinical features are anorexia, nausea, vomiting, polyuria, abdominal pain, hypotension, tachycardia, hyperventilation, altered consciousness or coma in untreated cases
↑ Acetyl coA (substrate for ketone production)
Treatment of precipitating cause: infection, trauma, acute stress General measures: gastric aspiration, catheterization of urinary bladder, antibiotic cover
, hence IV infusion of isotonic saline should be started first after blood sample has been collected If serum sodium more than 150 mEq/L hypotonic saline is indicated When BSL reaches 250 mg% fluid should be changed to 5 % dextrose with concurrent insulin administration In order to avoid hypoglycemia, it takes time for acidosis to get corrected than blood glucose Care should be taken
With this regimen the plasma glucose level should fall at rate of 50 mg/hr it usually comes down to half the initial value in 6 to 8 hrs, if at the end of 2-3 hrs plasma glucose doesn’t show any predictable fall the doses od insulin infusion doubled 12 U/hr
In initial stage of treatment potassium not administered as in presence of acidosis there will be high potassium it begins to fall with tretment of DKA There is no definite guideline when to start potassium it can be started when urine output is good, potassium levels should be evaluated every 2 hrs or as necessary, tall T waves in ecg so ecg monitoring, ringer lactate and fructose should be avoided in DKA
Phosphates Serum phosphate changes similar to potassium May cause muscle weakness & lethargy Non availability of ideal preparationReplacement not very essential unless < 1 mEq/LSometimes potassium phosphate may be administered in place of KCL In absence of facilities to measure ph hurried respiration > 36 /min is clinical pointer to administer bicarboateWITH RESUMPTION OF ORAL FLUID MILK REPLINISHES THE PHOSPHATES RAPIDLY
Hormone sensitive lipase is concerned with mobilization of fatty acids Cvp Monitoring is necessary in this syndrome There is high mortality rate in HONK
Acute: develops rapidly & is of short duration , infection, trauma, emotional stress, corticosteroids , ketoacidosisChronic: generally seen in patients treated for years with conventional insulin preparations, antibodies to homologus contaminating proteins are formed which also bind insulin. Common in type II Development of such insulin resistance is an indicator to switch over to newer preparations
Long term effect with lungs unclear Cannot use if smoker, start smoking, or if you quit smoking less than 6 months ago Adaptation of dose unclear in smokers, asthma, pneumonia & COPD Inhalation devices clumsy bulky, fragile and/or weighty Larger dose necessary compared to SC insulin Difficult to achieve with pts on large doses of insulinNasal insulin was not successful because of variable absorption withdrawn from the US marketOral insulin preparation are under trial
Hepatic degradation of insulin is slowed Extrapancreatic actions: sensitize the target
I. SU binds to specific binding sites (SUR-1) on the pancreatic β-cell plasma membrane that are coupled to ATP – dependent K+ channelsII. Closure of ATP – dependent K+ channels & inhibition of efflux of K+III. Depolarization of the plasma membrane & opening up of L-type voltage dependent Ca2+ channelsIV. Influx of Ca2+ into the cytosolV. Stimulation of extrusion of both mature & immature insulin granules
DIRA – Duodenal Insulin Releasing Agent – a gut factor2 polar active metabolites
The pharmacokinetics, the PPHG and overall glycaemic control make repaglinide suitable for administration preprandiallyMetabolised by liver Eliminated via the biliary routeWith the opportunity for flexible meal arrangements, including skipped meals, Without the risk of hypoglycaemia allow for flexible meal schedules
Little or no hypoglycemia in non diabetics even in diabetics the episodes of hypoglycemia to due to metformin are rare, they do not stimulate pancreatic beta cells
Do not cause insulin release but presence of some insulin is essential for their action Suppress hepatic gluconeogenesis & glucose output from liver : major action
Reduces FPG by 16 %Reduces PPG by 25 %Reduces all cause mortality by 36 %Action in Fasting & Prandial state.Better action in milder disease.No Hypoglycemias.
PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA RECEPTORS Reverse insulin resistance by stimulating GLUT 4 EXPRESSion and translocation and entry of glucoseThe first thiazolidinedione, ciglitazone, was synthesized in 1982(1). It was soon thereafter discovered that ciglitazone reduced insulin resistance in obese and diabetic animals. Because of their effects on insulin resistance, thiozolidinediones have been developed as pharmacological agents for the management of type 2 diabetes, although they were initially synthesized as potential lipid-reducing agents. Since their discovery, three thiozolidinediones have been introduced to the market in the U.S. : troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). In March 2000, troglitazone was withdrawn from the market because of liver toxicity. Reset glucose fatty acid cycle by reduction in circulating free fatty acids and by transcription of several genes that are imp for otimal insulin sensitivity as well as glucose and fat metabolism
[Note: Whether the adipogenic effects can be separated from those of increased insulin sensitivity is the subject of much research, particularly because of the role of obesity in this disease.] Pioglitazone and rosiglitazone can be used as monotherapy or in combination with other hypoglycemics or with insulin. The dose of insulin required for adequate glucose control in these circumstances may have to be lowered. The glitazones are recommended as a second-line alternative for patients who fail or have contraindications to metformin therapy.
FAILURE OF ORAL CONTRACEPTION CAN OCCUR WITH PIOGLITAZONE THERAPY, KETOCONAZOLE INHIBITS METABOLISM OF PIOGLITAZONE Duration of effect lasts more than 24 hours
Suppresses & Prevents TNF alfa
Thus slows down digestion and absorption of polysaccharides In diabetics also reduces cardiovascular events, Acarbose is not hypoglycemic drug, may be used as adjuvant to diet in type II DM with or without sulfonylurea in obese diabetics Can be used as monotherapy in early type ii diabetes, and with sulfonylureas in obese type II diabetes.
Flatulence, diarrhoea, abdominal pain: due to fermentation of undigested carbohydrates in lower GIT
Glucagon like peptide I is a hormone released from intestinal L cells in response to orally ingested nutrients. The GLP I hormone is an incretin hormone which has got potent antihyperglycemic action by amplifying nutrient insulin secretion, it is advantageous as this hormone will not produce hypoglycemia when administered, GLP-I is administered subcutaneously is susceptible for enzymatic degradation by dipeptidyl peptidase IV(DPP-IV) , this has prompted the researchers to develop GLP-I analogs which are resistant to DPP-IV degrdationIs released from L cells in ileum and colon– Stimulates insulin response From β cells in a glucose dependent manner– Inhibits gastric emptying– Reduces food intake and body weight– Inhibits glucagon secretion from α cells in a glucose- dependent manner– Effect on β-cell turnover in preclinical models
Current indication as an additional drug with metformin or SU in type II diabetics who have inadequate response to oral hypoglycemics
Prevents degradation of endogenous GLP-I potentiating there action Undergoing trial as an add on drug for treatment of type II DM with SU/Metformin
Amylin: a polypeptide produced by pancreatic beta cells which reduces glucagon secretion from alpha cells and delays gastric emptying Duration of action is 2-3 hours, has been marketed as an adjuvant to insulin, SU, Metformin, for control of meal time glycemia in both type I and type II diabetics.
Lean impaired renal function Secretagogues (short acting SU)--No control TZD or GLP Over weight with impaired hepatic function give secretagogue if suboptimal control Suboptimal controlBasalInsulin