ANTIDIABETIC DRUGS

Prof.MUDr Jiřina Martínková, CSc 2006/2007

ANTIDIABETIC DRUGS
Classification and the nomenclature of diabetes mellitus (DM):

DM is a chronic metabolic disorder characterised by a high blood
glucose concentration-hyperglycemia (fasting plasma glucose > 7.0 mmol//L, or plasma glucose > 11.1 mmol/L 2hr after a meal) caused by insulin deficiency, often combined with insulin resistance. Hyperglycemia occurs because of uncontrolled hepatic glucose output and reduced uptake of glucose by skeletal muscle with reduced glycogen synthesis. When the renal threshold for glucose reabsorption is exceeded, glucose spills over into the urine glycosuria and causes an osmotic diuresis - polyuria, which in turn, results in dehydration, thirst and increased drinking – polydipsia. Diabetic ketoacidosis is an acute emergency- it develops because of accelerated fat breakdown to acetyl-CoA, which, in the absence of aerobic carbohydrate metabolism, is converted to acetoacetate and beta-hydroxybutyrate (which cause acidosis) and acetone (a ketone)

ANTIDIABETIC DRUGS
Various complications develop as a consequence of the metabolic derangements in DM, often over many years Many of these are the results of disease of blood vessels, either large (macrovascular disease) of small (microangiopathy). Macrovascular disease consists of acclerated atheroma, which is much more common and severe in diabetic patients. Microangiopathy particularly affects the retina (blindness), kidney (chronic renal failure) and peripheral nerves (diabetic neuropathy,which is associated with accumulation of osmotically active metabolites of glucose. Coexisting hypertension promotes progressive renal damage.

Type 2 diabetes consists of combined defects of insulin secretion and action ranging from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance. .ANTIDIABETIC DRUGS Classification and the nomenclature of diabetes mellitus (DM): Type 1 diabetes encompasses cases resulting from pancreatic B cell destruction (immune-mediated in most cases).

the nonobese. Type 2 diabetes (DM2) represents a heterogenous group comprising milder forms of DM that occur predominantly in adults. plasma glucagon elevated.2). It is a catabolic disorder form in which circulating insulin is virtually absent.ANTIDIABETIC DRUGS Type 1 diabetes (DM1) is a severe form associated with ketosis in the untreated state. . It occurs most commonly in juveniles but occasionaly in adults. and the pancreatic B cells fail to respond to insulinogenic stimuli (Fig. Circulating endogenous insulin is often subnormal or relatively inadequate because of tissue insensitivity. is a common risk factor. Obesity. which generally results in impaired insulin action.1). there is an accompanying deficiency of the pancreatic B cells´s response to glucose (Fig. In addition to tissue insensitivity to insulin. and most patients with DM2 are obese.

Fig. Schematic diagram of two-phase release of insulin in response to a constant glucose infusion glucose Arb. units prediabetes/diabetes Type 2 Basal level early phase normal Type 1 late phase permitted . 1.

presumably by hydrolysis of the disulfide connection between the A and B chains through insulinase. I . Degradation The liver and kidney are the two main organs that remove I from the circulation. I is released from pancreatic B cells at a low basal rate and at much higher stimulated rate in response to a variety of stimuli.ANTIDIABETIC DRUGS INSULIN (I) is a small protein which contains two chains (A and B) linked by disulfide bridges. this ratio is reversed. with the kidney removing 35-40% of the endogenous hormone. in insulin-treated diabetics receiving s. Further degradation by proteolysis occurs. especially glucose. .c. In contrast. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas as the terminal of portal vein blood flow.

g. and a beta subunit. which spans the membrane. Finally.The beta subunit contains a tyrosine kinase. the insulin-receptor complex is internalised. which is entirely extracellular and constitues the recongition site. liver. Selfphosphorylation of the beta portion results in translocation of certain proteins such as glucose transporter from sequestered sites within adipocytes and muscle cells to exposed locations on the cell surface. 1) The full insulin receptor consists of two heterodimers. muscle and adipose tissue (Fig. . it is bound by specialised receptors identified in only a few target tissues (e. each containing an alpha subunit.ANTIDIABETIC DRUGS The insulin receptor Once I has entered the circulation. tyrosine kinase activity is stimulated in the beta portion (nine substances have been identified for the activated insulin receptors to be phosphorylated). When insulin binds to alpha subunit at the outside surface of the cells.

Fig. 2. INSULIN RECEPTOR Binding sites Cell membrane Intracellular space Tyrosin kinase . Schematic diagram of the two-phase release of insulin in response to a constant glucose infusion.

The first phase is missing in DM2 and both are missing in DM1. gastrointestinal tract hormones (gastrin. Insulin release is inhibited by the sympathetic nervous system (the role of alpha2adrenoceptors) and several peptides (somatostatin) . such as obesity of insulinoma. glucagon.ANTIDIABETIC DRUGS Downregulation of insulin receptors: appears in clinical situation associated with elevated blood levels. secretin). 2). which are released by eating. In contrast. Other stimuli include fatty acids. the parasympathetic nervous system stimulation. and drugs that act on sulfonylurea receptors. Schematic diagram of the two-phase release of insulin in response to a constant glucose infusion (Fig. it is produced by aminoacids.

ANTIDIABETIC DRUGS Effects of insulin (I) on its targets I promotes the storage of fat as well as glucose (both sources of energy) within specialised target cells and influences cell growth and metabolic functions of a wide variety of tissues. 1.Action of insulin on glucose transporters I has an important effect on several transport molecules that facilitate glucose movement across cell membranes (GLUT 1-GLUT 4) GLUT-4 (inserted into the membranes of muscle and adipose cells) is responsible for insulin-mediated uptake of glucose GLUT-2 (B-cells of pancreas) mediates transport of glucose into pancreatic B-cells. Its defects may contribute to the reduced insulin secretion that characterizes DM2 .

where it acts to: increase storage of glucose and to reset the liver to the fed state by reversing a number of catabolic mechanisms associated with the postabsorptive state:glycogenolysis. and increases potassium and phosphate uptake by the organ. Action of insulin on liver The first major organ reached by endogenous insulin via portal circulation in the liver.ANTIDIABETIC DRUGS 2. and gluconeogenesis These effects are brought about directly through activation or repression of selective enzymes or indirectly by reducing fatty acids flux to the liver via antilipolytic action on adipocytes. In addition I decreases urea production. protein catabolism. . promotes triglycerides synthesis. ketogenesis.

ANTIDIABETIC DRUGS 3. 4. Effect of insulin on muscle promotes protein synthesis by increasing amino acid transport and by stimulating ribosomal activity. It also promotes glycogen synthesis to replace glycogen stores expended by muscle activity. Effect of insulin on adipose tissue I acts to reduce circulating free fatty acids and to promote triglyceride storage in adipocytes (the most efficient means of storing energy). .

Treatment of DM Diet is the cornestone. combined with increased exercise Insulin is essential for the treatment of DM1 .

. coli or yeast and treating the extracted proinsulin to form the human insulin molecule. Pulmonary absorption occurs and inhalation of an aerosol is a new route of administration. .coli is available for clinical use as Humulin and dispensed as either regular. i.Pharmacokinetics Insulin is destroyed in the GIT. NPH. it is inactivated enzymatically in the liver and kidney Species of insulin Beef (slightly more antigenic) and purified monospecies pork insulin.m.c. lente or ultralente Humulin. and must be given parenterally (s. i. Once absorbed. Declining costs for biosynthesis of human insulin generally supplanted purified pork insulins. insulin has an elimination half-life of approximately 10 min. H u m a n i n s u l i n s are produced by recombinant DNA techniques – by inserting the human proinsulin gene into E.. Human insulin from E.v.).

in which two aminoacids (proline and lysine) have been reversed in their position without any influence on receptor binding. ultra-short acting insulin. .Insulin lispro monomeric insulin produced by recombinant technology. varying in the timing of their peak affect and duration of action (Fig. Various formulations of insulin are available.Insulin Insulin analogues . Its use is associated with significantly improved glycemic control (without increasee incidence of hypoglycemia). The advantage is quick dissociation into monomers and rapid absorption. 3). Used for emergency (ketoacidosis). Insulin lispro (ultra-short acting insulin) and glargine ultra-long acting insulin are the first to use. for rapid response (surgery). Peak serum value is reached in 1 hr.alteration of the insulin peptide provides an opportunity to change the absorption rate of the molecule.

neutral protamine or isophane insulin) is an intermediate insulin with the delayed onset of action achieved by combining appropriate amount of insulin and protamine.acting and long. NEPHAN INSULIN (NPH.v. thus forming finely divided amorphous solid or relatively insoluble crystals.Insulin short .acting insulin are made by precipitating insulin with protamine or zink. soluble crystalline zinc insulin.acting insulin regular insulin (HM-R). the only type of insulin that should be administered i. These preparations include isophane insulin and amorphous or crystalline insulin zinc suspension. intermediate . . which are injected as a suspension from which insulin is slowly absorbed.

injection the crystalline depot to provide a peakless basal insulin replacement that can last more than 24 hours. ultra-long acting insulin.an amorphous precipitate of insulin with zinc ions in acetate buffer that has a relatively rapid onset of action + 70% of ultralente insulin. peakless. GLARGINE – soluble. ULTRALENTE INSULIN –HUMULIN ULTRALENTE – a poorly soluble crystal zinc insulin that has a delayed onset and prolonged duration of action. This is needed in type1 patients to achieve basal insulin concentratin throughout the 24 hrs that are comparable to those achieved in normal subjects by basal endogenous secretion. The attachment of two arginine molecules to the chain B and substitution of a glycine for asparagine created an analogue.c. which precipitates after s.Insulin LENTE INSULIN is a mixture of 30% semilente . .

5-1 1-2 3-4 Onset (min/hr) 0.Insulin Tab.5-1 missing Duration (hr) 6-8 12-18 18-26 Duration (hr) 3-5 30 ANALOGUES Lispro glargine . 1 HUMAN INSULINS and ANALOGUES INSULINS NPH Lente Ultralente Onset (hr) 0.15-15 (min) 3-4 (hr) Maximum (hr) 2-3 4-10 10-15 Maximum (hr) 0.

Fig. 3 lispro arbitrary units permitted .

c. Continuous subcutaneous insulin infusion device (insulin pumps): the devices have a manually programmable pump that delivers individualized basal and bolus insulin replacement based on blood glucose self-monitoring results. injections of insulin. portable pen-sized injectors have been developed.Insulin INSULIN DELIVERY SYSTEMS Insulin pen injectors: to facilitate multiple s. It is usually placed on a belt or in a pocket . These contain replaceable cartridges of U100 human insulin and retractable needles. the 24hours basal rates are relatively constant from day to day. and the insulin is infused through thin plastic tubing that is connected . insulin lispro.Normally. NPH insulin. Disponsable insulin pens are also available for regular insulin. though temporarily altered rates can be superimposed to adjust for a short-term change in requirement. Pens eliminate the need to carry syringes and bottles of insulin to the workplace and while traveling.

and infusion set need to be changed using sterile techiques every 2 or 3 days. Inhaled insulin has a rapid onset and a relatively short duration of action. The use is encouraged for individuals who are unable to obtain target control while on multiple injection regimens and in circumstances where excellent glycemic control is desired (pregnancy).Insulin INSULIN DELIVERY SYSTEMS (to continue) to the subcutaneously inserted infusion set. It should be used to cover mealtime insulin requirements or to correct high glucose levels. The insulin reservoir. . tubing. A regular insulin is the only insulin specifically approved for pump use.

Portable pen injectors permitted .Fig. 4.

Insulin Adverse effects: .allergy is unusual but can occur as local or systemic reactions . bizarre behavior. can cause brain damage. are mainly symptoms of impaired function of the CNS : mental confusion. ultimately coma The treatment is to take a sweet drink or snack. tremulousness (the sympathetic nerv syst. or. hunger --convulsions + coma (parasympathetic hyperactivity). palpitations. to give i. In older diabetics. sweating.hypoglycemia common and. in those taking longer-acting insulins. glucose or i. if severe. . if the patient is unconscious.v.m. Warning signals of more rapid development due to regular insulin:tachycardia. glucagon. hyperactivity) + nauzea.

An intermediate-acting preparation is often combined with a short-acting preparations taken before meals .soluble insulin is used (i.patients with DM1 require long-term maintenance treatment with insulin.short-term treatment of patients with DM2 or impaired glucose tolerance during intercurrent events (operations.Insulin Clinical uses of insulin: .) in emergency treatment of hyperglycemic diabetic emergencies (ketoacidosis) . myocardial infarction) .v.emergency treatment of hyperkalemia: insulin is given with glucose to lower extracellular K+ via redistribution into cells .many patients with DM2 ultimately require insulin treatement . infections.

Oral hypoglycemic agents Biguanides Sulfonylureas Meglitidines Thiazolidinediones Alpha-glucosidase inhibitors .

increases glucose uptake and utilisation in muscle + reduces hepatic glucose production (gluconeogenesis) Adverse effects: . diarrhea) = transient . It does not cause hypoglycemia . heart failure…) Use: DM2.lactic acidosis rare but potencially fatal Metformin should be avoided in patients who predispose to lactic acidosis (renal and hepatic disease.Oral hypoglycemic agents Biguanides -Metformin Lowers blood glucose. patients obese and who fail treatment with diet alone.GIT disturbancies (anorexia + weight loss.

Oral hypoglycemic agents Sulfonylureas stimulate insulin secretion by B-cells (the equivalent of phase 1secretagogues) and thus reducing plasma glucose. cross the placenta severe hypoglycemia at birth s. . are generally contraindicated in pregnancy . Pharmacokinetics: . . all bind strongly to plasma albumin and compete for these binding sites with salicylates and sulfonamides. most are excreted in the urine their action is increased in the elderly and in patients with renal disease . well absorbed orally.

glipizide .Oral hypoglycemic agents First generation: Tolbutamide Second generation glibenclamide.

. with a peak concentration and peak effect within approximately 1 hour after digestion.Oral hypoglycemic agents Meglitidines A new class of insulin secretagogues modulates B cell insulin release by regulating potassium efflux through the potassium channels repaglinid has a very fast onset of action.

Oral hypoglycemic agents Thiazolidinediones a recently introduced class of drugs that enhance target tissue insulin sensitivity. Alpha-glucosidase inhibitors Acarbose and miglitol are competitive inhibitors of the intestinal enzymes and modulate the postprandial digestion and absorption of starch and disacharides. pioglitazone Their main action is to diminish insulin resistance by increasing glucose uptake and metabolism in muscle and adipose tissues. .rosiglitazone.

Oral hypoglycemic agents Clinical uses of oral hypoglycemic drugs: -DM2 as a supplement to diet and excercise to reduce symptoms from hyperglycemia . .drugs that act on the sulfonylurea receptors are well tolerated but often promote weight gain.metformin is preferred for obese patients unless contraindicated by factors that predispose to lactic acidosis .

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