Endocrine pharmacologyEndocrine pharmacologyInsulin and oral Insulin and oral

hypoglycemic drugshypoglycemic drugsDMDM

Summary of drugs used in the treatment of diabetes Summary of drugs used in the treatment of diabetes

Overview

• The pancreas is both an endocrine gland that produces the peptide hormones insulin, glucagon, and somatostatin and an exocrine gland that produces digestive enzymes. The peptide hormones are secreted from cells located in the islets of Langerhans ( cells produce insulin, cells produce glucagon, and cells produce somatostatin). These hormones play an important role in regulating the metabolic activities of the body, particularly the homeostasis of blood glucose ز

Diabetes MellitusDiabetes Mellitus

• DiabetesDiabetes is a heterogeneous group of syndromes is a heterogeneous group of syndromes all characterized by an elevation of blood glucose all characterized by an elevation of blood glucose caused by a relative or absolute deficiency of caused by a relative or absolute deficiency of insulin .insulin .

• Diabetes can be divided into two group based on Diabetes can be divided into two group based on their requirement for insulin : their requirement for insulin :

1- IDDM ( absolute deficiency of insulin )1- IDDM ( absolute deficiency of insulin )

2- NIDDM ( insulin resistance ).2- NIDDM ( insulin resistance ).

Pathophysiology of T2DM

Blood glucose

diet

Hepatic glucose outputINSULIN

PeripheralTissueUptake

+

_

Major factors contributing to hyperglycemia observed in Type 2 diabetes

Major factors contributing to hyperglycemia observed in Type 2 diabetes

InsulinInsulin

• Latin: Latin: insulainsula – “island.” Produced in the – “island.” Produced in the Islets of Langerhands in the pancreas.Islets of Langerhands in the pancreas.

• Regulates carbohydrate metabolism in the Regulates carbohydrate metabolism in the body.body.

• 7%7% of the population has of the population has diabetesdiabetes, due to , due to defects in insulin production.defects in insulin production.

Insulin Insulin It is a 51 amino acid protein consisting of two It is a 51 amino acid protein consisting of two

polypeptide chains connected by disulfide bounds .polypeptide chains connected by disulfide bounds .

• It binds to tyrosine kinase receptor on the cell membrane It binds to tyrosine kinase receptor on the cell membrane in every tissue but the most important target organs are : in every tissue but the most important target organs are :

- liver- liver

MuscleMuscle

-Adipose tissue-Adipose tissue

• Effects on cellular metabolismEffects on cellular metabolism

LiverLiver

• Increased uptake of amino acids and glycerol;Increased uptake of amino acids and glycerol;

• Increased production of nicotinamide adenine dinucleotide Increased production of nicotinamide adenine dinucleotide phosphate dehydrogenase (NADPH);phosphate dehydrogenase (NADPH);

• Increased synthesis of glycogen, proteins, triglycerides and Increased synthesis of glycogen, proteins, triglycerides and very low density lipoproteins (VLDLs);very low density lipoproteins (VLDLs);

• Inhibition of glycogenolysis, promoting glycogen storage;Inhibition of glycogenolysis, promoting glycogen storage;

• Inhibition of gluconeogenesis;Inhibition of gluconeogenesis;

• Inhibition of ketogenesis, i.e. conversion of fatty acids and Inhibition of ketogenesis, i.e. conversion of fatty acids and amino acids to keto acids.amino acids to keto acids.

Skeletal muscleSkeletal muscle

• Increased uptake of glucose and amino acidsIncreased uptake of glucose and amino acids

• Increased synthesis of glycogenIncreased synthesis of glycogen

• Inhibition of ketone body formationInhibition of ketone body formation

• Inhibition of triglyceride utilisationInhibition of triglyceride utilisation

• Inhibition of proteolysis: reduced protein Inhibition of proteolysis: reduced protein catabolismcatabolism

• Increased protein synthesis.Increased protein synthesis.

• Adipose tissueAdipose tissue

• Increased uptake of chylomicrons and VLDLs Increased uptake of chylomicrons and VLDLs and of glucoseand of glucose

• Increased uptake and utilisation of glucoseIncreased uptake and utilisation of glucose

• Inhibition of lipolysisInhibition of lipolysis

• Increased triglyceride synthesisIncreased triglyceride synthesis

Types of insulinTypes of insulin

Synthetic human insulin preparations: s.cSynthetic human insulin preparations: s.c..

• Rapidly-actingRapidly-acting (e.g., Insulin lispro): (e.g., Insulin lispro): pharmacokinetics mimic pharmacokinetics mimic physiologic insulin; injected before meals to prevent meal-physiologic insulin; injected before meals to prevent meal-induced sharp increase in plasma glucose. Duration ≈3h.induced sharp increase in plasma glucose. Duration ≈3h.

• Short actingShort acting (e.g., Regular insulin): Duration ≈6h. (e.g., Regular insulin): Duration ≈6h.

• Intermediate-actingIntermediate-acting (e.g., NPH):Neutral protamine Hagedorn (e.g., NPH):Neutral protamine Hagedorn used to prolong duration. used to prolong duration.

• Pre-mixedPre-mixed: rapid-acting + regular insulin in a single injection : rapid-acting + regular insulin in a single injection to optimize postprandial control of glucose.to optimize postprandial control of glucose.

• Long actingLong acting (e.g., glargine): usually given at bedtime to (e.g., glargine): usually given at bedtime to prevent nocturnal hyprevent nocturnal hypopoglycemia. Last 24 h.glycemia. Last 24 h.

The standard route for the administration The standard route for the administration of insulin is of insulin is SCSC injection but for emergency injection but for emergency hyperglycemia lispro and regular insulin is hyperglycemia lispro and regular insulin is given given IVIV . .

Inhalation route under trial.Inhalation route under trial.

Route for the administration of insulinRoute for the administration of insulinRoute for the administration of insulinRoute for the administration of insulin

Adverse effects of insulinAdverse effects of insulin– Hypoglycemia Hypoglycemia – Insulin allergy Insulin allergy

( immunoglobulin E )( immunoglobulin E )– Insulin antibody Insulin antibody

( immunoglobulin G ) ( immunoglobulin G ) – Lipodystrophy .Lipodystrophy .

Oral hypoglycemic agentsOral hypoglycemic agents

Oral hypoglycemic agentsOral hypoglycemic agents

• Sulfonylureas Sulfonylureas • Meglitinide analogsMeglitinide analogs • Biguanides Biguanides • Alpha glucosidae inhibitorsAlpha glucosidae inhibitors• ThiazolidinedioneThiazolidinedione

SulfonylureaSulfonylurea

Classification:Classification:

1- first generation 1- first generation • chlorpropamide long acting .chlorpropamide long acting .

• tolbutamide tolbutamide

• autohexamide autohexamide

2- second generation 2- second generation • glyburide ( high potency)glyburide ( high potency)

• GlipizideGlipizide

• glimepiridglimepirid

Mechanism of action:Mechanism of action:These include These include 1) 1) stimulation of insulin release from the Bstimulation of insulin release from the B cells of the cells of the

pancreas by blocking the ATP-sensitive K+ pancreas by blocking the ATP-sensitive K+ channels, resulting in depolarization and Ca2+ channels, resulting in depolarization and Ca2+ influx influx

2) reduction in hepatic glucose production2) reduction in hepatic glucose production 3) increase in peripheral insulin sensitivity.3) increase in peripheral insulin sensitivity.4)- increase binding of insulin to target tissues and 4)- increase binding of insulin to target tissues and

receptors.receptors.

SulfonylureaSulfonylurea

Adverse effects of sulfonylureaAdverse effects of sulfonylurea

HypoglycemiaHypoglycemiaWeight gainWeight gain

GIT distress ,PruritusGIT distress ,Pruritus NauseaNausea

Agranulocytosis and aplastic anemiaAgranulocytosis and aplastic anemia

Drug interactionDrug interaction Drugs potentate the effect of sulfonylureas Drugs potentate the effect of sulfonylureas ((decrease glucose decrease glucose

levellevel ) ):: 1- Aspirin 1- Aspirin 2- MAOI2- MAOI 3- Ethanol 3- Ethanol

4- phenylbutazone 4- phenylbutazone 5- probenecid5- probenecid

6- Allopurinol6- Allopurinol 7- Anticoagulant 7- Anticoagulant Drugs reduce the effect of sulfonylureas Drugs reduce the effect of sulfonylureas ( Increase glucose ( Increase glucose ) ) ::

1- Glucocorticoid 1- Glucocorticoid 2- Beta blocker2- Beta blocker3- Rifampin3- Rifampin4- cholestyramine4- cholestyramine5-loop and thiazide diuretics5-loop and thiazide diuretics

Meglitinide analogs

• This class of agents includes This class of agents includes repagliniderepaglinide ] and ] and nateglinide .nateglinide . Although they are not sulfonylureas, they have common Although they are not sulfonylureas, they have common actions.actions.

• Mechanism of actionMechanism of action: Like the sulfonylureas, their action is : Like the sulfonylureas, their action is dependent on functioning pancreatic cells. They bind to a dependent on functioning pancreatic cells. They bind to a distinct site on the sulfonylurea receptor of ATP-sensitive distinct site on the sulfonylurea receptor of ATP-sensitive potassium channels, thereby initiating a series of reactions potassium channels, thereby initiating a series of reactions culminating in the release of insulin.culminating in the release of insulin.

•

• Adverse effects:

• Although these drugs can cause hypoglycemia, the incidence of this adverse effect appears to be lower than that with the sulfonylureas.

• Weight gain is less of a problem with the meglitinides than with the sulfonylureas.

BiguanidesBiguanides Types: Types:

1- Metformin ( glucophage ) 1- Metformin ( glucophage ) Mechanism of actionMechanism of action::

The exact mechanism is not known , The exact mechanism is not known , probably it stimulate glycolysis in peripheral probably it stimulate glycolysis in peripheral tissues and reduced hepatic gluconeogenasis .tissues and reduced hepatic gluconeogenasis .

• These agent dose not induce hypoglycemia even in These agent dose not induce hypoglycemia even in overdoses , they are excreted unchanged in the overdoses , they are excreted unchanged in the urineurine . .

• Other usesOther uses: In addition to the treatment of Type 2 : In addition to the treatment of Type 2 diabetes, metformin is effective in the treatment of diabetes, metformin is effective in the treatment of polycystic ovary disease. Its ability to lower insulin polycystic ovary disease. Its ability to lower insulin resistance in these women can result in ovulation resistance in these women can result in ovulation and, possibly, pregnancy.and, possibly, pregnancy.

Adverse effects :Adverse effects :– Fatal lactic acidosis (Rarly) Fatal lactic acidosis (Rarly) – GIT ( diarrhea , nausea )GIT ( diarrhea , nausea )– Decrease absorption of vitamine B12 and folate Decrease absorption of vitamine B12 and folate

if it taken for long time.if it taken for long time.

Contraindications of BiguanideContraindications of Biguanide

Renal or liver diseaseRenal or liver disease

Renal or liver diseaseRenal or liver disease

Chronic lung diseaseChronic lung disease

))Alpha glycosidase inhibitorsAlpha glycosidase inhibitors( ( Acarbose and MiglitolAcarbose and Miglitol

It delays the absorption of glucose from It delays the absorption of glucose from the GIT.the GIT.

-it does not cause hypoglycemia .-it does not cause hypoglycemia .

-it metabolized extensively in GIT by intestinal -it metabolized extensively in GIT by intestinal bacteria and digestive enzymes ,only about bacteria and digestive enzymes ,only about one third is excreted in the urine one third is excreted in the urine

Their main adverse effects are GITTheir main adverse effects are GIT disturbance ( flatulence and diarrhea )disturbance ( flatulence and diarrhea )

Thiazolidinedione (Troglitazone )Thiazolidinedione (Troglitazone ) • Another group of agents that are insulin sensitizers are the Another group of agents that are insulin sensitizers are the

thiazolidinediones (TZDs) or, more familiarly the thiazolidinediones (TZDs) or, more familiarly the glitazones.glitazones.

• two members of this class are available, two members of this class are available, • pioglitazone pioglitazone andand rosiglitazone rosiglitazone

It lower the blood glucose level by improving target cell It lower the blood glucose level by improving target cell response to insulin, it decrease hepatic glucose output and response to insulin, it decrease hepatic glucose output and increase disposal of glucose into skeletal muscle. increase disposal of glucose into skeletal muscle.

It metabolized in the liverIt metabolized in the liverOther usesOther uses: As with metformin, the relief of insulin resistance : As with metformin, the relief of insulin resistance

with the TZDs can cause ovulation to resume inwith the TZDs can cause ovulation to resume inTheir main adverse effects are:Their main adverse effects are:

- hepatotoxicity- hepatotoxicity- hypoglycemia- hypoglycemia- headache .- headache .