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Lecture on PCO 354 �(Antidiabetic drugs)

Aprioku JS

Department of Pharmacology & Toxicology

Niger Delta University

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Diabetes

Diabetes mellitus is a chronic metabolic disorder which occurs when there is reduced (or absent) secretion of insulin, often combined with reduced sensitivity to its action (insulin resistance).

The disease is characterised by a high blood glucose concentration or hyperglycaemia (i.e., when fasting plasma glucose > 7.0 mmol/l, or plasma glucose > 11.1 mmol/l, two hours after a meal).

Hyperglycaemia occurs because of uncontrolled hepatic glucose output and reduced uptake of glucose by skeletal muscle with reduced glycogen synthesis.

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Diabetes

Characteristic signs of diabetes mellitus are glycosuria (glucose in urine), polyuria (excess urine formation), polydipsia (dehydration, thirst and water intake).

Disease also cause wasting through increased breakdown and reduced synthesis of proteins and diabetic ketoacidosis.

There are two main types of diabetes mellitus:

Type 1 diabetes (insulin-dependent diabetes mellitus-IDDM-or juvenile-onset diabetes).
Type 2 diabetes (non-insulin-dependent diabetes mellitus-NIDDM-or maturity-onset diabetes).

Gestational diabetes occurs during pregnancy.

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Diabetes

Secretion of insulin
Insulin is secreted by the pancreatic islets of Langerhans.

The pancreatic islets of Langerhans contain four main cells (β or B, A, D and PP cells) which secrete peptide hormones.

The B cells secrete insulin and also amylin. Amylin delays gastric emptying and opposes insulin by stimulating glycogen breakdown in striated muscle.

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Diabetes

A cells secrete glucagon, D cells secrete somatostatin, PP cells secrete pancreatic polypeptide.

Glucagon opposes insulin, increasing blood glucose and stimulating protein breakdown in muscle.
Somatostatin inhibits secretion of insulin and glucagon. It is widely distributed outside the pancreas and is also released from the hypothalamus.

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Diabetes

Mechanism of insulin secretion
ATP-sensitive potassium channels (K_ATP) determine the resting membrane potential in B cells.

Glucose enters B cells via a membrane transporter called Glut-2, and its subsequent metabolism via glucokinase and glycolysis increases intracellular ATP. This blocks K_ATP channels, causing membrane depolarisation and opening of voltage-dependent calcium channels, leading to Ca²⁺ influx.

The resulting increase in cytoplasmic Ca²⁺ triggers insulin secretion.

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Diabetes

Actions of insulin- Insulin is an anabolic hormone: its overall effect is to conserve fuel by facilitating the uptake and storage of glucose, amino acids and fats after a meal. Insulin reduces blood sugar, and fall in plasm insulin increases blood glucose.
Carbohydrate metabolism- In liver, insulin inhibits glycogenolysis, gluconeogenesis while stimulating glycolysis and glycogen synthesis (glycogenesis). Overall, insulin increases hepatic glycogen stores. In the muscle, insulin increases glucose uptake by Glut-4 in adipose tissue as well as in muscle.
Fat metabolism- Insulin increases synthesis of fatty acid and triglyceride in adipose tissue and inhibits lipolysis.
Protein metabolism- Insulin stimulates uptake of amino acids into muscle and increases protein synthesis. Decreases protein catabolism & inhibits oxidation of amino acids in liver.

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Treatment of diabetes

Diet is the cornerstone in treatment of diabetes combined with increased exercise.

Oral agents are used to control symptoms from hyperglycaemia, as well as to limit microvascular complications.

Combination of dietary measures and statins is used to prevent atheromatous disease most cases.

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Insulin

Insulin was initially derived from pancreas of freshly slaughtered pig (porcine insulin) or cow (bovine insulin) for clinical use, and currently by recombinant DNA technology (human insulin). Porcine and bovine insulins differ from human insulin in their amino acid sequence. Bovine insulin is more immunogenic than porcine, and recombinant human insulin is least immunogenic.

The amino acid sequence of insulin has been determined since 1955 by the Sanger's group in Cambridge. It has two peptide chains (A and B) which have 21 and 30 amino acid residues, respectively.

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Insulin

Mechanism of action of insulin
Insulin binds to a specific receptor on the surface of its target cells. The signal transduction mechanisms that link receptor binding to the biological effects of insulin are complex and responsible for the actions of insulin.

Pharmacokinetics of insulin
Insulin is given only parenterally because it is destroyed in the GIT. The usual route is sc, but in emergency situations, it can be given IV or IM.
Half-life of insulin is about 10 m, metabolized in the liver and kidney, and about 10% is excreted in the urine, so renal impairment reduces insulin requirement.

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Insulin

Insulin formulations
Soluble insulin- produces a fast onset (2-4 h) and short duration (6-8 h). Given IV.
Isophane insulin- intermediate insulin. Prepared by precipitating insulin with protamine to form crystalline suspensions.
Insulin zinc suspension- long-acting insulin- Prepared by precipitating insulin with zinc
Insulin analogs- insulin lispro, insulin glargine
Insulin pumps- used in hospitals which use blood glucose measuring sensors to regulate the dose.
Generally, multiple daily injections of short-acting insulins with meals, and a longer-acting insulin at night helps in the blood glucose control.

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Insulin

Clinical uses of insulin
Type 1 diabetes who require long-term insulin: normally given combination of an intermediate-acting preparation (e.g. isophane insulin) and short acting insulin (soluble insulin) twice daily before breakfast and before the evening meal.
Diabetic ketoacidosis. Soluble insulin is used (IV)
Type 2 diabetes.
Gestational diabetes in pregnant whose blood glucose levels are not controlled by diet alone.
Hyperkalaemia: insulin is given with glucose to lower extracellular K⁺ via redistribution into cells

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Insulin

Adverse effects of insulin
The major adverse effect of insulin is hypoglycaemia, and can cause brain damage in severe cases. Hypoglycaemia can be treated by simply taking a sweet drink or snack, and when patient is in coma, IV glucose or IM glucagon can be given.

Insulin-induced hypoglycaemia can cause rebound hyperglycaemia because of release of counter-regulatory hormones.

Allergy, but is uncommon with human insulin

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Biguanides

Example, Metformin
Mechanism of action- not completely understood. Increase glucose uptake and utilisation in skeletal muscle (thereby reducing insulin resistance) and reduce hepatic glucose production (gluconeogenesis). It reduces LDL and VLDL. Metformin, does not cause hypoglycaemia.

Pharmacokinetics of metformin
Half-life about 3 h, excreted unchanged in the urine

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Biguanides

Clinical uses of metformin
Type 2 diabetes. It does not stimulate appetite so it is first-line drug for obese patients. It can be combined with sulfonylureas, glitazones or insulin.

Adverse effects of metformin
The commonest is gastrointestinal disturbances (e.g. anorexia, diarrhoea, nausea).
Lactic acidosis (so avoid in renal or hepatic disease, hypoxic pulmonary disease, heart failure or shock, pregnancy).
Long-term use may interfere with absorption of vit. B₁₂

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Sulphonylureas

The sulfonylureas were developed following the chance observation that a sulfonamide derivative (used to treat typhoid) caused hypoglycaemia.
These drugs all contain the sulfonylurea moiety and act in the same way, but different substitutions result in differences in pharmacokinetics and hence in duration of action.

First generation sulphonylureas- tolbutamide, chlorpropamide
Second generation sulphonylureas- glibenclamide, glipizide

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Sulphonylureas

Chlorpropamide has long duration of action, excreted in the urine, and causes severe hypoglycaemia particularly in the elderly. It causes flushing after alcohol because of a disulfiram-like effect when taken together with alcohol, and produces water intoxication due to its antidiuretic hormone like effect on the distal tubule. Chlorpropamide is no longer in popular use.

The second-generation sulfonylureas are more potent but they do not have overall higher hypoglycaemic effect or efficacy in blood glucose control.

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Sulphonylureas

Mechanism of action of sulfonylureas
The sulfonylureas act primarily on B cells causing stimulation of insulin secretion, resulting in reduction of glucose level in plasma.

They bind to sulfonylureas receptors present in the K_ATP channels in B-cell plasma membranes and block the channel.

Blockade of K_ATP channel by sulfonylurea drugs causes depolarisation, influx Ca²⁺ into the cell and insulin secretion.

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Sulphonylureas

Pharmacokinetics of sulfonylureas
Sulfonylureas are well absorbed after oral administration, peak plasma concentrations are attained within 2-4 h in most of them, but they have different durations of action. Strongly bound to plasma protein (90-95%).
Some amount of glibenclamide is oxidised in the liver to active products and is excreted in urine; 50% is excreted unchanged in the faeces.
Most sulfonylureas (or their active metabolites) are excreted in the urine. Half-life of glibenclamide 18-24 h, glipizide 16-24 h, tolbutamide 6-12 h
Most sulfonylureas cross the placenta and enter breast milk; contraindicated in pregnant/breastfeeding mothers.

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Sulphonylureas

Clinical uses of sulfonylureas
Sulfonylureas require functional B cells, so they are useful in the early stages of type 2 diabetes. They can be combined with metformin or thiazolidinediones.

Adverse effects of sulfonylureas
Sulfonylureas stimulate appetite (probably via their effects on insulin secretion and blood glucose) and often cause weight gain.
Hypoglycaemia (especially glipizide, glibenclamide)
Glibenclamide should be used with caution in the elderly and patients with renal disease
Tolbutamide contraindicated in liver failure
Allergic skin rashes, bone marrow damage

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Sulphonylureas

Drug interactions with sulphonylureas
Non-steroidal anti-inflammatory drugs, alcohol, monoamine oxidase inhibitors, antibacterial drugs (including sulfonamides, trimethoprim, and chloramphenicol), coumarins, sulfinpyrazone cause severe hypoglycaemia when used concurrently with sulfonylureas.

The interactions may be resulting from competition for metabolising enzymes and interference with plasma protein binding or excretion.

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Other insulin secretagogues

E.g., repaglinide, nateglinide
These drugs lack the sulfonylurea group in their structure but able to stimulate insulin secretion. They have similar mechanism of action as the sulfonylureas, blocking the sulfonylurea receptor on K_ATP channels in pancreatic B cells to promote secretion of insulin. Nateglinide has rapid onset of action and short duration of action (half-life 3 h) and low risk of hypoglycaemia.
They may cause less weight gain than conventional sulfonylureas.
They are more selective for K_ATP channels on B cells than sulphonylureas

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