Oral Hypoglycemic Drug- Sulphonylureas: Mechanism, Indication, Side Effects

Mechanism of action of Sulfonylureas (Glibenclamide) / oral hypoglycemic drug:

I. Pancreatic action: 

a. They are effective only in the presence of functioning pancreas at least 30% β- cell should be active.
At pancreatic beta cell membrane there is ATP dependent K+ channel. Sulfonylurea bind to sulfonylurea receptor and blocks the ATP dependent K+ channel. So inhibits the efflux of K+ ion, through the channel resulting depolarization. Depolarization causes opening of voltage gated Ca++ channel leading to influx. This Ca++ then induces insulin secretion. This endogenous release insulin then lowers the blood glucose level. Sulfonylurea acts only in presence of viable pancreatic beta cell that is when at least 30% pancreatic beta cell is viable. It is indirect action of sulfonylurea.

b. Reduction of serum glucagons concentration:
Increase release of both insulin and somatostatin causes inhibition of α cells which leads to reduction of glucagons release

II. Extra pancreatic action:
Sulfonylurea binds to its receptor in K+ channel in extrapncreatic tissue also and may potentiate the action of insulin by –
o    Increase number of insulin receptors in tissue
o    Increase binding affinity of insulin receptor for insulin
o    Increase glucose transport into the cell by glucose transporter
o    Decrease release of catecholamines
o    Inhibit glycogenolysis by inhibiting phosphorylase enzymes

Three mechanism of Sulfonylureas action have been proposed. Sulfonylureas indirectly decrease blood sugar:
By –
1. Release of insulin from pancreatic beta cell.
2. Reduction of serum Glucagon level.
3. Potentiate the action of insulin on its target tissue & extra pancreatic effect.

Adverse effect of Sulfonylureas:

1. Hypoglycaemia.
It is not frequently occurs but when occurs tends to be prolong. It is particularly seen with Chlorpropamide, Glibenclamide & elderly patient with impaired hepatic & renal function.

2. GIT upset.

• Nausea
• Vomiting.
• Diarrhea

3. Haemotological reaction.

• Neutropenia
• Agranulocytosis
• Thrombocytopenia
• Aplastic anemia

4. Cholestatic jaundice & intolerance to alcohol Chlorpropamide can induce hepatic microsomal enzyme particularly in high doses & due to disulfiram like reaction.

5. Allergic skin reaction – skin rash, exfoliative dermatitis

6. Weight gain – due to increase appetite

7. Muscular weakness, ataxia, dizziness, mental confusion

8. Teratognensis

9. Drug interaction:  Sulfonylureas are protein-binding drug so drug interaction occurs with protein binding drugs.

• Sulfonamide
• Salicylate
• Phenylbutazone
• Warfarin

These drugs displace Sulfonylureas & produce antidiabetic effect & cause hypogylcaemia.

Indications of Sulfonylureas:

1. Sulfonylureas are used for the treatment of NIDDM who can’t be controlled by diet, exercise & weight reduction. It is usually used in non-obese non-insulin dependent patient.

Contraindications of Sulfonylureas:

1. In insulin dependent diabetes mellitus (IDDM).
2. Diabetes with complication e.g. diabetic keto acidosis, diabetic nephropathy etc.
3. Diabetes with surgery.
4. Diabetes with pregnancy & lactation.
5. Hepatic & renal impairment.

N.B:
Combined therapy with Sulfonylureas & insulin: 
It is used in cases where daily insulin requirement is very high. Since Sulfonylureas drug not only increase the pancreatic beta cell secretion of insulin but also increase peripheral tissue sensitivity to insulin. So use of Sulfonylureas has been advocated to reduce the total insulin dose.

How Insulin Reduces Blood Glucose Level; Indication of Insulin

Insulin reduce blood glucose level by –

1. Increase glycogenesis by increase glucose uptake & increase deposition of glycogen.
2. Decrease glycogenolysis by decrease phosphorylase & decrease cAMP.
3. Decrease neoglucogenesis by decrease enzymes concerned with neoglucogenesis

Indications of insulin

1. Insulin dependent diabetes mellitus (IDDM-Type I).
2.  Non -insulin dependent diabetes mellitus (NIDDM- Type II) when oral hypoglycemic drug failed.
3. Diabetes with complication such as -
•    Diabetic keto acidosis
•    Diabetic retinopathy
•    Diabetic nephropathy
•    Diabetic neuropathy
•    Diabetic acidosis.
These are emergency condition. Here we use short acting insulin & it is administered in I/V route.

4. Diabetes with acute infection & acute MI.
5. Diabetes with surgery. Before surgery, during surgery & after surgery insulin is required.
6. Diabetes with pregnancy (gestational diabetes). During pregnancy diabetes is controlled by insulin, here oral hypoglycaemic drug should not be used because it can cross-placental barrier & have teratogenic effect.
Insulin has large molecular weight & does not cross placenta & have no teratogenic effect.
7. Diabetes with pancreatectomy.

Synthesis and Pharmacological Properties of Insulin

Islets of langerhans of pancreas contains 4 types of cells –

I. α / A cell	20%	Secretes glucagons ( increase blood glucose level)
II. β/ B cell	68%	Secretes insulin ( decreases blood glucose level)
III. δ / D cell	10%	Secretes somatostatin ( inhibit both insulin and glucagons release)
IV. PP/ F cell	2%	Secretes pancreatic polypeptide ( stimulation of gastric and intestinal enzymes and inhibition of intestinal motility)

   

Insulin is a large polypeptide hormone. It is synthesized in beta cell of pancreas. It consists of 51 amino acid & they are arranged in A chain & B chain. A chain contains 21amino acid & B chain contains 30 amino acid. A chain & B chain are linked together by disulfide bond. In addition, A chain contains another disulfide bond. Disulfide bond are essential for biological activity. Oral administration of insulin; disulfide bond are destroyed by proteolytic enzyme pepsin not by HCl.

Source:

a. Human.

b. Porcine.

c. Bovine

Synthesis of insulin:

Site: Rough endoplasmic reticulum of β cell.

Steps:  Glucose enters in to the cell → converts into glucose metabolites → stimulates RER (rough endoplasmic reticulum)→ synthesis of preproinsulin → which converted to proinsulin → proinsulin transported into golgi complex → & converted into insulin by the enzyme trypsin like enzyme.(These trypsin like enzyme are transmitted genetically into the individual , the person had lack of these enzyme who has suffer  DM). Then insulin is packaged into the granules→ granule fused with cell membrane →exocytosis of insulin →release of insulin into the capillary blood.

Insulin exists in our body in 3 forms:

1. Monomers-single molecule active form.

2. Dimer –double molecule inactive form.

3. Hexamer- It is storage form of insulin in granules of β cell. It is stored in the form of crystal & consists of 2 molecule of zinc & 6 molecule of insulin.

Daily release of insulin is 18- 40 units.

It is metabolized by enzyme insulinase.

M/A of insulin (cellular/molecular mechanism):

Insulin receptor is a tetramer made up of two alpha (α) & two beta (β) glycoprotein subunits & binds by disulfide bonds. The a subunit binds with insulin extra cellularly & β subunit is transmembrane protein & its intracellular end has tyrosine kinase activity. Binding of insulin triggers the tyrosine activity of the β subunits producing autophosphorylation of the β subunits on the tyrosine residue.

Autophophorylation of the β subunit leads to phosphorylation of some enzyme in the cytosol .The activated enzyme then produce action.

Pharmacological properties of insulin

Insulin promotes storage of fat, as well as glucose (both are sources of energy) in target cell & influences growth of cells & metabolic function of tissue.

A. Action of insulin on glucose transports: Insulin has an important effect on several transport molecules that facilitates glucose transport or movement across the cell membrane. These transporters play a role in etiology as well as manifestation of diabetes. There are 5 types of transporters.

GLUT -4 is important for lowering blood glucose.

Defect in GLUT-2 mediates transport of glucose into pancreatic β-cells may cause reduced insulin liberation that characterized NIDDM.

B. Action of insulin on liver:

1. Decreased blood glucose level by –

a. Increase glycogenesis by increase glucose uptake & increase deposition of glycogen.

b. Decreased glycogenolysis by decrease phospholipase & increased cAMP.

c. Decreased neoglucogenesis by decrease enzymes concerned with neoglucogenesis

2. Decrease TG synthesis & VLDL formation?

3. Decrease protein catabolism.

4. Increased K⁺ & phosphate uptake by liver.

5. Inhibit formation of keto acid, fatty acid & protein.

C. Action of insulin on muscle:

1. Increase protein synthesis by amino acid transport & increased ribosomal protein synthesis.

2. Increase glycogen synthesis by glucose transport. Induce glycogen synthetase & inhibit phosphorylase.

D. Action of insulin on adipose tissue:

Decrease circulating free fatty acid & promotes TG storage in adipose tissue by-

1. Lipoprotein lipase is induced & activated by insulin to hydrolyze TG from lipoprotein.

2. Glucose transport into cell to form glycerophosphate as a metabolic product which permits esterification of fatty acid.

3. Intracellular lipase is inhibited by insulin & inhibition of lipolysis of stored TG

Antidiabetic Drugs or Hypoglycemic Agents

A. Injectible hypoglycaemic drug:

Insulin preparations are:

a. Ultra short acting insulin, very rapid onset of action –

• Insulin lispro (duration of action 3-4hrs)
• Insulin Aspart
• Insulin glulisine

b. Short acting insulin, rapid onset action, Soluble insulin –

• Regular humulin (D/A 6-8 hrs)
• Regular novolin
• Velosulin BR
• Semilente insulin (prompt insulin zinc suspension) (D/A 12-14hrs)

c. Intermediate acting insulin (slower action) – Isophane insulin suspension (NPH- neutral protamine hydrogen) (D/A is 7-14 hrs), Lente insulin (insulin zinc suspension)

d. Long acting insulin (slower onset of action) –

• Insulin detemir
• Insulin glargine
• Protamine zinc insulin suspension (PZI) D/A is 24-36hrs
• Ultralente insulin (Extended insulin zinc suspension)

e. Premixed insulin (%NPH + % regular), Biphasic insulin -

• Humulin 70/30
• Novolin 70/30
• 50/50 NPL, Lispro
• 75/25 NPL, Lispro
• 70/30 NPA, Aspart

  

B. Oral hypoglycaemic drug:

I. Insulin secretagogues:

1. Sulfonylureas:

a. First generation-

·         Tolbutamide.                                           

·         Chlorpropamide.

·         Acetohexamide.                                      

·         Tolazamide.

b. Second generation-

·         Glyburide

·         Glibenclamide.                         

·         Glipizide.

·         Glimepiride

·         Gliclazide

2. Meglitinides:

• Repaglinides

3. Diphenylalanine derivative

• Nataglinide

II. Biguanide:

·         Phenformin.                                                             

·         Metformin.

·         Buformin.

Types of Diabetes Mellitus

1. IDDM (Type -1) Insulin dependent diabetes mellitus: It is severe form of diabetes mellitus, it occurs in juvenile period i.e. child & younger. Here, circulating insulin is virtually absent because β cell are damaged & β cell failed to secrete enzyme.

 

Criteria:

• Autoimmune type is commoner than idiopathic type
• Age <30yrs
• Abrupt onset
• Not obese when they first develop symptom
• Polyuria, polydipsia, polyphagia
• Due to absolute deficiency of insulin resulting form autoimmune destruction of beta cell
• Treatment – diet control and insulin
• Without insulin the treatment of such patient will die ultimately with diabetic ketoacidosis
• Diabetic ketoacidosis only occur in type I

2. NIDDM (Type-2) or maturity onset DM: It is milder form of diabetes, it occurs in adult. Here circulating insulin level is present but insufficient to reduce blood sugar level.

Criteria:

• Have genetic predisposition – about 90-95% sufferer have family history
• Age > 40
• Gradual onset
• Usually obese
• Usually asymptomatic
• Due to both by insulin resistance and impaired insulin secretion
• Treatment:

o    Initially diet control alone

o    Diet control + oral hypoglycemic drug

o    1/3^rd patient require insulin

§  Ketoacidosis is usually absent

3.  Type – 3 mellitus:

i. Drugs –

§  Corticosteroids

§  Thiazide diuretics

§  Phenytoin

ii. Some non pancreatic disease –

§  Acromegaly

§  Cushing’s syndrome

§  Pheocromocytoma

§  Hyperthyroidism

4. Type 4 DM:

• It is known as gestational diabetes (GDM)
• GDM is defined as any abnormality in glucose level for the 1^st time during pregnancy

Hormone: Definition and Its Type

Definition:

Hormone is a chemical substance secreted directly in to the body fluid by a cell or a group of cells or glands which exerts physiological controlling function on other cells or organ of the body.

Chemistry of hormone:

Chemically hormones are three types –

1. Steroid hormone:

a. Adrenal cortex hormone e.g. cortisol, Aldosterone.

b. Hormone of ovaries e.g. Estrogen, Progesterone.

c. Hormone of testes e.g. Testosterone.

2. Derivatives of amino acid tyrosine:

a. Thyroid gland hormone e.g. Thyroxin (T₄), Tri-iodothyronin (T₃).

b. Adrenal medullary hormone e.g. Adrenalin, nor adrenalin, dopamine

3. Protein or polypeptide hormones:

a. Posterior pituitary hormone / small polypeptide hormone. e.g. ADH (number of amino acid is 8), Oxytocin.

b. Large polypeptide hormone (number of amino acid is >10); e.g. Insulin, Glucagon, Parathormone.

c. Most hypothalamic hormone

d. Hormones of anterior pituitary – LH, GH etc.

Diabetes Mellitus: Definition and Classification

In this post I am gonna discuss about Diabetes mellitus.

Diabetes Mellitus:

It is a chronic metabolic disorder characterized by a high blood glucose concentration (hyperglycemia) and disturbances of carbohydrate, fat and protein metabolism caused by deficiency of insulin in the body or resistance to the action of insulin.

• DM affects about 5-8% of population
• In DM fasting plasma glucose > 7.0mmol/L
• DM is confirmed by GTT

Symptoms:

3P

• Polyphagia
• Polydypsia
• Polyuria

Treatment:

3D

• Discipline
• Diet
• Drugs

Complication of uncontrolled DM:

I. Micro vascular:

§  Retinopathy

§  Nephropathy

§  Neuropathy

§  Cataract

II. Macro vascular: Atherosclerosis following dyslipidemia leading to IHD and CVA

When the renal threshold for glucose reabsorption is exceeded, glucose come into urine (glycosuria), causes osmotic diuresis ( polyuria), which in turn result in dehydration, thirst and increased dinking tendency ( polydypsia) 

Types of Diabetes Mellitus:

1. IDDM (Type -1) Insulin dependent diabetes mellitus: It is severe form of diabetes mellitus, it occurs in juvenile period i.e. child & younger. Here, circulating insulin is virtually absent because β cell are damaged & β cell failed to secrete enzyme.

Criteria:

• Autoimmune type is commoner than idiopathic type
• Age <30yrs
• Abrupt onset
• Not obese when they first develop symptom
• Polyuria, polydipsia, polyphagia
• Due to absolute deficiency of insulin resulting form autoimmune destruction of beta cell
• Treatment – diet control and insulin
• Without insulin the treatment of such patient will die ultimately with diabetic ketoacidosis
• Diabetic ketoacidosis only occur in type I

2. NIDDM (Type-2) or maturity onset DM: It is milder form of diabetes, it occurs in adult. Here circulating insulin level is present but insufficient to reduce blood sugar level.

Criteria:

• Have genetic predisposition – about 90-95% sufferer have family history
• Age > 40
• Gradual onset
• Usually obese
• Usually asymptomatic
• Due to both by insulin resistance and impaired insulin secretion
• Treatment:

o    Initially diet control alone

o    Diet control + oral hypoglycemic drug

o    1/3^rd patient require insulin

§  Ketoacidosis is usually absent

3.  Type – 3 mellitus:

i. Drugs –

§  Corticosteroids

§  Thiazide diuretics

§  Phenytoin

ii. Some non pancreatic disease –

§  Acromegaly

§  Cushing’s syndrome

§  Pheocromocytoma

§  Hyperthyroidism

4. Type 4 DM:

• It is known as gestational diabetes (GDM)

GDM is defined as any abnormality in glucose level for the 1^st time during pregnancy

HIV : New Hope to Cure!

The discoverer of HIV (Human Immunodeficiency Virus) Nobel Winner Françoise Barré-Sinoussi  is hopeful to find a way to cure AIDS very soon.

More than 30 million of people died of AIDS since HIV was discovered in 1980. Till now there is no effective remedy for this virus.

Professor Francoise Barre Sinoussi said to BBC "We are so hopeful to discover the vaccine for HIV cause we have a lot of evidences in our hand.

Scientists was hapless a few days ago with discovery of HIV vaccine. But recent intervention of two HIV patients keeps the hope alive to discover the HIV vaccine.

European scientists are saying that an HIV patient is cured by Bone transplantation. Another 50 years old HIV  patient is said to be cured by Gene therapy without any other drugs. And these two incidence keep the hope alive.

Here to mention that, French virologist Professor Francoise Barre Sinoussi had been keep trying to discover the remedy to HIV after she discoverd HIV in 1980.

She won Nobel Prize with her colleague Luke Montegnier in 2008 for discovery of HIV.