Drugs for the treatment of diabetes mellitus

Drugs for the treatment of diabetes mellitus

Characteristics
• Type 1 (10%)

Type 2

Onset (age)
Usually  30
Usually >40
Type of onset
• Abrupt

• gradual

• Nutritional status

Usually thin

• Usually obese


• Ketosis

Frequent

Usually absent
endogenous insulin
Absent
Present but usually ineffective
Insulin therapy
Required
Required in only 20-30%
• Hypoglycemic drugs

Should not be used

Clinically indicated

Insulins

1- Ultra-Short acting insulin
2- Short-acting (regular) insulin
3- Intermediate-acting insulin
4- Long-acting insulin
Insulins are administered SC
Ultra short and short insulin can be given IV in emergency cases

Insulins

1- Ultra-Short acting insulin
(Lispro, aspart)
Onset within 5 minutes and duration 2-4 hours
2- Short acting insulin (regular)
(Humulin, Novolin )
Onset of action within 30-45 minutes and duration 6-8 hours

Insulins

3- Intermediate-acting insulins
(isophane (NPH), Lente insulin)
• Onset of action 1-2 hr and duration of action 13-20 h
4- Long-acting insulins
(Insulin glargine, ultralente)
Onset of action 2 hr and duration of action up to 24 hr


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KATP Channel Structure and Function
NBF
Nucleotide Binding Fold = site of ATP/ADP binding

Four copies of each subunit combine to form an active KATP channel

NBF
NBF
Sulfonylurea Receptor Inwardly Rectifying
K+ Channel

K+

ATP-sensitive K+ Channel (KATP Channel)

ADP
ADP
glucose
Membrane
Depolarization
insulin secretion


ATP
ATP

ATP

Voltage-dependent

Ca2+ Channel

glucose

metabolism

Ca2+

Influx

9

IRS-1/2

Mechanism of Insulin Action

Glucose

Glucose
Transporter
Insulin
Receptor


P
P
P

P

P

IRS-1/2

P

P

P

P

P

P


Translocation
of
Glucose
Transporters
Skeletal muscle
Adipose Tissue

Recruitment of Effectors

Protein:Protein Interactions
Signal Transduction Networks
Activation of Phosphorylation Cascades
Biologic Response

Glargine

Profile of Insulin Glargine vs NPH



NPH
Glargine

complications of insulin therapy

• 1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening
• Overdose of insulin
• Excessive (unusual) physical exercise
• A meal is missed
• 2. Weight gain
• 3. Local or systemic allergic reactions (rare)
• 4. Lipodystrophy at injection sites
• 5. Insulin resistance
• 6. Hypokalemia

Oral Hypoglycemics

1- Sulphonylureas
First generation- chloropropamide
Second generation-
Short acting- glipizide
Long acting- Glibenclamide, glimipride
2- Biguanides
Metformin


3- Meglitinides
Repaglinide, Nateglinide
4- Thiazolidinediones
Rosiglitazone, Pioglitazone
5- α-Glucosidase Inhibitors
Acarbose

1- Sulphonylureas

Mechanism of action of sulphonylureas

• 1) Release of insulin from β-cells

• 2) Reduction of serum glucagon concentration
• 3) Potentiation of insulin action on target tissues

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Mechanism of Sulfonylurea Action

NBF
NBF
Sulfonylurea Receptor Inwardly Rectifying
K+ Channel


K+

ATP-sensitive K+ Channel (KATP Channel)

Membrane
Depolarization

Ca2+

Influx
insulin secretion

Voltage-dependent

Ca2+ Channel
ADP
ADP
ATP
ATP

Sulphonylureas

Side effects
• 1) Nausea, vomiting, abdominal pain, diarrhea
• 2) Hypoglycaemia
• 3) Blood dyscrasias
• 5) Weight gain


2- BIGUANIDES (group)
Metformin
Mechanism of action
1- Increase peripheral glucose utilization
2. Inhibits gluconeogenesis
3. Impaired absorption of glucose from the gut

BIGUANIDES (group)Metformin

Uses
It is used in obese patients with type 2 diabetes
It does not cause hypoglycemia or weight gain (causes anoroxia)
It can be used in combination with sulphonylureas
It used in polycystic ovary disease.

2- BIGUANIDES (group)Metformin

Side effects
• 1. Metallic taste in the mouth
• 2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort)
• 3. Vitamin B 12 deficiency (prolonged use)
4.Lactic acidosis in hepatic and renal failure.


3- Meglitinides (group) Repaglinide, Nateglinide
• Mechanism of action
• Bind to the same KATP Channel as do Sulfonylureas, to cause insulin release from β-cells

3- Meglitinides (group) Repaglinide, Nateglinide

Uses
• Approved as monotherapy and in combination with metformin in type 2 diabetes
• Taken before each meal, 3 times / day
• It s main advantage by reducing postprandial blood glucose
• Side effects
• Hypoglycemia
• Wt gain ( less than Sufonylureas)

Thiazolidinedione

New class of oral antidiabetics
• Rosiglitazone
• Pioglitazone

Mechanism of action

• Increase target tissue sensitivity to insulin by:
• reducing hepatic glucose output & increase glucose uptake & oxidation in muscles & adipose tissues.


Uses
• Type II diabetes alone or in combination with
• metformin or sulfonylurea or insulin in patients
• resistant to insulin treatment.

Adverse effects

• Mild to moderate edema, wt gain, myalgia
• hepatotoxicity ?

α-glucosidase inhibitors Acarbose

Mechanism of action
• Inhibits intestinal alpha-glucosidases and
• delays carbohydrate absorption, reducing postprandial increase in blood glucose

α-GLUCOSIDASE INHIBITORSMECHANISM OF ACTION

Acarbose

Acarbose
Acarbose


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α-Glucosidase inhibitors

•

α-glucosidase inhibitors Acarbose

Uses
• Patients with Type II inadequately controlled by
• diet with or without other antidiabetic drugs
• may be helpful in obese Type II patients
• (similar to metformin)

α-glucosidase inhibitors Acarbose

• Side effects
• Flatulence, loose stool or diarrhea, abdominal pain, alone does not cause hypoglycemia