DRUGS FOR THE TREATMENT OF

DIABETES MELLITUS

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 DIABETES MELLITUS

One of the leading cause of death by disease

(cardiovascular problems, stroke)

One of the leading cause of blindness

One of the leading cause of renal failure

One of the leading cause of impotence(males)

Risk of foot ambutation

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TYPES OF DIABETES
1. Type 1 (formerly IDDM or Juvenile)
2. Type 11(formerly NIDDM or adult)
3. Secondary diabetes
4. Gestational diabetes

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 Characteristic Type 1 ( 10% ) Type 2 (90%)
Onset (Age) Usually < 30 Usually > 40
Type of onset Abrupt Gradual
Nutritional status Usually thin Usually obese
Clinical symptoms Polydipsia, polyphagia, Often asymptomatic
polyurea, Wt loss
Ketosis Frequent Usually absent
Endogenous insulin Absent Present, but relatively
ineffective
Related lipid Hypercholesterolemia Cholesterol & triglycerides
abnormalities frequent, all lipid fractions often elevated; carbohydrate-
elevated in ketosis induced hypertriglyceridemia
common
Insulin therapy Required Required in 20 - 30% of
patients
Hypoglycemic drugs Should not be used Clinically indicated
Diet Mandatory with insulin Mandatory with or without
drug

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 EFFECTS OF INSULIN

FAT
CARBOHYDRATES
GLUCOSE UPTAKE LIPOLYSIS

GLYCOGEN SYNTHESIS( STORAGE)

PROTEIN
GLUCONEOGENEIS(LIVER)
AMINO ACID UPTAKE
GLYCOLYSIS (MUSCLE)
(PROTEIN SYTHESIS)
CONVERSION OF CARBOHYDRATE
POTASSIUM
TO FAT (LIPOGENESIS)
K+ UPTAKE
INTO CELLS
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 INSULIN DEFICIENCY – DIABETES MELLITUS

GLUCOSE UPTAKE AA LIPOLYSIS POTASSIUM

mobilization
K+ UPTAKE
PLASMA FFA INTO
HYPERGLYCEMIA CELLS
PLASMA AA

KETOSIS

Glucose
GLYCOSURIA

ACIDOSIS 56
• Insulin Degradation
• Hydrolysis of the disulfide linkage between A&B
chains.
• 60% liver, 40% kidney(endogenous insulin)
• 60% kidney,40% liver (exogenous insulin)
• Half-Life 5-7min (endogenous insulin)
Delayed-release form( injected one)
• Category B ( not teratogenic)
• Usual places for injection: upper arm, front& side
parts of the thighs& the abdomen.
• Not to inject in the same place ( rotate)
• Should be stored in refrigerator& warm up to
room temp before use.
• Must be used within 30 days.

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8
 TYPES OF INSULIN PREPARATIONS

A) Insulins used to control post prandial hyperglycemia and

emergency ketoacidosis
1. Ultra-short-acting ( e.g. insulin lispro, insulin aspart)
2. Short-acting (Regular)(e.g. Novolin R, Humulin R)

B) Insulins used for maintenance treatment of type 1 DM

3. Intermediate-acting(NPH, Lente insulin)

4. Long-acting( Glargine ,Ultralente )

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 Short-acting (regular) insulins Ultra-Short acting insulins
e.g. Humulin R, Novolin R e.g. Lispro, aspart, glulisine
Uses Designed to control postprandial Similar to regular insulin but
hyperglycemia & to treat designed to overcome the
emergency diabetic ketoacidosis limitations of regular insulin

Physical Clear solution at neutral pH Clear solution at neutral pH

characteristics
Chemical Hexameric analogue Monomeric analogue
structure
Route & time of S.C. 30 – 45 min before meal S.C. 5 min (no more than 15 min)
administration I.V. in emergency before meal
(e.g. diabetic ketoacidosis) I.V. in emergency
(e.g. diabetic ketoacidosis)
Onset of action 30 – 45 min ( S.C ) 0 – 15 min ( S.C )
Peak serum levels 2 – 4 hr 30 – 90 min

Duration of action 6 – 8 hr 3 – 4 hr

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Usual 2 – 3 times/day or more 2 – 3 times / day or more
administration
 Advantages of Insulin Lispro vs Regular Insulin:

1) Rapid onset of action ( pts will not wait long

before they eat ).
2) Its duration of action is no longer than 3-4 hrs
regardless of the dose.
3) Decreased risk of postprandial hypoglycemia.
4) Decreased risk of hyperinsulinemia.

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 3. Intermediate - acting insulins

Isophane (NPH) (Humulin N; Novolin N, etc.)

Turbid suspension
Injected S.C.(Only)
Onset of action 1 - 2 hr
Peak serum level 5 - 7 hr
Duration of action 13 - 18 hr
Insulin mixtures
75/25 70/30 50/50 ( NPH / Short or ultra short
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)
3. Intermediate - acting insulins (contd.)
Lente insulin (Humulin L; Novolin L).

Turbid suspension
Mixture of 30% semilente insulin
70% ultralente insulin
Injected S.C. (only)
Onset of action 1 - 3 hr
Peak serum level 4 - 8 hr
Duration of action 13 - 20 hr
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3. Intermediate - acting insulins (contd.)

Lente and NPH insulins

Are roughly equivalent in biological effects.
They are usually given once or twice a day.
N.B: They are not used during emergencies
(e.g. diabetic ketoacidosis).

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 4. Long – acting insulins
e.g. Glargine ( Lantus )
Insulin glargine
Onset of action 2 hr
Absorbed less rapidly than NPH&Lente insulins.
Duration of action upto 24 hr
Designed to overcome the deficiencies of intermediate
acting insulins
Advantages over intermediate-acting insulins:
Constant circulating insulin over 24hr with no pronounced peak.
More safe than NPH&Lente insulins ( reduced risk of
hypoglycemia,esp.nocturnal hypoglycemia).
Clear solution( does not require resuspention before administration).
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Glargine

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Profile of Insulin Glargine vs NPH
NPH
Glargine

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 Methods of Adminisration
• Insulin Syringes
• Pre-filled insulin pens
• External insulin pump
Under Clinical Trials
• Oral tablets
• Inhaled aerosol
• Intranasal, Transdermal
• Insulin Jet injectors
• Ultrasound pulses
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19
Inhaled Aerosol

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 COMPLICATIONS OF INSULIN THERAPY
1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening
Overdose of insulin
Excessive (unusual) physical exercise
A meal is missed
How it is treated ?
2. Weight gain
3. Local or systemic allergic reactions (rare)
4. Insulin resistance ( IgG anti-insulin antibodies,
infections, expired insulin)(rare).
5. Lipohypertrophy at injection sites
6. Hypokalemia 21
 Severe insulin reaction Diabetic coma
(Hypoglycemic Shock) (Diabetic Ketoacidosis)
Onset Rapid Slow- Over several days
Insulin Excess Too little
Acidosis & No Ketoacidosis
dehydration
Signs and symps
B.P. Normal or elevated Subnormal or in shock
Respiration Normal or shallow Deep & air hunger
Skin Pale & Sweating Hot & dry
CNS Tremors, mental confusion, General depression
sometimes convulsions
Blood sugar Lower than 70 mg/100cc Elevated above 200 mg/100cc
Ketones Normal Elevated

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 Oral Hypoglycemics
All taken orally in the form of tablets.
Pts with type11 diabetes have two
physiological defects:
1. Abnormal insulin secretion
2. Resistance to insulin action in target
tissues associated with decreased number
of insulin receptors
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 Oral Anti-Diabetic Agents
1. Sulfonylureas e.g. Tolbutamide, Glyburide.
2. Meglitinides e.g. Repaglinide, Nateglinide.
3. Biguanides e.g. Metformin.
4. Alpha-glucosidase inhibitors e.g. Acarbose.
5. Thiazolidinediones e.g. Pioglitazone.
6. Dipeptidyl peptidase-4 inhibitors e.g. Sitagliptin, vildagliptin

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 Sulfonylureas

First generation Second generation

Short Intermediate Long Short Long

acting acting acting acting acting

Glyburide
Tolbutamide Acetohexamide Chlorpropamide Glipizide
(Glibenclamide
Tolazamide Gliclazide 25
Glimepiride
 FIRST GENERATION SULPHONYLUREA COMPOUNDS

Tolbutamid Acetohexamide Tolazamide Chlorpropamide

short-acting intermediate- intermediate- long- acting
acting acting

Absorption Well Well Slow Well

Metabolism Yes Yes Yes Yes
Metabolites Inactive* Active +++ ** Active ++ ** Inactive **
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of Short Intermediate Intermediate Long
action (6 – 8 hrs) (12 – 20 hrs) (12 – 18 hrs) ( 20 – 60 hrs)
Excretion Urine Urine Urine Urine

* Good for pts with renal impairment

** Pts with renal impairment can expect long t1/2 26
 SECOND GENERATION SULPHONYLUREA
COMPOUNDS

Glipizide Glibenclamide Glimepiride

Short- (Glyburide) Long-acting
acting Long-acting
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
action
Excretion Urine Urine Urine
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 MECHANISM OF ACTION OF
SULPHONYLUREAS

1) Release of insulin from β-cells(hence, no use in

type 1 DM)

2) Reduction of serum glucagon concentration

3) Potentiation of insulin action on target tissues

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 Sulphonylureas ( Cont.)
• CLINICAL USE
• Approved as monotherapy and in
combination with metformin or
thiazolidinediones in type 2 diabetes
• Taken before each meal, 1-2 times / day

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 SIDE EFFECTS OF SULPHONYLUREAS

1) Nausea, vomiting, abdominal pain, diarrhea

2) Hypoglycaemia
3) Dilutional hyponatraemia & water intoxication
(Chlorpropamide)
4) Disulfiram-like reaction with alcohol
(Chlorpropamide)
5) Weight gain

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 CONTRAINDICATIONS OF
SULPHONYLUREAS

1) Type 1 DM ( insulin dependent)

2) Parenchymal disease of the liver or kidney

3) Pregnancy, lactation

4) Major stress

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 DRUGS THAT AUGMENT THE
HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
SULFONAMIDES
WARFARIN
SALICYLATES
PROPRANOLOL
ALCOHOL(acute)
Liver enzymes inhibitors

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 DRUGS THAT ANTAGONIZE THE
HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
THIAZIDE DIURETICS
CORTICOSTEROIDS
Epinephrine
Liver enzymes inducers
ALCOHOL ( chronic pts )

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 MEGLITINIDES

e.g. Repaglinide, Nateglinide

PHARMACOKINETICS
Taken orally
Rapidly absorbed ( Peak approx. 1hr )
Metabolized by liver
t1/2 = 1 hr
Duration of action 4-5 hr
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 MEGLITINIDES (Contd.)

MECHANISM OF ACTION

Bind to the same KATP Channel

as do Sulfonylureas,
to cause insulin release from β-cells.

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 MEGLITINIDES (Contd.)

CLINICAL USE
Approved as monotherapy and in combination with
metformin in type 2 diabetes
Taken before each meal, 3 times / day
Does not offer any advantage over sulfonylureas;
Advantage: Pts. allergic to sulfur or sulfonylurea
SIDE EFFECTS:
Hypoglycemia
Wt gain ( less than SUs )
Caution in pts with renal & hepatic impairement.36
 BIGUANIDES
e.g. Metformin

PHARMACOKINETICS

Given orally
Not bind to plasma proteins
Not metabolized
Excreted unchanged in urine
t 1/2 2 hr
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 BIGUANIDES (Contd.)

MECHANISM OF ACTION

1. Increase peripheral glucose utilization

2. Inhibits gluconeogenesis

3. Impaired absorption of glucose from the gut

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Advantages of Metformin over SUs

Does not cause hypoglycemia ( why ? )

Does not result in wt gain ( why ? )
( Ideal for obese pts )

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 BIGUANIDES (Contd.)

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 ( rare – 01/ 30,000-exclusive in

renal failure) 40
 BIGUANIDES (Contd.)

CONTRAINDICATIONS

1. Hepatic impairment

2. Renal impairment

3. Alcoholism

4. Heart failure
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 BIGUANIDES (Contd.)

INDICATIONS

1. Obese patients with type 11 diabetes

2. Alone or in combination with sulfonylureas or

meglitinides.

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 α-GLUCOSIDASE INHIBITORS
e.g. Acarbose

PHARMACOKINETICS

Given orally

Not absorbed from intestine except small amount

t1/2 3 - 7 hr

Excreted with stool

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 α-GLUCOSIDASE INHIBITORS
(Contd.)

MECHANISM OF ACTION

Inhibits intestinal alpha-glucosidases and

delays carbohydrate absorption, reducing
postprandial increase in blood glucose ( designed
to slow and not to prevent glucose absorption
from intestine).

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α-GLUCOSIDASE INHIBITORS (Contd.)

MECHANISM OF ACTION

Acarbose

Acarbose

Acarbose

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α-GLUCOSIDASE INHIBITORS (Contd.)

MECHANISM OF ACTION

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 α-GLUCOSIDASE INHIBITORS
(Contd.)

SIDE EFFECTS

Flatulence

Loose stool or diarrhea

Abdominal pain

Alone does not cause hypoglycemia 47

 α-GLUCOSIDASE INHIBITORS
(Contd.)

INDICATIONS

Patients with Type 11 inadequately controlled by

diet with or without other agents( SU, Metformin)

Can be combined with insulin

may be helpful in obese Type 11 patients

(similar to metformin)
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 THIAZOLIDINEDIONE DERIVATIVES
e.g.: Pioglitazone

PHARMACOKINETICS
- 99% absorbed
- Metabolized by liver
- 99% of drug binds to plasma proteins
- Half-life 3 – 4 h
- Eliminated via the urine 64% and feces 23%
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 THIAZOLIDINEDIONE DERIVATIVES
(Contd.)

MECHANISM OF ACTION

- Increase target tissue sensitivity to insulin by:

reducing hepatic glucose output & increase
glucose uptake & oxidation in muscles & adipose
tissues.

They do not cause hypoglycemia (similar to

metformin and acarbose ) .
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 THIAZOLIDINEDIONE DERIVATIVES
(Contd.)

ADVERSE EFFECTS
- Mild to moderate edema
- Wt gain
- Headache
- Myalgia
- Hepatotoxicity ?
- Congestive heart failure?
- Alone does not cause hypoglycemia.
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 THIAZOLIDINEDIONE DERIVATIVES
(Contd.)

INDICATIONS

Type 11 diabetes alone or in combination with

metformin or sulfonylurea or insulin in patients

resistant to insulin treatment.

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Dipeptidyl peptidase-4 inhibitors
(DPP- 4 inhibitors)
e.g. Sitagliptin, vildagliptin
Mechanism of action
Inhibit DPP-4 enzyme and leads to an
increase in incretin hormones levels.This
results in an increase in insulin secretion &
decrease in glucagon secretion.

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Clinical uses
Type 2 DM as an adjunct to diet & exercise as
a monotherapy or in combination with other
antidiabetic drugs.

Adverse effects
Nausea, abdominal pain, diarrhea
Nasopharyngitis
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