DRUGS FOR THE DRUGS FOR THE TREATMENT OF TREATMENT OF

DIABETES MELLITUSDIABETES MELLITUS

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• One of the leading cause of death by

diseases (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 amputation

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N.B.

IDDM: insulin dependent diabetes mellitus.

NIDMM: non-insulin dependent diabetes mellitus.

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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

Diet Mandatory with insulin Mandatory with or without drug (can be controlled by diet & exercise)

Hypoglycemic drugs

Should not be used Clinically indicated

Clinical symptoms Polydipsia, polyphagia, polyurea, weight loss

Often asymptomatic due to insulin’s presence

Ketosis Frequent (acetone aroma)

Usually absent

Endogenous insulin Absent Present, but relatively ineffective

Related lipid abnormalities

Hypercholesterolemia frequent, all lipid fractions elevated in ketosis

Cholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemiaInsulin therapy Required Required in 20 - 30% of patients (for postprandial hyperglycemia)

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Glucose is reabsorbed in the kidney tubules in the form of glucose 6 phosphate.

In diabetic patients glucose filtration floods the renal tubules exceeding 180 g/dl, threshold for glucose’s reabsorption, leading to the appearance of glucose in the urine (glucosuria). This results in osmotic dragging of water into the tubules resulting in polyuria with subsequent polydypsia.

Hydrolysis of the disulfide linkage between

α & β chains.Metabolism of insulin:

Endogenous: 60% in liver & 40% in kidney (because it goes directly to the liver by the portal circulation).

Exogenous: 60% kidney & 40% liverHalf-Life 5-7min (endogenous insulin)

Delayed-release form( injected one)

• Pregnant women with type II or gestational DM should take insulin by injection and avoid taking oral hypoglycemics. 8

Insulin Degradation

cont’d

Category B (not teratogenic)The site of injection should be changed every once in

a while,(Injection in same place hypertrophy to subcutaneous

tissue ↓ absorption)Should be stored in refrigerator & warm up to room

temp before use.Must be used within 30 days.

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Fast action Fast action of insulin of insulin

in the in the abdomenabdomen

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TYPES OF INSULIN PREPARATIONS

A) Insulin used to control postprandial (after meals) hyperglycemia and emergency ketoacidosis

1. Ultra-short-acting ( e.g. insulin lispro, insulin aspart)( e.g. insulin lispro, insulin aspart)

2. Short-acting -Regular- (e.g. Novolin R, Humulin R)

B) Insulin used for maintenance treatment of type I DM

• Intermediate-acting (NPH, Lente insulin)

4. Long-acting (Glargine ,Ultralente )

Clear liquid

Turbid suspension عكر

N.B.

NPH = Neutral protamine Hagedorn

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Advantages of Insulin Lispro (ultra-short) vs Regular Insulin (short acting) :1) Rapid onset of action ( patients 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

hypoglycemia4) Decreased risk of hyperinsulinemia

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قواعد جوهرية

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In emergency you can use either ultra-

short or regular insulin (no difference in the duration

of action because it is

given IV)

In postprandia

l hyperglycemia you can

use both but

Ultra-short has less duration of action

no hypoglycemia

Use ultra-short, wait for 5 minutes before

having a meal while in regular, wait for 30

minutes

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

• Turbid suspension (shaken before use)

• 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 ( mix isophane with ultra-short or

short acting insulin).

3. Intermediate - acting insulins

Isophane (NPH)Isophane (NPH)

Ultra-short or short actingUltra-short or short acting

Insulin mixture is given to patients with high postprandial

hyperglycemia

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(contd.) Lente insulin (Humulin L; Novolin L).

Turbid suspension

Mixture of 30% semilente insulin small crystals

rapidly acting 70% ultralente insulin large crystals

slow acting with prolonged duration

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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Cont’d

Lente and NPH insulins

• have the same effect.

• 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 or Lente insulins

Duration of action up to 24 hr

Advantages• Constant circulating insulin over 24 hr with no pronounced peak (see next

slide)• Safer than NPH & Lente insulins ( less risk of nocturnal hypoglycemia)

• Clear solution (does not require resuspension before administration)

Designed to overcome the disadvantages of intermediately

acting insulins

Nocturnal = أثناء النوم

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Profile of Insulin Glargine vs NPH

Glargine NPH

glargine

(plateau )

In the previous figure NPH gives a peak risk of hypoglycemia

But glargine doesn’t give a peak risk of hypoglycemia

N.B: intermediate & long acting use for maintenance of blood sugar during 24 hr in type I DM

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GlargineGlargine

Methods of Adminisration

Insulin Syringes (most common)

Pre-filled insulin pens (expensive)

External insulin pump

Under Clinical Trials1. Oral tablets2. Inhaled aerosol (still undergoing trials)

3. Intranasal, Transdermal 4. Insulin Jet injectors (needle less)5. Ultrasound pulses

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COMPLICATIONS OF INSULIN THERAPY

1. Severe Hypoglycemia (< 50 mg/dl ) life-threatening

2. Weight gain

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3. Local or systemic allergic reactions (rare)

4. Insulin resistance (when the patient needs more than

200 units/day) (IgG anti-insulin antibodies, infection, expired insulin(rare)).

5. Lipohypertrophy at injection sites

6. Hypokalemia

Cont’d

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Severe insulin reaction

(Hypoglycemic Shock)

Diabetic coma

(Diabetic Ketoacidosis)Onset Rapid Slow- Over several days

Insulin Excess Too little

Acidosis & dehydration

No Ketoacidosis

Signs and symptoms

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, sometimes convulsions

General depression

Blood sugar Lower than 70 mg/100cc Elevated above 200 mg/100cc

Ketones Normal Elevated

Oral Hypoglycemics All taken orally in the form of tablets.

Patients with type II diabetes have two physiological defects:

1. Abnormal insulin secretion (most important)

2. Resistance to insulin action in target tissues associated with decreased number of insulin receptors

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Oral Anti-Diabetic Agents1. 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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More selective an

smaller dose

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FIRST GENERATION SULPHONYLUREA COMPOUNDS

* Good for patients with renal impairment Good for patients with renal impairment

** Patients with renal impairment can expect long t1/2

*** Chlorpropamide isn’t well metabolized

N.B. All 1st

G Metabolized in liver.

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GlipizideShort- acting

Glibenclamide

(Glyburide)Long-acting

Glimepiride

Long-acting

Absorption Well Well Well

Metabolism

Yes Yes Yes

Metabolites

Inactive Inactive Inactive

Half-life 3 – 4 hrs Less than 3 hrs (hit and run)

5 - 9 hrs

Duration of action

10 – 16 hrs

12 – 24 hrs 12 – 24 hrs

Excretion Urine Urine Urine

SECOND GENERATION SULPHONYLUREA COMPOUNDS

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MECHANISM OF ACTION OF SULPHONYLUREAS (SU)

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

DM).

2) Reduction of serum glucagon concentration.(in long

term use)

3) Potentiation of insulin action on target tissues.- SU’s binds to k+ channel no efflux depolarization Opening of voltage gated Calcium channel insulin release

Sulphonylureas ( Cont.)CLINICAL USE:Approved for monotherapy and in

combination with metformin or thiazolidinediones in type II DM

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) because it ↑ADH

4) Disulfiram*-like reaction with alcohol (Chlorpropamide) “contain sulfur”

Disulfiram R: Ingestion of chlorpropamide with alcohol hyperemic flush

5) Weight gain alcoholism* Disulfiram is a drug used to support the treatment of chronic

alcoholism by producing an acute sensitivity to alcohol.

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CONTRAINDICATIONS OF SULPHONYLUREAS

1) Type 1 DM ( insulin dependent)

2) Parenchymal disease of the liver or kidney. metabolism excretion

3) Pregnancy, lactation (due to the physiologic stress, not teratogenicity)

4) Major stress.

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DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF

SULPHONYLUREAS

Sulfonamides (increase insulin secretion)

Warfarin (displace the drugs ↑t1/2 )

Salicylates (displace the drugs ↑t1/2 )

Propranolol (mask the hypoglycemia)

Alcohol (acute)

Liver enzymes inhibitors ↑SU conc.

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DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF

SULPHONYLUREAS

Thiazide diuretics (a K+ opener hyperpolarization no release of insulin)

Corticosteroids

Epinephrine

Liver enzymes inducers e.g. alcohol (in chronic alcohlic patients )

↓sensitivity of insulin

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MEGLITINIDES

e.g. Repaglinide, Nateglinide (SU without sulfur)

PKs: Taken orally Rapidly absorbed ( Peak approximately 1hour ) 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 for monotherapy and in combination with metformin in type 2 diabetes

Taken before each meal, 3 times / day

Does not offer any advantage over sulfonylureas

SIDE EFFECTS:

Hypoglycemia

Weight gain( less than sulfonylureas )Caution in patients with renal & hepatic impairement.

We can use it if the patient is allergic to sulfonylurea

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BIGUANIDES

e.g. Metformin

PKs: Given orally

Do 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 (increase insulin

receptor sensitivity thus is insulin dependent)

2. Inhibits gluconeogenesis

3. Impaired absorption of glucose from the gut

Advantages of Metformin over SUlfonylurea

Does not cause hypoglycemia because they don’t stimulate the release of insulin from pancreas no hypoglycemia

Does not result in weight gain because they ↓appetite.

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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) (they ↑anerobic glycolysis ↑lactic acid) this

phenomenon is treated with NaHCO3.

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1. Hepatic impairment

2. Heart failure

3. Renal impairment

4. Alcoholism

BIGUANIDES (Contd.)

CONTRAINDICATIONS

In these situations the body is more sensitive to

lactic acidosis

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1. Obese patients with type II diabetes

2. Alone or in combination with sulfonylureas or

meglitinides.

BIGUANIDES (Contd.)

INDICATIONS

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α-GLUCOSIDASE INHIBITORS

e.g. Acarbose

PKs:

• Given orally.

• Not absorbed from intestine except small

amount (hence, no systemic effect).

• t1/2 3 - 7 hr.

• Excreted with stool.

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MECHANISM OF ACTION

α-GLUCOSIDASE INHIBITORS(Contd.)

With the use of drugs,

there is no sharp rise in blood

sugar

مايشطح )السكر بعد

(األكل

They delay the

absorption but don’t inhibit it

α-GLUCOSIDASE INHIBITORS (Contd.)It is a competitive inhibitor of glucosidase

enzyme (has more affinity than sugar ).It used as supportive not as treatment .Also can be used in border line patients.It can be use with type I DM but not alone.

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SIDE EFFECTS

• Flatulence sugar fermentation

• Loose stool or diarrhea results in gas formation

• Abdominal pain

• Alone does not cause hypoglycemia

α-GLUCOSIDASE INHIBITORS(Contd.)

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INDICATIONS Patients with Type II inadequately controlled by diet with or without other agents( SU, Metformin)

Can be combined with insulin to reduce postprandial hyperglycemia

Maybe helpful in obese Type II patients (similar to metformin)

α-GLUCOSIDASE INHIBITORS can also be used with type I DM with meals.

α-GLUCOSIDASE INHIBITORS(Contd.)

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e.g.: Pioglitazone

PKs:

99% absorbed

Metabolized by liver

99% of drug binds to plasma proteins

T1/2 = 3 – 4 h

Eliminated via the urine 64% and feces 23%

THIAZOLIDINEDIONE DERIVATIVES

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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 ) .

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

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ADVERSE EFFECTS

- Mild to moderate edema

- Weight gain

- Headache

- Myalgia (muscle pain)

- Hepatotoxicity ? Thus a liver function test is done before giving

this drug.

- Congestive heart failure?

- Alone does not cause hypoglycemia.

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

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INDICATIONS

Type II diabetes alone or in combination with

metformin , sulfonylurea or insulin in patients

resistant to insulin treatment.

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

Dipeptidyl peptidase-4 inhibitors (DPP- 4 inhibitors)

e.g. Sitagliptin, vildagliptinMechanism of action

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Dipeptidyl pepidase (enzyme) incretininactivate

DPP-4 inhibitors

Clinical usesUsed in type II DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Is also used in

borderline patients.

Adverse effectsNausea, abdominal pain, diarrhea

Nasopharyngitis

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