Diabetes Mellitus: Lestari Rahayu

Diabetes mellitus Lestari Rahayu

Diabetes- What is it? • Body is not producing or has lost sensitivity to insulin. • Insulin is a hormone that is needed to convert sugar, starches and other food into energy. • Insulin is produced in the body by the pancreas.

Types of Diabetes There are several types of diabetes: • Type I - body does not produce any insulin. • Type II- body is not making enough or is losing sensitivity to insulin made.

Types of Diabetes • Secondary - a consequence from another disease. For example, pancreatitis. • Gestational Diabetes- diabetes during pregnancy. • Impaired Glucose Tolerance- an intermediate between normal and diabetes.

Type I • Usually diagnosed in children and young adults. • Must take daily insulin shots to stay alive. • Type I accounts for 5-10% of the population with diabetes.

Type II • The most common form of the disease. • Approximately 50% of men and 70% of women are obese at the time of diagnosis.

Characteristic

Type 1 ( 10% )

Type 2

Onset (Age)

Usually < 30

Usually > 40

Type of onset

Abrupt

Gradual

Nutritional status

Usually thin

Usually obese

Clinical symptoms

Polydipsia, polyphagia, polyurea, Wt loss

Often asymptomatic

Ketosis

Frequent

Usually absent

Endogenous insulin

Absent

Present, but relatively ineffective

Related lipid abnormalities

Hypercholesterolemia Cholesterol & triglycerides frequent, all lipid fractions often elevated; elevated in ketosis carbohydrate- induced hypertriglyceridemia common Required Required in only 20 - 30% of patients

Insulin therapy Hypoglycemic drugs

Should not be used

Clinically indicated

Diet

Mandatory with insulin

Mandatory with or without drug

Gestational Diabetes • Pregnant women have a higher insulin level. • If woman has hyperglycemia, her blood glucose crosses the placenta but her insulin does not. • This can cause a high birth weight for baby.

What are the Symptoms? • • • • • •

Polyphasia- excessive eating Polyurea- excessive urination Polydypsia-excessive fluid intake Blurred vision Poor wound healing Irritability

Diagnosis DM • • • •

In order to be diagnosed with diabetes: Person must have symptoms of diabetes Fasting blood glucose of >126 mg/dl 2-hour post prandial plasma glucose >200 mg/dl

Who’s at risk? ADA now recommends that screening for diabetes should be considered for all patients at age 45. If the results are normal it should be repeated every 3 years. Screening should be considered at a younger age if patient meets following risk factors:

Who’s at risk? • • • •

Obesity First degree relative with diabetes Belongs to a high-risk ethnic group Was diagnosed with gestational diabetes or delivered a baby whose birth weight >9 lbs. • Hypertension • HDL level<35 or triglycerides >250 • Found to have impaired glucose tolerance or impaired fasting on a previous test.

I’ve got Diabetes, now what? • After diagnosis, there is a great need for education. • A diabetic diet is no different from anyone else’s but they must keep track of what they eat. • Serving sizes must be emphasized. • Carbohydrates are the component of food that causes an increase in blood sugar.

Blood Glucose Monitoring • All diabetics must keep track of blood glucose levels. • This is the only way to know if the treatment is effective. • Gives the diabetic a good indication of what affects their blood sugar level. • Must check at least 2 times a day and four times a day for at least 3 days a week.

Dietary Guidelines • • • • • •

Eat a diet low in saturated and total fat. Eat a diet moderate in sodium and sugar. Eat 5 or more fruits and vegetables a day. Choose a diet rich in whole grains. Moderate use of alcohol Eat at the same time everyday , at least within 1 hour of regular time. • Eat about the same amount of carbohydrate with each meal.

Other Treatments • Type I and sometimes Type II patients need to be treated with insulin. • There are more than 20 types. • They differ in how they are made, how they work in the body and their cost.

TYPES OF INSULIN PREPARATIONS

1. Ultra-short-acting 2. Short-acting (Regular) 3. Intermediate-acting 4. Long-acting

Short-acting (regular) insulins e.g. Humulin R, Novolin R

Ultra-Short acting insulins e.g. Lispro, aspart, glulisine

Uses

Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis

Similar to regular insulin but designed to overcome the limitations of regular insulin

Physical characteristics

Clear solution at neutral pH

Chemical structure

Hexameric analogue

Route & time of administration

S.C. 30 – 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis)

S.C. 5 min (no more than 15 min) before meal 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

Usual

2 – 3 times/day or more

2 – 3 times / day or more

Clear solution at neutral pH Monomeric analogue

3. Intermediate - acting insulins e.g. isophane (NPH) 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 / Regular )

3. Intermediate - acting insulins (contd) Lente insulin 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

4. Long – acting insulins e.g.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 due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia). Clear solution that does not require resuspention before administration.

Glargine

Efek Samping Insulin 1. Hipoglikemia, biasanya terjadi karena over dosis insulin atau pasien lupa makan sesudah mendapat insulin 2. Rx hipersensitifitas, biasanya disebabkan pembentukan antibodi terhadap protein asing terutama bila diberi insulin sapi. 3. Lipoatrofia (susutnya lemak subkutan ditempat injeksi) biasanya disebabkan karena salah teknik injeksi atau kurang sering mengganti tempat injeksi 4. Gangguan akomodasi akibat terlalu berfluktuasinya kadar glukosa darah yang biasanya terjadi pada 6 minggu pertama terapi

Oral Medications

Used to treat Type II diabetics. There are four basic types: • Sulfonylurea-stimulates the body to make more insulin. Meglitinides • Biguanides-lowers blood sugar by helping the insulin work better • Thiazolidinediones- increases muscle sensitivity to insulin. • Alpha-glucosidase inhibitors- slow the process of carbohydrate digestion.

Primary Sites of Action of Oral Antihyperglycemic Agents Stomach

-glucosidase inhibitors

Carbohydrate

Gut

I G

I

G

I G

G

PancreasG I I

G G

I

Insulin

Adipose tissue G

Insulin secretagogues

Glucose (G)

I

G

I

G

I

G

I

G

Liver Biguanides Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

Muscle Thiazolidinediones

Oral Anti-Diabetic Agents

Sulfonylureas

Drugs other than Sulfonylurea

Sulfonylureas (Oral Hypoglycemic drugs)

First generation

Second generation

Short

Intermediate

Long

Short

Long

acting

acting

acting

acting

acting

Tolbutamide

Acetohexamide Tolazamide

Chlorpropamide

Glipizide

Glyburide

(Glibenclamide Glimepiride

FIRST GENERATION SULPHONYLUREA COMPOUNDS Tolbutamid short-acting

Acetohexamide intermediateacting

Tolazamide intermediateacting

Chlorpropamide long- 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 action

Short (6 – 8 hrs)

Intermediate (12 – 20 hrs)

Intermediate (12 – 18 hrs)

Long ( 20 – 60 hrs)

Excretion

Urine

Urine

Urine

Urine

* Good for pts with renal impairment ** Pts with renal impairment can expect long t1/2

SECOND GENERATION SULPHONYLUREA COMPOUNDS Glipizide Shortacting Absorption Metabolism Metabolites Half-life Duration of action Excretion

Well Yes Inactive 3 – 4 hrs 10–16 hrs Urine

Glibenclamide Glimepiride (Glyburide) Longacting Long-acting Well Yes Inactive Less than 3 hrs 12 – 24 hrs

Well Yes Inactive 5 - 9 hrs 12 – 24 hrs

Urine

Urine

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

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

SIDE EFFECTS OF SULPHONYLUREAS (contd) 6) Blood dyscrasias (not common; less than 1% of patients) - Agranulocytosis - Haemolytic anaemia - Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9) Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use ??

CONTRAINDICATIONS OF SULPHONYLUREAS 1) Type 1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney 3) Pregnancy, lactation 4) Major stress

DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONE PROPRANOLOL CHLORAMPHENICOL FLUCONAZOLE

DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE CORTICOSTEROIDS ORAL CONTRACEPTIVES PHENYTOIN, PHENOBARB., RIFAMPIN ALCOHOL

Efek yang berbahaya terjadi NSH (Nocturnal Symptomless Hypoglicaemia) yaitu Hipoglikemia yang terjadi pada malam hari saat pasien tidur sehingga tanpa gejala Untuk mengatasi NSH tubuh akan mengatasi dengan mengeluarkan katekolamin dan glukokortikoid Apabila terjadi terus-menerus akan mengakibatkan ANGIOPATI (kerusakan pembuluh darah) efek yang timbul - impotensi - gagal ginjal - penglihatan berkurang

Drugs other than Sulfonylurea

Meglitinides

Biguanides

α-Glucosidase

Thiazolidinediones

Inhibitors

Repaglinide Nateglinide

Metformin

Acarbose

Rosiglitazone Pioglitazone

e.g.

MEGLITINIDES Repaglinide, Nateglinide

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

MECHANISM OF ACTION Bind to the same KATP Channel as do Sulfonylureas, to cause insulin release from β-cells.

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.

BIGUANIDES e.g. Metformin PHARMACOKINETICS Given orally Not bind to plasma proteins Not metabolized Excreted unchanged in urine t 1/2 2 hr

MECHANISM OF ACTION 1. Increase peripheral glucose utilization 2. Inhibits gluconeogenesis 3. Impaired absorption of glucose from the gut

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 & hepatic failure)

BIGUANIDES CONTRAINDICATIONS 1. Hepatic impairment 2. Renal impairment 3. Alcoholism 4. Heart failure INDICATIONS 1. Obese patients with type 11 diabetes 2. Alone or in combination with sulfonylureas

α-GLUCOSIDASE INHIBITORS e.g. Acarbose PHARMACOKINETICS •

Given orally

•

Not absorbed from intestine except small amount

-

t1/2 3 - 7 hr

-

Excreted with stool

MECHANISM OF ACTION • Inhibits intestinal alpha-glucosidases • delays carbohydrate absorption, • reducing postprandial increase in blood glucose

α-GLUCOSIDASE INHIBITORS MECHANISM OF ACTION

Acarbose

Acarbose

Acarbose

α-GLUCOSIDASE INHIBITORS MECHANISM OF ACTION

α-GLUCOSIDASE INHIBITORS SIDE EFFECTS • Flatulence • Loose stool or diarrhea • Abdominal pain • Alone does not cause hypoglycemia 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)

THIAZOLIDINEDIONE DERIVATIVES New class of oral antidiabetics e.g.: Rosiglitazone 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% INDICATIONS Type 11 diabetes alone or in combination with metformin or sulfonylurea or insulin in patients resistant to insulin treatment.

THIAZOLIDINEDIONE DERIVATIVES MECHANISM OF ACTION Increase target tissue sensitivity to insulin by: reducing hepatic glucose output increase glucose uptake increase oxidation in muscles & adipose tissues. They do not cause hypoglycemia (similar to metformin and acarbose ) ADVERSE EFFECTS Mild to moderate edema, Wt gain, Headache, Myalgia Hepatotoxicity ?

Diabetes Complications Diabetes complications are the seventh leading cause of death. They include: • Blindness- caused by diabetic retinopathy. • Kidney Disease- diabetic nephropathy • Heart Disease and Stroke • Nerve disease and amputations • Impotence

How to Avoid Complications • • • • • • • •

Control weight Eat a healthy well-balanced diet. Get regular exercise Have regular checkups Check feet everyday for cuts and blisters Do not smoke! Keep blood sugars normal Avoid the 2 common diabetic problems, hypoglycemia and hyperglycemia

Hypoglycemia • Hypoglycemia- low blood sugar • Happens to everyone with diabetes • Symptoms include shakiness, dizziness, sweating, hunger, headache, pale skin, sudden moodiness, clumsy or jerky movements, difficulty paying attention, and tingling sensations around mouth.

Hypoglycemia How to treat Hypoglycemia: • Quickest way to raise blood glucose is with some form of sugar. • 3 glucose tablets, 1/2 cup of fruit juice, 5-6 pieces of candy. • Wait 15-20 minutes and test blood sugar again. If still low retreat. • If hypoglycemia goes untreated, patient could get worse and pass out! • Stress the importance of a night time snack in older patients.

How to treat Hyperglycemia • Usually can lower it by exercising, or injecting more insulin, be careful of the somogyi effect. The somogyi effect is the condition of hypoglycemia resulting from the treatment of hyperglycemia.