Clinical Case 9

1. Clinical Case 9 G. V., a 42-year-old male showbiz personality was known to have “Juvenile-onset” diabetes. For one week, he complains of feeling bloated or full despite minimal food intake, nausea and vomiting. His blood sugar level is poorly controlled. Question: 1.What is your diagnosis and proper therapeutic management of this case? 2.What are prokinetic agents? 3.Give the pharmacokinetics, clinical uses and side effects of the different prokinetic drugs.

2. Diagnosis: Diabetes mellitus with hyperglycemia. • Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism. A relative or absolute deficiency in insulin secretory response, which translates into impaired carbohydrate (glucose) use, is a characteristic feature of diabetes mellitus, as is the resulting hyperglycemia.

3. Classification of Diabetes Mellitus • Type I • Type II • Others specific type.

4. Type I Diabetes Mellitus • Insulin-dependent diabetes mellitus or juvenile-onset diabetes. • Younger people and usually diagnosis before age 30. • <10% of all DM cases. • Definition is hyperglycemia resulting from autoimmune destruction of the insulin-producing beta cells of pancreas. • 80% have HLA (HLA-DR3 and DR4) phenotypes associated with anticytoplasmic antibodies directed toward pancreatic beta cells (islet cell antibodies) and to glutamic acid decarboxylase (GAD anti bodies). • Extrinsic factors that affect β cell function include damage caused by viral such as mumps or coxsackie B4 virus and exposure to cow’s milk instead of human milk during infancy.

5. Recent studies indicate there are two subgroups of type I diabetes: 1. Type 1A DM (immune-mediated type) results from autoimmune beta cell destruction, which leads to insulin deficiency. 2. Type 1B DM (idiopathic type) lack immunologic markers indicative of an autoimmune destructive process of the beta cells. However, they develop insulin deficiency by unknown mechanisms and are ketosis prone.

6. Signs and Symptoms • Polyuria. • Polydipsia. • Polyphagia with weight loss. • Recurrent blurred vision. • Foot ulcers. • Will suffer from Diabetic Ketoacidosis (DKA).

7. Laboratory Founding • Fasting serum glucose is >126 mg/dl. • Glucosuria (causes an osmotic diuresis that leads to the dehydration). • HbA1c is a measure (it can provides an index of the average blood glucose levels over the 120 day life span of erythrocytes).

8. Type II Diabetes mellitus • Non-insulin-dependent diabetes mellitus or adult-onset diabetes. • >80% of diabetes cases which predominantly in >30 age adults, but occasionally in adolescents and children due to incidence of obesity and sedentary lifestyle. • Epidemiologic data indicate strong genetic influences, since in monozygotic twins is >90% (<50% type I). • Definition is hyperglycemia due to insulin resistance. The syndrome of insulin resistance involves hyperglycemia leading to obesity, hypertension, hyperlipidemia, and coronary artery disease.

9. Signs and Symptoms • May be asymptomatic. • Complication of diabetes, such as a soft tissue infection etc. • Signs of hyperglycemia. • Increase susceptibility to fungal infections (cell-mediated immunity is impaired by acute hyperglycemia). • The nonketotic hyperglycemic – hyperosmolar coma (NKHC) is also a rare presenting situation.

10. Laboratory Founding • Random glucose >200 mg/dl. • Asymptomatic patients require a fasting glucose of > 126 mg/dl on two separate occasions. • The oral glucose tolerance test is a plasma glucose >200 mg/dl at two hours (or at any time up to two hours) after ingesting 75g of glucose in solution.

11. Treatment • Education for when to seek medical attention, side effects of medications, proper foot care, ophthalmology visits, and symptoms of hyperglycemia and hypoglycemia. • Diet recommendations for limit cholesterol to 300 mg daily, advise a daily protein intake of 10~20%, and carbohydrate intake of 55~60% of total calories. And Insoluble fiber diet which tend to retard nutrient absorption rates so that glucose absorption is slower and hyperglycemia may be slightly diminished. • Exercise. • Medication therapy. For the type I diabetes the mainstay of therapy is insulin injection.

12. NPH – Neutral Protamine Hagedorn. PZI – Protamine Zinc Insulin suspension.

13. Mechanisms: • It’s major anabolic hormone. It’s necessary for • Transmenbrane transport of glucose and amino acids. • Glycogen formation in the liver and skeletal muscles. • Conversion of glucose to triglycerides. • Nucleic acid synthesis. • Protein synthesis. • Because insulin is a polypeptide, it is degraded in the gastrointestinal tract if taken orally. It therefore is generally administered by subcutaneous injection.

14. Symptoms Confusion Nausea Hunger Tiredness Perspiration Headache. Heart palpitations. blurred vision Numbness around the mouth, tingling in the fingers Tremors Muscle weakness Cold temperature Excessive yawning Irritability Loss of consciousness Side effect: Hypoglycemia is the most common side effect that may occur during insulin therapy.

15. For the type II diabetes is oral hypoglycemic agents: • First-generation sulfonylureas Generic name: Tolbutamide • Second-generation sulfonylureas Generic name: Glipizide, Glyburide, Glimepiride Mech. Of action: Stimulate insulin secretion.

16. Pharmacokinetics: • Given orally, these drugs bind to serum proteins, are metabolized by the liver, and are excreted by the liver or kidney. Tolbutamide has the shortest duration of action (6~12 hr), whereas the second-generation agent last about 24hr. Adverse effects: • Weight gain, hyperinsulinemia, and hypoglycemia which delayed excretion of the drug-resulting in its accumulation.

17. Meglitinide analogs Generic name: Nateglinide, Repaglinide Mech. Of action: Stimulate insulin secretion. Pharmacokinetics: • These drugs are well absorbed orally after being taken one to thirty minutes before meals. Both meglitinides are metabolized to inactive products by CYP3A4 in the liver and are excreted through the bile. Adverse effects: • Although these drugs can cause hypoglycemia, the incidence of this adverse effect appears to be lower than with the sulfonylureas.

18. Biguanides Generic name: Metformin Mech. Of action: Decreased endogenous hepatic production of glucose. Pharmacokinetics: • Metformin is well absorbed orally, is not bound to serum proteins, and is not metabolized. The highest concentrations are in the saliva and intestinal wall. Excretion is via the urine. Adverse effects: • Nausea.

19. Thiazolidinediones (glitazones) Generic name: Pioglitazone, Rosiglitazone Mech. Of action: Binds to peroxisome proliferators-activated receptor-γ in muscle, fat and liver to decrease insulin resistance. Pharmacokinetics: • Both pioglitazone and rosiglitazone are absorbed very well after oral administration and are extensively bound to serum albumin. Both undergo extensive metabolism by different cytochrome P450. The metabolites are primarily excreted in the urine, but the parent agent leaves via the bile. Adverse effects: • Weight gain and risk of heptotoxicity

20. α-Glucosidase inhibitors Generic name: Acarbose, Miglitol Mech. Of action: Decreased glucose absorption. Pharmacokinetics: • Acarbose is poorly absorbed. It’s metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine. On the other hand, miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney. Adverse effects: • The major side effects are flatulence, diarrhea, and abdominal cramping. Patient with inflammatory bowel diease, colonic ulceration, or intestinal obstruction should not use these drugs.

21. The first and scond-generation sulfonylureas and meglitinide have risk of hypoglycemia. • The classification, or type, of diabetes is determined by the underlying cause of the diabetes, not the type of therapy that is used to treat the diabetes. Many patients with type 2 diabetes will progress insulin to control of blood glucose levels, but these patients are still type 2 diabetics.

22. Note: 1. Hyperglycemia A condition in which an excessive amount of glucose circulates in the blood plasma. Caused by : • Impaired secretion of insulin. • Decreased insulin effectiveness at glucose uptake. • Impair inhibition of hepatic gluconeogenesis. Sign and Symptom • Extreme thirst. • Hunger. • Headache. • Blurred vision. • Dry skin. • Feeling drowsy. • Feeling sick with stomach.

23. 2. Diabetic Ketoacidosis (DKA) It is metabolic acidosis due to ketoacid accumulation due to severely depressed insulin levels. Blood sugar levels exceed 240 mg/dl for an extended period of time the diabetic is at risk of going into diabetic ketoacidosis. Cause by: • Severe insulin deficiency so lead the body to switch from metabolizing carbohydrates to metabolizing and oxidizing lipids. • Precipitated by lapse in insulin treatment, acute infection, or major trauma. Sign and Symptom • Polyuria, nausea, vomiting. • Signs of dehydration and hypotensive and tachycardic. • Kussmaul respirations (rapid deep breaths). • Aceton (fruity) odor breath.

24. Complications of Diabetes (Types I and II) • Hypoglycemia may be cause by injecting too much insulin (overdose) or not eating enough food during a daily diet regimen so lead blood sugar level below the normal which is 70~120mg/dl. • Diabetic Ketoacidosis (usually type I). • Nonketotic hyperosmolar coma (usually type II). • Retinopathy. • Stroke, MI. • Renal insufficiency. • Neuropathy. • Infection.

25. Others Specific Type of Diabetes Mellitus 1. Maturity-onset diabetes of the young (MONDY) • This subgroup is a relatively rare monogenic disorder characterized by non-insulin-dependent diabetes with autosomal dominant inheritance and an age at onset of 25 years or younger. 2. Gestational diabetes mellitus (GDM) • It’s happen during pregnancy. But in the serum, the HbA1c detect is normal and it will become normal after delivery of six-week. 3. Impaired glucose tolerance (IGT) The before and after meal’s sugar blood level are between normal and diabetes mellitus.