1 Antidiabetic Drugs

Antidiabetic Drugs Dr. Entisar Al-Mukhtar

The pancreas acts as:
1. Exocrine gland ? digestive enzymes
2. Endocrine gland ? peptide hormones including ? insulin (from ?- cell), glucagons (from ?- cell) & somatostatin (from ?- cell)
• A relative or absolute lack of insulin can cause serious hyperglycemia, which if left untreated, retinopathy, nephropathy, neuropathy & CV complications may result.
Diabetes mellitus (DM)
Diabetes is a heterogeneous group of syndromes characterized by an elevation of blood glucose.
Four clinical classifications of DM:
1. Type 1 DM (insulin dependent diabetes mellitus "IDDM").
2. Type 2 DM (non-insulin dependent diabetes mellitus "NIDDM").
3. Gestational diabetes.
4. Diabetes due to other causes (eg. genetic defects or medications).
• Uncontrolled gestational diabetes (a carbohydrate intolerance with onset or first recognition during pregnancy) can lead to fetal macrosomia (abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia. Diet, exercise, and/ or insulin administration are effective in this condition.
• Glyburide and metformin may be safe alternatives to insulin therapy for gestational diabetes.

Type 1 diabetes
• Commonly occurs in puberty or early adulthood.
Characterized by an absolute deficiency of insulin due to ?-cell destruction attributed to an autoimmune-mediated processes, and it may be triggered by viruses or other environmental toxins.
Classic symptoms of type1DM insulin deficiency include polydipsia, polyphagia, polyuria & weight loss.
Type1DM require exogenous insulin to avoid severe hyperglycemia & life-threatening catabolic state of ketoacidosis.
Cause:
Normally the maintenance of low basal levels of circulating insulin (during postabsorptive period) suppress lipolysis, proteolysis & glycogenolysis. A burst of insulin secretion occurs within 2 minutes after meal ingestion, which lasts for up to 15 minutes, then followed by postprandial secretion of insulin.
Treatment:
Exogenous insulin must be used to control hyperglycemia, avoid ketoacidosis, and maintain
acceptable levels of glycosylated hemoglobin (HbA1c). [Note: The HbA1c formation is proportional to the average blood glucose concentration over the previous 3 months].

Type 2 diabetes
• Most (>90%) diabetic patients have type 2 DM.
• Type 2 DM is influenced by genetic factors, aging, obesity & peripheral insulin resistance (IR), rather than by autoimmune processes.
• The metabolic alterations observed are milder than those described for type 1 (eg. type 2 patients typically are not ketotic), but the long-term clinical consequences are similar.
Cause:
• Type 2 DM characterized by a lack of sensitivity of target organs to insulin.
• In contrast to type1, the type2 diabetics are often obese (but not all obese individuals become diabetic). Obesity contributes to IR, which is considered the major underlying defect of type 2 diabetes
Treatment:
• In some of type 2 diabetics, weight reduction, exercise & dietary modification decrease IR & correct the hyperglycemia.
• Most patients need a pharmacologic intervention with oral glucose-lowering agents.
As the disease progresses, ?-cell function declines & insulin therapy is often required.
Insulin and its analogs
• Insulin is a polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds.
• Synthesized as a precursor (proinsulin) that undergoes proteolytic cleavage to form insulin & C-peptide [Note: as insulin undergoes significant hepatic extraction, the measurement of circulating C-peptide provides a better index of insulin levels].


Insulin secretion
• Regulated not only by blood glucose levels but also by certain amino acids, other hormones, and autonomic mediators.
• Secretion is commonly triggered by high blood glucose, which is taken up into the pancreatic ? cells. Metabolic products of glucose enter the mitochondrial respiratory chain and generate ATP. Raised ATP levels blocks K+ channels, leading to membrane depolarization and an influx of Ca 2+, this in turn causes
Drugs for Diabetes

INSULIN
Insulin aspart NOVOLOG
Insulin detemir LEVEMIR
Insulin glargine LANTUS
Insulin glulisine APIDRA
Insulin lispro HUMALOG
NPH insulin suspension HUMULIN N, NOVOLIN N
Regular insulin HUMULIN R, NOVOLIN R

A AMYLIN ANALOG MY
Pramlintide SYMLIN

INCRETIN MIME INCRETIN MIMETIC TIC
Exenatide BYETTA, BYDUREON
Liraglutide VICTOZA
LinagliptinTRADJENTA
Alogliptin NESINA
Canagli_ozin INVOKANA
Bromocriptine CYCLOSET
Colesevelam WELCHOL
Dapagliflo zin FARXIGA
pulsatile insulin exocytosis.
• Sulfonylureas & glinides inhibit K+ channels.
[Note: Orally given glucose stimulates production of incretin hormones by the gut, which in turn, stimulates insulin secretion. Thus, injected glucose has a weaker effect on insulin secretion than orally taken glucose.]

Pharmacokinetics
• Human insulin is produced by recombinant DNA technology.
• Modifications of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties.
• For example, insulin lispro, aspart & glulisine, have a faster onset and shorter duration of action than regular insulin.
• Dose, site of injection, blood supply, temperature & physical activity can affect the onset & duration of various insulin preparations.
• Orally taken insulin is degraded in the GIT, therefore, insulin is generally administered by SC injection. (Note: In hyperglycemic emergency, regular insulin is injected IV).
• Continuous SC insulin infusion (CSCII) (insulin pump), it is a pump programmed to deliver a basal rate of insulin, it also allows the patient to control delivery of a bolus of insulin to cover mealtime high blood glucose.
Adverse reactions to insulin
• Hypoglycemia is the most serious & common adverse reaction to an excessive dose of insulin.
Note: long term diabetic patients commonly do not produce adequate amounts of the counter regulatory hormones (glucagon, epinephrine, cortisol & GH).
• Weight gain, lipodystrophy (less common with human insulin), allergic reactions & local injection site reactions.
• Renal insufficiency require adjustment of the insulin dose.

Insulin preparations & treatments
It is important that clinicians exercise caution when making any change in insulin treatment, paying strict attention to the dose.

A. Rapid-acting and short-acting insulin preparations
Include four preparations:
Regular insulin, insulin lispro, insulin aspart & insulin glulisine.
• Regular insulin is a short-acting, soluble, crystalline zinc insulin, given SC ( & IV in emergencies).
• Modification of the amino acid sequence of regular insulin produces analogs that are rapid-acting insulins (rapid onset) and with a shorter duration of action including insulin lispro, aspart, and glulisine.
• Peak levels of insulin lispro are seen at 30 to 90 minutes, as compared with 50 to 120 minutes for regular insulin.
• Rapid- or short-acting insulins mimic the prandial (mealtime) release of insulin and to control postprandial glucose. They are usually used in conjunction with a longer-acting basal insulin that provides control of fasting glucose.
• All are administered SC.
• Rapid-acting insulins are commonly used in external insulin pumps, and they are suitable for IV administration, although regular insulin is most commonly used when the IV route is needed.
• Regular insulin should be injected SC 30 minutes before a meal, whereas rapid-acting insulins are administered in the 15 minutes proceeding a meal or within 15 to 20 minutes after starting a meal.

B. Intermediate-acting insulin
Neutral protamine Hagedorn (NPH) (isophane) insulin
• Suspension of crystalline zinc insulin combined with protamine at neutral pH forming a less-soluble complex, resulting in an intermediate duration of action.
• NPH insulin should only be given SC (never IV) & is useful in treating all forms of diabetes except diabetic ketoacidosis and emergency hyperglycemia.
• Used for basal (fasting) control and is usually given along with rapid- or short- acting insulin for mealtime control.

C. Long-acting insulin preparations
1. Insulin glargine:
• The low pH of insulin glargine cause its precipitation at the injection site and extending its action.
• Its onset is slower than NPH insulin and has a flat, prolonged hypoglycemic effect with no peak.

2. Insulin detemir:
• Has a fatty-acid side chain which enhance its association to albumin from which it is dissociated slowly results in long-acting properties.
• Long–acting insulin should only be given SC & should not be mixed in the same syringe with other insulins to avoid the alteration in pharmacodynamic properties (they may precipitate due to the higher pH of the other products).

Insulin combinations: Various premixed combinations of insulins are available such as 70% NPH insulin plus 30% regular insulin or 50 % of each of them.

Standard treatment versus intensive treatment
• The ADA recommends a target mean blood glucose level of 154 mg/dL or less
(HbA1c ? 7 %) for diabetic, & this can be achieved with intensive treatment (3 ? injections daily).
Note: Normal mean blood glucose is approximately ? 115 mg/dL (HbA1c < 5.7 %).
The frequency of hypoglycemic episodes, coma & seizure is higher with intensive insulin regimens, however, intensive therapy show a significant reduction in long-term complications as compared to standard therapy (twice injection daily).
• Intensive therapy should generally not be recommended for patients with longstanding diabetes, significant microvascular complications, advanced age, and those with hypoglycemic unawareness.
• Intensive therapy doesn t significantly reduce macrovascular DM complications.

Synthetic amylin analog:
Amylin is a hormone that is cosecreted with insulin from ? cells following food intake, it delays gastric emptying, decreases postprandial glucagon secretion & improves satiety.
Pramlintide
• A synthetic amylin analog used as an adjunct to mealtime insulin therapy in type 1 & type 2 diabetes.
• Injected SC immediately prior to meals &the dose of rapid- or short-acting insulin should be decreased by 50 %.
• It may not be mixed in the same syringe with insulin.
• Adverse effects are mainly GI.
• Should be avoided in patients with diabetic gastroparesis (delayed stomach emptying), cresol hypersensitivity, or a history of hypoglycemic unawareness

Incretin mimetics (Exenatide & liraglutide )
• Higher secretion of insulin occurs with an orally given glucose than that when an equal load of glucose is given IV, this is referred to as the “incretin effect”, which is attributed to the release of incretin hormones (notably GLP-1 & glucose-dependent insulinotropic polypeptide) from the gut in response to a meal, these hormones are responsible for 60 - 70 % of postprandial insulin secretion.
• The incretin effect it is markedly reduced in type 2 diabetes, thus incretin mimetics are used as adjunct therapy in patients with type 2 DM.
MOA:
1. Improve glucose- dependent insulin secretion.
2. Slow gastric emptying time, decrease food intake by enhancing satiety.
3. Decrease postprandial glucagon secretion.
4. Promote ?-cell proliferation.
kinetics:
• Must be administered SC.
• Liraglutide has a long half-life, allowing for once-daily dosing.
• Exenatide should be injected twice daily (short duration of action) within 60 minutes prior to morning & evening meals.
• A once-weekly preparation of exenatide is available.
• Exenatide should be avoided in patients with severe renal impairment.
• Incretin mimetics may cause GI adverse effects & pancreatitis.