Anti-Diabetic Drugs

Bassim I Mohammad

Specialist Physician-Assistant Professor

College of Pharmacy/ Al Qadisiyah University

Iraq

DM is an elevated blood glucose level associated with absent ,

or inadequate pancreatic insulin secretion, with or without

concurrent impairment insulin action

Diabetes Mellitus (Definition)

TYPE 1: characterized by beta cell destruction and severe or

absolute insulin deficiency (immune form)

TYPE 2: characterized by tissue resistance to the action of insulin

combined with a relative deficiency in insulin secretion

TYPE 3: refers to multiple other specific causes of an elevated

blood glucose: pancreatectomy, pancreatitis, drug therapy…etc)

TYPE 4:Gestational diabetes is defined as any abnormality in

glucose levels noted for the first time during pregnancy

Diabetes Mellitus (Classification)

Diabetes Mellitus (Clinical Features)

Polyuria

Polydipsia

Polyphagia

Weight loss

Criteria for the Diagnosis of Diabetes

A1C ≥6.5%

OR

Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)

OR

2-h plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT

OR

A random plasma glucose ≥200 mg/dL (11.1 mmol/L)

ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S9; Table 2.1

FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFG

OR

2-h plasma glucose in the 75-g OGTT 140–199 mg/dL (7.8–11.0 mmol/L): IGT

OR

A1C 5.7–6.4%

*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range.

ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S10; Table 2.3

Categories of Increased Risk for Diabetes (Prediabetes)*

DM (Complications)

1) Acute Complications:

Diabetic ketoacidosis

Nonketotic hyperosmolar coma

2) Chronic Complications:

(micro/macrovascular)

Type 1: Insulin is a must, education and nutrition control

Type 2: education, Food control, exercise, OAD

(1) Increase insulin secretion;

(2) Increase the sensitivity of target organs to insulin;

(3) Decrease glucose absorption

(4) Insulin needed serious complications or an emergency

Gestational Diabetes (Insulin)

Diabetes Mellitus (Treatment Strategies)

Insulin

Oral Anti-Diabetic Agents

Diabetes Mellitus (Treatment)

Chemistry , Physiology

Pharmacological Effect

Mechanism of action

Clinical Uses

Types and Preparations and mixtures

Delivery systems

Complications

Insulin

Insulin is a small protein contains 51 amino acids arranged in

two chains (A and B) linked by disulfide bridges.

Proinsulin in the Golgi apparatus of beta cells, packaged into

granules, and hydrolyzed into insulin and C-peptide by removal

of four amino acids

Insulin and C-peptide (has no physiological action) are secreted

in equimolar amounts in response to all insulin secretagogues.

Insulin (Chemistry and Physiology)

Insulin is released from pancreatic beta cells at a low basal

rate and at a much higher stimulated rate in response to a

variety of stimuli, especially glucose.

Oral glucose elicits more insulin secretion than dose IV

glucose; because oral administration of glucose elicits gut

hormones which augment the insulin response

Insulin (Chemistry and Physiology)

Insulin release Stimulators/ Inhibitors

Stimulators Inhibitors

Glucose (most important) α-Adrenergic stimulation inhibits release

(most important)

β-Adrenergic stimulation Glucagon

Amino acid Somatostation

Cholecystokinin Leptin

Elevated intracellular Ca2+ Hypoxia

Drugs (eg sulfonylureas) Drugs ( eg e diazoxide, colchicine)

The liver and kidney are the two main organs that remove

insulin from the circulation

Endogenous insulin: 60% liver, 40% kidney

Exogenous insulin: 60% kidney,40% liver

The half-life of circulating insulin (endogenous) is 3–5

minutes

Is not teratogenic

Insulin (Degradation)

Carbohydrate metabolism: reducing blood glucose levels by

glycogenolysis ↓, glycogen synthesis ↑, gluconeogenesis ↓

(ketone badies )

Lipid metabolism: fat synthesis ↑, lipolysis↓ , plasma FFA ↓

Protein metabolism: active transport of aa ↑, incorporation of

amino acids into protein ↑, protein catabolism ↓

HR↑ , myocardial contractility, renal blood flow ↓

Potassium: k+ uptake into cells ↑

Insulin (Pharmacological effects)

Action of Insulin on Various Tissues

Liver Muscle Adipose

↓ glucose production ↑ Glucose transport ↑ glucose transport

↑ glycolysis ↑ glycolysis ↑ lipogenesis&

lipoprotein lipase

activity

↑ TG synthesis ↑ glycogen deposition ↓ intracellular

lipolysis

↑ Protein synthesis ↑ protein synthesis

Insulin binds to specialized receptors (found on the

membranes of most tissues particularly target tissues, ie, liver,

muscle, and adipose tissue) with high specificity and affinity.

Insulin receptor consists of two subnits. An α subunit, which

constitutes the recognition site and β subunits, which contains

a tyrosine kinase.

Insulin (Mechanism of action)

The binding of an insulin molecule to the α subunits activates

the receptor and through a conformational change, facilitates

mutual phosphorylation of tyrosine residues on the β subunits

and tyrosine kinase activity.

These process results in multiple effects, including increase in

glucose uptake (translocation of GLUT 4), increased glycogen

synthase activity and increased glycogen formation; multiple

effects on protein synthesis, lipolysis, and lipogenesis ..etc

Insulin (Mechanism of action)

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Effect of insulin on glucose uptake and metabolism. Insulin binds to its

receptor (1) which in turn starts many protein activation cascades (2). These

include: translocation of Glut-4 transporter to the plasma membrane and influx

of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

Insulin-dependent patients with diabetes mellitus (type 1 diabetes mellitus)

Insulin-independent patients: failure to other drugs

Diabetic complications: diabetic, hyperosmotic nonketotic coma

Critical (stress) situations of diabetic patients: fever, severe infection,

pregnancy, trauma, operation

Others: promotion of K+ uptake into the cells, pshychiatric disorders

Insulin (Clinical uses)

Commercial insulin preparations differ in a number of ways,

recombinant DNA production techniques, amino acid

sequence, concentration, solubility, and the time of onset and

duration of their biologic action

Insulin (Available Preparations)

Insulin (4 Injectable Available Preparations)

1. Rapid (Ultra-short) acting (very fast onset and short duration)

2. Short-acting (Regular) (rapid onset of action)

3. Intermediate-acting

4. Long-acting (slow onset of action)

Rapid acting and short-acting insulins are dispensed as clear solutions at

neutral pH and contain small amounts of zinc to improve their stability

and shelf life

Intermediate-acting NPH insulin have been modified to provide

prolonged action and are dispensed as a turbid suspension at neutral pH

with protamine in phosphate buffer (neutral protamine Hagedorn [NPH]

insulin)

Insulin glargine and insulin detemir are clear, soluble long-acting insulins

Insulin (Available Preparations)

Three rapid-acting Insulin analogs Are Commercially Available (Insulin

lispro, Insulin aspart, Insulin glulisine)

Permit more physiologic prandial insulin replacement because their rapid

onset and early peak action more

Their duration of action is 4–5 hours, which decreases the risk of late

postmeal hypoglycemia

Have the lowest variability of absorption (approximately 5%) of all

available commercial insulins

Rapid-acting Insulin

Its effect appears within 30 minutes, peaks between 2-3 hours after

subcutaneous injection, and generally lasts 5–8 hours

The hexameric nature of regular insulin causes a delayed onset and

prolongs the time to peak action

After S/C injection, the insulin hexamersare too large and bulky to be

transported across the vascular endothelium into the bloodstream. As the

hexamers break down into dimers and finally monomers. This results in

three rates of absorption of the injected insulin, with the final monomeric

phase having the fastest uptake out of the injection

Short-acting (Regular) Insulin

Clinically, when regular insulin is administered at mealtime, the blood

glucose rises faster than the insulin with resultant early postprandial

hyperglycemia and an increased risk of late postprandial hypoglycemia.

Therefore, regular insulin should be injected 30–45 or more minutes

before the meal to minimize the mismatching

Short-acting (Regular) Insulin

The delayed absorption, dose-dependent duration of action, and variability

of absorption (∼ 25%) of regular human insulin frequently results in a

mismatching of insulin availability with need, and its use is declining

It is particularly useful for IV therapy in the management of DKA and

when the insulin requirement is changing rapidly, such as after surgery or

during acute infections.

Limitations of regular insulin, namely, highly dose dependent PKs and

PDs profiles, and variability in absorption

Short-acting (Regular) Insulin

NPH insulin is an intermediate-acting insulin is a suspension of

crystalline zinc insulin combined with protamine (a polypeptide).

The conjugation with protamine delays its onset of action and prolongs it

effectiveness.

Has an onset of approximately 2–5 hours and duration of 4–12 hours and

is usually mixed with regular, lispro, aspart, or glulisine insulin

The action of NPH is highly unpredictable, and its variability of

absorption is over 50%

Intermediate-acting NPH (neutral protamine Hagedorn, or

isophane) Insulin

Insulin glargine is a soluble, “peakless” (ie, having a broad plasma

concentration plateau), long-acting insulin analog

Achieves a maximum effect after 4–6 hours. This maximum activity is

maintained for 11–24 hours or longer. Glargine is usually given once daily

Should not be mixed with other insulins (separate syringes must be used)

Long-acting Insulin (Glargine)

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Profile of Insulin Glargine vs NPH

Glargine

NPH

This insulin is the most recently developed long-acting insulin analog

Has the most reproducible effect of the intermediate- and long-acting

insulins, and its use is associated with less hypoglycemia than NPH

insulin

Has a dose-dependent onset of action of 1–2 hours and duration of action

of more than 12 hours.

It is given twice daily to obtain a smooth background insulin level.

Long-acting Insulin (Insulin detemir)

Because NPH insulins require several hours to reach adequate therapeutic

levels, their use in diabetic patients usually requires supplements of rapid- or

short-acting insulin before meals.

These are often mixed together in the same syringe before injection. Insulin

lispro, aspart, and glulisine can be acutely mixed (ie, just before injection)

with NPH insulin without affecting their rapid absorption.

Premixed formulations of 70%/30% NPH/regular continue to be available.

These preparations have all the limitations of regular insulin, namely, highly

dose dependent PKs and PDs profiles, and variability in absorption

Mixtures (combinations) Of Insulins

Standard Delivery (conventional disposable syringes)

Portable Pen Injectors

Continuous Subcutaneous Insulin Infusion Devices ( Insulin Pumps)

Inhaled Insulin (dry powder formulation) used in adult, peak level reached

15 minutes and last for 3 hours (faster onset and shorter duratio than SC )

Insulin Delivery Systems

Insulin Delivery Systems

1) Hypoglycemia:

is the most common complication of insulin therapy. They usually result from

(Overdose of insulin, Excessive (unusual) physical exercise, meal is missed)

Mild Hypoglycemia and conscious patient treated by dextrose tab, glucose

gel or any sugar containing food or beverages

Severe hypoglycemia and disoriented or unconscious patient best treated by

IV 20-50 ml of 50% glucose over 2-3 minutes. Alternatively SC or IM 1mg

of glucagon. If patient still stuporus or glucagon not available, small amount

of honey or syrup can be inserted into buccal pouch.

Complications of Insulin Therapy

2) Immunopathology of Insulin Therapy:

Local or systemic allergic reactions

Immune insulin resistance, A low titer of circulating IgG anti-insulin

antibodies that neutralize the action of insulin to a negligible extent develops

in most insulin-treated patients.

3) Lipodystrophy at Injection Sites (with new prparation, atrophy less,

hypertrophy more)

4) Weight gain

Complications of Insulin Therapy

Promising

Thank You