Pharmacology Notes

Diabetes mellitus, or simply diabetes, is a chronic disease of insulin deficiency or resistance. It’s characterized by disturbances in carbohydrate, protein, and fat metabolism. This leads to elevated levels of the sugar glucose in the body. The disease appears in two primary forms:

The endocrine system consists of glands, which are specialized cell clusters, and hormones, the chemical transmitters secreted by the glands in response to stimulation.

Insulin, a pancreatic hormone, and oral antidiabetic drugs are classified as hypoglycemic drugs because they lower blood glucose levels. Glucagon, another pancreatic hormone, is classified as a hyperglycemic drug because it raises blood glucose levels.

Insulin isn’t effective when taken orally because the GI tract breaks down the protein molecule before it reaches the bloodstream.

All insulins, however, may be given by subcutaneous (subQ) injection. Absorption of subQ insulin varies according to the injection site, the blood supply, and degree of tissue hypertrophy at the injection site.

Regular insulin may also be given by I.V. infusion as well as in dialysate fluid infused into the peritoneal cavity for patients on peritoneal dialysis therapy.

Insulin is an anabolic, or building, hormone that helps:

Although it has no antidiuretic effect, insulin can correct the poly-uria (excessive urination) and polydipsia (excessive thirst) associated with the osmotic diuresis that occurs in hyperglycemia by decreasing the blood glucose level. Insulin also facilitates the movement of potassium from the extracellular fluid into the cell. 

Insulin is also used to treat two complications of diabetes: diabetic ketoacidosis, more common with type 1 diabetes, and hyperosmolar hyperglycemic nonketotic syndrome, which is more common with type 2 diabetes.

Insulin is also used to treat severe hyperkalemia (elevated serum potassium levels) in patients without diabetes. Potassium moves with glucose from the bloodstream into the cell, lowering serum potassium levels.

Oral antidiabetic drugs are well absorbed from the GI tract and distributed via the bloodstream throughout the body. Because repaglinide has a short duration of action, it’s given before meals.

It’s believed that oral antidiabetic drugs produce actions both within and outside the pancreas (extrapancreatic) to regulate blood glucose.

Oral antidiabetic drugs probably stimulate pancreatic beta cells to release insulin in a patient with a minimally functioning pancreas. Within a few weeks to a few months of starting sulfonylureas, pancreatic insulin secretion drops to pretreatment levels, but blood glucose levels remain normal or near-normal. Most likely, it’s the actions of the oral antidiabetic agents outside of the pancreas that maintain this glucose control.

Oral antidiabetic drugs provide several extrapancreatic actions to decrease and control blood glucose. They can go to work in the liver and decrease glucose production (gluconeogenesis) there. Also, by increasing the number of insulin receptors in the peripheral tissues, they provide more opportunities for the cells to bind sufficiently with insulin, initiating the process of glucose metabolism.

Other oral antidiabetic agents produce specific actions:

Combinations of multiple oral antidiabetic drugs or an oral antidiabetic drug with insulin therapy may be indicated for some patients who don’t respond to either therapy alone.

Hypoglycemia may occur when sulfonylureas are combined with alcohol, anabolic steroids, chloramphenicol, cimetidine, clofibrate, coumadin, fluconazole, gemfibrozil, MAOIs, phenylbutazone, ranitidine, salicylates, or sulfonamides. It may also occur when metformin is combined with cimetidine, nifedipine, procainamide, ranitidine, or vancomycin. Hypoglycemia is less likely to occur when metformin is used as a single agent.

Hyperglycemia may occur when sulfonylureas are taken with corticosteroids, dextrothyroxine, rifampin, sympathomimetics, and thiazide diuretics.

Because metformin given with iodinated contrast dyes can cause acute renal failure, metformin doses should be withheld in patients undergoing procedures that require I.V. contrast dye and
not restarted for at least 48 hours after the procedure. 

After subQ, I.M., or I.V. injection, glucagon is absorbed rapidly. Glucagon is distributed throughout the body, although its effect occurs primarily in the liver.

Glucagon regulates the rate of glucose production through:

Glucagon is used for emergency treatment of severe hypoglycemia. It’s also used during radiologic examination of the GI tract to reduce GI motility.

Glucagon interacts adversely only with oral anticoagulants, increasing the tendency to bleed. Adverse reactions to glucagon are rare.

Estrogens are used to correct estrogen-deficient states and, along with hormonal contraceptives, prevent pregnancy.

Estrogens that treat endocrine system disorders include:

Anterior pituitary drugs aren’t given orally because they’re destroyed in the GI tract. Some of these hormones can be administered topically, but most require injection.

Anterior pituitary drugs exert a profound effect on the body’s growth and development. The hypothalamus controls secretions of the pituitary gland. In turn, the pituitary gland secretes hormones that regulate secretions or functions of other glands.

The concentration of hormones in the blood helps determine hormone production rate. Increased hormone levels inhibit hormone production; decreased levels raise production and secretion.

Because enzymes in the GI tract can destroy all protein hormones, these drugs can’t be given orally. Posterior pituitary drugs may be given by injection or intranasal spray.

Under neural control, posterior pituitary hormones affect:

ADH increases cyclic adenosine monophosphate (cAMP), which increases the permeability of the tubular epithelium in the kidneys, promoting reabsorption of water. High dosages of ADH stimulate contraction of blood vessels, increasing the blood pressure.

Desmopressin reduces diuresis and promotes clotting by increasing the plasma level of factor VIII (antihemophilic factor).

In pregnant women, oxytocin may stimulate uterine contractions by increasing the permeability of uterine cell membranes to sodium ions. It also can stimulate lactation through its effect on mammary glands.

Desmopressin is the drug of choice for chronic ADH deficiency and is administered intranasally. It’s also indicated for primary nocturnal enuresis. Desmopressin has a long duration of action and relatively few adverse effects.

Short-term ADH treatment is indicated for patients with transient diabetes insipidus after head injury or surgery; therapy may be lifelong for patients with idiopathic hormone deficiencies. Used for short-term therapy, vasopressin elevates blood pressure in patients with hypotension caused by lack of vascular tone. It also relieves postoperative gaseous distention.

Natural thyroid drugs are made from animal thyroid and include:

Synthetic thyroid drugs are actually the sodium salts of the L-isomers of the hormones. These synthetic hormones include:

Thyroid hormones increase heart rate and cardiac output (the amount of blood pumped by the heart each minute). They may even increase the heart’s sensitivity to catecholamines and increase the number of beta-adrenergic receptors in the heart (stimulation of beta receptors in the heart increases heart rate and contractility).

Thyroid hormones may increase blood flow to the kidneys and increase the glomerular filtration rate (the amount of plasma filtered through the kidney each minute) in hypothyroid patients, producing diuresis.

Levothyroxine is the drug of choice for thyroid hormone replacement and thyroid-stimulating hormone suppression therapy.

Thioamides and iodides are absorbed through the GI tract, concentrated in the thyroid, metabolized by conjugation, and excreted in urine.

Drugs used to treat hyperthyroidism work in different ways.

Thioamides block iodine’s ability to combine with tyrosine, thereby preventing thyroid hormone synthesis.

Stable iodine inhibits hormone synthesis through the Wolff-Chaikoff effect, in which excess iodine decreases the formation and release of thyroid hormone.

Radioactive iodine reduces hormone secretion by destroying thyroid tissue through induction of acute radiation thyroiditis (inflammation of the thyroid gland) and chronic gradual thyroid atrophy. Acute radiation thyroiditis usually occurs 3 to 10 days after administering radioactive iodine. Chronic thyroid atrophy may take several years to appear.

To treat hyperthyroidism, the thyroid gland may be removed by surgery or destroyed by radiation. Before surgery, stable iodine is used to prepare the gland for surgical removal by firming it and decreasing its vascularity.

Stable iodine is also used after radioactive iodine therapy to control symptoms of hyperthyroidism while the radiation takes effect.

Propylthiouracil, which lowers serum T₃ levels faster than methimazole, is usually used for rapid improvement of severe hyperthyroidism.

Propylthiouracil is preferred over methimazole in pregnant women because its rapid action reduces transfer across the placental barrier and it doesn’t cause aplasia cutis (a severe skin disorder) in the fetus.

Propylthiouracil and methimazole appear in breast milk, so it’s recommended that mothers taking these drugs shouldn’t breast-feed. If a breast-feeding woman must take one of these drugs, propylthiouracil is the preferred drug.

Because methimazole blocks thyroid hormone formation for a longer time, it’s better suited for administration once per day to patients with mild to moderate hyperthyroidism. Therapy may continue for 12 to 24 months before remission occurs.