Medical Pharmacology Topics
| Preliminary Outline |
Insulin Preparations |
There are two kinds of diabetes mellitus: Type 1 and Type 2. Type 1, also known as juvenil-onset or insulin-dependent diabetes mellitus (IDDM), is an autoimmune disorder in which pancreatic b-cells are destroyed, and is rapidly fatal without treatment. Type 2, also known as adult-onset or non-insulin-dependent diabetes mellitus (NIDDM) is a condition were tissues are insensitive to insulin, and is an insiuous chronic disease. As insulin resistance persist over time, insuline secretory reserves diminish, leaving patients in a situation similar to IDDM.
The hazards of untreated diabetes include hyperglycemia-induced tissue damage (especially blood vessels) and perturbation of metabolism. Major complications include premature atherosclerosis, retinopathy, neuropathy and nephropathy.
The goal of diabetes treatment is to combin life-style changes with the appropriate drugs to reduce health risks and increase quality of life. The patient must match caloric intake, blood glucose and drug therapies in order to return blood glucose and lipids towards normal levels.
The treatment of NIDDM begins with control of diet and life-style modifications. In many patients the reduction of excessive body weight may rresult in improved glucose control. This is combined with the administration of hypoglycemic or antihyperglycemic agents if necessary, or insulin injections in some cases.
Patients with IDDM require insulin replacement terapy. The regime of insulin injections must match insulin activity, caloric intake and excersise, and is accompained by self-monitoring og blood glucose. Current insulin therapy for IDDMinvolves the use of intermediate or long acting preparations in order to provede a constant low basal level f insulin activity, in combination with an injection of short-acting insulin prior to meals in order to prevent hypergycemia after meals.
Insulin
Insulin is a peptide hormone synthesized and released by b-cells in pancreatic islets. Proinsulin is synthsized as a single chain with several disulfide bridges. Active insulin is formed by cleavage of the "C-peptide" portion of proinsulin.
Insulin readily forms a
dimer in solution. When three dimers combine with Zn
,
they form a hexamer, which is the strage form in b-cells.
Hexamers are also the basic building blocks of insulin fromulations. Small aounts
of both C-peptide and proinsulin are released along with insulin.
Insulin secretion may be affected by neural and hormonal signals, However, the major stimulus for insulin release is the prescence of glucose in the circulation. The three major organs of insulin action (in order of importance) are the liver, fat cells and muscle. Because insulin is released into the portal circulation, it reaches the liver first in relatively high concentration compared to other target tissues.
Circulating insulin has 30 min half-life, owing its rapid inactivation to receptor-mediated processes and non-specific enzymatic destruction. This occurs primarily in the liver, where almost half the insulin secreted is degraded. The kidney also removes insulin from the circulation.
At its target tissue, insulin combines with its specific receptor to trigger the phosphorylation of a variety of intracellular substrates, resulting in a range of effects that remove glucose from the circulation and promotes its storage. In the liver, it increases glycogen and VLDL synthesis, and inhibits glycogenolysis and gluconeogenesis. In adipocytes it increases fatty acid synthesis and inhibits lipolysis. In muscle it stimulates glucose and amino acid uptake.
Insulin secretion is subject to feedback inhibition by insulin, low blood glucose and the CNS. Excersise and leaness enhance insulin action, while obesity and a sedentary lifestyle opposes its efficient action. Glucagon, epinephrine, cortisol and groth hormone oppose the metabolic action of insulin, and are said to induce a state of insulin insensitivity.
Insulin Preparations
Insulin must be given parenterally,
usually subcutaneously. Although insulin by itself has a short half-life, different
formulations allow for rapid, intermediate or slow absorption from the site
of injection. The different pharmacokinetics of varoius preparations lies in
the tendency of insulin to associate with Zn
to form hexamers.
The crystaline hexamers
are absorbed from subcutaneous injectionmuch more slowly, thus prolonging duration
of action (4-6 hrs). Formulations of intermediate absorpion rate (1-2 hrs) are
obtained by complexing insulin with protamine or by mixing crystalline Zn
complexes with amorphous Zn
complex precipitates. Some of the ultrashort formulations (minuts) use synthetic
insulin mutated at only two amino acids (a proline and a lysine) which leave
the molecules with a greately reduced affinity for each other. Some commonly
used formulatins are:
In a typical "split-mixed" regime, intermediate-acting insulin is taken twice a day and regular insulin is taken before breakfast and before dinner. Ultralente can be used to ahieve a more stable basal activity, with doses of regular insuline before each meal.
Therapeutic insulines are prepared from either animal sources (porcine or bovine) or synthetic or recombinant human insuline. The animal nsulins are more antigenic, and generation of antibodies rarely result in allergy or varying degrees of insulin resistance. Other complications of insulin therapy include weight gain and hypoglycemia. Insulin is the only agent tat can be used safely to control diabetes during pregnancy.
Hypoglycemic and Antihyperglycemic Agents
The hypoglicemic agents used to treat NIDDM include the sulfonylureas and insulin analogs. Antihyperglycemic agents that sensitize tissue to insulin include the biguanides and peroxisome proliferator-activated receptor (PPARg) agonists. Glucosidase inhibitors preventglucose absorption.
The sulfonylureas act on
pancreatic b-cells to enhance the release of insulin. Glucose is thought to
trigger the release of insulin by increasing the intracellulr ATP/ADP ratio.
This in turn inhibits ATP-sensitive K
channels, resulting in membrane depolarization and influx of Ca
causing the release of insulin. Sulfonylureas appear to bind to and directly
inhibit this ATP-sensitive K
channel, thus facilitating the ability of glucose to promote insulin release.
Second generation sulfonylureas like glyburide and glipizide are more potent than first generation sulfonylureas like tolbutamide and tolazamide. They are all highly protein bound and metabolized primarily in the liver with the metabolites undergoing renal excretion. Adverse side effects include hypoglycemia, weight gain, increased plasma lipids and slightly increased blood pressure. Sulfonylureas should not be used during pregnancy.
The mechanism of action of biguanides like metformin is not well understood. However, they increase insulin-stimulated glucose transport by skeletal muscle and adipocytes, inhibit hepatic gluconeogenesis and promote weight loss. Metformin is used alone or with a sulfonylurea or with insulin.
In contrast with sulfonylureas, metformin may actually reduce blood presure and circulating insulin levels, does not causes hypoglycemia and may cause plasma lipid profiles to improve. It is contraindicated during pregnancy and in patients with predisposition to lactic acidosis, or with hepatic or renal failure, and may cause GI complaints. It has a 50-60% oral bioavilability, is excreted unchanged in urine and has a half-life of 1.5-5 hrs.
The PPAR are members of the nuclear receptor superfamily of ligand activated transcription factors that include steroid, thyroid and vitamin D receptors. There are three PPAR subtypes: a, b and g. The name PPAR comes from the observation that PPARa induces hepatic peroxisomal proliferation and increased fatty acid synthesis in rodents, but not in humans. PPARs are functinal as trascription factors only after heterodimerization with a 9-cis-retinoic acid activated (RXRa) receptor. Activation of PPARs alter the rate of expression of a number of genes ncoding proteins involved in regulating lipid metabolism and perhaps glucose metabolism.
There is an inverse relationship between improved insulin sensitivity and systemic availability of free fatty acids, which is belieed to be related to high concentrations of PPARg in addipose tissue. In insulin-resistant states, PPARg agonists like thiazolindinedione (TZD), rosiglitazone and proglitazone reduce hyperglycemia and hyperinsulinemia by lowering free fatty acids and triglycerides and by enhancing insulin sensitivity. TZD is no longer available due to sporadic hepatic failure, but rosiglitazone and proglitazone are still available. Other similar agents are under delopment.
PPARg agonists have a slow onset of action, up to 16 weeks to achieve maximum effects. TZD is metabolized by CYP3A4, but neither rosiglitazone nor proglitazone are, and have not shown significat drug interactions. These agents are less l;ikely than sulfonylureas to provoke hyperglycemia and weight gain. They can produce additive (perhaps synergistic) effects in combination with metphormin, sulfonylureas and insulin.
Glucosidase inhibitors like acarbose, voglibose and militol reduce or delay the absorption of glucose by inhibiting a-glucosidase, an intestinal brush border enzyme responsible for the breakdown of poly- and oligosacharides into absorbable sugars. As a result, they slow the absorption of glucose and "flatten" the peaks of plasma glucose after meals. Up to 36% of patients report flatulence, diarrhea or abdominal pain. These drugs are not useful as single agents.
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