Diabetes mellitus (D.M)
Diabetes mellitus is a clinical syndrome characterized by hyperglycaemia due to absolute (type 1) or relative (type 2) deficiency of insulin . It has multiple etiologies and segregates into two major forms. Type 1 diabetes is an autoimmune disease in which the patients own immune system reacts against islet antigens and destroys the beta cell. Type 2 diabetes is a polygenic syndrome with multiple etiologiesInsulin
Physiological action: Insulin secreted from -cells directly in an unbound form, having half life 6 minutes so cleared from the blood rapidly.
Effects of insulin on the metabolism of carbohydrate, fats, and proteins:
On carbohydrate, it promotes glucose uptake and utilization, increase hepatic glycogen formation and inhibits hepatic gluconeogenesis.
It inhibits lipolysis and increase protein synthesis.
Differentiation by species
Animal Insulin
Until 1980 insulin was obtained by extraction and purification from pancreata of cows and pigs (bovine and porcine insulin).
Human Insulin is produced in two ways:
By enzymatic modification of porcine insulin by introduction of human insulin genes into E.coli and yeasts.
Recently, protein engineering techniques that alter the amine acids of insulin have been used to produce analogue of insulin which are more rapidly absorbed from the side of injection (insulin Lispro and aspart).
Insulin preparation
Fast-acting insulin: insulin lispro and aspart: effects begin within 5 to 15 min. and persist for 6-8hrs. Make them an ideal mealtime insulin and even after eating in contrast regular insulin is generally administered 30- 60min. before meal.., and persist for 6-8hrs.
short-acting insulin (soluble, regular or neutral insulin) considered a meal time insulin.
onset within 0.5- 1 houre,peak effect 2-4 hours,duration 4-8 hours. And therefore has significant activity after food is absorbed.. is dispensed as a clear solution and is the only form that can be administered intravenously .
-Intermediate-acting: Lente and NPH :
Lente insulin is produced by comlexing regular insulin with zinc.
NPH ( Neutral Protamin Hagedorn) is prepared by by conjugating regular insulin with protamine, the presence of protamine and zinc decrease the solubility of NPH and lente insulin respectively ,and thereby retard absorption., as a result onset is delayed and duration is extended (onset within 2.5 hours, duration up to 24 hours).
.The humnan lente insullin have a longer pharmacokinetic patern than NPH insulin (isophane) and some clinicians prefer Lente insulin to NPH
Pre-mixed: contain both a fast- and an intermediate-acting NPH insulin ( mostly used 30% short-acting and 70% NPH
onset within 30-45 min,
peak effect 412 hours,
duration up to 24 hours .
long acting insulin ; ultralente insulin , onset within 2-4hr. And dutation up to 24hrs.
Starting insulin therapy:
there is no standard calculation which will establish the correct starting dose of insulin ,the usual daily dose is around 0.5 i.u /kg. Body weight, larger doses are needed for overweight people, those with concurrent illness, very high glucose concentration, ketosis.
-Smaller doses are needed for slim people, those who exercise regulary, and those who have residual insulin (those in whom oral hypoglycemic drugs are only just inadequate.
-Doses above 1 i.u/kg. suggest insulin resistance. The total daily dosage is divided by the rule of thirds: two-thirds before breakfast and one third before the evening meal; at each time of administration two-thirds intermediate or long acting insulin and one third of short acting.
Oral hypoglycemic agents
Various classes of oral hypoglycaemic are available for treatment of NIDDM that target the different pathophyisological factors contributing to diabetes.
Sulphonylureas
Sulfonylureas that are currently available are : gliclazide,glimepiride,glyburide and glibenclamide (daonil). These agents are generally comparable in their effectiveness in reducing hyperglycaemia, difference in pharmacokinetics and pharmacodynamics may influence the choice in an individual patient.
o.m.: in the morning
** tds: three times a dayMechanism of action:
Bind to sulphonylureas receptors on the surface of pancreatic cells resulting in increase influx of calcium that cause microtubules to contract and exocytosis of insulin from vesicles leading to release of insulin in response to glucose.
Some evidence suggests that sulphonylureas reduce hyperglycemia by methods other than augmentation of insulin secretion by:
Increasing insulin receptor binding.
Increase numbers of insulin recepters on cell membrane
Improve insulin sensitivity in peripheral tissues.
Reduction in hepatic glucose output.
Therfore they are of no value in treating patients who are severely insulin deficient.
Efficacy and clinical uses:
Drugs in this class have similar efficacies and particulary used for the non-obese patients.Side effects and limitations:
SUs are not always effective, ~25% (primary failure), 5-10% yearly (secondary failure)
60% failure in 6 years of SU monotherapy
SUs mainly improve mean blood glucose not post prandial glycaemia
Inducing continous hyperinsulinemia - risk of hypoglycaemia and weight gain.
Others : GIT disturbances, skin rashes, a plastic anaemia.
Non- Sulphonylureas Meglitinides
This relatively new class of insulin secretagues repressented by nateglinide and repaglanide introduced in used un 1998.
Mechanism of action:
The mechanism of action is similar to that of sulphonylureas; how ever ,they bind to sulphonylureas receptor at different site and with different kinetics,those the onset of action is faster which result in prief stimulation of insulin secretion and for a short period, i.e. insulin secretion is stimulated only at the time when needed mealtime
Repaglanide:NovoNorm (Prandin),
Nateglinide: Starlix
Efficacy and clinical uses
The efficacy of repaglinide appears to be similar to that of sulphonylureas) and the efficacy of nateglinide appears to be somewhat less .These medications can be used either as monotherapy or in combination with other oral hypoglycemic agents (but not sulphonylureas), they are preferred for elderly patients and patients with impaired renal functions because is metabolized in the liver and excreted mainly via bile .Because of its rapid onest and short duration of actions, they are indicated for use in controlling postprandial glucose excursions.
Repaglanide should be taken before each main meal ( 15 min. before a meal).
If no meal is taken, no tablet is taken
Dosing:
Start with 0.5mg before each meal
Patients transferred from SU with 1.0mg each meal
Dose is increased weekly until target FBG
Side Effects :As with sulphonylureas, the main side effect of this class is hypoglycemia, the risk of hypoglycemia is lower than that with sulphonylureas .
The amount of weight gain appears to be less than that seen with sulphonylureas, perhaps because of the limited duration of elevated insulin secretion.
Biguanides :Metformin(glucophage),
Mechanism of action:
-Decrease liver glucose production, by inhibiting hepatic gluconeogenesis.
-Increase glucose uptake by the muscles and supress appetite.
-Inhibite intestinal glucose absorption.
Efficacy and Clinical Use
The efficacy of metformin monotherapy is equivalent to that of sulfonylurea monotherapy. It is associated with weight loss, or at least with no weight gain.
Metformin is approved for use in diabetes either as monotherapy or incombination with other oral hypoglycemic agents, as well as with insulin. It is recommended as first line therapy for overweight patients with type 2 diabetes.
Metformin should never be used in patients with renal impairment because of the risk of lactic acidosis.
Side effects:
Gastrointestinal complaints (frequent and transient)
Lactic acidosis (rare and serious)
Since insulin secretion is not altered, hypoglycemia is not aside effect.
Weight gain is not a side effect and some patients experience weight loss.
Contraindications:
Renal and hepatic dysfunction
Hypoxic conditions
Elderly ?
Alpha- glucosidase inhibitors(Acarbose and Miglitol)
class of oral hypoglycemic agents inhibits enzymes in small intestinal brush border that are responsible for the breakdown of oligosacchrides and disaccrides into monosaccharides suitable for absorption .It works mainly in - glucosidase which is found in the proximal half of small intestine, therefore the absorption of carbohydrate is delayed and shifted to more distal parts of the intestine and colon, this retards glucose entry into the systemic circulation and lower post prandial glucose levels .
Efficacy and Clinical Uses:
The blood glucose lowering effect of alpha- glucosidase inhibitors is less than that of most of other classes of oral hypoglycemic agents , thus they are rarely used alone, and most useful in combination with other hypoglycemic agents.
Side effects: G.I.T disturbances (bloating, abdominal discomfort, diarrhea and flatulence occure in about 20% of patients.
Intestinal lipase inhibitor (orlistat).
In the 2003 ,orlistat was added to the list other oral hypoglycemic agents . it is antiobesity agent that act as inhibitor of of gastric and pancreatic lipases and thereby inhibits the hydrolysis of dietary fat into absorbable free fatty acids and monoglycerides which result in decreased energy intake and weight loss.
Orlista
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Side effects:
G.I.T side effect occure in the first 3months of treatment, this include flatulence with discharge, oily spotting, fecal urgency and steatorhea .