Insulin and oral hypoglycemic drugs.
The pancreas is both an endocrine gland that produces the peptide hormones ,Insulin, Glucagon, and Somatostatin and an exocrine gland that produces digestive enzymes .The peptide hormones are secreted from cells located in the Islets of Langerhans (β or B cells produce INSULIN, α 2 or A cells produce Glucagon and α 1 or D cells produce Somatostatin ).these hormones play an important role in regulating the metabolic activates of the body, particularly the blood glucose .
Relative or absolute lack of insulin can cause serious hyperglycemia such as in Diabetes mellitus ,if untreated can lead to more complications e.g. retinopathy ,nephropathy, neuropathy and cardiovascular complications .
Diabetes mellitus is a heterogeneous group of syndromes characterized by an elevation of blood glucose caused by a relative or absolute deficiency of insulin ,but hyperglycemia considered to be due to insulin receptor defect ;DM, can be divided into two main groups according to their requirements for insulin :
1:- Type 1; formerly called insulin-dependent diabetes mellitus (IDDM). Usually occur in young age group these patients don’t secret insulin from their pancreas ,so, require insulin for their treatment and survival
2:- Type 2 ;formerly called non- insulin dependent D.M. (NIDDM); usually occur in older age group ,these patients retain the capacity to secret insulin ,but have some resistance to it especially obese people ;this type can be treated by diet alone or with the use of an oral hypoglycemic drugs ; if no response insulin is used .
3:- Type 3 ; called maturity onsent diabetes of young (MODY); it’s a heterogeneous group of disorders in which dysregulation of insulin secretion is due to mutations of particular genes ,it is inherited as autosomally dominant fashion ,it is occur before 25 years of age and patient be mot obese and no resistance for insulin .
4:- Type ; gestational D.M.:- it is glucose intolerance associated with pregnancy diet ,exercise and /or insulin administration are effective in this condition .
Insulin:- it is a hormone secreted from β- cells of Islets of Langerhans of the pancreas ,it is polypeptide in nature of two peptide chains( A chain 21 a.a, ;B chain with 30 a.a. ; linked by disulfide bonds .
It is synthesized as precursor (pro- insulin.), that undergoes proteolytic cleavage to form insulin and peptide C, both of which are secreted by the β – cells of the pancreases (daily secretion 30-40 unites );where measurement of circulating C-peptide provides a better idea of insulin levels ; metabolized or inactivation by reducing insulinase in the liver and kidney with half life 5 minutes .
Sources of insulin:-
1:- Human insulin ; is produced by recombinant DNA technology using special strains of E.C. or yeast that have been genetically altered to contain the gene for human insulin ; or by enzyme modification of porcine insulin .Modification of the amino acids sequence of human insulin have produce insulin with different pharmacokinetic and pharmacodynamic properties e.g. Lispro ,Aspart and glulisine – have a faster onsent of action and shorter duration of action than regular insulin ,because they don’t aggregate or form a complexes ;on other hand, insulin glargine and insulin Detimir are long acting insulins and show prolonged flat levels of the hormone following a single injection .
2:- Bovine insulin; differs from human insulin by 3 a.a. and it is more antigenic to man .
3:- Porcine insulin ;is differs from human insulin by only one a.a. ,from pork .
Insulin administration :-
Because insulin is a poly peptide ;it is degraded in the GIT, If taken orally ,it therefore is generally administered by subcutaneous injection ,I.V. ,continuous sub cutenous insulin infusion has become popular ,because it doesn’t require multiple injections an aerosol preparation that is inhaled and absorbed in the lung is undergoing trials .
Insulin receptors :-
The receptors of insulin are present on surface of the target organs cells mostly liver, adipose tissue and muscles , the insulin binds to the α –subunit of its receptor(which is extracellular ) ,the β –subunit is a tyrosine kinase which is activated by insulin binding lead to auto phosphorylated and phosphorylates other substrates lead to action of insulin intracellular .
When ,there is high concentration of insulin in the blood ,the number of insulin receptors usually declines (down regulation )and responsiveness to insulin also declines lead to insulin resistance and inversely ,when there is low concentration of insulin in blood there will be increase in the number of receptors (up regulation) and the responsiveness increase .
Actions of insulin :-
1:- Reduction in blood glucose due to increase glucose uptake in the peripheral tissues which convert it into glycogen or fat ) . as well as ,reduction of hepatic output of glucose (inhibits glycogenlysis and gluconeogenesis ) .
2:- Other metabolic effect; in addition to enabling glucose to pass a cross cell membrane ,the transit of a.a. and potassium into the cells is enhanced .
3:- Regulate CHO utilization and energy production ,it enhance protein synthesis and inhibits breakdown of fat (lipolysis ) .
Indications of insulin.
1:- Diabetes mellitus is the main indication(both IDDM-90% and NIDDM -20%).
2:- Insulin promotes the passage of potassium simultaneously with glucose into the cells and this effect is utilized to correct hyperkalemia .
3:- Insulin induced hypoglycemia can also be used as a test of anterior pituitary gland function (Growth hormone and ACTH are released ).
Adverse effects of insulin :-
1:- Hypoglycemia ; is the most common complication –due to either high insulin dosage or due to unusual physical exertion or delay eating ; manifested as palpitation ,sweating ,tremor ,hunger and nausea , treated by glucose administration for mild reaction orally ,for more sever hypoglycemia (lead to coma ,convulsion, and even death ),treated by I.V. infusion of hypertonic glucose .
2:- Lipodystrophy :- ( either atrophy or hypertrophy ) at the injection sites (rare with pork or human insulin); Lipodystrophy occur due to inject the insulin repeatedly at the same site .(liposuction can correct or by rotating the site of injection .
3:- Insulin allergy :- immediate type hypersensitivity reaction represented by generalized allergic reactions are very rare ,but may occur to any insulin ; used highly purified insulin preparation decrease this allergy .
4:- Insulin resistance :- which is may be due to a decline in the number and or affinity of receptors or due to defect in post receptor mechanism (a diabetic patient required more than 200 i.u. /day insulin .) .responsiveness to insulin may sometimes be restored by immune suppression e.g. adrenocortico steroids like Predinisolone due to formation IgG against insulin receptors .
Preparations of insulin :-
1:- Rapid –onset and ultra short- acting insulin preparation .
Four insulin preparations fall into this category :Regular insulin, insulin lispro, insulin aspart, insulin glulisine. Regular insulin is a short-acting ,soluble ,crystalline zinc insulin ,it is usually given S.C. ,orI.V.in emergency ,and it rapidly lowers blood sugar ,onset of action 30 min. and duration of action is 5-7 h. ,it is safely used in pregnancy ,whereas use of the other three preparations is advised in pregnancy only if clearly needed .
Lispro insulin differs from regular insulin in that lysine and proline at positions 28 and 29 in the B chain are reversed ,this result in more rapid absorption after S.C. injection than is seen with regular insulin as a consequence ,Lispro insulin acts more rapidly ,Lispro insulin is usually administered 15 minutes prior to a meal ,peak levels of Lispro insulin are seen at 30-90 minutes after injection, as a compared with 50-120 minutes for regular insulin , duration of action of lispro insulin is 3-4 h.
Aspart, glulisine and Lispro insulin are administrated to mimic the prandial(meal time ) release of insulin .
They are usually not used alone ,but rather with a long –acting insulin .
2:-Intermediate –acting insulin preparations
a)Lente insulin:-it is an amorphous precipitate of insulin with zinc ion in acetate buffer combined with 70% ultra Lente insulin ;onset of action and peak effect are slower than those of regular insulin ,but are sustained for a longer period. It is not suitable for I.V. administration .
b) Isophane NPH insulin suspension:-
Neutral Protamine Hagedorn (NPH) insulin is a a suspension of crystalline zinc insulin combined at neutral pH with a positively charged polypeptide ,its duration of action is intermediate ,this due to delayed absorption of the insulin ,because of its conjugation with Protamine ,forming a less –soluble complex .
NPH insulin should only be given S.C. (never I.V.),and useful in treating all forms of diabetes except diabetic ketoacidosis or emergency hyperglycemia ,it is usually given with regular insulin (similar compound called neutral Protamine (NPL) insulin ,has been prepared that is used only in combination with Lispro insulin .
3:- Prolonged –acting insulin preparations :-
a)Ultra Lente insulin ,sometimes referred to as extended zinc insulin, it is a suspension of zinc insulin crystals in acetate buffer ,this produce large particles that are slow to dissolve ,resulting in a slow onset of action and a long-lasting hypoglycemia .
b)Insulin glargine :- it is precipitated at the injection site ,thereby extending its action it is slower in onset than NPH insulin and has a flat ,prolonged hypoglycemic effect without peak .
like the other insulin, it must be given S.c.
c) insulin detimir ;has fatty –acid side chain ,it associates with tissue –bound albumin at the injection site, and has properties similar to those of insulin glargine .
4:- Insulin combinations :-
Various combinations of human insulins, such as 70% NPH insulin plus 30%regular insulin, 50%of each of these ,or 75%NPL insulin plus 25% lispro insulin ,are also available .
Oral anti diabetic drugs:-
These agents are useful in the treatment of patients who have Type 2 (non-insulin dependent diabetes )who can't be managed by diet alone .Oral hypoglycemic drugs shouldn't be given to patients with Type 1 diabetes .
1:- Insulin secretagogues; Drugs of this group ,promote insulin release from the β –cells of the pancreas include :-
A) Sulfonylureas .
B)Meglitinide analogs .
1:- Sulfonylureas group (related to sulphonamide ),two generations.
first generation includeChlorpropamide (duration of action very long 60 h. and has more unwanted side effects than others especially in elderly ;not used nowadays ) .
Tolbutamide; well absorbed, short duration of action (6-12 hours) ,safe for use in the elderly .
Tolazamide, short duration of action ,comparable to Chlorpropamide in potency ,with slow absorption .
Second generation Sulfonylureas include
Glipizide (duration of action 20 h.) ,Glyburide (24h.), Glimepiride (16-24h.) Glibenclamide (12-24 h.)
Several Sulfonylureas are available ,choice is determined by the duration of action ,the patient's age ,renal function and unwanted side effects ,e.g. Tolbutamide or Glipizide are preferred especially in elderly ,since they are not excreted by the kidney and short duration of action .
Mechanism of action:- they activated β-cells of pancreas to enhance release of stored insulin in response to glucose by blocking the ATP- sensitive potassium channels on β-cells plasma membrane ,resulting in depolarization and calcium ions influx ; but they don’t increase insulin formation .
They enhance insulin action on the target tissues liver, muscles and adipose tissue by increasing insulin receptors number and enhancing the post –receptor enzyme reactions ,modulated by insulin lead to decrease hepatic glucose output and increase glucose uptake in muscle .
Also these drugs reduce the serum Glucagon levels .
Pharmacokinetic :-
Given orally ,bind to plasma proteins ,metabolized by liver and excreted through the kidney or liver ,taken 30 minutes before the meal, they are used in Type 2D.M. unless resistance has been developed .
Drugs interactions :-
Phenylbutazone ,monoaminoxidase inhibitor ;Chloramphenicol ;Dicumarol all lead to reduce hepatic metabolism of Sulfonylureas lead to increase the hypoglycemic effect .
Clofibrate ,Salicylates, Sulfonamides ,Allopurinol cause displace them from plasma protein and decrease urinary excretion and increase hypoglycemic action .
Adverse effects :-
1-Weight gain .
2-Hyperinsulinemia and hypoglycemia .
3-Allergic skin reactions .
4-Alcohol intolerance (Disulfiram like reaction ).
5-Secondary failure (after months or years )occurs due to declining β –cells function and insulin resistance
Contraindications:-
1-hepatic or renal insufficiency,( delay secretion and accumulation) .
2-pregnancy, (cross placenta lead to fetal hypoglycemia ).
Meglitinide analogs ; this class include:-
1-Repaglinide (duration of action is 3-4) .
2- Nateglinide (duration of action is 2-3h.) , although they are not Sulfonylureas ,they have common actions .
Mechanism of action :- like Sulfonylureas ,block ATP-sensitive potassium channels of β-cells of pancreas .
in contrast to Sulfonylureas ,the Meglitinide have a rapid onset and short duration of action , they are particularly effective in the early release of insulin, that occurs after a meal and thus are given post prandial (after meal) ,combined therapy of these agents with Metformin or with Glitazones has been shown to be better than mono therapy .(so given 3 time/day after meal with Metformin ).
P/K :- Well absorbed from GIT, metabolized in the liver and excretion through the bile .
Side effects :-
1-hypoglycemia (the incidence appears to be lower than the Sulfonylureas ).
2-weight gain is also less than with Sulfonylureas .
3- Repaglinide cause severe hypoglycemia in patients taking the lipid lowing drug (Gemfibrozil) .
Drug interactions :- Those drugs inhibit the hepatic (CYP3A4), like Ketoconazole ,Itraconazole, Fluconazole, Erythromycin, and Clarithromycin may enhance the glucose –lowering effect of Repaglinide ,whereas drugs those induce these enzymes such as Barbiturates , Carbamazepine, Rifampicin ,have the opposite effect .
Insulin sensitizers ,include
1-Biguanides (Guanidine derivative ).2-Thiazolidinediones (Glitazones ).
The agents of these two groups lower blood sugar by improving target cell response to insulin without increasing pancreatic insulin secretion .
1-Biguanides ,they in use since 1957,while the first Sulfonylureas were introduced into clinical practice in 1054 .
Metformin is the only Biguanides in current use ,it is a major agent in management of type 2 D.M. especially those newly diagnosed ,it is classed as an insulin sensitizer ,that is increases glucose uptake and utilization by target tissues ,thereby , decrease insulin resistance ;Metformin requires insulin for its action and be ineffective in absence of insulin .
It doesn’t promote insulin secretion ,so, hyperinsulinemia and risk of hypoglycemia is not a problem and far less than with Sulfonylureas agents ,only occur if Metformin taken in combination with one of the other agents as well as with insulin or when there is more exercise or low caloric intake .
Mechanism of action :-
1-reduce hepatic glucose output by inhibition hepatic gluconeogenesis .
2-slows intestinal absorption of sugars .
3- increase glucose uptake and utilization by target tissues and decrease insulin resistance .
4- it has ability to reduce LDL and VLDL cholesterol concentrations and increase HDL cholesterol ,which noticed after 4-6 weeks of use and by this it is the only hypoglycemic drug proven to decrease cardiovascular mortality .
P/K :- it well absorbed orally ,it is not bound to plasma proteins and it is not metabolized ,highly concentrated in saliva and intestinal wall ,excretion is via the urine ,should not used in renal function impairment (t1/2=5h.). it is taken with or after meal ,its chief use is in the obese patients with type 2 D.M. either alone or in combination with a Sulfonylureas .it has mild anorexic effect which help to reduce weight in the obese ,this effect may be enhance by Cimetidine ,Furosemide ,Nifedipine and others .
Side effect:-
1- GIT disturbance from diarrhea ,metallic taste ,anorexia may lead to loss of weight .
2- Long-term use may interfere with vitamin B12 absorption .
3-Ketonurea may occur in presence of normal blood glucose responded to reduce the dose of Metformin.
4- More serious ,but rare is lactic acidosis ,when this condition occur indicate serious underlying medical state such as renal impairment ,liver failure , cardiogenic or septic shock ; treated with large I.V. doses of isotonic sodium bicarbonate .
Other uses of Metformin is in treatment of polycystic ovary syndrome ,its ability to lower insulin resistance in those women can result in ovulation and possible pregnancy .
Contraindications:-
Metformin is contraindication in renal and /or hepatic disease and in diabetic ketoacidosis .
Should discontinued in acute myocardial infarction ,exacerbation of congestive heart failure ,and sever infection
4:- Thiazolidinediones (Glitazones):-
Another group of agents that are insulin sensitizers ;although insulin is required for their action ,not promote its release ; thus hyperinsulinemia doesn't result include :-1-Troglitazone ;withdrawal after a number of deaths due to hepatic toxicity .
2-Pioglitazone .
3-Rosiglitazone .
Mechanism of action : They are known to target the Peroxisome proliferator –activated receptors –Y (PPAR-Y ), a nuclear hormones receptor that regulate adipocyte production and secretion of fatty acids as well as glucose metabolism ,resulting in increase insulin sensitivity in liver, muscles ,and adipose tissues .
P/K:- Very well absorbed after oral administration and are extensively bound to plasma albumin ,undergo extensive metabolism by liver ,primarily excreted in the urine ,taken once daily dose ,used in combination with Metformin or Sulfonylureas
Side effects :-
1-Weight gain due to increase subcutaneous fat or due to fluid retention and edema .
2- Headache and anaemia .
3-Hepatic toxicity in patients taking Troglitazone ,so liver enzyme measurements is mandatory .
Other uses ;like Metformin, relief of insulin resistance with TZDs, can cause ovulation in women with PCOS.
Contraindications :- in cardiac or hepatic failure .
5)α- glucosidase inhibitors ;this group include
1-Acarbose .2-Miglitol
Are orally active drugs used for treatment of patients with Type 2 D.M.
Mechanism of action :-
these drugs are taken at the beginning of meals ,they act by delaying the digestion of carbohydrate thereby decreasing glucose absorption ,both drugs exert their effects by reversibly inhibiting membrane –bound α –glucosidase in the intestinal brush border .this enzyme responsible for the hydrolysis of oligosaccharides to glucose and other sugars ,they don’t stimulate release of insulin and not increase its sensitivity in target tissues and don’t cause hypoglycemia .
P/K:-
Acarbose is poorly absorbed, it is metabolized primarily by intestinal bacteria ,some metabolites are absorbed and excreted into the urine ,Miglitol is very well absorbed ,but has no systemic effect and excretion un change by the kidney .the usual dose is 50-300 mg./day .and can be combined with Sulfonylureas
Side effects :- flatulence ,diarrhea ,and abdominal cramping ,decrease the bioavailability of Metformin ,so concurrent use should avoided . patients with inflammatory bowel disease ,colonic ulceration or intestinal obstruction should not use these drugs .
6) Gastrointestinal hormones :-
Oral glucose result in a higher secretion of insulin than occurs when an equal load of glucose is given I.V. ,this effect is referred as the ( incretin effect ) ,which is reduced in type 2 DM. It demonstrates the important role of the gastrointestinal hormones notably glucose dependant insulinotropic polypeptide, Glucagon –like peptide -1 (GLP-1) ,and the gastric inhibitory polypeptide (GIP ),in digestion and absorption of nutrients including glucose , these incretin hormones are responsible for 60-70% of postprandial insulin secretion .Exenatide :-
Is a polypeptide sequence about 50% homologues to GLP-1 ,has been introduced, mediated its effect through GLP-1 receptors ,it is improve insulin secretion and slows gastric empting time and promotes β –cells regeneration ,and decrease postprandial glucagon secretion ;consequently , weight gain ,post prandial hyperglycemia are reduced , and HbA1C levels decline . must be administration parentally ,usually S.C. , used as adjunct therapy in patients on a Metformin , Sulfonylureas ,a Glitazones or as combination therapy . Exenatide is eliminated mainly via kidney ,it has short half life injected twice daily within 60 minutes prior to morning and evening meals .Side effects :- the main side effects nausea ,vomiting, diarrhea, and constipation .
GIP and GLP-1 are rapidly degraded in the circulation by enzyme called dipeptidyl peptidase-4 (DPP-4) ,Sitagliptin and Saxagliptin :-
Is an oral DPP-4 inhibitor ,prolonging the activity of incretin hormones result in increase insulin release and a reduction in secretion of glucagon it is used in combination with Metformin ,Sulfonylureas ,or with Glitazones ,insulin or as triple therapy ,the dose is 100mg once daily taken with or without food in treatment type 2 DM. or in inadequate glycemic control .Side effects :- may associated with increase infection e, g, upper respiratory tract infection (nasopharyngitis) urinary infection ; headache also common with dizziness . pancreatitis has occurred with use of Sitagliptin . Ketoconazole and Clarithromycin may increase level of Saxagliptin .
Contraindications :- in patients with moderate to severe renal insufficiency and in pregnancy or breast feeding .
Vildagliptin :-
Is an oral DPP-4 inhibitor ,dose 50mg in the morning and the evening ,unlike Sitagliptin and Exenatide ,the Vildagliptin not lanced to used in triple therapy ,present in combination with Metformin only ; has the same indications for Sitagliptin .Side effects :- headache more common, rarely hepatic dysfunction ,and unlike Sitagliptin risk of infection is absent .
Contraindications :- liver function abnormalities ,moderate to severe renal insufficiency and in pregnant women or breast feeding .