Antidiabetic drugs

Anti-Diabetic
The pancreas :
• Endocrine gland that produces the peptide hormones insulin, glucagon, somatostatin
• Exocrine gland that produces digestive enzymes.
The peptide hormones are secreted from cells located in the islets of Langerhans (? cells produce insulin, ? cells produce glucagon, and ? cells produce somatostatin).
Hyperinsulinemia cause severe hypoglycemia.
Diabetes mellitus can cause serious hyperglycemia.
Complications: retinopathy, nephropathy, neuropathy, cardiovascular
Administration of antidiabetic agents can prevent morbidity & reduce mortality.
DIABETES MELLITUS:
• is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
• fasting plasma glucose > 7.0 mmol/l, or plasma glucose> 11.1 mmol/l 2 hours after a meal caused by
• insulin deficiency
• insulin resistance
TYPES OF DM:
• Type 1 diabetes (insulin dependent diabetes mellitus) IDDM
• Type 2 diabetes (non-insulin dependent diabetes mellitus) NIDDM
• Gestational diabetes
Diabetes due to other causes (e.g: genetic defects or medications).
• Gestational diabetes as carbohydrate intolerance with onset or first recognition during pregnancy.
• It is important to maintain adequate glycemic control during pregnancy.
• because uncontrolled gestational diabetes can lead to fetal macrosomia (abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia.
• Diet, exercise, and/ or insulin administration are effective in this condition.
A. Type 1 IDDM
• Classic symptoms of insulin deficiency (polydepsia, polyphagia, polyuria, weight loss).
• Require exogenous insulin to avoid the catabolic state & is c.c.c by hyperglycemia & life threatening ketoacidosis.
• The development & progression of neuropathy, nephropathy, & retinopathy are directly related to the extent of glycemic control.
• measured as blood levels of glucose &/or hemoglobin A1c [HbA1c].
Treatment:
• IDDM must rely on exogenous (injected) insulin to control hyperglycemia
• Avoid ketoacidosis
• Maintain acceptable levels of glycosylated hemoglobin (HbA1c). Bl. glucose concentrations as close to normal as possible
• Avoid long-term complications.
Continuous SC insulin infusion (insulin pump) is another method of insulin delivery.
• Other methods of insulin delivery, such as transdermal, buccal, & intranasal.
B. Type 2 diabetes NIDDM
• is influenced by genetic factors, aging, obesity, peripheral insulin resistance, rather than by autoimmune processes or viruses
• The pancreas retains some ?-cell fX, but variable insulin secretion is insufficient to maintain glucose homeostasis.
• Frequently accompanied by the lack of sensitivity of target organs to either endogenous or exogenous insulin.
• Resistance to insulin is considered to be a major cause of this type of diabetes.
Treatment:
• Maintain bl. glucose concentrations within normal limits
• Prevent the development of long-term complications.
• Weight reduction, exercise, dietary modification decrease insulin resistance & correct the hyperglycemia.
• Most patients are dependent on pharmacologic intervention with oral glucose-lowering agents.
• As the disease progresses, ?-cell Fx declines & insulin Rx required to achieve satisfactory S. glucose levels.
SIGNS & SYMPTOMS OF DM
• Insulin deficiency causes hyperglycaemia leading to glycosuria
• Increased catabolism:
• Increased lipolysis(in adipose tissue)
Increased fatty acids (in plasma)
• Oxidation(in liver)
• Decreased anabolism:
• Osmotic diuresis
• Dehydration & loss of electrolytes
(KETOACIDOSIS, DIABETIC COMA)
TYPES OF DIABETES FEATURE TYPE1DM TYPE2 DM Frequency 10-20% 80-90% Age at onset Early (below 35) Late (after 40) Type of onset Abrupt and severe Gradual & insidious Weight Normal Obese HLA Linked to HLA DR3,4,DQ - Family history <20% About 60% Genetic locus - Chromosome 6 Pathogenesis Autoimmune destruction of B- pancreatic cells Insulin resistance Islet cell antibodies present - Decreased insulin Normal or increased insulin Clinical management Insulin & diet Diet,exercise,oral drugs,insulin Acute complications Ketoacidosis Hyperosmolar coma
INSULIN
• A polypeptide hormone with two peptide chains that are connected by disulfide bonds.
• Synthesized as a precursor (pro-insulin) that undergoes proteolytic cleavage to form insulin and C peptide, both of which are secreted by the ? cells of the pancreas triggered by high bl. glucose..
• Insulin & glucagon regulate bl. glucose levels.
ACTIONS :
• Metabolism, Actions on liver, muscle and fat.
• Conserves fuel by facilitating the uptake & storage of glucose, amino acids & fats after a meal
Insulin secretion is regulated by:
• Bl.glucose levels
• Certain amino acids
• Other hormones
• Autonomic mediators.
High blood glucose is taken up by the glucose transporter into the ? cells of the pancreas. it is phosphorylated by glucokinase, which acts as a glucose sensor. The products of glucose metabolism enter the mitochondrial respiratory chain & generate adenosine triphosphate (ATP).
The rise in ATP levels causes a block of K+ channels, leading to membrane depolarization and an influx of Ca2+. The increase in intracellular Ca2+ causes pulsatile insulin exocytosis. The sulfonylureas and glinides owe their hypoglycemic effect to the inhibition of K+ channels.
Sources of insulin:
• Human insulin is produced by recombinant DNA technology using special strains of Escherichia coli or yeast that have been genetically altered to contain the gene for human insulin.
• Modifications of the amino acid sequence of human insulin have produced insulins with different pharmacokinetic properties.
• e.g :Lispro, Aspart, Glulisine, have a faster onset & shorter duration of action than regular insulin, because they do not aggregate or form complexes.
• Glargine & Detemir : long-acting & prolonged, flat levels of the hormone following injection.
M of Action:
Acts on insulin receptors on liver cells ,fat cells and stimulates glucose transport across membrane by ATP dependent transporters like GLUT 4 &GLUT 1
Insulin administration
• Insulin is a polypeptide, it is degraded in the GIT. Therefore, it is generally administered SC.
• In a hyperglycemic emergency, regular insulin is injected IV.
• Insulin preparations vary primarily in their onset of activity & in duration of activity. This is due to differences in the a.a sequences of the polypeptides.
• Dose, site of injection, blood supply, temperature, and physical activity can affect the duration of action of the various preparations.
• Insulin is inactivated by insulin-degrading enzyme (also called insulin protease ), which is found mainly in the liver and kidney.
Adverse reactions to insulin
• Hypoglycemia are the most serious & common adverse reactions to an excessive dose of insulin.
• Long term DM commonly do not produce adequate amounts of the counter-regulatory hormones (glucagon, epinephrine, cortisol, GH), which normally provide an effective defense against hypoglycemia.
• Other S E : weight gain, lipodystrophy (less common with human insulin), allergic reactions, local injection site reactions.
INSULIN PREPARATIONS and TREATMENT
A. Rapid-acting & short-acting insulin preparations
4 preparations: regular insulin, insulin lispro, insulin aspart, insulin glulisine.
• Regular insulin is a short-acting, soluble, crystalline zinc insulin, usually given Sc or IV in emergencies)
• It rapidly lowers bl. glucose.
• Regular insulin, insulin lispro, and insulin aspart are pregnancy category B
• Insulin glulisine is pregnancy category C.
• Insulin lispro differs from regular insulin in that lysine and proline at positions 28 and 29 in the B chain are reversed. This results in more rapid absorption after SC than is seen with regular insulin.
• Consequently, it acts more rapidly. Peak levels are seen at 30-90 min after injection, as compared with 50-120 min for regular insulin. It also has a shorter duration of activity.
• Insulin aspart and insulin glulisine have pharmacokinetic and pharmacodynamic properties similar to those of insulin lispro.
They are administered to mimic the prandial (mealtime) release of insulin, and they are usually not used alone but with a longer-acting insulin to ensure proper glucose control.
• Like regular insulin, they are administered subcutaneously.
B. Intermediate-acting insulin :
• Neutral protamine Hagedorn (NPH) insulin is a suspension of crystalline zinc insulin combined at neutral pH with a positively charged polypeptide, protamine
• Delayed absorption of the insulin because of its conjugation with protamine, forming a less-soluble complex
3.Long-acting insulin preparations :
a. Insulin glargine
b. Insulin detemir
The length of time to onset is 3-4 hrs and the max duration is 20-24 hrs.
B. Intermediate-acting insulin
• (NPH) insulin : Another name is insulin isophane.
• Its duration of action is intermediate because of the delayed absorption from its conjugation with protamine, forming a less-soluble complex.
• NPH insulin should only be given SC (Never IV) and is useful in treating all forms of DM except diabetic ketoacidosis and emergency hyperglycemia.
• It is used for basal control & is usually given along with rapid- or short-acting insulin for mealtime control.
• A similar compound called neutral protamine lispro NPL insulin has been prepared that is used only in combination with insulin lispro.]
C. Long-acting insulin preparations
1. Insulin glargine:
• Slower in onset than NPH insulin, flat, prolonged hypoglycemic effect with no peak. Like the other insulins, it must be given SC
2. Insulin detemir:
• Has a fatty-acid side chain. This addition enhances association to albumin.
• Slow dissociation from albumin results in long-acting properties similar to those of insulin glargine.
• Neither insulin detemir nor insulin glargine should be mixed in the same syringe with other insulins, because doing so may alter the pharmacodynamics and pharmacokinetic properties.
D. Insulin combinations
• Various premixed combinations of human insulins, such as 70% NPH insulin + 30% regular insulin, 50 % of each of these, and 75% NPL insulin plus 25% insulin lispro, are also available.
E. Standard treatment versus intensive treatment
• Standard? injection of insulin 2x /d.
• Intensive treatment ? normalize bl glucose through more frequent injections of insulin 3 or > x /d in response to monitoring bl glucose levels).
• Target mean bl glucose level of 154 mg/dL or less with DM.
• The frequency of hypoglycemic episodes, coma, and seizures due to excessive insulin is higher with intensive treatment regimens.
Regular Human Insulin
• A short-acting preparation
FDA approved to treat IDDM & NIDDM and for hyperglycemia during pregnancy.
• Administered SC as with other insulins (the only preparation that may be administered IM and IV)
• This insulin acts within 15-30 minutes and lasts from 1-12hrs.
Pharmacokinetics of Insulin
• Destroyed in the GIT, and must be given parentrally-usually SC, but IV or occasionally IM in emergencies
• Insulin should be administered 15-20 mins prior to meal
Insulin Delivery Devices
• INSULIN SYRINGES: Prefilled disposible syringes with regular or modified insulins
• PEN DEVICES: Fountain pen like :insulin cartridges
• INHALED INSULIN: Fine powder delivered through nebuliser,rapid absorption
• INSULIN PUMPS: Portable infusion devices connected to subcutaneously placed cannula(continuous insulin infusion)
• INSULIN PATCH-PEN: A small (two inches long, one inch wide and ¼ inch thick) plastic device is designed to be worn on the skin like a bandage
• IMPLANTABLE PUMPS: electromechanical mechanism regulates insulin delivery from percutaneously refillable reservoir
• Mechanical pumps, fluorocarbon propellants &osmotic pumps are also being developed
OTHER ROUTES:
• Oral (liposome)
• Nasal
• Intraperitoneal
SYNTHETIC AMYLIN ANALOG
Pramlintide
• Synthetic amylin analog (indicated as adjunct to mealtime insulin therapy with IDDM and NIDDM.
• By acting as an amylinomimetic
• Delays gastric emptying, decreases postprandial Glucagon secretion, improves satiety.
• Administered by SC injection and should be injected immediately prior to meals.
• When initiated, the dose of rapid- or short-acting insulin should be decreased by 50% prior to meals to avoid a risk of severe hypoglycemia.
• May not be mixed in the same syringe with any insulin preparation.
• S E: mainly GIT, nausea, anorexia, and vomiting.
Alternative Medicine
• Medicinal plants have been studied for the treatment of diabetes, however there is insufficient evidence to determine their effectiveness e.g:
? Cinnamon
? Chromium supplements
? Vanadyl sulfate a salt of vanadium
? Thiamine
Oral hypoglycemic Agents
Oral hypoglycemic
• Orally to reduce the bl glucose levels in NIDDM who cannot control by diet alone.
• DM after age 40 and have had DM less than 5 yrs are those most likely to respond well to oral glucose lowering agents.
• Long-standing disease may require a combination of glucose-lowering drugs with or without insulin to control their hyperglycemia.
Oral anti-diabetic drugs :
? Biguanides : Metformin
? Sulfonylureas:
Glimepiride, Glyburide, Tolbutamide,
Glibenclamide, Glipizide
? Meglitinides : Nateglinide, Repaglinide
? Thiazolidinediones :
Pioglitazone, Rosiglitazone
? Alpha -glucosidase inhibitors:
Acarbose, Miglitol
A. Sulfonylureas
Insulin secretagogues, because they promote insulin release from the ? cells of the pancreas. The primary drugs used today are the second-generation drugs (Glyburide, Glipizide, and Glimepiride).
Mechanism of action:
1) Stimulation of insulin release from the ? cells of the pancreas by blocking the ATP-sensitive K+ channels, resulting in depolarization and Ca2+ influx
Reduction in hepatic glucose production
3) Increase in peripheral insulin sensitivity.
Pharmacokinetics : Orally, drugs bind to serum proteins, metabolized by the liver, excreted by the liver or kidney. The duration of action ranges from 12 -24 hours.
Adverse effects:
• Weight gain, hyperinsulinemia, hypoglycemia.
• should be used with caution in patients with hepatic or renal insufficiency (accumulation= hypoglycemia.
• Renal impairment is a particular problem in the case of those agents that are metabolized to active compounds such as Glyburide.
• Glyburide has minimal transfer across the placenta and may be a reasonably safe alternative to insulin therapy for diabetes in pregnancy.
Sulfonylureas
• 1st gen : Tolbutamide and Chlorpropamide
• 2nd gen : Glibenclamide, Glipizide, Glimperide
MOA : Acts on B cells stimulating insulin secretion and thus reducing plasma glucose
Tolbutamide : half-life : 6-12 hrs
Pharmacokinetics :
• Orally, Some converted in liver to weakly active hydroxytolbutamide, some carboxylated to inactive compound. Renal excretion.
Side Effects:
• Hypoglycaemia.
May decrease iodide uptake by thyroid.
• Contraindicated in liver failure, renal failure
Glibenclamide :
• half life : 18-24 hrs
Pharmacokinetics : Orally, Some is oxidised in the liver to moderately active products, excreted in urine; 50% is excreted unchanged in the faeces.
Side Effects: May cause hypoglycaemia. The active metabolite accumulates in renal failure.
Glipizide : half-life : 16-24 hrs
Pharmacokinetics:
• Peak plasma levels in 1 hour.
• Most is metabolised in the liver to inactive products, which are excreted in urine; 12% is excreted in faeces.
SideEffects
• Causes hypoglycaemia, has diuretic action
• Most sulfonylureas cross the placenta and enter breast milk; as a result, use of sulfonylureas is contraindicated in pregnancy and in breast feeding
Drug interactions: NSAIDs, MAOI, anti bacterials, anti fungals
B. Meglitinides (Glinides)
Repaglinide and Nateglinide. Like sulfonylureas, they have common actions.
Mechanism of action: dependent on functioning pancreatic ? cells. They bind to a distinct site on the sulfonylurea receptor of ATP sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin. However, in contrast to the
sulfonylureas, they have a rapid onset and a short duration. They are particularly effective in the early release of insulin that occurs after a meal and are categorized as postprandial glucose regulators.
Pharmacokinetics :
• well absorbed orally.
• Both Glinides are metabolized to inactive products by cytochrome P450 3A4 in the liver and are excreted through the bile.
Adverse effects:
• can cause hypoglycemia, the incidence of this adverse effect appears to be lower than that with the sulfonylureas.
• Repaglinide (Reported to cause severe hypoglycemia in those who taking the lipid-lowering drug
Gemfibrozil : (the lipid-lowering drug)
• Concurrent use is contraindicated.
• Weight gain is less of a problem with the Glinides than with the sulfonylureas.
• These agents must be used with caution in patients with hepatic impairment.
Meglitinides
• Act like the sulfonylureas, but they don’t have sulfonylurea moiety.
• Include Repaglinide and Nateglinide
MOA :
• Same as sulfonylureas .
• Short duration of action, low risk of hypoglycaemia.
• Given orally, rapidly metabolized by liver enzymes
Oral antidiabetic drugs are of value only in the treatment of type 2 (NIDDM) whose condition cannot be controlled by diet alone.
• May also be used with insulin in the management DM
• Use of an oral antidiabetic drug with insulin may decrease the insulin dosage in some individuals.
C: Biguanides
Metformin: It does not cause hypoglycaemia
MOA:
Increase glucose uptake + utilisation in skeletal muscle (thereby reducing insulin resistance) and reduce hepatic glucose production (gluconeogenesis).
Pharmacokinetic:
Metformin :half-life of about 3 hours and is excreted unchanged in the urine.
Oral agents : Insuline sensitizers
• 2 classes of oral agents, the Biguanides and Thiazolidinediones, improve insulin action.
• These agents lower blood sugar by improving target-cell response to insulin without increasing pancreatic insulin secretion.
Metformin
• Classed as an insulin sensitizer.
• increases glucose uptake and use by target tissues, thereby decreasing insulin resistance.
• Metformin differs from the sulfonylureas in that it does not promote insulin secretion.
• Therefore, the risk of hypoglycemia is far less than that with sulfonylurea agents.
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MOA:
• The main mechanism is reduction of hepatic glucose output, largely by inhibiting hepatic gluconeogenesis.
• Metformin also slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization.
• An important property of this drug is its ability to reduce hyperlipidemia.
• Metformin as the drug of choice for newly diagnosed type 2 DM.
Metformin
• may be used alone or in combination with one of the other agents as well as with insulin.
Pharmacokinetics:
• Metformin is well absorbed orally, is not bound to serum proteins, and is not metabolized. Excretion is via the urine.
Adverse effects:
• Largely gastrointestinal.
• Metformin is contraindicated in DM + renal and/or hepatic disease and in those with diabetic ketoacidosis (DKA).
• Should be discontinued in cases of acute MI, exacerbation of CHF, severe infection.
• Metformin should be used with caution in older than age 80 years and in those with a Hx of CHF or alcohol abuse.
• Should be temporarily discontinued in patients undergoing diagnosis requiring IV radiographic contrast agents.
• Rarely, potentially fatal lactic acidosis has occurred.
• Long-term use may interfere with vitamin B12 absorption.
Other uses:
• In addition to the treatment of type 2 DM
• Metformin is effective in the treatment of polycystic ovary disease.
Its ability to lower insulin resistance in these women can result in ovulation and, therefore, possibly pregnancy.
Side effects:
• Dose-related gastrointestinal disturbances
• Lactic acidosis is a rare but potentially fatal toxic effect
• Long-term use may interfere with absorption of vitamin B12
Contraindications: Metformin should not be given in
? Renal failure
? Hepatic disease
? Hypoxic pulmonary disease
? Heart failure or shock
D: Thiazolidinediones (Glitazones)
? Insulin sensitizers (TZDs) or also called the Glitazones.
? Although insulin is required for their action, these drugs do not promote its release from the pancreatic ? cells, so hyperinsulinemia is not a risk.
? Troglitazone was the first of these to be approved for the treatment of type 2 DM but was withdrawn after a number of deaths from hepatotoxicity were reported.
? The two members of this class currently available are Pioglitazone and Rosiglitazone.
Glitazones
MOA :
• Bind to a nuclear receptor called the peroxisome proliferator-activated receptor-? (PPAR?), which is complexed with retinoid X receptor (RXR).
• PPAR?-RXR complex bind to DNA, promoting transcription of several genes with products that are important in insulin signalling.
Pharmacokinetics :
• Orally
• high plasma protein bound,
• peak plasma concentration-within 2 hrs
• Metabolized by liver enzymes.
• Rosiglitazone metabolites in urine
• Pioglitazone metabolites in bile
Side effects :
• Weight gain
• Fluid retention, headache, fatigue and gastrointestinal disturbances.
• Thiazolidinediones are contraindicated in pregnant or breast-feeding women and in children.
E: ?-Glucosidase inhibitors
Acarbose : An inhibitor of intestinal ?-glucosidase, is used in type 2 DM.
MOA : Delays CHO absorption, reducing the postprandial increase in blood glucose .
Side effects:
flatulence, loose stools or diarrhoea, and abdominal pain and bloating.
• Like Metformin, it may be particularly helpful in obese type 2 DM, and it can be co-administered with Metformin.
RECENT DRUGS
PEPTIDE ANALOGS
Injectable Incretin mimetics (insulin secretagogues)
? Molecules that fulfill criteria for being an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP)
? Both GLP-1 and GIP are rapidly inactivated by enzyme dipeptidyl peptidase-4 (DPP-4).
? Exenatide (first GLP-1 agonist)
? Liraglutide (a once-daily)
? Taspoglutide
? Side-effects:
? Decreased gastric motility
? Nausea
? weight loss
DIPEPTIDYL PEPTIDASE-4 INHIBITORS (DPPI)
• Increase blood concentration of the incretin GLP-1 by inhibiting its degradation by dipeptidyl peptidase-4.
• Vildagliptin (Galvus) EU Approved 2008
• Sitagliptin (Januvia) FDA approved Oct 2006
• Saxagliptin (Onglyza) FDA Approved July 2009

Linagliptin (Tradjenta) FDA Approved May 2, 2011
• DPP-4 inhibitors lowered haemoglobin A1C values by 0.74%, comparable to other anti-diabetic drugs
Sitagliptin :
• Well absorbed through GIT
• 80% excreted unchanged in urine
• half-life :8 -14 hours
Injectable Amylin analogues
• Slow gastric emptying
• Suppress glucagon.
Pramlintide
• (the only clinically available amylin analogue: administered by SC-injection)
• Typical reductions in A1C values are 0.5–1.0%.
Adverse effect :nausea