Antidiabetic Agents

Introduction
• The pancreas produces the peptide hormones insulin, glucagon and
somatostatin
• These hormones help to regulate metabolism especially glucose
homeostasis
• An absolute or relative lack of insulin, eg in DM, can cause serious
hyperglycaemia
• Prolonged hyperglycaemia results in retinopathy, nephropathy,
neuropathy, and cardiovascular complications
• Administration of insulin or other glucose-lowering preparations can
reduce morbidity and mortality
Introduction
• Diabetes is a heterogenous group of syndromes which are
characterised by elevated blood glucose due to an absolute or relative
lack of insulin
Four clinical types
• Type 1 diabetes
• Type 2 diabetes
• Gestational diabetes
• Diabetes from genetic defects or medications
Type1 diabetes(IDDM)
Type 1 DM (IDDM)
• Commonly affects children, adolescents, or young adults
• Characterised by an absolute deficiency of insulin due to destruction
of beta cells
• The loss of beta cell function results from autoimmune processes
which may be triggered by viruses or other environmental toxins
• The pancreas fails to respond to glucose
• They show the classic symptoms of insulin deficiency- polyuria,
polyphagia and polydipsia
Type1 diabetes(IDDM)
• Type 1 diabetics require exogenous insulin to avoid severe
hyperglycaemia and life threatening ketosis
Treatment
• Exogenous insulin to control hyperglycaemia, avoid ketosis, and
maintain acceptable levels of glycosylated haemoglobin (HbA1c)
• The goal of insulin therapy is to maintain blood glucose as close to
normal as possible and avoid wide swings in glucose
Type 2 diabetes (NIDDM)
• Accounts for 90% of cases of DM
• Influenced by genetic factors, aging, obesity, peripheral insulin resistance,
rather than autoimmune processes
• Metabolic changes are milder than in type 1
• They do not have ketosis
• Long term consequences are similar
Cause
• Characterised by a lack of sensitivity of target organs to insulin
• The pancreas retains some beta cell function, but insulin secreted is not
enough to maintain glucose homeostasis
Type 2 diabetes (NIDDM)
• There is increasing insulin resistance
• Type 2 patients are usually obese, as compared to Type1 patients
• The obesity contributes to insulin resistance which is the major
underlying defect of Type 2 DM
Treatment
• Goal : to maintain normal glucose levels, to prevent long term
complications
• Weight reduction, exercise, and dietary modification decrease insulin
resistance and may correct hyperglycaemia
Type 2 diabetes (NIDDM)
• Most pts however need oral glucose-lowering agents
• As the disease progresses, beta cell function declines, and insulin
therapy may be needed to achieve satisfactory glucose levels
Insulin and Insulin analogues
• Human insulin is a polypeptide of 51 amino acids
• It is formed by removing a connecting ‘C’ peptide from proinsulin
• It has A and B chains joined by 2 disulphide bridges
• It is secreted by the beta cells of the pancreas
• Glucose is the most potent stimulus for insulin release
• It enters the beta cells of the islets of Langerhans in the pancreas
• This closes K channels and causes depolarisation, and Ca influx which
triggers insulin release
Insulin and Insulin analogues
• In health there is a continuous basal insulin release which is
supplemented by bursts when plasma glucose rises
• After release its carried to the liver where glucose is converted to
glycogen
• Insulin binds to insulin receptor to perform its function
• Insulin affects carbohydrate, fat and protein metabolism
• It facilitates hepatic uptake of glucose and its conversion to glycogen
• Glycogenolysis is inhibited
• Fat deposition is increased, Lipolysis is inhibited
Insulin and Insulin analogues
• Storage of amino acids as proteins is promoted and catabolism is inhibited
Preparations
• Used to be extracted from porcine or beef pancreas , but now produced
by recombinant DNA technology, using E coli
• Preparations are classified as short, medium or long acting
Short acting – a simple solution of insulin that may be administered
intravenously for rapid effect
Medium and long acting-when insulin is complexed with zinc or protamine,
or produced as crystals, its solubility decreases and its absorption is
prolonged
Insulin and Insulin analogues
• This extends the duration of action of insulin to 16-35 hrs
• Dose, injection site, blood supply, temperature and physical activity
can also affect onset and duration of action
• Because insulin is a, polypeptide, it is degraded in the GIT if taken
orally
• Therefore it is generally administered by subcutaneous injection
• In a hyperglycaemic emergency, insulin may be given IV
Insulin and Insulin analogues
Treatment
• Standard insulin therapy involves twice daily injections
• Intensive therapy however uses three or more injections daily with
frequent monitoring of glucose levels
• The frequency of hypoglycaemia, coma and seizures is higher with
intensive therapy
Insulin and Insulin analogues
Side effects
• Hypoglycaemia, if calorie intake insufficient, if untreated leads to
coma and death
• Weight gain
• Immunogenic reactions
• Localised lipodystrophy
• Dose must be reduced with renal insufficiency
Oral antidiabetic agents
• Useful in treatment of patients with NIDDM /Type 2 DM not
controlled with diet
• Patient with long standing disease may require insulin as well
Oral agents
Sulphonylureas
• 2 generations exist
• First generation: chlorpropamide, tolbutamide, acetohexamide
• Second generation: glibenclamide, gliclazide, glipizide
Uses
• To control type 2DM or NIDDM but should not replace dietary control
• Mechanism of action
• Work at pancreas by displacing insulin from beta cells in islets of
Langerhans (increase insulin secretion)
Oral agents
• They are thus not effective in IDDM who have no functioning beta
cells
Pharmacokinetics
• Well absorbed from gut with oral bioavailability >80%
• Albumin binds the drugs extensively
• All the drugs except chlorpropamide are extensively metabolised in
the liver to inactive metabolites except glibenclamide
• Chlorpropamide is less metabolised by liver
• Metabolites are excreted in urine and faeces
Oral agents
• Cimetidine inhibits their metabolism and hence potentiates their
actions
• Drugs that increase blood sugar like thiazides, corticosteroids,
phenothiazines antagonise the effects of sulfonylureas and make
diabetic control harder
• The second generation bind to albumin by nonionic forces. Thus
anionic drug as like phenylbutazone, warfarin and salicylate do not
displace 2nd generation drugs
• They are thus safer during concurrent therapy
Oral agents
Other effects
• Mild gastrointestinal disturbances and rashes
Chlorpropamide:
• Its long half life and greater renal elimination results in greater chance
of hypoglycaemia, esp in elderly
• May cause facial flushing and vomiting following alcohol
• Hyponatremia
• Photosensitivity
Oral agents
Tolbutamide may be associated with cholestatic jaundice, deranged
liver function
• Blood dyscrasia
• Weight gain
• Hyperinsulinaemia
• Hypoglycaemia

• Gliburide has minimal transfer across placenta so may be alternative

to insulin for diabetes in pregnancy
Biguanides
Metformin
• Only currently available one
Mechanism of action
• Delayed uptake of glucose from gut
• Increased peripheral insulin sensitivity
• Inhibits hepatic and renal gluconeogenesis
Other effects
• GIT effects like diarrhoea, but mild
• Can precipitate severe lactic acidosis, esp with alcohol abusers and renal
impairment
Pharmacokinetics
• Slowly absorbed from gut with BA of 60%
• Not bound by plasma proteins
• Not metabolised
• Excreted unchanged in the urine
• Renal impairment significantly prolongs its actions
• Weight loss may occur because metformin causes loss of appetite
• It can be used alone or with other oral agents or insulin
Oral agents
• Risk of hypoglycaemia is far less than with sulfonylureas
• May also be used to treat polycystic ovarian disease
Other antidiabetic agents
Acarbose
• It is a competitive inhibitor of intestinal glucosidase, acting specifically
on sucrase
• Polysaccharides are therefore not metabolised to their absorbable
monosaccharide forms
• The delay in absorption reduces the post prandial hyperglycaemia in
diabetics
• It is not absorbed significantly, and has few systemic effects
• Side effects: borborygmi, flatulence and diarrhea
Thiazolidinediones
Rosiglitazone and Pioglitazone
• They have a high oral bioavailability
• Their effects may take weeks to be established due to their
mechanism of action
Mechanism of action
• They regulate a number of genes involved in glucose and lipid
metabolism, and hence improve insulin sensitivity
Other effects
• Fluid retention
Thiazolidinediones
Pharmacokinetics
• They are metabolised extensively by the liver, with some active and
inactive metabolites which are excreted by kidney
• No drug interactions
Meglitinides /glinides

Repaglinide , nateglinide
• Oral antidiabetic agents
• Useful for patients with erratic eating habits, because they are short
acting
• They are taken just before meals
• Repaglinide has BA of 50%, 98% plasma protein bound
• Metabolised by the liver, potentially susceptible to drug interactions
• Elimination half life is 1 hour
Glinides
• They increase insulin secretion like the sulfonylureas
• They however have a rapid onset and a shorter duration of action
• Glinides should not be used combined with sulfonylureas due to
overlapping mechanism of action
• May result in serious hypoglycaemia
• Should be taken prior to a meal
Glinides
Adverse effects
• Hypoglycaemia
• Weight gain
• Drugs like itraconazole, fluconazole, eryhtromycin and clarithromycin
may enhance glucose lowering effect
• Drugs like barbiturates , carbamazepine and rifampin may potentiate
their effects
• Use with caution in renal impairment
Dipeptidyl peptidase 4 inhibitors
Aloglipin, linagliptin, saxagliptin
• Used to treat NIDDM
• Promote insulin release
• Well absorbed after oral administration
• Alo and Saxa excreted unchanged in urine
• Saxa metabolised in liver to active metabolite, excreted in urine
• Lina is excreted via enterohepatic route hence safe in renal
dysfunction
Dipeptidyl peptidase 4 inhibitors
• Most common adverse effects are nasopharyngitis and headache
Sodium glucose co transporters
Canagliflozin, Dapagliflozen
• They decrease reabsorption of glucose from kidney, increase glucose
excretion and lower blood glucose
• They are given once daily in the morning
• They are metabolised by liver to inactive metabolites
• Excretion through urine or faeces
• Avoid in renal dysfunction
• Commonest side effects are female genital fungal infections, UTIs and
urine frequency