PHARMACOTHERAPY OF

DIABETES MELLITUS
BY JAYA PRAKASH K
5 TERM
MODERATOR : DR NEEPUGOWDA
INTRODUCTION
• Diabetes mellitus is a metabolic disorder characterized by
hyperglycaemia(fasting plasma glucose >126mg/dl and
>200mg/dl 2hrs after 75g oral glucose ),glycosuria
,hyperlipidaemia , negative nitrogen balance and sometimes
ketonaemia.
• Enhanced non-enzymatic glycosylation of tissue proteins due
to persistent exposure to high glucose concentration and
accumulation of large quantities of sorbitol in tissue believed
to be causative in pathological changes in diabetes.
• TYPES :
1)Type1 diabetes mellitus : insulin dependent diabetes mellitus
(IDDM)/juvenile onset diabetes mellitus . There is beta cell destruction
in pancreatic islets(majorly autoimmune,type1A), some are idiopathic
(type1B) .

2)Type 2 diabetes mellitus : non insulin dependent diabetes mellitus

(NIDDM)/maturity onset diabetes mellitus . There is no loss or
moderate reduction in beta cell mass.
APPROACH TO DRUG THERAPHY IN TYPE1 DM
• In type 1 diabetes mellitus the circulating insulin level is low .

• Insulin as subcutaneous injection is given .

APPROACH TO DRUG THERAPHY IN TYPE2 DM
• IMPROVE INSULIN AVAILABILITY : Exogenous insulin , sulfonylureas,
phenylalanine analogues , dipeptidase-4 inhibitors(DPP-4Is) ,GLP-1
receptor agonist.

• OVERCOME INSULIN RESISTANCE : Metformin , pioglitazone , alpha

glucosidase inhibitors.
PREPARATIONS OF INSULIN
 INSULIN
• It is secreated by endocrine part of pancreas .
• Insulin is two chain polypeptide have 51 amino acids and MW about
6000.The A chain has 21 while B chain has 30 amino acids .
USE IN DIABETES MELLITUS
• The purpose of therapy in diabetes mglycaemiaellitus is to
restore metabolism to normal , symptoms of hypoglycaemia
and glycosuria .
• The criteria for adequate glycaemia control in adult diabetic
treated with insulin or antidiabetic are
1. Fasting (morning) blood glucose levels 90 -130 mg/dl .
2. Blood glucose levels < 150mg/dl 2hours after meal.
3. HbA1c levels <7%
• Many type2 cases can be controlled by lifestyle measured
like diet , reduction in body weight and appropriate exercise
supplemented , if required , by oral antidiabetics . Insulin is
needed in patients when :
1. Not controlled by diet and exercise or when they are are
practicable.
2. Primary or secondary failure of oral antidiabetics or when
these drugs are not tolerated .
3. Under weight patients .
4. Temporarily to tide over infection , trauma, surgery,
pregnancy. In the perioperative period during labour ,
mentioned i.v insulin infusion is preferable.
5.Any complication of diabetes , e.g ketoacidosis , nonketoic
hyperosmolar coma, gangrene of extremities.
• Most type 1 diabetes mellitus patients require
0.4-0.8U/kg/day .
• In type 2 patients insulin dose varies (0.2-1.6U/kg/day) with
severity of diabetes and body weight .
• SPLIT MIXED REGIMEN : a frequently selected regimen
utilizes mixture of regular with lente or isophane insulin . The
total daily dose of 30:70 or 50:50 mixture of regular and NPH
insulin is usually split into two and injected s.c before
breakfast and dinner . Advantage is that only two daily
injection are required .
USE IN DIABETES KETOACIDOSIS
• Ketoacidosis of different grade occurs in insulin dependent diabetics
and is due to inadequate /no insulin replacement .
• Patients may present with varying severity . Typically they are
dehydrated , hyperventilating and impaired consciousness.
• Regular insulin is used to rapidly correct the metabolic abnormalities
.A bolus dose of 0.1-0.2U/kg /hr infusion, the rate is doubled if no
significant fall in blood glucose occurs in 2 hrs . Fall in blood glucose
level by 10% per hour can be considered adequate response .
• Correction of dehydration by i.v fluids , kcl , sodium bicarbonate (
acidosis), phosphate .
• HYPEROSMOLAR ( NON KETOTIC HYPERGLYCAEMIC ) COMA :
characterized by high blood glucose (>600mg/dl) and serum
osmolality (>320mOsm/L) along with deteriorating mental status .

• Occurs in elderly type2 patients .

• The treatment is same as for ketoacidotic coma except fast fluid

replacement is to be instituted , insulin replacement is lower , less
potassium replacement needed
• FATE OF INSULIN : insulin is distributed only extracellularly ,
gets degraded in git if given orally ,
metabolised in liver and smaller extent in muscle and kidney ,
plasma half life is 5-9 min ,
during biotransformation the disulphide bonds are reduced – A and B
chains , further broken down to constituent amino acids .
REACTIONS TO INSULIN :
• Hypoglycemia : the symptoms are divided into those due to counter
regulatory sympathetic stimulation viz sweating , anxiety, palpitation,
tremor and those due to deprivation of glucose –dizziness , headache,
behavioural behaviour , visual disturbance, hunger, fatigue, weakness,
muscular incordination, fall in BP. When blood glucose falls below
40mg/dl mental confusion, abnormal behaviour, seizures and coma
can occur .
• Local reaction : lipodystrophy, swelling , erythema and stinging occur
• Allergy : utricaria, angioedema and anaphylaxis .
• Edema : is short lived dependent edema ( retention of Na+ ).
ORAL ANTIDIABETIS DRUGS
• These are the drugs that lower glucose in diabetes and are effective
orally
SULFONYLUREAS
• They lower blood glucose levels in type 2 diabetics but not in type 1
diabetics .
• TOLBUTAMIDE , GLIBENCLAMIDE , GLIPIZIDE, GLICLAZIDE ,
GLIMEPIRIDE.
• MECHANISM OF ACTION : they bind to specific sulfonylurea receptor (
SUR1) located on pancreatic beta cell membrane and provoke brisk
release of insulin .
• PHARMACOKINETICS : well absorbed orally , 90% plasma protein
bound , low volume of distribution , metabolized , excreted in urine
• ADVERSE EFFECTS : hypoglycaemia , gain of weight , nausea ,
vomiting, headache , rashes , photosensitivity , purpura , leukopenia
• Flushing and disulfiram like reaction after alcohol is reported .
• Tolbutamide reduced iodide uptake but hypothyroidism does not
occur
• Not recommended during pregnancy.
• Drugs that enhance SU action : display from protein binding –
salicylates , phenylbutazone , inhibit metabolism – ketoconazole,
warfarin , chloramphenicol, prolong pharmacodynamics –
propranolol, salicylates
• Drugs that decrease SU action : induce metabolism – phenytoin,
phenobarbitone , suppress insulin release – thiazides, furosemide ,
corticosteroids
MEGLITINIDE /D-PHENYLALANINE
ANALOGUES
• These are Katp channel blockers with quick and short lasting insulinemia
action
• REPAGLINIDE : it acts by binding to SUR

closure of ATP sensitive K+ channel

depolarisation

insulin release
• It is absorbed quickly and rapidly metabolised .
• It is administered before each major meal to control postprandial
hypoglycaemia .
• Side effects: mild headache, arthralgia, weight gain and dyspepsia .
• Indicated in selected type2 diabetics who suffer pronounced post-
prandial hyperglycaemia , avoided in liver disease.
• NATEGLINIDE : fast onset and shorter lasting hypoglycaemia
• Episodes of hypoglycaemia is less frequent .
• Side effects are dizziness, nausea , flue like symptoms and joint pain .
BIGUANIDE (AMPK ACTIVATOR )
• Two biguanides antidiabetic , metformin and phenformin
• MECHANISM OF ACTION : activation of AMP –dependent protein
kinase (AMPK) ,suppress hepatic and renal gluconeogenesis ,
increases uptake and utilization of glucose by skeletal muscle , inhibits
alimentary absorption of glucose , interfere with mitochondrial
respiratory chain .
• PHARMACOKINETICS : taken orally, not metabolized , excreted
unchanged in urine .
• It accumulates in renal failure and increases risk of lactic acidosis .
• ADVERSE EFFECTS : metallic taste , loss of weight, skin rashes, lactic
acidosis ( rare), vitb12 deficiency , anorexia , vomiting, nausea,
diarrhoea .
• CONTRAINDICATIONS : renal failure , alcohol abusers, pregnancy ,
cardiac disease.
• Used as first choice drug for all type 2 DM patients.
• ADVANTAGES are : antihyperglycaemic not hypoglycaemic, weight
loss promoting, prevent macrovascular and microvascular
complication of DIABETES , HbA1c reduction by 0.8 -1.2% , can be
combined with any other oral or injectable antidiabetic .
• Metformin is found to improve ovulation and infertility women in
polycystic ovary .
THIAZOLIDINEDIONES
• Pioglitazone lowers serum triglycerides levels and raises HDL level without
much change to LDL ( expression of reverse cholesterol transportor )

• PHARMACOKINETICS : completely absorbed orally , high plasma binding ,

metabolized by CYP2C8( rosiglitazone ) and CYP2C8 and CYP3A4(
pioglitazone ).
• Metabolites of rosiglitazone is excreted and urine and pioglitazone in bile
• ADVERSE EFFECTS : weight gain due to fluid retention , worsening of CHF,
increased deposition of subcutaneous fat , mild anemia ( hemodilution ),
hepatotoxicity, increased risk of fractures( rosiglitazone ).
• PIOGLITAZONE – 15 to 45 mg once daily orally, ROSIGLITAZONE -4to 8 mg
once daily .
• Used in type2 DM with substantial amount of insulin resistance and
reduces HbA1c by 0.5-1.2% without increasing circulating insulin.
• Pioglitazone is primarly used to supplement SUs/ metformin in case
of insulin resistance .
• Should not be used during pregnancy .
ALPHA GLUCOSIDASE INHIBITORS
• ACARBOSE, MIGLITOL, VOGLIBOSE
• ACARBOSE : complex oligosaccharide , reversible alpha glucosidase
inhibitor

• Mild antihyperglycaemic not a hypoglycaemic , 50to 100mg TDS before

food

• ADVERSE EFFECTS : flatulence , diarrhoea , abdominal pain

• VOGLIBOSE : advantages over acarbose and miglitol

1. 20-30 times more potent .
2. Does not affect digoxin bioavailability
3. Superior tolerability
4. No dose adjustment required in renal impairment unlike miglitol
5. Dose – 0.2 to 5 mg
DIPEPTIDYL PEPTIDASE -4 INHIBITORS
• Sitagliptin , saxagliptin and linagliptin .
• Increases circulation of GLP1 .
• Sitagliptin : oral BA-85%
plasma t1/2 – 1-4 hrs , duration >12 hours
metabolism –liver , excreted- kidney
S/E: nasopharyngitis , upper respiratory infections ,
headaches, hypoglycaemia, acute pancreatitis .
• Vildagliptin : long duration ( 12-24hrs) despite short t1/2 ( 2-4hrs )
• Saxagliptin : drug interaction with CYP3A4 inhibitors