INSULIN AND

ORAL
HYPOGLYCEMIC
DRUGS
DIABETES MELLITUS (DM)

a metabolic disorder characterized by hyperglycaemia,

glycosuria, hyperlipidaemia, negative nitrogen
balance ± ketonaemia
Pathologically:
thickening of capillary basement membrane, increase
in vessel wall matrix & cellular proliferation=
vascular complications e.g lumen narrowing, early
atherosclerosis, sclerosis of glomerular capillaries,
retinopathy, neuropathy and peripheral vascular
insufficiency
 TYPES

 Type I Insulin-dependent diabetes mellitus

(IDDM)/juvenile onset diabetes mellitus:
 β cell destruction; usually autoimmune that destroy β cells

2. Type II Noninsulin-dependent diabetes mellitus

(NIDDM)/maturity onset diabetes mellitus:
Over 90% cases of diabetes are type 2 DM
There is no loss or moderate reduction in β cell mass; insulin
in circulation is low, normal or even high
 has a high degree of genetic predisposition; generally has
a late onset
 INSULIN
 Insulin polypeptide hormone is the mainstay for treatment
of all types of diabetes
 Various insulins are available to manage diabetes.

 These medications differ in their onset, peak, and duration

 Insulin may be administered IM , IV, SC.

 long term treatment relies on subcutaneous injections of

the hormone.
 INSULIN
 MOA

1. Facilitates glucose transport across cell membranes

2. Facilitates glycogen synthesis from glucose in liver,
muscle and fat by stimulating the enzyme glycogen
synthase. It also inhibits glycogen degrading enzyme
phosphorylase → decreased glycogenolysis in liver
3. Inhibits gluconeogenesis (from protein, FFA and
glycerol) in liver by gene mediated decreased synthesis
of phosphoenol pyruvate carboxykinase
4.Inhibits lipolysis in adipose tissue and favours
triglyceride synthesis
5.Enhances transcription of vascular endothelial
lipoprotein lipase and thus increases clearance
of VLDL and chylomicrons
6.Facilitates AA entry and their synthesis into
proteins, as well as inhibits protein breakdown
in muscle and most other cells
 TYPES OF INSULIN
 There are three main groups of insulins: Fast-
acting, Intermediate-acting and Long-acting
insulin.
5 TYPES
1. Rapid -acting (insulin Aspart)-analogs
2. Short acting (Humulin)-regular
3. Intermediate acting (NPH)
4. Premixed
5. Long -acting lantus (glargine), Levemir (detemir)
 FAST-ACTING INSULIN

 Is absorbed quickly from your fat tissue

(subcutaneous) into the bloodstream.
 Is used to control the blood sugar during

meals and snacks and to correct high blood

sugars
 Includes:
 Rapid Acting Insulin Analogs
 Regular Human Insulin
 RAPID ACTING INSULIN ANALOGS

Insulin Aspart, insulin Lyspro, Insulin Glulisine)

 Onset of action of 5 to 15 minutes, peak effect in 1

to 2 hours and duration of action that lasts 4-6

hours.
 With all doses, large and small, the onset of action

and the time to peak effect is similar,

 The duration of insulin action is, however, affected

by the dose – so a few units may last 4 hours

 insulins have duration of action of 4 hours.
 REGULAR HUMAN INSULIN

 Onset of action of 1/2 hour to 1 hour,

peak effect in 2 to 4 hours, and duration
of action of 6 to 8 hours.
 The larger the dose of regular the faster

the onset of action, but the longer the

time to peak effect and the longer the
duration of the effect.
 INTERMEDIATE-ACTING INSULIN
 Is absorbed more slowly, and lasts longer
 Is used to control the blood sugar overnight, while fasting and

between meals
Includes:

NPH Human Insulin (Neutral Protamine Hagedorn)-Humilin N

 Also called isophane insulin
 Onset of insulin effect of 1 to 2 hours, a peak effect of 4 to 6 hours,
and duration of action of more than 12 hours.
 Very small doses will have an earlier peak effect and shorter
duration of action, while higher doses will have a longer time to
peak effect and prolonged duration.
Pre-Mixed Insulin
 Is NPH pre-mixed with either regular human insulin or

a rapid- acting insulin analog.

 The insulin action profile is a combination of the short

and intermediate acting insulins.

LONG-ACTING INSULIN:
 Is absorbed slowly, has a minimal peak effect, and a

stable plateau effect that lasts most of the day.

 Is used to control the blood sugar overnight, while

fasting and between meals


Long acting insulin analogs (Insulin
Glargine( luntus), Insulin Detemir)
 which have an onset of insulin effect in 1.5 -2 hours.
 The insulin effect plateaus over the next few hours

and is followed by a relatively flat duration of action

that lasts 12-24 hours for insulin detemir and 24
hours for insulin glargine.
 TYPES OF PREPARATION
 Soluble insulin -RBS
 Mixtard insulin-Fasting ,OD
 P/KINETICS

 Distributed only extracellularly-

 When given orally is degraded in GIT
 Metabolized in liver ,kidney and muscles
 First pass metabolism
 INDICATIOS OF INSULIN
DM in the following cases:
1. Not controlled by diet and exercise or when these are not
practicable.
2. Primary or secondary failure of oral hypoglycemics or when these
drugs are not tolerated.
3. Under weight patients.
4. Temporarily to tide over infections, trauma, surgery, pregnancy. (In
the peri-operative period and during labour, monitored i.v. insulin
infusion is preferable.)
5. Any complication of diabetes, e.g. ketoacidosis, nonketotic
hyperosmolar coma, gangrene of extremities.
 DI
 Beta blockers prolong hypoglycemia
 Thiazides,oral contraceptives, phenothiazines,
hypothyroid drugs,niacin, and steroids raises
blood glucose
 Acute alcohol ingestion increases hypoglycemia
 Monoamine oxidase inhibitors
(MAOIs) ,ACE ,sulfa antibiotics ,beta
blockers,oral hypoglycemics and aspirin causes
hypoglycemia-enhance insulin secrection
SE
 Hypoglycemia
 Allergic reactions –very rare
 Local redness ,itching-self limiting
 Systemic allergy -angioedema,anaphaylaxix
 Insulin lipohypertrophy
 Insulin lipoatrophy
 Peripheral edema -insulin has salt retaining

properties
 weight gain
CI

 Diarrhoea,fever,infection,sx,th

yroid disease, trauma,

vomiting
 Hepatic disease, renal failure

and impairement

ORAL HYPOGLYCEMIC
A. Those that Enhance insulin secretion

1. Sulfonylureas (KATP Channel blockers)

 First generation: Tolbutamide
 Second generation: Glibenclamide (Glyburide), Glipizide, Gliclazide,
Glimepiride

2. Meglitinide/phenylalanine analogues: Repaglinide, Nateglinide

3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable

drugs): Exenatide, Liraglutide

4. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin,

Vildagliptin, Saxagliptin, Alogliptin, Linagliptin
B. Overcome Insulin resistance
1. Biguanide : Metformin
2. Thiazolidinediones : Pioglitazone

C. Miscellaneous antidiabetic drugs

1. α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose

2. Amylin analogue: Pramlintide

3. Dopamine-D2 receptor agonist: Bromocriptine

4. Sodium-glucose cotransport-2 (SGLT-2) inhibitor: Dapagliflozin

 SULPHONYLUREAS

 Enhance the release of insulin from the beta cells in

the pancreas
 Decrease liver glycogenesis (breakdown of
glycogen stored in the liver) and gluconeogenesis
(formation of glycogen from fatty acids and proteins
rather than from CHO)
 Increase cellular sensitivity to insulin in body tissue
 For DM 2 use
EXAMPLES
1ST GENERATION 2ND GENERATION

 Tolbutamide(Orinase),  Glipizide (Glucotrol),

 Chlorpropamide  Glyburide (DiaBeta),
(Diabinese)  Glimepiride (Amaryl)
 P/KINETICS
Well absorbed after oral administration
Highly protein bound
Metabolized in liver
Excreted in kidney
Caution in kidney/ liver disease
 DI
 Displaced by Phenylbutazone, sulfinpyrazone, salicylates,
sulfonamides from binding sites
 Cimetidine, ketoconazole, sulfonamides, warfarin, chloramphenicol,
acute alcohol intake (also synergizes by causing hypoglycaemia)
inhibit metabolism and excretion of sulphonylureas
 Salicylates, propranolol, sympatholytic antihypertensives, lithium,
theophylline, alcohol (by inhibiting gluconeogenesis): Synergize
with or prolong pharmacodynamic action
 Phenobarbitone, phenytoin, rifampicin, chronic alcoholism Induce
metabolism of sulphonylureas
 Corticosteroids, thiazides, furosemide, oral contraceptives have
opposite action/suppress insulin release:
 Beta-blockers may hide signs of hypoglycemia.
 ACE inhibitors, anticoagulants ,MAOIs, NSAIDs,
salicylates may increase risk of hypoglycemia.
 CCBs, corticosteroids, decongestants, diuretics,
hormonal contraceptives, albuterol, epinephrine,
thyroid supplements may result in hyperglycemia.
SE
 Hypoglycemia
 Weight gain
 GIT upsets
 Headache
 Paresthesia
 Hypersensitivity: rashes, photosensivity,
transient leukopenia
 Rare: jaundice, hepatitis, hepatic failure
 MEGLITINIDE / D-PHENYLALANINE
ANALOGUES

– KATP Channel blockers)

Repaglinide
Stimulate pancreatic beta cells to secrete insulin
– Improve insulin secretion in response to incr
glucose levels
– Shorter acting than sulfonylurea
 MOA

Binds to sulfonylurea receptors → closure of ATP dependent

K+ channels → depolarisation → insulin release

Quickly absorbed and rapidly metabolized

 It induces fast onset short-lasting insulin release
Indicated only in selected type 2 diabetics who suffer
pronounced post prandial hyperglycaemia, or to
supplement metformin/long-acting insulin
ADR: mild headache, dyspepsia, arthralgia and
weight gain
 DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

Sitagliptin
MOA:
Increase levels of natural substances( incretins) which
control blood glucose by boosting post prandial insulin release,
decreases glucagon secretion and lowers meal-time & fasting
blood glucose in type 2 diabetics
Well absorbed orally, is little metabolized and is largely
excreted unchanged in urine with a t½ averaging 12 hours
ADR: nausea, loose stools, headache, rashes, allergic
reactions , edema, nasopharyngitis & cough; rarely:
pancreatitis
 BIGUANIDES -METFORMIN

1. Suppresses hepatic gluconeogenesis and glucose output

from liver ( reduce hepatic glucose production)
2. Enhances insulin-mediated glucose uptake and disposal in
skeletal muscle and fat. i.e improves glucose receptor
sensitivity
3. Interferes with mitochondrial respiratory chain and
promotes peripheral glucose utilization through anaerobic
glycolysis
Reduces glucose absorption
i.e Decreases hepatic production of glucose from stored
glycogen. Lowers the glucose absorption of glucose from
ADR: Abdominal pain, anorexia, bloating,
nausea, metallic taste, diarrhoea & tiredness;
rarely: lactic acidosis and Vit B12 deficiency
NB: Metformin does not cause hypoglycaemia
except in overdose.
 DI
May potentiate hypoglycemia when used with
ACE inhibitors,
ARBS, CCBs,beta-blockers,
procainamide,digoxin, furosemide, alcohol,
cimetidine
 THIAZOLIDINEDIONE
Pioglitazone(Actos) etc
 Reduction in hepatic glucose production

 –Enhanced cellular response to insulin Via

activation of peroxisome proliferator-activated
receptors (PPARs
 Lowers serum triglyceride level and raises HDL level
without much change in LDL level
ADR: plasma volume expansion, edema, weight gain,
headache, myalgia ,anaemia, hepatic dysfunction,
 α Glucosidase inhibitors E.g Acarbose, miglitol,
Voglibos
 They inhibit α Glucosidase which is responsible for the
digestion of carbohydrates in the brush border of small
intestine mucosa i.e
 Delay digestion and absorption of CHO in the small
intestine
 Do not increase insulin secretion and therefore do
not cause hypoglycemia
 Dopamine D2 agonist :Bromocriptine
Taken early in the morning it acts on the hypothalamic
dopaminergic control of the circadian rhythm of hormone
(GH, prolactin, ACTH, etc.) release and reset it to reduce
insulin resistance
 Sodium-glucose co-transport-2 (SGLT-2) inhibitor

Dapagliflozin : After single daily dose it produces round-the-

clock glucosuria and lowers blood glucose levels
END