ANTIDIABETIC

DRUGS
ANTIDIABETIC DRUGS

Classification and the nomenclature of diabetes mellitus (DM):

DM is a chronic metabolic disorder characterised by a high blood
glucose concentration-hyperglycemia (fasting plasma glucose > 7.0
mmol//L, or plasma glucose > 11.1 mmol/L 2hr after a meal) -
caused by insulin deficiency, often combined with insulin resistance.
ANTIDIABETIC DRUGS

Hyperglycemia occurs because of uncontrolled hepatic glucose output and

reduced uptake of glucose by skeletal muscle with reduced glycogen
synthesis. When the renal threshold for glucose reabsorption is exceeded,
glucose spills over into the urine -glycosuria and causes an osmotic diuresis -
polyuria, which in turn, results in dehydration, thirst and increased drinking
polydipsia.

Diabetic ketoacidosis is an acute emergency- it develops because of

accelerated fat breakdown to acetyl-CoA, which, in the absence of aerobic
carbohydrate metabolism, is converted to acetoacetate and beta-
hydroxybutyrate (which cause acidosis) and acetone (a ketone)
Various complications develop as a consequence of the metabolic derangements in
DM, often over many years

Many of these are the results of disease of blood vessels, either large (macrovascular
disease) of small (microangiopathy).

Macrovascular disease consists of acclerated atheroma, which is much more common

and severe in diabetic patients.

Microangiopathy particularly affects the retina (blindness), kidney (chronic renal

failure) and peripheral nerves (diabetic neuropathy,which is associated with
accumulation of osmotically active metabolites of glucose.

Coexisting hypertension promotes progressive renal damage.

ANTIDIABETIC DRUGS

Classification and the nomenclature of diabetes mellitus (DM):

Type 1 diabetes encompasses cases resulting from pancreatic

B cell destruction (immune-mediated in most cases).
Type 2 diabetes consists of combined defects of insulin
secretion and action ranging from predominantly insulin
resistance with relative insulin deficiency to a predominantly
secretory defect with insulin resistance.
 Type 1 diabetes (DM1) - is a severe form associated with ketosis
in the untreated state. It occurs most commonly in juveniles
but occasionaly in adults, the nonobese. It is a catabolic
disorder form in which circulating insulin is virtually absent,
plasma glucagon elevated, and the pancreatic B cells fail to
respond to insulinogenic stimuli.
 Type 2 diabetes (DM2) - represents a heterogenous group
comprising milder forms of DM that occur predominantly in
adults. Circulating endogenous insulin is often subnormal or
relatively inadequate because of tissue insensitivity. Obesity,
which generally results in impaired insulin action, is a common
risk factor, and most patients with DM2 are obese. In addition to
tissue insensitivity to insulin, there is an accompanying
deficiency of the pancreatic B cellss response to glucose
Oral hypoglycemic agents

Biguanides
Sulfonylureas
Meglitidines
Thiazolidinediones
Alpha-glucosidase inhibitors
 Oral hypoglycemic agents

Biguanides -Metformin
Lowers blood glucose- increases glucose uptake and utilisation in muscle + reduces hepatic
glucose production (gluconeogenesis)
Adverse effects:
- GIT disturbancies (anorexia + weight loss, diarrhea) = transient
- lactic acidosis rare but potencially fatal
Metformin should be avoided in patients who predispose to lactic acidosis (renal and
hepatic disease, heart failure)
Use: ,
DM2 patients obese and who fail treatment with diet alone. It does not cause
hypoglycemia
BIGUANIDES (metformin)

MECHANISM OF ACTION
exerts its effect by activating adenosine monophosphate (AMP)
kinase in the hepatocytes, an important enzyme in metabolic
control: hepatic glucose production (gluconeogenesis)
- glucose uptake and utilization in skeletal muscles (reduce insulin
resistance)
- carbohydrate absorption
- fatty acid oxidation
- circulating LDL and VLDL
Cont.

UNWANTED EFFECTS AND CONTRAINDICATIONS

- Gastrointestinal disturbaces most common = 30%
( anorexia, diarrhoea, nausea, Flactulence, bloating)
- Lactic acidosis is rare but fatal : should be avoided in
patients with renal / hepatic disease/ hypoxic pulmonary
disease or shock
- Long term use may interfere with absorption of vit B12
Oral hypoglycemic agents

Sulfonylureas
stimulate insulin secretion by B-cells (the equivalent of phase 1-
secretagogues) and thus reducing plasma glucose.
Pharmacokinetics:
. well absorbed orally,
. all bind strongly to plasma albumin and compete for these binding
sites with salicylates and sulfonamides,
. most are excreted in the urine their action is increased in
the elderly and in patients with renal disease
. cross the placenta severe hypoglycemia at birth
s. are generally contraindicated in pregnancy
Mechanism of Action
Cont.

ADVERSE EFFECTS
Weight gain
Hypoglycemia (chlorpropamide, glibenclamide)
GI symptoms
Skin eruptions
Bone marrow suppression
CLINICAL USE
Type 2 diabetes
Cont.

CONTRAINDICATIONS
Renal impairment
Severe liver dysfunction
Caution in elderly
Allergies
DRUG INTERACTIONS
NSAIDs
Monoamine oxidase inhibitors
Antibacterial (trimethoprim, sulfonamides, chlorampenicol)
 Doses

Glibenclamide: Starting dose 2.5 mg once daily; maximal dose 15 mg daily. Doses
exceeding 10 mg per day to be given in two divided doses.

Gliclazide: Starting dose 40 mg once daily; maximal dose 320 mg daily. Doses
exceeding 80 mg per day to be given in two divided doses.

Gliclazide modified-release: Starting dose 30 mg once daily; maximal dose 120 mg

once daily.

Glimepiride: Starting dose 1 mg daily; maximal dose 6 mg once daily.

Glipizide: Starting dose 2.5 mg once daily; maximal dose 40 mg daily. Doses
exceeding 15 mg per day to be given in two divided doses.
Oral hypoglycemic agents

First
Tolbutamide
generation:

Second glibenclamide,
generation: glipizide
Oral hypoglycemic agents

Meglitidines
A new class of insulin secretagogues modulates B
cell insulin release by regulating potassium efflux
through the potassium channels
Repaglinid has a very fast onset of action, with a
peak concentration and peak effect within
approximately 1 hour after digestion.
Oral hypoglycemic agents

Thiazolidinediones
a recently introduced class of drugs that enhance target tissue insulin

rosiglitazone, pioglitazone
sensitivity-
Their main action is to diminish insulin resistance by increasing glucose uptake
and metabolism in muscle and adipose tissues.

Alpha-glucosidase inhibitors
Acarbose and miglitol are competitive inhibitors of the
intestinal enzymes and modulate the postprandial digestion and absorption of
starch and disacharides.
ADVERSE EFFECTS AND CONTRAINDICATIONS

Weight gain
Fluid retention
Increased risk of fracture with chronic use
Headache, fatigue, GI symptoms
Cardiovascular complications
Contraindicated in pregnancy/ breastfeeding women,
ALPHA-GLUCOSIDASE INHIBITORS

Acarbose
MECHANISIM OF ACTION
- Competitively inhibits alpha glucosidase on the brush
border of the small intestine. This inhibits the conversion
of complex carbohydrates into monosaccharides, and
results in a reduction and delay in the absorption of
glucose
ADVERSE EFFECTS AND DOSING

GI symptoms : Flactulence, diarrhoea, bloating, abd pain

may aggravate hypoglycaemia caused by sulphonylureas and

insulin.

Start with 50 mg once daily with meals, and increase by 50

mg every two weeks if tolerated. The maximum dose is 100
mg three times daily,
Oral hypoglycemic agents

Clinical uses of oral hypoglycemic drugs:

DM2 as a supplement to diet and excercise to reduce
symptoms from hyperglycemia
Metformin is preferred for obese patients unless
contraindicated by factors that predispose to lactic
acidosis
Drugs that act on the sulfonylurea receptors are well
tolerated but often promote weight gain.