PHARMACOLOGY

OF
INSULIN
AND
ORAL HYPOGLYCAEMIC
DRUGS
Prof. HYA LAU
Department of Pharmacology
26 Oct 2006
INSULIN AND ORAL HYPOGLYCAEMIC DRUGS

Rang, Dale & Ritter, Pharmacology (5e), Chapter 25

Katzung, Basic & Clinical Pharmacology (9e), Chapter 41

Synthesis and structure of insulin.

Distribution, metabolism, and half-life of insulin.
Therapeutic use of insulin : formulation, duration of
action, uses and side-effects.
Mechanisms of action of oral hypoglycaemic agents

H.Y.A. LAU
Room 404B, Basic Medical Sciences Building
[email protected]
INSULIN

Preproinsulin
• Synthesised in ER

Proinsulin

• Proteolytic cleavage product of preproinsulin in the Golgi body

• Single chain 86 a.a. polypeptide

Insulin
• Conversion of proinsulin by 2 distinct endopeptidases
• 2 chains (A chain 21 a.a. and B chain 30 a.a.)
• Stored in granules
PHARMACOKINETICS OF INSULIN
Endogenous insulin

• Secreted into the portal circulation

• Circulate in blood as monomer
• Plasma half life of 5 to 6 min

• Hydrolysis of disulphide bonds between A & B chains

by glutathione insulin transhydrogenase (insulinase)
• Degradation mainly in liver
PHARMACOKINETICS OF INSULIN
Exogenous Insulin

• Dimers in solution due to hydrogen-bonding between

the C-termini of B chains.
• In the presence of zinc ions, insulin dimers associate
into hexamers
• Variable duration of action
• Metabolised mainly by the kidneys
Treatment of Diabetes
• Relieve the immediate signs and symptoms
• Prevent the development of long term complications
• Proper glycaemic control
¾ Type 1:
- Insulin therapy
¾ Type 2:
- Appropriate diet: low sugar, low fat, high fibre
- Regular exercise
- Maintenance of a reasonable body weight
- Oral anti-diabetic agents / insulin therapy
Treatment of Diabetes
Insulin Therapy

Aim to reproduce normal pancreatic secretion

• Basal output
¾ Nearly constant day long insulin level
¾ Suppress hepatic glucose production between meals
and overnight fasting

• Meal time surge

¾ Immediate rise and sharp peak at 1 hour
¾ Limit postprandial hyperglycaemia
Insulin Therapy
Insulin Preparations

• Human insulin by recombinant technique

• 100 U/ml solution or suspension for subcutaneous
injection

• Various formulations varying in peak effect & duration

¾ Avoid wide variations in plasma concentration
Insulin Preparations

Pharmacokinetics

Onset Peak (h) Duration (h)

Human Insulin
Regular 30 min 2-4 5-7
NPH 1h-3h 5-7 10 - 20
Lente 1h-3h 4-8 10 - 20
Ultralente 2h-4h Unpredictable 16 - 20
Insulin Analogs
Lispro 15 min 1 4-5
Aspart 15 min 1 4-5
Glargine 1h–2h Flat 24

Variations between patients, or at different times in the same patient

Insulin Preparations

Short acting
Regular (soluble) insulin

• Clear neutral solutions of regular, crystalline zinc insulin

• Only type for i.v. route (emergency treatment of ketoacidosis)

• Administer 20-40 min prior meal

• Aim to reproduce meal time surge
• Self-associate into dimers & hexamers after s.c. injection
• Risk of premeal hypoglycaemia if meal is delayed
• Duration longer than physiologic insulin peak
¾ risk of postprandial hypoglycaemia
Insulin Preparations

Intermediate acting

Isophane Insulin (neutral protamine Hagedorn)

• Suspension of insulin with protamine
Lentes Insulin (Insulin Zinc Suspensions)
• A mixture of amorphous and crystalline insulin

• Formulated to dissolve more gradually after s.c. injection

• For maintaining basal insulin level, 1 or 2 daily doses
• Requiring rigid time schedule for meal intake
• Pronounced peak effect and prolonged effect may induce
late postprandial and nocturnal hypoglycaemia
Insulin Preparations

Long acting

Ultralente insulin (extended insulin zinc suspension)

• Suspension of crystalline insulin

• For maintaining basal insulin level

• Duration shorter than the ideal 24 h effect
• Substantial day-to-day variability with erratic peaks
¾ Unpredictable hypoglycaemia
Insulin Treatment

Side effects

Insulin Oedema
• Initial transient blurring of vision & oedema of feet.

Lipohypertrophy
• Benign proliferation of subcutaneous adipose
tissues at recurrent injection site.
• Lipogenic effect of insulin

Allergy
• Rare
• Associated with protamine added
Insulin Treatment

Side effects

Hypoglycaemia
• Overdose, missed meal or excess exercise.
• Autonomic symptoms: hunger, palpitation, sweating,
trembling, tingling round mouth.
• Neuroglycopenia: difficult in concentrating, confusion,
weakness, drowsiness, blurred vision.
• Coma, convulsions and even death.

• Treated by replenishing glucose.

• Injection of glucagon (i.v., i.m. or s.c.) in severe cases.
• Extract from bovine or porcine pancreas
Treatment of Diabetes

Type 2 Diabetes

• Weight loss: reduce fasting and postprandial glucose level

• Increasing physical activities: improves insulin sensitivity
• Glycaemic control provided by oral anti-diabetes agents
¾ Sulphonylureas
¾ Meglitinides ↑ Insulin secretion
¾ Biguanides
↑ Insulin sensitivity
¾ Thiazolidinedione derivatives
¾ α-glucosidase inhibitors ↓ Glucose absorption
• Exogenous Insulin
ORAL ANTI-DIABETES AGENTS
ORAL HYPOGLYCAEMIC AGENTS
O

Sulphonylureas R1 SO2 NH C NH R2

First Generation
• Tolbutamide (R1 = CH3, R2 = C4H9)

Second Generation > 100x more potent

• Glibenclamide (R1 = H3C CONH(CH2)2 , R2 = )

N
[Glyburide] OCH3
Cl

• Glipizide (R1 = CONH(CH 2)2

, R2 = )
OCH3
 ORAL HYPOGLYCAEMIC AGENTS

Sulphonylureas Mechanism of Actions

K+ATP channel

Closes KATP channels Ca2+ channels

(Depolarisation) (Depolarisation opens)

Ca2+
Sulphonylureas bind to
high affinity receptors on
K+ATP channel
Insulin release

• ↑ basal insulin release & ↓ glucagon concentration.

• Improves tissue sensitivity to insulin.
¾ ↓ hepatic glucose output & ↑ glucose uptake in muscle.
 ORAL HYPOGLYCAEMIC AGENTS

Sulphonylureas

• Well absorbed orally (30 min prior breakfast/ meal)

• 90% to 99% bound to plasma protein, especially albumin
• Metabolized by the liver; metabolites excreted in the urine

Duration & (t1/2) h Comments

Tolbutamide (1) 6-12 (4) Safe, least hypoglycaemic, frequent

administration; active metabolites
Glipizide (100) 16-24 (7) Once a day, hypoglycaemia

Glibenclamide (150) 18-24 (10) 1 or 2 times a day, hypoglycaemia;

(Glyburide) non-ionic protein bound

Glimepride (500) 12-24 (5) Once a day, hypoglycaemia

Sulphonylureas

Unwanted Effects

• Severe hypoglycaemia.
¾ Related to potency & duration of action, hence least with
tolbutamide
¾ Potentiated in patients with renal and hepatic deficiency
• Stimulate appetite and hence weight gain
• <3% patients suffer from mild G.I. disturbances &
allergic rashes
• Rare but severe bone marrow damage
Sulphonylureas

Drug Interaction

• Hypoglycaemic effect enhanced by drugs which compete

for metabolising enzyme, interference with plasma protein
binding or with excretion

e.g. NSAIDs, MAOI, alcohol, some antibacterials &

antifungals
ORAL HYPOGLYCAEMIC AGENTS

Meglitinides

Repaglinide & nateglinide

• Acts like an extremely short acting sulphonylurea

• Blocks the KATP channels in B cells
• Repaglinide binds to distinct site from sulphonyl ureas

• Rapidly & completely absorbed from the G.I. tract

• Rapid onset (N=15 min, R=30 min) with short half life (1 h)
• When taken prior meal, replicates physiological insulin profile
• Prandial Glucose Regulation
• Extensive hepatic metabolism; contraindicated in patient with
liver disease
 ORAL ANTI-HYPERGLYCAEMIC AGENTS

Biguanides
Metformin
• Complex action, incompletely understood
• Do not cause insulin release from B cells
• Do not cause hypoglycaemia in normal or diabetic patients

• ↓ gluconeogensis: ↓ hepatic glucose production

• ↑ insulin sensitivity: ↑ muscular glucose uptake and utilization
• ↓ plasma glucagon level
• Anorexic, hence reduce weight in the obese
• Slightly delay intestinal glucose absorption
• ↓ low and very low density lipoproteins → ↓ atheroma
ORAL ANTI-HYPERGLYCAEMIC AGENTS

Biguanides

• Orally active, plasma t1/2 = 3 h

• Taken with or after food (2-3 time/day).
• Excreted unmetabolized in the urine

• Transient gastrointestinal disturbance

• Rare but potentially fatal lactic acidosis
• Accumulation of lactate in patients with renal diseases
(reduced drug elimination) or cardiac diseases (increased
anaerobic metabolism)
• Contraindicated in patients with liver diseases, alcoholism
or before X-ray examinations with iodinated contrast
materials
ORAL ANTI-HYPERGLYCAEMIC AGENTS
CH3

N N
Thiazolidinedione derivatives O
O
S

Pioglitazone & rosiglitazone rosiglitazone NH

O
• Act on the peroxisome proliferator-activated receptor-
gamma (PPARγ) in the nucleus
• Modulate the transcription of insulin responsive genes
involved in the control of glucose and lipid metabolism
• Maximum effects achieved after 1-2 months
• Enhance actions of insulin
• Promote glucose utilization in peripheral tissues and
suppress gluconeogenesis in the liver
ORAL ANTI-HYPERGLYCAEMIC AGENTS

Thiazolidinedione derivatives
• Rapid and almost complete absorption after ingestion
• Peak plasma level within 2 h
• Both are highly protein bound (>99%)
• Short plasma half life: <7 h
• Metabolised to active metabolites in the liver with
plasma half-life of more than 150 h
• Metabolites of rosiglitazone are eliminated mainly in
urine whereas those of pioglitazone mainly in the bile
• Once or twice daily improves both fasting and
postprandial hyperglyaemia.
ORAL ANTI-HYPERGLYCAEMIC AGENTS

Thiazolidinedione derivatives

• Triglycerides may decline

• Slight increase in cholesterol (LDL/HDL ratio unaltered)
• Fluid retention
• Weight gain
• Increase in extravascular fluid and plasma volume
• Reduction of haemoglobin concentration
• Contraindicated in patients with liver diseases
 ORAL ANTI-HYPERGLYCAEMIC AGENTS

α-glucosidase inhibitors
• Acarbose & miglitol
• Reversible, competitive inhibitor of intestinal α-glucosidase

• Slows the digestion of polysaccharides to monosaccharides

• Delays absorption of the component sugars
• Postprandial glycaemic rise is reduced and its peak delayed
• Allowing the sluggish insulin secretion to catch up with
carbohydrate absorption

• Not absorbed & act in the intestinal lumen

• No risk of weight gain or hypoglycaemia
• Adverse effects include abdominal bloating & diarrhoea