Antidiabetic Drugs
Kaukab Azim, MBBS, PhD
Drug List - INSULINS
Preparation
Onset of effect
Peak
Activity duration
(hours)
Rapid-acting insulins
Insulin Lispro ☛ 10 – 20 minutes
Insulin Aspart ☛
Short-acting insulins
Regular insulin ☛
30 – 60 minutes
30 – 60 minutes
3–5
1 – 2 hours
5–7
6 – 12 hours
18 – 24
16 – 18 hours
No peak
24 – 36
24
Intermediate-acting
NPH (Neutral ☛ 1 – 2 hours
protamine Hagedorn)
Insulin Lente ☛
Long-acting insulins
Insulin Ultralente ☛ 4 – 6 hours
Insulin glargine ☛ 1 – 2 hours
Note: All are administered subcutaneously; Regular insulin can be administered I.V., especially in the management
of diabetic ketoacidosis; surgery and during acute infections.
Drug List – Oral Antidiabetics
Insulin secretagogues
Biguanides
Sulfonylureas
Thiazolidinediones
Meglitinides
α-glucosidase
inhibitors
Tolbutamide*
Chloroprapamide*
Glyburide**
Glipizide**
Repaglinide
Metformin
Rosiglitazone
Acarbose
Miglitol
Glimepiride**
(amaryl)
* 1st generation sulfonylureas, ** 2nd generation sulfonylureas
(GLIP ih zyd), (glye-MEP-ir-ide), (met FOR min), (thy-a-zoll-i-deen-dye-ones)
Learning Outcomes
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List the main factors regulating insulin secretion.
Explain the mechanism of action of insulin and glucagon.
Explain the mechanism of action of each class of oral antidiabetic drugs.
Describe the major effects of insulin upon carbohydrate, lipid and protein
metabolism.
Contrast the actions of insulin and the counter regulatory hormones on liver and
muscle.
Describe the major effects of oral antidiabetic agents.
List the main factors affecting insulin absorption.
List the routes of administration and the duration of action of various insulin
preparations.
List the duration of action of the oral antidiabetic agents.
Describe the adverse effects of insulin, glucagon,. and oral antidiabetic agents
Describe the clinically relevant interactions between antidiabetic drugs and other
drugs.
List the main contraindications of antidiabetic drugs.
Explain the choice of an insulin regimen in diabetics.
List the main events requiring an increase in the dosage of insulin in the diabetic
patient.
Outline the use of oral antidiabetic agents in the treatment of diabetes mellitus.
List other therapeutic uses of sulfonylureas.
List the therapeutic uses of glucagon.
Insulin Synthesis and Secretion
Synthesis
Golgi apparatus of B cells synthesizes insulin from
proinsulin. Insulin is stored in secretory granules.
Secretion
a.
b.
Basal release (in pulses every 15-30 minutes)
Glucose stimulated release:
1. Early, rapid phase (stored insulin is secreted)
2. Later, slower phase (newly synthesized insulin is
secreted).
A Simplified Model of Glucose
stimulated release of Insulin
1
2
Metabolism of glucose increases
intracellular ATP
3
ATP closes ATP-dependent K+
channels
4
Decrease efflux of K+ causes
depolarization
Depolarization opens voltagegated Ca++ channels
5
Ca++ triggers insulin release by
exocytosis
Factors Regulating Insulin Secretion
Factor
Increased Secretion
Decreased Secretion
Alimentary
Certain amino acids (leucine, arginine)
Fatty acids
Metabolic
Hyperglycemia*
Hyperkalemia
Hypoglycemia
Hypokalemia
Hormonal
Intestinal hormones
(glucagon-like peptide, gastrin, secretin, VIP,
cholecystokinin)
Somatostatin
Amylin
Neural
Sympathetic stimulation (beta2 receptors)
Vagal stimulation (muscarinic receptors)
Sympathetic stimulation
(alpha2 receptors)
Beta2 agonists
Sulfonylureas
Meglitinides
Alpha2 agonists
Phenytoin
Ca++ blockers
Loop diuretics
Thiazide
Diazoxide
Drugs**
* Hyperglycemia is the only factor that stimulates both phases of insulin secretion
** Many drugs can affect secretion indirectly by causing hyper or hypoglycemia
Mechanism of Action of Insulin
✐ Insulin binds to a specific transmembrane tyrosine-kinase linked
receptor located in cell membranes of most tissues. The receptor
consists of two alpha subunits linked to two beta subunits.
(the affinity of insulin for its receptor is lowered by corticosteroids and
increased by growth hormone; at concentration of insulin that produce
maximal effects only 10% of the receptors are occupied)
✐ Insulin binding to the alpha subunits causes the activation of the
beta receptor subunit, which contain the tyrosine kinase. The
enzyme is phosphorylated and this turn leads to the following two
cascade pathways:
1.
2.
IRS-1 Pathway
IRS-2 Pathway
Mechanism of Action of Insulin
The insulin receptor
✐ A specific transmembrane tyrosine-kinase linked receptor
located in cell membranes of most tissues.
✐ Activation of this receptor, triggers the phosphorylation of a
tyrosine kinase enzyme which in turn leads to the following
two cascade pathways:
1. Insulin receptor substrate-1 (IRS-1) pathway: Leading to
a.
b.
Regulation of proliferation and differentiation of several cell types
Regulation of DNA synthesis
2. Insulin receptor substrate-2 (IRS-2) pathway: Leading to
a.
b.
c.
Increased glucose uptake by the lipid and muscle cells
Increased glycogen formation
Regulation of gene transcription
Pharmcodynamics of Insulin
The general physiological function of insulin is to conserve fuel
by facilitating the uptake, utilization and storage of glucose,
amino acids and fats after meals.
Effects on carbohydrate metabolism
✐ Increased glucose transport into the cells (several glucose
transporters are activated).
✐ Increased glycogen synthesis (glycogen synthase is
stimulated)
✐ Increased glycolysis (the activity of several key enzymes is
stimulated)
✐ Decreased glycogenolysis (glycogen phosphorylase is
inhibited).
✐ Decreased gluconeogenesis (many gluconeogenic enzymes
are depressed).
Pharmcodynamics of Insulin
The ultimate effect of insulin is to control the intracellular utilization of
glucose, as follows:
✐ 50% of ingested glucose is converted to energy (glycolysis)
✐ 10% of ingested glucose is converted to glycogen (glycogen
synthesis)
✐ 40% of ingested glucose is converted to fat
Effects on lipid metabolism
✐ Increased triglyceride formation and storage (lipoprotein lipase is
induced and activated to hydrolyze triglycerides from lipoproteins.
Glycerol phosphate generated from glucose permits esterification
of fatty acids).
✐ Decreased lipolysis (direct inhibition of hormone-sensitive
intracellular lipase)
✐ Increased lipogenesis (glucose is converted to fat)
Pharmcodynamics of Insulin
Effects on protein metabolism
✐ Increased amino acid transport into the cells.
✐ Increased protein synthesis.
Other metabolic effects
✐ Increased transport into cells of K+, Ca++, nucleosides and
phosphate.
Long-term actions
✐ Stimulation of cell proliferation
SUMMARY OF MAIN INSULIN EFFECTS ON CARBOHYDRATE, FAT, AND PROTEIN
METABOLISM IN LIVER, ADIPOSE TISSUE AND MUSCLE
Liver
Adipose Tissue
Muscle
Glucose uptake 
Glycogen synthesis 
Sugar
Glycolysis 
Glycogenolysis 
Glucose uptake 
Glycerol synthesis 
Glucose uptake 
Glycolysis 
Glycogen synthesis 
Gluconeogenesis 
Fat
Lipogenesis 
Triglyceride synthesis 
Lipolysis 
Lipolysis 
Amino acid uptake 
Protein
Protein breakdown 
Protein synthesis 
Protein breakdown 

Increases

Decreases
Pharmacokinetics of Insulin
ABSORPTION
✐
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Bioavailability:
NO ORAL BIOAVAILABILITY
SC, IM: good.
Nasal: good (investigational).
DISTRIBUTION
✐ Bound in plasma: < 5%.
✐ Vd (70 Kg): . 15 L.
BIOTRANSFORMATION
✐ All insulin is metabolized in liver, kidney, and muscle (internalized with insulin
receptors and destroyed intracellularly)
✐ (50% of insulin secreted by pancreas into the portal vein does not reach the
general circulation).
EXCRETION
✐ None
✐ Total Clearance: 800-2500 mL/min (70 Kg)
Half-life: 5-10 minutes
Diabetes Mellitus
Definition
A syndrome characterized by hyperglycemia resulting from impaired insulin secretion
and/or effectiveness, associated with risks for diabetic ketoacidosis (DKA) or nonketotic
hyperglycemic-hyperosmolar coma (NKHHC), and a group of late complications
including retinopathy, nephropathy, atherosclerotic coronary and peripheral arterial
disease, and peripheral and autonomic neuropathies.
Different Types of Diabetes
General
Both genetic and environment factors are involved in causation of diabetes
a. Type I (formerly called insulin-dependent)

b.
A serious form of diabetes characterized by destruction of pancreatic beta
cells and by severe or absolute insulin deficiency.
Type II (formerly called non insulin-dependent)

A milder form of diabetes characterized by tissue resistance to the action of
insulin combined with a relative deficiency of insulin secretion.
Specific
c.
Type III (also called secondary)

d.
Diabetes secondary to other diseases (Cushing’s disease, acromegaly,
chronic pancreatitis, genetic syndromes, etc.) or drug therapy.
Type IV (also called gestational diabetes)

Any abnormality in glucose level noted for the first time during pregnancy (it
occurs in about 4% of all pregnancies in USA)
Characteristics of Major Types of Diabetes Mellitus
Type 1
Type 2
% of all cases
10 – 20
80 – 90
Age of onset (years)
Generally < 30
Generally > 30
Associated obesity
No
Very common
Propensity for DKA
Yes
No
Endogenous insulin
secretion
Extremely low
Significant but variable
Islet cell antibodies
Yes
No
Islet pathology
Loss on most beta cells
Smaller, normal, appearing
islets
Associated risks
Present
Present
Response to sulfonylureas
No
Yes, initially in many patients
Insulin Therapy
All available insulin preparations are either human insulin (produced
by recombinant DNA techniques) or human analog insulin (some
amino acids in the molecule are substituted or changed in position)
Main insulin preparations
1.
Lispro (human insulin analog): two amino acids near the end chain
have been reversed in position.
2.
Aspart (human insulin analog): proline is substituted with aspartic
acid at the B28 position.
Regular: crystalline insulin-zinc (IZ) salt solution.
3.
4.
5.
6.
7.
NPH (Neutral Protamine Hagedorn): suspension of insulin in a
complex with zinc and protamine.
Lente: suspension of large IZ particles.
Glargine: glycine is substituted for asparagine at the A21 position
and two arginine molecules are attached to the B chain.
Ultralente: suspension of very large IZ particles.
Insulin Therapy
Administration


Insulin is administered either IV, IM or SC.
Administration of insulin differs from
physiological secretion of insulin because:
a. The kinetics does not reproduce the normal rapid
rise and decline of insulin secretion in response of
ingestion of nutrients.
b. The insulin diffuses into the peripheral circulation
instead of being released into the portal circulation.
Therefore the direct effects of insulin on hepatic
metabolic processes are eliminated.
Insulin Therapy
Factors affecting SC insulin absorption
 The site of injection (absorption is most rapid from the
abdominal wall, followed by the arm, buttock and thigh).
 The deep of injection (IM absorption is faster than SC
absorption).
 The type of insulin.
 Subcutaneous blood flow (in the upright posture sc blood
flow diminish considerably in the legs)
 Regional muscular activity at the site of injection.
 Volume and concentration of the injected insulin (a large
volume can lead to an initial "lag phase" of absorption)
Insulin Therapy
The duration of action of insulin can be varied by:
1. Modification of the insulin molecule (by
recombinant technology)
2. Conjugation of insulin with protamine in a low
soluble complex. After injection proteolytic
enzymes degrade protamine so allowing
absorption of insulin.
3. Combination of insulin with zinc, to form zinc
salts. After injection the salt precipitates and
insulin is slowly released.
Duration of Action of Insulin Preparations
Type
Administration
Action
Onset*
Peak
Length
IV, SC
IV, SC
15 Min
15 Min
1–2h
1h
3–4h
3–5h
IV, SC
45 Min
1.5 – 4 h
5–8h
SC
SC
1–2h
1–2h
6 – 12 h
6 – 12 h
16 – 24 h
16 – 24 h
SC
SC
4–6h
1–2h
16 – 18 h
4–5h
20 – 36 h
> 24 h
Ultra-rapid-acting
Lispro insulin
Aspart insulin
Rapid-acting
Regular insulin
Intermediate-acting
NPH insulin (isophane)
Lente insulin
Long-acting
Ultralente insulin
Glargine insulin
☛ Ultra-rapid-acting insulins permit a more physiologic prandial insulin replacement.
They can be taken 5 minutes before meal and their short duration of action
decreases the risk of late postmeal hypoglycemia
☛ Regular insulin is the only insulin that can be administered IV. It is particularly
useful (given by IV infusion) for the management of diabetic ketoacidosis
* Onset refers to SC administration
Adverse Reactions to Insulin
Hypoglycemia
✐ It is the most common complication of insulin therapy.
✐ It can be also due (in long-term diabetics) to an inadequate production of counterregulatory hormones that normally provide an effective defense against hypoglycemia.
Symptoms and signs
They are first discerned at a plasma level of 60 to 80 mg/DL and include:
1.
Signs of autonomic hyperactivity. Both sympathetic (tachycardia, sweating,
tremulousness, anxiety) and parasympathetic (hunger, nausea)
2.
Signs of impaired function of the central nervous system. They are also named
neuroglycopenic symptoms (headache, mental confusion, weakness, dizziness,
blurred vision, drowsiness, bizarre behavior, convulsions and coma).
Therapy
•
•
Conscious patients: oral glucose
Unconscious patients: IV glucose or glucagon IM
Adverse Reactions to Insulin
Immunological problems
Allergic reactions
✐ They are generally mediated by IgE antibodies and are
often due to noninsulin protein contaminants.
Immune insulin resistance
✐ It is exceedingly rare with human purified insulin.
Local reactions at the injection sites
✐ Hypertrophy of subcutaneous fatty tissue can occur after
month of repeated injections on the same site (it remains
a problem ,even with purified insulin)
✐ Atrophy of subcutaneous fatty tissues (rare today).
✐ Localized infections.
Interaction of Insulin with Other Drugs
Drug
Interaction
Clinical
Relevance
Alcohol
Hypoglycemia (ethanol inhibits gluconeogenesis)
High
Beta-blockers
Prolonged hypoglycemia and masking of certain
symptoms of hypoglycemia
High
Salicylates
Hypoglycemia, with large doses (mechanism
unknown)
Medium
Fenfluramine
Hypoglycemia (the drug increases the uptake of
glucose into striated muscle)
Medium
MAO inhibitors
Hypoglycemia (MAO inhibit gluconeogenesis)
Medium
Glycemic Control in Diabetes
✐ The short-term benefits of tight blood glucose control in diabetics
are well established.
✐ Recent evidence (DCCT Research Group, 1993) indicates that
meticulous blood glucose control can also dramatically reduce
and slow the development of tissue complications in type 1
diabetes.
✐ Patients receiving meticulous blood glucose control however have
a threefold greater risk of severe hypoglycemic episodes.
✐ The consensus of the ADA is that tight blood glucose control
should become standard therapy in type I as well as in type II
diabetes after the age of puberty.
✐ BEWARE OF HYPOGLYCEMIA
Events Requiring an Increase in
Dosage of Insulin in Diabetic Patients
✐ Infections
✐ High fever
✐ Trauma, surgical operations
✐ Myocardial infarction
✐ Pregnancy
✐ Hyperthyroidism
✐ Diabetic ketoacidosis
Oral Antidiabetic Drugs
Insulin Secretagogues
Sulfonylureas
Meglitinides
Short-acting
Tolbutamide
Intermediate acting
Glyburide
Long-acting
Chloropropamide
Repaglinide
Euglycemic Agents
Biguanides Metformin
Thiazolidinediones Pioglitazone
Glucose Absorption Inhibitors
Alpha-glucosidase inhibitors Miglitol
Pharmacology of Sulfonylureas
Mechanisms of action
1. Increased pancreatic response to glucose (the main mechanism) by:
Binding to a specific receptor associated with a ATP-sensitive K+ channel in
beta cell membranes (the channel is normally blocked by glucose-induced
increase in ATP)

Blockade of K+ efflux (depolarization)

Opening of voltage-gated Ca++ channels

Release of insulin by exocytosis
(Insulin synthesis is not affected)
2. Reduction of plasma glucagon levels after chronic treatment
(mechanism is unclear but could be related to the enhanced release of both
insulin and somatostatin, which inhibit A cell secretion.)
Pharmacology of Sulfonylureas
Pharmacological effects
✐ Hypoglycemic effect (only if insulin is
available)
✐ Stimulation of somatostatin release from
pancreatic D cells.
✐ The hypoglycemic effect of sulfonylureas
decreases over time (secondary failure).
Pharmacokinetics of Sulfonylureas
The major differences between various sulfonylureas
reside in their pharmacokinetic profiles
Drug
Half Life
Duration of Action
First generation
Tolbutamide
5 – 7 hours
6 – 12 hours
Chloropropamide
25 – 35 hours
40 – 60 hours
3 – 4 hours
10 – 24 hours
Second generation
Glyburide
Adverse Effects of Sulfonylureas
(overall incidence of adverse effects ~ 4%)
Metabolic effects
• Hypoglycemic reactions (up to 20%)(more likely with
compounds having longer half-lives)
Allergic skin reactions
• Itching (3%), skin rashes (1%), urticaria (1%).
Other effects
• Disulfiram-like reaction in patients ingesting alcohol
(10-15%) (chlorpropamide)
• Dilutional hyponatremia (1-5%), SIADH (with symptoms
of water intoxication) (mainly with chlorpropamide)
Drug Interactions with Sulphonylureas
Hypoglycemic action is increased by:
Insulin*
Alcohol*
Sulfonamides
Probenecid
Chloramphenicol
Hypoglycemic action is decreased by:
CorticosteroidsΩ
Hormonal contraceptivesΩ
Loop and thiazide diureticsΩ
Rifampin✜
* Intricsic hypoglycemic action
 Inhibition of hepatic metabolism of sulfonylureas
Inhibition of urinary secretion of sulfonylureas
Ω Intrinsic hyperglycemic action
✜ Stimulation of hepatic metabolism of sulfonylureas
Contraindications and Precautions of
Sulfonylureas
✐ Type I diabetes (as sole therapy)
✐ Pregnancy (risk of hypoglycemia in the
newborn).
✐ Severe liver or kidney disease.
✐ Sulfa drug hypersensitivity.
Therapeutic Uses of Sulfonylureas
THERAPEUTIC USES of SULFONYLUREAS
1. Treatment of diabetes mellitus
✏ Sulfonylureas are used to control hyperglycemia in
type II diabetic patients who cannot achieve
appropriate control with changes in diet alone.
2. Treatment of diabetes insipidus
✏ Chlorpropamide can reduce or eliminate the need for
vasopressin in some patients with central diabetes
insipidus when partial ADH secretion is present.
Pharmacology of Meglitinides and
congeners
Drugs
✐ Repaglinide and nateglinide are the drugs on the market.
Mechanism of action
✐ Stimulation of insulin release by closing ATP-dependent K+
channels in pancreatic beta cells (the mechanism is very
close to that of sulfonylureas)
Pharmacokinetics
✐ Repaglinide has a fast onset (less than 30 minutes) and a
short duration of action (about 4 hours). Repaglinide is >
95% metabolized by the liver
Pharmacology of Meglitinides and
congeners
Adverse effects
✐
✐
Hypoglycemic reaction (up to 15%)
Upper respiratory tract infections (10%)
Contraindications and precautions
✐
✐
✐
Type I diabetes (as sole therapy)
Severe hepatic disease.
Pregnancy (risk of hypoglycemia in the newborn).
Therapeutic uses
✐
To control hyperglycemia in type II diabetic patients who cannot achieve
appropriate control with changes in diet alone. (unlike sulfonylureas they
have a rapid onset and a short duration of action so that they are given
with meals to enhance postprandial glucose utilization)
Pharmacology of Biguanides
Drugs
✐ Metformin is the only drug on the market in USA.
Mechanism of action
✐ It is still uncertain. Proposed mechanisms include:
1.
Inhibition of hepatic gluconeogenesis (likely the main mechanism)
2.
Direct stimulation of glucose uptake and utilization (glycolysis) in
peripheral tissues.
3.
Reduction of plasma glucagon levels.
Pharmacological effects
✐ Biguanides are antihyperglycemic, not hypoglycemic. They do not
cause hypoglycemia, even in large doses, but they prevent
postprandial hyperglycemia.
Pharmacology of Biguanides
Pharmacokinetics
✐ Oral bioavailability: . 60%
✐ All the drug is excreted unchanged in the urine
✐ Half-life: . 6 hours
Adverse effects
✐ Anorexia, nausea and vomiting, metallic taste,
abdominal discomfort, diarrhea (up to 20%)
✐ Lactic acidosis (rare but fatal in 50% of cases) (by
inhibiting gluconeogenesis the drug impairs the hepatic
uptake of lactic acid)
✐ Vit B12 deficiency
Pharmacology of Biguanides
Contraindications and cautions
✐ Type I diabetes
✐ All conditions that predispose to acidosis (alcoholism, hepatic
diseases, hypoxemia, chronic hypoxic lung diseases, low
calorie diet, myocardial infarction, septicemia, dehydration,
major surgery, therapy with ACE inhibitors, etc.)
✐ Renal impairment (kidney function must be controlled since
the drug is excreted unchanged in the urine).
Therapeutic uses
✐ In type II diabetes (alone or in combination with sulfonylureas
when diabetes does not respond to diet or sulfonylurea
therapy alone).
Pharmacology of Thiazolidinediones
Drugs
✐ Pioglitazone and rosiglitazone are the drugs on the market.
Mechanism of action
✐ These drugs are ‘insulin sensitizers’.
✐ They bind to a nuclear receptor (peroxisome proliferator
activated receptor, PPAR), located mainly in adipose tissue,
skeletal muscle and liver, which regulates the transcription
of several insulin responsive genes.
✐ The overall effect is an enhancement of tissue sensitivity to
insulin (that is a reduction in insulin resistance). Therefore
the need of exogenous insulin is reduced.
Pharmacology of Thiazolidinediones
Pharmacological effects
✐ Reduction of hyperglycemia, hyperinsulinemia and
hypertriglyceridemia that are characteristic of insulin-resistant
states.
✐ The drugs are antihyperglycemic, not hypoglycemic. They do
not cause hypoglycemia when given alone, but can prevent
postprandial hyperglycemia.
✐ Clinical effect is not observed for 6 to 12 weeks.
Adverse effects
✐ Diarrhea (13%)
✐ Upper respiratory tract infections (10%)
✐ Anemia (7%),
Pharmacology of Thiazolidinediones
Contraindications and cautions
✐ Type I diabetes
✐ Severe heart failure (because of drug-induced edema)
✐ Liver disease (the first drug of this class, troglitazone,
was withdrawn from the marked because of serious
liver toxicity)
Therapeutic uses
✐ In combination with insulin, biguanides or
sulfonylureas, in type II diabetes which exhibits insulin
resistance.
Pharmacology of Alpha-Glucosidase Inhibitors
Drugs
✐ Miglitol and acarbose are the compounds on the
market.
Mechanism of action
✐ The drugs are competitive inhibitors of the intestinal
brush border enzyme alpha-glucosidase involved in
the breakdown of starches into simple sugars.
✐ Absorption of monosaccharides from duodenum and
upper jejunum is reduced.
Pharmacology of Alpha-Glucosidase Inhibitors
Pharmacological effects
✐ Postprandial glucose levels is reduced both in normal and
diabetic subjects, so creating an insulin sparing effect.
✐ The efficacy of the drugs is small.
✐ Hypoglycemia does not occur even in overdosage.
Pharmacokinetics
✐ Oral bioavailability: acarbose 2%; miglitol >90%
✐ Elimination: miglitol > 90% by the kidney
Adverse effects
✐ Flatulence (up to 40%) due to the appearance of undigested
carbohydrates in the colon where they ferment, so releasing gas.
✐ Diarrhea (up to 20%), abdominal pain (7%).
Pharmacology of Alpha-Glucosidase Inhibitors
Contraindications and cautions
✐ Inflammatory bowel disease
✐ Gastrointestinal conditions worsened by gas or distension
✐ Renal disease
Therapeutic uses
✐ Type II diabetes as monotherapy or in combination with
sulfonylureas or insulin.
✐ As monotherapy in elderly patients or in patients with
predominantly postprandial hyperglycemia.
☛ Note: if hypoglycemia occurs when administered with insulin
or sulfonylureas, oral administration of sugars other than
glucose is ineffective.
Pharmacology of Glucagon
Chemistry
✐ A single chain polypeptide of 29 amino acids.
Mechanism of action
✐ Most glucagon effects result from activation of specific receptors
which leads to an increase in adenylyl-cyclase activity and
production of cAMP.
Metabolic effects
✐
✐
✐
✐
Stimulation of glycogenolysis.
Stimulation of gluconeogenesis.
Inhibition of glycogen synthesis.
Inhibition of glucose oxidation.
☛ These effect are mainly on the liver. Glucagon is the most potent
hyperglycemic drug.
Pharmacology of Glucagon
Other effects
✐ Inotropic and chronotropic effect on the heart, due to the increase in
cAMP.
✐ Profound relaxation of intestinal smooth muscle (mechanism still
uncertain).
Pharmacokinetics
✐ Rapidly inactivated in liver, kidney and other tissues. Half-life: 3-6
min.
Adverse effects
✐ Nausea and vomiting (risk of aspiration in unconscious patients)
✐ Hypotension (after IV administration)
Pharmacology of Glucagon
Therapeutic uses
✐ For the emergency treatment of severe
hypoglycemic reactions (but high doses stimulate
insulin release)
✐ For reversing the cardiac effect of an overdose of
beta-blocking agents