CARDIOVASCULAR DRUGS IIA
LECTURE ONE
INTRODUCTION AND GENERAL CLASSIFICATION OF
DRUGS USED FOR THE TREATMENT OF SUGAR DISORDERS
Lecture Outline
1.1 Introduction
1.2 Objectives
1.3 The endocrine functions of the pancreas
1.4 Diabetes mellitus
1.4.1 Definition
1.4.2 Classification of diabetes mellitus
1.4.2.1 Insulin dependent diabetes mellitus
1.4.2.2 Non-insulin dependent diabetes mellitus
1.4.2.3 Other types of diabetes mellitus
1.4.2.3.1 Gestational diabetes mellitus
1.4.2.3.2 Maturity onset diabetes of the young
1.4.2.3.3 Metabolic syndrome
1.4.2.3.4 Drug-induced diabetes mellitus
1.5 Hypoglycemia
1.6 Classification of drugs used for treatment of sugar disorders
1.6.1 Hypoglycemic agents
1.6.1.1 Insulin and insulin analogues
1.6.1.1.1 Insulin
1.6.1.1.2 Insulin analogues
1.6.1.2 Insulin secretagogues
1.6.1.2.1Sulfonylureas
1.6.1.2.2Meglitinides
1.6.1.2.3Glucagon-like peptide-1 agonists
1.6.1.2.4Dipeptidyl peptidase 4 inhibitors
, 1.6.1.3 Insulin sensitizers
1.6.1.3.1 Biguanides
1.6.1.3.2 Glitazones
1.6.1.3.3 Dual PPARα and PPARγ coactivators
1.6.1.4 Other hypoglycemic agents
1.6.1.4.1 Glucosidase inhibitors
1.6.1.4.2 Amylin agonists
1.6.1.4.3 Sodium-glucose transporter inhibitors
1.6.1.5 Adjuncts to diabetes mellitus treatment
1.6.1.5.1 Alpha-Aldose reductase inhibitors
1.6.1.5.2 Sweeteners
1.6.2 Hyperglycemic agents
1.6.2.1 Glucose
1.6.2.2 Glucagon
1.6.2.3 Diazoxide
1.7 Activity
1.8 Summary
1.9 References
,LECTURE TWO
INSULIN AND INSULIN ANALOGUES
A. Insulin
A1. Bovine and porcine insulin
Initially, the only source of exogeneous insulin was bovine or porcine insulin because the amino
acid sequence homology of insulin from these animals was the closest to that of human beings.
However, patients on these types of insulin developed high and low-affinity insulin antibodies
leading to immunologic insulin resistance.
A2. Human insulin
In 1963 complete synthesis of human insulin was achieved and by 1978, human insulin was
produced by recombinant DNA methods using Escherichia coli. Following clinical trials in
1980, humulin (regular insulin) became the first genetically engineered drug to be approved by
the Food and Drug Administration (FDA) of the USA. Since then, there have been many
preparations of insulin and we will now discuss them.
Regular insulin
Regular insulin is also referred to as ‘insulin injection’ or ‘crystalline zinc insulin’. It is an
acidified or neutral solution of insulin and it has a rapid action insulin. Its action is observed
within 0.5-1 hour and it has a duration of action of 8-12 hours.
Prompt insulin zinc suspension
This is also called ‘semi-lente insulin’ and it is made by addition of small amounts of zinc
chloride to hexameric insulin with two zinc ions in neutral acetate buffer. The insulin precipitates
in several forms with varying rates of dissolution and gives a rapidly soluble amorphous insulin.
Its onset is 1-1.5 hours and duration of action is 12-16 hours.
Isophane insulin suspension
Isophane insulin is also called ‘Neutral protamine Hegadorn’ (NPH) and its action starts after 1-
1.5 hours and lasts upto 24 hours. It is insulin precipitated in the presence of zinc ions and
protamine. It is classified as an insulin of intermediate duration of action.
Insulin zinc suspension
This is a sterile suspension of insulin in buffered water for injection, which has been modified
using zinc chloride to give a mixture of crystalline and amorphous insulin. It has an intermediate
duration of action of about 24 hours. It has the advantage of not having proteins.
, Extended insulin zinc suspension
This is also called ultra-lente insulin and it is a crystalline form of a hexameric four-zinc insulin.
Its onset of duration is 4-8 hours and a duration of action of 36 hours.
Protamine zinc insulin suspension
Protamine zinc insulin suspension is prepared by precipitation of insulin in the presence of zinc
ions (ZnCl2) and protamine, a basic protein. It contains two zinc ions in each hexamer. It has an
onset of 4-8 hours and a duration of action of almost 36 hours.
B. Insulin analogues
Structure activity relationships have revealed that variations and removal of amino acids from
the C-terminus of the B chain does not drastically change the biological activity, but it can
influence dimer formation or separation. Recombinant DNA methods have been used to produce
analogues in which dimer formation is inhibited and therefore are rapid acting, as well as
analogues with longer duration of action through additions to the C terminus.
Short-acting human insulin analogues
Both insulin lispro and insulin aspart are fast acting analogues which can be injected
immediately before meals and they can be used in combination with regular or NPH insulin.
Both of them dissociate into monomers very fast causing a fast onset of action. For example,
insulin lispro has an onset of action of 15 minutes and a duration of 6-8 hours. Insulin glulisine
(Apidra®, Sanofi-Aventis) when injected subcutaneously, it appears in the blood earlier than
human insulin.
Long-acting human insulin analogues
Insulin glargine has minimum peak effects and a duration of action of about 22 hours. Insulin
detemir is a newer long acting analogue which is injected twice daily.
Ultralong-acting human insulin analogues
Insulin degludec is an ultralong-acting basal insulin analogue being developed by Novo Nordisk
under the brand name Tresiba®.
Inhalable insulin
The first inhalable insulin product to be marketed was Exubera® (Pfizer), a powdered form of
recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed.
After the withdrawal of the only inhalable formulation, all currently available insulin
formulations are administered by subcutaneous or intravenous injection. However, several other
LECTURE ONE
INTRODUCTION AND GENERAL CLASSIFICATION OF
DRUGS USED FOR THE TREATMENT OF SUGAR DISORDERS
Lecture Outline
1.1 Introduction
1.2 Objectives
1.3 The endocrine functions of the pancreas
1.4 Diabetes mellitus
1.4.1 Definition
1.4.2 Classification of diabetes mellitus
1.4.2.1 Insulin dependent diabetes mellitus
1.4.2.2 Non-insulin dependent diabetes mellitus
1.4.2.3 Other types of diabetes mellitus
1.4.2.3.1 Gestational diabetes mellitus
1.4.2.3.2 Maturity onset diabetes of the young
1.4.2.3.3 Metabolic syndrome
1.4.2.3.4 Drug-induced diabetes mellitus
1.5 Hypoglycemia
1.6 Classification of drugs used for treatment of sugar disorders
1.6.1 Hypoglycemic agents
1.6.1.1 Insulin and insulin analogues
1.6.1.1.1 Insulin
1.6.1.1.2 Insulin analogues
1.6.1.2 Insulin secretagogues
1.6.1.2.1Sulfonylureas
1.6.1.2.2Meglitinides
1.6.1.2.3Glucagon-like peptide-1 agonists
1.6.1.2.4Dipeptidyl peptidase 4 inhibitors
, 1.6.1.3 Insulin sensitizers
1.6.1.3.1 Biguanides
1.6.1.3.2 Glitazones
1.6.1.3.3 Dual PPARα and PPARγ coactivators
1.6.1.4 Other hypoglycemic agents
1.6.1.4.1 Glucosidase inhibitors
1.6.1.4.2 Amylin agonists
1.6.1.4.3 Sodium-glucose transporter inhibitors
1.6.1.5 Adjuncts to diabetes mellitus treatment
1.6.1.5.1 Alpha-Aldose reductase inhibitors
1.6.1.5.2 Sweeteners
1.6.2 Hyperglycemic agents
1.6.2.1 Glucose
1.6.2.2 Glucagon
1.6.2.3 Diazoxide
1.7 Activity
1.8 Summary
1.9 References
,LECTURE TWO
INSULIN AND INSULIN ANALOGUES
A. Insulin
A1. Bovine and porcine insulin
Initially, the only source of exogeneous insulin was bovine or porcine insulin because the amino
acid sequence homology of insulin from these animals was the closest to that of human beings.
However, patients on these types of insulin developed high and low-affinity insulin antibodies
leading to immunologic insulin resistance.
A2. Human insulin
In 1963 complete synthesis of human insulin was achieved and by 1978, human insulin was
produced by recombinant DNA methods using Escherichia coli. Following clinical trials in
1980, humulin (regular insulin) became the first genetically engineered drug to be approved by
the Food and Drug Administration (FDA) of the USA. Since then, there have been many
preparations of insulin and we will now discuss them.
Regular insulin
Regular insulin is also referred to as ‘insulin injection’ or ‘crystalline zinc insulin’. It is an
acidified or neutral solution of insulin and it has a rapid action insulin. Its action is observed
within 0.5-1 hour and it has a duration of action of 8-12 hours.
Prompt insulin zinc suspension
This is also called ‘semi-lente insulin’ and it is made by addition of small amounts of zinc
chloride to hexameric insulin with two zinc ions in neutral acetate buffer. The insulin precipitates
in several forms with varying rates of dissolution and gives a rapidly soluble amorphous insulin.
Its onset is 1-1.5 hours and duration of action is 12-16 hours.
Isophane insulin suspension
Isophane insulin is also called ‘Neutral protamine Hegadorn’ (NPH) and its action starts after 1-
1.5 hours and lasts upto 24 hours. It is insulin precipitated in the presence of zinc ions and
protamine. It is classified as an insulin of intermediate duration of action.
Insulin zinc suspension
This is a sterile suspension of insulin in buffered water for injection, which has been modified
using zinc chloride to give a mixture of crystalline and amorphous insulin. It has an intermediate
duration of action of about 24 hours. It has the advantage of not having proteins.
, Extended insulin zinc suspension
This is also called ultra-lente insulin and it is a crystalline form of a hexameric four-zinc insulin.
Its onset of duration is 4-8 hours and a duration of action of 36 hours.
Protamine zinc insulin suspension
Protamine zinc insulin suspension is prepared by precipitation of insulin in the presence of zinc
ions (ZnCl2) and protamine, a basic protein. It contains two zinc ions in each hexamer. It has an
onset of 4-8 hours and a duration of action of almost 36 hours.
B. Insulin analogues
Structure activity relationships have revealed that variations and removal of amino acids from
the C-terminus of the B chain does not drastically change the biological activity, but it can
influence dimer formation or separation. Recombinant DNA methods have been used to produce
analogues in which dimer formation is inhibited and therefore are rapid acting, as well as
analogues with longer duration of action through additions to the C terminus.
Short-acting human insulin analogues
Both insulin lispro and insulin aspart are fast acting analogues which can be injected
immediately before meals and they can be used in combination with regular or NPH insulin.
Both of them dissociate into monomers very fast causing a fast onset of action. For example,
insulin lispro has an onset of action of 15 minutes and a duration of 6-8 hours. Insulin glulisine
(Apidra®, Sanofi-Aventis) when injected subcutaneously, it appears in the blood earlier than
human insulin.
Long-acting human insulin analogues
Insulin glargine has minimum peak effects and a duration of action of about 22 hours. Insulin
detemir is a newer long acting analogue which is injected twice daily.
Ultralong-acting human insulin analogues
Insulin degludec is an ultralong-acting basal insulin analogue being developed by Novo Nordisk
under the brand name Tresiba®.
Inhalable insulin
The first inhalable insulin product to be marketed was Exubera® (Pfizer), a powdered form of
recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed.
After the withdrawal of the only inhalable formulation, all currently available insulin
formulations are administered by subcutaneous or intravenous injection. However, several other
