Zarqa University

Pharmacy school
Clinical Pharmacy Department

Pharmacology II

Drugs for diabetes

Dr. Haneen Basheer

Dr. Shourok Ibrahim

2nd semester 2022.2023

 Overview
• The endocrine pancreas in the adult human
consists of approximately 1 million islets of
Langerhans interspersed throughout the
pancreatic gland.
 Hormone products include:

• Insulin the storage and anabolic hormone of the body;

• Islet amyloid polypeptide (IAPP, or amylin), which
modulates appetite, gastric
emptying, glucagon and insulin secretion
• Glucagon, the hyperglycemic factor that mobilizes
glycogen stores;
• Somatostatin, a universal inhibitor of secretory cells;
• Pancreatic peptide, a small protein that facilitates
digestive processes by a mechanism not yet clarified;
and ghrelin, a peptide known to increase food intake
Pro-Insulin structure
 Insulin secretion
• Insulin is released from pancreatic beta cells at a low
basal rate and at a much higher stimulated rate in
response to a variety of stimuli, especially glucose
• Other stimulants such as other sugars (eg, mannose),
amino acids, hormones such as glucagon-like
polypeptide 1 (GLP-1), glucose-dependent insulinotropic
polypeptide (GIP), glucagon, cholecystokinin, high
concentrations of fatty acids, and β-adrenergic
sympathetic activity are recognized.
• Stimulatory drugs include sulfonylureas, meglitinide
and nateglinide, isoproterenol, and acetylcholine.
 Cont
• Inhibitory signals are hormones
including insulin itself, islet amyloid
polypeptide, somatostatin, and leptin; α-
adrenergic sympathetic activity; chronically
elevated glucose; and low concentrations of
fatty acids.
• Inhibitory drugs:
include diazoxide, phenytoin, vinblastine,
and colchicine.
Insulin secretion
 Insulin Degradation
• The liver and kidney are the two main organs that
remove insulin from the circulation.
• The liver normally clears the blood of approximately 60% of
the insulin released from the pancreas by virtue of its location
as the terminal site of portal vein blood flow, with the kidney
removing 35–40% of the endogenous hormone.
• However, in insulin-treated diabetics receiving
subcutaneous insulin injections, this ratio is reversed, with as
much as 60% of exogenous insulin being cleared by the kidney
and the liver removing no more than 30–40%.
• The half-life of circulating insulin is 3–5 minutes.
 The Insulin Receptor

•kinases are the docking

proteins: insulin recepto
r substrates (IRS)
 Cont
• Various hormonal agents (eg, glucocorticoids)
lower the affinity of insulin receptors for insulin;
growth hormone in excess increases this affinity
slightly.
• Aberrant serine and threonine phosphorylation
of the insulin receptor β subunits or IRS
molecules may result in insulin resistance and
functional receptor down-regulation.
Effects of Insulin on Its Targets
 Diabetes mellitus
• Is defined as an elevated blood glucose
associated with absent or inadequate
pancreatic insulin secretion, with or without
concurrent impairment of insulin action.
• The disease states underlying the diagnosis of
diabetes mellitus are now classified into four
categories: type 1, type 2, other,
and gestational diabetes mellitus
 Types of DM
Type 1 DM (insulin deficient) Type 1 diabetes is further subdivided into
immune-mediated (type 1a) and idiopathic
causes (type 1b)
Insulin therapy is essential
Type 2 DM (insulin resistance combined circulating endogenous insulin is sufficient
with β-cell dysfunction). to prevent ketoacidosis, it is inadequate to
prevent hyperglycemia.
Patients with type 2 diabetes can initially be
controlled with diet, exercise and oral
glucose lowering agents or non-insulin
injectables.
Some patients have progressive beta cell
failure and eventually may also
need insulin therapy.
Gestational diabetes Most women become normoglycemic after
pregnancy; however, 30% to 50% of these
women develop type 2 DM later in life

Other other specific causes of an elevated blood

glucose: pancreatectomy, pancreatitis, non-
pancreatic diseases, drug therapy
 Clinical presentation
• Individuals with type 1 DM are often thin and are
prone to ketoacidosis if insulin is withheld or under
conditions of severe physiological stress.
• Symptoms such as polyuria, polydipsia, polyphagia,
weight loss, and lethargy are common at the time of
initial presentation.
• In the outpatient setting, some patients present with
vague complaints of weight loss and fatigue but other
symptoms may not be apparent unless a
comprehensive history is taken.
 Cont
• Twenty percent to 40% of patients with type 1
DM present with diabetic ketoacidosis (DKA)
after several days of polyuria, polydipsia,
polyphagia, and weight loss.
 DM2
• Patients with type 2 DM often present without
symptoms, but the presence of microvascular
complications at the time of diagnosis suggest that
many patients have had hyperglycemia for years.
• Often patients with type 2 DM are diagnosed during
routine blood testing or screening. Lethargy, polyuria,
nocturia, and polydipsia can be seen at diagnosis in
some patients with type 2 diabetes, but significant
weight loss is less common.
• Most patients with type 2 DM are overweight or obese
Classical signs of DM
 Complication of Diabetes
• Acute complications:
– Ketoacidosis (Type 1)
– The hyperglycemic hyperosmolar nonketotic
syndrome(Type 2)
– Hypoglycemia
• Chronic complications:
– Disorders of the microcirculation
• Neuropathies
• Nephropathies
• Retinopathies
– Macrovascular complications
– Foot ulcers
• Hyperglycemia and glycosuria may influence the
growth of microorganisms and increase the severity
of the infection
 DKA and HHS
• In DKA, metabolic acidosis is often the major
finding, while the serum glucose
concentration is generally below 800 mg/dL
(44.4 mmol/L) and often approximately 350 to
500 mg/dL (19.4 to 27.8 mmol/L).
• DKA is characterized by ketoacidosis and
hyperglycemia, while HHS usually has more
severe hyperglycemia but no ketoacidosis
 DKA and HHS
clinical presntation
• Diabetic ketoacidosis (DKA) usually evolves rapidly, over a
24-hour period. In contrast, symptoms of hyperosmolar
hyperglycemic state (HHS) develop more insidiously with
polyuria, polydipsia, and weight loss, often persisting for
several days before hospital admission.
• The earliest symptoms of marked hyperglycemia are
polyuria, polydipsia, and weight loss. As the degree or
duration of hyperglycemia progresses, neurologic
symptoms, including lethargy, focal signs, and obtundation,
can develop. This can progress to coma in later stages.
Neurologic symptoms are most common in HHS, while
hyperventilation and abdominal pain are primarily limited to
patients with DKA.
Copyrights apply
 Treatment Goals of DM
• Reduce risk for microvascular & macrovascular
disease complications
• Ameliorate symptoms
• Prevent acute complications from high blood
glucose levels
• Minimizing hypoglycemic episodes
• Reduce mortality
• Improve quality of life
Glycemic goals