PHARMACOLOGY

Topic: Antidiabetic Drugs

Chapter: 41

THE ENDOCRINE PANCREAS

 Consists of approximately 1 million islets of Langerhans interspersed
throughout the pancreatic gland
Within the islets, at least five hormone producing cells are
present

 Hormone products:
o Insulin
The storage and anabolic hormone of the body
Figure Above: Structure of human proinsulin and insulin
o Islet amyloid polypeptide (IAPP or amylin)
Proinsulin (C-peptide plus A and B chains)
Modulates appetite, gastric emptying, and glucagon
Insulin is shown as the shaded (orange color) peptide chains, A and B
and insulin secretion

 Granules within the beta cells store the insulin in the form of crystals
o Glucagon
consisting of two atoms of zinc and six molecules of insulin
Hyperglycemic factor that mobilizes glycogen stores
 The entire human pancreas contains up to 8 mg of insulin,
representing approximately 200 biologic units
o Somatostatin
Originally, the unit was defined on the basis of the hypoglycemic
A universal inhibitor of secretory cells
activity of insulin in rabbits
o Pancreatic peptide
 With improved purification techniques, the unit is presently defined
A small protein that facilitates digestive processes by
on the basis of weight, and present insulin standards used for assay
a mechanism not yet clarified
purposes contain 28 units per milligram
o Ghrelin
Insulin Secretion
A peptide known to increase pituitary growth
hormone release  Insulin is released from pancreatic beta
 Stimulants of Insulin Release:
o Glucose – major
o Other sugars (eg, mannose)
o Gluconeogenic amino acids (eg, leucine, arginine)

 Amplifiers of Glucose-Induced Insulin Release: (Hormones)

o Glucagon-like polypeptide 1 (GLP-1)
o Glucose-dependent insulinotropic polypeptide (GIP)
o Glucagon
o Cholecystokinin
o High concentrations of fatty acids
o β-adrenergic sympathetic activity

 Stimulatory Drugs:
o Sulfonylureas
o Meglitinide & Nateglinide
o Isoproterenol
o Acetylcholine
INSULIN
Chemistry
 Inhibitors of Insulin Release:
 A small protein with a molecular weight in humans of 5808
o Neural: α-sympathomimetic effect of catcholamines
 It contains 51 amino acids arranged in two chains (A and B) linked
o Humoral: somatostatin, leptin
by disulfide bridges
o Drugs: diazoxide, phenytoin, vinblastine, colchicine
There are species differences in the amino acids of both chains
Insulin Degradation
 Proinsulin, a long single-chain protein molecule, is processed within
 Endogenous insulin (coming from the pancreas):
the Golgi apparatus of beta cells and packaged into granules, where
o Liver – 60% of endogenous insulin is cleared
it is hydrolyzed into insulin and C-peptide
o Kidney – 35-40% of endogenous insulin is cleared
C-peptide is a residual connecting segment as a result of removal
of four amino acids
 In insulin-treated diabetics receiving SQ insulin injections:
o Kidney – 60% of exogenous insulin is cleared
 Insulin and C-peptide are secreted in equimolar amounts in response
o Liver – 30-40% of exogenous insulin is cleared
to all insulin secretagogues; a small quantity of unprocessed or
partially hydrolyzed proinsulin is released as well
NOTE: You will notice that the ratio is reversed if the insulin is
 Proinsulin may have some mild hypoglycemic action
coming from an exogenous source
 C-peptide has no known physiologic function
 Insulin Half-life: 3-5 minutes

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Circulating Insulin Metabolism

 Basal serum insulin values 5–15 μU/mL (30–90 pmol/L)  Glucagon is extensively degraded in the:
 Peak rise  60–90 μU/mL (360–540 pmol/L) during meals o Liver
o Kidney
Effects of Insulin on its Targets o Plasma
 Insulin affects many organs: o Tissue receptor sites
o It stimulates skeletal muscle fibers  Glucagon Half-life: 3-6 minutes (similar with insulin)
o It stimulates liver cells
o It acts on fat cells Pharmacologic Effects of Glucagon
o It inhibits production of certain enzyme A. Metabolic Effects
In each case, insulin triggers these effects by binding to the  The first six amino acids at the amino terminal of the glucagon
insulin receptor molecule bind to specific Gs protein–coupled receptors on liver cells
↓
↑ in cAMP, which facilitates catabolism of stored glycogen and ↑
gluconeogenesis and ketogenesis
↓
↑ blood glucose at the expense of stored hepatic glycogen

 There is NO effect on skeletal muscle glycogen, presumably because

of the lack of glucagon receptors on skeletal muscle
 Pharmacological amounts of glucagon causes:
o Release of insulin from normal pancreatic beta cells
o Release of catecholamines from pheochromocytoma
o Release of calcitonin from medullary carcinoma cells

B. Cardiac Effects
 Glucagon has a potent inotropic and chronotropic effect on the heart
(mediated by the cAMP mechanism )
 Thus, it produces an effect very similar to that of β-adrenoceptor
agonists without requiring functioning β receptors

C. Effects on Smooth Muscles

 Large doses of glucagon produce profound relaxation of the
intestine

Clinical Uses
 Severe Hypoglycemia
The major clinical use of glucagon is for emergency treatment of
severe hypoglycemic reactions in patients with type 1 diabetes
Recombinant glucagon is currently available in 1-mg vials for
parenteral (IV, IM, or SC) use (Glucagon Emergency Kit)

 Endocrine Diagnosis
The Insulin Receptor Several tests use glucagon to diagnose endocrine disorders

 Beta-Adrenoceptor Blocker Overdose

Glucagon is sometimes useful for reversing the cardiac effects of
an overdose of β-blocking agents because of its ability to ↑ cAMP
production in the heart independent of β-receptor function
NOT clinically useful in the treatment of heart failure

GLUCAGON  Radiology of the Bowel

Chemistry Glucagon has been used extensively in radiology as an aid to x-ray
 It is synthesized in the alpha cells of the pancreatic islets of visualization of the bowel because of its ability to relax the
Langerhans intestine
 It is a peptide—identical in all mammals—consisting of a single chain
of 29 amino acids, with a molecular weight of 3485 Adverse Reactions
 Selective proteolytic cleavage converts a large precursor molecule of  Transient nausea & occasional vomiting
approximately 18,000 MW to glucagon
 Glicentin Contraindication:
A precursor intermediate which consists of a 69-amino-acid  Patients with pheochromocytoma
peptide and contains the glucagon sequence interposed between
peptide extensions

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

DIABETES MELLITUS Laboratory Findings

Diabetes Mellitus:
 An elevated blood glucose associated with absent or inadequate
pancreatic insulin secretion, with or without concurrent impairment
of insulin action

Classification:
 Type 1 Diabetes Mellitus
 Type 2 Diabetes Mellitus
 Gestational Diabetes Mellitus
 Other Specific Type of Diabetes Mellitus

Type 1 Diabetes Mellitus

 Selective beta cell (B cell) destruction and severe or absolute insulin Additional Information from Manual:
deficiency ADA CRITERIA FOR THE DIAGNOSIS OF DIABETES (2018)
 Further subdivided: FPG >/=126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for
o Type 1a – immune mediated (most common) at least 8 h.*
o Type 1b – idiopathic cause OR
 <30 years of age at the time of diagnosis 2-h PG >/=200 mg/dL (11.1 mmol/L) during OGTT. The test should be
But the onset can occur at any age performed as described by the WHO, using a glucose load containing the
equivalent of 75-g anhydrous glucose dissolved in water.*
 Highest incidence is in people from: OR
o Northern Europe A1C >/=6.5% (48 mmol/mol). The test should be performed in a laboratory
o Sardinia using a method that is NGSP certified and standardized to the DCCT assay*
 At the time of diagnosis they have: OR
o One or more circulating antibodies to glutamic acid In a patient with classic symptoms of hyperglycemia or hyper glycemic
crisis, a random plasma glucose >/=200 mg/dL (11.1 mmol/L)
decarboxylase 65 (GAD 65)
*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat
o Insulin autoantibody testing
o Tyrosine phosphatase IA2 (ICA 512)
o Zinc transporter 8 (ZnT8) Pathogenesis of Type 2 Diabetes (Based on Manual)
These antibodies facilitate the diagnosis of type 1a diabetes I. Ominous Octet
and can also be used to screen family members at risk for
developing the disease

 Latent Autoimmune Diabetes of Adulthood (LADA)

Up to 10–15% of “type 2” patients may actually have this milder
form of type 1 diabetes (LADA)

Type 2 Diabetes Mellitus

 A heterogenous group of conditions characterized by tissue
resistance to the action of insulin combined with a relative deficiency
in insulin secretion
 A given individual may have more resistance or more beta-cell
deficiency, and the abnormalities may be mild or severe
 Although the circulating endogenous insulin is sufficient to prevent
ketoacidosis, it is inadequate to prevent hyperglycemia
 Patients with type 2 diabetes can be controlled with:
o Diet II. Egregorious Eleven
o Exercise
o Oral glucose lowering agents
o Non-insulin injectables
o Insulin therapy
Used only when there is progressive beta cell failure

Gestational Diabetes Mellitus

 Abnormality in glucose levels noted for the first time during
pregnancy
 The placenta and placental hormones create an insulin resistance
that is most pronounced in the last trimester

Other Specific Types of Diabetes Mellitus

 The “other” designation refers to multiple other specific causes of an
↑ blood glucose: pancreatectomy, pancreatitis, nonpancreatic
diseases, drug therapy

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

III. Dirty Dozen  Colesevelam is a novel 2nd generation bile acid sequestrant which
In 2013, Kalra et al took a further step, describing the “Dirty was observed to mediate modest reduction in glucose in T2DM when
Dozen” in diabetes with 4 additions to the octet: Dopamine, used as an adjunct to other agents. The exact mechanism of action is
Vitamin D, Testosterone, and Renin Angiotensin System not yet identified and potential mechanism include effect on bile acid
receptors in the intestine as well as in the liver to reduce endogenous
Dopamine glucose production
 Dopamine is a neurotransmitter in the brain which has lower plasma
levels during insulin-resistant state and increased to normal following Gut Microbiota
restoration of the insulin-sensitive state  Role of colonic microbiome on pathogenesis of diabetes
 Bromocriptine administration in insulin-resistant animals lead to a  Patients with type 2 diabetes exhibited a moderate intestinal
decreased in elevated ventromedial hypothalamus noradrenergic dysbiosis, which included decrease in butyrate produce Roseburia
and serotonergic levels with a decline in hepatic gluconeogenesis, intestinalis and F. prausnitzii, while healthy control samples were
reduced adipose lipolysis, and improved insulin sensitivity enriched with various butyrate producing bacteria (Clostridiales sp.,
 It is postulated that hypothalamic dopamine is decreased in the early Eubacterium rectale, F. prausnitzii, R. intestinalis)
morning in diabetic patients causing increased hepatic  It is postulated that the gut dysbiosis exert enrichment in membrane
gluconeogenesis and lipolysis resulting in glucose intolerance, transport of sugars, branched chain amino acid and sulfate reduction,
insulin-resistance and dyslipidemia decrease butyrate biosynthesis and modifications in the secretion of
the incretin and possibility of an increase in oxidative stress response
Vitamin D
which may represent a link to the pro-inflammatory observed in
 Vitamin D has been shown to stimulate insulin secretion by regulating T2DM patient
intracellular calcium, modulating pancreatic beta-cell insulin release
and prevention of apoptosis
MEDICATIONS FOR HYPERGLYCEMIA
Insulin Preparations
Testosterone
 Human insulin is dispensed as:
 Low serum testosterone levels is associated with T2DM and o Regular (R) formulation
metabolic syndrome o Neutral protamine hagedorn (NPH) formulations
 Androgen replacement in hypogonadal men has shown to improve  There are 6 analogs of human insulin
insulin sensitivity and glycemic levels, reduce insulin requirements o 3 of which are rapidly acting:
and improvement in the other metabolic parameters 1) Insulin glargine
2) Insulin detemir
Renin Aldosterone System 3) Insulin degludec
 Renin aldosterone system (RAS) blockage with ACE inhibitor (ACEI)  Animal insulins are available in other parts of the world (not in U.S.)
and Angiotensin receptor blockers (ARBs) plays a major role in o Pork and beef preparations:
management of diabetic nephropathy  Isophane, neutral, 30/70
 Postulated mechanism for RAS blockage resulting in improved insulin  Lente
sensitivity include; improvement of blood flow & microcirculation in  All the insulins are available in a concentration of 100 units/ML
skeletal muscles and facilitating insulin signaling at cellular level and (U100) and dispensed as:
improvement of insulin secretion by pancreatic beta cells o 10-mL vials
o 0.3-mL cartridges
IV. Unlucky Thirteen o Prefilled disposable pens
 As the Dirty Dozen doesn’t complete the full spectrum of Several insulins are also available at higher
pathogenesis of diabetes, a proposed 13th mechanism in the concentrations in the prefilled disposable pen form:
pathogenesis of diabetes  the role of gut in diabetes mellitus  Insulin glargine 300 units/mL (U300)
 Insulin degludec (U200)
Gut in Diabetes Mellitus  Insulin lispro 200 units/mL (U200)
 The primary driver in the diabetic pandemic across the world is an  Regular insulin 500 units/mL (U500)
increase in mean caloric intake. Hence it is appropriate that this is
also the 13th unlucky pathophysiologic mechanism Principal Types of Insulin
 The only class of drug which utilize this mechanism for treatment of 1.) Short-Acting Insulin Preparations
diabetes is Alpha Glucosidase Inhibitor  It includes:
o Drugs: Acarbose, Voglibose, Miglitol o Regular human insulin
o AGIs delay carbohydrate absorption from proximal small o 3 rapidly acting insulin analogs
intestine and thus have a lowering effect on postprandial  All are clear solutions at neutral pH
blood glucose and insulin levels  The insulin molecules exist as dimers that assemble into hexamers in
 Sodium Glucose Co-transporter 1 (SGLT-1) is the transporter the presence of two zinc ions
responsible for glucose absorption and SGLT-1 is also involved in 10% The hexamers are further stabilized by phenolic compounds such
of renal glucose reabsorption as phenol and meta-Cresol
 Combined SGLT-1/SGLT-2 inhibitor LX4211 (Sotagliflozin) has shown
to increase urinary glucose excretion, delay intestinal glucose  The mutations engineered into the rapidly acting insulin analogs are
absorption, and increase circulating GLP-1 levels designed to disrupt the stabilizing intermolecular interactions of the
dimers and hexamers, leading to more rapid absorption into the
circulation after SQ injection

Continued next page…..

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Short-acting Insulin Preparations….. Long-acting Insulin Preparations…..

 Regular Insulin  Insulin glargine
o Short-acting o Soluble
o Soluble crystalline zinc insulin o “Peakless” (having a broad plasma concentration plateau)
o Onset: 30 minutes o Long-acting insulin analog
o Peak: 2 hours o Two arginine molecules are attached to the B-chain
o Duration: 5-7 hours carboxyl terminal and glycine is substituted for
o Should be injected 30-45 minutes before meal asparagine at the A21 position
o Administered IV This created an analog that is soluble in an acidic
Useful in diabetic ketoacidosis and during the solution but precipitates in the more neutral body pH
perioperative management of insulin-requiring after SQ injection
diabetics
o Individual insulin molecules slowly dissolve away from
 Rapidly-acting Insulin Analogs the crystalline depot and provide a low, continuous level
o Insulin lispro (Humalog) of circulating insulin
An insulin analog in which the proline at position B28 o Onset: 1-1.5 hours
is reversed with the lysine at B29 o Maximum effect: 4-6 hours
o Duration: 11-24 hours or longer
o Insulin aspart (Novolog) o Given once a day
A single substitution of proline by aspartic acid at
position B28  Insulin detemir
o The terminal threonine is dropped from the B30 position
o Insulin glulisine (Apidra) and myristic acid (a C-14 fatty acid chain) is attached to
Differs from human insulin in that the amino acid the B29 lysine
asparagine at position B3 is replaced by lysine and the These modifications prolong the availability of the
lysine in position B29 by glutamic acid injected analog by:
 Increasing both self-aggregation in
o Taken 15 minutes before meals subcutaneous tissue
o Preferred for use in continuous SQ infusion devices  Reversible albumin binding
o Quickly dissociate into monomers
o Absorbed very rapidly o Its affinity is 4-5x lower than that of human soluble
o Peak: 1 hour insulin
o Available in powder form for alveolar absorption o Injected SQ
 Human insulin recombinant inhaled o Administered once or twice a day
o Duration: about 17 hours
 The rapidly acting analogs are commonly used in insulin pumps
 Insulin aspart has been approved for IV use (eg, in hyperglycemic  Insulin degludec
emergencies) o The threonine at position B30 has been removed and the
But there is NO advantage in using insulin aspart over regular lysine at position B29 is conjugated to hexadecanoic acid
insulin by this route via a gamma-l-glutamyl spacer
o In the vial, in the presence of phenol and zinc, the insulin
is in the form of dihexamer
But when injected SQ, it self-associates into large
multihexameric chains consisting of thousands of
dihexamers

o The chains slowly dissolve in the subcutaneous tissue,

2.) Long-acting Insulin Preparations and insulin monomers are steadily released into the
 NPH (neutral protamine Hagedorn, or isophane) insulin systemic circulation
o An intermediate-acting insulin whose absorption and o Injected SQ
onset of action are delayed by combining appropriate o Administered once or twice a day
amounts of insulin and protamine so that neither is o Half-life: 25 hours
present in an uncomplexed form (“isophane”) o Onset: 30-90 hours
o After SQ injection, proteolytic tissue enzymes degrade o Duration: >42 hours
the protamine to permit absorption of insulin
o Onset: 2-5 hours  Mixtures of Insulin
o Peak: 4-10 hours o Premixed insulins (70% NPH and 30% regular insulin)
o Duration 4-12 hours o Neutral protamine lispro (NPL) + Insulin lispro = Human
Mix 75/25, Humalog Mix (50/50)
More rapid onset of glucose-lowering activity, can be
given within 15 minutes before or after starting a
meal

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Mixtures of Insulin continued….. Insulin Delivery Systems

o 70% insulin degludec + 30% insulin aspart (injected once
or twice daily)
o Insulin glargine or insulin detemir CANNOT be mixed
with either regular insulin or the rapid-acting insulin
analogs
 Insulin Syringes and Needles
 Insulin Pens
Eliminate the need for carrying insulin vials and syringes.
Facilitate multiple SQ injections
 Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin
Pumps)
Encouraged for individuals who are unable to obtain target
control while on multiple injection regimens & where excellent
glycemic control is desired, such as during pregnancy
Velosulin (reg. insulin) & insulin aspart and lispro

 Inhaled Insulin
Have rapid route and a relatively short duration of action
Used to cover mealtime insulin requirements to correct high
glucose levels

Factors that Affect Insulin Absorption

 Site of injection: abdomen, buttock, anterior thigh, or dorsal arm
 Type of insulin
 Subcutaneous blood flow: massage, hot baths, or exercise
 Smoking
 Regional muscular activity at the site of the injection
 Volume & concentration of injected insulin
 Depth of injection

Complications of Insulin Therapy

 Hypoglycemia
o Mechanism and diagnosis
 Result from a delay in taking a meal
 Unusual physical exertion
 Dosage error
o Clinical Manifestations
 Tachycardia, palpitations, sweating,
Insulin Time Action Curve:
tremulousness, hunger, nausea, convulsion,
coma
o Treatment
 Glucose administration
 Glucagon 1 mg SQ or IM
 Honey or syrup

 Immunopathology of Insulin Therapy

o Insulin Allergy
 An immediate type of hypersensitivity (IgE-
antibodies)
 Tx: antihistamines, corticosteroids &
desensitization
Figure Above:
o Immune Insulin Resistance (IgG antibodies)
Extent and duration of action of various types of insulin as indicated by the
glucose infusion rates (mg/kg/min) required to maintain a constant glucose  (+) circulating antibodies that neutralize the
concentration. The durations of action shown are typical of an average dose action of insulin to a small extent
of 0.2–0.3 U/kg. The durations of regular and NPH insulin increase  Tx: switching to a lesser antigenic purified
considerably when dosage is increased insulin
 Lipodystrophy at injection site
Additional from Manual: o Injection of animal insulin preparations sometimes led to
Species of Insulin atrophy of subcutaneous fatty tissue at the site of
Beef & Pork Insulin Human Insulin injection
- The beef insulin differs by 3 amino acids - Less expensive, less immunogenic
o Since the development of human and analog insulin
- The pork insulin differs by 1 amino acid - Production by recombinant DNA
- The beef hormone is most antigenic techniques preparations of neutral pH, this type of immune
complication is almost never seen
 Purity of Insulin  chromatography o Hypertrophy of subcutaneous fatty tissue remains a
 Concentrations: 100 units, 500 units problem if injected repeatedly at the same site 
Corrected by avoidance of that specific site

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

MEDICATIONS FOR TREATMENT OF TYPE 2 DIABETES DOA T½

Sulfonylurea Dosage S/E
Several categories of glucose-lowering agents are available for patients with type (Hrs.) (Hrs.)
2 diabetes: 2nd Generation
Glyburide 10-24 5-10 mg/d Hypoglycemia, flushing
 Sulfonylureas, Meglitinides, d-phenylalanine derivatives
Glipizide 10-24 2-4 (shortest) 5-20 mg/d Hypoglycemia
Agents that bind to the sulfonylurea receptor and stimulate Glimepiride 12-24 5-9 1 mg/d
insulin secretion Gliclazide 10 40-320 mg/d

 Biguanides, Thiazolidinediones Meglitidine Analogs

Agents that lower glucose levels by their actions on liver, muscle,
 Repaglinide
and adipose tissue
o 1st member of the meglitinide group of insulin
secretagogues
 α-glucosidase inhibitors
o MOA: Modulate beta-cell insulin release by regulating
Agents that principally slow the intestinal absorption of glucose
potassium efflux through the potassium channels
o No direct effect on insulin exocytosis
 GLP-1 receptor agonists, Dipeptidyl peptidase 4 [DPP-4] inhibitors
o Peak concentration & peak effect: within 1 hour
Agents that mimic incretin effect or prolong incretin action o Fast onset & duration of action: 5-8 hrs.
o T ½: 1 hour
 Sodium-glucose co-transporter inhibitors (SGLTs) o Hepatically cleared by CYP3A4
Agents that inhibit the reabsorption of glucose in the kidney o Indication: controlling postprandial glucose excursions
o Dosage: 0.25-4 mg
 Pramlintide, Bromocriptine, Colesevelam o S/E: hypoglycemia
Agents that act by other or ill-defined mechanisms o Caution: hepatic & renal impairment

Drugs that Primarily Stimulate Insulin Release by Binding to the  Mitiglinide

Sulfonylurea Receptor (Insulin Secretagogues) o Benzylsuccinic acid derivative
Sulfonureas o Binds to the sulfonylurea receptor and is similar to
Mechanism of Action: repaglinide in its clinical effects
 To increase insulin release from pancreatic B cells o Approved for use in Japan
 Sulfonylureas bind sulfonylurea receptor that is associated with a
beta-cell inward rectifier ATP-sensitive potassium channel  D-Phenylalanine Derivative
inhibits efflux of K+  depolarization  opens a voltage-gated Ca2+  Nateglinide
channel  results in Ca2+ influx and the release of preformed insulin o Stimulates rapid and transient release of insulin from
 Reduction of serum glucagon concentrations beta cells through closure of the ATP-sensitive K+ channel
Chronic administration of sulfonylureas to type 2 diabetics o May suppress glucagon release early in the meal and
reduces serum glucagon levels result in less endogenous or hepatic glucose production
 Potentiation of insulin action on target tissues o Has minimal effect on overnight or fasting blood glucose
levels
1st Generation Sulfonylureas o Ingested just prior to meals
 Tolbutamide o Absorption: within 20 minutes
 Tolazamide o Peak concentration: <1 hour
 Chlorpropamide o Metabolized by CYP2C9 & CYP3A4
 Acetohexamide o T ½: 1.5 hours
o Duration: <4 hours
2nd Generation Sulfonylureas
o S/E: Hypoglycemia (lowest)
 Glyburide o Advantage: sage in those with renal impairment & elderly
 Glipizide
 Gliclazide Drugs that Primarily Lower Glucose Levels by their Action on the Liver,
 Glimepiride Muscle & Adipose Tissue
Biguanides
DOA T½
Sulfonylurea Dosage D/I S/E  Drugs:
(Hrs.) (Hrs.)
o Metformin – The only biguanide currently available
1st Generation
Dicumarol, o Phenformin – Discontinued due to lactic acidosis
0.5-2 Phenylbutazo Skin rash,
Tolubutamide 6-12 4-5
gm/dose ne, hypoglycemia Mechanism of Action:
Sulfonamides
 Reduce hepatic glucose production through activation of the enzyme
500 mg in/
Tolazamide 10-14 7 Hypoglycemia AMP-activated protein kinase (AMPK)
doses
Hypoglycemia,  Impairment of renal gluconeogenesis
Dicumarol, jaundice,  Slowing of glucose absorption from the GIT, with increased glucose
250 mg phenylbutazo hyperemic flush, to lactate conversion by enterocytes
Chlorpropamide 60 32
daily ne, transient
sulfonamide leukopenia,  Direct stimulation of glycolysis in tissue
thrombocytopenia  With increased glucose removal from blood
Acetohexamide 8-24 4-6
0.25-0.5  Reduction of plasma glucagon levels
g/d

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Biguanides continued…..  Major site of action: adipose tissue  promotes glucose uptake and
Metabolism & Excretion: utilization and modulate synthesis of lipid hormone or cytokines and
 Half-life: 1.5-3 hours other proteins involved in energy regulation
 Duration of action: 10-12 hours  Have slow onset and offset of activity
 Not bound to plasma proteins
 Not metabolized Drugs:
 Excreted by the kidneys as active compound  Pioglitazone
 May impair the hepatic metabolism of lactic acid  Rosiglitazone
 Troglizatone – withdrawn from the market due to hepatic toxicity
Clinical Uses:
 1st line therapy for type 2 diabetes Pioglizatone Rosiglizatone
 Refractory obesity whose ↑ blood sugar is due to ineffective insulin Actions Have PPAR-α and PPAR-γ activity PPAR-γ activity
action (insulin resistance syndrome) Rapid
Absorption Within 2 hours
Highly protein bound
Only anti-diabetic drug that has been proven to reduce the
Metabolism CYP2C8 and CYP3A4 CYP2C8 & CYP2C9
complications of diabetes, as evidenced in a large study of
Dosage 15-30 mg 4-8 mg
overweight patients with diabetes (UKPDS, 1998)
Frequency o.d o.d or b.i.d
Oral contraceptive Used as monotherapy or in
 Use as in combination with sulfonylureas or thazolidinediones in Used as monotherapy or in combination with
T2DM in whom oral monotherapy is inadequate Interaction combination with sulfonylureas, sulfonylureas, metformin &
 Useful in prevention of T2DM metformin & insulin insulin
 Dosage: 500 mg TID
Advantages:
Toxicities:  Thiazolidinedione + Metformin  advantage is no hypoglycemia
 Anorexia, nausea, vomiting, abdominal discomfort, and diarrhea  Improves the biochemical and histologic features of nonalcoholic
 Interferes with the calcium-dependent absorption of vitamin B12– fatty liver disease
intrinsic factor complex in the terminal ileum  Have positive effect on endothelial function
Vitamin B12 deficiency can occur after many years of metformin
use  peripheral neuropathy, macrocytic anemia Specific Side Effects:
 Pioglitazone:
 Lactic acidosis (rare) o ↓ triglycerides
o ↑ HDL cholesterol
Contraindications: o No effect on total cholesterol and LDL cholesterol
 Renal diseases o ↓ neointimal proliferation after coronary stent
 Hepatic diseases placement
 Alcoholism  Rosiglizatone:
 Chronic cardiopulmonary dysfunction o ↑ total cholesterol, HDL cholesterol, and LDL cholesterol
o No significant effect on triglycerides
o ↓ microalbuminuria
Thiazolidinediones
 Act to decrease insulin resistance
Adverse Effects:
↑ the sensitivity of muscle, fat & liver to endogenous &
 ↑ risk of angina pectoris and MI – Rosiglitazone
exogenous insulin (“insulin sensitizers”)
 Fluid retention
 Macular edema
 They are ligands of peroxisome proliferator-activated receptor
 Loss of bone mineral density
gamma (PPAR-γ)
↑ atypical extremity bone fractures in women  due to
They bind to and activate the gamma isoform of the PPAR-γ
decreased osteoblast formation
PPAR-γ  is a member of the steroid thyroid nuclear receptor
superfamily, and is found in adipose tissue, cardiac and skeletal
muscle, liver and placenta  Anemia
 Weight gain
Observed Effects:  Bladder tumors – Pioglitazone
 ↑ GLUT-1 and GLUT-4  Fatal liver failure - Troglitazone
 ↓ free fatty acid levels
 ↓ hepatic glucose output Contraindications:
 ↑ adiponectin  Pregnancy
 ↓ release of resistin from adipocytes  Significant liver disease
 ↑ differentiation of preadipocytes to adipocytes  Heart failure
 ↓ levels of the following:
o Plasminogen activator inhibitor type 1
o Matrix metalloproteinase 9
o C-reactive protein
o IL-6

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Drugs that Affect Absorption of Glucose Glucagon-like Peptide-1 (GLP-1) Receptor Agonists
α-glucosidase inhibitors Drugs:
 Competitively inhibit the intestinal α-glucosidase enzymes  Exenatide
 Reduce post-meal glucose excursions by delaying the digestion and  Liraglutide
absorption of starch and disaccharides  lowering post-meal  Albiglutide
glycemic excursions (45-60 mg/dL) and creating an insulin-sparing  Dulaglutide
effect
Exenatide
Drugs:  Derivative of the exendin-4 peptide in Gila monster venom
 Acarbose Has 53% homology with native GLP-1 and a glycine substitution to
 Miglitol reduce degradation by DPP-4
 Voglibose – available in Japan, Korea, India
 Approved as an injectable, adjunctive therapy in persons T2DM
Action: treated with metformin or metformin + sulfonylureas who still have
 Acarbose & Miglitol suboptimal glycemic control
o Potent inhibitors of glucoamylase, α-amylase, and  Dispensed as fixed-dose pens (5 mcg and 10 mcg)
sucrase but have less effect on isomaltase and hardly any  Injected SQ within 60 minutes before breakfast and dinner
on trehalase and lactase  Given twice daily
 Peak concentration: 2 hours
Pharmacokinetics:  Duration: 10 hours
 Taken in doses of 25-100 mg just prior to ingesting the first portion  Exenatide LAR
of each meal Once-weekly preparation that is dispensed as a powder (2 mg)
 Both are absorbed from the gut
 A/E: nausea (major), ↓ HbA1c, weight loss
Adverse Effect:
 Flatulence, diarrhea, abdominal pain
Liraglutide
Contraindications:  Soluble fatty acid-acylated GLP-1 analog
 Chronic or inflammatory bowel disease  T ½: 12 hours
 Renal impairment  Once daily dosing
 Hepatic disease (Acarbose)  Approved in patients with T2DM who achieve inadequate control
with diet and exercise and are receiving concurrent treatment with
Drugs that Mimic Incretin Effect or Prolong Incretin Action metformin, sulfonylureas, or thiazolidinediones
 An oral glucose load provokes a ↑ insulin response compared with  Also approved for weight loss (3 mg daily)
an equivalent dose of glucose given IV  A/E: nausea (28%), vomiting (10%), ↓ HbA1c, weight loss
This is because the oral glucose causes a release of gut hormones
(“incretins”): Albiglutide
 GLP-1  Human GLP-1 dimer fused to human albumin
 Glucose-dependent insulinotropic peptide (GIP)  T ½: 5 days
Incretins amplify the glucose-induced insulin secretion  Steady state is reached after 4-5 weeks of once weekly
administration
 GLP-1 infusion  stimulates insulin release  ↓ glucose levels  Usual dose: 30 mg weekgly (SQ injection)
GLP-1 effect is glucose dependent in that the insulin release is  A/E: nausea, injection-site erythema, weight loss (less common)
more pronounced when glucose levels are elevated but less so
when glucose levels are normal  Therefore lower risk of Dulaglutide
hypoglycemia (compared with sulfonylureas)  Consists of two GLP-1 analog molecules covalently linked to an Fc
fragment of human IgG4
 Additional Effects of GLP-1:  It has amino acid substitutions that resist DPP-4 action
o Suppresses glucagon secretion  T ½: 5 days
o Delays gastric emptying  Usual dose: 0.75 mg weekly (SQ injection)
o Reduces apoptosis of human islets in culture  A/E: nausea, diarrhea, vomiting
o Inhibits feeding by a CNS mechanism
T2DM on GLP-1 therapy are less hungry Common Adverse Effects:
 ↑ risk of pancreatitis
 GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and
 Persistent severe abdominal pain
other enzymes such as endopeptidase 24.11
 Renal impairment
 It is cleared by the kidney Exenatide
 Acute renal injury
 Stimulate thyroidal C-cell (parafollicular) tumors (Exenatide &
Liraglutide)

Contraindications:
 Medullary thyroid cancer
 Multiple endocrine neoplasia (MEN) syndrome type 2

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Dipeptidyl Peptidase 4 (DPP-4) Inhibitors Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

Drugs:  SGLT2 accounts for 90% of glucose reabsorption
 Sitagliptin  SGLT2 inhibition causes glycosuria  ↓ glucose levels in patients
 Saxagliptin with T2DM
 Linagliptin It ↓ glucose levels by changing the renal threshold and not by
 Alogliptin insulin action
 Vildagliptin (available in Europe)
Drugs:
Sitagliptin  Canagliflozin
 Given Orally  Dapagliflozin
 100 mg, once daily  Empagliflozin
 Bioavailability: 85%
 Peak concentrations: 1-4 hours Canagliflozin
 T ½: 12 hours  ↓ the threshold for glycosuria from a plasma glucose threshold of
 Excreted in urine approximately 180 mg/dL to 70–90 mg/dL
 Hepatic metabolism is limited and mediated by:  ↓ HbA1c (0.6-1.0%) when used alone or in combination with other
o CYP3A4 oral agents or insulin
o CYP2C8  Dosage: 100 mg daily
 It is used as monotherapy and in combination with metformin,  A/E: modest weight loss (2-5 kg)
sulfonylureas, and thiazolidinediones
 ↓ HbA1c (0.5-1.0%) Dapagliflozin
 A/E: nasopharyngitis, upper respiratory infections, headaches,  ↓ HbA1c (0.5-0.8%) when used alone or in combination with other
hypoglycemia (if combined with insulin or insulin secretagogues), oral agents or insulin
acute pancreatitis, severe allergic & hypersensitivity reactions  Dosage: 10 mg daily, 5 mg (if with hepatic failure)
 A/E: modest weight loss (2-4 kg)
Saxagliptin
 Given Orally Empagliflozin
 2.5-5 mg, daily  ↓ HbA1c (0.5-0.7%) when used alone or in combination with other
 Maximum concentration: within 2 hours (4 hours- active metabolites) oral agents or insulin
 Minimally protein bound  Dosage: 10-25 mg daily
 Hepatic metabolism – CYP3A4/5  A/E: modest weight loss (2-3 kg), death from CVS cause
 Excreted renal and hepatic
 T ½: 2.5 hours (3.1 hours- active metabolites) Contraindications:
 Approved as monotherapy and in combination with biguanides,  Canagliflozin & Empagliflozin  not used if with GFR <45 mL/min per
sulfonylureas, and thiazolidinediones 1.73m2
 ↓ HbA1c (0.4-0.9%)  Dapagliflozin  not used if with GFR <60 mL/min per 1.73 m2
 A/E: ↑ rate of infections (upper respiratory and urinary tract),
headaches, hypersensitivity reactions (urticaria, facial edema), Adverse Effects:
hypoglycemia (if combined with insulin or insulin secretagogues),  ↑ genital infections & UTI
heart failure  Intravascular volume contraction & hypotension
 ↑ in LDL – Canagliflozin & Empagliflozin
Linagliptin  Breast & bladder cancer – Dapagliflozin
 ↓ HbA1c (0.4-0.6%) when added to metformin, sulfonylurea, or  ↓ bone mineral density at the lumbar spine & hip – Canagliflozin
pioglitazone  ↑ risk of fractures – Canagliflozin
 Dosage: 5 mg daily, orally  Diabetic ketoacidosis
 Primarily excreted in bile
 A/E: nasopharyngitis, hypersensitivity reactions (urticaria, OTHER HYPOGLYCEMIC DRUGS
angioedema, localized skin exfoliation, bronchial hyperreactivity), ↑ Pramlintide
risk of pancreatitis  An islet amyloid polypeptide (IAPP, amylin) analog
IAPP is a 37-amino-acid peptide present in insulin secretory
Alogliptin granules and secreted with insulin
 ↓ Hb1ac (0.5-0.6%) when added to metformin, sulfonylurea, or
pioglitazone  Has approximately 46% homology with the CGRP and physiologically
 Dose: 25 mg daily, orally acts as a negative feedback on insulin secretion
 A/E: Hypersensitivity reactions (anaphylaxis, angioedema, Stevens-
Johnson syndrome), hepatic failure Effects:
 Reduces glucagon secretion, slows gastric emptying by a vagally
Vildagliptin mediated mechanism, and centrally decreases appetite
 ↓ HbA1c (0.5-1.0%) when added to the therapeutic regimen of
patients with T2DM Clinical Use:
 Dosage: 50 mg orally, once or twice daily  Approved for use in insulin-treated type 1 and type 2 patients who
 A/E: upper respiratory infections, nasopharyngitis, dizziness, and are unable to achieve their target postprandial blood glucose levels
headache, hepatitis

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Pramlintide continued…..  Mediterranean-style eating pattern  a diet supplemented with

 Rapidly absorbed after SQ injection before eating walnuts, almonds, hazelnuts, and olive oil
 Peak level: 20 minutes It has been shown to improve glycemic control and lower
 Duration: <150 minutes combined endpoints for cardiovascular events and stroke
 Metabolized & excreted renally
 Modulated postprandial glucose levels in T1DM & T2DM  Caloric restriction and weight loss is an important goal for the obese
patient with type 2 diabetes
Adverse Effects:
 Hypoglycemia Education
 Nausea & vomiting  The patient should be informed about the kind of diabetes he or she
 Anorexia has and the rationale for controlling the glucose levels
 Self-monitoring of glucose levels should be emphasized, especially if
Colesevelam Hydrochlorine the patient is on insulin or oral secretagogues that can cause
hypoglycemia
 Bile acid sequestrant
 The patient on insulin therapy should understand the action profile
 A cholesterol-lowering drug
of the insulins
 He or she should know how to determine if the basal insulin dose is
Clinical Use:
correct and how to adjust the rapidly acting insulin dose for
 Approved as an antihyperglycemic therapy for persons with T2DM
carbohydrate content of meals
who are taking other medications or have not achieved adequate
 Insulin adjustments for exercise and infections should be discussed
control with diet and exercise
 The patient and family members also should be informed about the
signs and symptoms of hypoglycemia
Mechanism of Action:
 Presumed to involve an interruption of the enterohepatic circulation
Glycemic Targets
and a ↓ in farnesoid X receptor (FXR) activation
 The American Diabetes Association criteria for acceptable control
FXR is a nuclear receptor with multiple effects on cholesterol,
glucose, and bile acid metabolism. Bile acids are natural ligands include:
of the FXR o HbA1c of less than 7% (53 mmol/mol)
o Pre-meal glucose levels of 90–130 mg/dL (5–7.2 mmol/L)
 It may also impair glucose absorption o <180 mg/dL (10 mmol/L) one hour and 150 mg/dL (8.3
 ↓ HbA1c (0.3-0.5%) mmol/L) two hours after meals
 While the HbA1c target is appropriate for individuals treated with
Adverse Effects: lifestyle interventions and euglycemic therapy, it may need to be
 Constipation modified for individuals treated with insulin or insulin secretagogues
due to their increased risk of hypoglycemia
 Indigestion
 Flatulence  Less stringent blood glucose control also is appropriate for children
as well as patients with a history of severe hypoglycemia, limited life
 Exacerbate hypertriglyceridemia
expectancy, and significant microvascular and macrovascular
disease. For the elderly frail patient an HbA1c greater than 8% may
Bromocriptine be appropriate
 Dopamine agonist
 ↓ HbA1c (0-0.2%) Treatment
 The mechanism by which it lowers glucose levels is not known  Treatment must be individualized on the basis of the type of diabetes
and specific needs of each patient
Adverse Effects:
 Nausea Type 1 Diabetes
 Fatigue  At least 3 or 4 insulin injections a day are necessary for safe and
 Dizziness effective control of glucose levels
 Vomiting  A combination of rapidly acting insulin analogs and long-acting
 Headache insulin analogs allow for more physiologic insulin replacement

MANAGEMENT OF THE PATIENT WITH DIABETES Type 2 Diabetes

Diet
 A well-balanced, nutritious diet remains a fundamental element of
therapy for diabetes
 It is recommended that the macronutrient proportions
(carbohydrate, protein, and fat) be individualized based on the
patient’s eating patterns, preferences, and goals
 Limiting the carbohydrate intake and substituting some of the
calories with monounsaturated fats, such as olive oil, rapeseed
(canola) oil, or the oils in nuts and avocados, can lower triglycerides
and increase HDL cholesterol
 Normalization of glucose levels can occur with weight loss and
improved insulin sensitivity in the obese patient with T2DM
 A combination of caloric restriction and increased exercise is
necessary if a weight reduction program is to be successful
 Non-obese patients with T2DM frequently have ↑ visceral
adiposity—the so-called metabolically obese normal weight patient
There is less emphasis on weight loss in such patients, but
exercise is important

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Type 2 Diabetes Treatment continued….. Treatment:

 Hypoglycemia:
o Glucose administration
 DKA:
o IV hydration
o Insulin therapy
o Maintenance of K+ and other electrolyte levels
 HHS:
o Rehydration
o Restoration of glucose
o Electrolyte homeostasis

Chronic Complications of Diabetes

 Pathologic changes that involve:
o Small and large blood vessels
o Cranial and Peripheral nerves
o Skin
Figure Above: Suggested algorithm for the treatment of type 2 diabetes o Lens of the eye
The seven main classes of agents are metformin, sulfonylureas (includes  These lesions lead to:
nateglinide, repaglinide), pioglitazone, GLP-1 receptor agonists, DPP-4 o Hypertension
inhibitors, SGLT2 inhibitors, insulins. o End-stage chronic kidney disease
α-Glucosidase inhibitors, colesevelam, pramlintide, and bromocriptine NOT o Blindness, autonomic and peripheral neuropathy
included because of LIMITED EFFICACY and SIGNIFICANT ADVERSE EFFECTS o Amputations of the lower extremities
o Myocardial infarction
Acute Complications of Diabetes o Cerebrovascular accidents
 Hypoglycemia
 In patients with type 1 diabetes, complications from end-stage
Are the most common complication of insulin therapy. It can also chronic kidney disease are a major cause of death
occur in any patient taking oral agents that stimulate insulin
 In patients with type 2 diabetes, they are more likely to have
secretion (eg, sulfonylureas, meglitinide, d-phenylalanine
analogs), particularly if the patient is elderly, has renal or liver macrovascular diseases leading to myocardial infarction and stroke
disease, or is taking certain other medications that alter as the main causes of death
metabolism of the sulfonylureas (eg, phenylbutazone, Cigarette use adds significantly to the risk of both microvascular
sulfonamides, warfarin). It occurs more frequently with the use of and macrovascular complications in diabetic patients
long-acting sulfonylureas

 Diabetic Coma References:

o Diabetic Ketoacidosis  Basic & Clinical Pharmacology by Katzung
Diabetic ketoacidosis (DKA) is a life-threatening (14th ed.)
medical emergency caused by inadequate or absent  Pharmacology Lecture Guide (2020)
insulin replacement, which occurs in people with type
1 diabetes and infrequently in those with type 2
diabetes. It typically occurs in newly diagnosed type 1
patients or in those who have experienced
interrupted insulin replacement, and rarely in people
with type 2 diabetes who have concurrent unusually
stressful conditions such as sepsis or pancreatitis or
are on high-dose steroid therapy

o Hyperosmolar Hyperglycemic Syndrome

Hyperosmolar hyperglycemic syndrome (HHS) is
diagnosed in persons with type 2 diabetes and is
characterized by profound hyperglycemia and
dehydration. It is associated with inadequate oral
hydration, especially in elderly patients; with other
illnesses; with the use of medication that elevates the
blood sugar or causes dehydration, such as phenytoin,
steroids, diuretics, and calcium channel blockers; and
with peritoneal dialysis and hemodialysis. The
diagnostic hallmarks are declining mental status and
even seizures, a plasma glucose >600 mg/dL, and a
calculated serum osmolality >320 mmol/L
Persons with HHS are NOT acidotic unless DKA is also
present

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PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

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