THYROID AND ANTITHYROID

DRUGS

 Two major thyroid hormones: •

Triiodothyronine (T3)

the most active form (is about 10 times more

potent than T4)
 Thyroxine (T4)
peroxidase to iodine
3. Tyrosine in thyroglobulin is iodinated and forms
-The thyroid gland also secretes the hormone
MIT & DIT
CALCITONIN
4. Iodotyrosines condensation MIT+DIT→T3;
- a serum calcium-lowering hormone
DIT+DIT→T4
Although the thyroid gland is not essential for life,
THYROID HORMONE SYNTHESIS AND SECRETION
inadequate or excessive secretion of thyroid
hormone can result to adverse reactions.
Antibodies to thyroid peroxidase are diagnostic for
Hashimoto's thyroiditis.
• Hypothyroidism (Low)
• chronic lymphocytic thyroiditis
• Hyperthyroidism (High)
• an autoimmune disease in which the thyroid
gland is attacked by a variety of
THYROID HORMONE SYNTHESIS AND SECRETION
cell- and antibody-mediated processes
1. Iodide (I ) uptake
Regulation of secretion:
2. Oxidation to iodine (I2) by a peroxidase
• Hypothalamic TRH (thyrotropin-releasing
3. Iodination of tyrosines on thyroglobulin. (iodine
hormone )
organification)
• Secretion of thyroid-stimulating hormone (TSH;
4. Condensation of two diiodotyrosine residues
thyrotropin) by the anterior pituitary
gives rise to T4
5. Condensation of a monoiodotyrosine residue
with a diiodotyrosine residue generates T3, which
is still bound to the protein.
6. The hormones are released following proteolytic
cleavage of the thyroglobulin.

Synthesis of thyroid hormones Thyroid hormones

triiodothyronine (T3)
tetraiodothyronine (T4, thyroxine)

Materials
Regulation of secretion:
iodine & tyrosine
• The hypothalamus releases a hormone called
Steps
thyrotropin releasing hormone (TRH)
1. Iodide is trapped by sodium-iodide symporter
2. Iodide is oxidized by
• TRH sends a signal to the pituitary to release
thyroidal
thyroid stimulating hormone (TSH).
• In turn, TSH sends a signal to the thyroid to
release thyroid hormones.
• Most of the hormone (T3 and T4) is bound to
thyroxine-bindingglobulin in the plasma.
• It must dissociate from thyroxine-binding plasma
proteins
• Thyrotropin stimulates the uptake of iodide as
well as synthesis and release of thyroid hormone.
• It also has a growth-promoting effect that causes
thyroid cell hyperplasia and an enlarged gland
(goiter).
THYROID HORMONE
Mechanism of action:
• T4 is enzymatically deiodinated to T3, which
enters the nucleus and attaches to specific
receptors.
Pharmacokinetics:
• Both T4 and T3 are absorbed after oral
administration.
• Food, calcium preparations, and aluminum-
containing antacids can decrease the absorption of
T4 but not of T3.
HYPOTHYROIDISM
There are three types of hypothyroidism:
• Primary
• Secondary
• Tertiary
Primary Hypothyroidism
•Due to a defect in the gland, the thyroid cannot
make enough T3 and T4
•The most common cause of primary
hypothyroidism in the United States is the
destruction of the thyroid gland by the immune
system (Hashimoto’s thyroiditis)
Other causes include:
• certain drugs such as lithium
• radiation exposure to the neck
• radioactive iodine used for treatment of
hyperthyroidism
• special x-ray dyes
• surgical removal of part or all of the thyroid gland
• some women develop after pregnancy
(postpartum thyroiditis)
Secondary Hypothyroidism
•the thyroid gland produces too little hormone due
to disorders of the pituitary gland (i.e. pituitary
hypothyroidism)
Tertiary Hypothyroidism
•Tertiary hypothyroidism is caused by disorders of

Physiological actions of thyroid hormones

To normalize growth and development, body

temperature, and energy levels
▲Insufficiency→ cretinism (infant & child), and
myxedema (adult);
▲Excess→hyperthyroid

-To enhance CNS excitability & sensitivity of CVS to

NA the hypothalamus

#T3 is 3 to 4 times more potent than T4 in heat Early Symptoms

production; • Cold intolerance
# T4 in colloid is about 4 times more numerous • Depression
than T3 ; • Muscle or joint pain
• Paleness • Abnormal secretion of TSH
• Thin, brittle hair and fingernails • Thyroiditis (inflammation of the thyroid
• Dry, itchy skin
gland)
• Weight gain and water retention
- Constipation • Excessive iodine intake
- Fatigue
- Weakness Graves' Disease
• Caused by a generalized overactivity of
TREATMENT: the thyroid gland
• Treatment is to replace the thyroid hormone that
• an autoimmune disorder wherein the B
is lacking
• It is treated with levothyroxine (T4) lymphocytes produce an antibody that
• T3 (liothyronine) is faster acting but has a shorter activates the TSH receptor and can cause
half-life and is more expensive thyrotoxicosis.
• T4 is used most often, but a combination of T4
and T3 is also used • The most common cause of
•Receive the lowest dose that relieves symptoms
hyperthyroidism
and brings blood tests to a normal range
•Periodic monitoring of TSH levels • Triggers: stress, smoking, radiation to the
•Requires life-long therapy, can be completely neck, medications, and infectious organisms
controlled with early treatment such as viruses.

TOXICITY: Symptoms:
• thyrotoxicosis
• Excessive sweating
•Older patients, those with cardiovascular disease,
and those with longstanding hypothyroidism are - Weight loss
highly sensitive to the stimulatory effects of T4 on • Heat intolerance
the heart. • Increased bowel movement
•Such patients should receive lower initial doses of • Tremor (usually fine shaking)
T4. • Nervousness, agitation
• Decreased concentration
HYPERTHYROIDISM
• Irregular and scant menstrual flow
- Fatigue
Hyperthyroidism is a condition in which an
overactive thyroid gland is producing an
Treatment:
excessive amount of thyroid hormones that
• Treating the symptoms • Antithyroid
circulate in the blood.
drugs
•Thyrotoxicosis is a toxic condition that is
• Radioactive iodine
caused by an excess of thyroid hormones
• Surgery
from any cause.

Causes:
• Graves' Disease
• Functioning adenoma ("hot nodule") and
Toxic Multinodular Goiter (TMNG)
• Excessive intake of thyroid hormones

Inhibition of the synthesis of T3 & T4
Mechanism
All thioamides inhibit peroxidase-catalyzing
reactions
Iodine organification-iodination of the
tyrosine residues of thyroglobulin
Iodotyrosines condensation-coupling of DIT
and MIT
Propylthiouracil (first choice for thyroid
crisis ) and, to a much lesser extent,
methimazole also inhibit T4 converting to
T3
Characteristics
1 Result appears slowly: in 3-4 w
hyperthyroid ameliorated, and in 2-3
months BMR normalized;
2 Long-term use leads to thyroid
hyperplasia
3 Methimazole is 10 times as potent as
propylthiouracil
THIOAMIDES
• The thioamides can be used by the oral
route and are effective in young patients
with small glands and mild disease.
• Methimazole is generally preferred
because it can be administered once per
day.
• PTU is preferred in pregnancy because it
is less likely than methimazole to cross the
placenta and enter breast milk.
Clinical use
treatment of hyperthyroid
1. Mild hyperthyroid and those surgery &
131I not permitted;
2. Operation preparation;
3. Thyroid crisis (comprehensive therapy).
Adverse reactions
1. Long-term use leads to thyroid
hyperplasia;
2. Pruritic maculopapular rash is the most
common
adverse raaction
3. The severe adverse reaction is
agranulocytosis, vasculitis,
hypoprothrombinemia, and liver
dysfunction.
IODIDE SALTS AND IODINE
Raising the plasma iodide concentration to
a level above 5 μg/dl results in a complete
& temporary inhibition of iodide
organification by the thyrotoxic gland.
• The usual forms of this drug are Lugol’s
solution (iodine and potassium iodide) and
saturated solution of potassium iodide.
Iodides (NaI, KI)
Pharmacological action
Inhibition of T3 & T4 release and synthesis
Decrease of size & vascularity of the
hyperplastic gland
Clinical use
Ministrant treatment of hyperthyroid 1.
Operation preparation;
2. Thyroid crisis.
Adverse reactions
1. Acneiform rash (similar to that of
bromism);
2. Swollen salivary glands, mucous
membrane ulcerations
 3. drug fever, metallic taste, bleeding
disorders, and, rarely, anaphylactic
reactions
RADIOACTIVE IODINE
131I is the only isotope for treatment of
thyrotoxicosis.
• Its therapeutic effect depends on emission
of β rays with an effective half-life of 5 days
& a penetration range of 0.4-2 mm.
• CI: woman in pregnancy or lactation.
• The radioactive iodine is picked up by the
active cells in the thyroid and destroys
them. Since iodine is only picked up by
thyroid cells (and picked up more readily by
over-active thyroid cells), the destruction is
local, and there are no widespread side
effects with this therapy.
• Unlike the thioamides and iodide salts, an
effective dose of 131I can produce a
permanent cure of thyrotoxicosis without
surgery.
ANION INHIBITORS
• thiocyanate (SCN−) and perchlorate
(ClO4−)
• MOA: block the uptake of iodide by the
thyroid gland through
competitive inhibition of the iodide
transporter
• Their effectiveness is unpredictable and
ClO4− can cause aplastic anemia, so these
drugs are rarely used clinically.
BETA BLOCKERS
• βblockers are effective in treatment of
thyrotoxicosis.
• useful in controlling the tachycardia and
other cardiac abnormalities of severe
thyrotoxicosis
• Propranolol is the most widely studied
and used.
• Propranolol also inhibits the peripheral
conversion of T4 to T3.
• Nonselective beta blockers such as
propranolol (Inderal) should be prescribed
for symptom control because they have a
more direct effect on hypermetabolism.
• 10 to 20 mg every six hours
AMIODARONE
•Iodine-containing antiarrhythmic drug
• can cause hypothyroidism through its
ability to block the peripheral conversion of
T4 to T3
•It also can cause hyperthyroidism either
through an iodine-induced mechanism in
persons with an underlying thyroid disease
such as multinodular goiter or through an
inflammatory mechanism that causes
leakage of thyroid hormone into the
circulation.
•Amiodarone-associated hypothyroidism is
treated with thyroid hormone.
•Iodine-associated hyperthyroidism caused
by amiodarone is treated with thioamides,
whereas the inflammatory version is best
treated with corticosteroids.
RADIOCONTRAST MEDIA
•Iodinated radiocontrast media
•Oral diatrizoate and Intravenous Iohexol
• rapidly suppress the conversion of T4 to
T3 in the liver, kidney, and other peripheral
tissues
<<<<END OF TRANSCRIPT FOR THYROID>>>
DIABETES MELLITUS

Pancreas
-Consists of approximately 1 million
-Four hormone-producing cells are present

Pancreatic Hormones
1. Insulin
2. Islet Amyloid Polypeptide 3. Glucagon
4. Somatostatin
5. Gastrin
6. Pancreatic polypeptide (PP)
Diabetes Mellitus
It is defined as an elevated blood glucose
associated with absent or inadequate
pancreatic insulin secretion, with or
without concurrent impairment of insulin
action.
Four Categories of Diabetes Mellitus:
Type I, Type II , Type III , Type IV
1. Insulin-Dependent Diabetes Mellitus
(IDDM): pancreatic B cell destruction
(immune-mediated in most cases)
2. Non-Insulin-Dependent Diabetes
Mellitus (NIDDM): >90%, defects of insulin
secretion and action, insulin resistance.
Type 1 Diabetes Mellitus (10-15%)
– results when the body’s immune system
destroys its own beta cells in the pancreas.
No insulin production is then possible.
Type 2 Diabetes Mellitus (85-90%) results
from either insulin resistance
(overweight people) or inadequate insulin
production (lean people) or a combination
of both
Gestational Diabetes
– Diabetes diagnosed during pregnancy
– Carbohydrate intolerance with onset or
first recognition during pregnancy.
– Increased health risk to mother and baby
– May require insulin injections
– Goes away after birth, but increased risk
of developing Type 2 DM for mother and
child
What is Insulin Resistance?
– condition in which the body does not
utilize
insulin efficiently
– Insulin resistance is the decreased
response of the liver and peripheral tissues
(muscle, fat) to insulin
– Insulin resistance is a primary defect in
the majority of patients with Type 2
diabetes
TYPE 1 DIABETES MELLITUS
• The disease is characterized by an
absolute deficiency of insulin caused by
massive β-cell necrosis.
• Type 1 diabetic shows classic symptoms of
insulin deficiency (polydipsia, polyphagia,
polyuria, and weight loss).
Treatment:
• A Type 1 diabetic must rely on exogenous
(injected) insulin to control hyperglycemia,
avoid ketoacidosis, and maintain acceptable
levels of glycosylated hemoglobin (HbA1c).
Glycosylated Hemoglobin (HbA1c)
– HbA1c is a measure of the average blood
glucose
level over the previous 2 – 3 months
– It measures how much glucose is attached
to the hemoglobin on red blood cells
– It is expressed as a percentage, not
mmol/l ie HbA1c and BGL are two different
measurements
– Normal HbA1c is 4 - 6%
– with diabetes aim for ≤ 7%
Clinical Manifestations:
– Polyuria – increased urine
– Polydipsia – increased thirst
– Polyphagia – increased hunger
– Weight loss
– Fatigue
– Nausea, vomiting
– Ketoacidosis may be a presenting sign
TYPE 2 DIABETES MELLITUS
• The disease is influenced by genetic
factors, aging, obesity, and peripheral
insulin resistance.
• In Type 2 diabetes, the pancreas retains
some β-cell function, but variable insulin
secretion is insufficient to maintain glucose
homeostasis
Treatment Goal
– to maintain blood glucose
concentrations within normal limits
– to prevent the development of long- term
complications of the disease.
Treatment
– Weight reduction
– Exercise
– Dietary modification
– Oral hypoglycemic drugs
– As the disease progresses, β-cell function
declines, and insulin therapy is often
required to achieve satisfactory serum
glucose levels.
Clinical Manifestations:
– Polydipsia – increased thirst
– Polyuria – increased urine
– Polyphagia – increased hunger – Fatigue
– Blurred vision
– Slow healing
– infections
– Impotence in men
INSULIN & ITS ANALOGS
• Insulin is a polypeptide hormone
consisting of two peptide chains that are
connected by disulfide bonds.
• It is synthesized as a precursor (pro-
insulin) that undergoes proteolytic cleavage
to form insulin and C peptide.
• Pro-insulin
– 86-amino-acid single-chain polypeptide
– Cleavage result in the 2-chain 51-peptide
insulin molecule and a 31-amino-acid
residual C-peptide
• Normal person = low-level of precursor
• Type II = high level of precursor
• Secretion is regulated by blood, amino
acids, other hormones, autonomic
mediators
Glucose is taken up causing increased in
ATP, blocking K channels and influx of Ca
which leads to insulin release
From specials strains of E. Coli or yeast
(recombinant DNA technology)
• Not administered orally
• Generally administered SC
• Continuous insulin infusion
Mechanism of Action:
– When activated by the hormone, the
insulin receptor, a transmembrane tyrosine
kinase, phosphorylates itself and a variety
of intracellular proteins when activated by
the hormone.
Effects (Liver)
– Insulin increases the storage of glucose as
glycogen in the liver.
– This involves the insertion of additional
GLUT2 glucose transport molecules in cell
plasma membranes; increased synthesis of
the enzymes pyruvate kinase,
phosphofructokinase, and glucokinase; and
suppression of several other enzymes.
– Insulin also decreases protein catabolism.
Effects (Skeletal Muscle)
– Insulin stimulates glycogen synthesis and
protein synthesis.
– Glucose transport into muscle cells is
facilitated by insertion of GLUT4
transporters into cell plasma membranes.
Effects (Adipose Tissue)
– Insulin facilitates triglyceride storage by
activating plasma lipoprotein lipase,
increasing glucose transport into cells via
GLUT4 transporters, and reducing
intracellular lipolysis.
Rapid onset & ultra-short acting
– Regular insulin
– Insulin lispro
– Insulin aspart
– Insulin glulisine
• Regular insulin, insulin lispro, and insulin
aspart are pregnancy category B.
• Insulin glulisine has not been studied in
pregnancy
Insulin Preparations:
– Rapid-acting: e.g. insulin lispro, insulin
aspart, and insulin glulisine
– Short-acting: e.g. Regular insulin
– Intermediate-acting: e.g. Neutral
protamine Hagedorn insulin (NPH insulin)
– Long-acting: e.g. Insulin glargine and
insulin detemir
Rapid onset & ultra-short acting
– have rapid onsets and early peaks of
activity that permit control of postprandial
glucose levels
– have small alterations in their primary
amino acid sequences that speed their
entry into the circulation without affecting
their interaction with the insulin receptor
– The rapid-acting insulins are injected
immediately before a meal and are the
preferred insulin for continuous
subcutaneous infusion devices.
– They also can be used for emergency
treatment of uncomplicated diabetic
ketoacidosis.
Rapid onset & ultra-short acting
• Lispro = 15 minutes before a meal or
immediately after a meal
• Glulisine = 15 minutes before or within 20
minutes after starting a meal
• Aspart = just prior to meal
• Peak levels of lispro are seen 30-90
minutes
• Peak levels of regular are seen 50-120
minutes
Short acting
– Regular insulin is used intravenously in
emergencies or administered with
intermediate- or long-acting preparations.
– Before the development of rapid-acting
insulins, it was the primary form of insulin
used for controlling postprandial glucose
concentrations, but it requires
administration 1 h or more before a meal.
ordinary maintenance regimens,
subcutaneously in alone or mixed
Intermediate-acting
– Neutral protamine Hagedorn insulin (NPH
insulin) is a combination of regular insulin
and protamine.
– exhibits a delayed onset and peak of
action
– NPH insulin is often combined with
regular and rapid-acting insulins.
– Lente insulin – amorphous precipitate of
insulin with zinc ion in acetate buffer
combined with 70% ultralente insulin
– Isophane NPH (Neutral protamine
Hagedorn) – suspension of crystalline zinc
insulin combined at a neutral pH with
protamine
– NPH insulin should only be given
subcutaneously (never intravenously)
Prolonged acting
– Ultralente insulin – susp of zinc insulin
crystals in
acetate buffer
– Insulin glargine
– Insulin detemir
– Insulin glargine and insulin detemir are
modified forms of human insulin that
provide a peakless basal insulin level lasting
more than 20 h, which helps control basal
glucose levels without producing
hypoglycemia.
INSULIN & ITS ANALOGS
Combinations
– 70% NPH + 30% regular or 50% each
– 75% NPL (neutral protamine lispro)+ 25%
lispro
Insulin delivery systems
– The standard mode of insulin therapy is
subcutaneous injection with conventional
disposable needles and syringes.
– Portable pen-sized injectors are used to
facilitate subcutaneous injection.
– Continuous subcutaneous insulin infusion
devices avoid the need for multiple daily
injections and provide flexibility in the
scheduling of patients’ daily activities.
Adverse effect
– Hypoglycemia
– Lipodystrophy
– Allergic reactions
Hazards of Insulin Use
– The most common complication is
hypoglycemia, resulting from excessive
insulin effect.
– To prevent the brain damage that may
result from hypoglycemia, prompt
administration of glucose (sugar or candy
by mouth, glucose by vein) or of glucagon
(by intramuscular injection) is essential.

– The most common form of insulin-
induced immunologic complication is the
formation of antibodies to insulin or
noninsulin protein contaminants, which
results in resistance to the action of the
drug or allergic reactions.
SYNTHETIC AMYLIN ANALOG
• Pramlintide
– Administered by subcutaneous injection
– should be injected immediately prior to
meals
– It is used in combination with insulin to
control postprandial glucose levels.
– When pramlintide is initiated, the dose of
rapid- or short-acting insulin should be
decreased by 50% prior to meals to avoid a
risk of severe hypoglycemia.
• Mechanism of Action
– Amylin contributes to glycemic control by
activating high-affinity receptors that are a
complex of the calcitonin receptor and a
receptoractivity modifying receptor (RANK).
– Pramlintide suppresses glucagon release,
slows gastric emptying, and works in the
CNS to reduce appetite.
• Toxicity
– hypoglycemia
– gastrointestinal disturbances
ORAL HYPOGLYCEMICS
• Insulin Secretagogues
- Sulfonylureas
– Meglitinide Analogs
• Insulin Sensitizers
– Biguanides
– Thiazolidenediones/Glitazones
• α-Glucosdase Inhibitors
• Dipeptidyl Peptidase-IV Inhibitors
• Incretin Mimetics
SULFONYLUREAS
Tolbutamide,Glyburide, Glipizide,
Chlorpropamide, Glimepiride
• MOA
– Stimulation of insulin release
– Reduction in hepatic glucose production –
Increase in peripheral insulin sensitivity
– Insulin secretagogues stimulate the
release of endogenous insulin by promoting
closure of potassium channels in the
pancreatic B- cell membrane
– Channel closure depolarizes the cell and
triggers insulin release.
– Insulin secretagogues are not effective in
patients who lack functional pancreatic B
cells.
Pharmacokinetics
– Given orally, bind to serum proteins,
metabolized by the liver, excreted by the
liver & kidney
– Tolbutamide – has the shortest duration
of action
– The second-generation sulfonylureas
(glyburide, glipizide, glimepiride) are
considerably more potent and used more
commonly than the older agents.
• Adverse effects
– Weight gain
– rash or other allergic reactions
– Hyperinsulinemia
– Hypoglycemia
– Can cross the placenta (except Glyburide)
– CI to liver or renal failure
– The older sulfonylureas (tolbutamide and
chlorpropamide) are extensively bound to
serum proteins
MEGLITINIDE ANALOGS
• Repaglinide, nateglinide
• D-phenylalanine derivative
• MOA
– Bind to a distinct site on the sulfonylurea
receptor
– Have rapid onset of action and short
duration of action
– Postprandial glucose regulators
–Meglitinides should not be used in
combination with sulfonylureas.
• Pharmacokinetics
– Well absorbed orally from 1-30 minutes
before meals
– Metabolized to inactive metabolites and
excreted in the bile
• Adverse effects
– Hypoglycemia*
– Ketoconazole, itraconazole, fluconazole
erythromycin, clarythromycin - inhibit
CYP3A4
– Barbiturates, rifampin, carbamazepine –
induce CYP3A4
– Severe hypoglycemia has been reported
with gemfibrozil
BIGUANIDES
Metformin is the primary member of the
biguanide group EUGLYCEMIA
• Does not promote insulin secretion
• reduces postprandial and fasting glucose
levels
• stimulates glucose uptake and glycolysis
in peripheral tissues
• reduces glucose absorption from the
gastrointestinal tract
• decreases of plasma glucagon levels
• Mechanism of Action
– Reduces hepatic glucose output by
inhibiting gluconeogenesis
– The molecular mechanism of biguanide
reduction in hepatic glucose production
appears to involve activation of an AMP-
stimulated protein kinase.
– Also slows intestinal absorption of sugars
– In patients with insulin resistance,
metformin reduces endogenous insulin
production presumably through enhanced
insulin sensitivity.
– metformin is increasingly the drug of first
choice in overweight patients with type 2
diabetes.
• Reduces hyperlipidemia
• The ADA treatment algorithm
recommends metformin as the drug of
choice for newly diagnosed Type 2
diabetics.
• Metformin is also used to restore fertility
in anovulatory women with polycystic ovary
disease (PCOD) and evidence of insulin
resistance.
• Pharmacokinetics:
– Absorbed orally, not protein bounded and
metabolized, excreted in the urine
– Adverse effects are on the GI (nausea,
diarrhea)
– CI to diabetics with renal/hepatic failure,
cardiac/ respiratory insufficient, ROH abuse,
severe infection & pregnancy (can cause
lactic acidosis)
THIAZOLIDINEDIONES/ GLITAZONES
• Troglitazone*, Pioglitazone, Rosiglitazone
Mechanism of Action
– Target the PPAR-γ (peroxisome
proliferator– activated receptor-γ) resulting
in insulin sensitivity in adipose tissue, liver
and skeletal muscle
– This nuclear receptor regulates the
transcription of genes encoding proteins
involved in carbohydrate and lipid
metabolism.
• Effects
– increases glucose uptake in muscle and
adipose tissue
– inhibit hepatic gluconeogenesis and have
effects on lipid metabolism and the
distribution of body fat
– Corrects hyperglycemia, hyperTAGemia,
hyperinsulinemia and elevated HbA1C
levels
– HDL increase in both drugs
– Thiazolidinediones reduce both fasting
and postprandial hyperglycemia.
– Like metformin, the thiazolidinediones
have been shown to reduce the risk of
diabetes in high-risk patients.
• Pharmacokinetics
– Absorbed orally, bounded to plasma
protein, metabolized by the liver, excreted
in the urine (parent compound-bile)
– Possible hepatotoxicity may occur,
headache, anemia, weight increase
– Not taken by nursing mothers
• Toxicity
– hypoglycemia is extremely rare
– can cause fluid retention, which presents
as mild anemia and edema and may
increase the risk of heart failure
– increased risk of myocardial infarction
(Rosiglitazone)
– hepatotoxicity (Troglitazone)
– Female patients taking thiazolidinediones
appear to have an increased risk of bone
fractures.
– Pioglitazone and troglitazone, but not
Rosiglitazone, induce cytochrome P450
activity (especially the 3A4 isozyme) and
can reduce the serum concentrations of
drugs that are metabolized by these
enzymes (eg, oral contraceptives,
cyclosporine).
α GLUCOSIDASE INHIBITORS
• ACARBOSE & MIGLITOL are carbohydrate
analogs that act within the intestine to
inhibit alpha- glucosidase
• Delay CHO digestion
• α-glucosidase is responsible for the
hydrolysis of oligosaccharides to glucose
and other sugars.
• Taken at the beginning of meals
• postprandial hyperglycemia is reduced by
these drugs
• Acarbose also inhibits α-amylase
• Do not increase insulin release or action
• These drugs lack an effect on fasting blood
sugar.
• Acarbose
– Poorly absorbed, metabolized by
intestinal bacteria, some are excreted in the
urine
• Miglitol
– very well absorbed and excreted
unchanged in the urine
• Toxicities
– flatulence, diarrhea, cramping or
abdominal pain resulting from increased
fermentation of unabsorbed carbohydrate
by bacteria in the colon
– CI to inflammatory bowel disease, colon
ulceration, intestinal obstruction
– Decrease bioavailability of metformin
– Patients taking an α-glucosidase inhibitor
who experience hypoglycemia should be
treated with oral glucose (dextrose) and not
sucrose, because the absorption of sucrose
will be delayed.
DIPEPTIDYL PEPTIDASE IV INHIBITOR
• Sitagliptin
• inhibits the enzyme DPP-IV, which is
responsible for the inactivation of incretin
hormones, such as glucagon-like peptide-1
(GLP-1).
• It is approved for use in type 2 diabetes as
monotherapy or in combination with
metformin or a thiazolidinedione.
• Sitagliptin promotes insulin release,
inhibits glucagon secretion, and has an
anorexic effect.
• Well absorbed after oral administration
• Food does not affect the extent of
absorption.
• Excreted unchanged in the urine
• Dosage adjustments are recommended
for patients with renal dysfunction.
• The most common adverse effects being
nasopharyngitis, headache, and upper
respiratory tract infection.
INCRETIN MIMETICS
• Exenatide
• Incretin
– Group of GI hormones that cause an
increase in the amount of insulin
released from the beta cells after eating,
even before blood glucose become
elevated.
– Inhibit glucagon release
• Glucagon-like peptide-1 (GLP-1) is a
member of the incretin family of peptide
hormones
• The GLP-1 receptor is a G protein- coupled
receptor (GPCR) that increases cAMP and
also increases the free intracellular
concentration of calcium.
• Exenatide, a long-acting injectable
peptide analog of GLP-1, is used in
combination with metformin or a
sulfonylurea for treatment of type 2
diabetes.
• 50% homologous to GLIP-1
• Effects
– Improves insulin secretion
– Slows gastric emptying time
– Decreases food intake
– Increase glucose suppression of glucagon
release
– Promote B-cell regeneration
– Admin. SC
• Toxicity
– gastrointestinal disturbances, particularly
nausea during initial therapy
– hypoglycemia when exenatide is
combined with a sulfonylurea
– The drug has also caused serious and
sometimes fatal acute pancreatitis.
TREATMENT OF TYPE 1 DIABETES
MELLITUS
• Dietary instruction
• Parenteral insulin
• Pramlintide
• Careful attention by the patient to factors
that change insulin requirements: exercise,
infections, other forms of stress, and
deviations from the regular diet.
• Because type 2 diabetes is usually a
progressive disease, therapy for an
individual patient generally escalates over
time.
• It begins with weight reduction and
dietary control.
• Initial drug therapy usually is oral
monotherapy with metformin.
• Noninsulin antidiabetic agents are being
used in combination with each other or
with insulin to achieve better glycemic
control and minimize toxicity.
• Because type 2 diabetes involves both
insulin resistance and inadequate insulin
production, it makes sense to combine an
agent that augments insulin’s action
(metformin, a thiazolidinedione, or an α-
glucosidase inhibitor) with one that
augments the insulin supplies (insulin
secretagogue or insulin).
– Glucagon increases heart rate and force of
contraction, increases hepatic
glycogenolysis and gluconeogenesis, and
relaxes smooth muscle. The smooth muscle
effect is particularly marked in the gut.
• Glucagon is used to treat severe
hypoglycemia in diabetics, but its
hyperglycemic action requires intact hepatic
glycogen stores.
• It is given intramuscularly or
intravenously.
• In the management of severe β-blocker
overdose, glucagon may be the most
effective method for stimulating the
depressed heart because it increases
cardiac cAMP without requiring access to β
receptors
<<<<<<<END OF TRANSCRIPT FOR DM>>>>

• Long-acting drugs (sulfonylureas,

metformin, thiazolidinediones, exenatide,
sitagliptin, some insulin formulations) help
control both fasting and postprandial blood
glucose levels
• Short-acting drugs (α-glucosidase
inhibitors, repaglinide, pramlintide, rapid-
acting insulins) primarily target postprandial
levels.

HYPERGLYCEMIC DRUGS: GLUCAGON

• Glucagon is a protein hormone secreted
by the α cells of the endocrine pancreas.
• Mechanism of Action
– Acts through G protein-coupled receptors
in
heart, smooth muscle, and liver