Thyroid & Antithyroid Drugs

1
 Thyroid Physiology

The normal thyroid gland secretes sufficient

amounts of the thyroid hormones:
1. Triiodothyronine- (T3) and
2. Tetraiodothyronine (T4 ) Thyroxine

2
 Biosynthesis of Thyroid Hormones

3
 HORMONE TRANSPORT

1. After TSH stimulation of the thyroid gland, T3

and T4 are cleaved from thyroglobulin and
released into the circulation.
2. When in the circulation, thyroid hormone
transported is bound to several plasma proteins.
3. Most thyroid hormone is transported by
THYROXINE-BINDING GLOBULIN (TBG).
Prealbumin and albumin also serves as carriers.
4
 HORMONE METABOLISM

5
 HYPOTHYROIDISM

 Is the inability of the thyroid gland to supply

sufficient thyroid hormone.
 Is a syndrome resulting from deficiency of thyroid
hormones and is manifested largely by a
reversible slowing down of all body functions.
Conditions:
 Cretinism (children), Myxedema (adults)
 Hashimoto’s disorder
 Endemic and Sporadic goiter
6
 CLASSIFICATION
PRIMARY SECONDARY TERTIARY

7
 Signs & Symptoms:

1. Early clinical features tend to be

somewhat vague: lethargy, fatigue,
forgetfulness, sensitivity to cold,
unexplained weight gain and constipation.

8
 Thyroid Preparations

DESSICATED THYROID PREPARATIONS

 at one time the agent of choice, dessicated
thyroid has fallen out of favor since standardized
synthetic levothyroxine preparations have
become available.      

9
 FIXED RATIO (LIOTRIX®) PREPARATIONS

 4:1 ratio (T4:T3)

 The T3 component proved unnecessary (because

T4 is metabolized to T3) and even
disadvantageous because of T3-induced adverse
effects (e.g., tremor, headache, palpitations,
diarrhea)

10
 LEVOTHYROXINE

 Predictable results and lack of T3-induced side

effects have made levothyroxine the agent of
choice.
 The two major brand of levothyroxine
preparations (Levothroid®, Synthroid®) have
been compared for bioequivalence and were
shown to be equivalent in patients with
hypothyroidism.

11
 Hyperthyroidism

 It is the clinical syndrome that results when tissues

are exposed to high levels of thyroid hormone.
 a.k.a. “thyrotoxicosis”

Conditions:
 Grave’s disease
 Toxic Uninodular Goiter & Toxic Multinodular Goiter
 Subacute Thyroiditis
 Thyroid Storm

12
 Signs & Symptoms
1. Diffusely enlarged nontender goiter
2. Nervousness, irritability, anxiety, and insomnia
3. Heat intolerance and profuse sweating
4. Weight loss despite of increased appetite
5. Tremor and muscle weakness
6. Palpitations and tachycardia
7. Exopthalmos, stare, and lid lag
8. Diarrhea
9. Thrill and abute over the thyroid
13 10. Periorbital edema
 Thioamides

1. Methimazole (Tapazole®)

2. Propylthiouracil

14
 Anion Inhibitors

 Monovalent anions such as perchlorate (ClO4–),

pertechnetate (TcO4 –), and thiocyanate (SCN–) can
block uptake of iodide by the gland through
competitive inhibition of the iodide transport
mechanism.

 Since these effects can be overcome by large doses

of iodides, their effectiveness is somewhat
unpredictable.
15
 Iodides

 Prior to the introduction of the thioamides in the

1940s, iodides were the major antithyroid agents;
today they are rarely used as sole therapy.

16
 Iodinated Contrast Media

 The iodinated contrast agents—ipodate and

iopanoic acid by mouth, or diatrizoate
intravenously—are valuable in the treatment of
hyperthyroidism, although they are not labeled
for this indication.

 These drugs rapidly inhibit the conversion of T4

to T3 in the liver, kidney, pituitary gland, and
brain.
17
 Radioactive Iodine

 131I is the only isotope used for treatment of

thyrotoxicosis (others are used in diagnosis).

 Administered orally in solution as sodium 131I, it is

rapidly absorbed, concentrated by the thyroid,
and incorporated into storage follicles.

18
 Adrenoceptor-Blocking Agents

 Beta blockers without intrinsic sympathomimetic

activity are effective therapeutic adjuncts in the
management of thyrotoxicosis since many of
these symptoms mimic those associated with
sympathetic stimulation.

 Propranolol has been the -blocker most widely

studied and used in the therapy of thyrotoxicosis.

19
 Thyroidectomy

 A near-total thyroidectomy is the treatment of

choice for patients with very large glands or
multinodular goiters.
 Patients are treated with antithyroid drugs until
euthyroid (about 6 weeks).
 In addition, for 2 weeks prior to surgery, they
receive saturated solution of potassium iodide, 5
drops twice daily, to diminish vascularity of the
gland and simplify surgery.
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 21

Pancreatic Hormone

&

Antidiabetic Drugs
 Pancreatic Hormones
22
 Diabetes Mellitus
23

 It is defined as an elevated blood glucose

associated with absent or inadequate pancreatic
insulin secretion, with or without concurrent
impairment of insulin action.
 Diabetes Mellitus Classification:
24

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.
 Diabetes Mellitus Classification:
25

3. Type III Diabetes Mellitus:

> refers to multiple other specific
causes of an elevated blood glucose.

4. Type IV Diabetes Mellitus:

> a.k.a Gestational diabetes(GDM)
 Insulin
26

1. IDDM (type 1)
2. NIDDM (type 2) which cannot be
controlled by diet therapy or oral
hypoglycemic agents.
3. Diabetes with acute or severe
complication.
4. Diabetes accompanied severe infection,
wasting disease high fever, pregnancy,
trauma and operation.
5. Intracellular K+ deficiency.
 Mechanism of Action
27

 Facilitates the transport of glucose across the

cell membrane transported through a special
carrier or glucose transporter (GLUT 1 &
GLUT 4) by means of facilitated diffusion.
 Glucose Transporters
28
 Other Mechanisms:
29

 Increase glucose uptake and utilization by

peripheral tissues.
 Increase glycogenesis.
 Decrease glycogenolysis.
 Decrease gluconeogenesis.
 Decrease lipolysis and ketogenesis.
 Increase formation of protein from amino acids.
 Increase of adipose tissues from triglycerides
and fatty acids.
 CHARACTERISTICS OF AVAILABLE
INSULIN PREPARATIONS
30

A. Principle types and duration of insulin

preparation:
1) Rapid-acting with very fast onset and
short duration
2) Short-acting with rapid onset of action
3) Intermediate-acting
4) Long acting with slow onset of action
 1.Rapid acting insulin:
31

Three injected rapid-acting insulin:

 Insulin lispro
 Insulin aspart
 Insulin glulisine
 Permit more physiologic prandial insulin
replacement and it closely mimic normal
endogenous prandial insulin
 Lowest variability of absorption with 5%
 2.Short acting Insulin:
32

 Is a short-acting soluble crystalline zinc

insulin.
 Its effect within 30 minutes and peaks
between 2 and 3 hours.
 The clinical consequence is when regular
insulin is administered at mealtime.
 It is the only type that should be
administered intravenously.
 3.Intermediate-acting Insulin
33

a. NPH (neutral protamine hagedorn, or

isophane)insulin
 Absorption are delayed by
combining appropriate amounts of
insulin and protamine that present in
an uncomplexed form (“isophane”).
 The action of NPH is highly
unpredictable. While the clinical use
is waning of its adverse
pharmacokinetics.
 4. Long-acting Insulin
34

b.Insulin glargine “soluble, peakless”

 To provide reproducible, convenient,
background insulin replacement and has a
slow onset of action.

c. Insulin detemir
 This insulin is the most recently developed
long acting insulin analog it has the most
reproducible effect of the intermediate and
long acting insulin and its use as associated
with less hypoglycemia than NPH insulin.
 Insulin treatments of special circumstances:
35

A. Diabetic Ketoacidosis (DKA)

 Is a life-threatening medical emergency
caused by inadequate or absent insulin
replacement which occurs in people
with type I and type II diabetes mellitus.

 It includes aggressive intravenous

hydration and insulin therapy and
maintenance of potassium and other
electrolyte levels.
 Insulin treatments of special circumstances:
36

B.Hyperosmolar Hyperglycemic Syndrome(HHS)

 Is diagnosed in persons with type II diabetes
and is characterized by profound
hyperglycemia and dehydration.

 The treatment of HHS centers around

aggressive rehydration and restoration of
glucose and electrolyte homeostasis
 Insulin Therapy
Complications
37

A. Hypoglycemia

I. Mechanism and diagnosis

 The most common complication of
insulin therapy. Rapid development of
hypoglycemia in person with intact
hypoglycemia awareness cause signs of
autonomic hyperactivity.
 Insulin Therapy
Immunology
38

I. Insulin allergy
 is a rare condition in which local or
systemic urticaria result from histamine
release from tissue mast cells sensitized by
anti-insulin IgE antibodies in severe cases
cause anaphylaxis.
II. Immune insulin resistance
 That neutralize the action of insulin to
negligible extent develops in most insulin
treated patients
 Insulin Therapy
Immunology
39

III. Lipodystrophy at injection sites

 Injection of animal insulin
preparation sometimes led to atrophy
of subcutaneous fatty tissue at the
site of injection.
 Oral Hypoglycemics
40

1. Insulin Secretagogues
a. Sulfonylureas
b. Meglitinides
2. Insulin Sensitizers
a. Biguanides
b. Thiazolidinediones
3. Alpha-Glucosidase Inhibitors
 ORAL ANTIDIABETIC AGENTS
Insulin Secretagogues (Sulfonylureas )
41

Mechanism of action
To increase release from the pancreas
A reduction of serum glucagon levels and
closure of potassium channels.
 First Generation of Sulfonylureas
42

Tolbutamide(Orinase®)

Chlorpropamide
(Diabinese®)

 Tolazamide (Tolinase®)
 Second Generation of Sulfonylureas
43

-Should be used in caution

with cardiovascular disease.

Glyburide
(Micronase®)
-is metabolized in
liver into products with
very low hypoglycemic
activity.
 Second Generation of Sulfonylureas
44

Glipizide(Glucotrol®)
-this agent should be
ingested 30 minutes before
breakfast because absorption is
delayed when the drug is taken
with food.

Glimepiride (Amaryl®)
 Insulin Secretagogues:
45

MEGLITINIDE

Repaglinide (Prandin®) –
is the first member that
modulate beta-cell insulin
release by regulating
potassium efflux through
the potassium channels
previously discussed .
 Insulin Secretagogues:
46

D-PHENYLALANINE
DERIVATIVE
Nateglinide (Starlix®) –
a D-phenylalanine
derivatives, is the latest
insulin secretagogue and
it stimulate very rapid and
transient release of insulin
from beta cells.
 Biguanides
47

Metformin (Glucophage®),
“Phenformin”.

Phenformin was discontinued in

the USA because of its
association with lactic acidosis
and because there was no
documentation of any long-term
benefit from its use. Not bound to
plasma proteins, not metabolized,
excreted by the kidneys as the
active compound.
 Clinical Uses:
48

1. for patients with refractory obesity

whose hyperglycemia is due to
ineffective insulin action. Biguanides is
an insulin-sparing agent and does not
increase weight or provoke
hypoglycemia.

2. In combination with sulfonylureas in

type 2 diabetics in whom sulfonylureas
therapy alone is inadequate.
 Adverse Reactions:
49

 lactic acidosis
 ketonemia gastrointestinal
 anorexia
 nausea
 vomiting
 abdominal discomfort,
 diarrhea
 THIAZOLIDINEDIONES
50

Acts to decrease insulin resistance this are a

ligands of peroxisome proliferator- activated
receptor- gamma (PPAR-γ)

 Pioglitazone(Actos®)- is metabolized by
CYP 2C8 and CYP 3A4 to active
metabolites a monotherapy combination
with metformin
Rosiglizone(Avandia®)- is approve for
use in type II diabetes as montherapy in
double combination therapy with biguanide
 Alpha-Glucosidase Inhibitors

1. Acarbose (Precose®)
2. Miglitol (Glyset®)

Indication:
Used in individuals with significant postprandial
hyperglycemia.

Mechanism of Action:
Inhibition of the intestinal enzyme α-
glucosidase retards the degradation and thus
increase the absorption of carbohydrates.
51
PRAMLINTIDE(Symlin®):
52

A synthetic analog of amylin

Agent that modulates postprandial glucose

levels

Is a suppresses glucagon release via

undetermined mechanism.

The major adverse effects of pramlintide are

hylpoglycemia and gastrointestinal symptoms
including nausea ,vomiting and anorexia.
EXENATIDE(Byetta®):
53

A synthetic analog of glucagon like polypeptide

1
Is absorbed equally from arm, abdomen or
thigh injection sites, reaching a peak
concentration in approximately 2 hours with
duration of action of up to 10 hours.
SITAGLIPTIN(Januvia®):

An inhibitor of dipeptidyl peptidase

Can be given as monotherapy or combined with
metformin or Tzds.
 54

HYPOTHALAMIC &
PITUITARY HORMONES

CHAPTER 37
 Pituitary Gland
55

 It weighs about 0.6 g and rests at the base of

the brain in the bony sella turcica near the
optic chiasm and the cavernous sinuses.
 It consists of an anterior lobe and a posterior
lobe.
 It is connected to the overlying hypothalamus
by a stalk of neurosecretory fibers and blood
vessels, including a portal venous system
that drains the hypothalamus and perfuses
the anterior pituitary.
 Anterior Pituitary Gland
56

 Somatotrophins -HGH
 Thyrotrophins-TSH
 Corticotrophins-ACTH, Beta-Endophin
 Lactotrophins-Prolactin
 Gonadotrophins-LH, FSH
 Melanotrophins-MSH
 Posterior Pituitary Gland
57

 Oxytocin

 Vasopressin
 Hypothalamus
58

 It is a portion of the brain that contains a

number of small nuclei with a variety of
functions.
 The hypothalamus is located below
the thalamus, just above the brain stem. In the
terminology of neuroanatomy, it forms
the ventral part of the diencephalon.
 One of the most important functions of the
hypothalamus is to link the nervous system to
the endocrine system via the pituitary gland.
59
 PREPARATIONS AVAILABLE
60

 Mecasermin
 Pegvisomant
 Somatostatin Analogs
(Octreotide, Lantreotide)
 Menotrophins
 FSH: Urofollitropin, Follitrophin alfa, &
Follitropin beta
 LH-Leutropin alfa
 HCG-Choriogonadotropin alfa
 PREPARATIONS AVAILABLE
61

 GnRH Agonist-Gonadorelin, Goserilin,

Histrelin, Leuprolide, Nafarelin, Triptorelin
 GnRH Receptor Antagonist-Ganirelix,
Cetrorelix, Abarelix, Degarelix
 Dopamine Agonist-Bromocriptine,
Cabergoline, Quinagolide
 Oxytocin Antagonist-Atosiban
 Vasopressin Antagonist-Conivaptan,
Tolvaptan
 62

ADRENOCORTICOSTEROIDS
& ADRENOCORTICAL
ANTAGONISTS
CHAPTER 39
 Adrenocorticosteroids
63

 These are steroid molecules produced and

released by the adrenal cortex.
 Both natural and synthetic corticosteroids are
used for the diagnosis and treatment of
disorders of adrenal function.

 They are also used—more often and in much

larger doses—for treatment of a variety of
inflammatory and immunologic disorders.
 Adrenocorticosteroids
64

 The hormonal steroids may be classified as:

 those having important effects on
intermediary metabolism and immune
function (glucocorticoids),
 those having principally salt-retaining
activity (mineralocorticoids), and
 those having androgenic or estrogenic
activity.
65
66
 Clinical Pharmacology
67

Adrenal Insufficiency
 ADDISON’S DISEASE

 Adrenocortical insufficiency is characterized by

weakness, fatigue, weight loss, hypotension,
hyperpigmentation, and inability to maintain the
blood glucose level during fasting. In such
individuals, minor noxious, traumatic, or infectious
stimuli may produce acute adrenal insufficiency with
circulatory shock and even death.
 Clinical Pharmacology
68

Adrenocortical Hyperfunction
 CUSHING'S SYNDROME

 Cushing's syndrome is usually the result of bilateral

adrenal hyperplasia secondary to an ACTH-secreting
pituitary adenoma (Cushing's disease) but
occasionally is due to tumors or nodular hyperplasia
of the adrenal gland or ectopic production of ACTH
by other tumors.
 Clinical Pharmacology
69

 ALDOSTERONISM
 Primary aldosteronism usually results from the
excessive production of aldosterone by an adrenal
adenoma.
 However, it may also result from abnormal
secretion by hyperplastic glands or from a
malignant tumor.
 The clinical findings of hypertension, weakness,
and tetany are related to the continued renal loss
of potassium, which leads to hypokalemia,
alkalosis, and elevation of serum sodium
concentrations.
 MINERALOCORTICOIDS
70

 Aldosterone

 Deoxycorticosterone

 Fludrocortisone
 ADRENOCORTICAL ANTAGONISTS
71

 Metyrapone
 Aminogluthetimide
 Ketoconazole
 Mitotane
 Trilostane
 Abiraterone
 Mifepristone
 MINERALOCORTICOIDS ANTAGONISTS
72

 Spironolactone

 Eplerenone

 Drospirenone
 73

GONADAL HORMONES &

ANTAGONIST
CHAPTER 40
 ESTROGEN
74

 The major estrogens produced by women are

estradiol (estradiol-17 , E2), estrone (E1), and
estriol (E3).

 Synthetic, steroidal: Ethinylestradiol,

Mestranol, Quinestrol

 Synthetic non steroidal: Dienestrol,

Diethylstilbestrol, Benzestrol, Hexestrol,
Methestrol, Chlorotrianisene,
 PROGESTINS
75

 Natural Progestins: Progesterone

 Synthetic Progestins:
 Progesterone derivatives: hydroxyprogesterone
caproate, medroxyprogesterone acetate, megestrol
acetate
 Testosterone derivative: dimethisterone

 19-nortestosterone derivatives: norethynodrel,

lynestrenol, norethindrone and its acetate,
ethynodiol diacetate, l-norgestrel
 13-ethyl 19-nortestosterone derivatives- less
 OTHER OVARIAN HORMONES
76

 The normal ovary produces small amounts of

androgens, including testosterone,
androstenedione, and
dehydroepiandrosterone.

 The ovary also produces inhibin and activin.

 Relaxin
 Hormonal Contraception (Oral, Parenteral, &
Implanted Contraceptives)
77

Two types of preparations are used for oral

contraception:
(1) combinations of estrogens and progestins and

(2) continuous progestin therapy without concomitant

administration of estrogens.

The combination agents are further divided into:

 monophasic forms (constant dosage of both components

during the cycle) and

 biphasic or triphasic forms (dosage of one or both

components is changed once or twice during the cycle).

 Hormonal Contraception (Oral, Parenteral, &
Implanted Contraceptives)
78

Progestins Only Contraceptives

 slightly less efficacious than combination type

 Minipill- low dose progestins (350 ug norethindrone

or 75ug norgestrel)
 Implant – subdermal implant of 216 mg of norgestrel
(Norplant) effective for 5 years
 Intramuscular – given every 3 months: 150mg
medroxyprogesterone acetate (Depo-Provera)
 Intrauterine device - for yearly insertion:
Progestasert
 Hormonal Contraception (Oral, Parenteral, &
Implanted Contraceptives)
79

Post-Coital Contraceptives
 “Morning After Pills”

 “Ethinylestradiol + Norgestrel, Ethinyl estradiol,

Conjugated estrogens, Estrone, DES”
 ESTROGEN & PROGESTERONE INHIBITORS &
ANTAGONISTS
80

 Tamoxifen
 Toremifene
 Raloxifene
 Clomiphene
 Mifepristone
 Danazol

Ovulation Drugs
 Clomiphene
 OTHER INHIBITORS
81

 Anaztrozole
 Letrozole
 Exemestane
 Fadrozole
 Fulvestrant
 Nafarelin
 Buserelin
 ANDROGENS & ANABOLIC STEROIDS,
ANTIANDROGENS, & MALE CONTRACEPTION
82

 Testosterone, Methyltestosterone,
Fluoxymesterone, Oxymetholone,
Oxandrolone, Nandrolone

ANTIANDROGENS
 Ketoconazole
 Abiraterone
 Finasteride
 Dutasteride
 RECEPTOR INHIBITORS
83

 Cyproterone
 Flutamide
 Bicalutamide
 Nilutamide
 Spironolactone

GOSSYPOL
 Extensive trials of this cottonseed derivative have
been conducted in China. This compound destroys
elements of the seminiferous epithelium but does not
significantly alter the endocrine function of the testis.