Pharmacology of the endocrine

system
By : Fantu.K (Bpharm, Msc,assit.prof)
Objectives
• Describe thyroid hormones secretion, their effect
on body and management of thyroid hormones
abnormalities
• Explain body effects of hormones secreted by
adrenal cortex and clinical indications of steroids.
Introduction…
 Introduction…
Control of hormonal secretions
• First of all, the HYPOTHALAMUS secretes hormones that
target the anterior pituitary gland.
A. The ANTERIOR PITUITARY GLAND(which hangs from the
base of the brain) may then secrete 6 different
hormones:
1. Human Growth Hormone (HGH)
a. controls growth of the body;
b. targets the bone, muscle and adipose tissue.
2.Thyroid stimulating hormone (TSH)
a. controls the secretion of hormones by the thyroid
gland;
b. targets thyroid gland.
 Introduction…
Control of hormonal secretions
3. Adrenocorticotropic Hormone (ACTH)
a. controls the secretion of hormones by the adrenal cortex;
b. targets the outer portion of the adrenal gland (cortex).
4. Prolactin (PRL)
a. stimulates the production of milk by the mammary glands;
• targets the mammary glands.
5. Follicle Stimulating Hormone (FSH)
• In females, FSH stimulates maturation of an ovarian follicle and
ovum;
• In males, FSH stimulates the maturation of sperm in the testes;
 Introduction…
Control of hormonal secretions
6. Luteinizing Hormone (LH)
• In females, LH causes ovulation;
• In males, LH causes secretion of testosterone.
 Introduction…
• The posterior PITUITARY GLAND secretes 2 hormones:
a. Anti-Diuretic Hormone (ADH):
targets the kidney tubules (DCT);causes the kidney tubules to
reabsorb water back into the bloodstream, and therefore controls
water balance and BP.
• Clinical uses
• Diabetes insipidus,
• Nocturnal enuresis (by decreasing nocturnal urine production)
Synthetic ADH drugs
– Vasopressin: IV, IM
– Desmopressin: IV, IM. PO, intranasal
 Introduction…
b. Oxytocin (OT):
• targets uterine smooth muscle and breasts;
• causes uterine muscle contraction and milk production.
• It is an effective stimulant of uterine contractions & is used
intravenously to induce or reinforce labor .
Clinical uses of oxytocin
IV, IM
• Induction of labor
• Control of postpartum bleeding
A/E :
fetal distress, placental abruption, or uterine rupture
excessive fluid retention
 Introduction…
C. The THYROID GLAND
• is located below larynx and around trachea;
• produces 3 hormones when stimulated by TSH:
• a. Thyroxine (T4)& Triiodothreonine (T3):
increase basal metabolic rate by stimulating cellular oxygen
use to produce ATP;
• regulate metabolism.
b. Calcitonin:
• release is triggered by an increase in blood calcium levels;
• targets bone cells (inhibits osteoclast activity) & kidney
tubules (causes secretion of calcium into urine).
 Introduction…
D. The PARATHYROID GLANDS:
1. consist of 4 small glands;
2. are located within the thyroid gland;
3. produce a hormone called Parathyroid Hormone (PTH):
a. release is stimulated by a decrease in blood Ca++ levels;
b. PTH targets bone cells (activates osteoclasts) and kidney
cells (causes kidney tubules to reabsorb more calcium);
c. Therefore, causes an increase in blood calcium and
phosphate levels to normal.
4. PTH and calcitonin together maintain the homeostasis of
Ca++ in the blood.
 Introduction…
E. The ADRENAL GLANDS
1. are located atop the kidneys;
2. are divided into an outer adrenal cortex and an inner adrenal
medulla.
a. The ADRENAL MEDULLA:
• is located in the central portion of the adrenal glands;
• produces 2 closely related hormones which function in the
sympathetic division of the autonomic nervous system:
1. epinephrine;
2. norepinephrine.
These hormones target:
1. the heart (increased heart rate and blood pressure);
2. smooth muscle contraction (blood vessels,);
3. the lungs (increased breathing: rate, rhythm, depth).
 Introduction…
F. The PANCREAS:
a. is located behind the stomach on the left side of abdomen;
b. functions as both an exocrine gland (digestion) and endocrine
gland
c. contains endocrine organs called Islets of Langerhans which
produce 2 hormones:
1. Insulin:
• is produced by Beta cells
• decreases blood glucose levels (i.e. moves glucose from
bloodstream into cells and promotes glycogen formation
[liver/muscle]).
2. glucagon:
• is produced by Alpha cells
• increases blood glucose levels (i.e. causes breakdown of
glycogen and release of glucose into bloodstream).
 Introduction…
G. The THYMUS GLAND:
1. is located in the mediastinum region behind sternum;
2. produces a hormone called thymosin that affects the
maturation of lymphocytes (T-cells);
3. plays an important role in lymphatic system and immunity;
4. decreases in size as we age.
H. The PINEAL GLAND:
1. is attached to the thalamus of the brain stem;
2. secretes a hormone called melatonin:
a. production is stimulated by daylight (circadian rhythm);
b. affects moods, emotions, etc.
 Introduction…
I. The OVARIES:
1. Stimulation by FSH results in maturation of ovarian follicle
a. The developing follicle secretes estrogen:
• develops and maintains female secondary sexual characteristics;
targets:
1. hair follicles;
2. mammary glands/ breasts;
3. adipose tissue.
2. LH causes the follicle to rupture and release the ovum
(ovulation); the follicle becomes the corpus luteum.
• a. The corpus luteum secretes progesterone:
• prepares the uterus for implantation of the zygote
• Lutropin alfa, approved for use in combination with follitropin
alfa for stimulation of follicular development in infertile women
with profound LH deficiency.
 Introduction…
J. The TESTES:
1. FSH causes the production of sperm.
2. LH causes the production of testosterone:
a. develops and maintains male secondary sexual
characteristics; targets:
• hair follicles;
• muscle, bone;
• larynx.
 The Thyroid Gland
• Secretes two hormones that regulate metabolic
rate and one hormone that control plasma
calcium level(calcitonin).
– Thyroxine (T4) – contains four iodine atoms
– Triiodothyronine (T3) – contains three iiodine
atoms
– Insufficient iodine impairs T3 and T4 synthesis
– T3 is three to five fold more active than T4.
Regulation of the Thyroid Gland
 Actions of the thyroid hormones
Effects on metabolism
• Increase metabolism of
– Carbohydrate
– Fat and
– Protein
• There is an increase in oxygen consumption and
heat production .
• The calorigenic action is important as part of the
response to a cold environment.
 Effects on growth and development
 Thyroid hormones have a critical effect on growth.
 Also important for skeletal development.
 They are particularly necessary for normal growth
and maturation of the CNS

Effects on sympathetic nervous system

 Elevate sensitivity of sympathetic - adrenal system
– Nervousness , heartbeat speed up blood
pressure increase
 Abnormalities of thyroid function
Hypothyroidism
 Classified into
– Primary(95%)

– Secondary

– Tertiary

– Peripheral
 Treatment of Hypothyroidism
 The only effective treatment of hypothyroidism,
unless it is due to iodine deficiency (treated with
iodide) is
 To administer the thyroid hormones themselves
– Thyroxine (levothyroxine, T4) is the standard
replacement therapy
– Triiodothyronine (liothyronine, T3) being reserved
for the rare condition of myxoedema coma when
more rapid action is required for emergency
treatment.
 Levothyroxine Sodium

 Sodium salt of the naturally occurring

levorotatory isomer of T4.

 Preparation of choice for maintenance of plasma

T4 and T3 concentrations

 It is absorbed intact from the gastrointestinal

tract, and its long half-life allows for convenient
once daily administration
 Liothyronine Sodium
- Liothyronine is generally not used for maintenance thyroid
 hormone replacement therapy because of its short plasma
 half-life and duration of action
 - The use of T3 alone is recommended only in special
 situations, such as in the initial therapy of myxedema and
 myxedema coma and the short-term suppression of TSH in
 patients undergoing surgery for thyroid cancer
 - Useful in 5-deiodinase deficiency
Liotrix
▫ is a 4:1 mixture of levothyroxine sodium and liothyronine
sodium
▫ used for thyroid hormone replacement therapy in
hypothyroid patients
 Adverse effects of treatment
with thyroid hormone
The most common adverse effects (i.e., symptoms of
hyperthyroidism) are the result of a drug overdose;
they include
▫ Cardiac palpitation and arrhythmias, tachycardia,
▫ Weight loss, tremor, headache, insomnia, and heat
intolerance

 Cautions and Contraindications of
treatment with thyroid hormone
Thyroid hormone therapy
• is contraindicated in patients with myocardial
infarction

• should be used with caution in patients

– With cardiovascular disease, diabetes, adrenal
insufficiency
– Who are elderly
Treatment of Hyperthyroidism
The goal of therapy is to decrease synthesis and/or
release of additional hormone.
• Removal of part or all the thyroid gland
▫ Surgically
▫ Radioiodine 131 I
 Radioiodine 131 I :- by destruction of the gland by beta
particles emitted
– It is a first line treatment
– It has a half-life of eight days
– Hypothyroidism will eventually develop, but is easily
managed by replacement therapy with thyroxine.
– It is best avoided in children and also in pregnant
patients because of potential damage to the fetus.
 Inhibition of thyroid hormone synthesis
(Antithyroid Drugs)

– Thioureylenes/Thioamides
• Includes carbimazole, methimazole, propylthiouracil
 Mechanism of Action
• Accumulate within the thyroid and destroy
overactive tissue or inhibit the incorporation
of iodine for production of T3 and T4
• They do not inhibit secretion of stored thyroid hormone
• Propylthiouracil has the additional effect of reducing the
de-iodination of T4 to T3 in peripheral tissues.
Use
 The thionamide drugs are used in the
management
– Hyperthyroidism
– Thyrotoxic crisis and
– In the preparation of patients for surgical
subtotal thyroidectomy
 Although thionamides may be used to treat
hyperthyroidism during pregnancy, they should be
given in minimally effective doses to avoid
– Inducing infantile hypothyroidism and
– Thyroid enlargement in the developing fetus
 Iodine
▫ It is converted in-vivo to iodide which temporarily inhibits
the release of thyroid hormones.
▫ There is inhibition of secretion of thyroid hormones and over
a period of 10– 14 days, a marked reduction in vascularity of
the gland, which becomes smaller and firmer.
▫ Iodine solution in KI (Lugol’s iodine) is given orally.
 Mechanism of Action
▫ It may inhibit iodination of thyroglobulin.
▫ High concentration limits its own transport and it prevents
iodination process.
▫ It inhibits release of the thyroid hormone.
 KI + propylthiouracil in the management of thyrotoxic crisis to
rapidly inhibit thyroid hormone secretion.
 Iodide plus a thionamide has also been used in the immediate
preoperative preparation of patients about to undergo total
or subtotal surgical thyroidectomy
 Adverse reactions to iodine can be divided into
– Intrathyroidal reactions
• Iodine-induced thyrotoxicosis
• Iodide goiter or hypothyroidism
– Extrathyroidal reactions
• Rash ,drug fever
• Conjunctivitis and rhinitis
• Vasculitis
 Potassium Perchlorate
 The perchlorate ion of potassium perchlorate, KClO4, is a
competitive inhibitor of thyroidal I transport via the
Sodium Iodide Symporter (NIS)
 This drug can cause fatal aplastic anemia and gastric ulcers
and is now rarely used
 effective in treating iodine-induced hyperthyroidism

Others
– Beta adrenoceptor antagonists e.g. propranolol
• For blunting the widespread sympathetic
stimulation.
 Thyroid Treatment: Potential Drug
Interactions
 Drugs that reduce thyroid hormone production
▫ Lithium
▫ Iodine-containing medications
▫ Amiodarone (Cordarone)
 Drugs that reduce thyroid hormone absorption
▫ Sucralfate (Carafate)
▫ Ferrous sulfate (Slow Fe)
▫ Cholestyramine (Questran)
▫ Colestipol (Colestid)
▫ Aluminum-containing antacids
▫ Calcium products
 Drugs that increase metabolism of thyroxine
– Rifampin (Rifadin)
– Phenobarbital
– Carbamazepine (Tegretol)
– Warfarin (Coumadin)
– Oral hypoglycemic agents
 Drugs that displace thyroid hormone from protein
binding
– Furosemide (Lasix)
– Mefenamic acid
– Salicylate
Pharmacology of drugs affecting
adrenal cortex
• adrenal gland

CORTEX Medulla

corticosteroids Androgene Catecholamine

Glucocorticoids mineralocorticoids

• The adrenal cortex has three zones, and each zone synthe-
sizes a different type of steroid hormone from cholesterol.
• The outer zona glomerulosa produces mineralocorticoids (for ex-
ample, aldosterone) that are responsible for regulating salt and
water metabolism.

• Production of aldosterone is regulated primarily by the renin–

angiotensin system.

• The middle zona fasciculata synthesizes glucocorticoids (for ex-

ample, cortisol) that are involved with metabolism and response
to stress.

• The inner zona reticularis secretes adrenal androgens

• Secretion by the two inner zones and, to a lesser extent, the

outer zone is controlled by pituitary adrenocorticotropic hor-
mone (ACTH; also called corticotropin), which is released in re-
sponse to hypothalamic corticotropin-releasing hormone (CRH).
Glucocorticoids serve as feedback inhibitors of ACTH and CRH se-
cretion.
Mineralocorticoids

• Mineralocorticoids help to control fluid status and con-

centration of electrolytes, especially sodium and potas-
sium.
• Aldosterone acts on distal tubules and collecting ducts
in the kidney, causing reabsorption of sodium, bicar-
bonate, and water.
• Conversely, aldosterone decreases reabsorption of
potassium, which, with H+, is then lost in the urine.
• Enhancement of sodium reabsorption by aldosterone
also occurs in gastrointestinal mucosa and in sweat and
salivary glands.
 Mineralocorticoids
1.Deoxycortisone (DOC) – serves as precursor of
aldosterone
2. Fludrocortisone – most widely used; both
mineralocorticoid and glucocorticoid activity; potent salt-
retaining activity
Uses:
A. Diagnosis and treatment of disorders of adrenal
function(adrenocortical insufficiency)
B. Treatment of inflammatory and immunologic disorders
Glucocorticoids
• Cortisol is the principal human glucocorticoid. Normally,
its production is diurnal, with a peak early in the morning
followed by a decline and then a secondary, smaller peak
in the late afternoon.
• Factors such as stress and levels of the circulating steroid
influence secretion.
• The effects of cortisol are many and diverse.
 Glucocorticoids
Cortisol – carbohydrate metabolism regulating,
intermediary metabolism; immune function
- 10-20 mg daily
- bound to CBG (90%), albumin (5%)
- t ½ =60-90 mins.;
- liver (glucoronic acid or sulfates)
- 1/3 excreted as 17-hydroxysteroids while 1% is
unchanged
 Glucocorticoids
• May be categorized as
– Short-acting
• Cortisone and hydrocortisone
– Intermediate-acting
• Prednisone, prednisolone, sodium succinate,
methylprednisolone, methylprednisolone
acetate, and triamcinolone
– Long-acting
• Dexamethasone, betamethasone, and
fluocinolone
Mechanism of Action
GC inhibition

phospholipase A2
 In general, all glucocorticoids:
1.Promote normal intermediary metabolism: Glucocortico
ids favor gluconeogenesis through increasing amino acid
uptake by the liver and kidney and elevating activities of
gluconeogenic enzymes.
• They stimulate protein catabolism (except in the liver)
and lipolysis, thereby providing the building blocks and
energy that are needed for glucose synthesis.
• [Note: Glucocorticoid insufficiency may result in hypo-
glycemia (for example, during stressful periods or fast-
ing).]
2. Increase resistance to stress: By raising plasma glucose
levels, glucocorticoids provide the body with energy to
combat stress caused by trauma, fright, infection, bleedi
ng or the like
3. Alter blood cell levels in plasma: Glucocorticoids cause a
decrease in eosinophils, basophils, monocytes, and lymph
ocytes by redistributing them from the circulation to lymp
hoid tissue. Glucocorticoids also increase hemoglobin, ery
throcytes, platelets, and polymorphonuclear leukocytes.
4. Have anti-inflammatory action: The most important ther
apeutic properties of the glucocorticoids are their potent
anti-inflammatory and immunosuppressive activities. The
y produce this effect because:
1.They lower circulating lymphocytes
2. They inhibit the ability of leukocytes and macrophages to
respond to antigens.
3. Glucocorticoids also decrease the production and release
of pro-inflammatory cytokines.
Anti-inflammatory action…
• They inhibit phospholipase A2, which blocks the release
of arachidonic acid from membrane-bound phospholipid.
• The decreased production of prostaglandins and leukotrie
nes is believed to be central to the anti-inflammatory action.
• Lastly, these agents influence the inflammatory response by
stabilizing mast cell and basophil membranes, resulting in
decreased histamine release.
 Therapeutic uses of the corticosteroids
1. Replacement therapy for primary adrenocortical insuf-
ficiency (Addison disease): Addison disease is caused
by adrenal cortex dysfunction (as diagnosed by the lack
of response to ACTH administration).
• Hydrocortisone which is identical to natural cortisol, is
given to correct the deficiency. Failure to do so results in
death.
• The dosage of hydrocortisone is divided so that two-
thirds of the daily dose is given in the morning and one-
third is given in the afternoon.
• Administration of fludrocortisone a potent synthetic
mineralocorticoid with some glucocorticoid activity, may
also be necessary to supplement mineralocorticoid defi-
ciency.
 Therapeutic uses of the corticosteroids
2. Replacement therapy for secondary or tertiary adren
ocortical insufficiency: These disorders are caused by
a defect in CRH production by the hypothalamus or in A
CTH production by the pituitary.
• [Note: Under these conditions, the synthesis of mineralo-
corticoids in the adrenal cortex is less impaired than that
of glucocorticoids.]
• Hydrocortisone is used for treatment of these deficiencies
3. Diagnosis of Cushing syndrome: Cushing syndrome is caus
ed by hypersecretion of glucocorticoids (hypercortisolism)
that results from excessive release of ACTH by the anterio
r pituitary or an adrenal tumor.
 Therapeutic uses of the corticosteroids
• [Note: Chronic treatment with high doses of glucocorticoids is a
frequent cause of iatrogenic Cushing syndrome.]
• Cortisol levels (urine, plasma, and saliva) and the dexamethasone
suppression test are used to diagnose Cushing syndrome.
• The synthetic glucocorticoid dexamethasone suppresses cortisol
release in normal individuals, but not those with Cushing syn-
drome
5. Relief of inflammatory symptoms:
A- significantly reduce the manifestations of inflammation
associated with rheumatoid arthritis and inflammatory
skin conditions, including redness, swelling, heat, and t
enderness that may be present at the site of inflammation
B- maintenance of symptom control in persistent asthma, as
well as management of asthma exacerbations
C- active inflammatory bowel disease.
 Therapeutic uses of the corticosteroids
6. Treatment of allergies: Corticosteroids are beneficial in
the treatment of allergic rhinitis and asthma as well as d
rug, serum, and transfusion allergic reactions.
• Fluticasone and others are applied topically to the respi-
ratory tract through inhalation from a metered dose dis-
penser. This minimizes systemic effects and allows the pa-
tient to reduce or eliminate the use of oral corticosteroid.
7.Acceleration of lung maturation: Respiratory distress syn
drome is a problem in premature infants. Fetal cortisol is
a regulator of lung maturation. Consequently, a regimen
of betamethasone or dexamethasone administered intra-
muscularly to the mother within the 48 hours proceedin
g premature delivery can accelerate lung maturation in
the fetus.
 Pharmacokinetics
1. Absorption and fate:
• Orally administered corticosteroid preparations are read-
ily absorbed.
• Selected compounds can also be administered intra-
venously, intramuscularly, intra-articularly (for example,
into arthritic joints), topically, or via inhalation or in-
tranasal delivery.
• All topical and inhaled glucocorticoids are absorbed to
some extent and, therefore, have the potential to cause
hypothalamic–pituitary–adrenal (HPA) axis suppression.
• Greater than 90% of absorbed glucocorticoids are bound
to plasma proteins, mostly corticosteroid-binding globu-
lin.
• Corticosteroids are metabolized by the liver microsomal
oxidizing enzymes. The metabolites are conjugated to
glucuronic acid or sulfate, and the products are excreted
by the kidney.
Pharmacokinetics
• [Note: The half-life of corticosteroids may increase
substantially in hepatic dysfunction.]
• The drug of choice during pregnancy is prednisone
because it minimizes steroid effects on the fetus.
• It is a pro-drug that is not converted to the active
compound, prednisolone, in the fetal liver.
• Any prednisolone formed in the mother is biotrans-
formed to prednisone by placental enzymes.
Side Effects
• Immunosuppression
• Cataracts may also occur with long-term corticosteroid
therapy.
• Hyperglycemia due to increased gluconeogensis, insulin resis-
tance.
• Steroid-induced osteoporosis: reduced bone density (osteoporo-
sis)
• Redistribution of body fat: moon face, buffalo.
• Adrenal insufficiency
• Muscle breakdown (proteolysis), weakness; reduced muscle
mass
and repair
• Growth failure
• Increased plasma amino acids, increased urea formation;
• Delay wound healing
• Increase risk of infection
• May cause GI ulceration and bleeding
Steroid Contraindications
• Patients with systemic fungal infections
• Local viral herpes infections
• Live virus vaccinations.
• Topical application to the eyes or orbital area.