Download Antithyroid agents

THYROID
Anatomy
Over Trachea
Two lobes connected together by isthmus
15 to 20 gms weight
Thyroid Gland
• Second largest endocrine gland in body
• Small butterfly shaped gland located at base of neck below the
sternocleidomastoid muscles
• Thyroid is controlled
by the hypothalmus
and pituitary
The thyroid’s job is to
make thyroid hormone,
which is secreted into the
blood and then carried to
every tissue in the body.
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 The thyroid gland is to take iodine,
found in many foods, and convert it into
thyroid hormones: thyroxin (T4) and
triiodothyronine (T3).
 The thyroid gland is controlled by the
PITUTARY GLAND which produces a
hormone called Thyroid stimulating
hormone (TSH). Its level goes up when the
level of thyroid hormones comes down
and vice versa.
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Thyroid gland
• Thyroid gland is composed over a million cluster of
follicles
• Follicles are spherical & consists of epithelial cells
surrounding a central mass (colloid)
• Normal thyroid gland secretes thyroid hormones
• Natural hormone compounds having biological activity
(Iodide containing ):
• L-Thyroxine (T4 or tetraiodo-L-thyroxine)
• Liothyronine (T3 or triiodo-L-thyronine)
• Both forms are available for oral use
• Parafollicular (C) cells produce calcitonin
Follicular Cells – the functional unit
Thyroid hormones – 2 important biological
functions
1. Normal human growth & development, esp.CNS
2. In adults,maintain metabolic homeostasis, affecting all organ systems
Large preformed hormone stores in thyroid
Metabolism of thyroid hormone occurs in liver and brain
TSH regulates serum thyroid hormones by a negative feedback system
Bind to nuclear thyroid hormone receptors, modulates gene transcription
HORMONES
T4
T3
Calcitonin
Biosynthesis of thyroid hormones
Synthesis Of Thyroid hormone
Steps
1. Transport of iodide into the thyroid gland by sodium-iodide
symporter
2. Iodide is oxidized by thyroidal peroxidase to iodine
3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT- iodide
organification ( MIT- monoiodotyrosine, DIT- Diiodotyrosine)
4. Iodotyrosines condensation within thyroglobulin molecule
MIT+DIT→T3; DIT+DIT→T4
5. T4, T3, MIT & DIT - released from thyroglobulin by exocytosis &
proteolysis of thyroglobulin .
6. The MIT and DIT are deiodinated within the gland, and the
iodine is reutilized.
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1) Iodide uptake or pump
• Rate –limiting step in thyroid hormone synthesis which
needs energy
• Follicles have in their basement membrane an iodide
trapping mechanism which pumps dietary I - into the cell
• Normal thyroid: serum iodine is 30-40:1
• Iodide uptake enhancers:
• TSH
• Iodine deficiency
• TSH receptors antibody
• Iodide uptake inhibitors
• Iodide ion
• Drugs
• Digoxin
• Thiocynate
• perchlorate
2) Iodide oxidation to iodine and
Organification
• Inside the cells, iodide is oxidized by membrane bound peroxidase system to
more reactive iodine (Iodinium or I+), or HOI or E-OI
• Iodine immediately reacts with tyrosine residue on a thyroid glycoprotein
called “thyroglobulin” to form: MIT and DIT
• Both processes are catalyzed by thyroid peroxidase enzyme
3) Coupling
• T1& T2 couple together to form T3 & T4
• MIT +DIT = T3 (Tri-iodothyronine)
• DIT + DIT = T4 (Thyroxine)
• Normally high amount of T4 is formed
• Homeostasis: In case of Iodine deficiency more MIT is formed and
hence more T3 – leading to more active hormone with less Iodine
Thyroxine and its precursors: Structure &
Synthesis
Figure 23-8: Thyroid hormones are made from tyrosine and iodine
4) Storage and release
• MIT, DIT, T3 and T4 - all attached to thyroglobulin and stored in the colloid
Thyroglobulin molecule
• This process is stimulated by TSH
• Taken up by follicular cells by the process of endocytosis and broken down
by lisosomal proteases
• T3 and T4 released and also MIT and DIT
• MIT and DIT are deiodinated and reutilized
• T4 & T3 enter circulation directly from follicular cells
• Free (unbound) hormone is a small percentage, 0.03%T4 and 0.3%T3 of the
total plasma hormone
• Only unbound form has metabolic activity
5) Peripheral conversion
• Peripheral tissues – liver and kidney
• T4 to T3
• 1/3rd of T4 undergoes these changes and most of T3 available are derived
from liver
• Equal amounts of T3 are produced in periphery
• Drugs like Propylthiourcil, propranolol and glucocorticoids inhibit peripheral
conversion
Transport, Metabolism and Excretion Kinetics
• Highly bound to plasma protein
• Only 0.04% of T3 and 0.2% T4 are in free form
• All Protein Bound Iodine (PBI) in plasma is thyroid hormone – 95%
is T4
• Main Plasma proteins for T4 are – TGB, TBP and albumin
• Only free form of hormone is available for action and metabolism
• Metabolism occurs by deiodination and conjugation, mainly in liver
and kidneys
• T4 is deiodinated to T3 (active) or rT3 (inactive) by deiodination
• Conjugated products are excreted in bile – enterohepatic
circulation
• Finally excreted in urine
T3 Vs T4
• T3 is 5 times more potent > T4
• Half life of T4 is 6-7 days and T3 is 1-2 days – hyper and hypothyroidism
• T4 is the major circulating hormone – bound more to plasma proteins
• T4 is less active and a precursor of T3 - the major mediator of physiological
effects
• The term thyroid hormone is used to comprise both T4 plus T3
• T4 deiodination to T3 or reverse T3
• T3 & reverse T3 deiodination
iodothyronines,
deiodinated
monoiodothyronines - (inactive)
to
three
to
ditwo
Thyroid hormones regulation
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●Regulation
of thyroid function
TRH: thyrotropin-releasing hormone
TSH: thyroid-stimulating hormone
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THYROID HORMONE ACTIVATION OF TARGET CELLS
Physiological actions of thyroid
hormones
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Growth & Development
Essential for normal growth and development
Congenital deficiency results in Cretinism
Milestones of development delayed
Retardation and nervous deficit
synapse formation and myelination impaired
Intelligence is impaired, slowness of movements
Metabolic Effects: Lipids
↑ lipolysis, Free fatty acids levels ↑.
Potentiates catecholamines and lipolytic hormones
Suppresses Phosphodiesterase
Cholesterol metabolism accelerates
Hypercholesterolemia and ↓ LDL in
Hyperthyroidism
Metabolic Effects: Carbohydrates
Carbohydrate metabolism stimulated
Utilization of sugar is enhanced
↑ Glycogenolysis and gluconeogenesis
Faster absorption of glucose
Hyperglycemia and insulin resistance in
hyperthyroidism
Metabolic Effects: Proteins
Catabolic effects
Protein used as energy source
Negative Nitrogen balance and tissue wasting
Weight loss in Hyperthyroidism
Calorigenesis
↑ BMR – stimulates cellular metabolism
Excess energy released as heat.
Metabolic rate in Brain, Gonads, uterus, Spleen and
Lymph node not affected
Cardio Vascular System
Hyperdynamic state of circulation: ↑ peripheral
demand
Heart rate, contractility and output ↑: fast,
Bounding Pulse
Up regulation of β receptors
Cardiovascular System
Atrial fibrillation and other arrhythmias in
Hyperthyroidism
Precipitate CHF and Angina, ↑ BP
Reduced myocardial O2 demand in Hypothyroidism
Nervous System
Mental retardation in cretinism, Sluggishness
Hyperthyroid persons are
oAnxious, Nervous, excitable
oExhibit tremors
oHyperreflexia
Skeletal Muscles
Flabby and weak in myxedema
Increased muscle tone, Tremors and weakness in
thyrotoxicosis
Gastro Intestinal System
 Increased peristalsis
Constipation: Hypothyroidism
Diarrhoea: Hyperthyroidism
Kidney
Increased urine flow when Patients treated
with Thyroid Hormones
Haemopoesis
T4 is facilitator for erythropoiesis
 Certain Patient who are not responding to
hematinic respond to thyroid hormone
 Hypochromic, Normochromic in Hypo
 Normochromic in Hyper
Reproduction
Impaired Fertility, Oligomenorrhoea in
hypothyroidism
Normal thyroid function is required for
maintenance of pregnancy and lactation
Infertility in Hypo and Hyper in females
Males - ↓Libido, Impotence, Oligozoospermia
Therapeutic Uses
• As Replacement therapy in deficiency states
• Available as l-thyroxine sod. 100, 50, 25 mcg tablets
• Liothyronine is available as 5, 25 mcg tabs and Injection
• Mixture of T3 and T4 tablets
• T4 - consistent potency and prolonged duration ofaction.
• 50% - 80% GIT absorption.
• T3 for quicker onset of action as in myxedema coma or
preparation of a patient for I131 therapy in thyroid cancer
Thyroid hormone replacement
therapy
• Cretinism
( is a condition of severely stunted physical and mental growth due to
untreated congenital deficiency of thyroid hormones (congenital
hypothyroidism) due to maternal nutritional deficiency of iodine.)
• Adult hypothyroidism
• Myxoedema
(A disease caused by decreased activity of the thyroid gland in adults an
d characterized by dry skin, swellings around the lips andnose, mental d
eterioration, and a subnormal basal metabolic rate.)
• Non toxic goitre
• Thyroid nodule (Thyroid nodules are lumps which commonly arise
within an otherwise normalthyroid gland.)
• Carcinoma of thyroid
Thyroid inhibitors
Hormone Synthesis Inhibitors (THIOAMIDES)
- Propylthiouracil, Methimazole, Carbimazole
Hormone release Inhibitors
- Iodine, NaI, KI
Damage to Thyroid tissue
- I131
Ionic Inhibitors
-Thiocynate (SCN-), Perchlorates(ClO4-), Nitrates (NO3-)
 β-adrenergic blocking drugs
- Propranolol, Atenolol.
Hormone Synthesis Inhibitors
Inhibit peroxidase → inhibit Hormone synthesis
 Inhibit iodination and Coupling
Onset of action requires 3-4 weeks to develop
Peripheral conversion of T4 to T3 only inhibited by
Prophylthiouracil
MECHANISM OF ACTION
• Iodide peroxidase
iodine
• Iodine + tyrosine
• MIT + DIT
iodotyrosines
T3
Pharmacokinetics
Rapidly absorbed, widely distributed and
concentrated in thyroid tissue
Peak effect with in 1 hour but longer duration(PTU)
Carbimazole → Methimazole
 Cross Placenta and secreted in milk
 Propylthiouracil can be given in pregnancy
Propylthiouracil Vs Carbimazole
Less Potent
3 times more potent
T1/2- 75 minutes
6-8 hours
Strongly PPB
Less PPB
Less crossing by placenta and in
milk
readily cross placenta and
secreted in milk
No active metabolite
Active metabolite – Methimazole
inhibit peripheral conversion
No effect on peripheral
conversion
Adverse effects
Hypothyroidism
Skin Rashes
Uncommon - Nausea, headache, Pain, Stiffness,
Skin Pigmentation, Loss/Graying of Hairs
Rare- Granulocytopenia, Hepatitis, Hepatic failure
with Propylthiouracil
 Use:
◦ Thyrotoxicosis (autoimmune hyperthyroidism) : life long
◦ Pre operatively to make euthyroid
(is the state of having normal thyroid gland function).
 Advantage –
◦ Less surgical complication
◦ If hypothyroidism develops then therapy can be stopped  normal function
 Disadvantage –
◦ Long term therapy
◦ Not practicable in unconscious patient
◦ Toxicity specially in pregnancy
INHIBITORS OF HORMONE RELEASE
IODIDES
IODIDE THERAPY
• Lugol's solution (5 % iodine + 10 % potassium iodide)
orally
• Potassium iodide orally 60 mg
MECHANISM OF ACTION
• Most important action is inhibition of hormone release-'thyroid
constipation’.
• The mechanism of action is not clear.
• Attenuate the effect of TSH on the thyroid gland, so decrease the size &
vascularity.
• Decrease exocytosis and proteolysis of thyroglobulin.
• Excess iodide inhibits its own transport in thyroid cells
• Alter the redox potential of cells, thus interfering with iodination
• Decrease release of T4 & T3
ADVERSE EFFECTS
On Acute Administration
 Hypersensitivity – Angioedema, Swelling of Larynx,
Swelling of Lips and eyelid.
Multiple Cutaneous Hemorrhage
Serum Sickness – fever, Arthralgia, Thrombocytopenia,
Lymphadenopathy (swollen/enlarged lymph nodes)
ADVERSE EFFECTS
On Chronic use (Dose Related)
 Brassy taste, Burning in mouth, Tenderness of teeth
and gums
 Rhinorrhea
( persistent watery mucus discharge from the nose),
lacrimation, Sneezing, Swelling of eyelids, Skin rashes.
Irritation of bronchial mucous glands
Enlargement of salivary glands
Hypothyroidism and goiter
USES
• Large doses for thyroid crisis – to reduce release
• Preparation for thyroidectomy (Surgical removal of the thyroid gland.)
• To make the gland firm, less vascular and easy to operate
• Prophylaxis of endemic goitre
• Thyroid storm
(The condition resulting from excessive activity of the thyroid gland, char
acterized by increased basal metabolism.)
• Antiseptic on skin / surgical scrub, expectorant
RADIOACTIVE IODINE
• Administered orally in solution as sodium 131I
MECHANISM OF ACTION:
• It is rapidly absorbed, concentrated by the thyroid, &
incorporated into storage follicles  emits β particles &
X rays  β particles damage the thyroid cells  thyroid
tissue
destroyed
by
piknosis
(a degenerative state of the cell nucleus)  replaced by
fibrosis
ADVANTAGE OF I131
Low treatment cost
Convenient, can be given on Out Patient Basis
Surgery can be avoided
Permanent control
DISADVANTAGE OF I131
Permanent Hypothyroidism
Lifelong Treatment by Thyroid Hormones
Delayed onset of action
 Can not be used in pregnancy
Carcinogenic – avoided in young patients
• C/I : Pregnancy
Young patients
• Adverse effect :
• Hypothyroidism
• crosses the placenta to destroy the fetal thyroid gland & is excreted in breast milk
(baby become hypothyroid)
THERAPEUTIC USES
Grave’s disease
(a disease characterized by an enlarged thyroid and increased bas
al metabolism due to excessive thyroid secretion) – failure of
Antithyroid drugs
 Elderly – who can not undergo thyroidectomy
 Toxic Nodular Goiter
(an enlarged thyroid gland characterized by numerous discrete no
dules and hypersecretion of thyroid hormones)
 Patient with existing heart disease
IONIC INHIBITORS
• Thiocynate (SCN-), Perchlorates (ClO4-), Nitrates (NO3- )
Inhibit iodide trapping → inhibit Synthesis
• Perchlorate, Thiocyanate - block uptake of iodine by the gland
through competitive inhibition of the iodide transport mechanism.
• Were used, Not Now.
Thiocynate – Hepatic, Renal, Brain and Bone marrow toxicity
Perchlorates – Aplastic anemia, Agranulocytosis, Rashes, Fever
Nitrates–Methaemoglobinaemia
(The presence of methemoglobin in the circulating blood)
β- adrenergic blocker
• Increased tissue
hyerthyroidism
sensitivity
to
catecholamine
in
• increased no. of “β” adrenoceptors (up regulation)
• Increased second messenger i.e. cAMP responses
• Some symptoms are adrenergic – palpitation, tremor,
nervousness, myopathy and sweating etc.
• β- blocker provides quick relief (propranolol 20-80mg 6-8
hrly)
• Not used as sole therapy – awaiting Carbimazole or I131
response,
preoperative
treatment
of
subtotal
thyroidectomy and Thyroid crisis
• Do not alter course of disease and thyroid function tests
Other drugs in Hyperthyroidism
β Blockers
 To control Tachycardia, Palpitation, tremors and
Tachyarrhythmia.
No effect on thyroid function
Propranolol, Atenolol. Esmolol
Propranolol inhibit peripheral conversion
Other Drugs in Hyperthyroidism
Calcium Channel Blockers: Diltiazem and Verapamil
 To control tachycardia and tachyarrhythmia
To inhibit peripheral conversion
Corticosteroids, Propranolol, Iopanoic Acid
To bind thyroid hormone in Gut
Cholestyramine
THANK YOU
-PHARMA STREET