Download Anti-thyroid agent

ANTI-THYROID AGENTS
Thyroid Gland
 Over Trachea
 Two lobes connected together by isthmus
 15 to 20 gms weight
 Second largest endocrine gland in body
 Small butterfly shaped gland located at base of neck below the
sternocleidomastoid muscles
 Thyroid is controlledby 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.
 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 pituitary 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.
 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
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
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.
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
a. Iodide uptake enhancers:
i. TSH
ii. Iodine deficiency
iii. TSH receptors antibody
b. Iodide uptake inhibitors
i. Iodide ion
ii. Drugs
1. Digoxin
2. Thiocynate
3. 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
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
• T4deiodination to T3 or reverse T3
• T3& reverse T3deiodination to three di-iodothyronines, deiodinated to two
monoiodothyronines - (inactive)
Mechanism of Action
 Produce action by combining with TR (Nuclear Thyroid hormone receptor)
 TR reside in nucleus bound to Thyroid Hormone Response Element (TRE).
 When T3 Bind to TR it heterodimerizes with Retinoid X receptor (RXR)
undergoes conformational change and bind to Co-Activator
 Induces gene transcription – Produces specific mRNA and Specific Protein
synthesis
Physiological actions of thyroid hormones
1) 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
2) Metabolic Effects: Lipids
- ↑ lipolysis, Free fatty acids levels ↑.
- Potentiates catecholamines and lipolytic hormones
- Suppresses Phosphodiesterase
- Cholesterol metabolism accelerates
- Hypercholesterolemia and ↓ LDL in Hyperthyroidism
3) Metabolic Effects: Carbohydrates
- Carbohydrate metabolism stimulated
- Utilization of sugar is enhanced
- ↑Glycogenolysis and gluconeogenesis
- Faster absorption of glucose
- Hyperglycemia and insulin resistance in hyperthyroidism
4) Metabolic Effects: Proteins
- Catabolic effects
- Protein used as energy source
- Negative Nitrogen balance and tissue wasting
- Weight loss in Hyperthyroidism
5) Calorigenesis
- ↑ BMR – stimulates cellular metabolism
- Excess energy released as heat.
- Metabolic rate in Brain, Gonads, uterus, Spleen and Lymph node not affected
6) Cardio Vascular System
- Hyperdynamic state of circulation: ↑ peripheral demand
- Heart rate, contractility and output ↑: fast, Bounding Pulse
- Up regulation of β receptors
- Atrial fibrillation and other arrhythmias in Hyperthyroidism
- Precipitate CHF and Angina, ↑ BP
- Reduced myocardial O2 demand in Hypothyroidism
7) Nervous System
- Mental retardation in cretinism, Sluggishness
- Hyperthyroid persons are
o Anxious, Nervous, excitable
o Exhibit tremors
o Hyperreflexia
8) Skeletal Muscles
- Flabby and weak in myxedema
- Increased muscle tone, Tremors and weakness in thyrotoxicosis
9) Gastro Intestinal System
- Increased peristalsis
- Constipation: Hypothyroidism
- Diarrhoea: Hyperthyroidism
10) Kidney
- Increased urine flow when Patients treated with Thyroid Hormones
11) 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
12) 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 and characte
rized by dry skin, swellings around the lips andnose, mental deterioration, and a s
ubnormal basal metabolic rate.)
Non toxicgoitre
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
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
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 iodideorally 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)
 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, characterize
d 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 basal metabolism du
e 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 nodules and hypers
ecretion 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 sensitivity to catecholamine in hyerthyroidism
– 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 I131response, 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
 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