Summary of thyroid and antithyroid drugs -Introduction -Synthesis -Pharmacological Action -Mechanism of action -Drugs in Hypothyroidism -Thyroid Inhibitors -Drugs in Hyperthyroidism

1. THYROID AND ANTI-THYROID
DRUGS
Prepared By-
Shadab Khan
Guided By-
Dr. Dharmesh Sisodiya

2. THYROID GLAND
 It is an Endocrine Gland, found at
the front of Neck below Adam’s
Apple.
 Produces three Hormones:-
 Thyroxine T4
 Triidothyronine T3
 Calcitonin
 T4 and T3 have same Biological
activity and termed as “Thyroid
Gland” secreted by Folliclular cell.
 Calcitonin is produced by C Cells
which regulate Ca2+ metabolism.

3. CHEMISTRY AND SYNTHESIS
 T4 and T3 are iodine containing thyronine derivatives:-
2tyrosineThyronine + 3I-  3,5,3’triiodothyronine (T3)
+ 4 I- 3,5,3’,5’tetraiodothyronine (T4)
 Iodide Uptake
 Oxidation and Iodination
 Coupling
 Storage and Release
 Peripheral Conversion of T4 to T3

4. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
TSH
Stimulates gene
transcription for
this carrier
I-I-
IODIDE UPTAKE
Iodine obtain from food and water
Body Contains 30-50 mg out of which
1/5th in Thyroid
Actively transported by Na+: Iodide
Symporter (NIS) from blood to follicle
TSH stimulate uptake by 100 folds

5. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
TSH
Stimulates gene
transcription for
this carrier
I-I-

6. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
I-I-
Thyroperoxidase
TG
T
DIT
MITMIT
T T
T
DIT
TG
T
T
T
T
T
Protein Synthesis
OXIDATION AND IODINATION
Follicle iodide carried across apical
membrane by Pendrin(PDS)
Iodide oxidized by Thyroid Peroxidase
which easily binds to tyrosil to form MIT
and DIT which are attached to
Thyroglobulin

7. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
I-I-
Thyroperoxidase
TG
T
DIT
MITMIT
T T
T
DIT
TG
T
T
T
T
T
Protein Synthesis

8. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
I-I-
Thyroperoxidase
TG
T
DIT
MITMIT
T T
T
DIT
TG
T
T
T
T
T
Protein Synthesis
COLLOID
MIT+DIT =Triidothyronine T3
DIT+DIT =Thyroxine T4
COUPLING AND STORAGE
Tyrosil Residue Couple to Form T4 and
T3
TSH stimulate both Coupling and
Oxidation
Thyroglobulin transported to Colloid
present interior of follicle

9. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
I-I-
Thyroperoxidase
TG
T
DIT
MITMIT
T T
T
DIT
TG
T
T
T
T
T
Protein Synthesis
COLLOID
MIT+DIT =Triidothyronine T3
DIT+DIT =Thyroxine T4

10. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
I-I-
Thyroperoxidase
TG
T
DIT
MITMIT
T T
T
DIT
TG
T
T
T
T
T
Protein Synthesis
COLLOID
MIT+DIT =Triidothyronine T3
DIT+DIT =Thyroxine T4
T
G
TG
L
T4
T3
T4
T3
MIT
DIT
I-
deiodination
RELEASE AND CONVERSION
 Thyroid Colloid is taken by endocytosis
Broken by Lysosymal Protease
T4 and T3 are released while MIT and DIT
are re-utilized
Normal Human Secretes 60-90μg of T4
and 10-30μg of T3
Peripheral tissue, Liver, Kidney convert
about 1/3rd T4 to T3 by Iodothyronine
deiodinase
Target tissue take up T3 for metabolic need

11. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
I-I-
Thyroperoxidase
TG
T
DIT
MITMIT
T T
T
DIT
TG
T
T
T
T
T
Protein Synthesis
COLLOID
MIT+DIT =Triidothyronine T3
DIT+DIT =Thyroxine T4
T
G
TG
L
T4
T3
T4
T3
MIT
DIT
I-
deiodination

12. REGULATION OF SECRETION

13. ACTION
 T4 and T3 have same quantitatively action
 Growth and Development:-
 Essential for normal growth
 Control protein synthesis
 Hypothyrodism suffer nervous system mostly
 Cause impaired intelligence and slow movement
 Intermediary Metabolism:-
 Lipid:
 Indirectly enhance lypolysis
 Results in increase plasma free fatty acid
 Hyperthyroidism cause hypocholesterolemia
 Carbohydrates:
 Metabolism Stimulated
 Increase utilization of sugar
 Absorption from intestine is faster causes
hyperglycaemia

14.  Protein:
 Regulate Protein Synthesis, mainly catabolise
 Weight Loss in Hyperthyroidism
 Calorigenesis:-
 Increase BMR by stimulating cellular metabolism and resets energy state
 CVS:-
 Increase peripheral demand
 Increase cardiac actions:- HR, FOC and output
 Myocardial O2 consumption is decreased in hypothyroidism
 Nervous System:-
 Hypothyroidism: mental retardation (cretinism),
sluggishness (myxoedema)
 Hyperthyroidism: anxiousness, nervousness, excitable,
Tremor and weakness
 GIT:-
 Propulsive activity of gut is increased-
 Diarrhea: hyperthyroidism
 Constipation: Hypothyroidism

15. MECHANISM OF ACTION
 T4 and T3 penetrate cell by active transport and produces action
by combining with nuclear Thyroid Hormone Receptor (TR)
bound to TRE in enhancer region of target gene along with co-
repressor causes gene transcription suppression
 When T3 bind to ligand binding domain of TR, TR heterodimerizes
and undergoes conformational change
 This causes corepressor release and coactivator binding these
induces gene expression
Gene transcrtiption  Production of mRNA  Protein Synthesis
 various metabolic and anabolic effect
 Repression by T3: The unliganded TR allow gene transcription
while binding of T3 to TR halt process
 Tachycardia, high BP, tremor, hyperglycemia are mediated by
sensitization of adrenergic receptors to catecholamines

16. Mechanism of action of thyroid hormone on nuclear thyroid hormone receptor (TR).
T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR—
Retinoid Xreceptor; mRNA—Messenger ribonucleic acid; 5’DI—5’Deiodinase

17. DRUG IN HYPOTHYROIDISM
 Clinically, 1-thyroxine is preferred because of more sustained and uniform
action as well as lower risk of cardiac arrthymias
 Pharmacokinetic: ~ 75% oral bioavailability
 Uses:
 Cretinism: Failure or defect in thyroid development, usually in infants,
treatment should be fast (8-12 μg/kg daily)
 Adult Hypothyroidism (Myxoedema): Disorder caused by autoimmmune
thyroiditis or thyroidectomy, Simple Goiter in iodine deficiency, Antibodies
against thyroid H2O2 / Thyroglobulin, Drugs such as 131I iodide, Li also
causes (start low dose 50μg daily& increased every 2-3 week to 100-200μg)
 Myxoema Coma: Emergency caused by progressive mental deterioration,
Rapid thyroid replacement (200-500μg i.v. followed by
100μg OD till oral therapy instituted)
 Nontoxic Goitre, Thyroid Nodule, Empirical Use:
Mental depression, Obstimate Constipation
 Marketed Preparation: Eltroxin 25μg, 50μg, 100μg tab;
Thyronorm tab

18. THYROID INHIBITORS
 These drugs lower the functional capacity of the hyperactive thyroid
gland (treat hyperthyroidism)
 Thyrotoxicosis is due to excessive secreation of thyroid hormone two
main causes:-
 Grave’s Disease: Autoimmune disease, IgG antibodies to TSH receptor
bind and show TSH like effect, feedback mechanism is inhibited because
TSH levels are low
 Toxic Nodular Goiter: Produces thyroid hormone independent of TSH
 CLASSIFICATION:-
 Inhibit Hormone Synthesis (Anti thyroid Drugs):-
 Propylthiouracil, Methimazole, Carbimazole
 Inhibit Iodide Trapping (Ionic Inhibitors):-
 Thiocynates (-SCN), Perchlorates (-ClO4), Nitrates(-NO3)
 Inhibit Hormone Release:-
 Iodine, Iodides of Na and K, Organic Iodide
 Destroy Thyroid Tissue:-
 Radioactive Iodine (131I, 125I, 123I)

19. ANTITHYROID DRUGS (THIOAMIDES)
 Propylthiouracil
 Methimazole
 Carbimazole
 Mode of Action:-
 Bind to Thyroidperoxidase and prevent oxidation of iodide residue,
thereby:-
 Inhibition of iodination of tyrosine residues in thyroglobulin
 Inhibition of coupling of iodotyrosine residue
 They do not interfere with trapping of iodide and do not modify T3 and T4
action
 They do not affect release of T3 and T4 and show no effect till thyroid is
depleted
 Propylthiouracil inhibit T4 to T3 conversion while Methimazole and
Carbimazole cannot while they antagonizes former
 Pharmacokinetic: All drugs are quickly absorbed orally and widely
distributed in body

20. FOLLICLE CELL
NIS PDS
P
P
PLASMA FOLLICLE LUMEN
I-I-
Thyroperoxidase
TG
T
DIT
MITMIT
T T
T
DIT
TG
T
T
T
T
T
Protein Synthesis
COLLOID
MIT+DIT =Triidothyronine T3
DIT+DIT =Thyroxine T4
T
G
TG
L
T4
T3
T4
T3
MIT
DIT
I-
deiodination
Thioamides and Excess I-
Propylthiouracil Methimazole
Carbimazole

21.  Adverse Effect:-
 Hypothyroidism and goiter can occur due to overtreatment of drug but
reversible on stopping treatment
 GI intolerance, Skin Rashes and Joint Pain
 USES:-
 Controls thyrotoxicosis in both Grave’s disease and toxic nodule goiter
 Clinical improvements starts after 1-2 weeks or more
 Advantage:- No surgical risk, reversible hypothyroidism, use for children
 Disadvantage:- Prolonged treatment, Drug toxicity
 Marketed Preparation:-
 Propylthiouracil: 50-150 mg TDS followed by 25-50 mg BD-TDS
for maintenance PTU 50 mg
 Methimazole: 5-10 mg TDS initially, maintenance dose
5-10 mg OD-BD
 Carbimazole: 5-15 mg TDS initially, maintenance dose
2.5-10 mg OD-BD Neo Mercazole, Thy rozole, Antithyrox

22. IODINE AND IODIDES
 Constituent of thyroid hormone and potentiate thyrotoxicosis but excess
causes inhibition of hormone release “Thyroid Constipation”
 Endocytosis of colloid and proteolysis of thyroglobulin comes to a halt
 USE:-
 Preoperative preparation for thyoidectomy in Grave’s disease
 Thyroid storm
 Prophylaxis of endemic goiter
 Antiseptic
 Adverse effect:-
 Acute: Swelling of lips, eyelids, fever joint pain
 Chronic: Inflammation of mucous membrane, salivation, headache,rashes
 Marketed Preparations:-
 Lugol’ Solution (5% iodine in 10% KI solution)
Lugol’s Solution; Colloid Iodine 10% Collosol 5 mg

23. REGULATION OF SECRETION

24. RADIOACTIVE IODINE
 Stable isotope 131I is medicinal important (half life 8 days)
 Both diagnostic and therapeutic use:-
 Diagnostic: γ-rays are useful in tracer studies 25-100 μCurie is given,
counting or scanning is done at intervals, No damage to thyroid at this dose
 Thrapeutic: β-particles are used for their destructive effectb on thyroid
cells 131I concentrated in thyroid colloid and emit radiation from within and
penetrates only 0.5-2 mm
Average 3-6 mCurie is used on the basis of thyroid size. The response is
slow and starts after 2 weeks
 Advantage:-
 Simple an inexpensive
 No surgical Risk, Scar or Injury
 Cure is permanent after control
 Disadvantage:-
 Hypothyroidism
 Long latent response period
 Not suitable for young patients

25. THANK YOU