Summary of thyroid and antithyroid drugs
-Introduction
-Synthesis
-Pharmacological Action
-Mechanism of action
-Drugs in Hypothyroidism
-Thyroid Inhibitors
-Drugs in Hyperthyroidism
2. THYROID GLAND
īĸ It is an Endocrine Gland, found at
the front of Neck below Adamâs
Apple.
īĸ Produces three Hormones:-
ī Thyroxine T4
ī Triidothyronine T3
ī Calcitonin
īĸ T4 and T3 have same Biological
activity and termed as âThyroid
Glandâ secreted by Folliclular cell.
īĸ Calcitonin is produced by C Cells
which regulate Ca2+ metabolism.
3. CHEMISTRY AND SYNTHESIS
īĸ T4 and T3 are iodine containing thyronine derivatives:-
2tyrosineīŽThyronine + 3I- īŽ 3,5,3âtriiodothyronine (T3)
+ 4 I- īŽ3,5,3â,5âtetraiodothyronine (T4)
īĸ Iodide Uptake
īĸ Oxidation and Iodination
īĸ Coupling
īĸ Storage and Release
īĸ 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
īIodine obtain from food and water
īBody Contains 30-50 mg out of which
1/5th in Thyroid
īActively transported by Na+: Iodide
Symporter (NIS) from blood to follicle
īTSH stimulate uptake by 100 folds
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
īFollicle iodide carried across apical
membrane by Pendrin(PDS)
īIodide oxidized by Thyroid Peroxidase
which easily binds to tyrosil to form MIT
and DIT which are attached to
Thyroglobulin
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
īTyrosil Residue Couple to Form T4 and
T3
īTSH stimulate both Coupling and
Oxidation
īThyroglobulin 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
ī Thyroid Colloid is taken by endocytosis
īBroken by Lysosymal Protease
īT4 and T3 are released while MIT and DIT
are re-utilized
īNormal Human Secretes 60-90Îŧg of T4
and 10-30Îŧg of T3
īPeripheral tissue, Liver, Kidney convert
about 1/3rd T4 to T3 by Iodothyronine
deiodinase
īTarget 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
13. ACTION
īĸ T4 and T3 have same quantitatively action
īĸ Growth and Development:-
ī Essential for normal growth
ī Control protein synthesis
ī Hypothyrodism suffer nervous system mostly
ī Cause impaired intelligence and slow movement
īĸ Intermediary Metabolism:-
ī Lipid:
īĸ Indirectly enhance lypolysis
īĸ Results in increase plasma free fatty acid
īĸ Hyperthyroidism cause hypocholesterolemia
ī Carbohydrates:
īĸ Metabolism Stimulated
īĸ Increase utilization of sugar
īĸ Absorption from intestine is faster causes
hyperglycaemia
14. ī Protein:
īĸ Regulate Protein Synthesis, mainly catabolise
īĸ Weight Loss in Hyperthyroidism
īĸ Calorigenesis:-
ī Increase BMR by stimulating cellular metabolism and resets energy state
īĸ CVS:-
ī Increase peripheral demand
ī Increase cardiac actions:- HR, FOC and output
ī Myocardial O2 consumption is decreased in hypothyroidism
īĸ Nervous System:-
ī Hypothyroidism: mental retardation (cretinism),
sluggishness (myxoedema)
ī Hyperthyroidism: anxiousness, nervousness, excitable,
Tremor and weakness
īĸ GIT:-
ī Propulsive activity of gut is increased-
īĸ Diarrhea: hyperthyroidism
īĸ Constipation: Hypothyroidism
15. MECHANISM OF ACTION
īĸ 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
īĸ When T3 bind to ligand binding domain of TR, TR heterodimerizes
and undergoes conformational change
īĸ This causes corepressor release and coactivator binding these
induces gene expression
Gene transcrtiption īŽ Production of mRNA īŽ Protein Synthesis
īŽ various metabolic and anabolic effect
īĸ Repression by T3: The unliganded TR allow gene transcription
while binding of T3 to TR halt process
īĸ 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).
T3âTriiodothyronine; T4âThyroxine; TREâThyroid hormone response element; RXRâ
Retinoid Xreceptor; mRNAâMessenger ribonucleic acid; 5âDIâ5âDeiodinase
17. DRUG IN HYPOTHYROIDISM
īĸ Clinically, 1-thyroxine is preferred because of more sustained and uniform
action as well as lower risk of cardiac arrthymias
īĸ Pharmacokinetic: ~ 75% oral bioavailability
īĸ Uses:
ī Cretinism: Failure or defect in thyroid development, usually in infants,
treatment should be fast (8-12 Îŧg/kg daily)
ī 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 50Îŧg daily& increased every 2-3 week to 100-200Îŧg)
ī Myxoema Coma: Emergency caused by progressive mental deterioration,
Rapid thyroid replacement (200-500Îŧg i.v. followed by
100Îŧg OD till oral therapy instituted)
ī Nontoxic Goitre, Thyroid Nodule, Empirical Use:
Mental depression, Obstimate Constipation
īĸ Marketed Preparation: Eltroxin 25Îŧg, 50Îŧg, 100Îŧg tab;
Thyronorm tab
18. THYROID INHIBITORS
īĸ These drugs lower the functional capacity of the hyperactive thyroid
gland (treat hyperthyroidism)
īĸ Thyrotoxicosis is due to excessive secreation of thyroid hormone two
main causes:-
ī Graveâs Disease: Autoimmune disease, IgG antibodies to TSH receptor
bind and show TSH like effect, feedback mechanism is inhibited because
TSH levels are low
ī Toxic Nodular Goiter: Produces thyroid hormone independent of TSH
īĸ CLASSIFICATION:-
ī Inhibit Hormone Synthesis (Anti thyroid Drugs):-
īĸ Propylthiouracil, Methimazole, Carbimazole
ī Inhibit Iodide Trapping (Ionic Inhibitors):-
īĸ Thiocynates (-SCN), Perchlorates (-ClO4), Nitrates(-NO3)
ī Inhibit Hormone Release:-
īĸ Iodine, Iodides of Na and K, Organic Iodide
ī Destroy Thyroid Tissue:-
īĸ Radioactive Iodine (131I, 125I, 123I)
19. ANTITHYROID DRUGS (THIOAMIDES)
ī Propylthiouracil
ī Methimazole
ī Carbimazole
īĸ Mode of Action:-
ī Bind to Thyroidperoxidase and prevent oxidation of iodide residue,
thereby:-
īĸ Inhibition of iodination of tyrosine residues in thyroglobulin
īĸ Inhibition of coupling of iodotyrosine residue
ī They do not interfere with trapping of iodide and do not modify T3 and T4
action
ī They do not affect release of T3 and T4 and show no effect till thyroid is
depleted
ī Propylthiouracil inhibit T4 to T3 conversion while Methimazole and
Carbimazole cannot while they antagonizes former
īĸ 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. īĸ Adverse Effect:-
ī Hypothyroidism and goiter can occur due to overtreatment of drug but
reversible on stopping treatment
ī GI intolerance, Skin Rashes and Joint Pain
īĸ USES:-
ī Controls thyrotoxicosis in both Graveâs disease and toxic nodule goiter
ī Clinical improvements starts after 1-2 weeks or more
īĸ Advantage:- No surgical risk, reversible hypothyroidism, use for children
īĸ Disadvantage:- Prolonged treatment, Drug toxicity
īĸ Marketed Preparation:-
ī Propylthiouracil: 50-150 mg TDS followed by 25-50 mg BD-TDS
for maintenance PTU 50 mg
ī Methimazole: 5-10 mg TDS initially, maintenance dose
5-10 mg OD-BD
ī Carbimazole: 5-15 mg TDS initially, maintenance dose
2.5-10 mg OD-BD Neo Mercazole, Thy rozole, Antithyrox
22. IODINE AND IODIDES
īĸ Constituent of thyroid hormone and potentiate thyrotoxicosis but excess
causes inhibition of hormone release âThyroid Constipationâ
īĸ Endocytosis of colloid and proteolysis of thyroglobulin comes to a halt
īĸ USE:-
ī Preoperative preparation for thyoidectomy in Graveâs disease
ī Thyroid storm
ī Prophylaxis of endemic goiter
ī Antiseptic
īĸ Adverse effect:-
ī Acute: Swelling of lips, eyelids, fever joint pain
ī Chronic: Inflammation of mucous membrane, salivation, headache,rashes
īĸ Marketed Preparations:-
ī Lugolâ Solution (5% iodine in 10% KI solution)
Lugolâs Solution; Colloid Iodine 10% Collosol 5 mg
24. RADIOACTIVE IODINE
īĸ Stable isotope 131I is medicinal important (half life 8 days)
īĸ Both diagnostic and therapeutic use:-
ī Diagnostic: Îŗ-rays are useful in tracer studies 25-100 ÎŧCurie is given,
counting or scanning is done at intervals, No damage to thyroid at this dose
ī 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
īĸ Advantage:-
ī Simple an inexpensive
ī No surgical Risk, Scar or Injury
ī Cure is permanent after control
īĸ Disadvantage:-
ī Hypothyroidism
ī Long latent response period
ī Not suitable for young patients