Pharmacotherapy of thyroid disorders

1. Thyroid disorders
Dr. Sujay Patil

2. Thyroid gland
– serves a cosmetic function of giving grace to
the contour of the neck ”
- Wharton (1656)

3. History
• Described by Galen
• Wharton (1656) - glandulae thyroideae
• Hyperthyroidism – Parry 1825
- Graves 1835
- Basedow 1840
• Murray (1891) - treated case of hypothyroidism
• Magnus Levy (1895) – effect of thyroid on metabolic rate
• Kendell(1915) – isolated thyroxine in crystalline form
• Harrington and Barger (1927) - synthesized thyroxine

4. Introduction
• Thyroid gland – a large gland in neck, secrete hormones that regulate
growth and metabolism.
• Weight – 25 -35 gm.
• Basic unit of thyroid gland – thyroid follicle
• Follicular cells secrete T3 and T4 & Parafollicular cells (C- cells)
secrete Calcitonin under TSH influence.

5. Chemistry and Synthesis
• T3 & T4 – iodine containing derivatives of thyronine
• Thyroxine (T4) – 3,5,3’,5’ tetroidothyronine
(T3) – 3,5,3’ tridothyronine
• Thyroid hormones are stored in thyroid follicle as part of TGB
molecule

8. Steps involved in Synthesis
1) Iodide trap by follicular cells
Trap with help of N+/I- Symporter in to follicular cells
2) Oxidation & Iodination
Pendrin transport Iodide into cytosol
Iodide oxidized Thyroid peroxidase Iodinium(I+)
H2O2 Hypoiodus acid (HOI)
Enzyme linked hypoiodate
(E-OI)
These combine with tyrosil residues of TGB to form MIT & DIT.

9. 3) Coupling
Iodinated tyrosil residues couple together under thyroid peroxidase
enzyme influence.
MIT + DIT – T3
DIT + DIT – T4
Oxidation and coupling both under TSH influence
4) Storage & Release
Iodinated Tyrosil & Thyronil reisdues remain as colloid & later
transported into interior of cells by endocytosis. Lysosomes engulf
colloid and acted upon by proteolytic enzymes. TSH influence present.
Free T3 & T4 released, MIT & DIT deiodinated.

10. 5) Transport of T3 & T4 into plasma & their protein binding
TBG – 75 % T3,T4 TBPA – 15 – 20 % TBA – 12 – 15 %
Free T3 – 0.5% Free T4 – 0.05%
6) Peripheral conversion of T4 to T3
Liver & kidney convert T4 T3
Target tissue need T3 for metabolic action
T4 DID – 1 T3 (Active) Propylthiouracil inhibit DID -1
DID – 2
Amiodarone inhibit DID – 1 & 2
T4 DID – 1 rT3 (Inactive)
DID – 3

11. Transport, Metabolism & Excretion
• Same as discussed
• Glucoronide / sulfate conjugation of hormones & deiodinated
products.
• Liver (primary), kidney & salivary glands are other metabolic sites.
• Conjugated metabolites excrete in bile followed by deconjugation in
intestines & again reabsorbed (Enterohepatic circulation).
• T ½ T4 – 6-7 days
T3 – 1-2 days

12. Regulation of Thyroid hormone Secretion

13. • Action of TRH on pitutary & TSH on thyroid mediated by enhanced
cAMP synthesis.
• Proterelin – another synthetic tripeptide acting like TRH.

14. Mechanism of action of Thyroid Hormone

15. • T3, T4 penetrate by active transport in cell & bind to thyroid hormone
receptor (TR).
• Usually TR is in inactivated state & is bound to thyroid response
element (TRE) along with corepressors keeping gene transcription
suppressed.
• T3 bind to TR binding leads to heterodimerization with Retionoid X
Receptor (RXR). Conformational change releasing corepressor and
binding co-activator.
• Induces gene transcription, pattern specific mRNA, protein synthesis
& metabolic effects.

16. Physiological Actions
1. Growth & development
Mainly Milestone & CNS development
2. Intermediary metabolism
Lipids – enhance lipolysis (catecholamine's, lipolytic hormones)
Carbohydrate – Increased glucose utilization by cells
Glycogenolysis & Gluconeogenesis
Increased absorption
Diabetic like state
Proteins – Prolong action of T3 results in – ve nitrogen balance & tissue
wasting (Weight loss).

17. 3. Calorigeneis
Uncoupling of oxidative phosphorylation release excess energy & heat.
4. CVS
Increased peripheral demand, contractility & CO (Hyper dynamic state).
Up regulate Beta receptors.
5. Nervous system
Behavioural & functional effects.
6. Skeletal Muscle
Low – Weak & flabby muscles, High - tone, tremor

18. 7. GIT
Low - GI motility – Constipation
High - GI motility – Diarrhoea
8. Kidney
Increased urine frequency
9. Haemopoesis
Facilitate erythropoiesis. If low – anemia occurs.
10. Reproduction
Normal pregnancy & lactation. If Low – fertility impaired.

19. Thyroid Disorders
 Hypothyroidism
 a syndrome due to deficiency of thyroid hormones.
 Irreversible mental retardation in children
 More common in women.

20. 1. Cretinism
Hypothyroidism during foetal life
Mental retardation, pot bellied, yellow skin dwarfs (Cretins).
More weight due to decreased BMR
 Due to Iodine deficiency OR presence of TSH receptor – blocking
antibodies.
Insulin resistance
Endemic cretinism – mother is iodine deficient

21.  Rx
• Initial daily dose - L-T4 10–15 mcg/kg
• Doses adjusted at
4–6-week intervals during first 6 months,
2-month intervals during the 6–18-month,
then 3–6-month intervals
• Goal - maintain serum free T4 levels in the upper half of the
normal range, or slightly above the normal range, with a normal
TSH.

22. 2. Myxoedema
 Hypothyroidism during adult years.
 Antibodies against thyroid peroxidase or thyroglobulin
 Severe hypothyroidism in which there is accumulation of
hydrophilic mucopolysaccharides in the skin and other tissues
making face to swell and look puffy.
 Increased deposition of glycosamino glycan's.
 Common in women.

23.  Rx
• Supportive care and treatment of the precipitating cause
L-T4 - loading dose 200–300 mcg
- 24 hours later 100 mcg
IV daily maintenance dose
• Add - L-T3 - 10 mcg IV 8 hourly ( in young pts.)
• Overly aggressive treatment – may be associated with increased
mortality

24. 3. Myxoedema Coma
 Medical emergency
 Uncommon but life threatening form of untreated hypothyroidism
with physiological decompensation.
 Occurs in patients with long standing hypothyroidism.
 Precipitated by a climate induced hypothermia, infection, drug
therapy and other systemic conditions
 Progressive mental deterioration
 Increased mortality risk

25.  Rapid Rx required
 Ventilate pt. if respiratory acidosis is significant.
 Immediate IV levothyroxine given
 Loading dose of 500 - 800mcg followed by 50 – 100mcg daily.
 Hydrocortisone 100 mg IV
 Treatment of associated infection.
 Correction of hyponatremia with saline.
 Correction of hypoglycemia with IV dextrose.

26. 4. Hashimoto’s thyroiditis
 Immune reaction against TG
 Autoimmune destruction of thyroid gland
 Low T3, T4 & TSH
 Rx – L-thyroxine
Mild: 50 -75 µg/day
Moderate & severe: 1.6 µg/kg body weight.

27. 5. Non – toxic goitre
 Endemic or Sporadic
 Endemic – deficiency of iodine
 Sporadic – Defect in hormone synthesis
 Low T3, T4 Increased TSH Thyroid gland enlargement
more iodide trapped increased T3 synthesis
demands met patient euthyroid.
 Rx – 150 – 200 µg of iodine daily ( iodized edible salt)

28. 6. Thyroid nodule
 Excess TSH release causes a thyroid nodule
 Rx – T4 therapy 2.6 µg/kg single oral daily dose
 Stop Rx if no reduction in 6 months
7. Papillary Carcinoma of Thyroid
 Excess TSH
 Rx – T4 therapy 2.5 – 3.5 µg/kg/day
8. Hypothyroidism during pregnancy
 Maternal TBG levels, so less free T4. Rx – L – thyroxine on
demand

29.  Hyperthyroidism
 Hyperthyroidism - T3, T4 production
 Thyrotoxicosis - ingestion of thyroid hormones
1. Grave’s disease
 Most common
 Autoimmune disorder
 Pt. produce TSH receptor stimulating Ab’s mimicking action of TSH,
no negative feedback.
 T3, T4, TSH – R Ab’s & TSH is low.

30.  Enlarged thyroid, exophthalmos are evident.
 Rx
• Immediate control: Propranolol 40mg/6hr orally.
• Long term control: Anti thyroid drugs – Carbimazole 15mg TDS
initially and then reducing it to 5mg TDS for 12-18 months.
• Radio iodine ablation – Postmenopausal women and elderly
men.
• Thyroidectomy – If presence of large goitre and poor drug
compliance.

31. 2. Toxic – nodular goitre
 Single adenoma – Plummer’s disease
 Multiple adenoma – Multinodular goitre
 Usually disease progress from non-toxic to toxic phase
 Excess T3, T4
 Rx - same as that of Grave’s disease but surgery is preferred.

32. 3. Subacute thyroiditis
 Viral infection Enlarged & tender thyroid
 Resolve over weeks or months.
 If non – tender – called silent thyroiditis
 Initially, T4 & T3 are elevated and TSH is low, but as the disease
progresses T4 & T3 will drop and TSH will rise
Rx
• In most cases only symptomatic Rx is necessary e.g.
acetaminophen 0.5 g four times daily

33. • If pain, fever, and malaise, a short course of NSAID or a
glucocorticoid such as prednisone 20mg three times daily for 7-
10 days may be necessary to reduce the inflammation.
• L-thyroxine is indicated during the hypothyroid phase of the
illness. 10% of the patients will require L-thyroxine long term.

34. 4. Thyroid storm
 Extreme manifestation of thyrotoxicosis
 Fatal & occurs in association with Grave’s or Toxic Nodular Goitre.
 More common in pts. who are incompletely / not treated for
thyrotoxicosis.
 Due to cytokine release & acute immunological disturbance.
 If pt. not rendered euthyroid before surgery, increased risk.
 CF – Fever, sweating, tachycardia, arrhythmias, diarrhoea, delirum,
Pul. Edema, stupor, coma & death.

35.  Rx Aim
• To decrease both synthesis & release of thyroid hormones
• Block increased adrenergic activity
• Supportive measures
Propylthiouracil – 250 µg QID orally
Collosal Iodine (saturated KI solution) > 6 mg daily orally
OR
Sodium ipodate 1 g orally daily
 Propranolol 1 – 2 mg slow IV f/b 40 – 80 mg oral
 Hydrocortisone 100 mg IV f/b oral prednisolone
 Diltiazem ( if propranolol CI) 60 – 120 mg BD oral

36.  Rehydration, anxiolytics, external cooling & antibiotics.
If above measures fail, Plasmapheresis recommended.

37. 5. Neonatal Hyperthyroidism
 Some neonates born to mothers with Graves’ disease will be
hyperthyroid at delivery
 Antithyroid drug therapy up to 12 weeks
• Propylthiouracil 5–10 mg/kg per day or
• Methimazole 0.5–1 mg/kg per day
 One drop per day of SSKI (Saturated Solution of Potassium Iodide)
in the first few days.

39. Thyroid Drugs
1. Levo-thyroxine (T4) Sodium
Preferred over Liothyronine (T3)
Sustained & uniform action
Low arrhythmic risk
Easily deiodinated to T3
Good oral BA
Long t ½ - once daily dose.
Sucralfate, iron, Ca+ & PPI reduce absorption (empty stomach).

40. 2. Liothyronine (T3) Sodium
 Not freely available
 Occasionally used IV along with L-thyroxine in myxoedema coma.
 Costly, short t ½ .
 Used in short term suppression of TSH in pts. undergoing thyroid
cancer surgery & in case of DID deficiency who fail to convert T4 to
T3.

41.  Adverse effects
 Tachycardia, palpitation, weight loss, diarrhoea, insomnia, heat
intolerance.
 Rapid correction of hypothyroidism in IHD pts. can precipitate
angina.
 Drug Interactions
 TH therapy increase insulin requirement in diabetic pts.
 Pts. on TH therapy need large doses of digoxin.
 During concomitant therapy, doses of anticoagulants need to be
reduced.

42. Thyroid Inhibitors
A. Inhibit Thyroid Hormone synthesis (Thioamides)
 Propylthiouracil, Methimazole & Carbimazole.
 Bind to thyroid peroxidase enzyme & inhibit oxidation, iodination
& coupling.
 Thyroid colloid depletes & blood levels of T3, T4 fall.

43.  Goitre may occur with treatment.
 Methimazole – active metabolite of Carbimazole & 10 times more
potent than Propylthiouracil.
 Orally absorbed, wide distribution, metabolized/excreted in urine.
 Adverse effects
 Reversible hypothyroidism & goitre ( TSH ) - overtreatment.
 GI intolerance, skin rash, joint pain.
 Loss of hair & taste, fever, cholestatic jaundice, lupus like reaction.
 Rare important S/E – Agranulocytosis.

44.  Doses
• Propylthiouracil – 50 – 150 mg TDS (MD: 25 – 50 mg TDS)
• Methimazole – 5 – 10 mg TDS (MD: 5 – 15 mg OD)
• Carbimazole – 5 – 15 mg TDS (MD: 2.5 – 10 mg OD)
 Uses
Grave’s disease, Toxic Nodular Goitre (I 131).
Preoperatively – render pts. euthyroid.
 Along with I 131 ( to prevent initial hyperthyroidism following I
131due to release of stored T4).

45.  Advantages
 No surgical risk, scar or injury.
 Reversible hypothyroidism
 Used in children / young adults.
 Disadvantages
 Long Rx / Relapse rate high.
 Uncooperative / Unintelligent pt.
 Drug toxicity

46. B. Inhibit Iodide Trapping ( Ionic Inhibitors)
 Thiocynates, Perchlorates & Nitrates.
 Block N+/ I+ symporter (NIS).
 Perchlorates 10 more times potent than thiocynates in blocking
NIS.
 These drugs not used due to toxicity.

47. C. Inhibit Hormone Release ( Iodine & Iodides)
 Commonly used preps. are Lugol’s Iodine (collosal iodine 0.16 % or
aqueous KI solution).
Oldest remedy for thyroid disorder.
 Excess iodide if introduced, shows Wolff Chaikoff effect resulting in
decreased T3, T4.
 Inhibit hormone release ( Thyroid constipation), less vascular.
 Effect fades after few days, gland escapes and hormone synthesis
resumes.

48.  Uses
 Preoperatively – surgery preparation in Grave’s disease. Lugol’s
Iodine given 10 days before surgery. Carbimazole added before
starting iodide to render euthyroid.
 Thyroid storm – L.I. solution (6 – 10 drops) orally lowers hormone
release & conversion.
 Prophylaxis of Goitre – as iodized salt
 As antiseptic – tincture iodine, povidone iodine.
 Adverse events
 Acute reaction – iodine sensitive pts.

49.  Chronic overdose (Iodism) – Inflammation of mucous membrane,
salivation, lacrimation, rhinorrhoea, burning sensation in mouth.
 Iodide cause acne flare up.
D. Destroy Thyroid Tissue
 Radioactive Iodine I 131, t ½ - 8 days.
 I 131 emit X rays & Beta particles (destructive effect).
 Large dose – concentrate colloid – destroy cells from inside.
 Pyknosis, necrosis & fibrosis takes place.
 Taken as sodium salt of I 131 in water orally.

50. Diagnostic dose: 25 -100 µ curie
Therapeutic dose: 3 – 6 m curie ( Grave’s ds. & TNG)
 Advantage
 Simple, inexpensive & OPD basis.
 No surgical risk, scar, injury.
 Once hypothyroidism corrected, cure is permanent.
 Disadvantage
 Hypothyroidism – supplemental Thyroxine needed.
 Latent reponse

51. Contraindicated during pregnancy.
Not suitable to young pts. (Risk of Hypo)
Rx of choice in cardiac pts.

52. E. Iodinated Contrast Media
 Oral Ipodate, Ipanoic acid, Diatrizoate IV.
 Richly iodinated compounds inhibit DID – 1 & 2. Also peripheral
conversion inhibited.
 Used as adjunctive therapy with Thioamides.
 Can develop resistance. Used for short term treatment of severe
hyperthyroidism (control T3).