THIS CLASS IS IN BRIEF FOR UNDERGRADUATE UNDERSTANDING AND EXAMINATION PURPOSE

1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1

2. Thyroid gland secretes 2 hormones :
Thyroxine (tetraiodothyronine or T4)
Triiodothyronine (T3)
Secretion ratio T4 to T3 is 15:1
Iodine is attached to tyrosine amino acid residues
of thyroglobulin in the gland (organification)
Coupling of these residues then produces T4 & T3
Thyroid Physiology

3. Thyroid Physiology
T4 & T3 released by the gland are bound & transported
by serum proteins :
Thyroxine-Binding Globulin (TBG) : 75 %
Thyroxine-Binding Prealbumin (TBPA)
Albumin
The free (or unbound) hormone levels are the levels
which are maintained constant by feedback & regulate
thyroid function
Total measured serum T4 includes bound & unbound

4. Thyroxine Binding Proteins
Causes of increased TBG levels :
Pregnancy, estrogens, cirrhosis, hepatitis,
porphyrias
Causes of decreased TBG levels :
Protein malnutrition, nephrotic syndrome, hepatic
failure, androgenic steroids, high dose
glucocorticoids
Free T4 (FT4) usually constant in the above conditions

5. Thyroid Hormone
T4 deiodonated in periphery to T3
This is 80 % of T3 produced
Other metabolite of T4 is reverse T3 (rT3) which is
metabolically inactive
T3 enters cells & binds to group of nuclear receptors,
then affects wide range of cellular metabolic functions
Thyroid hormone required for normal cell metabolism

6. Step 1-Iodide trapping
Step 2-Oxidation of iodide to iodine
Step -3 Iodide Organification
Step -4 Formation of T4 and T3
Step -5 Release of T4 and T3

8. Peripheral metabolism of thyroid hormones
The primary pathway for the peripheral metabolism of thyroxine (T4) is
deiodination  deiodination of T4 may occur by monodeiodination of the outer
ring, producing 3,5,3'-triiodothyronine (T3), which is three to four times more
potent than T4

9.  Free form of T3 and T4 enter cell by diffusion /active
transport . T4 is converted to T3 and enters nucleus and binds
to T3 receptors, this leads to increased formation of mRNA
and subsequent protein synthesis.
9

10. T4, best absorbed in duodenum and ileum, this can be altered
by food and drugs, such as calcium preparations and antacids
containing aluminum, intestinal flora .
Absorption of T4 is 80% and of T3 is 95%.
Absorption is not affected by mild hypothyroidism but impaired
in myxedema with illeus, in this condition parental route is
preferred.
10

11. T4 production is more than T3
T4 is converted to T3 in periphery
T3 is more potent than T4
T3 acts faster thanT4
T3 enters cell easily than T4
T3 binds to receptors in nucleus.
11

12. Regulation of Thyroid Hormone
Normal regulation requires intact hypothalamic-
pituitary system
Hypothalamus secretes Thyrotropin-Releasing
Hormone (TRH)
TRH then stimulates synthesis & release of thyrotropin
(Thyroid Stimulating Hormone or TSH) by the anterior
pituitary
TSH then stimulates the thyroid gland to uptake iodine,
synthesize & release T4 & T3
T4 & T3 levels feedback to both hypothalamus &
pituitary affecting TRH & TSH release

13. Regulation of Thyroid Hormone
Normal regulation requires intact hypothalamic-
pituitary system
Hypothalamus secretes Thyrotropin-Releasing
Hormone (TRH)
TRH then stimulates synthesis & release of thyrotropin
(Thyroid Stimulating Hormone or TSH) by the anterior
pituitary
TSH then stimulates the thyroid gland to uptake iodine,
synthesize & release T4 & T3
T4 & T3 levels feedback to both hypothalamus &
pituitary affecting TRH & TSH release

14. 14
Hypothalamic –pitutary – thyroid axix
Thyroid regulation

15. Hypothyroidism
Cold intolerance
Dyspnea
Anorexia
Constipation
Menorrhagia or amenorrhea
Arthralgias, myalgias
Fatigue
Depression
Irritability
Decreased attention & memory
Paresthesias

16. 16

17. Hypothyroidism
Signs
Dry, yellow (carotenemic ) skin
Weight gain (41 % of cases)
Thinning, coarse hair
Myxedema signs (mucopolysaccharide
deposition in tissues) :
Puffy eyelids
Hoarse voice
Dependent edema
Carpal tunnel syndrome
Anemia

18. Primary Hypothyroidism
Autoimmune : most common
Some have lymphocytic infiltration variant
Post surgical thyroidectomy
External radiation
Iodine 131 Rx for hyperthyroidism
Severe prolonged iodine deficiency
Antithyroid medications (such as lithium)
Inherited enzymatic defects
True idiopathic

19. Hypothyroidism and Myxedema Coma
Hypotension
Bradycardia
Pericardial effusion
Low voltage EKG
Prolonged QT interval
Inverted / flattened T waves

20. Thyroid Function Tests
Free T4 Index (FT4I)
Correlates with level of Free T4
T3 radioimmunoassay (less useful)
Normal 75 to 195 ng / dl
Serum TSH
Normal is 0.3 to 5.0 mcU / ml
TRH Stimulation Test
Measures TSH response to TRH IV injection
Normal is increase in TSH to 30 mcU / ml

21. LEVOTHYROXINE:(T4)
This is the preparation of choice for thyroid replacement and
suppression therapy, because it is stable and has a long (7 days) half
life, to be administered once daily.
Oral preparations available are from 0.025 to 0.3 mg tablets
For parentral use 200-500µg (100µg/ml when reconstituted) for
injection.
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22. LIOTHYRONINE(T3):
This is more potent (3-4 times) and rapid acting than levothyroxine
but has a short half life (24 hours) compared to levo, is not
recommended for routine replacement therapy, it requires multiple
dosing in a day.
It should be avoided in cardiac patients.
Oral preparation available are 5-50µg tablets
For parentral use 10µg/ml
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Thyroid hormone preparations

23. Treatment of Myxedema Coma
O2 +/- intubation / ventilation if resp. failure
Rapid blood glucose check +/- IV D50 +/-
Hydrocortisone 100 to 250 mg IV
Cautious slow rewarming (warm O2, scalp, groin, & axilla
warm packs, +/- NG lavage)
Thyroxine (T4) 500 mcg IV, then 50 mcg IV q day
Add 25 mcg T3 PO or by NG q 12 h (if T4 to T3 peripheral
conversion possibly impaired)
Careful IV fluid rehydration (watch for CHF)

24. Disorders of Thyroid Hormone
Excess
"Thyrotoxicosis" is the term for all disorders with
increased levels of circulating thyroid hormones
"Hyperthyroidism" refers to disorders in which the
thyroid gland secretes too much hormone
Radioactive iodine uptake test (RAUI) distinguishes
hyperthyroidism from other forms of thyrotoxicosis

25. Thyrotoxicosis with Elevated RAUI
Graves' Disease
Pituitary tumor secreting excess TSH
Pituitary insensitivity to feedback
Hydatidiform mole
Choriocarcinoma
Testis embryonal carcinoma
Toxic multinodular goiter
Toxic uninodular goiter
Drugs inducing hyperthyroidism
Iodine
Amiodarone
Lithium

26. Features of Graves' Disease
(Toxic Diffuse Goiter)
Most common cause of hyperthyroidism (70 to 85 % of all cases)
Caused by thyroid stimulating immunoglobulins
Mainly in young adults ages 20 to 50
5 times more frequent in women
Half of cases have infiltrative ophthalmopathy with exopthalmos (not
seen with other causes of hyperthyroidism)
5 % have pretibial myxedema
Toxic multinodular goiter-Second most common cause of
hyperthyroidism
Most cases in women in 5th to 7th decades
Often have long standing goiter
Symptoms usually develop slowly

27. Symptoms of Thyrotoxicosis
Nervousness, restlessness, shortened attention span,
emotional liability, difficulty sleeping
Increased appetite
Weight loss
Heat intolerance, fever
Diaphoresis,
Weakness
Menstrual irregularities

28. Signs of Thyrotoxicosis
Sinus tachycardia, Atrial fibrillation
Tremor, hyper-reflexia, muscle wasting
Warm, erythematous, moist skin
Alopecia, nail friability & separation from bed
Hyperventilation
Eyelid retraction, lid lag, persistent stare
Hyperactive bowel sounds
With Graves' : may have exopthalmos, tender enlarged
thyroid, & pretibial myxedema

29. Thioamides
METHIMAZOLE
CARBIMAZOLE
PROPYLTHIOURACIL
Radioactive iodine
131IODINE
Iodides
aqueous potassium iodide solution- LUGOL’S IODINE
Iodinated contrast media
ORAL IPODATE AND IPANOIC ACID-DIATRIAZOATE
Mechanism
Agents which interfere production of thyroid hormone
Agents which modify tissue response to thyroid hormones
Glandular destruction with radiation or surgery.
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30. 30
Methimazole, Carbimazole, Propylthiouracil
Methimazole is 10 times more active than
Propyl thiouracil.
They act by:
Inhibiting thyroid peroxidase –catalysed reaction to block
iodine organification.
They block coupling of iodotyrosine
They inhibit peripheral Deiodination of T4 to T3.
Onset of drug is slow requiring 3-4 weeks
before stores of T4 are depleted.

31. 31
Propylthiouracil Methimazole
Absorption Rapid but incomplete At variable rates but
complete
Vol.of Dist. Approximates body waters Similar
Protein binding more less
accumulation In thyroid Similar
Excretion Kidneys as inactive
Glucuronide in 24 hrs
Excretion slow,60-70%
of drug is recovered in
urine in 48 hrs

32. 32
Propylthiouracil Methimazole
Half life 1.5 hrs 6 hrs
Administration Every 6-8 hrs As a single dose in 24
hrs
Duration of activity 100 mg inhibits iodine
organification for 7 hrs
30 mg exerts
Antithyroid effect for
longer than 24 hrs
Pregnancy Preferred, though cross
placenta and is conc .in
fetal thyroid but is highly
protein bound ,cross
placenta less readily
Cross placenta and
concentrated by fetal
thyroid
Nursing mothers Less secreted in breast
milk
secreted

33. 33
It occurs in 3-12 % of treated patients
Maculopapular rash and fever are earlier effects.
Urticarial rash, vasculitis, arthralgia, cholestatic jaundice,
lymphadenopathy, and hypoprothrombinemia.
Most dangerous complication is agranulocytosis this is infrequent but
may be fatal.

34. 34
Well and rapidly absorbed from intestines
Rapidly taken by thyroid gland and concentrated there
Moderate increase leads to hormone secretion but substantial excess
inhibits hormone release and promotes its storage, making the organ
less vascular and firmer.
Iodides stores in thyroid delays response to thioamides
They inhibit organification and hormone release.
With a dose of > 6 mg /day.
They should be initiated after onset of thioamides therapy.
It also decreases the vascularity of hyperplastic gland
Improvement is rapid within 2-7 days (valuable in thyroid storm)

35. 35
Should not be used as a single therapy
Should not be used in pregnancy
May produce iodism causing acneform rash, swelling of salivary
glands, mucous membrane ulceration, metallic taste bleeding
disorders and rarely anaphylaxis.

36. 36
131 I isotope, administered orally
It is rapidly absorbed, concentrated in thyroid gland and stored in
follicles. It has a half life of 8 days and emits gamma rays and beta
particles. The beta particles get accumulated in gland and destroy
parenchyma.
It is easy to administer, effective, painless and less expensive
It causes destruction of parenchyma, necrosis and follicular disruption
Therapeutic effect is due to emission of β-rays.
Patients with age above 40 years only can be treated with this
It crosses placenta and excreted in breast milk
It may cause genetic damage and leukemia and neoplasia, it may be
carcinogenic

37. Iodinated constrast medias
Oral ipodate and ipanoic acid and
IV diastrizoate
These are richly iodinated compounds which inhibit 5-
deiodinase enzymes and prevent conversion of t4 to t3 in liver,
kidney, pituitary gland and brain

38. Drugs causing Euthyroid
Hyperthyroxinemia
Oral contraceptives
Narcotics (methadone, heroin)
Perphenazine
Clofibrate
5-flurouracil
Heparin
Amiodarone
Iodine contrast agents

39. Thyroid Storm
(hyperthyroidism crisis)
"Exaggerated or florid state of thyrotoxicosis"
"Life threatening, sudden onset of thyroid
hyperactivity"
May represent end stage of a continuum :
Thyroid hyperactivity to thyrotoxicosis to thyrotoxic
crisis to thyroid storm
"Probably reflects the addition of adrenergic
hyperactivity, induced by a nonspecific stress, into the
setting of untreated or undertreated hyperthyroidism"

40. Thyroid Storm
Most cases secondary to Graves' disease
Some due to toxic multinodular goiter
Rare causes :
Acute thyroiditis
Factitious
Malignancies (most do not efficiently produce
thyroid hormones)

41. Thyroid Storm
Important features :
High fever (usually over 40 degrees C)
Significantly abnormal mental status
Agitation, confusion, psychosis, coma
Marked tachycardia
Vomiting, diarrhea
Jaundice (in 20 %)
Associated signs of Graves' disease

42. Thyroid Storm treatment
High flow O2
Rapid cooling if markedly hyperthermic
Ice packs, cooling blanket, mist / fans, nasogastric tube
lavage, acetominophen (Salicylates contraindicated
because cause peripheral deiodination to T3)
IV fluid bolus if dehydrated
May need inotropes instead if in CHF
Propranolol 1 mg doses or labetolol 10 to 20 mg doses IV &
repeat doses as needed

43. IV diltiazem +/- digoxin for rate control for atrial fib
IV diuretics if in CHF
IV hydrocortisone (or equivalent) 100 mg
Propylthiouracil (PTU) 600 to 1200 mg PO or by NG
Sodium iodide 1 gram IV one hour after the PTU
Find and treat the precipitating cause
Thyroid Storm treatment

44. THANKYOU
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