Thyroid and antithyroid drugs

1. Dr M.KARTHIGA

2. OVERVIEW
 SYNTHESIS AND REGULATION OF THYROID
HORMONE
 HYPOTHYROIDISM
 HYPERTHYROIDISM
 THYROID CANCER

4. THYROID GLAND
• TSH- 0.5-4.7mIU/L
• T4- 4.5-10.9mcg/dl
• Ft4- 0.8-2.7 ng/dl
• T3- 60-182ng/dl

6. BIOSYNTHESIS
1)UPTAKE OF
IODIDE
2)OXIDATION
AND
IODINATION
3)FORMATION OF
T3 & T4 from
IODOTYROSINES
RDA
• 90 -120 mcg –
Children
• 150 mcg – Adults
• 220 mcg – Pregnanc
• Iodides/Iodates to
NaCl to prevent
Endemic Goitre

7. ORGANIFICATION

8. CONJUGATION IN LIVER
 BOUND TO THYROXINE BINDING GLOBULIN
 TRANSTHYRETININ
 EXCRETED IN BILE AND FECES

9. TRANSPORT
 MCT8
 MCT10
 OAT1

10. T3 T4
DAILY PRODUCTION 30-40mcg 80-100mcg
Functional turnover 60% 10%
ORAL ABSORPTION 95% 70%
METABOLISM 40%-
DEIODINATION to
T3 /rT3
PLASMA LEVELS 1/100th of T4
60–180 ng/dL
4.5 to 11 μg/dL
POTENCY T3>T4 (4) 1
Vd 40L 10L
METABOLIC CLEARANCE 40% 10%
T1/2 1 day 6-8 days

11. REGULATION
Gs-adenylyl
cyclase–
cyclic AMP
pathway
• STRESS
• ACUTE PSYCHOSIS
• CIRCADIAN
RHYTHM

12. RESISTANCE TO TR

15. NON GENOMIC EFFECTS
 Truncated form of TRα1
 rapid T3-dependent NO production
 Activation of ERK and Akt

16. FUNCTIONS
METABOLIC EFFECTS
• Inc. hepatic LDL receptors
• Dec. apolipoprotein B levels through non-LDL receptor
pathways
• Dextro –thyroxine (D-T4) and TETRAC are usedclinically as
serum cholestrol lowering agents inatherosclerosis
• Thyrotoxicosis - insulin-resistant state
• enhanced gluconeogenesis,
• increased glucose absorption from the gut.
• Compensatory increases in insulin secretion result in
hyperinsulinemia.
1)OBLIGATORY
2)FACULTATIVE

17. UPREGULATION DOWNREGULATION
TRα in cardiomyocytes
SARCAase (LUSITROPIC ) PHOSPHOLAMBAN
RYANODIN CHANNELS
MHCα (INOTROPIC) MHCβ
If current in SA Node
(CHRONOTROPIC)

18. VITAMINS HEPATIC CONVERSION OF BETA
CAROTENE TO VIT A
REPRODUCTIVE SYSTEM 1. GONADAL DEVELOPMENT
AND SECONDARY SEXUAL
CHARACTERISTCS
2. MENSTRUAL CYCLE
3. MAINTENANCE OF LACTATION
ANS Inc expression of sympathetic nervous
system
GIT 1. Inc GI motility
2. Diarrhoea

21. THYROID FUNCTION TESTS
 fT4 and fT4 – ELISA
 DISADVANTAGE- Influenzed By altered serum-
binding proteins, nonthyroid disease states, acute
illnesses, and other drugs.
 Equilibrium dialysis of undiluted serum and
radioimmunoassay for FT4 in the dialysate
represent the gold standard
 TSH – TEST OF CHOICE

23. HYPOTHYROIDISM

24. HYPOTHYROIDISM

25. THYROID PREPARATIONS
 Levothyroxine
 Liothyronine
 Liotrix (Synthetic T4:T3= 4:1)
 Dessicated thyroid (animal origin )
T4
• Long half-life (7 days)
• Stability,uniform content
• Less allergic
T3
• T1/2 – 1 day
• Only short term
suppression
• Cardiotoxic
Dessicated Thyroid
• Protein
antigenicity
• Unstable

26. LEVOTHYROXINE
 80% Absorption
 Inc when taken empty stomach
 Tmax-3-4 hrs
 Replacement dose - 1.7 μg/kg/day body weight
(100mcg/day) ADULTS
 10-15mcg/kg/day – Children
 SUPPRESSION THERAPY- 2.2 mcg/kg/day

28.  Elders >60yrs
 suspected cardiac disease
 areas of autonomous thyroid function.
 increased by 25 μg/d every 6 weeks until the TSH is
normalized
 Dose missed- to take a double dose the next day.
 Follow-up blood tests - 6 weeks after any dosage change
Subreplacement dose
of L-T4 (12.5–50 μg/d)

29. LIOTHYRONINE
 Absorption is nearly 100%,
 Tmax 2–4 h
USES
 Myxedema coma,
 Preparing a patient with thyroid cancer for 131I
therapy..

30.  Reduced circulating levels of free T4 and T3.
 Children who are hypothyroid from birth or before
are called cretins
CRETINISM
ENDEMIC
(Iodine
deficiency)
SPORADIC
• T4 – 10-15mcg/day
• Every 2 n 4 weeks after t/t
• 1-2 months in first 6 months
• 2-3 mpnths b/n 6 months – 3
yrs
• 6months- 1 yr from 3 yrs till
growth
• Iodine supplementation in
pregnant mothers

31. MYXEDEMA COMA
• HYPOTHERMIA
• RESP
DEPRESSION
• DECREASED
CONSCIOUSNESS

33. HYPOTHYROIDISM IN
PREGNANCY
EFFECTS
 miscarriage,
 fetal distress,
 preterm delivery,
 impaired psychoneural and motor development in
the progeny
 Levothyroxine dose increased by 30%
 Adjustment based on TSH
1. Inc TBG
2. Placent
al
transfer

35. HYPERTHYROIDISM

36. HYPERTHYROIDISM

37.  Increased iodine uptake by the thyroid gland, as
established by the measurement of the percentage
uptake of 123I or 131I in a 24-h RAIU test.
1. THYROIDITIS
2. EXCESSIVE
SUPPLY OF T4
Subclinical
hyperthyroidism
1. subnormal serum TSH
2. normal free T4 and T3

38. GRAVES DISEASE
 Thyroid stimulating Antibodies TSAb
 Increased T4 and T3 levels
 Goitre
 Exophthalmopathy
 Pretibial edema
 Thyroid Acropachy

40.  Antithyroid drugs, which interfere directly with the
synthesis of thyroid hormones
 Ionic inhibitors, which block the iodide transport
mechanism
 High concentrations of iodine, which decrease
release of thyroid hormones from the gland and also
may decrease hormone synthesis
 Radioactive iodine, which damages the thyroid
gland with ionizing radiation

41. THIOAMIDES
 PROPYLTHIOURACIL & METHIMASOLE
 MOA- thyroid Peroxidase inhibitor
IODINATION COUPLING
PERIPHERAL
CONVERSION OF T4-T3
300 mg /day 30-40 mg/day
12 WEEKS
• THYROID STORM
• 1ST LINE IN 1ST 6 MONTHS
OF PREGNANCY

42. USES
GRAVES DISEASE
BEFORE RAI
PREPARATION FOR
THYROID Sx

43. ADVERSE EFFECTSHYPOTHYROIDIDM
CHECKED - every 2–4
months.
Followed up every 4-6
months once
euthyroidism is
established
Maculopapular rash,
paresthesias, headache,
nausea, skin
pigmentation, and loss
of hair. Drug fever,
hepatitis, and nephritis
are rare,
AGRANULOCYTOSIS
Sore throat,malaise
t/t –
Discontinue drug
Granulocyte colony
stimulating factor
BENIGN
NEUTOPHILIC
LEUKOPENIA

44. IONIC INHIBITORS
 competitive inhibition of NIS
 IODIDE UPTAKE INHIBITION.
 Perchlorate - 750 mg daily
 Lithium decreases secretion of T4 and T3, which can
cause overt hypothyroidism in some patients taking
Li+ for the treatment of mania
1. Thiocyanate,
2. Perchlorate,
3. Fluoroborate

45. IODIDE
 Inhibition of Release >>
Synthesis
 Rapid
1. THYROTOXIC CRISIS
2. Preparation for
thyroidectomy
3. NUCLEAR WAR -
THYROSHIELD
 130 mg /day
 WOLF CHAIKOFF
EFFECT
 JOD BASEDOW
PHENOMENON
1. LUGOLS
IODINE(8 mg )
2. KISS
(50 mg)

46. A/E HYPERSENSITIVITY
Serum sickness
Angioedema
TTP
 Hypothroidism
 Aggrevate thyrotoxicosis
in MNG
 IODISM
 T/T-Renal excretion of I−
Cl− excretion (e.g.,
osmotic diuresis,
chloruretic diuretics, and
salt loading

48. RADIOACTIVE IODINE
 I131 , I123
 MOA –
 γ rays and β particles emitted accumulates in
thyroid follicles
DESTRUCTION OF THYROID FOLLICLES
T1/2 – 8 days (I131,) 13 hours (I123)

49. USES
 HYPERTHYROIDISM
1. Elderly
2. Cardiac patients
3. S/p Subtotal
thyroidectomy
4. Remission after
antithyroid drugs
 TOXIC NODULAR
GOITRE
 THYROID CANCER
 METASTASIS
4–15 mCi based on
the 24-h radioiodine
uptake
2-3 MONTHS
CURE RATE –
90%

50. ADVANTAGES DISADVANTAGES
1. Low cost
2. No Hospitalization
3. Higher cure rate
1. Delayed Hypothyroidism
2. Radiation thyroiditis
3. Sialoadenitis
4. Fertility problems
5. Cancer in stomach,liver
6. Limitations in children
7. CI – pregnant

51. ADJUVANT THERAPY
 .
The β Adrenergic receptor. tachycardia, tremor, and stare—
and relieving palpitations,
anxiety, and tension.
1. propranolol, 20–40 mg four
times daily, or
2. atenolol, 50–100 mg daily, is
usually given initially
Ca2+ channel blockers diltiazem, 60–120 mg four times
daily)
1. tachycardia
2. supraventricular
tachyarrhythmias
The B-lymphocyte–depleting
agent rituximab,
Graves hyperthyroidism and
ophthalmopathy.

52. THYROID STORM
 Precipitating factors –
 infections, stress, trauma, thyroidal or nonthyroidal
surgery, diabetic ketoacidosis, labor, heart disease,
and, rarely, radioactive iodine treatment

53. PREGNANCY NEONATAL/PEDIATRIC
• No weight gain
• Persistent tachycardia
• PTU – 1st trimester
• 300 mg
• 150 mg after 4-6 wks
• MMU – 2nd n 3rd trimester
• Dose reduced last as
TSAbs decline
• PTU 5-10 mg/kg/day
• MMU – 0.5- 1.0 mg/kg/day
• 8-12 wks
• Iodides

54. THYROID CANCER
FOLLICULAR AND
PAPPILLARY CARCINOMA
MEDULLARY CARCINOMA
• Surgery
• RAI
An ablative dose of 131I
ranging from 30 to 150 mCi.
Recombinant thyrotropin alpha
(recombinant human TSH).
Thyroid hormone withdrawal for
6 weeks
• LIOTHYRONINE- to maintain
low TSH
TYROSINE KINASE
INHIBITORS
VANDETENIB
CARBOZANTENIB

55. RADIORESISTANT
SORAFENIB LENVATINIB
Multiple kinase inhibitor of
VEGFR
ADME -t1/2 -20-27 hrs
CYP3A4
Kidney
VEGFR-1, -2, and -3 as well as
FGFRs, PDGFR
ADME -t1/2 -20-27 hrs
CYP3A4
Kidney
400 mg twice daily without food. 24 mg once daily with or without
foo
Vascular toxicities,palmar-plantar
erythrodysesthesia, diarrhea,
alopecia, fatigue, weight loss,
hypertension,
hypertension, diarrhea, fatigue,
decreased appetite, decreased
weight, nausea, stomatitis, and
musculoskeletal pain

57. VANDETENIB CARBOZANTIB
MOA-multikinase inhibitor of
VEGFRs, the EGFR/HER family,
RET, BRK, TIE2, and members of
the EPH receptor and SRC kinase
families
ADME – t1/2 -19 days
CYP3A4
Kidney,bile
MOA- Multiple kinase inhibitor,
VEGFR,RET,MET
ADME- t1/2- 99 hrs
CYP3A4
Kidney,bile
300 mg once daily with or without
food.
60 to 100 mg on an empty
stomach, which may be titrated to
140 mg as tolerated.
QT prolongation.
diarrhea, rash, nausea,
hypertension, headache, and
others.
GI perforations and fistulas
(especially in patients receiving
prior radiation therapy) and
hemorrhage.
BP Monitoring
diarrhea, palmar-plantar

58. RECENT DRUGS
 Dabrafenib capsules, in combination wth trametinib
tablets,- MAY 2018- ANAPLASTIC THYROID CA
 Toclizumab –Mild - moderate TED
 Vemurafenib and nivolumab,
 Pembrolizumab (PD-1 antagonists)
 Atezolizumab (PD-L1 antagonist)
UNDER
TRIALS FOR
USE IN
THYROID
CA

60. SUMMARY

62.  Non adherence – Weekly dose of levothyroxine
 RAI with subtotal thyroidectomy prior to getting
pregnant to avoid exacerebration of
hyperthyroidism after pregnancy