PATHOLOGY

SHIFT
THYROID AND ANTI-THYROID
#4
DRUGS; ANTI-OSTEOPOROSIS REVIEWER #5
REVIEWER | MAY 2020

OUTLINE Metabolic clearance More

I. Thyroid III. Bone Remodeling and Biologic half life 7 days 1 day
Amount bound 99.96% 99.6%
A. Thyroid Hormone Hemostasis
Amount free 0.04% 0.4%
Biosynthesis A. Calcium and Bone Biologic potency 1 4
B. Thyroid Hormone Remodeling Oral absorption 80% 95%
II. Drugs Used in Thyroid B. Parathyroid Hormone
Disorders C. Vit D3 Formation • T3 is more widely distributed, has less stores, shorter half-life,
A. Hypothyroidism D. Calcitonin more potent, almost completely absorbed
B. Hyperthyroidism IV. Osteoporosis • T4 more bound to TBG
C. Adjunct Drugs for the A. Pharmacotherapy
Thyroid V. References General Action of Thyroid Hormone
VI. Appendices • MOA: Free T4 and T3 enters the cell, T4 is converted to T3 (via
deiodinase)
LEGEND • Regulates growth and development through protein synthesis
MUST KNOW SAMPLEX
→ Critical role in brain development
• Calorigenic effects
*hello, this is very summarized from the lecture, please study the
→ Increased oxygen consumption
powerpoint and read the book also
→ Increased BMR
I. THYROID • Cardiovascular effects
→ Increased sensitivity to catecholamines (increased number of
A. THYROID HORMONE BIOSYNTHESIS beta-adrenergic receptors)
1. Iodide trapping → Excess catecholamines would lead to overactive expression
• Iodide is taken up Lid lags, retraction, tremors, increased sweating, anxiety,
2. Translocation of iodide nervousness
3. Oxidation of iodide to iodine • Metabolic effects
4. Iodination (Organification) → Increased metabolism leads to weight loss (in hyperthyroid
state)
• Incorporation of iodide into tyrosine residues within
thyroglobulin in colloid II. DRUGS USED IN THYROID DISORDERS
5. Conjugation B. HYPOTHYROIDISM
• Clinical features: slowing down of bodily functions
• “coupling” reaction
• Goals of treatment
• Combination of DIT+DIT = T4, DIT+MIT = T3 → Replace the thyroid hormone
6. Uptake of thyroglobulin from colloid into follicular cells by → Avoid overcorrection
endocytosis, fusion of thyroglobulin with a lysosome, proteolysis Will lead to hyperadrenergic reactions (tachycardia,
and release of T4, T3, DIT, MIT into circulation palpitations, atrial fibrillation, tremors, increased bone
• Oxidation, Iodination/Organification, Conjugation – catalyzed by resorption)
thyroid peroxidase enzyme Thyroid Preparations
• Synthetic thyroid preparation
B. THYROID HORMONE
→ Levothyroxine (T4)
• T4 is best absorbed (70 to 80%) in the duodenum and ileum.
→ Liothyronine (T3)
• T3 is almost completely absorbed (95%) → Liotrix (mix T4/T3)
• Taken 1 hour before breakfast, 4 hours after the last meal, or at • Natural hormone extracts
bedtime → Desiccated thyroid
• T4 metabolism • Indicated for hypothyroidism, simple goiter
→ Deiodination to active T3 by 5’ deiodinase enzyme Synthetic Thyroid Preparations
→ Deiodination to reverse T3 (Inactive) by 5 deiodinase enzyme • Levothyroxine T4 – preparation of choice for replacement
therapy
Thyroid Hormone Carriers
→ Long half-life (7 days), but is given 1/day
• Thyroxine binding globulin – major carrier for both T4 and T3
→ Does not have T3, but this is derived from peripheral
→ Bind more T4 than T3
conversion of T4
Free T3 is 10x more than free T4. Disease states can alter
→ Less cardiotoxic than liothyronine
this.
• Liothyronine T3 – 3-4x more potent than levothyroxine
→ Increased TBG = decreased free hormone, vice versa
→ No longer recommended
• Transthyretin binds only T4
• T3/T4 Liotrix
• Albumin
→ Good for those who lack 5’ deiodinase enzyme
Table 1. T4 vs T3
Needed to convert T4 to T3
Parameter T4 T3
Volume of distribution 10L 40L → Potentially cardiotoxic cause of T3
Extrathyroidal pool More Natural Hormone Extracts
Daily production More
• No longer recommended
Reviewer PREPARED BY: Velasco, Jacqueline 1 of 6
#4.5
 PATHO REVIEWER 4.5: Thyroid and Antithyroid Drugs, Antiosteoporosis 2 of 6

→ Unstable Table 2. PTU vs Methimazole

Characteristics PTU Methimazole
→ Protein antigenicity
Absorption Rapid Complete but variable
→ Hard to monitor Bioavailability 50-80% >95%
Precautions T1/2 1.5 hrs 6 hrs
Excretion Faster Slower
• Thyroid hormones are not effective and not indicated in:
Duration of action Short Long
→ Obesity Relative potency 1 10
→ Dyslipidemia Dosing 100-200 mg TID 10-30 mg OD
→ Abnormal vaginal bleeding Dose response Lower Higher
→ Depression Toxicity Idiosyncratic Agranulocytosis
Effect on liver Hepatitis Cholestatic jaundice
• Do not give levothyroxine unless proven that patient has
Albumin binding More Less
hypothyroidism Placental passage Less More (congenital
B. HYPERTHYROIDISM malformation)
Breast milk Low levels Low levels
• Acceleration of body functions
Blocks peripheral Extensive None
• Goal of treatment conversion T4 to T3
→ Eliminate excess thyroid hormone DOC 1st trimester First line
→ Prevent acute complications (thyroid storm) and long-term pregnancy, thyroid
storm
complications (thyrotoxic heart disease)
Treatment of Hyperthyroidism General Categories Iodides
• Antithyroid drugs • MOA: (if used >6mg/day)
→ Inhibit synthesis of T4 and T3 → Inhibits iodination/organification – Wolff-Chaikoff effect
• Radioactive iodine therapy Iodide in small amounts can stimulate thyroid hormone
production, but in large amounts can inhibit it
→ Iodine 131 taken up by thyroid can destroy the glands
→ Inhibits hormone release (seen in 2-7 days)
• Surgical resection
→ Decreases size and vascularity of hyperplastic gland
Antithyroid Drugs Good for preop of thyroid surgery to reduce bleeding
• Anion inhibitors • Preparation:
→ Perchlorate → Lugol’s solution or SSKI saturated solution
→ Pertechnetate • Indication:
→ Thiocyanate → Thyroid storm
• Thioamides → Preoperative prep for thyroid surgery
→ Propylthiouracil (PTU) → Protection of thyroid against fallout in nuclear accident
→ Thiamazole (Methimazole) • Disadvantages:
→ Carbimazole → If used more than 2 weeks – Jod Basedow Phenomenon
• Iodides “escape”, iodide is used for hormone synthesis
→ Lugol’s solution → Can cause fetal goiter in pregnancy
Anion Inhibitors → May delay onset of thioamide therapy
• Block iodide trapping/uptake of iodide by thyroid • Iodide toxicities
• MOA: competitive inhibition of iodide transport (Na-Iodide → Uncommon (includes acneiform rash, rhinorrhea, etc.)
symport) C. ADJUNCT DRUGS FOR THE THYROID
• Compete with iodide (effects can be overcome with large doses • Don’t directly interfere with thyroid hormones
of iodide) • Add-ons to thioamides
• Associated with aplastic anemia
Beta Blockers (Propanolol)
Thioamides • Blocks peripheral effects of thyroid hormone
• Block thyroid peroxidase • At >160 mg/day: block peripheral conversion of T4 to T3
→ Rate limiting enzyme of thyroid synthesis • For thyroid storm: dose is 40-80 mg q6
• Structure: has thiocarbamide group (essential for anti-thyroid
Lithium
activity)
• Blocks release of thyroid hormone
• MOA: Prevents hormone synthesis via inhibition of thyroid
peroxidase catalyzed reactions (oxidation, organification, • Last resort alternative to iodides and thioamides
coupling) • Toxicity: nephrogenic diabetes insipidus
→ PTU inhibits peripheral conversion of T4 to T3 Prednisone
→ Does not block uptake of iodide nor release of thyroid • Anti-inflammatory
hormones → Useful in grave’s ophthalmopathy
• Adverse reactions Swelling of orbital fat pad due to TSH receptor antibody
→ Most common: Maculopapular rash +/- fever cross reaction, lead to eye proptosis
→ Methimazole • Blocks conversion of T4 to T3
Altered sense of smell, cholestatic jaundice → Useful in thyroid storm
Agranulocytosis – most dreaded Radioactive Iodine
− Leukopenia, neutropenia can lead to severe infections • I131
Cutis aplasia birth defect
• MOA: Destroy thyroid gland through ionizing radiation beta rays
→ PTU
→ Epithelial swelling and necrosis, follicular disruption, edema,
Increase risk of severe hepatitis
and leukocyte infiltration
→ Switching from PTU to methimazole for severe reactions not
→ Thyroid gland shrinks within 6-12 weeks
recommended (has 50% cross reactivity)
• More definitive treatment but there is delay in control of
hyperthyroidism
• Pretreatment with anti-thyroid drug to achieve euthyroid state
before radioactive iodine therapy is desired
 PATHO REVIEWER 4.5: Thyroid and Antithyroid Drugs, Antiosteoporosis 3 of 6

• Disadvantage: develop hypothyroidism • Kidneys

• Indications: preferred treatment for those who → Increases calcium reabsorption
→ Fail to respond to drug therapy → Increases phosphorus reabsorption
→ Had ADR with other treatments D. CALCITONIN
→ Had recurrence of hyperthyroidism even after surgery • T1/2 = 10 min
→ Are poor surgical risks (elderly, cardiac, debilitated patients) • Secreted by Parafollicular C cells of Thyroid in response to
III. BONE REMODELING AND HEMOSTASIS increased calcium
A. CALCIUM AND BONE PHYSIOLOGY • Actions:
• 99% of calcium found in bone → Increase osteoclastic resorption in bone
• Bone → Increase renal Ca and PO4 excretion
→ Dynamic reservoir with constant remodeling readily → Salmon calcitonin has longer half-life
exchanges Ca with ECF Bone Remodeling Cycle
→ Disturbances lead to osteoporosis and problems in • Osteoclasts resorb lacuna, form a cavity (break bone)
coagulation • Osteoblasts deposit new bone
Calcium IV. OSTEOPOROSIS
• Functions: nerve conduction, second messengers, coagulation • Bone resorption exceeds bone formation
• Average diet: 600 to 1000 mg per day (10-25% absorbed in • Compromised bone strength
small intestine) • Increased risk of fracture
→ Enhanced by Vit D • Associated with:
→ Decreased by PPI → Menopause (loss of estrogen production)
• Preparations → Ca/Vit D deficiency
→ Calcium carbonate is the preparation of choice → Drugs: steroids
Highest elemental calcium (40%) → Inadequate peak bone mass
Give with meals to increase absorption
A. PHARMACOTHERAPY
→ Calcium citrate
• Goal: Block osteoclast, promote osteoblast
Can be taken anytime but with low elemental calcium
(21%) • Anti-resorptive agents (inhibit osteoclast)
→ Calcium gluconate → Bisphosphonates
IV form → Salmon calcitonin
For hypocalcemic tetany → Estrogen
→ SERM (Raloxifene)
B. PARATHYROID HORMONE
→ Denosumab
• Major regulator of calcium and phosphorous metabolism
• Anabolic agent (stimulate osteoblast)
• Stimulus for release: low calcium level
→ Teriparatide
• Half-life 2-5 min
• Dual effect (antiresorptive and anabolic)
• 90% clearance by liver and kidneys
→ Strontium ranelate
• PTH on Calcium Metabolism:
→ Net effect: Increase serum Ca, Decrease serum PO4 Bisphosphonates
→ PTH promotes bone reabsorption • MOA: inhibits farnesyl pyrophosphate synthetase (key enzyme
→ Ca in circ, in kidney activate 1-alpha-hydroxylase enzyme to in mevalonic acid pathway needed for osteoclast survival)
convert Vitamin D into calcitriol (active form) → When embedded in bone matrix binds to hydroxyapatite
→ Active Vit D will enhance Ca and PO4 absorption in intestine → Retards dissolution of hydroxyapatite crystals within and
→ PTH also increases reabsorption of Ca and increases PO4 outside bone
excretion • Oral preparation: alendronate, risedronate, ibandronate
→ Take on empty stomach
C. VIT D3 FORMATION
• IV preparation: zoledronate, pamidronate
• Skin has 7-dehyrocholesterol, converted by UV B rays into
→ Zoledronate: retained for months or year
previtamin D3
• Excreted in kidney
• This will form cholecalciferol (not yet active)
• Drug effect:
• Cholecalciferol is acted by 25-hydroxylase (from liver), and 1a -
→ Provide greatest increase in bone mineral density
hydroxylase (from kidney) to become calcitriol (1,25
dihydrocholecalciferol; active form) → Decrease spine and hip fractures
• DOC: prevention and treatment of postmenopausal
Vitamin D and the Hydroxycholecalciferols osteoporosis, osteoporosis in men, glucocorticoid induced
• Fat soluble, absorbed from intestine osteoporosis
→ Enhanced by bile salts • Side effects:
• Bound to Vit D binding globulin in circulation → Oral: cause esophageal and gastric irritation, GERD
• 25 OH Vit D3 – storage form in adipose tissue → Contraindicated in hypocalcemia
→ Best index for Vit D sufficiency → Atypical femur fractures or subtrochanteric femoral fractures
• Calcitriol or 1,25-Dihydroxycholecalciferol due to over suppression of bone turnover
→ Active form Solution: drug holiday after 5 years
→ Formulation needed when PTH is deficient Estrogen
Effect of Calcitriol on Calcium and Phosphorous • Estrogen receptors in bone favors bone formation
Metabolism • Safety issues: breast cancer, endometrial hyperplasia,
• Bone cardiovascular events
→ Promotes mineralization of bone • Indication: alleviation of postmenopausal vasomotor symptoms
• Gastrointestinal Tract Raloxifene
→ Increases calcium absorption
• Selective estrogen receptor modulator (SERM)
→ Increases phosphorus absorption
• Estrogenic in bones, antiestrogenic in breast and uterus
 PATHO REVIEWER 4.5: Thyroid and Antithyroid Drugs, Antiosteoporosis 4 of 6

• Uses: prevention and treatment of postmenopausal

osteoporosis
• Side effects: hot flushes, leg cramps, and a threefold increase in
the relative risk of venous thromboembolism.
→ Will not improve postmenopausal symptoms
Salmon Calcitonin
• Longer half-life than human calcitonin
• ADR: nasal irritation
• Inhibits osteoclastic resorption of bone, increase renal Ca and
PO4 excretion
• Use:
→ 2nd line treatment for postmenopausal osteoporosis if unable
to tolerate the other drugs
→ Lower calcium in hypercalcemia
→ Provide pain relief in vertebral fractures
Denosumab
• Human monoclonal antibody to RANKL
• Prevents RANKL binding to its receptor = osteoclast inhibition
• Reduces bone resorption and fracture risk
• Uses:
→ Postmenopausal osteoporosis
→ Prostate CA
→ Breast CA
• No dose adjustment for renal disease
• ADR:
→ Increased risk of infection (RANKL is present in immune
system)
→ Osteonecrosis of the jaw
→ Subtrochanteric fractures
Teriparatide
• Recombinant human PTH
• 1/day subcutaneous injection 20 mcg stimulates new bone
formation on trabecular and cortical bone surfaces
• Osteoblastic activity > osteoclastic activity
• Increases serum Ca and decreases serum PO4
• Indicated for those with high risk for fracture
→ Postmenopausal osteoporosis
→ Men with primary or hypogonadal osteoporosis
→ Glucocorticoid induced osteoporosis
• Treatment limited to 2 years then follow with antiresorptive
agent
• ADR: hypercalcemia, nausea, esophageal reflux, postural
hypotension, dizziness
• Osteosarcoma in rodents
Strontium Ranelate
• Inhibit osteoclast, promote osteoblast
• ADR: GI, allergic reactions
• Warning: cardiovascular events
• Take at bedtime, 2 hours after eating
REFERENCES
Dr. Jean Uy-Ho’s Powerpoint Lecture
END OF REVIEWER
Prepared by: Velasco, Jacqueline
 PATHOLOGY
SHIFT
THYROID AND ANTI-THYROID
#4
DRUGS; ANTI-OSTEOPOROSIS REVIEWER #5
REVIEWER | MAY 2020

UNIVERSITY OF SANTO TOMAS

FACULTY OF MEDICINE AND SURGERY
D2022 Reviewer
Sample EXAMINATION
May 2020

Instructions:
1. There are 20 items in this questionnaire
2. CHOOSE THE BEST ANSWER.
3. Try to answer on your own (without the use of reviewers/trances)
4. Answers are given in a separate document.
5. God bless!

------------------------------------------------------------------------------------------------------------------------------------------------------------------
CHOOSE THE BEST ANSWER

TRUE OR FALSE:

1. Methimazole can inhibit peripheral conversion of T4 to T3.

A. TRUE B. FALSE

2. Human calcitonin has a longer half-life than salmon calcitonin.

A. TRUE B. FALSE

3. Iodide 4mg/day elicits the Wolff-Chaikoff effect.

A. TRUE B. FALSE

4. Absorption of thyroid hormones is affected by food.

A. TRUE B. FALSE

5. Bisphosphonates are the drug of choice for postmenopausal osteoporosis.

A. TRUE B. FALSE

MULTIPLE CHOICE.

6. Which of the following is used to treat hypothyroidism?

A. SSKI B. Perchlorate C. Lithium D. Levothyroxine

7. The most common adverse effect of thioamides is:

A. Pruritus B. Hepatitis C. Maculopapular rash D. Sore throat

8. Agranulocytosis is a dreaded adverse reaction of which drug?

A. Bisphosphonates B. Radioactive Iodine C. Liotrix D. Methimazole

9. All of the following can be used for treating thyroid storm, EXCEPT:
A. PTU B. Iodides C. Prednisone D. none of the above

10. Perchlorate inhibits __ in thyroid hormone synthesis?

A. Organification B. Conjugation C. Oxidation D. Iodide trapping

11. What drug for hyperthyroidism is the drug of choice for patients in their 1st trimester of pregnancy?
A. Methimazole B. Pertechnetate C. PTU D. SSKI

Reviewer PREPARED BY: Velasco, Jacqueline 5 of 6

#4.5
 PATHO REVIEWER 4.5: Thyroid and Antithyroid Drugs, Antiosteoporosis 6 of 6

12. What is the storage form of Vit D?

A. Calcitriol B. Cholecalciferol C. 25 OH Vit D3 D. 7-Dehydrocholesterol

13. What is the mechanism of action of Zoledronate?

A. Blocks farnesyl pyrophosphate synthetase B. Antibody to RANKL
C. SERM D. Recombinant human PTH

14. Which of the following may provide pain relief in vertebral fractures?
A. Alendronate B. Raloxifene C. Salmon calcitonin D. Denosumab

15. Which of the following antiosteoporosis drugs has a dual effect?

A. Teriparatide B. Strontium C. Raloxifene D. Ibandronate

16. A 60-year old woman with osteoporosis will be started on an anti-resorptive drug. She requested for an IV drug
that is given once a year, which drug is it?
A. Zoledronate B. Strontium C. Ibandronate D. Calcitonin

17. The most appropriate drug for a 70-year-old male with osteoporosis that provides the greatest increase in bone
mineral density and fracture risk reduction is __?
A. Alendronate B. Calcitonin C. Teriparatide D. Cinacalcet

18. A 55-year-old female with metastatic breast cancer (to the spine and femur) and chronic kidney disease will
benefit most from this anti-resorptive agent:
A. Denosumab B. Alendronate C. Teriparatide D. Strontium

19. A hyperthyroid patient will be started on methimazole in a few days, which of the following should NOT be given
before starting the said drug?
A. Iodide B. Propranolol C. Prednisone D. Thiocyanate

20. A 15-year-old male presents with 3x4 cm anterior neck mass. Thyroid function tests revealed low TSH, elevated
free T4 and T3. The most appropriate drug to give is:
A. Methimazole B. Propranolol C. Iodides D. Perchlorate

JVLV2020

- END OF QUIZ-
GOD BLESS!