L89- Thy/Bone Pharmacology

Question 1

Describe the pathway of TH synthesis?

Answer 1

Iodide transport/trapping (need 150 mg/day or 200/day in pregnancy and get it from fish/seafood)

Iodide organification to Iodine

Tyrosine gets iodinated - MIT/DIT

Coupling of iodotyrosins to make T3/T4 and release by exocytosis and proteolysis T4:T3 in a 5:1 ratio

Transport by binding to TBG

Peripheral metabolism

Question 2

How is TH metabolised (aka what enzyme)? and what situations/drugs can alter this enzyme?

Answer 2

5- De-Iodinases

Beta Blockers and steroids, illness, starvation can inhibit 5’Diodinase and so get low T3 and less activation n tissues

Question 3

What happens when TH binds its receptors? What tissues are more/less responsive?

Answer 3

Binds to nuclear receptors which are Transcription Factors and increase RNA/Protein synthesis –> Esp of Na/K ATPases to cause increase in ATP turnover and oxygen consumption

Lag of hours or days to see effect bc nuclear receptors

More receptors/more responsive tumors on Pituitary, kidneys, heart, skeletal muscle, lungs, and intestine

Less responsive on Spleen and testes

Question 4

What happens in Thyroid Auto-reuglation?

Answer 4

Thyroid regulates its own uptake of Iodide and Hormone synthesis in non-TSH dependent manner

Large doses of Iodine inhibit Iodide organification for transient self-regulation

Question 5

What drugs are indicated for the management of Hypothyroidism? Esp in kids bc why?

Answer 5

TH analogues!!! Levothyroxine (T4 analogue), Liothyronine (t3 aka cytomel/triostat), Liotrox (T4/T3 analogue) or dessicated thyroid.

Especially important in kids bc hypothyroidism leads to irreversible mental retardation

Question 6

What is the best TH analogue to treat hypothyroidism with and why?

Answer 6

Levothyroxine bc T4 analogue

given as a single dose before breakfast

Long half life, stable, less toxicity

Converted to T3 peripherally as needed so less toxicity

Question 7

What drug would you use on someone who was Hypothyroid from a conversion problem? Whats bad about it?

Answer 7

Liothyronine (cytomel/triostat) = T3 analogue

fast acting but short half life

VERY potent bc T3 so lots of side effects

Question 8

Why do women tend to be hypothyroid in early pregnancy?

Answer 8

Modest increases in TBG leads to less free T4/T3 and so need increased doses for hypothyroid women who are pregnant

Question 9

What is Myxedema coma? How do you treat it? Problems w/ treatment?

Answer 9

Medical Emergency from untreated hypothyroid state

Progressive weakness, hypothermia, stupor, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock and death!

**AVOID EXCESSIVE WATER INTAKE!

Give Loading dose T4 to fill empty TBG and then can give IV T3 but watch out for cadiotoxicity!!!

Problem - treat cardiogenic shock w/ steroids but those prevent peripheral conversion of T4 to T3 so have to give combination drug like Liotrix!

Question 10

What are signs of Thyroid toxicity in adults and children?

Answer 10

Older patients = very sensitive to T4 levels and so watch for Angina Pectoris or Arrhythmia, AFIB and Accelerated Osteoporosis

Adults = increased anxiety, heat intolerance, tachycardia, weight loss

Children = resltessness, insomnia, accelerated bone maturation and growth

Question 11

When would you NOT treat someone > 21 yo w/ Grave’s Disease w/ Radioactive Iodine?

Answer 11

Unless they have EYE DISEASE!

Question 12

What are the two anti-thyroid drugs? Of those two, which one do you use in pregnancy and why?

Answer 12

Methimazole and Propylthiouracil (PTU)

PTU is the drug of choice in Pregnant women - more protein bound so less crosses the placenta and has less side effects (and potency)

Question 13

What is the mechanism of action for the anti-thyroid drugs?

Answer 13

PRevent hormone synthesis by inhibiting TPO catalyzed reactions, blocking Iodine organification, and blocking coupling of Iodotyrosines

They do NOT block uptake of IOdine

*PTU (less so methimazole) blocks peripheral de-iodinzation of T3 and T4

Question 14

What are the most worrisome side effects of Methimazole?

Answer 14

BM suppression and Liver toxicity!!

Question 15

What are the Anion Inhibitors? How / When are they used?

Answer 15

Perchlorate and Thiocyanate block uptake of iodide via Competitive Inhibition of Iodide transport and so can be used in Thyrotoxicosis or thyroid storm but can be overcome w/ large doses of Iodide

Question 16

How do Iodides work as Anti-thyroid drugs?

Answer 16

Used less nowadays but stun the thyroid acutely and can be valulable in thyroid storm and before surgery to reduce vascularity of the gland

*Delay on set of Thioamide therapy

Question 17

How does RAdioactive Iodine therapy work? Who should NOT receive this treatment?

Answer 17

Given orally and concentrated in thyroid - preferred treatment for adults in US

Destruction of thyroid parenchyma within a few weeks and can be seen w/ Epithlial swelling, follicular disruption and edema and leukocyte infiltratoin

Should NOT be given to pregnant or nursing women bc crosses placenta and secreted in breast milk

Question 18

What can be given to lessen the symptoms of thyrotoxicosis?

Answer 18

Propanolol - non-selective beta blocker!!!

Beta blockers w/ot intrinsic Sympathomimetic activity

(also blocks T4 to T3 peripherally which is additional benefit)

Question 19

Symptoms of Thyroid Storm? Treatment?

Answer 19

Excessive adrenergic activity and thyrotoxicosis crisis that is life threatening and presents with:

Fever, Flushgin, sweating, tachycardia, AFIB, high pulse pressure, restlessness, agitation, delirium, coma, N/V/D, HF or shock

Treatment - control cardiac symptoms and fever

Propanolol (or if have CHFthen give diltiazem)

KI or contrast media - blocks release of T3/T4 from TBG

PTU (or methimazole)

Hydrocortisone - stops peripheral conversion

Question 20

What are the principle regulators of Mineral homeostasis and what are the secondary regulators?

Answer 20

Principle REgulators: PTH (peptide) and Vitamin D (steroid)

Others - dont regulate but control for clinical effects

• CAlcitonin
• Prolactin
• GH
• Inuslin
• TH
• GC
• Sex steroids

Question 21

What is calcitonin? Where does it come from and what does it do?

When is it used clincially?

Answer 21

Secreted by Parafollicular Cells of thyroid

Lowers SErum Calcium and Phosphate at bone and kidney

• inhibits OC resporption of bone (initially but not very useful bc inhibits resporption and formation ultimately)

reduces serum CA and so can be used for Hypercalcemia and Paget’s Disease

Question 22

What role do glucocorticoids play in Calcium homeostasis etc? How are they used clinically?

Answer 22

Prolonged administration is common cause of Osteoporosis in adults and stunted skeletal development in kids bc they:

• Antagonize Vit - D stimulated GI Ca transport
• Stimulate renal Ca excretion
• block bone collagen synthesis
• increase PTH stimulate Bone resporption

Clinically: useful in reversing Hypercalcemia associated w/ Lymphomas and Sarcoidosis or Vit D intoxicaiton

Question 23

What role do estrogens have in Calcium homeostasis?

Answer 23

Estrogens reduce bone resporptive action of PTH

receptors found on bone suggestive of direct effect on bone remodeling

Question 24

What is the Selective Estrogen REceptor Modulator (SERM)? What is it used for? Side effects?

Answer 24

RALOXIFENE

Estrogenic actions (ER agonist) at bone BUT anti-estrogenic (ER antagonist) in breast and in uterus

Used for post-menopausal women to prevent osteoporosis due to decreasing estrogens

As effective as tamoxifen in reducing the risk of BC

Adverse reactions: Hot flashes, Blood clots, teratogenic

Question 25

What are the non-hormonal agents used to help w/ CA homeostasis?

Answer 25

Bisphosphonates

RANKL Inhibiotrs (Denosumab)

Fluoride

Question 26

What are bisphosphonates? How do they work?

Answer 26

Analogs of Pyrophospate (POP) but their bond is replaced by PCP which makes them bind to the bone and stay there

Therefore, they retard formation of Hydroxyapetitie crystals

They bind to bone and stay there and are resistant to chemical and enzymative hydrolysis

Alendronate, Pamodronate, Etidronate

Zoledronic ACid

Question 27

There are 2 variable groups on the PCP domain of Bisphonsphonates - what is each responsible for/ attributable to?

Answer 27

R1 domain = NH2, OH binding and determines the strength of the bond - varies adsorption to mineral

• nitrogenous stronger vs non-nitrogenous

R2 domain = N in ring , Antiresorptive potency

• how strong the drug is

Question 28

Discuss the mechanism of action of BPs?

Non-nitrogenous vs Nitrogenous

Answer 28

All start the same by binding to bone and then OC resportion occurs and they take up the bone w/ the BP on them and then….

Non-Nitrogenous: get metabolized into ATP analogues and cause all metabolism to get stuck and OC apoptosis

Nitrogenous: inhibit cholestrol synthesis w/ FPP Synthase resulting in inhibition of production of Isoprenoids that bind proteins involved in structural/functional features of OC

• aka no post-translational modifications of proteins and so no mature proteins for OC to function properly

Question 29

Side Effects of Bisphosphonates?

Answer 29

Atypical Subtrochanteric Femur fractures

Osteonecrosis of the jaw only seen in patients taking BP for cancer treatment (IV Zoledronic acid)

Question 30

What is the RANKL inhibitor? How does it work? When is it used?

Answer 30

Denosumab

Antibody against RANK ligant given as SC injection 2x/year

Prevent maturation of OC and so therefore causes OC suppression

Used - after failure w/ BP - see bone loss with BP or after 5 years of BP use

OR used as prevention in treatments where known side effect is Osteoporosis or where cancers are known to have bone metasasis to prevent bone mets:

Prostate cancer w/ Androgen deprivation therapy

Breast cancer w/ hormonal therapy like ARomatase inhibitors

Question 31

What are the 3 “other” agents in Calcium homeostasis and how are they used?

Answer 31

1) Fluoride - dental carries, _*IF used alone w/o Ca then = Osteomalacia!_
2) Plicamycin - for Paget’s Disease and Hypercalcemia, inhibits RNA synthesis and used at 1/10th dose it is used as for CTX
3) Thiazides - reduce renal CA excretion and increase effectiveness of PTH in stimulating renal Ca absorption