Describe the pathway of TH synthesis?
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
How is TH metabolised (aka what enzyme)? and what situations/drugs can alter this enzyme?
Beta Blockers and steroids, illness, starvation can inhibit 5'Diodinase and so get low T3 and less activation n tissues
What happens when TH binds its receptors? What tissues are more/less responsive?
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
What happens in Thyroid Auto-reuglation?
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
What drugs are indicated for the management of Hypothyroidism? Esp in kids bc why?
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
What is the best TH analogue to treat hypothyroidism with and why?
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
What drug would you use on someone who was Hypothyroid from a conversion problem? Whats bad about it?
Liothyronine (cytomel/triostat) = T3 analogue
fast acting but short half life
VERY potent bc T3 so lots of side effects
Why do women tend to be hypothyroid in early pregnancy?
Modest increases in TBG leads to less free T4/T3 and so need increased doses for hypothyroid women who are pregnant
What is Myxedema coma? How do you treat it? Problems w/ treatment?
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!
What are signs of Thyroid toxicity in adults and children?
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
When would you NOT treat someone > 21 yo w/ Grave's Disease w/ Radioactive Iodine?
Unless they have EYE DISEASE!
What are the two anti-thyroid drugs? Of those two, which one do you use in pregnancy and why?
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)
What is the mechanism of action for the anti-thyroid drugs?
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
What are the most worrisome side effects of Methimazole?
BM suppression and Liver toxicity!!
What are the Anion Inhibitors? How / When are they used?
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
How do Iodides work as Anti-thyroid drugs?
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
How does RAdioactive Iodine therapy work? Who should NOT receive this treatment?
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
What can be given to lessen the symptoms of thyrotoxicosis?
Propanolol - non-selective beta blocker!!!
Beta blockers w/ot intrinsic Sympathomimetic activity
(also blocks T4 to T3 peripherally which is additional benefit)
Symptoms of Thyroid Storm? Treatment?
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
What are the principle regulators of Mineral homeostasis and what are the secondary regulators?
Principle REgulators: PTH (peptide) and Vitamin D (steroid)
Others - dont regulate but control for clinical effects
- Sex steroids
What is calcitonin? Where does it come from and what does it do?
When is it used clincially?
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
What role do glucocorticoids play in Calcium homeostasis etc? How are they used clinically?
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
What role do estrogens have in Calcium homeostasis?
Estrogens reduce bone resporptive action of PTH
receptors found on bone suggestive of direct effect on bone remodeling
What is the Selective Estrogen REceptor Modulator (SERM)? What is it used for? Side effects?
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
What are the non-hormonal agents used to help w/ CA homeostasis?
RANKL Inhibiotrs (Denosumab)
What are bisphosphonates? How do they work?
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
There are 2 variable groups on the PCP domain of Bisphonsphonates - what is each responsible for/ attributable to?
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
Discuss the mechanism of action of BPs?
Non-nitrogenous vs Nitrogenous
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
Side Effects of Bisphosphonates?
Atypical Subtrochanteric Femur fractures
Osteonecrosis of the jaw only seen in patients taking BP for cancer treatment (IV Zoledronic acid)
What is the RANKL inhibitor? How does it work? When is it used?
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
What are the 3 "other" agents in Calcium homeostasis and how are they used?
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