Thyroid, Parathyroid & Adrenals Flashcards
What cells make thyroid hormone?
Follicular cells of the thyroid gland
What is the source of iodine in our body and how is it absorbed?
Diet, ionic form called iodide
How is iodide taken up and where does it concentrate?
Via Na-iodide symporter at the follicular cells, it concentrates as a result in the follicular cells
What are the 2 forms of thyroid hormone
Triiodothyronine (T3) and Tetraiodothyronine (T4)
Explain the synthesis of thyroid hormone
- Thyroid Peroxidase (TPO) oxidises iodide to iodine2. TPO couples iodine to tyrosine, this makes thyroglobulin. This process is called organification3. A diiodo and a monoiodo tyrosine residue gives you T3, while two diiodo tyrosine residues coupled together gives you T4; both T3 and T4 are stored as thyroglobulin in the follicular lumen.4. Follicular cells cleave T3 and T4 from follicular lumen
What is more potent? T3 or T4?
T3
What converts T4 to T3 in the peripheral tissue?
5’-deiodinase (it is deiodinized)
What is one effect of thyroid hormones on the peripheral tissues and as a result what drugs can we use for hyperthyroidism?
One of the effects of thyroid hormone is to increase the sensitivity of peripheral tissues to sympathetic stimulation by causing increased transcription of beta-receptors, which increases the body’s sensitivity to circulating catecholamines.As a result we can use beta blockers for symptomatic treatment of hyperthyroidism
What is the most common cause of hyperthyroidism?
Graves disease
Explain exophthalamous associated with Grave’s disease.Why does this exactly happen?
Grave’s ophthalmopathy = increased volume of retroorbital connective tissue, due to cellular proliferation, inflammation, and the accumulation of glycosaminoglycans.Happens due to auto antibodies associated with Grave’s disease.
Explain radioactive iodine treatment and what potential adverse effect can it lead to?
Radioactive iodine becomes concentrated inside the follicular cells via the Na+/Iodine symporter, it can potentially lead to hypothyroidism
What are the adverse effects of radioactive iodine treatment?In what condition is this therapy contraindicated?
It has a small risk of thyroiditis that causes severe thyroid pain and can exacerbate hyperthyroidism and Grave’s disease, worsening its symptoms (e.g. palpitations, tremors, exophthalmos). Ironically it is contraindicated in patients with exophthalmos due to risk of exacerbation of Grave’s disease
What drugs can be used to avoid exacerbation of Grave’s disease
Thionomides, they deplete iodine stores before being given ablative iodine treatment - that way, when the follicular cells are being destroyed, you won’t get too much T3/T4 leaking out
Give examples of thionomides
Propylthiouracil, Methimazole
Explain propylthiouracil and Methimazole MOA.How do they differ?
Propylthiouracil and Methimazole treat hyperthyroidism by directly inhibiting TPO - prevents the oxidation of iodine into iodide. Methimazole is 10x more potent than PTU but PTU also treats hyperthyroidism by inhibiting 5’ deiodinase -> leading to decreased conversion of T4 into T3.
Explain MOA of beta blockers in treating hyperthyroidism
Antagonizes adrenergic receptors AND inhibits 5’ deiodinase enzyme
Compare and contrast glucocorticoids and beta blockers use in treating Grave’s disease
Glucocorticoids don’t treat sympathetic symptoms but can reduce inflammation associated with Grave’s disease
Explain thyroid storm
Acute exacerbation of all the hypermetabolic and hyperadrenergic symptoms of thyrotoxicosis, presenting as a life-threatening syndrome. Thyroid storm (thyrotoxic crisis) can occur due to chronic untreated hyperthyroidism or can occur due to an acute event such as surgery, trauma, or infection.
Explain treatment of thyroid storm
1) blocking sympathetic effects (beta-blockers) and 2) blocking thyroid hormone synthesis (PTU), and 3) blocking conversion of T4 into T3 (beta-blockers, PTU, glucocorticoids).
How can we use anions to treat hyperthyroidism
Since I- requires a Na+/I- symporter to enter follicular cells, anions can be used as competitive inhibitors of I- transport
Name anions that are used for hyperthyroidism
perchlorate, pertechnetate, and thiocyanate
What are the adverse effects of PTU?
- Hepatoxicity and even liver failure2. Agranulocytosis (irregular bleeding)3. Causes maculopapular pruritic rash4. Aplastic anemia5. Lupus like syndrome6. ANCA associated vasculitisSafe to use in pregnancy!
What are the adverse effects of Methimazole?
agranulocytosis, aplastic anemia, drug induced lupus, teratogenic!
What is the most common cause of hypothyroidism
Hashimoto’s Thyroiditis
Whats the outcome of untreated hypothyroidism?
Untreated hypothyroidism can lead to myxedema coma (progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, death)
Levothyroxine
Synthetic T4
What is a common theme in bisphosphonates, SERMs, Calcitonin and Denosumab
Decrease osteoclastic activity but do not increase osteoblast activity in terms if new bone formation, as a result bone remodeling in inhibited
What is the first line treatment of osteoporosis?
Bisphosphonates, due to their efficiency and cheap price
Examples of bisphosphonates
alendronate, pamidronate, zoledronate
Bisphosphonates MOA
Have a similar structure to pyrophosphate, work by attaching to hydroxyapatite in bone, preferentially binding to areas of increased bone turnover. Osteoclasts bind to the bisphosphonate, inhibiting their adherence to the bony surface
What are the effects of bisphosphonates on osteoclasts?
Decrease development and recruitment of osteoclasts and induce apoptosis of osteoclasts
When are bisphosphonates especially useful other than for osteoporosis
Useful in acute treatment of hypercalcemia of malignancy, which can be lethal.In this case bisphosphonates are combined with calcitonin which enhances Ca clearance from the kidneys.Also useful for Pagets disease
AE of bisphosphonates and how can they be avoided?
Upper GI effects such as acid reflux, esophagitis, and even esophageal ulcers; side effects can be avoided by taking bisphosphonates with plenty of water and remaining upright for 30minIn rare cases they can cause osteonecrosis of the jaw.Also can cause hypocalcemia
Is estrogen used for osteoporosis?
Not anymore due to increased risk of breast and ovarian cancer and due to hypercoagulability
What drugs can be used instead of estrogen for osteoporosis?
Selective Estrogen Receptor Modulators (SERMs)
Give an example of SERM
Raloxifene
MOA of SERMs
SERMs can imitate or antagonize the effects of natural estrogen, depending on what locations they bind at in the body.Raloxifin has agonist activity in the bone and antagonist activity in the breast and in the uterus,
When is raloxifine used?
Raloxifene is a 2nd-line option used for patients who cannot take bisphosphonates.
What are the effects of PTH?
Parathyroid Hormone (PTH) stimulates osteoblasts to express Receptor Activator of Nuclear factor KappaB Ligand (RANKL). Rank is found on osteoclasts and this leads to increased osteoclast activity
What is the name of humanized monoclonal antibody against RANKL
Denosumab
Where does calcitonin comes from and what are its effects?
Calcitonin is a peptide hormone secreted by the parafollicular cells of the thyroid with the principal effect of lowering serum calcium and phosphate by its actions in the bone and kidney. Calcitonin “tones down” your calcium.Inhibits osteoclast bone reabsorption
When is calcitonin used?
Calcitonin effects on bone are not as significant as bisphosphonates and other drugs, so Calcitonin is not 1st-line therapy for osteoporosis. The ability of Calcitonin to lower serum calcium through decreased bone resorption and increased Ca2+ kidney excretion, makes calcitonin useful for acute treatment of severe hypercalcemia
What are the AE of calcitonin
Hypocalcemia
What is the component of bone that is deposited by osteoblast during bone building?
Hydroxyapatitie
What is teriparatide?What are its effects?
Recombinant PTH, increase Ca absorption at the kidneys, increase phosphate excretion at the kidneys, increase 1 alpha hydroxylase activity at the kidneys
What is the effect of Vitamin D and teriparatide on osteoblast and osteoclast?
Teriparatide and Vitamin D activate osteoblasts to promote bone formation.Teriparatide and Vitamin D indirectly activate osteoclasts to increase bone resorption/turnover. (Via RANK-RANKL pathway)Overall bone turnover is increased
List the effects of PTH on the body
- Increased development and recruitment of osteoblasts2. Increased Ca resorption at the kidneys at expense of phosphate3. Increase in RANKL, so increase in osteoclast activity4. Increase in 1-alpha hydroxyls activity in the kidney, leads to increased conversion of 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D (aka calcitriol).
Where is vitamin D2 and D3 obtained from?
Vitamin D3 (cholecalciferol) is obtained via dairy products or UVB radiation in sunlight.Vitamin D2 (ergocalciferol) is obtained via plants
What are the effects of calcitriol?
- Stimulates reabsorption of both calcium and phosphate.2. Stimulates intestinal absorption of both calcium AND phosphate.3. Cause osteoblasts to release RANKL → leading to osteoclast activity.4. Maturation of osteoblasts → leading to increased bone formation.5. Inhibits PTH production.
What is calcitriol used for?
Osteoporosis and in renal insufficiency when active form of vitamin D has to be given
What is the main effects of teriparatide?
Even though the net effect of endogenous PTH is bone resorption, the administration of low doses of exogenous PTH (e.g. Teriparatide) results in the net effect of bone formation.
Explain Cinacalcet effect and its use.
Cinacalcet (a calcimimetic) activates the calcium sensing receptor on the parathyroid gland → leading to decreased production of PTH.Useful in the treatment of hypercalcemia caused by hyperparathyroidism
Sevalamer
Non-absorbable phosphate binding polymer that decreases absorption of phosphate in the GI tract, used for hyperphosphatemia
What are the uses of calcitron?
- Topically used for psoriasis2. Long term treatment of hypocalcemia3. Treating rickers/osteomalacia
What are the adverse effects of calcitriol and teriparatide?
Hypercalcemia
What is the name of steroids receptor and where is it present?
Glucocorticoid Receptor Elements (GREs), in the cytoplasm
What does steroids form when they bind to their receptor?What is the function of this?
Glucocorticoid receptor complex (GRC)GRC unregulates transcription of inhibitors of PLA2, which is the first step in arachidonic acid pathway, inhibiting the production of COX and LOX. GRC also interacts with NF kappa B, inhibiting the synthesis of proinflammatory cytokines
Name examples of pro inflammatory cytokines
TNF alpha and IL 2
What is the function of TNF alpha
Involved in recruitment and proliferation of B and T lymphocytes
What are the effects of steroids on neutrophilsHow does this show in CBC?
Causes demmargination and decreased margination by down regulating neutrophil adhesion molecules so they can’t go to the site of inflammation.Shows in CBC as an acute increase in WBC
What are the effect of steroids on lymphocytes
Leukocyte and lymphocyte counts decrease due to apoptosis or inhibition and their redistribution to spleen
What is the main anabolic enzyme in the body?
Insulin
What are the effects of steroids on insulin and on liver in terms of glucose production?
Causes insulin resistance and stimulate hepatic gluconeogenesis, they also up regulate hepatic glycogen synthase and increase glycogen storage in the liver
What are the effects of steroids on pituitary?
Long-term glucocorticoid administration negatively feeds back on the anterior pituitary to suppress release of ACTH; less ACTH means less stimulation of the adrenal cortex -> and leads to adrenal cortical atrophy (secondary adrenal insufficiency).
What are the effects of steroids on the skin?
GCC’s inhibit fibroblast proliferation -> leading to skin thinning, striae, easy bruising impaired wound healing.
What are the effects of steroids on kidney function?
Exhibit mineralocorticoid effects leading to increased Na+ and fluid retention with increased K+ excretion -> leading to hypokalemia, similar to the effect of aldosterone’s effect on the collecting duct
