Pharmacology 26 (Thyroid And Antithyroid Drugs)

Front 1

what are the steps of thyroid hormone synthesis and storage?

Back 1

iodide is brought into follicular cells

iodine iodinates tyrosine residues with thyroglobulin to form MIT and DIT

2DIT -> T4
1DIT + 1MIT -> T3

secretion into colloid

when T3 and T4 are needed, endocytosis and proteolysis occur, leading to free T3 and T4

Front 2

which form of thyroid hormone is a prohormone?

Back 2

thyroxine (T4)

Front 3

which form of thyroid hormone is the active hormone?

Back 3

3,5,3'-triiodothyronine (T3)

1 iodine on outer ring
2 iodines on inner ring
(iodine removed from outer ring)

Front 4

what is reverse T3?

Back 4

3,3',5'-triiodothyronine

inactive hormone

2 iodines on outer ring
1 iodine on inner ring
(iodine removed from inner ring)

Front 5

how does the thyroid hormone receptor work?

Back 5

absence of thyroid hormone - TR:RXR heterodimer associates with corepressor complex, which binds promoter regions of DNA and inhibits gene expression

presence of T3 - co-repressor complex dissociates from TR:RXR heterodimer, coactivators are recruited, and gene transcription/translation is increased

Front 6

what are the actions of thyroid hormone?

Back 6

1) critical for nervous, skeletal, and reproductive tissues
- causes protein synthesis
- potentiates secretion & action of GH
2) increases basal metabolic rate
3) sympathomimetic effect
4) increases cholesterol metabolism

Front 7

what is the result of thyroid hormone deprivation in early life?

Back 7

irreversible mental retardation and dwarfism

Front 8

what is cretinism?

Back 8

severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormones (congenital hypothyroidism) usually due to maternal hypothyroidism

Front 9

what are the cardiovascular effects of thyroid hormone?

Back 9

sympathomimetic
a) indirect - increases CO (secondary effect of increased metabolic demand)
b) direct - increases sensitivity to catecholamines (does not decrease PSNS activity)

Front 10

how does thyroid hormone increase sensitivity to catecholamines?

Back 10

decreases phosphodiesterase activity leading to increased cAMP

increases number of beta-receptors in the heart

Front 11

what is a common metabolic finding in hypothyrodic patients?

Back 11

hypercholesterolemia

**thyroid hormone increases the metabolism of cholesterol**

Front 12

what is a common cardiovascular problem in hyperthyrodic patients? how do you treat this?

Back 12

arrhythmias

Tx: beta-blocker until hyperthyroidism is under control

Front 13

where does remodeling of bones occur?

Back 13

spongy trabecular bone (main component of the epiphysis)

b/c of this, conditions that disrupts mineralization and/or bone turnover affects regions of bone with large trabecular areas (vertebral bodies, neck of femur)

Front 14

what cells are the bone fillers?

Back 14

osteoblasts

Front 15

what cells are the bone diggers?

Back 15

osteoclasts

Front 16

physiological functions of calcium

Back 16

1) maintain integrity of nerve and muscle
2) cardiac function
3) maintenance of membrane integrity
4) blood coagulation

Front 17

what is caused by decreased calcium concentration?

Back 17

increased sodium permeability which leads to increased Na influx, and then spontaneous muscle contraction

Front 18

what is caused by increased calcium concentration?

Back 18

decreased sodium permeability which leads to decreased Na influx, and then arrhythmias

Front 19

what is the function of calcitonin?

Back 19

inhibition of osteoclasts
(decrease bone resorption in response to hypercalcemia)

Front 20

why is it important that phosphate excretion be increased in addition to increased reabsorption of calcium to correct hypocalcemia?

Back 20

the product of [Ca] and [PO4] remains constant, so if PO4 excretion isn't increased, any calcium that is maintained in the body quickly gets deposited in the bone matrix

Front 21

what is the primary effect of 1,25-dihydroxyvitamin D3 (active form of vitamin D)?

Back 21

increases intestinal absorption of calcium and phosphate

also enhances bone response to PTH, but this isn't so important

Front 22

what inhibits renal production of active vitamin D?

Back 22

phosphate

Front 23

how is urinary loss of calcium reduced in the case of hypocalcemia?

Back 23

hormonally-mediated increase in reabsorption (PTH)

diminished glomerular filtration of calcium b/c of decreased plasma calcium concentration

Front 24

what are the paradoxical effects of PTH on bone resorption?

Back 24

as long as PTH enters the bloodstream in a continuous fashion (endogenous secretion), it stimulates bone resorption

if PTH is administered once-daily (exogenous Tx with PTH), it stimulates new bone formation (accretion)

Front 25

where does the first step of vitamin D activation occur?

Back 25

skin (requires UV light)

Front 26

what are the forms of vitamin D?

Back 26

cholecalciferol
calcifediol
calcitriol

Front 27

what are the steps in the activation of vitamin D?

Back 27

7-dehydrocholesterol is converted in the skin to cholecalciferol by UV light

cholecalciferol is converted in the liver to calcifediol by hepatic microsomal enzymes (P450 system)

calcifediol is converted in the renal mitochondria to calcitriol

Front 28

what reaction is stimulated by PTH, but inhibitited by calcitonin?

Back 28

final step in producing active vitamin D
(conversion of calcifediol to calcitriol in renal mitochondria)

Front 29

causes of hypercalcemia

Back 29

ingestion (RARE)

hyperparathyroidism

**neoplasms that secrete PTH-like peptides (often of lymphoid origin)**

Front 30

treatments for hypercalcemia

Back 30

1) prednisone (steroids) - inhibits lymphomas
2) calcitonin - too mild
3) I.V. phosphates - emergency situation
4) pamidronate or zolendronate
5) furosemide - saline diuresis (inhibits loop reabsorption of Ca)

Front 31

why is furosemide an effective treatment for hypercalcemia?

Back 31

inhibits loop reabsorption of calcium

Front 32

what are the symptoms of hypocalcemia?

Back 32

tetany
tonic-clonic convulsions

Front 33

what are the etiologies which cause hypocalcemia?

Back 33

(1) renal insufficiency (chronic kidney disease)
(2) calcium and/or vitamin D deprivation (Rickets)
(3) hypoparathyroidism (congenital or surgically induced)
(4) pseudohypoparathyroidism (deficiency of vitamin D or of PTH receptors)

***(2), (3), and (4) are MUCH less common than (1)***

Front 34

why does renal insufficiency cause hypocalcemia?

Back 34

comrpomised renal function leads to decreased 1,25-dihydroxyvitamin D synthesis as well as decreased phosphate excretion

dec. vitamin D leads to decreased GI calcium absorption

inc. phosphate causes inc. new bone formation and deposition of calcium

by these mechanisms, chronic kidney disease leads to hypocalcemia

Front 35

what are the stimuli for PTH synthesis and secretion?

Back 35

hypocalcemia

decreased levels of 1,25-dihydroxyvitamin D

hyperphosphatemia

Front 36

what are the effects of low levels of 1,25-dihydroxyvitamin D on the parathyroid glands?

Back 36

(1) stimulate PTH synthesis
(2) stimulate parathyroid gland hyperplasia
(3) decrease number of calcium receptors on parathyroid gland chief cells
(4) elevates set-point for calcium regulation

Front 37

how does hyperphosphatemia cause increased PTH synthesis and secretion?

Back 37

directly
OR
indirectly (inc. levels of FGF-23, which leads to decreased levels of 1,25-dihydroxyvitamin D, which stimulates PTH synthesis and secretion)

Front 38

as a syndrome, what are the characteristics of hyperparathyroidism?

Back 38

(1) increased bone resorption
(2) increased amts of unmineralized osteoid
(3) osteitis fibrosa cystica

Front 39

what regulatory events lead to hyperparathyroidism during chronic renal disease?

Back 39

- hypocalcemia stimualting PTH
- decreased levels of 1,25-dihydroxy vitamin D stimulating PTH
- hyperphosphatemia stimulating PTH directly or indirectly

Front 40

how is Rickets treated?

Back 40

calcium

Front 41

what are the causes of hypoparathyroidism?

Back 41

congenital aplasia/dysplasia of parathyroid glands

surgical removal of the parathyroid glands (unintentional complication of thyroid gland removal)

Front 42

what are the causes of pseudohypoparathyroidism?

Back 42

deficiency of 1,25-dihydroxyvitamin D

defect in PTH receptors on target tissues

Front 43

why is PTH not a good treatment for pseudohypoparathyroidism?

Back 43

since these patients present with hypocalcemia, one would anticipate low levels of PTH, but in actuality these patients have normal or elevated levels of PTH

as the defect in pseudohypoparathyroidism is in PTH receptors or vitamin D synthesis, PTH offers no help when administered

Front 44

what are the treatments for hypcalcemia in general?

Back 44

calcium acetate
active vitamin D analogues

Front 45

what are the treatments for hypocalcemia caused by chronic renal disease?

Back 45

active vitamin D analogues (esp. dihydrotachysterol)
oral phosphate binders (calcium acetate, sevelamer)
calcimimetics (cinacalcet)

Front 46

how does bone mass change as a function of age?

Back 46

in both men and women, bone mass increases with age until a peak is reached in young adulthood (about 24/25 yo), after which bone mass gradually declines by about 0.7% per year

in women, onset of menopause precipitates a sharp decline in bone mass (dec. in estrogen causes inc. in bone resorption)

Front 47

what is the effect of estrogen on bone metabolism?

Back 47

decreases bone resorption

**in menopause, when a woman is no longer producing so much estrogen, there is a sharp decline in bone mass b/c decreased estrogen production leads to increased bone resorption**

Front 48

what causes osteoporosis?

Back 48

osteoclasts (responsible for bone resorption) outperform osteoblasts (responsible for bone deposition)

bone is constantly undergoing remodeling, but in osteoporosis this is out of balance (resorption>deposition)

Front 49

what forms the matrix of bone?

Back 49

mucopolysaccharides
- gives bone some flexibility

if the matrix gets old, bone loses flexibility and becomes very brittle

Front 50

what couples bone resorption with bone formation?

Back 50

interactions between osteoblasts and osteoclasts

Front 51

what stimuli cause osteoblast precursors to express RANKL?

Back 51

PTH
shear stress
TGF-beta

Front 52

what is RANKL? (relating to osteoporosis)

Back 52

receptor activator of NF-kappaB ligand

osteoclast differentiation factor expressed by osteoblast precursors to stimulate maturation and activity of osteoclasts

Front 53

what is RANK? (relating to osteoporosis)

Back 53

receptor activator of NF-kappaB

receptor expressed on osteoclast precursors which causes differentiation into mature osteoclasts

Front 54

what factors cause differentiation of osteoblast precursors into mature osteoblasts? where do these come from?

Back 54

TGF-beta
IGF-1
growth factors
cytokines

liberated from bone matrix (where they are bound/trapped) by osteoclast-mediated bone resorption

Front 55

what cytokine works together with the RANK-RANKL binding interaction to cause osteoclast precursors to differentiate into mature osteoclasts?

Back 55

macrophage colony stimulating factor (M-CSF)

Front 56

what is the theory behind antiresorptive therapy for osteoporosis? what are the drawbacks?

Back 56

enhance osteoblasts or inhibit osteoclasts, so that bone resorption is stopped/slowed

1) no substantial gains in bone mass
2) matrix gets old and brittle still

Front 57

why does antiresorptive therapy for osteoporosis not provide substantial increases in bone mass?

Back 57

osteoclasts are inhibited, and since they work cooperatively, osteoblasts (and thus bone formation) are inhibited as well

modest increases in bone mass are typically seen during the first year, but represent a constriction of the remodeling space to a new steady-state level, after which bone mass reaches a plateau

Front 58

how does calcium inhibit osteoclasts?

Back 58

decreases secretion of PTH, thereby indirectly inhibiting osteoclasts

Front 59

how does calcium treatment for osteoporosis compare with dietary calcium intake?

Back 59

normal dietary - 600 mg/day

Tx - 1600 mg/day (as calcium carbonate)

Front 60

how do vitamin D analogues inhibit osteoclasts?

Back 60

decreases secretion of PTH directly and increases calcium resorption from the GI tract which also decreases PTH secretion

decreased PTH causes decreased osteoclast activity

Front 61

what are the drawbacks which have limited the use of vitamin D analogues in osteoporosis patients?

Back 61

hypercalcemia
hypercalciuria (which leads to kidney stones)

Front 62

if estrogen has such great protective factors against osteoporosis, why is it not used as a clinical treatment?

Back 62

estrogen increases the incidence of breast cancer, strokes, and DVT

Front 63

what is the biggest drawback to therapy with raloxifine?

Back 63

increased risk for thromboembolic events (DVT/PE)

contraindicated in women with any tendency toward DVT/PE

Front 64

what are the side effects associated with raloxifene?

Back 64

increased DVT/PE
hot flashes (29% of patients)
leg pain (cramps)

Front 65

thyroid USP

Back 65

dessicated thyroid of a cow/pig formed into tablets

Highly variable T3/T4 ratio

Front 66

levothyroxine

Back 66

pure T4 salt

Amount stays pretty constant within one brand, but a lot of variety between brands

Front 67

liothyronine

Back 67

T3

Used for suppression tests
sometimes added to T4 for Tx

Front 68

propylthiouracil

Back 68

thioamine antithyroid drug

- Prevents thyroid hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions to block iodine organification
- Blocks the coupling of iodotyrosines
- Interferes with peripheral deiodination of T4 to T3

Clinical Uses:
(1) Definitive treatment while waiting for spontaneous remission of hyperthyroidism (which often occurs in mild hyperthyroidism)
(2) Used in conjunction with radioiodine before the radiation destroys the gland
(3) Pre-surgical control before removal of the gland

Front 69

methamizole

Back 69

thioamine antithyroid drug

Prevents thyroid hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions to block iodine organification
Blocks the coupling of iodotyrosines

Clinical Uses:
(1) Definitive treatment while waiting for spontaneous remission of hyperthyroidism (which often occurs in mild hyperthyroidism)
(2) Used in conjunction with radioiodine before the radiation destroys the gland
(3) Pre-surgical control before removal of the gland

Front 70

thiocyanate

Back 70

ionic inhibitor of thyroid hormone

Anion with approximately the same molecular radius as iodine

Inhibits iodide uptake by the thyroid (competitive inhibition at Na/I symporter)

Front 71

perchlorate

Back 71

ionic inhibitor of thyroid hormone

Anion with approximately the same molecular radius as iodine

Inhibits iodide uptake by the thyroid (competitive inhibition at Na/I symporter)

Front 72

iodide

Back 72

high concentrations inhibit iodide organification and thyroid hormone release; also decrease the size and vascularity of the hyperplastic thyroid gland

Tx for hyperthyroidism

Front 73

radioactive iodine

Back 73

I-131 usually used

trapped in the thyroid gland and stored in the colloid; radiation destroys parenchymal cells, but little damage is done to surrounding tissue

One dose cures 80%-90% of patients treated

During Tx, pt cannot hold babies (they are radioactively hot)

Front 74

parathyroid hormone (PTH)

Back 74

peptide hormone released from parathyroid glands

Increases bone resorption (inc. osteoclast activity; dec. osteoblast activity)
- Endogenous, continuous PTH secretion
- Exogenous, once-daily injections stimulate new bone formation (accretion)

Increases tubular resorption of calcium while decreasing reabsorption of phosphate

Indirectly increases intestinal absorption of calcium and phosphate by increasing renal formation of 1,25-dihydroxyvitamin D (active form)

Front 75

calcitonin

Back 75

peptide hormone released from the parafollicular C cells of the thyroid gland

Inhibits bone resorption by inhibiting osteoclasts

Can be used as a treatment for hypercalcemia, but is really too mild

Tx for osteoporosis (modest increase in bone mass, but unclear whether fx are decreased)

Available as a nasal spray or injectable form (protein, so must have parenteral administration)

Front 76

Na phosphate

Back 76

Given I.V. as Tx of emergent hypercalcemia

Phosphate binds calcium and leads to bone formation

Front 77

K phosphate

Back 77

Given I.V. as Tx of emergent hypercalcemia

Phosphate binds calcium and leads to bone formation

Front 78

pamidronate

Back 78

IV bisphosphonate

Binds to hydroxyapatite crystal of bone until it is ingested by osteoclasts, and then inhibits the osteoclasts

Given in high doses to treat hypercalcemia caused by lymphomas (main use)

Associated with osteonecrosis of the jaw, but only at very high doses

Not used to treat osteoporosis

Front 79

zolendronate

Back 79

IV bisphosphonate

Binds to hydroxyapatite crystal of bone until it is ingested by osteoclasts, and then inhibits the osteoclasts; since it binds to the bone plasma levels don’t have to be maintained for it to be working (only has to be given once a year)

Given in high doses to treat hypercalcemia caused by lymphomas (main use)

Associated with osteonecrosis of the jaw, but only at very high doses

Tx for osteoporosis (only use once per year)
- Discontinue after 5 yrs for a period of 2-3 years to allow for new matrix formation and then restart dosing

Front 80

calcium acetate

Back 80

oral phosphate binder

Binds phosphate in the gut and prevents its absorption; increases excretion of phosphate in the stool

Tx for hypocalcemia/hyperphosphatemia/hyperparathyroidism associated with chronic kidney disease

Front 81

sevelamer

Back 81

oral phosphate binder

Binds phosphate in the gut and prevents its absorption; increases excretion of phosphate in the stool

Tx for hypocalcemia/hyperphosphatemia/hyperparathyroidism associated with chronic kidney disease

Front 82

cinacalcet

Back 82

calcimimetic

Modulates the activity of calcium-sensing receptor on chief cells of the parathyroid gland, such that the receptor is activated at lower plasma calcium concentration (makes parathyroid cells more sensitive to calcium so they synthesize and secrete less PTH)

Tx for hyperparathyroidism associated with chronic kidney disease

Front 83

cholecalciferol

Back 83

vitamin D3 – active vitamin D analogue

Product of UV interaction with 7-dehydrocholesterol in the skin

With increased cholecalciferol available, more can be converted to active vitamin D (calcitriol)

Tx for hypocalcemia/hyperphosphatemia/hyperparathyroidism

Front 84

ergocalciferol

Back 84

vitamin D2 – active vitamin D analogue

Plant vitamin D, which is essentially identical in action to cholecalciferol (vitamin D3) in vivo

Added to milk

Effectively increases the vitamin D3 that can be converted to active vitamin D (calcitriol)

Tx for hypocalcemia/hyperphosphatemia/hyperparathyroidism

Front 85

calcifediol

Back 85

25-hydroxyvitamin D – active vitamin D analogue

Product of hepatic microsomal (P450) reactions on cholecalciferol

With increased calcifediol available, more can be converted into active vitamin D (calcitriol)

Tx for hypocalcemia/hyperphosphatemia/hyperparathyroidism

Front 86

calcitriol

Back 86

1,25-dihydroxyvitamin D – active vitamin D analogue

Product of 1alpha-hydroxylase reactions on calcifediol in kidneys

Active form of vitamin D, so it bypasses the renal 1alpha-hydroxylase reaction completely (this reaction is deficient in chronic kidney disease)

Increases GI calcium absorption and suppresses PTH secretion

Really it is too quick to be used as a Tx, but can be used as Tx for hypocalcemia/hyperphosphatemia/hyperparathyroidism

Front 87

dihydrotachysterol

Back 87

active vitamin D analogue

Synthetic compound that is activated by cleavage in the liver

Prodrug, so it has a long and sustained action

Since activation is via liver and not kidneys, can be used in renal failure as Tx for hypocalcemia/hyperphosphatemia/hyperparathyroidism

Front 88

alendronate

Back 88

oral bisphosphanate

Binds to the hydroxyapatite cristal of bone until ingested by osteoclasts, which it then inhibits

Associated with severe esophagitis, so pt must not lay down for 30 minutes after taking the pill

Low bioavailability, so pt must take with only wáter on an empty stomach

Tx for osteoporosis (only need to take once per week)
- Discontinue after 5 yrs for a period of 2-3 years to allow for new matrix formation and then restart dosing

Front 89

ibandronate

Back 89

oral bisphosphanate

Binds to the hydroxyapatite cristal of bone until ingested by osteoclasts, which it then inhibits

Associated with severe esophagitis, so pt must not lay down for 30 minutes after taking the pill

Low bioavailability, so pt must take with only wáter on an empty stomach

Tx for osteoporosis (only need to take once per month)
- Discontinue after 5 yrs for a period of 2-3 years to allow for new matrix formation and then restart dosing

Front 90

risedronate

Back 90

oral bisphosphanate

Binds to the hydroxyapatite cristal of bone until ingested by osteoclasts, which it then inhibits

Associated with severe esophagitis, so pt must not lay down for 30 minutes after taking the pill

Low bioavailability, so pt must take with only wáter on an empty stomach

Tx for osteoporosis (only need to take once per week)
- Discontinue after 5 yrs for a period of 2-3 years to allow for new matrix formation and then restart dosing

Front 91

raloxifene

Back 91

selective estrogen receptor modulator

stimulates estrogen receptors (partial agonist) in bone, but not in uterine or breast tissues (estrogen antagonist)

Tx for osteoporosis (not as effective as estrogen, but decreases incidence of invasive breast cancers)

decreases LDL

increases DVT/PE incidence
causes hot flashes (29%)
leg pain (cramps)