4. Pharmacology II Flashcards
Antithyroid and Thyroid drugs
• 3 Hormones secreted by thyroid gland
– ____ (Tetraiodothyronine) = T4
– ____ = T3
– ____ – decreases calcium in blood stream by decreasing osteoclast activity and increasing Ca excretion
thyroxine
triiodothyronine
calcitonin
• insulin is one of the endocrine hormones that don’t go through this hypothalamus pituitary
end organ access BUT there are releasing factors from the ____ (in this case thyrotropin releasing factor or hormone) that stimulates the ____ gland to secrete thyroid stimulating hormone which in fact then binds to receptors on the thyroid gland that releases T3 and T4
◦ if everything is working properly and you get too much T3 and T4 in the blood stream, there is negative feedback on the ____ and ____ to turn off the release of thyrotropin releasing hormone and thyroid stimulating hormone
• the hormones T3 and T4 (that have 3 and 4 ____ respectively) really rev things up:
◦ increasecellmetabolism
◦ help in growth and development
◦ make catecholamines work better, things like NE and Epinephrine work better in the body
‣ they have a so called ____ effect
• HOWEVER, when too many floating in body, the NE and E effects run wild and we’ll talk about
hyperthyroidism in a bit
hypothalamus
pituitary
pituitary
hypothalamus
permissive
Thyroid Hormone Synthesis
• this is the sythetic pathway to make thyroid hormone
• to make thyroid hormone you need ____ (get from diet- usually salted thing)
‣ obviously this is energy decent pump because this is an anion and charged things don’t like to easily go through tissues
◦ so it goes from blood into thyroid gland –>
◦ gets process by an enzyme (____) to form this reactive form of iodine (this is like iodine minus an electron) –>
◦ and then this will combine with tyrosine moieties, ____ within the gland to form
thyroglobulin T4 and thyroglobulin T3 (NOTE TYPO: the word “thyroglobulin is suppose to be
thyroglobulin) –>
◦ the thyroglobulin entity gets ____ and you get free T3 and T4 –>
◦ it gets released to the blood stream
‣ a little of it is T3 but most of it is ____
‣ but within the blood stream, some of the T4 can lose an iodine and become a ____
• so what’s important? these are all potential targets to treat hyperthyroidism!
◦ there were drugs that were developed to block places all along this mechanism that we’ll talk about
• in the end, in most hypothyroid people, these drugs eventually fail or the endocrinologists are tired of dealing with bouts of hypertension and cardiac arrhythmias and the gland gets fried :(
iodine peroxidase thyroglobulin cleaved T4 T3
Thyroid Hormone Characteristics • Can be \_\_\_\_ in gland for months • Highly \_\_\_\_ bound • Increases \_\_\_\_ activity • Increases \_\_\_\_ synthesis • Increases \_\_\_\_ growth • Increases \_\_\_\_ uptake, glycogenolysis, gluconeogenesis • Increases density of \_\_\_\_ receptors • Makes \_\_\_\_ nervous system work better
stored protein metabolic protein bone glucose alpha and beta sympathetic
Hypothyroidism • In adults also called \_\_\_\_ – Extreme somnolence – \_\_\_\_ and decreased cardiac output – Mental sluggishness – Weight \_\_\_\_ – Edema in extremities and elsewhere – Intolerance to \_\_\_\_ – Alopecia including eyebrows – \_\_\_\_ fragility
myxedema bradycardia gain cold capillary
Hypothyroidism continued • In child called “\_\_\_\_” – Failure of \_\_\_\_ growth – Mental retardation – Dental anomalies • \_\_\_\_ eruption • Under developed \_\_\_\_ giving appearance of severe maxillary prognathism – Unless recognized in first few months of childhood and thyroid replacement therapy is initiated CNS damage is \_\_\_\_
cretinism skeletal late mandible permanent
Causes of Hypothyroidism • Thyroid gland \_\_\_\_ • \_\_\_\_ • Lack of \_\_\_\_ in the diet • \_\_\_\_ iodide to treat hyperthyroidism • \_\_\_\_ of gland or too much of the gland to treat hyperthyroidism
atrophy autommune iodide radioactive removal
Hypothyroid Drugs (all are PO)
- Thyroid USP – ____ Combo (desiccated cow glands). 120-180 mg/day
- Levothyroxine (Synthroid®)–Synthetic ____. 200 μg/day (about 1000 X more potent). Since some T4 de-iodated essentially replace ____.
- Liothyronine (Cytomil®) – Synthetic ____. ____ half life than Levothyroxine. Greater risk of ____. 25 μg/day
- Liotrix (Euthroid®) Synthetic T3 + T4
Toxicity usually from therapeutic overdose. ____, tachycardia, arrhythmias, ____. Increased sensitivity to ____ (epinephrine) if blood levels too high.
T3 + T4 T4 both T3 shorter toxicity
HTN
anxiety
catecholamines
Hyperthyroidism (Thyrotoxicosis)
• Causes–____ nodule or a tumor, ____ Disease which is a profusely enlarged gland
• Symptoms Ø \_\_\_\_ and arrhythmias Ø Hypertension ØExtreme \_\_\_\_ to both endogenous and exogenous catecholamines (i.e. epinephrine) Ø Mydriasis Ø \_\_\_\_ sweating Ø CNS stimulation including tremors ØAcceleration of \_\_\_\_
hot
graves
tachycardia
sensitivity
excessive
osteoporosis
Treatment of hyperthyroidism
• this is the first place where we can treat hypothyroidism ◦ there are two drugs: perchlorate and thiocyanate
‣ perchlorate: isn’t available anymore because it’s found in ____ and sky rockets and regular rocket fuel and basically it’s really nasty!
‣ what it did was it fools the thyroid gland or iodide pump into sucking it up instead of the iodine anion but again this stuff was no good (nephrotoxic)
‣ Thiocyanate: now you think my god cyanide! well thiocyanate is kind of interesting it is often found in
crusiverous(?) vegetables like ____, cauliflower, and some green leafy things like kale and there is some controversy that maybe people should’t eat more than 4 servings of broccoli a week
• again it kind of tricked the iodide pump into sucking it up and not ____ iodine
‣ rarely used
• by the way this stuff is 100 to 1000 fold less powerful than pure ____: cyanide is a poison; cyanide ties up hemoglobin so that it can’t transport oxygen; the way to treat cyanide poisoning in the ER is inducing
____ so you can give an overdose of a drug like nitroglycerin to induce methemoglobinemia, when the iron goes from FE2+ to Fe3+ it spits the cyanide off and then get the person on dialysis and get rid of the cyanide and then you treat the methemoglobinemia with ____
‣ so this drug isn’t ____ but it does have the cyanide molecule in there, rarely used but a possibility
clorox broccoli anionic cyanide methemaglobenmia methylene blue toxic
Treatment of hyperthyroidism
• the 3 big uses of these , actually works at a couple different places on this pathway but this is the main spot where this ____, or this reactive form of iodine that’s missing an electron or two, it blocks, it’s combining with thyroglobulin to
form thyroglobulin T4 and thyroglobulin T3, so these are the drugs that you’re most likely to see people on
• other agents used: lugol solution, this is almost only solely used before ____
◦ this stuff tastes like drinking ocean water, it’ really really salty but the idea is you get this enormous amount of ____ in the blood stream and it kind of feeds back on the thyroid gland and says don’t release any more thyroid hormone in a while
◦ so when people are surgically manipulating the gland to get it out, you don’t squeeze out as much thyroid hormone
• the other things that show up in hyperthyroidism: ____,
◦ this makes sense because what’s one of the symptoms of hyperthyroidism?
‣ they’re ____ and have tachy arrhythmiaas so they’ll take care and dampen that, but for some reason beta blockers inhibit the conversion of T4 to T3 and T3 is the more powerful version of thyroid hormone
• ____ like cortisone do the same thing, they kind of will block the conversion of T4 to T3
• some other strategies:
◦ eventually all this drug therapies fail or the endocrinologist says you’re having too many bouts of hypertension and cardiac arrhythmia and says we need to fry the glands
hypoiodate
surgery
iodine
beta blockers
HTN
glucocorticoids
Other Treatments for Hyperthyroidism
• ____
• Radioactive ____ (usually PO)
• ____ (Inderal®) and other Beta Blockers
• ____ and other barbiturates
– Reduces T4 and T3 levels by ____ induction
– ____ effects of beneficial
surgery iodide propranolol phenobarbital enzyme sedative
Parathyroid and Bone Metabolism Drugs
• ____ glands located behind the thyroid gland
• Parathyroid hormone(PTH):
– Increases extracellular (blood) calcium levels by:
• Increasing bone ____
• Increasing kidney ____ of calcium
– Stimulation of PTH release caused by ____ calcium in blood stream. Remember that corticosteroids inhibit ____ absorption which in turn inhibits calcium absorption and decreases calcium blood levels. PTH secretion is then turned on leading to bone ____ and osteoporosis.
– Inhibition of PTH release caused by ____ calcium in blood and ____ in vitamin D in diet.
4
resorption
reabsoprtion
decreased
vitamin D
excess
increase
Other Substances Involved in Calcium Uptake
• Calcitonin (opposes ____ action)
– Released from ____ cells of thyroid
– Decreases blood calcium by:
• Decreasing ____ activity
• Increasing calcium ____ by kidney
– Used to treat osteoporosis and ____ Disease
• Intransasal formulation = Calcitonin ____ (Salmonine®), very expensive
• Vitamin D
– Increases blood calcium levels by:
• Increasing calcium ____ from GI tract • Decreases calcium ____ from kidney
PTH parafollicular osteoclastic excretion Paget's salmon
absorption
excretion
Osteoporosis and Bisphosphonate therapy
- Osteoporosis is a major cause of morbidity, functional dependence and institutionalization in older Americans. One out of every two ____ will sustain an osteoporosis related fracture (such as wrist, spine or hip) in their lifetime. An estimated 10 million Americans over the age of 50 have osteoporosis, while another 34 million are at risk. As the population ages, the number of hip fractures in the United States could triple by 2020.
- Bisphosphonates are analogs of inorganic ____ and are used to treat bone loss associated with osteoporosis and Paget’s disease of bone.
Bisphosphonates inhibit ____ differentiation, and induce osteoclast ____ resulting in an imbalance in the bone remodeling process. They, thereby, promote an increase in bone trabecular thickness and bone mass.
women
pyrophosphate
osteoclast
apoptosis
Alendronate (Fosamax®) Structure
• this is the gold standard drug!
• there’s the ____ group (the 2 p’s and the oxygen and one carbon) (the red I
circled is pyrophosphate group)
• this one’s ____ containing
pyrophosphate
nitrogen
Orally Administered Bisphosphonates
• so these are the players (they all end in ____)
• so any dronate is a bisphosphoante
• ones with asterisk don’t have the ____
• will show difference in how they ____ depending on whether or not they have nitrogen
• Fosamax Plus D is literally Fosamax plus ____ to increase calcium absorption
◦ now they have once a week Fosamax (which is what Mrs. Hersh takes)
dronate
nitrogen
work
vitamin D
Intravenously Administered Bisphosphonates
• some of these drugs via IV formulations are used in ____!
• reasons they’re used in cancer (mainly breast) but others that metastasize the bone also because when you get metastasis in bone, you get bone ____
• they’re used to prevent bone fractures and ____ (excessive levels of calcium)
◦ excessive levels of calcium can cause cardiac arrhythmias
‣ we have calcium channel blockers used in the heart so that’s one of the things that you can end up with in hypercalcemia
• the other thing that these drugs do:
• when used in cancer they’re not only given IV, they’re given more ____!
◦ they now have IV formulations that they give once or twice a week for osteoporosis
◦ but for cancer, they’re given ____ and much ____ doses
‣ and that’s why you see a higher incidence of ____ of the jaw with the IV formulations used for cancer compared to IV formulations used for osteoporosis and certainly oral formulations used for osteoporosis
‣ the blood levels are just much much higher in cancer chemotherapy
• now you might say Hersh, this doesn’t end in dronate, well, we can call it zoladronate (dw he won’t ask for the companies etc)
• he just wants us to know in general how these drugs work and a little bit of the differences
between nitrogen containing and non nitrogen containing
cancers
demineralization
hypercalcemia
frequently
weekly
higher
osteoradionecrosis
