Endocrine 3

Parathyroid Physiology

*Calcium sensing organ *Produce parathormone (PTH) -monitors serum calcium feedback mechanism -PTH stimulated when decrease in calcium level in blood -PTH acts on bones, kidneys, & intestines to leach calcium back into blood

Number needed to harm

1/attributable risk look at examples

Thyroid adenoma what are the diff types of throid cancers which is the most common tx includes lab monitoring of tumor markers used to detect recurrence

Benign tumor of the thyroid gland

population attributable risk

Percentage of disease incidence that would be eliminated if the risk factor were removed

give 4 glycoprotein hormones

ØThyroid-stimulating hormone (TSH; also called thyrotropin) ØLuteinizing hormone (LH; also called lutropin) ØFollicle-stimulating hormone (FSH; also called follitropin) ØHuman chorionic gonadotropin (hCG).

From a formulation perspective, our concern is stability and the two primary classifications of stability - chemical and phsyical - what does does the chemical and physical instabilities cause

• Chemical - changes to covalent bonding of the product components • For chemical instability, specific AA residues are chemically transformed, i.e. alteration of chemistry at the primary sequence level. • Physical - non‐covalent changes to the product components • For physical instability, the biologic residue sequence remains the same.

how does milk come out of the breasts oxytocin is synthesized by __________

•Stimulation of the breast through suckling or mechanical manipulation induces oxytocin secretion, causing contraction of the myoepithelium that surrounds alveolar channels in the mammary gland. • •This action forces milk from the alveolar channels into large collecting sinuses, where it is available to the suckling infant. • •Oxytocin is synthesized by hypothalamic neurons. CNS regulator of trust and of autonomic systems linked to anxiety and fear, sometimes referred to as the "Love" hormone.

role of oxytocine, pitocine, tractocile

•Synthetic oxytocin as a uterine-stimulating agent to induce or augment labor in selected pregnant women and to decrease postpartum hemorrhage • •Oxytocin (Pitocin) stimulates the frequency and force of uterine contractions. • •Oxytocin antagonist atosiban (Tractocile) is effective in suppressing preterm labor. • •Oxytocin plays an important physiological role in milk ejection.

PTH increases plasma calcium levels through what three body parts

Bone Increasing Ca++ resorption from bone = increasing osteoclast activity Breaking down BONE where 99% of body's calcium is stored Kidneys Increasing Ca++reabsorption from renal tubules = decreased Ca++ excretion through kidneys Synthesize 1,25-dihydroxyvitamin D (vitamin D3) = physiologically active form of vitamin D in the proximal renal tubules - PTH is needed to hydroxylate calcidiol (calcifediol) to active vitamin D3 GI Tract Increases GI tract absorption of Ca++ through increased synthesis of D3

other essentials of diagnosis of hypoparathyroidism

Chvostek's sign Trosseau's sign Tetany, carpopedal spasms, tingling of lips and hands, muscle cramps, irritability

Hyperthyroidism what is thyrotoxicosis

"Thyrotoxis refers to the clinical manifestations associated with elevated serum levels of T4 or T3

Naranjo's Causality Algorithm

1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or after a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drug in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?

limitations in spontaneous reports

1. Causality assessment is difficult. 2. Subject to underreporting. 3. Not possible to calculate an incidence rate; unreliable numerator and very limited ability to estimate the denominator. 4. Reporting rates vary with: the age of the drug, publicity, type of reaction, marketing promotion, local policy, indication for use, frequency of use. 5. Domestic reports should not be lumped with foreign reports or reports from studies.

Pharmacoepidemiology: Purpose of Studies most evaluated type of study evaluated so far

1. Describe Explain Control Predict the use and effects of drugs in a defined time, place, and population. 2. Determine how a drug performs in clinical practice (effectiveness, safety) a. socioeconomic effects b. comorbidity c. health care system d. compliance e. environment

ADR observational studies

1. Follow-up (cohort) methodology: a. more frequent events, shorter onset b. less frequent exposure (infrequently used medication) 2. Case-control methodology: a. rare event or long time to develop (outcome) b. frequent exposure (frequently used medication) 3. Neither work well: a. infrequent event b. infrequent exposure

purpose o pharmacoeconomic studies Identifies, measures, and compares what two things what is the definition it is a discipline devoted to..... its useful for....

1. Identifies, measures, and compares a. the cost (i.e. resources consumed) and b. consequences of pharmaceutical products and services (outcomes). 2. Definition: a. It is the description and analysis of the costs of drug therapy to health care systems and society. 3. It is a discipline devoted to contrasting the full range of consequences across alternative medical treatments to aid in decision-making under uncertainty. 4. Useful for: a. Making individual patient treatment decisions. b. Making decisions about formulary management. c. Developing drug-use guidelines. d. Evaluating disease management initiatives. e. Determining the value of existing and proposed pharmaceutical services.

Information for ADR case report

1. Patient demographics, diseases, drugs, reaction: a. age, race, gender b. primary and secondary diagnosis c. what medications were taken d. nature of the adverse event, supporting lab data. 2. Event development time course: a. Clinical course of event, signs, symptoms, intervention. b. How long was the patient taking the suspected drug? 3. Drug indication, dechallenge, rechallenge a. Why was the drug prescribed? b. Did the event abate when drug stopped, recur when restarted?

what is pharmacology epidemiology pharmacoepidemiology

1. Pharmacology is the study of the effects of drugs. 2. Epidemiology is the study of the distribution and determinants of diseases in populations. 3. Pharmacoepidemiology is the study of the use of and the effects (good and bad) of drugs in populations.

Management of Hypoparathyroidism Chronic hypocalcemia - 6 goals of treatment:

1. Prevent signs & symptoms of hypocalcemia 2. Maintain serum calcium concentration in low normal range 3. Maintain the calcium-phosphate product below 55mg2 /dL2 4. Avoid hypercalciuria 5. Avoid hypercalcemia 6. Avoid renal (nephrocalcinosis/nephrolithiasis) & other extraskeletal calcifications

Methods Used in Pharmacoepidemiology

1. Randomized controlled trials 2. Observational Studies (Automated databases facilitate observational studies.) a. Cohort (Follow-Up) studies b. Case control studies c. Cross-sectional studies 3. Descriptive studies - drug use, vital statistics, case reports.

Limitations of pre-marketing RCTs to detect ADR

1. Short duration 2. Narrow population 3. Narrow indications 4. Limited co-morbidities and co-therapies 5. ADRs that have a significant background incidence in population are even more difficult. 6. Small sample size: remember the "rule of three"; for 95% probability to detect an ADR, the number of subjects needed to be followed is 3 times the incidence of the event.

Pharmacoeconomic Modeling

1. Studies are often prospective observational studies, but can be retrospective and can be RCTs. 2. Very often they use economic modeling to provide a structure to organize the problem. - Allows for assumptions to be made transparent. 3. Facilitates comparisons (tradeoffs).

what occured in 1938 with levothyroxine

1938 the Food, Drug and Cosmetic Act passed; however, levothyroxine had a long‐established history of use and therefore it was grandfathered in without going through the rigorous New Drug Application (NDA) process. • Despite our best efforts, quality control issues and questions of bioequivalence persist.

Pharmacoepidemiology: Purpose of Studies cont

3. Frequently used for post-marketing surveillance. 4. Identify rare adverse events or events that occur in "special" populations. 5. Document new uses of approved drugs. 6. Determine long term effects of drugs, or effects on ultimate vs intermediate outcomes. 7. Used by the FDA to allow approval of priority drugs in shorter time (on condition of surveillance). 8. Used by the FDA to modify product labeling or approval status.

• The density for levothyroxine pentahydrate (the stable phase, which we'll talk about later) is 2.42 g/cm 3 because of ________ • In the ideal case, if we blend two powders together you end with a homogeneous binary phase (A) But blending is sensitive to both _________ and _________ For levothyroxine, a small particle size helps provide the necessary dose resolution. • Combined with high density leads to potential for particle segregation

4 iodine atoms. particle size (big particles vs. little particles) and particle density

thyroid cancer

6th most common cancer in women, most common cancer in women 20-34 years old overall, 5 year survival rate of 98%

Therapy is needed when patients develop symptomatic hypocalcemia or serum calcium levels fall below _________ Patients have reduced renal tubular reabsorption of calcium. they are prone to._______ what is the goal __________ and how its done

8.0 mg/dL

Ghrelin where is it synthesized what stimulates circulating ghrelin levels •The interaction of ghrelin with this receptor directly stimulates GH release by ______________. Thus, ghrelin and its receptor act in a complex manner to integrate the functions of ________, _________, _______

A hunger-arousing hormone secreted by an empty stomach •Ghrelin, a 28-amino acid peptide that is octanoylated at Ser3, also stimulates GH secretion. • •Ghrelin is synthesized predominantly in endocrine cells in the fundus of the stomach but also is produced at lower levels at a number of other sites. • •Both fasting and hypoglycemia stimulate circulating ghrelin levels. • •The interaction of ghrelin with this receptor directly stimulates GH release by isolated somatotropes. • •Ghrelin stimulates appetite and increases food intake, apparently by central actions on NPY and agouti-related peptide neurons in the hypothalamus. • •Thus, ghrelin and its receptor act in a complex manner to integrate the functions of the GI tract, the hypothalamus, and the anterior pituitary. • Peptide and nonpeptide agonists (termed GH secretagogues) and antagonists of the GH secretagogue receptor are undergoing evaluation as possible modulators of neuroendocrine function

Pro-opiomelanocortin (POMC)

A pro-hormone that can be cleaved to produce the melanocortins, which also participate in feeding control. One peptide produced from the POMC protein is called adrenocorticotropic hormone (ACTH). ACTH binds to melanocortin 2 receptor (MC2R), stimulating the release of a hormone called cortisol. This hormone helps maintain blood sugar levels, protects the body from stress, and stops (suppresses) inflammation •Pro-opiomelanocortin (POMC) ØCorticotropin (adrenocorticotrophic hormone, ACTH) Øα-melanocyte-stimulating hormone (α-MSH)

absolute risk difference

Absolute Risk Difference Risk of outcome with exposure - Risk of outcome without exposure • This difference can be: o Absolute Risk Reduction (positive treatment effect) or o Absolute Risk Increase (adverse event - harm)

levothyroxine is particularly challenging formulation perspective due to stability, high potency, low content why is the important to address

Addressing this challenge is important because, • Millions of levothyroxine prescriptions are filled per month Makes Synthroid® one of the most prescribed medicines in the world.

grwoth hormone in sports anti aging claims adverse effects

Apart from a therapeutic need, a large, illegal hGH market exists • Performance enhancement in sports? • Increased muscle growth? Yes. • Increased strength and performance? Not really supported by the data, but hGH is still banned. • Supported by broad claims of "anti‐ aging " • Anti‐aging regimens vary greatly, with a yearly cost from $6,000 - $12,000 fro 3 - 6 self‐injections/wk. But adverse effects may include carpal tunnel syndrome, swelling of the hands and/or feet, and aging ailments like heart disease and type 2 diabetes.

lowering risk of acquired hypoparathyroidism

Autotransplantation To avoid permanent postoperative hypoparathyroidism Implant glands with suspected vascular damage to sternocleidomastoid muscle Glands will develop their own vascular supply and secrete PTH

•CYP1α is subject to tight regulatory controls that result in changes in calcitriol formation to control calcium homeostasis. • •PTH stimulates _______ to form more calcitriol. • •Conversely, high calcium, high phosphate, and high vitamin D intake _________ resulting in the formation of less calcitriol.

CYP1α suppresses CYP1α

PTH is secreted seconds after _______ senses a small reduction in serum ionized calcium - PTH mobilizes (breaks down) bone in minutes! PTH release and synthesis is reduced by Negative feedback loop keeps serum _______levels tightly regulated

CaSR (calcium sensing receptor) Calcium (acts through calcium-sensing receptor [CaSR]) Vitamin D Fibroblast growth factor 23 (FGF23) - hormone that suppresses PTH secretion PTH

Hypocalcemia Symptoms Psychiatric symptoms

Can be mistaken for a psychiatric disorder, reversible with treatment Emotional instability Hyperirritability Anxiety/depression Impaired intellectual capacity Personality changes

dark side of HGH

Dark side of hGH - a crackdown began in 2006 to reduce the flow of illegal hGH from unregulated supplies from China, India and Mexico. • This attempt ultimately failed to stop due to rampant misuse. • From 2005 - 2011, inflation adjusted sales of hHG rose by 69%, whereas the average prescription drug rose by just 12% during the same period. • It's estimated that half of last year's sales likely went to patients not legally allowed to get the drug. And US pharmacies processed nearly 2x the expected # of prescriptions.

endogenous serum levels during the day have what release pattern when to adminster HGH

Endogenous serum levels of human growth hormone display a pulsatile secretion. • Consistent with a circadian rhythm, highest levels (in both men and women) at evening. • Generally, we recommend sc administration of hGH at night, just before bed.

hGH is primarily prescribed for

GH deficiency (in children and adults) accounting for approximately 50% of the US hGH market

most common causes of hyperthyroidism in US

Graves disease (60-80%) - more prevalent in women, strongly heritable, often have TSH receptor antibodies toxic multinodular goiter thryroiditis - all types can case hyperthyroidism (although usually just transiently), anti-TPO antibodies common

• Growth hormone sales in 2016 were 3 - 4 billion dollars globally. The US market alone constitutes ca. 50% of that market structure of growth hormone it is susceptible to _______ and very prone to __________ generally formulated as a

Growth hormone - single‐chain, polypeptide containing 191 AA. • Total MW = 22 kDa • Tertiary structure - 4 ‐helices, and 2 disulfide (cys - cys) bridges • hGH is susceptible to oxidation (methionine) and hydrolytic deamidation - chemical instability • Very prone to aggregation - physical instability • Generally formulated as a lyophilized powder for later reconstitution and SC injection • Stored cool, and cannot be frozen after reconstitution

most common causes of hypothyroidism in US

Hashimoto's thyroiditis - Hashimoto's thyroiditis, is an autoimmune disease that damages the thyroid gland. Hashimoto's disease affects more women than men. It is the most common cause of hypothyroidism (underactive thyroid) surgical or radio-iodine ablation iodine deficiency or excess drugs - lithium, amiodarone central causes (pituitary, hypothalamus)

Despite our best efforts to design a quality and stable drug product, levothyroxine continues to challenge our conventional strategies. MHRA reports of levothyroxine • In the UK, a 2013 study demonstrated that different brands displayed widely different dissolution performance. Note that this doesn't automatically mean the PK profiles are different.

In 2011, the MHRA (a drug regulator in UK) received several reports from health‐care professionals regarding Teva's levothyroxine product. • Additional reports about inconsistent levothyroxine tablets with 3% reporting adverse reactions after switching from a name brand to generic product.

biochemical markers to diagnoise hypoparathyroidism

Low serum parathyroid hormone (PTH) level with hypocalcemia High serum phosphate level (hyperphosphatemia) Normal alkaline phosphatase (ALP) level - Enzyme that liberates phosphate under alkaline conditions Urine calcium excretion is increased - PTH is a potent anticalciuric Serum magnesium levels may be low

what is trying to be created for HGH hormone daily injections but not approved yet in the US

OR rather than daily injections, depot formulations (extended release) are actively being sought • Loading of hGH into PLGA microspheres led to the development and licensure of Nutropin depot • Withdrawn in 2004 due to manufacturing difficulties. TV‐1106 is a genetically fused recombinant protein r‐hGH and human serum albumin • Reached Phase 3 clinical trials, but discontinued by TEVA Pegylated hGH results in reduced renal clearance to improve circulation half life • No current Pegylated‐hGH product currently available in the US, but there is a product available in China

osteoblasts and osteoclasts Calcium homeostasis involves the coordination of several hormones, including

Osteoblasts are terminally differentiated bone-marrow stem cells that synthesize dense cross-linked collagen in addition to hydroxyapatite, that is deposited to form a very strong and dense mineralized tissue. Osteoclasts resorb bone tissue by secreting enzymes that digest collagen and hydroxyapatite. Bone remodeling helps regulate calcium homeostasis which relies on complex signaling pathways. Calcium homeostasis involves the coordination of several hormones, including parathyroid hormone (PTH), vitamin D, and calcitonin.

Our primary mechanisms of chemical degradation, include:

Oxidation • Carbonyl‐Amine reactions • Proteolysis (Transpeptidation) • Disulfide formation • Deamidation • Racemization

Acute Postsurgical Hypoparathyroidism Manifestations due to acute hypocalcemia caused by insufficient _______ secretion "stunned gland" hallmark symptom what is chvostek's sign and trosseau sign

PTH

In 2008, the Endocrine Society decided to weigh on the question of bioequivalence, and their concerns are:

Patients are being put at risk by undisclosed substitution of different levothyroxine products • FDA should rescind their designation of bioequivalence for levothyroxine products • FDA should also include warning to consult your physician if the levothyroxine product is being switched.

growth hormone concern with m-cresol

Patients may have an adverse reaction to the preservative contained in the diluent. • Particularly notable for m‐cresol, hence formulations are moving to alternative preservatives e.g. benzyl alcohol • For patients with a severe reaction, the lyophilized protein may be reconstituted in sterile water • However, it would be recommended for single applications, and not a useful alternative for multi‐dose injectors

which hormones are feed forward regulators and which are negative regulators

Positive Feed-Forward Regulators. Hypothalamic Releasing Hormones •Corticotropin-releasing hormone (CRH) •Growth hormone-releasing hormone (GHRH) •Gonadotropin-releasing hormone (GnRH) •Thyrotropin-releasing hormone (TRH). Negative Regulators. •Somatostatin (SST), another hypothalamic peptide, negatively regulates secretion of pituitary GH and TSH. •Dopamine inhibits the secretion of prolactin by lactotropes.

relative risk

RR = Risk of outcome with exposure Risk of outcome without exposure

Rickets what is it caused by what was found to cure it? this lead to the discovery of

Rickets is one of the most frequent childhood diseases in many developing countries. Caused by vitamin D deficiency and a lack of adequate calcium in the diet due to malnutrition, famine or starvation during bone development in childhood. Prior to the discovery of vitamin D, a high percentage of urban children living in temperate zones developed rickets. Some researchers believed that the disease was due to lack of fresh air and sunshine; others claimed a dietary factor was responsible. Mellanby and Huldschinsky showed the addition of cod liver oil to the diet or exposure to sunlight prevented or cured the disease. In 1924, it was found that ultraviolet irradiation of animal rations was as efficacious at curing rickets as was irradiation of the animal itself. These observations led to the elucidation of the structures of cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2, plant derived) and eventually to the discovery that these compounds require further processing in the body to become active.

doses of synthroid how is synthroids therapeutic index

Synthroid® is available in multiple different doses: • 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200 and 300 mcg dose Levothyroxine is reported to have a narrow therapeutic index • Patient is titrated to the right dosage amount • Need to have exceptional control on the manufacturing to ensure the patient is getting the

diagnosis of thryoid disorders what are the biomarkers used what are some key points

TSH and free thyroxine (T4) are the front line lab tests UIHC has option to order TSH that reflexes to free T4 if TSH is abnormal more specialized tests can be helpful but are not always necessary be cautious about thyroid testing in acutely ill patients non thyroidal illness can cause a range of test abnormalities (euthyroid sick syndrome)

The pI for HGH was determine to be what are buffers for

The pI for hGH was determined to be 5. • Again, since we associate charged species with improved aqueous solubility. • Buffers (histidine, citrate, phosphate) are used to adjust the pH of the protein solution to be either above 6 - 8 or below 2 - 4. Remember, a buffer works best at its pKA.

Hypercalcemia of malignancy

Tumor secretes PTH-related protein --> hypercalcemia. Usually involves lung, breast, prostate, head, neck cancers.

somatotropic hormone what does it release (3)

a hormone secreted by the anterior pituitary gland that regulates the cellular processes necessary for normal body growth; also called the growth hormone •Somatotropic ØGrowth hormone (GH) ØProlactin ØLactogen.

So in addition to blending, we can granulate - a process that does what The idea being we can blend and stick (granulate) the particles together into BIG particle to limit __________ _________ process is chosen for low‐ dose formulations of potent drugs to improve content uniformity.

a process that combines smaller particles into bigger ones blend segregation. granulation

Review of study designs They can broadly split into two groups based on time

a. Cross-sectional studies - based on a snap shot in time. b. Longitudinal - studies where people or groups are followed over time.

IV bisphosphonates are potent inhibitors of __________

bone resorption

To help protect our protein against damage during the process of freeze‐drying (lyophilization), additional excipients include _____ and/or ___________ such as

bulking agents and/or stabilizers. • Glycine and mannitol are commonly used as bulking agents. • Disaccharides (e.g. sucrose) are used as stabilizers.

The rate of glucocorticoid secretion by the adrenal cortex is determined •Pituitary corticotropes are regulated by corticotropin-releasing hormone (CRH) and vasopressin released by . • •ACTH bind to MC2 receptors in the adrenal cortex to activate

by fluctuations in the release of ACTH by the pituitary corticotropes specialized neurons of the endocrine hypothalamus steroidogenesis.

Weaker bonds are susceptible to photolysis and the __________ bond Bond dissociation energy is ca. __________, which may potentially be broken by any of whichwavelengths, In addition, the atomic radii for iodine is large, relative to carbon, the valence (bonding) electrons are easy to push around Changing the electron density within the C‐I bond = chemistry!

carbon‐iodine bond is the weakest C‐X

Primary hypothyroidism

caused by destruction of thyroid tissue or defective hormone synthesis

thyrotoxicosis causes

condition caused by excessive thyroid hormones

Goiter may be a symptom of ........

enlargement of the thyroid gland may be a symptom of hyperthyroidism or of iodine deficiency - iodine deficiency is the most common cause fo preventable mental retardation in the word but is rare in the US

Goiter you will probably be diagnosed nontoxic and toxic goiter

enlargement of the thyroid gland •Swelling of the neck resulting from enlargement of the thyroid gland. • •A goiter can occur in a gland that is producing too much hormone (hyperthyroidism), too little hormone (hypothyroidism), or the correct amount of hormone (euthyroidism). • •A goiter indicates there is a condition present which is causing the thyroid to grow abnormally. • •If the thyroid is diffusely enlarged and you are hyperthyroid, your doctor will likely proceed with tests to help diagnose Graves' Disease. • •If you are hypothyroid, you may have Hashimoto's Thyroiditis and you may get additional blood tests to confirm this diagnosis. • •Diagnosing the cause of the goiter may include a thyroid scan, thyroid ultrasound, or a fine needle aspiration biopsy. • •Nontoxic goiter, results in low T4 due to lack of dietary iodine results in high levels of TSH, results in goiter. •Toxic goiter, results in to much T4 and T3 produced. Usually due to a thyroid tumor or Grave's Disease.

Hyperthyroidism what are symptoms usually caused by

excessive activity of the thyroid gland classic symptoms related to accelarated metabolism - rapid heart rate, anxiety, weight loss, heat intolerance, usually caused by disorders of the thyroid gland including auto-antibodies that stimulate TSH receptor (Graves Disease) central causes (pituitary, hypothalamus) are rare

Flip-flop kinetics

flip-flop phenomenon happens when a drug is released at a sustained rate instead of immediate release, such as sustained-release formulation vs. immediate-release formulation. In flip-flop kinetics, kₐ is much slower than kₑ. • Subcutaneously administered hGH is clear example of "flip‐flop" kinetics (ka << ke). The serum persistence of hGH is a result of the slow absorption kinetics (relative to its elimination) • Reminiscent of a controlled release mechanism hGH is a moderately sized protein (22 kDa), and thus absorption post‐sc injection is slow • Difficult to permeate capillary membranes effectively Systemic bioavailability of subcutaneous administration is reported to be ca. 50%. hGH is generally administered as either a subcutaneous or intramuscular injection. The far majority is SC administration

Somatostatin elevated GH leads to somatostatin inhibits

hormone that inhibits release of growth hormone and insulin •Cyclic 14-amino acid peptide produced by the hypothalamus. • •Inhibitor factor of growth hormone (GH) from the anterior pituitary. • •Elevated GH due to pituitary tumors leads to Acromegaly, excess growth hormone (GH) after the growth plates have closed. • •Somatostatin also inhibits the secretion of insulin, glucagon and a variety of intestinal peptides and proteases (gastrin, secretin, pepsin and renin). • •Half-life less than 3 min. No therapeutic uses.

thyroid gland regulate by ______ and _________ and produces T4 which is called

hypothalamus and anterior pituitry gland T4 = thyroxine

As mentioned earlier by Prof. Rice, growth hormone was previously extracted from the pituitary glands of cadavers. Some patients provided cadaver‐sourced hGH developed ____________ as a result ....

iatrogenic Creutzfeldt‐ Jakob disease (iCJD) Spurred significant development of genetically‐engineered, recombinant hGH (Genentech, Lilly) • First recombinant product approved for use in 1985

•Release of calcitriol into the circulation allows it to bind to receptors in the intestine where it causes an increase •Conversely, a rise serum Ca2 levels causes a decrease in •When the plasma Ca2+ concentration falls below 7 mg/dL excretion _______ as the remaining Ca2+ is almost completely reabsorbed despite reduced tubular capacity.

in the absorption of Ca2+ and phosphate. in the serum concentration of PTH. This not only diminishes CYP1α activity, but also depresses tubular reabsorption of Ca2+ and thereby increases urinary excretion of Ca2+. decreases

PTH _________ osteoclastic activity in bone, ________ renal tubular reabsorption of calcium, stimulates synthesis of active ________ in kidney, inhibits reabsorption of ______ and _______ by the renal tubule all these above cuase a net increase in __________

increases increases vitamin D phosphate and bicarbonate All of the above cause a net INCREASE in serum calcium - vs hypoparathyroidism (low PTH) where calcium is wasted

Our strategy for unstable drugs administered through an injection is to they are stored in ________ to protect against light • Note that this drug product is NOT a substitute for levothyroxine tablets, injection is indicated for

keep the drug and solution separate until they're needed, i.e. lyophilization. • Freeze‐drying process to remove excess water through sublimation. Stored in amber vials to protect against light • Remember, the color you see is the transmitted color and the complement is absorbed • An amber vial absorbs in the blue and purple color (high energy) wavelengths • Injection is indicated for myxedema coma, an extreme manifestation of hypothyroidism.

Drugs Associated with Hypocalcemia

not in picture Chemotherapy Cisplatin - causes hypomagnesemia 5-fluorouracil + leucovorin - decreases calcitriol production Up to 65% of patients on this combination will experience hypocalcemia

PTH decreases blood _________ levels

phosphate By decreasing phosphate & bicarbonate reabsorption by the renal tubules in the kidneys = increasing excretion of phosphate by kidneys

blending is not a trivial exercise. If a homogeneous blend isn't maintained throughout the manufacturing process, then each tablet (a sub‐sample of the blend) won't be the same. High density + small particles = __________ for tablets prepared by direct compression. Between 1990 - 1997, for levothyroxine alone there were 10 recalls which amounted to 150 lots or ca. 100 million tablets destroyed due to,

poor content uniformity due to • Sub‐potency, Super‐potency, stability failures, % content uniformity failures

The shelf life of the product (i.e. controlling for chemical instability) is another concern. Shown to the right is a study showing the crospovidone, povidone and sodium lauryl sulfate all increased the ___________ Mylan's product may have been bioequivalent at one point, but it's shelf life may be entirely different. • Despite the 1997 action by the FDA, levothyroxine tablets continued to display poor consistency leading to the 2006 FDA panel recommendation that _______________

rate of the levothyroxine degradation. the potency tolerance be narrowed.

•The secreted vasopressin increases the __________ in kidney tubule cells, causing the excretion of urine that is concentrated in Na+ and thus yielding a___________ • •Vasopressin deficiency leads to

reabsorption rate of water net drop in osmolarity of body fluids. watery urine and polydipsia, a condition known as diabetes insipidus.

hypothyroidism in infancy and childhood can result in ...... common symptoms and older childhood and adults....... if sever = life threatening

result in cretinism - Congenital iodine deficiency syndrome, also known as cretinism, is a condition of severely stunted physical and mental growth due to an untreated congenital deficiency of thyroid hormone, (congenital hypothyroidism) usually due to iodine deficiency. symptoms are weight gain, lethargy, mental slowing, cold intolerance, skin changes

Diagnosis of Hyperparathyroidism Biochemical workup: primary and secondary hyperparathyroidism s

serum calcium, albumin, PTH, phosphate, creatinine, 25-hydroxyl vitamin D, 24 hr. urine calcium & creatinine

• The challenge is water molecules in the lattice are ______ and ________ Depending upon the crystal structure may easily come out under heat. Dehydration may arise from any of the 3 unit operations, • Changing the hydration # (e.g. pentahydrate → dihydrate) can significantly change key performance properties such as

small and mobile. Drying in wet granulation • Pressure during compression in tableting • Milling and blending Solubility, dissolution rate, bioavailability, etc. • Just like any other instability leads to quality control failures and product recalls

parathyroid glands what d they secrete they are key to regulation of

small pea-like organs that regulate calcium and phosphate balance in blood, bones, and other tissues PTH controled by level of free (ionized calcium)

Lanreotide what is indicated for what does it block

somatostatin analog •Lanreotide (Somatuline) is long acting somatostatin analogue. • •It's peptide sequence contains an N-terminal D-Nal and an C-terminal Thr-NH2. • •H-D-2Nal-Cys(1)-Tyr-D-Trp-Lys-Val-Cys(1)-Thr-NH2 • •Indicated to treat acromegaly, metastatic gastroenteropancreatic, and neuroendocrine tumors. • •Blocks the release of GH, TSH, insulin and glucagon. • •Two formulations •Sustained release formulation (Somatuline LA'), i.m. every 10-14 days. • •Extended release formulation (Somatuline Depot) administered subcutaneously once monthly.

At the primary level, we're concerned with identifying

specific residues prone to specific chemical instability mechanisms.

Prolactin •The major regulator of prolactin secretion is __________ which is released by__________ to inhibit prolactin secretion when is prolactin dominant how is stimulated

stimulates milk production dopamine, which is released by tuberoinfundibular neurons and interacts with the D2 receptor, a GPCR on lactotropes, to inhibit prolactin secretion. •Prolactin acts predominantly in women, both during pregnancy and in the postpartum period in women who breast-feed. •During pregnancy, the maternal serum prolactin level starts to increase at 8 weeks of gestation, increases to peak levels of 250 ng/mL at term, and declines thereafter to prepregnancy levels unless the mother breast-feeds the infant. • •Suckling or breast manipulation in nursing mothers transmits signals from the breast to the hypothalamus via the spinal cord and the median forebrain bundle, which, in turn, stimulate circulating prolactin levels. • •Prolactin levels can rise 10- to 100-fold within 30 minutes of stimulation. This response is distinct from milk letdown, which is mediated by oxytocin release from the posterior pituitary gland.

absolute risk

the incidence of disease in a population Absolute risk equals the RR times the average probability of the event during the same time if the risk is absent. It is the probability of an event occurring during a specified period of time.

Denosumab

there was a recall •Denosumab (Prolia) is the first in class FDA approved (2010) fully human MAb to treat osteoporosis in post menopausal women. •Denosumab binds RANKL (the RANK-Ligand), blocking maturation of pre-osteoclasts into osteoclasts, protects bone from degradation, and helps to counter the progression of osteoporosis.

Increaed mobility leads

to an increased persistence of the denatured state may lead to irreversible aggregation • Not only reduces potency, but aggregates can stimulate an immunogenic response

• hGH (and really any protein with a tertiary structure) physical instability is sensitive to exposure to air After mixing, the cartridge in the injector pen should be

to stirring and aeration Transient exposure to air results in significant aggregation, but this is less of a concern for an injector system • hGH + diluent is contained in a cartridge with no significant exposure to air The patient does have to mix the contents, and in all cases, the package repeatedly states to do so gently. Remember, the intermolecular forces that maintain the functional (tertiary) protein form are weak and easily disturbed by any input of energy (heat or mechanical). clear with no visible particulates!

Direct compression has multiple advantages and generally a *first choice* for tablet manufacturing. Since the process includes only two, unit operations - blending and compression - translates to 3 benefits Elimination of heat and moisture (e.g. like the drying and granulation steps in wet granulation) increases ____________. 1. IF your API is particularly sensitive to heat/water, then ____________ is the method if the dosage form is going to be a tablet

translates to • 1. Reduced production time and costs. • 2. Less pieces of equipment, faster process validation • 3. Less risk (for certain instances) of batch‐to‐batch variation because fewer chances for variability to product stability direct compression

Two hormones regulate extracellular calcium and phosphate homeostasis

ØParathyroid Hormone (PTH) Ø1,25-dihydroxyvitamin D (Calcitriol)

•Low circulating levels of vitamin D have led to a re-emergence of vitamin D-dependent rickets in the US. what are some contriuting factors

Ødiminished consumption of vitamin D-fortified foods owing to concerns about fat intake Ø Øreduced intake of calcium-rich foods, including milk, in adolescents and young women of reproductive age Ø Øincreased use of sunscreens and decreased exposure to sunlight to reduce the risk of skin cancer and prevent premature aging from exposure to ultraviolet radiation Ø Øand an increased prevalence and duration of exclusive breast-feeding (the combination of human milk, a poor source of vitamin D, and the high prevalence of low circulating vitamin D levels in U.S. women, particularly African-American mothers

There are three primary ways to manufacture a tablet, and as you would expect, each have strengths and weaknesses. For levothyroxine tablets, our first challenge is ________

• 1. Direct compression - Blend the formulation together and go directly to compression. • 2. Dry granulation - API + excipient is also blended with binders and the overall is passed through a roller compactor, and broken back down to individual granules using the mill. • 3. Wet granulation - Same idea as dry granulation, but the binder is introduced as a liquid and the granulated product is dried. content uniformity.

An alternative approach would be formulate something other than a tablet, i.e. as solution for injection. what is the difficulty with this If you drug contains both a carbonyl group and a primary amine group, then there is potential for _____

• But ALL the chemical instabilities become magnified when in solution. • Because you have mobility! This is why solids generally display superior stability relative to solutions. • Aggregates will appear in levothyroxine solutions, because of the carbonyl‐amine reactivity • If you drug contains both a carbonyl group and a primary amine group, then there is potential for carbonyl‐amine oligomer formation. • Molecules may potentially start forming chains of molecules • This is distinct from aggregation (physical instability), because you're forming new chemical bonds. • This can occur for secondary amines, but the reactivity potential decreases.

• To further facilitate produce use and patient compliance, alternative routes of administration are being explored. • This is largely true for many biopharmaceutics, simply because injections are a pain, literally and figurately nasal adminstration pros and cons

• For nasal administration, an absorption enhancer helps significantly aids hGH • This is also generally true, and an active area of research in formulating biopharmaceutics for novel administration routes • Bile salts, adhesive microspheres, stimuli‐ responsive gels, chitosan and various surfactants BUT this approach (enhancing absorption) needs to be balanced against potential tissue irritation or damage

Our third challenge is the processing a hydrated form of the drug • This is less of a concern than the previous two. Hydrates contain a stoichiometric # of water molecules specifically positioned in the crystal lattice • Monohydrates, dihydrates, trihydrates, etc. • Distinct from adsorbed water • For the stable, tableted phase of levothyroxine, there are

• For the stable, tableted phase of levothyroxine, there are 5 water molecules per 1 levothyroxine molecule

Multiple chemical instabilities associated with levothyroxine, and this is our second challenge with preparing a quality formulation Chemical stability, however, changes the drug at the molecular level (bonds are being broken) 4 mechanisms available for chemical instability, we'll emphasize: Each of these all have opportunity to initiate chemical degradation, hence important to understand their role • Chemical instability may result in

• Hydrolysis - reactivity with water • Oxidation - reactivity with air • Photolysis - reactivity with light • Pyrolysis - thermal breakdown *oxidation and photolysis* - These two will be our emphasis for levothyroxine tablets, but levothyroxine is sensitive to light, heat, pH, oxygen and moisture. Chemical instability may result in, • Loss of purity/potency • Appearance of toxic by‐products • Color change

What patients say about hGH therapy... storage bruising mixing pain injector systems are designed for

• Injector systems are designed for patient convenience and ease of use • Easy and convenient = better patient adherence • What alternatives are being developed?

What is levothyroxine? it is an ampholyte, what does that mean? what is it solubility/permeability class

• Levothyroxine (L‐thyroxine, T4) - a synthetic prohormone prescribed primarily for hypothyroidism • Formulated as the salt form: Levothyroxin sodium We would classify levothyroxine as an ampholyte (having both acidic and basic character) with three ionizable functional groups. • Two acidic: Phenol and carboxylic acid. • One basic: Primary amine. • Use the carboxylic acid + NaOH for preparing the levothyroxine sodium salt. • Levothyroxine sodium is reported as a BCS class I (high solubility, high permeability) drug. • Log P(octanol/water) is approximately 3 • The reported solubility data is in question.

ocreotide acetate what does it do? indications? it inhibits _________ secretion otreoscan

• Octreotide acetate (Sandostatin) is a long acting analogue of somatostatin with a half-life of 1.5 hrs. • •Suppresses the secretion of gastroenteropancreatic peptides. • •Used for treatment of acute variceal bleeding and for perioperative prophylaxis in pancreatic surgery. •Used to treat metastatic tumors (endocrine, GI and lung). Used to treat symptoms associated with metastatic carcinoid tumors and adenomas secreting vasoactive intestinal peptide. •Used to treat acromegaly •Octreotide also inhibits TSH secretion. Used to treat thyrotrope adenomas that over secrete TSH that are not resectable. • •Octreotide labeled with indium and gallium (OctreoScan) have been used for diagnostic imaging (gamma scintigraphy) of neuroendocrine tumors such as pituitary adenomas and carcinoids.

typical pathologies that benefit from HGH therapy

• Typical pathologies that benefit from hGH therapy: • GH failure in childhood - results typically from mutations in the growth hormone releasing hormone receptor (GHRHR) and growth hormone (GH1) genes • GH deficiency in adulthood - commonly arises as a result of a pituitary adenoma • Turner syndrome ‐ partially missing X chromosome, only affects females • Prader‐Willi syndrome - genetic disorder (chromosome 15q, partial deletion) • Chronic renal insufficiency - variety of principle causes (e.g., diabetes and high blood pressure, kidney stones, polycystic kidney disease) • AIDS‐associated weight loss • Idiopathic short stature

Summary of growth hormone lecture

• hGH is a moderately sized protein (22 kDa) with specific modes of chemical instability • Deamidation and oxidation Chemical instability can facilitate physical instability, which generally manifests as irreversible aggregation Typically formulated as lyophilized powder to be combined with a specific diluent for multiple SC injections (one/day) • This approach helps to maximize shelf‐life hGH is a billion‐dollar market worldwide that helps to treat 1000's of legitimate patients • An illegal market also exists that contributes millions to the pharmaceutical industry.

•Two Phase response to ACTH binding. •Hypothalamus-Pituitary-Aldosterone (HPA) axis:

•1) The acute phase, seconds to minutes, largely reflects increased supply of cholesterol substrate to the steroidogenic enzymes. • •2) The chronic phase, hours to days, results increased transcription of the steroidogenic enzymes. •Hypothalamus-Pituitary-Aldosterone (HPA) axis: Ø 1. Diurnal rhythm in basal steroidogenesis Ø 2. Negative feedback regulation by adrenal corticosteroids Ø 3. Increases in steroidogenesis in response to stress.

Where is ADH synthesized? •Vasopressin is known as an __________ and the main regulator of __________ vasopressin is regulate by _________ which do what

•Antidiuretic Hormone (ADH or Vasopressin) is synthesized as a prohormone in neural cell bodies of the hypothalamus. •The axons terminate in the posterior pituitary, and the hormones are secreted directly into the systemic circulation. • •Vasopressin is known as an antidiuretic hormone (ADH) and the main regulator of body fluid osmolarity. • •Vasopressin secretion is regulated in the hypothalamus by osmoreceptors, which sense water concentration and stimulate increased vasopressin secretion when plasma osmolarity increases.

calcitonin is secreted by its actions generally oppose ________ its a potent inhibitor of _________

•Calcitonin is a single-chain peptide of 32 amino acids with one intramolecular disulfide bond between cysteine residues in positions 1 and 7. • •Calcitonin is secreted by thyroid parafollicular C cells and normally circulates at remarkably low levels •Calcitonin is a hypocalcemia hormone whose actions generally oppose those of PTH. • •It is a potent inhibitor of osteoclast-mediated bone resorption. It protects the skeleton during periods of "calcium stress," such as growth, pregnancy, and lactation. •In all species, 8 of the 32 residues are invariant, including the disulfide bond and a carboxy-terminal proline amide. • Salmon calcitonin is used therapeutically in part because it is cleared more slowly from the circulation compared to human calcitonin

calcitonin secretion increases when _________ is high Abnormally elevated levels of calcitonin are characteristic of Calcitonin actions are mediated by the calcitonin receptor (CTR) on ___________ to produce •Acute administration of pharmacological doses of calcitonin increases

•Calcitonin secretion increases when plasma Ca2+ is high and decreases when plasma Ca2+ is low. • •Circulating concentrations of calcitonin are normally low (<15 and 10 pg/mL). The circulating t1/2 of calcitonin is ~10 minutes. • •Abnormally elevated levels of calcitonin are characteristic of thyroid C-cell hyperplasia and medullary thyroid carcinoma. • •Calcitonin actions are mediated by the calcitonin receptor (CTR) on osteoclasts to produce a rapid decrease in ruffled border surface area, resulting in diminished resorptive activity. • •Acute administration of pharmacological doses of calcitonin increases urinary calcium excretion. • •Calcitonin increases urinary calcium excretion in a dose-dependent manner in subjects given a modest calcium load.

cinacalet use MOA etelcacetide use MOA

•Cinacalet (Sensipar), FDA approved in 2004, used to treat secondary hyperparathyroidism for patients on long-term dialysis. • •Used to treat hypercalcemia non-resectable parathyroid gland cancer. • •Acts as a calcimimetic by allosteric activation of the calcium-sensing receptor. • •Sensitizes calcium receptors on chief cells to reduce PTH secretion and decrease serum calcium levels. • •Drug interaction due to P450 metabolism. •Etelcalcetide (Parsabiv) FDA approved in Feb 2017, calcium-sensing receptor agonist. • •Indicated for the treatment of secondary hyperparathyroidism in adult patients with chronic kidney disease on hemodialysis. • •Functions by binding to and activating the calcium-sensing receptor in the parathyroid gland as an allosteric activator, resulting in reduced PTH secretion and lower calcium levels.

what is diabetes insipidus? vasopressin activates what receptors to do what can you use vasopressing to treat DI

•DI is a disease of impaired renal water conservation. • •Inadequate vasopressin secretion from the neurohypophysis (central DI) or insufficient renal vasopressin response (nephrogenic DI). • •Patients are polydipsic. Excrete 20 L per day of dilute (<200 mOsm/kg) urine. • •Vasopressin binds and activates both V1 and V2 receptors to mediate pressor responses (vasocontraction) and antidiuretic responses (water reabsorption). • •Vasopressin is not used to treat DI because of its short duration of action and V1 receptor-mediated side effects.

•Metabolism of thyroxine by__________ in peripheral tissues accounts for 80% of circulating thyronine (T3). Two types of deiodinases (D1, D2) convert thyroxine to thyronine. what are their roles and where are they expressed

•Daily production of thyroxine (T4) is estimated to range between 80 and 100 μg • •Thyronine (T3) is between 30 and 40 μg. • •Metabolism of thyroxine by 5'-deiodination in peripheral tissues accounts for 80% of circulating thyronine (T3). • •Two types of deiodinases (D1, D2) convert thyroxine to thyronine. • •D1 is expressed primarily in the liver, kidney, thyroid and pituitary. • •D1 is its inhibition by the anti-thyroid drug propylthiouracil (PTU). • D2 is expressed primarily in the CNS and is unaffected by PTU

Symptoms of HypothyAroidism

•Decrease metabolic rate • •High cholesterol. • •Slurred speech. • •Increase lethargy. Fatigue • •Increase weight. • •Decrease temperature tolerance. • •Hair loss. • •Decrease response. Slow speech.

what is the drug for diabetes insipidus what does it do? how is administered? what causes water conservation and release of blood coagulation factors. what other indications

•Desmopressin Acetate (DDAVP) is the drug of choice for treating lifelong DI. • •A vasopressin analogue V2 agonist devoid of an amino group on Cys and Arg 8 is D-isomer, that causes water conservation and release of blood coagulation factors. • •Desmopressin acetate treats central but not nephrogenic DI by decreasing symptoms of polyuria and polydipsia. •Intranasal dose has a duration of effect that lasts for 6-20 hours allowing twice daily dosing of a 10-40 μgs. •In some patients, chronic allergic rhinitis or other nasal pathology may preclude reliable peptide absorption following nasal administration. • •Oral administration in doses 10-20 times the intranasal dose provide blood levels to control polyuria. • •Subcutaneous administration of 1-2 μg daily of desmopressin also is effective to treat central DI. • •Also used for nocturnal enuresis (bed wetting). •Approved for reducing bleeding in hemophilia A and type I Von Willebrand's disease.

•Digestion of thyroglobulin by proteases yield MIT and DIT are recycled T4 is considered to be a ________ • •Conversion of T4 to T3 takes place in most extra thyroidal tissues by the action of what are the products ad percentages. •These reactions are catalyzed by a group of enzymes called

•Digestion of thyroglobulin by proteases yield MIT, DIT, T3 and T4. • •MIT and DIT are recycled • •T3 and T4 are excreted into the blood stream. • •T4 has a much longer half-life (6.7 days) than T3 (1 day). • • 8-10 times more T4 is released than T3. • •T4 is considered to be a prohormone. • •Conversion of T4 to T3 takes place in most extra thyroidal tissues by the action of 5'D (5'-deiodinase) • •33% of T4 becomes T3. • •40% undergoes de-iodination of the inner ring by 5-D (5-deiodinase) to yield rT3 which is inactive. • •These reactions are catalyzed by a group of enzymes called iodothyronine deiodinases.

follicur cells take up _______ from the follices by endocytosis digestion of __________ to generate thyroid hormins that are exocytosed into the blood

•Follicular cells take up iodinated thyroglobulin from the follicles by endocytosis • •Digest thyroglobulin to generated thyroid hormones that are exocytosed into the blood. • •Transported throughout the body where they control metabolism (which is the conversion of oxygen and carbohydrates to energy). • •Every cell in the body depends upon thyroid hormones for regulation of their metabolism.

growth hormone is secreted by..... detection in sports when is it high and low throughout life

•GH and prolactin are structurally related members of the somatotropic hormone family. • •GH is secreted by somatotropes as a heterogeneous mixture of peptides; the principal form is a single polypeptide chain of 22 kDa that has two disulfide bonds and is not glycosylated. • •Recombinant human GH consists entirely of the 22 kDa form, which provides a way to detect GH abuse for sports performance enhancement. • •GH secretion varies throughout life; secretion is high in children, peaks during puberty, and then decreases in an age-related manner in adulthood.

GH pulses role if IGF-1 role of SST

•GH is secreted in discrete but irregular pulses. Between these pulses, circulating GH falls to levels that are undetectable with most assays. The amplitude of secretory pulses is greatest at night, and the most consistent period of GH secretion is shortly after the onset of deep sleep. • •Insulin-like growth factor 1 (IGF-1) acts in a negative feedback loop to suppress GH secretion. IGF-1 directs its effects on the anterior pituitary gland. • •Negative feedback action of GH is mediated in part by somatostatin (SST).

GH stimulates growth of what GH causes differentiation GH has anti________ actions in both liver and peripheral sites to do what Growth hormone acts directly on adipocytes to

•GH stimulates longitudinal growth of bones and increases bone mineral density after the epiphyses have closed and longitudinal growth ceases. • •These effects oGf GH involve the differentiation of prechondrocytes to chondrocytes and stimulation of osteoclast and osteoblast proliferation. • •GH stimulates myoblast differentiation and increased muscle mass, increases glomerular filtration rate, and stimulates preadipocyte differentiation into adipocytes. • •GH has potent anti-insulin actions in both the liver and peripheral sites, decrease glucose utilization and increase lipolysis. • •Growth hormone acts directly on adipocytes to increase lipolysis and on hepatocytes to stimulate gluconeogenesis, but its anabolic and growth-promoting effects are mediated indirectly through the induction of IGF-1.

graves disease result form the formation of symptoms

•Graves Disease (hyperthyroidism) • •Most frequent hyperthyroidism. • •Autoimmune disease in which body produces to much thyroid hormone (T3 and T4). • •Also referred to as diffuse toxic goiter • •Results from the formation of thyroid stimulating autoantibodies (TSAb) that activate the TSH receptor. • •Symptoms Øprotruding eyes Øpatient hot and flushed ØIgG in patients stimulates the thyroid

Hashimoto's thyroiditis (hypothyroidism) causes what cells and tissues are destroyed symtpoms tx

•Hashimotos Thyroiditis (hypothyroidism) affects about 5% of the population at some point in their life. Most frequent hypothyroidism. •Begins between the ages of 30 and 50 and is much more common in women than men. • •Is thought to be due to a combination of genetic and environmental factors. Risk factors include a family history of the condition and having another autoimmune disease. • •Plasma cells, lymphocytes, and fibrous tissue destroyed by circulating antibodies. Destruction of thyroid follicular cells leads to the underproduction of T4 and T3. • •Over time the thyroid may enlarge forming a painless goiter. • •Symptoms include hypothyroidism, weight gain, feeling tired, constipation, depression, and general pains. • Can be treated with levothyroxine. Should avoid ingesting large amounts of iodine.

Human ACTH is dervied from Other biologically important peptides, including _____, ______, __________ are derived from the POMC precursor secondary adrenal and tertiary adrenal insufficiency

•Human ACTH is a 39 amino acid peptide. • •It is derived from a larger precursor protein, proopiomelanocortin (POMC). • •Other biologically important peptides, including endorphins, lipotropins, and the melanocyte-stimulating hormones (MSHs), are derived from the POMC precursor. • •Secondary adrenal insufficiency results from suppressed production of ACTH due to a impairment of the pituitary gland or hypothalamus • •Tertiary adrenal insufficiency is a disease of the hypothalamus, with a decrease in the release of corticotropin releasing hormone CRH.

Recombinant HGH where did HGH used to come from? what was wrong with it what is humatrope and what is indicated for? what is used to increase milk production in cows what is somavert and how is adminstered

•Humans do not respond to GH from nonprimate species. Prior to the 1980's GH for therapeutic use was purified from human cadaver pituitaries and available in very limited quantities • •In the mid-1980s cadaver hGH was linked to the transmission of Creutzfeldt-Jakob disease, a Neurodegenerative disease that is incurable and fatal (mad cow disease, bovine spongiform encephalopathy, BSE). • •Recombinant hGH (Humatrope) Indicated in children with growth failure due to Turners syndrome or Dwafism. • •HGH has been used by competitors in sports since at least 1982, and has been banned by the IOC and NCAA. • •A cow-specific form of GH called bovine somatotropin is used for increasing milk production in dairy cows. • •Pegvisomant (Somavert) is GH modified with 4-5 PEG attached to Lys. • •Induces the formation of specific antibodies in ∼15% of patients. • •Administered subcutaneously (40-mg dose) under physician supervision, followed by self-administration (10 mg per day). • •Pegvisomant provides a highly effective alternative for use in patients who have not responded to somatostatin analogs.

Physiological Effects of Thyroid Hormones

•Important in controlling O2 consumption and protein synthesis. •Increases basal metabolic rate (O2 consumed at rest). • •Regulates turnover of carbohydrates, lipids and proteins. • •Promotes glucose absorption. • •Promotes Hepatic and renal gluconeogenesis (formation of glucose). • •Promotes Hepatic glycogenolysis (break down of glycogen). • •Promotes utilization of glucose by muscle and adipose tissue. • •Increases cholesterol synthesis. • •Increases LDL degradation.

Symptoms of Hyperthyroidism

•Increase metabolic rate. • •Increase oxygen consumption. • •Decrease temperature intolerance. Facial flushing • •Increase heart rate and cardiac output and BP. • •Decrease weight. Muscle wasting. • •Edema. • •Decrease glucose tolerance. • •Enlarged thyroid gland. • •Bulging eyes.

D3 role where is it located D2 and D3 impt role

•Inner ring 5-deiodination is catalyzed mainly by type 3 deiodinase (D3), and to some extent also by D1. • •D3 is found at highest levels in the CNS and placenta, and it also is expressed in skin and uterus. It is highly expressed in hemangiomas. • •D2 and D3 also play important roles in regulating local T3 levels during development, during which thyroid hormone tends to promote differentiation and decrease proliferation.

Sodium Iodide Symtransporter •Iodine ingested in the diet reaches the circulation in the form of _________ • •The thyroid actively transports the I- into follicular cells via a specific membrane-bound protein, termed ___________ •NIS is regulated by____________ • •____________ stimulates NIS gene expression and promotes insertion of NIS into the membrane in a functional configuration. •Decreasing concentration of follicular cell iodide enhances

•Iodine ingested in the diet reaches the circulation in the form of iodide ion (I−). • •The thyroid actively transports the I- into follicular cells via a specific membrane-bound protein, termed the sodium-iodide symporter (NIS) •NIS is regulated by thyroid stimulating hormone or thyrotropin (TSH) released from the pituitary. • •Thyrotropin (TSH) stimulates NIS gene expression and promotes insertion of NIS into the membrane in a functional configuration. •The ratio of thyroid:plasma iodide concentration is usually between 20:1 to 50:1. •Decreasing concentration of follicular cell iodide enhances iodide uptake. • •Administration of iodide (Wolff-Chaikoff Block) can reverse this situation by decreasing NIS protein expression. • •A thyroid scan demonstrates the uptake of 131I- by normal thyroid compared to increase uptake in hyperthyroidism (Graves disease).

what is TBG T4 and T3 distributes to where The lower binding affinity of T3 for TGB results in •Once inside the cell, T3 and T4 associate with for women changes in ___________ can alter binding of thyroid hormones to plasma proteins

•Iodothyronines bind non-covalently with plasma proteins in the blood. • •Thyroid Binding Globulin (TBG) is the major carrier of thyroid hormones. T4 bound to TGB accounts for 75% of T4 storage. TGB binds T4 tightly than T3 is bound. Albumin also bind T4 10% of T4 storage. • •T4 mainly distributes to liver and kidney •T3 mainly distributes to muscle and brain. • •The lower binding affinity of T3 for TGB results in a more rapid onset of action and shorter biological half-life when thyronine is used as a thyroid hormone replacement. • •Once inside the cell, T3 and T4 associate with cytosolic proteins. • •Changes in circulating estrogens during pregnancy or during the administration of oral estrogens, can alter the binding of thyroid hormones to plasma proteins.

what is terlipressin what is for what is HRS

•Long acting form of vasopressin containing three additional Gly •Terlipressin (TerLyz) is preferred for bleeding esophageal varices because of increased safety compared with vasopressin and is designated as an orphan drug for this use. •Functions by lowering portal blood pressure • •Decreases bleeding in the esophagus. •Terlipressin has been granted priority review, orphan drug status, and fast-track designation by the FDA for type I hepatorenal syndrome (HRS). • •HRS symptoms include rapid deterioration in kidney function in individuals with cirrhosis or fulminant liver failure. HRS can be treated by kidney dialysis or liver transplant.

low levels of ca stimulate the release of ___________ elevated PTH serum concentrations increase ________ elevated PTH in serum also stimulate __________ to increase the conversion of

•Low levels of Ca2+ stimulate the release of PTH from the parathyroid gland. • •Elevated PTH serum concentrations increases Ca2+ and phosphate reabsorption in the kidney. • •Elevated PTH in serum also stimulate CYP1α to increase the conversion of calcifediol into calcitriol in the kidney.

how much calcium in body serium ca its a divalent cation

•Men and women have about 1300 and 1000 g calcium in their bodies, >99% is in bone and teeth. • •Serum calcium concentration ranges from 8.5-10.4 mg/dL. • •Intracellular Ca2+ is 100 nM in cells in their basal state. • •It is regulation over the 100 nM to 1 μM range. • •Ca2+ is the major extracellular divalent cation. • ØCa2+: ionized (50%), Øprotein-bound (40%), Øcomplexed (10%) • •Extracellular Ca2+ concentration is controlled by hormones that affect calcium entry at the intestine and its exit at the kidney • •Hormones also regulate Ca2+ withdrawal from the large skeletal reservoir

what are MIT and DIT what results in T4

•Monoiodotyroine (MIT) and Diiodotyrosine (DIT) are precursors of T3 and T4. • •Couple of Two DIT side chains results in T4, whereas coupling of one MIT and one DIT results in either T3 or rT3.

Where is calcium absorbed? why is there ca loss is it reabsorbed? •Bone deposition and reabsorption (remodeling) accounts for no net change in Ca2+.

•Normal daily intake of 800 mg leads to 300 mg is absorbed in the intestine. • •Daily intestinal calcium loss is 150 mg/day due to mucosal and biliary secretions and in sloughed intestinal cells. •The kidneys filters 9 g of Ca2+ each day and reabsorb nearly all with only 150 mg excreted in urine. • •Bone deposition and reabsorption (remodeling) accounts for no net change in Ca2+.

•Oxidation of iodide to its active form is accomplished by •__________ mediates the oxidation of iodide using the co-substrate H2O2, resulting in an enzyme-linked •TPO then transfers iodide to tyrosine residues in thyroglobulin to form •Next TPO conjugates iodotyrosyls (MIT and DIT) to form • •Two DIT couple to form _________ and 1 MIT couple to form ________. Each coupling generates an alanine.

•Oxidation of iodide to its active form is accomplished by thyroid peroxidase (TPO), a heme-containing enzyme. • •TPO is membrane bound and concentrated on the apical surface of the follicle cell near the lumen. • •TPO mediates the oxidation of iodide using the co-substrate H2O2, resulting in an enzyme-linked hypoiodate (HIO). • •TPO then transfers iodide to tyrosine residues in thyroglobulin to form iodotyrosyl residues (MIT and DIT). •Next TPO conjugates iodotyrosyls (MIT and DIT) to form iodothyronines T3 and T4 within thyroglobulin. • •Two DIT couple to form T4 or 1 DIT and 1 MIT couple to form T3. Each coupling generates an alanine. •

Negative-Feedback Control of PTH Release PTH functions to maintin constant concentration of _________ and ________ in the extracellular fluid. IT also regulates _______and _______ and bone _________ PTH secretion from parathyroid is triggered by changing ___________ changes in Calcium plasma concentration are monitored by _______________

•PTH functions to maintain a constant concentration of Ca2+ and Pi in the extracellular fluid. • •Regulates renal Ca2+ and Pi absorption and bone reabsorption. • •PTH secretion from the parathyroid is triggered by changing Ca2+ concentrations in the plasma controlled by a negative-feedback system • •Changes in plasma Ca2+ are monitored by calcium-sensing receptor (CaSR) on parathyroid cells.

as the calcium concentration diminshes, ______ increases conversely if the concentration of calcium is high then __________ decreases what metabolite directly suppresses PTH gene expression? •Changes in __________ concentration alter circulating Ca2+. Severe hypermagnesemia or hypomagnesemia can inhibit ____________

•PTH functions to maintain a constant concentration of Ca2+ and Pi in the extracellular fluid. • •Regulates renal Ca2+ and Pi absorption and bone reabsorption. • •PTH secretion from the parathyroid is triggered by changing Ca2+ concentrations in the plasma controlled by a negative-feedback system • •Changes in plasma Ca2+ are monitored by calcium-sensing receptor (CaSR) on parathyroid cells. • •As the concentration of Ca2+ diminishes, PTH secretion increases. • •Conversely, if the concentration of Ca2+ is high, PTH secretion decreases. • •Vitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol) , directly suppresses PTH gene expression. • •Changes in phosphate concentration alter circulating Ca2+. Severe hypermagnesemia or hypomagnesemia can inhibit PTH secretion.

a major proteolytic product of PTH is _________ which results in _______

•Parathyroid hormone (PTH) is an 84 amino acid protein produced by chief cells of the parathyroid gland. • •PTH is an 84 amino acid protein with MW of 9500 Da. • •Biological activity resided in the N-terminal residues 1-27. • •A major proteolytic product of PTH is PTH (7-84) which accumulates during renal failure. • •PTH has a t1/2 in plasma of 4 minutes. It is removal from plasma by the liver and kidney accounts for 90% of its clearance.

Peptide hormones consisting of what hormones what is MSH? An increase in MSH will cause when does MSH increases when hyperpigmentation

•Peptide hormones consisting of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating hormone (β-MSH), and γ-melanocyte-stimulating hormone (γ-MSH) that are produced by cells in the intermediate lobe of the pituitary gland. • •MSH stimulate the production and release of melanin (a process referred to as melanogenesis) by melanocytes in skin and hair. MSH actions in the brain have effects on appetite and sexual arousal. • •An increase in MSH will cause darker skin in humans. • •MSH increases in humans during pregnancy. This, along with increased estrogens, causes increased pigmentation in pregnant women. • •Hyperpigmentation occurs in Cushing's and Addison's disease due to excess adrenocorticotropic hormone (ACTH) because MSH and ACTH share the same PMOC precursor.

Primary adrenal insufficiency cushings disease cosyntropin

•Primary adrenal insufficiency (e.g. Addison's disease) occurs when adrenal gland production of cortisol is chronically deficient despite chronically elevated of ACTH. • •In Cushing's disease a pituitary tumor elevates ACTH which causes an excess of cortisol (hypercortisolism). • •Cosyntropin, first 24 amino acids of ACTH. Stimulates the release of cortisol from the adrenal. Used for the ACTH stimulation test to assess adrenal gland function.

primary, secondary, tertiary hyperparathyroidism

•Primary hyperparathyroidism occurs when one parathyroid gland grows into a tumor. • •Produces excess PTH that liberates calcium from the bones resulting in elevated calcium in your blood. •High calcium levels affects your brain, nervous system, bones, muscles (including your heart), kidneys, and intestinal function. • •Secondary hyperparathyroidism occurs in patients who have renal failure, and almost always in patients who have been on kidney dialysis for several years. • •The parathyroid glands overproduce PTH in response to the kidney disease. Results in 4-gland hyperplasia. • •Tertiary hyperparathyroidism occurs in patients who have mild secondary hyperparathyroidism and then get a functioning kidney transplant. Overactive parathyroid glands risk damaging the transplant kidney with the high calcium in the blood.

Primary hyperparathyroidism results when Secondary hyperparathyroidism results when hypoparathyroidism results from

•Primary hyperparathyroidism results from secretion of excess PTH by chief cells. Normally requires surgical resection. • •Secondary hyperparathyroidism results when renal disease results in excess calcium elimination causing the parathyroid gland to over compensate with excess PTH secretion. • Hypoparathyroidism results from decreased PTH production due to damage to the thyroid. Symptoms are those of decreased calciumand can be treated with Vitamin D analogues

RANKL binds to RANK on ___________ resulting in what decreasing levels of PTH leads to production of _________ __________ acts as a decoy ligand which binds to RANKL to form an __________ complex lack of free RANKL blocks

•RANKL binds to RANK on osteoblast precursor cells resulting in their differentiation into osteoclast. • •Decreasing levels of PTH leads to the production osteoprotegerin (OPG) from osteoblast precursors. • •OPG acts as a decoy ligand which binds to RANKL to form an RNKL/OPG complex. • •The lack of free RANKL blocks the differentiation of osteoblast precursors into osteoclasts.

mialcin and fortical indication side effects

•Salmon calcitonin (Miacalcin), a synthetic peptidefor injection (s.c. or i.m.), also available a nasal spray. • •Indication include Paget's Disease, Hypercalcemia and Postmenopausal Osteoporosis women greater than 5 years postmenopause. • •Side effects and precautions include hypersensitivity, hypocalcemia, and malignancy. • •Salmon calcitonin (Fortical), a recombinant peptide nasal spray. • •Indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. • •Recommended dose is 1 spray (200 International Units) per day intranasally, alternating nostrils daily. • •Patients who use Fortical nasal spray should receive adequate calcium (at least 1000 mg elemental calcium per day) and Vitamin D (at least 400 International Units per day).

does PTH bind to osteoclasts? increasing levels of PTH leads to binding and activation of

•Since PTH does not directly bind to osteoclasts, it acts indirectly to achieve bone resorption • Increasing levels of PTH leads to binding and activation of stromal cell osteoblasts to the increases expression of RANKL

Dietary Sources of Calcium

•Skeleton contains 99% of total body calcium in a crystalline form resembling the mineral hydroxyapatite [Ca10(PO4)6(OH)2] • •Bone is 70% hydroxyapatite. • •Microcrystalline hydroxyapatite is marketed as a "bone-building" supplement with superior absorption in comparison to calcium. • •Milk and dairy products provide 75% of dietary calcium. • •Recommended intake of 1300 mg/day in adolescents and 1000 mg/day in adults, over 50 years of age 1200 mg/day. • •Normal average intake is 800 mg.

T3 and T4

•T3 (3,5,3' Triiodo-L-thyronine), Thyronine, is fully active thyroid hormone. Whereas, reverse T3 (rT3), is an inactive geometric isomer of T3. • •T4, (3,5,3',5' tetraiodo-L-thyronine), Thyroxine, is a prohormone, which is converted into active T3 thyroid hormone in the peripheral tissues. •The 3,5 iodines on T3 and T4 restrict rotation of the two rings resulting in a biologically active conformation in which the rings are oriented perpendicular to one another.

teriparatide use indications administration side effects

•Teriparatide (Forteo) is recombinant parathyroid hormone consisting of the first N-terminal 34 amino acids. FDA approved in 2002. • •Anabolic bone growing agent used in the treatment of some forms of osteoporosis. • •While chronic exposure to high PTH levels causes osteoclasts to resorb bone, intermittent use of PTH activates osteoblasts more than osteoclasts, which leads to an overall increase in bone. • •Delivery s.c. via pen at a daily dose of 20 mg . • •Indicated in postmenopausal women with osteoporosis and at high risk of fractures. • •Indicated in men with primary hypogonadal osteoporosis with risk of facture to increase bone density. • •Indicated in men and women with osteoporosis associated with sustained systemic glucocorticoid therapy. • Side effects include headache, nausea, dizziness, and limb pain

function of parathyroid gland PTH increases PTH is major regulator of ___________ via actions on the kidney. it is also an inhibitor of

•The function of the parathyroid gland is to maintain calcium and phosphate homoeostasis by secreting parathyroid hormone (PTH). • •PTH increases blood calcium levels by mediating increased osteoclast bone resorption and release of calcium. •PTH increases gastrointestinal calcium absorption by activating vitamin D, and promotes calcium conservation (reabsorption) by the kidneys. • •PTH is the major regulator of serum phosphate concentrations via actions on the kidney. It is an inhibitor of proximal tubular reabsorption of phosphorus. Through activation of vitamin D the absorption of Phosphate is increased.

the posterior pituitary synthesizes arginine vasopressing and oxytocine

•The posterior pituitary contains the endings of nerve axons arising from distinct populations of neurons in the supraoptic and paraventicular nuclei of the hypothalamus that synthesize either arginine vasopressin or oxytocin. • •Arginine vasopressin plays an important role in water homeostasis. • •Oxytocin plays important roles in labor and parturition and in milk letdown.

thyroglobulin what does it contain what enhances degradation of thyroglobulin role of endopeptidases what products are liberated/released

•Thyroglobulin is a thyroid hormone storage glycoprotein composed of 2 x 330,000 g/mol subunits. • •Thyroglobulin represents 33% of the weight of the thyroid. • •Thyroglobulin contains 6 MIT, 5DIT, 0.3 T3 and 1 T4 • •The amount of thyroglobulin in the thyroid provides storage of T4 for 2 months without consuming iodide. •TSH enhances the degradation of thyroglobulin by increasing the activity of several thiol endopeptidases of the lysosomes. • •Endopeptidases selectively cleave thyroglobulin, yielding hormone-containing intermediates that subsequently are processed by exopeptidases. • •The liberated T3 and T4 hormones then exit the cell. • •MIT and DIT also are liberated but usually do not leave the thyroid; but are metabolized and the iodide (I−) is re-incorporated into thyroglobulin.

thyroid gland what secretes thyroid hormone in blood what produced calcitonin thryoglobulin

•Thyroid gland, is an endocrine gland found on the posterior side of the trachea. • •Thyroid follicular cells (endothelial cells) produce and secrete thyroid hormone(s) into the blood, which influence development, metabolic rate and protein synthesis. • •Thyroid C-cells produces calcitonin, involved in calcium homeostasis. • •Within the thyroid gland, follicular cells form spherical follicles surrounding a follicular lumen containing a viscous colloid glycoprotein (thyroglobulin). • •Thyroid epithelial cells specialize in taking up iodine and amino acids from the blood, and secreting thyroglobulin into the thyroid follicles to serve as depot of thyroid hormone.

action of thyroid hormones role of MCTB •Thyroid hormone action is mediated largely by the binding of ________ to thyroid hormone receptors (TRs), which are members of the nuclear receptor superfamily of transcription factors.

•Thyroid hormone crosses the cell membrane primarily via a specific transporter protein, monocarboxylic acid transporter 8 (MCT8). • •MCT8 is widely expressed, including in liver, heart, and brain. • •Thyroid hormone action is mediated largely by the binding of T3 to thyroid hormone receptors (TRs), which are members of the nuclear receptor superfamily of transcription factors. • •The TRs have the classic nuclear receptor structure consisting of an amino terminal domain, a centrally located zinc finger DNA binding domain, and a ligand binding domain that occupies the carboxyl terminal half of the protein. • •T3 binds to TRs with ∼10-fold greater affinity than does T4, and T4 is not thought to be biologically active in normal physiology. • •TRs bind to specific DNA sequences thyroid hormone response elements, TREs in the promoter/regulatory regions of target genes. • •The transcription of most target genes are repressed by un-liganded TRs and induced following the binding of T3. • •The binding of T3 causes replacement of the co-repressor complex by a co-activator complex that includes histone acetyltransferases, methyltransferases, and other proteins.

regulation of thyroid hormone production what is TRH what is TSH and what does it stimulate what happens with elevated T3 and T4 levels

•Thyroid releasing hormone (TRH) is a tripeptide (pGlu-His-Pro-NH2) released from hypothalamus. • •TRH causes the release of Thyroid Stimulating Hormone (TSH) (Thyrotropin) from the anterior pituitary. • •TSH is a glycoprotein hormone composed of an a and b subunit that bind to the TSH receptor on thyroid follicular cells to cause the production and release of T4 and T3 from the thyroid. • •TSH is a 28kDa heterodimer glycoprotein that stimulates: ØT3 and T4 excretion from the thyroid. Øthyroglobulin synthesis. Øincreases efficiency of NIS Øincreases TPO synthesis. •Elevated Iodothyronines (T3 and T4) levels cause negative feedback regulation of the hypothalamus and pituitary by inhibiting transcription of TSH and TRH, thereby inhibiting release of T3 and T4.

a-MSH Analogues Afamelanotide what does it what is bremelanotide HSDD

•Two synthetic analogues of α-MSH have been developed for human use. • •Afamelanotide (Scenesse) approved for the treatment of erythropoietic protoporphyria. • •Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 • •Darkens dermal pigmentation through melanogenesis. • •Reduces damage to UV light-exposed skin • •Bremelanotide (PT-141) is currently under development for its aphrodisiac effects. These effects are mediated by actions in the hypothalamus on neurons that express MC3 and MC4 receptors. • •Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH •Treatment of hypoactive sexual desire disorder (HSDD) in two late-stage phase III clinical trials were announced by Palatin on 1 November 2016. Approval of bremelanotide for this indication is expected in the United States in the second half of 2017.

•The major steps in the synthesis, storage, release, and interconversion of thyroid hormones are as follows: what is NIS, TPO know steps

•Uptake of iodide ion (I-) into the thyroid follicular cells by the sodium-iodide symtransporter (NIS). • •Oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin by thyroid peroxidase (TPO). • •Coupling of iodotyrosine residues by ether linkage to generate the iodothyronines by thyroid peroxidase (TPO). • •Resorption of the thyroglobulin colloid from the lumen into the cell. • •Proteolysis of thyroglobulin and the release of thyroxine and thyronine into the blood. • •Recycling of the iodine within the thyroid cell via de-iodination of mono- and diiodotyrosines and reuse of the I-. • •Conversion of thyroxine (T4) into thyronine (T3) in peripheral tissues as well as in the thyroid.

vitamin D is a hormone and not a vitamin exposure of skin converts what to what? recommended Daily intake

•Vitamin D is actually a hormone rather than a vitamin. • •Exposure of the skin to sunlight converts (provitamin) 7-dehydrocholesterol to cholecalciferol (vitamin D3), in plants vitamin D2 is formed. • •"Vitamin D" is the collective term used for vitamins D2 and/or D3 • •Sunlight provides adequate vitamin D supplies in the equatorial belt but insufficient in the winter in northern climates. • •The recommended dietary allowance of vitamin D for infants and children is 400 IU, or 10 μg, daily which approximates a teaspoon (5 mL) of cod liver oil. • •The adult dose was arbitrarily set at 200 IU. • •Premature and normal infant intake of 200 units per day of vitamin D from any source is considered adequate for optimal growth. • •Nutritionists now recommend high daily intake, up to 4000 IU/day.

•Vitamin D3 is converted into Calcitriol by two successive enzyme reactions as follows. where is Vitamin D3 stored? how is calcifedol formed? function of CYPa how is calcitriol formed

•Vitamin D3 is converted into Calcitriol by two successive enzyme reactions as follows. • •Vitamins D3 is absorbed from the small intestine. These circulates in the blood in association with vitamin D-binding protein with a plasma t1/2 of 20-30 hours. Vitamin D3 is stored in fat depots for prolonged periods. • •Vitamin D3 is first activation occurs in the liver, where D3 is hyroxylated at position 25 to form Calcifediol. Calicifediol enters the circulation and is carried by vitamin D-binding globulin. • •The second activation is accomplished by CYP1α responsible for 1α-hydroxylation of calcifediol in the mitochondria of the nephron proximal tubules to generate Calcitriol.