KOH

Both T3 and T4 are 99.5% bound to plasma proteins. The two main plasma proteins that bind them are thyroid-binding globulin and albumin.

• T3 activity is 5-10x greater than T4 activity

  • T4 is the main negative feedback hormone

• highly plasma protein bound

An ADH deficiency will lead to the condition known as central diabetes insipidus. Patients with this condition will experience polyuria, polydipsia, headaches, and other symptoms due to excess fluid loss and low plasma volume.

• diabetes insipidus

  • polyuria - increased urine production

  • polydipsia - increased thirst

  • headache

  • increased plasma osmolarity

  • seizures

• causes cns disturbances & ethanol can mimic this condition

Hormones typically work in concert to produce a desired effect or physiologic outcome

• the response is related to the dose

• hormones working together can produce effects 5x than what they would alone (response is exponential, not linear)

Most of the effects of GH are mediated by the production of IGF-1. IGF-1 is produced after GH binds the GH receptor on the cell membranes of liver cells.

• GH = growth hormone

• IGF-1 = insulin-like growth factor 1, mediated by STH

CHRISSOBOLIS

Estrogen is the dominant hormone in the follicular phase of the menstrual cycle and is secreted by the ovary. It can inhibit FSH release in the follicular phase after the dominant follicle has been recruited. It also promotes thickening of the endometrial lining of the uterus to prepare the uterus for embryonic implantation. Just before ovulation, estrogen promotes the LH surge from the pituitary which is necessary for ovulation to occur. It is secreted by the corpus luteum in the luteal phase of the cycle, but progesterone is the main hormone secreted by the corpus luteum in the luteal phase.

• FSH levels increase during the follicular phase for growth/development

• estrogen promotes LH surge during ovulation before the follicular rupture causing follicular maturation and ovulation

  • secreted by the corpus luteum during luteal phase

• FSH and LH are pulsatile and coordinate the menstrual cycle

Because insulin secretion/action is impaired in diabetes, the actions of insulin in the liver are impaired. There is therefore higher than normal gluconeogenesis and glycogenolysis, and subsequent glucose output. Since the actions of insulin are impaired both after meals and in the fasting state, liver glucose output is thus not properly suppressed after meals, and is also too high in the fasting state.

• insulin in liver = increased glucose uptake, lipogenesis, glycogenesis and decreased glucose output, gluconeogenesis, and glycogenolysis

• insluin in adipose tissue = increased glucose uptake and lipgenesis and decreased lipolysis

• insulin in skeletal muscle= increased glucose uptake, glycogenesis, and protein synthesis

• when insulin activity is impaired, these actions are opposed

Insulin resistance is the failure of normal amounts of insulin to elicit the expected response

• insulin in liver = increased glucose uptake, lipogenesis, glycogenesis and decreased glucose output, gluconeogenesis, and glycogenolysis

• insluin in adipose tissue = increased glucose uptake and lipgenesis and decreased lipolysis

• insulin in skeletal muscle= increased glucose uptake, glycogenesis, and protein synthesis

• insulin is still secreted by the pancreas yet the body does not fully react to its effects

Sulfonylureas act on SUR to inhibit ATP-sensitive K+ channels and ultimately stimulate insulin secretion from pancreatic ˟cells. Long-acting GLP-1 receptor agonists act on incretin receptors on pancreatic ˟cells to increase cAMP levels and ultimately stimulate insulin secretion. DPP-4 inhibitors inhibit the enzyme DPP-4. DPP-4 degrades GLP-1, so DPP-4 inhibitors increase GLP-1 levels in type 2 diabetes. GLP-1 can then act on pancreatic cells to promote insulin secretion.

• sulfonylureas major mechanism = increase insulin release from pancreatic beta cells by binding to and inhibiting the sulfonylurea receptor

• GLP-1 receptor agonists major mechanism = delay gastric emptying which causes decreased glucose entry into the duodenum and in turn in circulation, also can act on pancreatic cells to promote insulin secretion in type 2

• DPP-4 major mechanism = inhibits DPP-4 enzyme activity which inhibits the degradation of GLP-1

In the prandial state (ie. after a meal), pancreatic ˟cells secrete insulin. Insulin acts in the liver to promote glucose uptake, as well as glycogenesis (formation of glycogen from glucose). Insulin also inhibits gluconeogenesis (formation of glucose from fatty acids and amino acids) and glycogenolysis (breakdown of glucose into glycogen), as there is already large amounts of new glucose having been ingested with the meal. Insulin also promotes lipogenesis (formation of stored fat from glucose), which is another process involved in glucose metabolism.

• insulin in liver = increased glucose uptake, lipogenesis, glycogenesis and decreased glucose output, gluconeogenesis, and glycogenolysis

• insluin in adipose tissue = increased glucose uptake and lipgenesis and decreased lipolysis

• insulin in skeletal muscle= increased glucose uptake, glycogenesis, and protein synthesis

The main clinical benefit of metformin is reduced glucose production by the liver, which occurs mainly due to inhibiting gluconeogenesis in the liver. Metformin enters hepatocytes (liver cells) via a transporter. In the mitochondria, metformin acts at complex 1 to cause an increase in AMP levels. Increased AMP leads to decreased adenylate cyclase activity, and subsequent decreased cAMP levels and decreased PKA activity. The net result of this is inhibition of liver gluconeogenesis. This is the main reason that metformin is beneficial. Increased AMP levels can also increase AMP kinase activation, which leads to improved insulin receptor function, improved glucose transport, and reduced fatty acid synthesis. These all result in improved insulin sensitivity (recall that improved insulin sensitivity is a desired effect of pharmacotherapy since it is a reversal of insulin resistance). The main side effects of metformin are gastrointestinal (eg. nausea, diarrhea, vomiting), and vitamin B12 levels should be monitored, since vitamin B12 deficiency can occur with long-term use. Metformin use is contraindicated in patients with eGFR <30 mL/min/1.73m2.

• lowers glucose levels and increases insulin sensitivity

• inhibits gluconeogenesis

• GI side effects w a bbw of lactic acidosis

• contraindicated in pts with renal dysfunction

When used in oral contraceptives, progestins are very effective at blocking ovulation. They do this by preventing GnRH pulses from the hypothalamus, which in turn impairs the mid-cyle LH surge induced by estrogen (recall that ovulation cannot occur without the LH surge). Other actions of progestins which are important in their effectiveness when used in oral contraceptives include their ability to: cause endometrial atrophy (which renders the endometrial surface unreceptive to the fertilized ovum); slow uterine motility (which impairs ovum and sperm transport), and; promote cervical mucus thickening (which impairs the ability of sperm to penetrate the cervix).

• progestins block GnRH pulses which impairs the mid-cycle LH surge

• causes endometrial atrophy, slowing of uterine motility, and promotes cervical mucus thickening

ADANE

Review KDIGO CKD staging for end stage renal disease GFR cutoff

• Rise in SCr of ≥ 0.3 mg/dL within the past 48 hours

• Urine output (UOP) <0.5 ml/kg/hr for ≥ 6 hours

• 3 stages

Increasing the number of exchanges, the volume of dialysate and the concentration of dextrose increases the amount of fluid and solutes removed during peritoneal dialysis.

• PD dose is affected by the # of exhanges, volume of exchange, and concentration of dextrose in dialysate

• PD is less efficient than HD in removing waste

  • solutes + water to be removed from bood are not in intimate contact with the dialysis membrane w no easy way to regulate blood flow

If the relationship between drug clearance and creatinine clearance is given, calculate renal dose adjustment factor (Q). Q is calculated as the ratio of drug clearance in a renally impaired patient to that in a patient with normal renal function. Use Q to adjust dose (multiplying original dose by Q), interval (dividing original interval by Q) or both.

• use total body clearance equation then adjust the dose by using factor Q

recognize commonly used antimicrobial agents that do not need renal dose adjustment.

• drugs that NEED adjustment

  • cefepime

  • ceftriaxone

  • ceftaroline

  • azithromycin

  • clindamycin

  • daptomycin

  • ertapenem

  • nitrofurantoin

  • nafcillin

  • acyclovir

  • ganciclovir

Evaluate calcium phosphate product before recommending agents for hyperphosphatemia.

• multiply Ca and PO4 to determine calcium phosphate product

• max is 55 mg²/dl²

• calcium based binders, iron based, and resin based binders available

Recall the effect of kidney impairment on vitamin D metabolism and serum concentrations. Recognize formulations of vitamin D that are active.

• vit D analogs for CKD G4-G5 pts

• active: calcitrol vitamin D3 PO and IV, paricalcitol IV

• inactive: doxercalciferol IV

• in CKD kidneys are unable to convert inactive vit D to active vit D leading to deficiency

Review pharmacological management of myxedema coma.

• IV glucocorticoid

• levothyroxine ± liothyronine IV

• supportive care

Compare and contrast vascular access techniques in hemodialysis in terms of longevity and complications

• native arteriovenous (AV) fistula

  • surgically created

  • long time to mature

  • can be used for a long time w low complications

• synthetic AV graft

  • faster access time

  • associated with more complications and does not last as long

• venous catheters

  • easy to insert and can be used immediately

  • limited doses of dialysis, short life span, highest risk of infection

review medications that exacerbate overflow incontinence: eg. alpha adrenergic agonists and anticholinergics

• prazosin (alpha-adrenergic antagonist)

• lithium

• donepezil

Review how intradialytic hypotension is treated and/or prevented.

• acute management

  • patient positioning

  • fluid and electrolyte administration

• prevention

  • changing dialysis settings

  • midodrine → raises BP

differentiate between prerenal, intrinsic and postrenal AKI

• prerenal

  • volume depletion

  • functional (ACEI)

  • decrease in effective circulatory volume

• intrinsic

  • vascular damage

  • glomerular damage

  • ATN

  • acute interstitial nephritis

• postrenal

  • bladder

  • ureter

  • renal pelvis/tubule

Recognize medications that should be discontinued in patients with acute kidney injury and low blood pressure

• ACEI/ARBs

• NSAIDS/COX-2 inhibitors

• diuretics

Recognize medications that need dose reduction in renal impairment.

• examples from the lecture content

  • antimicrobials (aminoglycosides)

    • acyclovir

    • amikacin

    • cefazolin

    • ceftazidime

    • ciprofolxacin

    • gidoxin

    • ganicilovir

  • chemotherapy (cisplatin)

  • NSAIDs (ketorolac)

  • immunosupressants (tacrolimus)

Recall that acute kidney injury management requires supportive measures. Assess if patient is volume depleted or volume overloaded and whether patient is hypoalbuminemic. Crystalloids are indicated for volume depletion and BP pressure management and loop diuretics for volume overload.

• depletion vs overload must be determined

• depletion = crystalloids

• overload = diuretics

D’SOUZA

In patients with benign prostatic hyperplasia (BPH), the effect of androgens on the prostate tissue can be decreased using either an androgen receptor antagonist (flutamide, bicalutamide) or ˞reductase enzyme inhibitor (finasteride, dutasteride) or GnRH agonists (leuprolide, buserelin, nafarelin and goserelin) or a combination of the above mentioned drugs. (ADANE material)

• 5-alpha-reductase inhibitors are 2nd line

  • tadalafil for pts with erectile dysfunction (3rd line)

• alpha-adrenergic antagonists

  • first line

The enzyme responsible for conversion of testosterone to dihydrotestosterone is ˞reductase. Inhibin is secreted by Sertoli cells and is one of the hormones that acts as a feedback signal to regulate secretion of luteinizing hormone from the pituitary. Aromatase is one of the enzymes that plays a role in conversion of testosterone to estrogen.

• testosterone → dihydrotestosterone (5-alpha-reductase)

• inhibin inhibits luteinizing hormone from the pituitary

• testosterone → estrogen (aromatase)

AE

5-alpha reductase inhibitors decrease prostate size by inhibiting the peripheral activation of testosterone

• finasteride and dutasteride

BATES

Continuous IV insulin infusions are typically reserved for hospitalized patients who are in the intensive care unit or being treated for DKA or HHS.

• DKA = diabetic ketoacidosis

• HHS = hyperosmolar hyperglycemic state

• treatment

  • correct dehydration, hyperglycemia, and electrolyte abnormalities

  • fluid replacement, bicarb, insulin, electrolyte replacement

  • insulin is IV (regular insulin)

Fluids, bicarbonate, insulin, and electrolyte replacement are the 4 major treatment categories for patients with hyperglycemic crisis. Each treatment has specific criteria for when it is appropriate and these are important considerations for the managements of patients with DKA and HHS.

• fluid replacement

  • always a treatment

  • isotonic saline bolus followed by infusion

• bicarbonate

  • DKA only

    • to correct acidosis

  • only indicated if pH <6.9

• insulin

  • IV

  • important but fluids are more pressing

  • weight base

  • avoid overly rapid correction

• electrolyte replacement

  • pt specific based on deficiencies

Sliding scale insulin is universally recommended against in inpatient diabetes guidelines because it is reactive, often ordered without regard to meals, and is not individualized to meet patient needs in the hospital setting. Correction scale insulin can be added to mealtime insulin to correct hyperglycemia before meals or can be used without mealtime insulin in patients who are NPO or not eating. Most hospitals have various correction scales which can be tailored to meet the patientಬs needs.

• universally recommended against however still common in many institutions

• reactive instead of proactive

  • treats hyperglycemia after it occurs

  • often ordered without regards to meals

  • not individualized

The inpatient goal for glycemic control for most patients is 140-180 mg/dL.

• target glucose range is higher for patients in an inpatient setting

• more stringent goals for critically ill patients/post surgical patients and those with newly defined DM

Basal insulin would be an appropriate next step for a patient with Type 2 DM who is already on oral therapy and a GLP-1. The starting dose can either be 10 units/day or 0.1 -0.2 units/kg/day. Insulin glargine should be administered once daily, often at bedtime. Short acting insulin would not be started until the basal insulin is adequately titrated per the ADA guidelines.

• if a patient is failing on an oral therapy and an GLP-1, initiating insulin would be the next step in therapy

  • basal insulin is initiated first at 10 units or 0.1-0.2 units/kg/day

• meal time insulin would not be initiated unless patient reaches overbasalization once basal insulin has been titrated up

OLAH

Several often interrelated factors contribute to electrolyte disorders and mineral bone disease in CKD. Focus is often on handling of phosphate and calcium. Early on, phosphate excretion is impaired in CKD and this results in hyperphosphatemia (hi phosphate in plasma). The phosphate may interact with calcium and thus create a functional hypocalcemia. Increased secretion of PTH may compensate initially but eventually correction no longer occurs and the secondary hyperparathyroidism becomes pathologic. Additionally, the kidney is the site of synthesis of calcitriol (the active form of Vitamin D). With loss of kidney mass and other reasons, in latter stages of CKD there is a decreased production of calcitriol. This also contributes to the hypocalcemia of CKD.

• to treat hyperphosphatemia, use phosphate binders to prevent complications

Uremia is often defined as a pathologic increase in N-containing molecules in the plasma. In CKD, uremia often develops due to the decline in renal excretion of these molecules (which are typically excreted in the urine). These N-containing molecules include urea but often very many other compounds including low molecular weight proteins that may be pathologic. Importantly, the uremic condition can promote much of the pathology of CKD. This pathology spans nearly all organ systems including brain, liver, hematologic, etc.

Anemia occurs in a very high percentage of patients with latter stage CKD for multiple and often interrelated reasons. The primary and major cause is the decline in kidney size with loss of ಯperitubular interstitial cellsರThese cells within the kidney are responsible for oxygen sensing and in response to hypoxia these cells are the major source of erythropoietin (EPO). Cells sense hypoxia and allow HIF1-alpha mediated gene transcription to occur with resulting EPO production. With a decrease in the number of these cells in CKD, EPO production and release is greatly diminished. EPO is the major driver of erythropoiesis.

Uncontrolled diabetic nephropathy may advance to nephrotic syndrome. Nephrotic syndrome is frequently characterized by a massive proteinuria. This large loss of protein in the renal filtrate may occur with diabetic nephropathy as the glomerular filtration apparatus breaks down and becomes dysfunctional. For example, with diabetes there is loss of negative charge proteins and other molecules on glomerular endothelial cells and the basement membrane. Similarly, there is dysfunction and eventual loss of podocytes. These effects and others contribute to the proteinuria often observed in diabetes.

Several characteristics of the glomerulus are responsible for regulating glomerular filtration in regard to substances/proteins to be retained or filtered. Many of the cells as well as the basement membrane of the glomerulus contain negatively charged proteins. This negative charge serves to repel (and thus prevent the filtration) of many proteins that on strictly a size basis may be able to pass into the filtrate. Breakdown of this negative charge complex is responsible for the filtration of proteins (that would normally be retained) in glomerular diseases.

Causes of acute renal failure (ARF)/acute kidney injury are typically classified as pre-renal, intrinsic, or post-renal. Intrinsic implies damage directly to kidney tubules or parenchyma. Instrinsic damage may occur in response to instrinsic or extrinsic toxins (frequently drugs). An intrinsic toxin includes myoglobin that may be released due to severe skeletal muscle damage such as crush injury but also statin toxicity. The filtered myoglobin causes significant damage to renal tubules through multiple mechanisms. Rhabdomyolysis is the frequently used term to this myoglobin-induced kidney damage. Pre-renal most often implies a decrease in blood flow (hypoperfusion) of the kidneys. This may occur with systemic hypotension (sepsis, dehydration, anti-HTN drugs, etc) or pathologic events such as occlusion of the renal artery.

Review the mechanisms by which drugs may cause nephrotoxicity. The mechanisms are usually quite varied. Certain agents such as many antibiotics (penicillins, cephalosporins) and proton pump inhibitors are the most common cause of acute interstitial nephritis ದa Type IV hypersensitivity reaction. NSAIDS and COX-2 inhibitors disrupt renal function by allowing for a constriction of the glomerular afferent arteriole. In kidney disease and with aging, the afferent arteriole is partially dependent on certain prostaglandins to produce a vasodilation and thus maintain GFR. Other antibiotics such as the aminoglycosides and vancomycin are notorious renal toxins. These agents most frequently gain access to renal tubule epithelial cells (reabsorption from filtrate, specific basolateral transporters) and promote pathologic events that often result in epithelial cell apoptosis.

JARRELL

Relates to the following lecture objective: compare and contrast the four primary acid-base disorders; determine etiology of acid-base disorders and assess compensation. Students should be able to identify common causes of the four primary acid-base disorders.

• respiratory acidosis

  • acute causes

    • central respiratory center inhibition

    • cns depression

    • airway obstruction

  • chronic causes

    • neuromuscular disorder

    • restrictive lung diseases

    • copd

• respiratory alkalosis

  • acute causes

    • hyperventilation

    • central respiratory center stimulation

    • hypoxemia

  • chronic causes

    • pregnancy

    • hyperthyroidism

    • liver disease

• anion gap- metabolic acidosis

  • mud piles

    • methanol, metformin

    • uremia

    • diabetic ketoacidosis

    • paraldehyde or propylene glycol

    • isoniazid or iron

    • lactate

    • ethanol

    • salicylates

  non-anion gap - metabolic acidosis

  • used car

    • urteral diversion

    • saline fluid recitation

    • enterocutaneous fistula

    • diarrhea

    • carbonic anhydrase inhibitors

    • adrenal insufficiency

    • renal tubular acidosis

• metabolic alkalosis

  • causes

    • vomiting

    • nasogastric tube suctioning

    • loop/thiazide diuretics

    • increases mineralcorticoid activity

Students should be able to recognize which medications are associated with common electrolyte abnormalities and which are used to treat electrolyte abnormalities.

• hypotonic hyponatremia

  • hypovolemic

    • loss of total body water and salt

    • caused by diuretics, profuse sweating, burns, GI losses

    • stop offending meds

    • replace sodium and volume losses

  • euvolemic

    • excess free water in relation to sodium

    • caused by cns disorders, SIADH, carcinomas

    • treat underlying disorder or remove offending agents

    • restrict fluids

    • vasopressin

  • hypervolemic- think edema

    • excess TBW

    • caused by CHF, cirrhosis

    • restric fluids

    • may need to replace sodium

    • salt tabs

• hypertonic hyponatremia

  • typically caused by hyperglycemia

  • correct hyperglycemia

• correcting sodium deficits

  • 6-8 mEq/L in 24 hours

  • overly aggressive corrections may lead to permanent neurologic damage

EDDY/JEWELL

The ADA guidelines recommend outpatient pre-prandial glucose goals of < 7 % (unless other factors, peak glucose < 180 and pre-prandial glucose of 80-130.

To be diagnosed with Diabetes (Type 1 or Type 2) a patient should have an A1c of greater than or equal to 6.5%. The peptide value tells you the amount of insulin present. Patients with Type 2 will often have high c-=peptide in the beginning and that will wean off as the disease progresses and lead to often low or no c-peptide later in disease progression. Patients with Type 1 will often have low c-peptide. Autoimmune antibodies are present in Type 1 diabetes since it is an autoimmune disease where they are rarely if ever present in patients with Type 2 diabetes.

The GLP-1 RA medications have a known problem in causing GI distress mostly nausea and are the reason for the slow titration of liraglutide to prevent distress. Eating small meals and slow dose titration can help alleviate this problem.

TZDs (rosiglitazone and pioglitazone) have known side effects of weight gain, edema and therefore are contraindicated in patients with congestive heart failure. Medications that you worry about pancreatitis with include GLP1RA and DPP4i

According to the ADA the first injectable therapy that all patients should be started on is a GLP-1 RA. After that a basal insulin would be tried at a dose of 10 units nightly or 0.1-0.2 units/kg/day and then adding a bolus insulin at 4 units of 10% of the basal dose.

Their fasting is under control so the long-acting insulin should NOT be changed. The before lunch is under control so it should NOT be changed. The before dinner is high so I would increase the lunchtime insulin by 1-2 units or 10-15%.

American College of Obstetricians and Gynecologists (ACOG), Centers for Disease Control and Prevention (CDC) and Most Clinical Organizations state; Be ಯreasonably certainರthat a woman is not currently pregnant, Medical history and blood pressure measurement required prior to starting CHC. Other services can be done during routine annual office visits (Pelvic/breast exam, HPV vaccine, cervical cancer screening, STI testing and prevention counseling)- Not needed for starting contraception

Some important counseling points for the transdermal patch include; apply to upper arm, buttocks, lower abdomen or back at the beginning of the menstrual cycle and replace every week for 3 weeks. The 4th week is patch free. May be less effective in women weighing ุkg, exposes women to ~60% more estrogen than pills, and Application site reactions may occur

When first starting contraception pills you would determine if the pt is a good candidate for estrogen or not. If they are a fine candidate for estrogen then that would be the preferred option as it is more effective and better tolerated. Then when you start CHC you start monophasic and want to pick progesterone that has fewer androgen effects if that is something the patient is concerned with. Less androgen activity means it has more estrogen activity and is more likely to cause clots so you just have to balance the risk.

If treating VMS the best thing that we have to treat is HRT. If a woman has had a hysterectomy then just estrogen should be given but if they have not and they have an intact uterus then EPT is the most appropriate.

PCOS is comprised of several downstream effects directly related to hyperandrogenism; including infertility, insulin resistance, excessive hair growth, and irregular menstruation.

GnRH receptor antagonists cause Inhibition of gonadotropin secretion by competitive binding and subsequent downregulation of GnRH receptors causing hypoestrogenic state. They are expensive, higher-dose therapy use limited to 6 months due to risk of BMD loss, contraception recommended -for contraception and add back therapy, improves dyspareunia and dysmenorrhea. These are Newer promising because they donಬt cause the initial flare and serge like GnRH agonist.

Viagra should be taken 1 hour prior to sexual activity with a max of one dose per day. It should be taken as needed and there is no recommended daily dosing for Viagra. It takes 30-60 min for the onset of the medication and the duration of action is up to 12 hours.

Patients with type 2 diabetes often go undiagnosed for a while so it is important that they get screening exams as soon as possible to assess damage already done. Patients with Type 1 diabetes we generally recommend that screening for complications start 55 years after diagnosis since we believe that we usually diagnose Type 1 diabetes as soon as it presents.

Beta blockers can mask the symptoms of hypoglycemia except sweating. Patients might not feel tachycardia, palpitatons, or jittery feeling but likely will still have sweating as a symptom of hypoglycemia

medications most likely to cause hypoglycemia include insulin (especially fast-acting insulin) and sulfonylureas. GLP1, SGLT2i, TZDs and Metformin are all unlikely to cause hypoglycemia.