The Endocrine System - npcourses.com Handout Samples/Advanced... · Advanced Pharmacology: ... Acts in the kidney collecting duct cells to decrease the excretion ... Increased level

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Unit 6 ©2014 Barkley & AssociatesUnit 6 ©2014 Barkley & Associates

Advanced Pharmacology:Endocrine Pharmacology Part I

Thomas W. Barkley, Jr., PhD, ACNP‐BC, FAANPPresident, Barkley & Associates

www.NPCourses.comand

Professor of NursingDirector of Nurse Practitioner Programs

California State University, Los Angeles

Robert Fellin, Pharm.D., BCPSLecturer, Barkley & Associates

Clinical Pharmacist Cedars‐Sinai Medical Center

Los Angeles, CA


The Endocrine System• Comprised of various glands

that secrete hormones (chemical messengers released in response to a change in the body’s internal homeostasis)

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Hypothalamus and Pituitary: Physiology Review

• Hypothalamus: secretes releasing hormones pituitary

• Releasing hormones trigger the pituitary to know which hormones are to be released

• Hypothalamus secretes thyrotropin-releasing hormone (TRH) pituitary secrete TSH thyroid hormones

• Pituitary

• Anterior (adenohypophysis): consists of glandular tissue and secretes ACTH, TSH, growth hormone, prolactin, FSH and LH

• Posterior (neurohypophysis): contains nervous tissue rather than glandular, and neurons in the posterior pituitary store ADH and oxytocin (released in response from nerve stimulation in the hypothalamus)


Hypothalamic & Pituitary Hormones

Pharmacology for Nurses: A Pathophysiologic Approach (4th Edition)

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Hypothalamic & Pituitary Hormones

Hypothalamic Hormone

Anterior Pituitary Hormone

Target Organ

Primary Target Organ Hormone/Mediator

Growth hormone-releasing hormone

(GHRH) (+)Somatostatin (−)

Growth hormone(GH, somatotropin) Liver, bone,

muscle, kidney, and others

Insulin-like growth factor-I (IGF-I)

Thyrotropin-releasing hormone

(TRH) (+)

Thyroid-stimulating hormone(TSH)

ThyroidThyroxine,tri-iodothyronine

(+), stimulant; (–), inhibitor


Hypothalamic & Pituitary HormonesHypothalamic Hormone

Anterior Pituitary Hormone

Target Organ

Primary Target Organ Hormone/Mediator

Corticotropin-releasing hormone (CRH) (+)

Adrenocorticotropin(ACTH)

Adrenal cortex

Cortisol

Gonadotropin-releasing hormone (GnRH) (+)

Follicle-stimulating hormone(FSH)

Luteinizing hormone(LH)

GonadsEstrogen, progesterone, testosterone

Dopamine (−)Prolactin(PRL)

Breast

(+), stimulant; (–), inhibitor

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Clinical Uses of Hypothalamic Hormones

Hypothalamic Hormone Clinical UsesGrowth hormone-releasing hormone(GHRH)

Used rarely as a diagnostic test for GH and GHRH sufficiency

Thyrotropin-releasing hormone(TRH, protirelin)

May be used to diagnose TRH or TSH deficiencies

Corticotropin-releasing hormone(CRH)

Used rarely to distinguish Cushing's disease from ectopic ACTH secretion

Gonadotropin-releasing hormone(GnRH)

May be used in pulses to treat infertility caused by GnRH deficiency

Dopamine Dopamine agonists (bromocriptine, cabergoline) used for treatment of hyperprolactinemia


Anterior Pituitary AgentsGROWTH HORMONE (GH)somatropinMOA: Recombinant form of human GH; acts through GH

receptors to increase production of IGF-I

Effects: Restores normal growth and metabolic GH effects in GH-deficient individuals Increases final adult height in some children with short stature not due to GH deficiency

Clinical Applications:

Replacement in GH deficiency Increased final adult height in children with certain conditions associated with short statureWasting in HIV infectionShort bowel syndrome

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Anterior Pituitary AgentsSOMATOSTATIN ANALOGSoctreotide, lanreotide

MOA: Agonist at somatostatin receptors

Effects: Inhibits production of GH and, to a lesser extent, of TSH, glucagon, insulin and gastrin


Acromegaly and several other hormone-secreting tumors Octreotide: Acute control of bleeding from esophageal varicesLanreotide: similar to octreotide; available as a long-acting formulation for acromegaly


Anterior Pituitary AgentsIGF-I AGONISTmecaserminMOA: Recombinant form of IGF-I that stimulates IGF-I receptors

Effects: Improves growth and metabolic IGF-I effects in individuals with IGF-I deficiency due to severe GH resistance

Clinical Applications: Replacement in IGF-I deficiency that is not responsive to exogenous GH

GH RECEPTOR ANTAGONISTpegvisomantMOA: Blocks GH receptorsEffects: Ameliorates effects of excess GH production

Clinical Applications: Acromegaly

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Anterior Pituitary AgentsHormone Diagnostic Use

Thyroid-stimulating hormone(TSH; thyrotropin)

In patients who have been treated surgically for thyroid carcinoma, to test for recurrence by assessing TSH-stimulated whole-body 131I scans and serum thyroglobulin determinations

Adrenocorticotropin(ACTH, Cosyntropin)

In patients suspected of adrenal insufficiency, either central (CRH/ACTH deficiency) or peripheral (cortisol deficiency), in particular in suspected cases of congenital adrenal hyperplasia


Posterior Pituitary AgentsOXYTOCINMOA: Activates oxytocin receptorsEffects: Increased uterine contractionsClinical Applications:

Induction and augmentation of laborControl of uterine hemorrhage after delivery

OXYTOCIN RECEPTOR ANTAGONISTAtosibanMOA: Blocks oxytocin receptorsEffects: Decreased uterine contractionsClinical Applications:

Tocolysis for preterm labor

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Posterior Pituitary AgentsVASOPRESSIN RECEPTOR AGONISTSdesmopressin, vasopressinMOA: relatively selective vasopressin V2 receptor agonistEffects: Acts in the kidney collecting duct cells to decrease the excretion

of water; acts on extrarenal V2 receptors to increase factor VIII and von Willebrand factor


Pituitary diabetes insipidus; pediatric primary nocturnalEnuresis; Hemophilia A and von Willebrand disease

VASOPRESSIN RECEPTOR ANTAGONISTconivaptan, tolvaptanMOA: Antagonist of vasopressin V1a and V2 receptors

Effects: Increase in water excretion, decrease in urine osmolality, increased serum sodium concentration


Reduced renal excretion of water in conditions associated with increased vasopressin; hyponatremia in hospitalized patients


Thyroid Physiology• Thyroid gland secretes hormones to

normalize growth and development, body temperature and energy levels

• Follicular cells in the gland secrete thyroid hormone, which actually consists of two different hormones:

• thyroxine (T4)

• tri-iodothyronine (T3)

• Parafollicular cells secrete calcitonin, a hormone that is involved with calcium homeostasis

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Thyroid Physiology• Secretes sufficient amounts of the thyroid hormones (tri-

iodothyronine (T3) and thyroxine (T4)) to maintain the basal metabolic rate which ensures normal growth and development

• Hormones contain iodine as an essential part of the molecule

• Hashimoto’s thyroiditis: autoimmune destruction of thyroid; most common presentation of HYPOthyroidism

• Graves' disease: autoimmune disorder in which helper T lymphocytes stimulate B lymphocytes to synthesize antibodies to thyroidal antigens; most common form of HYPERthyroidism

• Adjunct therapy for hyperthyroidism: beta-adrenoceptor-

blocking agents


Values for Thyroid Function TestsTest Normal Value Results in

HypothyroidismResults in

Hyperthyroidism

Totalthyroxine (T4)

4.8-10.4 mcg/dL(62-134 nmol/L)

Low High

Totaltriiodothyronine(T3)

60-181 ng/dL(0.92-2.79 nmol/L)

Normal or low High

Free T4 (FT4) 0.8-2.7 ng/dL(10.3-34.7 pmol/L)

Low High

Free T3 (FT3) 230-420 pg/dL(3.5-6.47 pmol/L)

Low High

Thyrotropic hormone (TSH)

0.4-4 μIU/mL(0.4-4 mIU/L)

High Low

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Thyroid Agentslevothyroxine (T4) (Levothroid, Synthroid), liothyronine (T3) (Cytomel, Triostat), liotrix (Thyrolar),thyroid (Armour Thyroid, Thyroid USP)MOA: Activation of nuclear receptors results in gene

expression with RNA formation and protein synthesis

Indication: Hypothyroidism

Comments: Maximum effect seen after 6–8 weeks of therapyToxicity: symptoms of thyroid excess


Anti-Thyroid AgentsTHIOAMIDES:methimazole (Tapazole), propylthiouracil (PTU)

MOA: Inhibit thyroid peroxidase reactions block iodine organification inhibit peripheral deiodination of T4 and T3 (primarily PTU)

Indication: Hyperthyroidism

Comments: OralDelayed onset of actionMethimazole duration of action: 24 hoursPTU duration of action: 6–8 hours

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Anti-Thyroid AgentsIODIDES: Lugol's solution, potassium iodide

MOA: Inhibit organification and hormone release reduce the size and vascularity of the gland

Indication: Preparation for surgical thyroidectomy

Comments: Oral; acute onset within 2–7 days

RADIOACTIVE IODINE131I (RAI)

MOA: Radiation destruction of thyroid parenchyma

Indication: Hyperthyroidism

Comments: Oral; half-life 5 days; onset of 6–12 weeks, maximum effect in 3–6 months; patients should be euthyroid or on beta-blockers before RAI; avoid in pregnancy/nursing mothers


Adrenal Glands: Physiology ReviewSecrete 3 essential classes of steroids:1. Gonadocorticoids:

Androgens > estrogens (less than testes or ovaries)2. Mineralocorticoids:

Aldosterone accounts for 95% Primary function is to regulate plasma volume (promote Na reabsorption and K

excretion by the renal tubules) Decreased plasma volume kidneys secrete renin production of angiotensin II aldosterone secretion promotes Na and water retention

Hyperaldosteronism: excessive aldosterone secretion usually a result of adrenal tumors, characterized by HTN and hypokalemia

3. Glucocorticoids: More than 30 glucocorticoids are secreted Cortisol (hydrocortisone) secreted in highest amount Influence the function of most cells in the body

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Glucocorticoids• Wide range of physiologic effects, including regulation of intermediary

metabolism, cardiovascular function as well as growth and immunity

• Hydrocortisone (cortisol): most important pharmacologically; prepares the body for long-term stress

• Glucocorticoids & mineralocorticoids also called corticosteroids or adrenocortical hormones

• Glucocorticoid & corticosteroid often used interchangeably, however “corticosteroid” implies both glucocorticoid and mineralocorticoid activity

• Corticosteroids: primarily used as replacement therapy for adrenal insufficiency (lack of corticosteroid) and reduce inflammation & immune response


Glucocorticoid SecretionHypothalamus:

Secretes corticotropin-releasing factor(CRF; CRF= CRH)

travels toPituitary:

Causes release of ACTHtravels to

Adrenal cortex:Releases glucocorticoids

Increased level of cortisol in the blood provides negative feedback to the hypothalamus & pituitary

to shut off further release of corticosteroidsPharmacology for Nurses: A Pathophysiologic Approach (4th Edition)

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Effects of GlucocorticoidsPhysiologic Effects Permissive effects: without glucocorticoids many normal

functions become deficient: response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol and restored by physiologic amountsEffects are dose-related: become magnified when large amounts are administered

Metabolic Effects Influence carbohydrate, protein and fat metabolism; stimulategluconeogenesis

Catabolic and Anti-anabolic Effects

Involved in lymphoid and connective tissue, muscle, peripheral fat, bone and skin

Anti-Inflammatory & Immunosuppressive Effects

Reduce inflammation through suppression of inflammatory cytokines; inhibit macrophage function; reduce prostaglandin synthesis

Other Effects Influence the nervous system; produce behavioraldisturbances, suppress pituitary release of ACTH, GH, TSH


Select Indications for GlucocorticoidsIndication CommentsAdrenocortical Insufficiency Acute: Initiate treatment immediately

hydrocortisone (usually large doses initially) supplementation with mineralcorticoid (fludrocortisone) is delayed until hydrocortisone is reduced to 50 mg/day

Chronic(Addison's Disease):

Hydrocortisone supplemented with a mineralocorticoid (fludrocortisone)

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Select Indications for Glucocorticoids

Indication Comments

Use of Glucocorticoids for Diagnostic PurposesDexamethasonesuppression test

Diagnosis of Cushing's syndrome

Cosyntropin stimulation test

Diagnose or exclude primary and secondary adrenal insufficiency; Measurement of cortisol in serum for evaluation of adrenal dysfunctionCosyntropin 250 mcg IV x1 then check cortisol level at 30 minutes and 60 minutes


Select Indications for GlucocorticoidsIndication Comments

Hyperaldosteronism

Primary: usually results from excessive production of aldosterone by an adrenal adenoma

Secondary: spironolactone, an aldosterone receptor-blocking agent can be used

MiscellaneousCorticosteroids and stimulation of lung maturation in the fetus

When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone 12 mg, followed by an additional dose of 12 mg 18-24 hours later, is commonly used

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Select Indications for Glucocorticoids Nonadrenal Disorders

Allergies (seasonal rhinitis) Chronic inflammatory bowel disease Asthma and COPD Edematous states caused by hepatic, neurological and renal

disorders Neoplastic disease Post-transplant surgery Rheumatic diseases Shock Skin disorders (rashes, contact dermatitis, etc.)


Glucocorticoids Many drug-drug interactions

• Hyperglycemic effects may reduce effectiveness of the anti-diabetic agents

• Combining with NSAIDs increase risk for PUD

• Administering with non-potassium-sparing diuretics hypokalemia and hypocalcemia

Glucocorticoid prescribing strategies:

• Use lowest possible dose to achieve therapeutic effect

• Administer every other day to limit adrenal atrophy

• Acute conditions: large amounts for a few days, then gradually decrease the dose until discontinued

• Use inhalation, topical or intra-arterial routes to reduce the possibility of systemic effects

Long-term administration Cushing’s syndrome

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Select GlucocorticoidsAgent Anti-

Inflammatory*Topical* Salt-Retaining* Forms Available

Short- to medium-acting glucocorticoidsHydrocortisone (cortisol) 1 1 1 Oral, injectable, topical

Cortisone 0.8 0 0.8 OralPrednisone 4 0 0.3 OralPrednisolone 5 4 0.3 Oral, injectableMethylprednisolone 5 5 0.25 Oral, injectableIntermediate-acting glucocorticoidsTriamcinolone 5 53 0 Oral, injectable, topical

Long-acting glucocorticoidsBetamethasone 25-40 10 0 Oral, injectable, topical

Dexamethasone 30 10 0 Oral, injectable, topical

MineralocorticoidsFludrocortisone 10 0 250 Oral

* Potency relative to hydrocortisone


Diabetes

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Common Early MorningHyperglycemia Problems

Dawn Phenomenon: results when tissue becomes desensitized to insulin nocturnally – blood glucose becomes progressively elevated throughout the night

Tx: Add or increase the bedtime dose of insulin

Somogyi Effect: nocturnal hypoglycemia develops, stimulating a surge of counter regulatory hormones which raises blood sugar

Tx: Reduce or omit bedtime dose of insulin


BiguanidesIndications: DOC; first line therapy for Type 2 DMAgents: metformin (Glucophage)MOA: decreases hepatic gluconeogenesis, improves insulin

sensitivity, increases glucose utilization by muscle

Adverse

Effects:

nausea, vomiting, diarrhea, decreased appetite, lactic acidosis

Comments: Liver disease: avoid metformin

Contraindicated: renal dysfunction (serum creatinine >1.5 mg/dL (males) or 1.4 mg/dL (females)); monitor serum creatinine

Promotes weight loss

Special instructions for patients who require contrast

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Insulin SecretagoguesIndications: Monotherapy or combination therapy for Type 2 DMAgents: nateglinide (Starlix), repaglinide (Prandin)MOA: stimulates insulin release from pancreasAdverse

Effects:

hypoglycemia, diarrhea, arthralgia, headache, sinusitis, upper respiratory infection

Comments: Liver disease: use with caution

May require dose adjustment for renal dysfunction

Several drug-drug interactions

Rapid onset (given with meals)

Short duration of action (requires TID dosing)

Nonsulfonylureas (Glinides)


Insulin SecretagoguesIndications: Monotherapy or combination therapy for Type 2 DMAgents: chlorpropamide (Diabinese), tolazamide (Tolinase),

tolbutamide (Tol-Tab), glyburide (Diabeta, Micronase), glipizide (Glucotrol), glimepiride (Amaryl)

MOA: stimulates insulin release from pancreas, enhances beta cell sensitivity to glucose

AdverseEffects:

hypoglycemia, nausea, bloating, weight gain, photosensitivity, disulfiram reaction (chlorpropamide)

Comments: Use with caution in liver dysfunctionDose adjustment required for renal dysfunction Several drug-drug interactionsOver time response to therapy may diminishSulfonylureas

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ThiazolidinedionesIndications: Monotherapy or combination therapy for Type 2 DM

Agents: pioglitazone (Actos), rosiglitazone (Avandia)

MOA: increases receptor sensitivity to insulin, decreases both insulin resistance and hepatic gluconeogenesis

AdverseEffects:

hepatotoxicity, weight gain, peripheral edema, rash, macular edema, heart failure exacerbation, increased risk of MI (rosiglitazone)

Comments: Use with caution (if at all) in liver dysfunctionBaseline LFT’s then periodically thereafterSeveral drug-drug interactionsContraindicated in NYHA class III or IVMay increase risk of osteoporosisMay increase risk of bladder cancer (pioglitazone)REMS program (rosiglitazone)


Alpha-glucosidase InhibitorsIndications: Adjunct therapy only for Type 2 DMAgents: acarbose (Precose), miglitol (Glyset)MOA: reduces rate and extent of CHO digestion and

absorptionAdverseEffects:

flatulence, diarrhea, abdominal pain, decrease absorption of iron (anemia)

Comments: Do not use in renal dysfunction (creatinine > 2.0)Baseline LFT’s then periodically thereafter (acarbose)May influence the absorption of other drugsContraindicated in malabsorption, IBD or intestinal obstructionGlucose (dextrose) is recommended for treating hypoglycemia as sucrose metabolism is inhibited

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Glucagon-Like Peptide-1 AgonistsIndications: Monotherapy (exenatide) or combination therapy for Type 2

DM; generally considered as adjunctAgents: exenatide (Byetta), liraglutide (Victoza)MOA: increase insulin release in the presence of elevated glucose

concentrations, decrease glucagon secretion in a glucose-dependent manner and delay gastric emptying

AdverseEffects:

nausea, vomiting, diarrhea, headache, hypoglycemia, pancreatitis, teratogenic, injection site reactions, renal failure, thyroid tumors

Comments: Several drug-drug interactionsContraindicated in severe renal dysfunction (both), h/o pancreatitis (both) or h/o thyroid cancer (liraglutide)Does NOT replace insulinREMS program


Dipeptidyl Peptidase-4 InhibitorsIndications: Monotherapy or combination therapy for Type 2 DM;

generally considered as adjunct therapyAgents: sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin

(Tradjenta)MOA: Inhibit the degradation of GIP and GLP-1Adverse

Effects:

increased risk of infection, headache, hypoglycemia, pancreatitis, hypersensitivity reactions, peripheral edema (saxagliptin)

Comments: Several drug-drug interactions (saxagliptin)

Contraindicated in ESRD (sitagliptin, saxagliptin)

Dose adjustment in renal impairment (sitagliptin, saxagliptin)

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Unit 6 ©2014 Barkley & AssociatesUnit 6 ©2014 Barkley & Associateshttp://casesblog.blogspot.com/2006/11/dpp-4-inhibitors-for-treatment-of.html

GLP-1 and DPP-4 MOA:


Amylin Receptor AgonistsIndications: Adjunct therapy for Type 1 and Type 2 DM

Agents: pramlintide (Symlin)MOA: Inhibit the degradation of GIP and GLP-1AdverseEffects:

abdominal pain, loss of appetite, nausea, vomiting,hypoglycemia, dizziness, headache, cough, fatigue

Comments: Contraindicated in patients with hypoglycemic unawareness or gastroparesisBlack box warning for individuals while drivingSevere hypoglycemia with concurrent insulin or oral hypoglycemic agentWhen initiating pramlintide: reduce dose of any secretagogues; reduce insulin dose by at least 50%

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Sodium Glucose Cotransporter 2 (SGLT2) InhibitorIndications: Type 2 DM; place in therapy currently unclear

Agents: canagliflozin (Invokana)MOA: increases the excretion of urinary glucose

AdverseEffects:

polyuria, UTI, genital mycotic infections, hypovolemia, hyperkalemia, pancreatitis, renal impairment

Comments: Adjust dose in renal impairmentAvoid use in severe liver impairmentCan cause severe hypoglycemiaSafety/effectiveness not established in patients younger than 18 yearsLong-term safety issues (cardiovascular, cancer risk)Role not addressed in recent ADA guidelinesMore clinical trials will better establish their role


Insulin PreparationsInsulin Preparation Onset of Action

(hours)Peak Action

(hours)Duration of Action

(hours)

Rapid-Acting:

Insulin Lispro (Humalog)

5-15 minutes 30-90 minutes < 5Insulin Aspart (NovoLog)

Insulin Glulisine (Apidra)

Short-Acting:

Regular insulin (Humulin R)

0.5-1 2-4 5-7

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Insulin PreparationsInsulin Preparation

Onset of Action(hours)

Peak Action(hours)

Duration of Action(hours)

Intermediate-Acting:

NPH 2-4 4-12 12-18

Long-Acting:

Insulin glargine (Lantus)

1.5 No pronounced

peak

20-24

Insulin detemir (Levemir)

0.8-2 Relatively flat

5.7-23.2


Insulin PreparationsPremixed Insulin Brand Name

NPH/regular (70%/30%) Humulin 70/30Novolin 70/30

Insulin aspart protamine suspension/insulin aspart (70%/30%)

NovoLog Mix 70/30

Insulin lispro protamine suspension/insulin lispro (75%/25%)

Humalog Mix 75/25

Insulin lispro protamine suspension/insulin lispro (50%/50%)

Humalog Mix 50/50

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Unit 6 ©2014 Barkley & AssociatesUnit 6 ©2014 Barkley & Associateshttp://diabetesmanager.pbworks.com/w/page/17680289/Oral%20Pharmacological%20Agents%20for%20Type%202%20Diabetes

Unit 6 ©2014 Barkley & AssociatesUnit 6 ©2014 Barkley & AssociatesKoda-Kimble, Mary Anne. Applied Therapeutics: The Clinical Use of Drugs. 10th. Philadelphia, PA: Lippincott Williams & Wilkins, 2012

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Inzucchi SE, Bergenstal RM, Buse JB, et al.; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379


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The Endocrine System - npcourses.com Handout Samples/Advanced... · Advanced Pharmacology: ... Acts in the kidney collecting duct cells to decrease the excretion ... Increased level