Module 9 - Endocrine Drugs
N609

Type 1 diabetes mellitus (DM) (formerly known as insulin-dependent diabetes mellitus)
Type 2 DM (formerly known as non-insulin-dependent diabetes mellitus)
Gestational DM
Diabetes secondary to other conditions (e.g., hormonal abnormalities and pancreatic diseases)

Type 1 diabetes is thought to be an autoimmune disease in which pancreatic beta cells are destroyed.
In type 2 diabetes, adipose and muscle cells become less sensitive to the actions of insulin or the pancreas produces less insulin than the body needs. In either situation, glucose levels in the blood escalate.
In gestational diabetes, pregnancy causes the woman to become intolerant to glucose.

Family history of diabetes
Obesity; sedentary lifestyle
Race/ethnicity; age older than 45 years
Previously identified as having IFG
Hypertension
HDL <35 mg/dL or triglyceride level >250 mg/dL
History of gestational DM or delivery of babies >9 lb

Insulin resistance
Impaired insulin secretion
Elevated glucose production by the liver
Or all these components

Polyuria (excessive urination)
Polydipsia (increased thirst)
Weight loss
Polyphagia (increased hunger and caloric intake)
Blurred vision

A practitioner is caring for a patient who is diagnosed with prediabetes. What is the HbA1c range that denotes this impaired glucose metabolism?
A. 4% to 5.6%
B. 5.7% to 6.4%
C. 6.6% to 7%
D. >7%

B. 5.7% to 6.4%
Rationale: Impaired glucose metabolism (prediabetes) range is HbA1c 5.7% to 6.4%. Normoglycemia is HbA1c 4% to 5.6%, and DM is HbA1c >=6.5%.

Self-monitoring blood glucose (SMBG)
Medical nutrition therapy; regular exercise
Drug therapy individualized for each patient
Oral glucose-lowering agents for some type 2 patients
Instruction in the prevention and treatment of acute and chronic complications, including hypoglycemia
Continuing patient education and support
Periodic assessment of treatment goals

American Diabetes Association (ADA): HBA1c <7.0%.
American Association of Clinical Endocrinologist (AACE): HBA1c <=6.5%
Both ADA and AACE
Preprandial plasma glucose level 80 to 130 mg/dL
Postprandial plasma glucose level <180 mg/dL
Blood pressure: <140/90 mm Hg

Low-density lipoprotein (LDL) level <100 mg/dL-no overt CVD
Low-density lipoprotein (LDL) level <70 mg/dL-overt CVD
Triglyceride level <150 mg/dL
HDL level >40 mg/dL (men)
HDL level >50 (women)
Microalbumin (random collection) <30 mcg/mL creatinine

Degree of hyperglycemia and the presence or absence of symptoms
Presence of comorbidity
Patient motivation
Patient preference

Tolbutamide (Orinase): 0.25 to 3 g in one or two divided doses
Chlorpropamide (Diabinese): 100 to 750 mg QD
Tolazamide (Tolinase): initially 100 to 250 mg QD; increase weekly by 100 to 250 mg/d until desired blood glucose
Glyburide (DiaBeta, Micronase): initially 2.5 to 5 mg QD; increase by 2.5 mg/wk until desired blood glucose
Glyburide, micronized (Glynase): initially 1.5 to 3 mg QD; 0.75 mg in elderly

Glipizide (Glucotrol): initially 5 mg QD (2.5 mg in elderly); increase weekly to a maximum of 40 mg/d to desired blood glucose
Glimepiride (Amaryl): initially 1 to 2 mg with breakfast; increase by 2 mg/wk until desired blood glucose

Metformin (Glucophage): initially 500 mg BID; increase by 500 mg/wk until desired blood glucose

Thiazolidinediones
Rosiglitazone (Avandia): initially 4 mg/d in single dose; if response is inadequate after 12 weeks, increase to 8 mg/d in single dose
Pioglitazone (Actos): 15 to 30 mg/d; Maximum 45 mg/d as monotherapy and 30 mg/d as combined therapy
-Glucosidase inhibitors
Acarbose (Precose) and Meglitinide analogs: initially 25 mg TID with the first bite of a meal increase by 25 mg at 4- to 8-week intervals to a maximum of 300 mg

Repaglinide (Prandin): initially 0.5 mg with two to four meals daily if patient has never received other treatment for diabetes; if previous treatment, 1 to 2 mg with two to four meals daily; double dose weekly to a maximum of 16 mg/d
Nateglinide (Starlix): initially 120 mg before each meal to a maximum dose of 360 mg/d

Dipeptidyl peptidase-4 inhibitors
Sitagliptin (Januvia): 100 mg oral daily or 50 mg PO QD
Saxagliptin (Onglyza): 2.5 or 5 mg QD
Alogliptin (Nesina): 6.25 ng, 12.5 mg, or 25 mg QD
Linagliptin ( Tradjenta): 2.5 or 5 mg QD
Vildagliptin (Galvus): 50 or 100 mg QD

This class is approved for treatment of type 2 diabetes in adults. Liraglutide has the indication for treatment of adolescents over the age of 10

Dopamine receptor agonists are used as monotherapy in type 2 diabetes or secondary diabetes with substantial capacity for insulin production.
The mechanism by which dopamine receptor agonists improves glycemic control is unknown but it is theorized to be related to improved insulin sensitivity.
Following morning administration of bromocriptine mesylate (Cycloset), postprandial glucose levels are improved without increasing plasma insulin concentrations.

This class of medications binds to bile acids in the intestine thus preventing reabsorption.
As the bile acid pool is reduced, hepatic enzymes convert circulating cholesterol to bile acids, thereby upregulating hepatic LDL receptors and clearance of LDL-C from circulation.

A recombinant form of amylin is pramlintide (Symlin). This is an injectable agent that is a synthetic of the pancreatic neurohormone amylin, which is cosecreted with insulin from beta cells in response to food.
Pramlintide has three actions as an amylinomimetic agent. First, it helps to delay gastric emptying into the small intestine, which delays the rise in postprandial glucose release.
This effect lasts for approximately 3 hours and does not alter nutrient absorption. Second, pramlintide alters the release of additional inappropriate glucagon by pancreatic alpha cells. Finally, there is an increase in satiety, which decreases the total calorie intake and promotes weight loss.
Pramlintide is approved for use in adults with type 1 or type 2 diabetes. It is also approved for use with insulin.

Canagliflozin (Invokana): 100 or 300 mg QD
Dapagliflozin (Farxiga): 5 or 10 mg QD
Empagliflozin (Jardiance): 10 or 25 mg QD
Ipragliflozin (Suglat): 25, 50, or 100 mg QD

A practitioner is prescribing a sulfonylurea for a patient with diabetes. Which drug belongs to this category of antidiabetic agents?
A. Rosiglitazone
B. Acarbose
C. Repaglinide
D. Tolbutamide

D. Tolbutamide
Rationale: Tolbutamide is a sulfonylurea; rosiglitazone is a thiazolidinedione, acarbose is an -glucosidase inhibitor, and repaglinide is a meglitinide analog.

Very rapid acting
Short acting
Intermediate acting
Long acting
Combination
Inhaled rapid acting insulin

A practitioner is initiating second-line therapy for a patient with type 2 diabetes. What are the agents of choice?
A. Long-acting insulin along with short-acting insulin
B. SGLT-2, TZD, and SU/GLN
C. Monotherapy with an oral agent: biguanides, GLP-1, DPP4-i, and AG-i
D. Combination of an intermediate- and short-acting insulin

B. SGLT-2, TZD, and SU/GLN
Rationale: The second-line therapy for a patient with type 2 diabetes is SGLT-2, TZD, and SU/GLN. Sulfonylureas are the best choice if the patient is thin, older than age 40, has had diabetes for <5 years, and has a blood glucose >250 mg/dL. Glyburide is most effective in patients with fasting hypoglycemia, and glipizide is most effective in patients with postprandial hyperglycemia.

Pediatric/Adolescent
Geriatric
Pregnancy
Selecting the most appropriate agent
Patient education
Drug information
Nutritional and lifestyle changes
Complementary and alternative medicine

Diabetes mellitus is the term used to represent a clinically and genetically heterogeneous group of disorders characterized by abnormally high blood glucose levels (hyperglycemia) as a result of either insulin deficiency or cellular resistance to the action of insulin.
Diabetes was the seventh leading cause of death in the United States in 2006.

Physical examination may reveal thyromegaly, bradycardia, or peripheral edema.
Total cholesterol and low-density lipoprotein (LDL) levels may be elevated in 90% to 95% of patients.
Hypothyroidism nearly always results from a problem with the production or release (or both) of thyroid hormones.
Worldwide, iodine deficiency is most commonly the cause.

Primary hypothyroidism is confirmed by the finding of an elevated thyroid stimulating hormone (TSH) and a low free T4 level.
Secondary hypothyroidism, as a result of pituitary dysfunction, results in low free T4 and low TSH levels.
Tertiary hypothyroidism results from decreased production of thyroid releasing hormone (TRH) by the hypothalamus.
Secondary hypothyroidism can be distinguished from tertiary hypothyroidism by imaging of the pituitary and hypothalamus.

Goals of Drug Therapy
Restore thyroid hormones to normal levels
Relieve signs and symptoms of hypothyroidism
Prevent complications and long-term sequelae of hypothyroidism
Prevent neurological and developmental deficits in newborns and children

Exogenous thyroid hormone, whether synthetic or animal-derived, has the same action as endogenous thyroid hormone. It binds to thyroid receptors on cell nuclei to exert metabolic effect in tissues.
Mechanism of action
Dosage and administration
Time frame for response
Contraindications
Adverse drug reactions

A practitioner is prescribing Synthroid for a patient with hypothyroidism. What is the recommended starting dosage for this drug?
A. 75 to 150 mcg/d
B. 25 to 75 mcg/d
C. 12.5 to 100 mcg/d
D. 60 to 120 mcg/d

C. 12.5 to 100 mcg/d
Rationale: For levothyroxine (Synthroid, others), the start dosage is 12.5 to 100 mcg/d, and the maintenance dosage is 75 to 150 mcg/d.

Levothyroxine (LT4) remains the gold standard of therapy to treat hypothyroidism.

When left untreated chronically, hypothyroidism can advance to a decompensated condition known as myxedema coma, in which patients experience hypothermia, central nervous system (CNS) depression, respiratory depression, cardiovascular instability, electrolyte imbalances, delirium, and even coma.
It is a life-threatening condition

Patients with primary hypothyroidism most likely will require lifelong replacement with thyroid hormone.
Patients should not expect to see a difference in their symptoms until 2 to 4 weeks after beginning therapy.
Follow-up laboratory testing is necessary relatively frequently until a therapeutic dosage that results in a stable TSH is reached; at that point, testing should be done annually.
Patients on thyroid hormone replacement therapy should limit the use of adrenergic agents.

Results from the presence of an excess amount of thyroid hormone(s).
May result in thyrotoxicosis, a term that refers to the effect of inappropriately high thyroid hormone levels on tissues.
Graves disease, an autoimmune disease that occurs most commonly in patients ages 20 to 50 with a female-to-male ratio of 4 to 8:1, is the most common cause of overt hyperthyroidism.

Thyrotoxicosis associated with a normal or elevated radioiodine uptake over the neck
Graves disease
Toxic adenoma or toxic multinodular goiter
Trophoblastic disease
TSH-producing pituitary adenomas
Resistance to thyroid hormone (T3 [triiodothyronine] receptor mutation)

Thyrotoxicosis associated with a near-absent radioiodine uptake over the neck
Painless (silent) thyroiditis; amiodarone-induced thyroiditis
Subacute or acute thyroiditis
Iatrogenic thyrotoxicosis, struma ovarii
Factitious ingestion of thyroid hormone
Extensive metastases from follicular thyroid cancer

Symptoms of enhanced metabolic activity (i.e., palpitations, sweating, heat intolerance, weight loss).
Examination may reveal elevated blood pressure, tachycardia, a bruit over the thyroid gland, or exophthalmos in patients with Graves disease.
The diagnosis is confirmed by finding a low, or suppressed, TSH level with an elevated free T4 level.

First line: radioactive iodine
Usually recommended in patients older than age 40 but may be used for younger patients
Second line: antithyroid drugs
Often used in younger patients to induce remission of Graves disease
Third line: surgery
Usually reserved for patients with large goiters or suspected malignancy

A practitioner is treating a patient newly diagnosed with hyperthyroidism. What is the recommended first-line treatment?
A. Radioactive iodine
B. Synthroid
C. Antithyroid drugs
D. Surgery

A. Radioactive iodine
Rationale: Radioactive iodine is usually recommended in patients older than age 40 but may be used for younger patients with hyperthyroidism. Antithyroid drugs are the recommended second line of treatment, and surgery is the third line. Synthroid is used to treat hypothyroidism.

Reduce thyroid hormone to normal levels to achieve euthyroid state
Relieve signs and symptoms of hyperthyroidism
Prevent long-term complications of hyperthyroidism

Two antithyroid drugs (ATD) are available in the United States: methimazole (MMI) and propylthiouracil (PTU). They are most commonly used as first-line therapy for hyperthyroidism of Graves disease.
Thyroid hormones will usually drop after 2 to 3 weeks of therapy, and most patients will be euthyroid by 6 weeks.

Beta blockers
Iodine compounds
Treatment of ophthalmopathy of Graves disease

What is the correct starting dosage of methimazole (Tapazole) for treating hyperthyroidism?
A. 100 to 600 mg/d
B. 15 to 30 mg/d
C. 80 to 160 mg/d
D. 900 to 1,200 mg/d

B. 15 to 30 mg/d
Rationale: When using methimazole (Tapazole), the starting dose is 15 to 30 mg/d, and the maintenance dose is 5 to 15 mg/d.

Common (1%-5%)
Urticaria or other rash
Arthralgia
Fever
Transient granulocytopenia
Uncommon (<1%)
Gastrointestinal (GI) upset
Abnormalities of taste and smell

Uncommon (<1%) (cont.)
Arthritis
Rare (0.2%-0.5%)
Agranulocytosis
Very rare (<0.1%)
Aplastic anemia
Thrombocytopenia
Toxic hepatitis (PTU)
Cholestatic hepatitis (methimazole)

Very rare (<0.1%) (cont.)
Vasculitis, systemic lupus-like syndrome
Hypoprothrombinemia (PTU)
Hypoglycemia (due to anti-insulin antibodies) (methimazole)

Thyroid storm is a life-threatening condition that results from severe thyrotoxicosis (Idrose, 2015).
Triggers include infection, trauma, thyroidectomy, radioactive iodine treatment, and abrupt discontinuation of anti-thyroid medications.
The clinical presentation of thyroid storm includes signs and symptoms seen in hyperthyroidism but intensified, and can include high fever, tachycardia, atrial fibrillation, tachypnea, agitation, delirium, GI disturbances, and even seizure or coma. Treatment is aggressive and requires admission to the ICU.

Hyperparathyroidism presents as hypercalcemia as a result of overproduction of parathyroid hormone (PTH).
Primary hyperparathyroidism occurs when there is a pathophysiologic process with the parathyroid gland itself. It is most caused by a single benign adenoma on one of the parathyroid glands which leads the gland to become overactive and overproduce PTH.

The goals of therapy in managing primary hyperparathyroidism are:
Restore calcium levels to normal range
Resolve symptoms of hypercalcemia
Prevent complications of bone disease and nephrolithiasis

Occurs postpregnancy, and occasionally after an URI.
This condition is usually self-limited, so treatment is indicated only to relieve the symptoms of hyperthyroidism.
Symptoms may mimic postpartum depression.
Beta-blockers are the treatment of choice.

Population-based studies have found that hypothyroidism exists to some degree in 4.6% to 9.5% of individuals, with higher rates occurring in the elderly.
Studies found a 1.2% to 2.2% rate of hyperthyroidism.
Both hypothyroidism and hyperthyroidism have been associated with adverse cardiovascular outcomes.
If these conditions are not treated properly, their morbidity can be high. Therefore, clinicians should understand the therapeutic options for these conditions.