concentrated urine despite adequate levels of ADH.)
Antidiuretic Hormone Preparations
Two preparations with ADH activity are available: vasopressin [Vasostrict] and desmopressin [DDAVP, Stimate]. Vasopressin is identical in structure to naturally occurring ADH; desmopres-sin is a structural analog of natural ADH. The preparations differ with respect to route of administration, duration of action, and therapeutic applications (Table 59.2). They also differ in their ability to cause vasoconstriction.
Clinical Pharmacology
Adverse Effects
Water Intoxication. Excessive water retention can cause water intoxication. Early signs include drowsiness, listlessness, and headache. Severe intoxication progresses to convulsions and terminal coma. Patients experiencing early symptoms should notify their prescriber. Treatment includes diuretic therapy and restriction of fluid intake.
A major cause of intoxication is failure to reduce water intake once ADH therapy has begun. Because treatment prevents continued fluid loss, failure to decrease fluid intake will result in water buildup. Hence, at the onset of treatment, patients should be instructed to reduce their accustomed intake of fluid.
The risk of water intoxication is also increased by renal impairment. Accordingly, if creatinine clearance is below 50 mL/
min, ADH should not be used.
Physiology
Actions
ADH promotes renal conservation of water through action on the collecting ducts of the kidney to increase their permeability to water. This results in increased water reabsorption. Because water is withdrawn from the tubular urine (back into the extracellular space), urine that entered the collecting ducts in a relatively dilute state becomes highly concentrated by the time it leaves.
In addition to its renal actions, ADH can stimulate contrac-tion of vascular smooth muscle and smooth muscle of the GI tract. Because of its ability to cause vasoconstriction, ADH is also known as vasopressin. It should be noted that the plasma levels of ADH required to cause smooth muscle contraction are higher than those that occur physiologically.
Production, Storage, and Release
ADH is produced in neurosecretory cells of the hypothalamus, transported down their axons, and then stored in their terminals until released. Release is regulated by the hypothalamus—the brain center responsible for maintaining body fluids at their proper osmolality. When the hypothalamus senses that osmolal-ity has risen too high, it instructs the posterior pituitary to release ADH. The resultant increase in water reabsorption dilutes body fluids, causing osmolality to decline. Release of ADH can also be stimulated by hypotension and by reduced plasma volume.
Pathophysiology: Hypothalamic Diabetes Insipidus
Hypothalamic diabetes insipidus is a syndrome caused by partial or complete deficiency of ADH. The syndrome is characterized by polydipsia (excessive thirst) and excretion of large volumes
Drug Routes
Duration of
Antidiuretic Action (hr) Therapeutic Uses Usual Maintenance Dosage Desmopressin
[DDAVP, Stimate]
Intranasal, subQ, IV, PO
8–20 Diabetes insipidus Adults: 0.1–0.4 mL (10–40 mcg) intranasally 1–3 times/day or 0.25–0.5 mL subQ or IV twice daily or 0.1–1.2 mg PO daily in 2 or 3 doses
Children: 0.05–0.3 mL intranasally daily either as a single dose or in 2 doses Nocturnal enuresis 0.2–0.6 mg PO at bedtime (intranasal therapy
of enuresis is contraindicated)
Hemophilia See Chapter 54
Vasopressin
[Vasostrict] IM, subQa 2–8 Diabetes insipidus Adults: 5–10 units IM or subQ 2–3 times/day
Children: 2.5–10 units IM or subQ 2–3 times/day
Postoperative abdominal
distention 5 units IM initially; then 10 units IM every 3–4 hr
Abdominal radiography
(to dispel gas shadows) 10 units 2 hr before and again 30 min before the procedure
Cardiac resuscitation 40 units TABLE 59.2 ■ ADH Preparations
aSometimes administered intranasally or IV.
CHAPTER 59 Drugs Related to Hypothalamic and Pituitary Function
Conivaptan
Conivaptan [Vaprisol] is indicated for short-term IV therapy of hyponatremia in euvolemic and hypervolemic hospitalized patients. In patients with euvolemic or hypervolemic hyponatremia, levels of circulating vasopressin are usually high, causing retention of water by the kidney. Conivaptan blocks vasopressin V2 receptors in renal collecting ducts and thereby promotes “aquaresis” (renal excretion of free water), leaving sodium behind for reabsorption into the blood. As a result, the concentration of sodium in blood rises, thereby correcting the hyponatremia.
The most common adverse effects are infusion-site reactions. Other common reactions include hypokalemia, orthostatic hypotension, headache, fever, constipation, diarrhea, and vomiting. If blood sodium rises too rapidly (more than 12 mEq/L/24 hr), neurons can undergo osmotic demyelination, resulting in serious neurologic deficits (e.g., difficulty swallowing, inability to speak, affective changes, seizures, coma, and death). Accordingly, blood sodium should be monitored often and, if the rise is too fast, conivaptan should be interrupted.
Conivaptan is both a substrate for and inhibitor of CYP3A4 (the 3A4 isoenzyme of cytochrome P450). Accordingly, the drug must not be combined with strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, ritonavir), owing to a risk of conivaptan toxicity. Combined use with drugs that are substrates for CYP3A4 should be done with caution.
Conivaptan is supplied in solution (0.2 mg/mL) for IV administration.
Dosing consists of an initial loading dose (20 mg over 30 minutes) followed by a continuous infusion (20 mg over 24 hours). A maximum of three additional infusions (20 or 40 mg over 24 hours each) may be done as needed.
DRUGS FOR ACROMEGALY
As discussed earlier, acromegaly results from excessive production of GH by a pituitary tumor, and can be treated with three modalities: surgical excision of the pituitary, irradiation of the pituitary, and drug therapy. As a rule, drugs are reserved for patients who did not respond adequately to surgery and/or radiation, or for whom these modalities are not options. Two types of drugs are available: somatostatin analogs and GH receptor antagonists. Drug therapy is both prolonged and expensive.
Somatostatin Analogs
The somatostatin analogs—octreotide, pasireotide, and lanreotide—are our most effective drugs for suppressing GH release. Benefits derive from mimicking the suppressant actions of somatostatin on the pituitary (see Fig. 59.3). The somatostatin analogs can be used as primary therapy for acromegaly or as an adjunct to surgery and/or radiation. In both cases, the objective is to normalize levels of GH and IGF-1.
Octreotide is available in two formulations: an immediate-release product, sold as Sandostatin, and a sustained-release product, sold as Sandostatin LAR Depot. Sandostatin is available in solution for IM injection (50, 100, 200, 500, and 1000 mcg/mL) and Sandostatin LAR Depot is available in depot injections (10, 20, and 30 mg). The usual maintenance dosage is 100 mcg subQ 3 times a day (for Sandostatin) or 10 to 30 mg IM once a month (for Sandostatin LAR Depot). Gastrointestinal side effects (nausea, cramps, diarrhea, flatulence) are common initially, but subside in 1 to 2 weeks. Within a year, cholesterol gallstones develop in about 25% of patients, although they are usually asymptomatic.
Pasireotide [Signifor LAR] is supplied in 20-, 40-, and 60-mg vials of powder to be reconstituted for IM injection every 4 weeks. Doses start at 40 mg and can be titrated to effect. The most common side effects are diarrhea and hyperglycemia. Signifor may also cause QT prolongation and bradycardia.
Therapeutic Uses
Diabetes Insipidus. Diabetes insipidus may be treated with either desmopressin or vasopressin. However, desmopressin is the agent of choice because it has a long duration of action, is easy to administer (by mouth or intranasal spray), and lacks significant side effects, especially vasoconstriction. The response to treatment is rapid, and urine volume quickly drops to normal.
Because desmopressin is expensive and because excessive dosing can result in water intoxication, the smallest effective dosage should be employed.
Cardiac Arrest. For patients in cardiac arrest, vasopressin can be used to enhance cardiopulmonary resuscitation (CPR).
Benefits derive from vasopressin-induced vasoconstriction, which, in people receiving CPR, increases blood flow to the heart and brain, improves neurologic outcome, and increases the chances of successful resuscitation.
Other Uses. Vasopressin is indicated for postoperative abdominal disten-tion and preparadisten-tion for abdominal radiography. Desmopressin is indicated for nocturnal enuresis (bedwetting), hemophilia A, and von Willebrand’s disease. The drug decreases enuresis by reducing urine production, and helps patients with hemophilia A and von Willebrand’s disease by promoting the release of clotting factor VIII (see Chapter 54).
ANTIDIURETIC HORMONE (VASOPRESSIN) ANTAGONISTS
Antidiuretic hormone antagonists, also known as vasopressin antagonists, block the effects of ADH (vasopressin) in renal collecting ducts. By doing so, they increase the excretion of free water. Two vasopressin antagonists are available: conivaptan and tolvaptan. These drugs, also known as vaptans, have only one indication: treatment of hyponatremia in euvolemic or hyper-volemic patients. The principal difference between the two drugs concerns route of administration: conivaptan is administered IV, whereas tolvaptan is administered PO (Table 59.3).
Safety Alert
CARDIOVASCULAR EFFECTS OF VASOPRESSIN
Because of its powerful vasoconstrictor actions, vasopressin can cause severe adverse cardiovascular effects. (Desmopressin is a weak pressor agent, and hence does not adversely affect hemodynamics.) By constricting arteries of the heart, vasopressin can cause angina pectoris and even myocardial infarction—
especially in patients with coronary insufficiency. In addition, vasopressin may cause gangrene by decreasing blood flow in the periphery. Because it can reduce cardiac perfusion, vasopres-sin must be used with extreme caution in patients with coronary artery disease.
Drug Indications Adverse Effects Availability and Usual Adult Dosage
Conivaptan
[Vaprisol] Euvolemic and hypervolemic
hyponatremia Infusion site reactions, hypokalemia,
orthostatic hypotension IV: 20-mg loading dose followed by a 20-mg infusion over 24 hr. May repeat 24-hr infusion × 3.
Tolvaptan
[Samsca] Euvolemic and hypervolemic
hyponatremia Thirst, dry mouth, polyuria Tablets: Start 15 mg every 24 hr. May increase to 60 mg every 24 hr if tolerated.
TABLE 59.3 ■ Vasopressin Antagonists
symptoms and normalized IGF-1 levels in nearly all patients (97%). Pegvisomant is generally well tolerated. The most common side effects are injection-site reactions, nausea, diarrhea, chest pain, and flu-like symptoms. In a few patients, serum levels of hepatic transaminases rise, indicating liver injury. Monitoring of hepatic function is recommended. The only known drug interaction is an apparent reduction in pegvisomant effects by opioid analgesics. Why this occurs is a mystery. Pegvisomant is available as a powder (10, 15, and 20 mg) that must be reconstituted with sterile water before use. Administration is by subQ injection. Treatment consists of an initial 40-mg loading dose (given by the prescriber), followed by 10-mg doses injected once daily by the patient.
Every 4 to 6 weeks, the level of IGF-1 is measured, and dosage is increased by 5 mg (if the IGF-1 level is still above normal) or decreased by 5 mg (if the IGF-1 level is below normal). Treatment should continue indefinitely.
Lanreotide [Somatuline Depot] is supplied in single-use, pre-filled syringes (60, 90, and 120 mg) for deep subQ injection into the buttocks. Dosages range from 60 to 120 mg every 4 weeks. The most common side effect is diarrhea;
other common reactions include gallstones, bradycardia, injection-site reactions, and hypo- or hyperglycemia.
Pegvisomant, a Growth Hormone Receptor Antagonist
Pegvisomant [Somavert], a GH receptor antagonist, may be our most effective drug for acromegaly. The goal of therapy is to normalize serum levels of IGF-1. In clinical trials, treatment for 12 months or longer greatly reduced
KEY POINTS
■ Release of hormones from the anterior pituitary is stimulated by releasing factors from the hypothalamus and inhibited by negative feedback loops.
■ The growth-promoting actions of growth hormone (GH) are mediated by insulin-like growth factor-1 (IGF-1).
■ Pediatric GH deficiency causes short stature.
■ Adult GH deficiency causes reduced muscle mass, reduced exercise capacity, increased mortality from cardiovascular causes, and impaired psychosocial function.
■ Pediatric GH excess causes gigantism.
■ Adult GH excess causes acromegaly.
■ Among pediatric patients, GH is approved for growth promotion in children who are GH deficient and in children who are very short despite having normal GH levels.
■ Exogenous glucocorticoids can inhibit responses to GH.
■ GH can elevate glucose levels in patients with diabetes.
■ Acromegaly can be treated with three drugs: pegvisomant (a GH receptor antagonist) and two analogs of somatostatin—
octreotide and lanreotide—that suppress GH release.
■ Prolactin stimulates milk production after delivery.
■ Excessive production of prolactin can be suppressed with cabergoline and bromocriptine, drugs that mimic the inhibitory action of hypothalamic dopamine on the pituitary.
■ Antidiuretic hormone (ADH) acts on the kidney to cause reabsorption (conservation) of water.
■ ADH deficiency results in hypothalamic diabetes insipidus.
■ Hypothalamic diabetes insipidus can be treated by replace-ment therapy with desmopressin, a synthetic form of ADH.
■ When initiating ADH replacement therapy, warn the patient to decrease water intake, because failure to do so can cause water intoxication.
■ Vasopressin, a drug identical to natural ADH, can cause profound vasoconstriction.
■ By promoting vasoconstriction, vasopressin can be lifesav-ing in patients with cardiac arrest.
Please visit http://evolve.elsevier.com/Lehne for chapter-specific NCLEX® examination review questions.
Summary of Major Nursing Implications
aSOMATROPIN (HUMAN GROWTH HORMONE) The nursing implications here apply only to the use of GH in pediatric patients.
Preadministration Assessment Therapeutic Goal
Normalization of growth and development in children with (1) proven GH deficiency and (2) very short stature despite normal GH levels.
Baseline Data
Assess developmental status (height, weight, etc.) and obtain laboratory data on thyroid function and GH levels.
Identifying High-Risk Patients
GH is contraindicated during and after epiphyseal closure, and in children with PWS who are severely obese or have severe respiratory impairment.
Use with caution in children with diabetes mellitus and hypothyroidism.
Implementation: Administration Routes
SubQ (preferred) or IM.
Administration
Provide the following administration instructions:
• For powdered preparations, reconstitute with the appropri-ate volume of diluent. Mix gently; do not shake.
• Do not inject if the preparation is cloudy or contains particulate matter.
• Rotate the injection site to avoid localized tissue atrophy.
Ongoing Evaluation and Interventions Evaluating Treatment
Monitor height and weight monthly. Continue therapy until a satisfactory adult height has been achieved, until epiphyseal closure occurs, or until a response can no longer be elicited (usually by age 20 to 24).
CHAPTER 59 Drugs Related to Hypothalamic and Pituitary Function
aPatient education information is highlighted as blue text.
If no stimulation of growth occurs, discontinue treatment and re-evaluate the diagnosis of GH deficiency.
Minimizing Adverse Effects and Interactions
Hyperglycemia. GH can elevate plasma glucose levels in diabetics. Increase insulin dosage as needed.
Hypothyroidism. GH may suppress thyroid function.
Assess thyroid function before treatment and periodically thereafter. If levels of thyroid hormone fall, institute replace-ment therapy.
Fatality in PWS Patients. Owing to a risk of death, do not give GH to pediatric patients with PWS who are severely obese or who have severe respiratory impairment.
Interaction With Glucocorticoids. Glucocorticoids can oppose the growth-stimulating effects of GH. Carefully adjust glucocorticoid replacement dosage to avoid growth inhibition.
Neutralizing Antibodies. Antibodies that neutralize exogenous GH can develop over the course of treatment. If this happens, mecasermin (recombinant IGF-1) may be an effective alternative to GH.
ANTIDIURETIC HORMONE Desmopressin
Vasopressin
The nursing implications here apply only to the use of ADH preparations for hypothalamic diabetes insipidus.
Preadministration Assessment Therapeutic Goal
Normalization of urinary water excretion in patients with hypothalamic diabetes insipidus.
Baseline Data
Determine creatinine clearance and fluid and electrolyte status.
Identifying High-Risk Patients
Use vasopressin with caution in patients with coronary artery disease and other vascular diseases.
Implementation: Administration Routes
Desmopressin. Intranasal, PO, subQ, IV.
Vasopressin. IM, subQ.
Administration
Teach the patient the technique for intranasal administration.
To promote adherence, make certain the patient understands that treatment is lifelong.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
Teach the patient to monitor and record daily intake and output of fluid. If ADH dosage is correct, urine volume should rapidly drop to normal.
Minimizing Adverse Effects
Water Intoxication. Excessive retention of water can produce water intoxication—most often at the beginning of therapy. Instruct patients to decrease their accustomed fluid intake at the start of treatment. Inform patients about early signs of water intoxication (drowsiness, listlessness, headache), and instruct them to notify the prescriber if these occur.
Treatment includes fluid restriction and diuretic therapy. Avoid ADH in patients with creatinine clearance below 50 mL/min.
Cardiovascular Effects. Vasopressin, but not desmopres-sin, is a powerful vasoconstrictor. Excessive vasoconstriction can produce angina pectoris, myocardial infarction, and gangrene (from extravasation of IV vasopressin). Use vaso-pressin with caution, especially in patients with coronary insufficiency.
Summary of Major Nursing Implications
a—cont’d
60 Drugs for Disorders of the Adrenal Cortex
Physiology of the Adrenocortical Hormones, p. 732