PITUITARY AGENTS. THYROID
AND ANTITHYROID AGENTS. ANTIDIABETIC AGENTS.
The control
of metabolism, growth, and reproduction is mediated by a combination of neural
and endocrine systems located in the hypothalamus and pituitary gland. The pituitary
weighs about
The posterior lobe hormones are synthesized in
the hypothalamus and transported via the neurosecretory fibers in the stalk of
the pituitary to the posterior lobe, from which they are released into the
circulation.
Hypothalamic
and pituitary hormones (and their synthetic analogs) have pharmacologic
applications in three areas: (1) as replacement therapy for hormone deficiency
states; (2) as drug therapy and (3) as diagnostic tools for performing stimulation
tests.
Hypothalamic & Anterior Pituitary Hormones
Hypothalamic
regulatory hormones include growth hormone-releasing hormone (GHRH); a growth
hormone-inhibiting hormone (somatostatin); thyrotropin-releasing hormone (TRH);
corticotropinreleasing hormone (CRH); gonadotropin-releasing hormone (GnRH),
also called luteinizing hormone-releasing hormone (LHRH); and
prolactin-inhibiting hormone (dopamine).
Anterior
pituitary hormones include growth hormone (GH), thyrotropin (TSH),
follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL),
and adrenocorticotropin (ACTH). Another peptide, -lipotropin ( -LPH), is
derived from the same prohormone, proopiomelanocortin, as ACTH. -LPH is
secreted from the pituitary (along with ACTH), and is a precursor of the opioid
peptide –endorphin.
Mechanisms of Hormone Action
The
hypothalamic and pituitary hormones are all peptides that exert their effects
by binding to target cell surface membrane receptors with high specificity and
affinity.
Acronyms
ACTH: Adrenocorticotropic
hormone
CRH: Corticotropin-releasing
hormone
FSH: Follicle-stimulating
hormone
GHBP: Growth
hormone-binding protein
GHRH: Growth
hormone-releasing hormone
GnRH: Gonadotropin-releasing
hormone
GRH: Growth
hormone-releasing hormone
IGF-I, -II: Insulin-like
growth factor -I, -II
LH: Luteinizing
hormone
LHRH: Luteinizing
hormone-releasing hormone
-LPH: -Lipotropin
PRL: Prolactin
rbGH: Recombinant
bovine growth hormone
rhGH: Recombinant
human growth hormone
rhTSH: Recombinant
human thyroid-stimulating hormone
SRIH: Somatotropin
release-inhibiting hormone (somatostatin)
TRH: Thyrotropin-releasing
hormone
TSH: Thyroid-stimulating
hormone (thyrotropin)
GHRH, Somatostatin, TRH, TSH, CRH, ACTH, GnRH, FSH, LH, & Dopamine
The receptors
for these hormones are typical seven-transmembrane-domain serpentine peptides.
Each hormone acts as a ligand within a receptor
pocket,
inducing conformational activating changes in the receptor. The conformational
changes in the receptor's intracellular third loop and carboxyl terminal tail
activate an adjacent intracellular G protein. The G14 protein is associated
with the receptors for GnRH and TRH, Gi with the dopamine receptor, and Gs
protein with the receptors for the other hormones listed above.
GHRH, CRH, GnRH, TSH, ACTH, FSH,
LH, and Dopamine
The G
protein-GTP complexes related to receptors for these hormones activate adenylyl
cyclase, which synthesizes the second messenger cAMP. Cyclic AMP activates
protein kinases, which phosphorylate certain intracellular proteins (eg,
enzymes), thus producing the hormonal effect. Conversely, dopamine binding to
lactotroph receptors causes conformational changes in its Gi protein that
reduce the activity of adenylyl cyclase and inhibit the secretion of prolactin.
Somatostatin
The -GTP
complexes related to somatostatin receptors exert effects on potassium
channels, thereby inhibiting GH secretion.
Thyrotropin-Releasing Hormone
The G protein
complexes related to thyrotrophs' TRH receptors affect
phosphoinositide-specific phospholipase C, which increases intracellular
cytoplasmic free calcium, thereby stimulating TSH secretion.
Growth Hormone & Prolactin
The receptors
for both GH and PRL consist of similar single peptides. The two types of
receptors have extracellular amino terminal hormone-binding domains. Both
receptors pass through the cell membrane, where an intracellular carboxyl
terminal sequence activates a tyrosine kinase, JAK2, causing phosphorylation on
tyrosines of intracellular proteins and gene regulation. Fragments of GH
receptors circulate in plasma (GH binding protein, GHBP), binding about 50% of
the circulating growth hormone.
Growth Hormone-Releasing Hormone (GHRH) & Growth Hormone-Releasing
Peptides (GHRPS)
Growth
hormone-releasing hormone is a peptide hormone found in the hypothalamus that
stimulates synthesis and release of growth hormone (GH) from the pituitary. It
is sometimes abbreviated GRH and was originally named growth hormone-releasing
factor (GRF). It was first isolated from rare pancreatic tumors that caused
acromegaly by stimulating excessive GH secretion by pituitary somatotroph cells
(an unusual cause—almost all cases of acromegaly are caused by pituitary
tumors). In the hypothalamus, cells in the arcuate nuclei secrete GHRH into
thehypophysial-pituitary portal venous system.
Absorption, Metabolism, and Excretion
GHRH is not
currently available commercially; in research use it may be administered
intravenously, subcutaneously, or intranasally, and the relative potencies (defined
as incremental growth hormone release) by these three routes are 300, 10, and
1, respectively. Intravenous GHRH (1 g/kg) has a distribution half-life of 4
minutes and an elimination half-life of 53 minutes.
Subcutaneous GHRH has a similar elimination
half-life but a distribution half-life of about 10 minutes. Peak serum levels
of GHRH (1 g/kg) are 37 times higher after intravenous administration compared
with subcutaneous injection. Sermorelin, 2 g/kg subcutaneously, reaches peak
serum concentrations in 5–20 minutes; its bioavailability is 6%. The half-life
of sermorelin is about 12 minutes after either subcutaneous or intravenous
injection.
Clinical Pharmacology
Diagnostic Uses
GHRH is not
currently available commercially. GHRH or GHRPs such as sermorelin may be given
intravenously to test pituitary GH secretory capacity as part of the clinical
evaluation of childhood short stature. It is used after GH deficiency has
already been established by clinical criteria, including testing with
conventional stimuli for GH secretion, ie, exercise, insulin-induced
hypoglycemia, intravenous arginine, oral carbidopa/levodopa, and oral
clonidine. In such children, a normal GH response to GHRH indicates that GH
deficiency is due to hypothalamic dysfunction. A subnormal response is not
diagnostic. A rise in the serum growth hormone level demonstrates the
somatotrophs' ability to produce GH and predicts a favorable response to GHRH
therapy.
The response
of GH to GHRH can be blunted by prior treatment with octreotide, glucocorticoids,
and cyclooxygenase inhibitors such as aspirin or indomethacin. GH response to
GHRH is also blunted in hypothyroidism, in obesity, and in adults over 40 years
of age. Exogenous growth hormone therapy should be discontinued for at least a week
prior to GHRH testing.
Therapeutic Uses
Synthetic
human growth hormone is now usually used for treatment of growth hormone
deficiency.
Sermorelin is commercially available (see above).
It and other GHRH analogs, given
subcutaneously, can also stimulate GH (and
thereby growth) in certain GH-deficient children withshort stature. Sermorelin
is given only to children who have had a positive growth hormoneresponse to the
diagnostic test and who have a bone age of less than 7.5 years (girls) or 8
years (boys). A physician experienced in its use must carefully monitor
treatment. If successful in promoting growth, treatment is continued until the
desired height is reached or the epiphyses have
fused, whichever comes first. Children who have
an inadequate response are evaluated for hypothyroidism and considered for
growth hormone therapy.
Dosage
Diagnostic Use
Sermorelin
may be used as a diagnostic test for pituitary GH reserve according to the
following protocol: After an overnight fast, the patient has blood drawn for GH
at –15 and 0 minutes; sermorelin 1 g/kg is injected intravenously, followed by
a 3 mL normal saline flush of the infusion line. Blood for GH is then drawn at
15, 30, 45, and 60 minutes following the injection. Serum GH levels must reach
a peak of over 2 ng/mL to be considered a positive response.
Therapeutic Use
Sermorelin
is usually given subcutaneously at a dosage of 0.03 mg/kg body weight once
daily at bedtime. Alternative regimens include GHRH, 2–5 g/kg subcutaneously
every 6–12 hours. GHRP- 2 has been administered intranasally in doses of 5–20
g/kg. Hexarelin has clinical activity in dosesof 20 g/kg intranasally.
Toxicity
Intravenous
GHRH usually causes acute but transient adverse effects lasting several
minutes. These effects include flushing, injection site pain and erythema,
nausea, headache, metallic taste, pallor, and chest tightness.
Chronic
subcutaneous GHRH therapy causes injection site reactions (pain, swelling,
erythema) in about 20% of patients. Other reported adverse reactions have
included headaches, flushing, dysphagia, dizziness, hyperactivity, somnolence,
and urticaria.
GHRH analogs
are not known to cause or stimulate malignancies, and long-term carcinogenic
potential has not been studied. It is recommended that GHRH treatment be
terminated if a malignancy is detected. GHRH treatment is not recommended for
patients with GH deficiency due to an intracranial neoplasm.
Somatostatin
(Growth Hormone-Inhibiting Hormone, Somato-Tropin Release-Inhibiting Hormone)
Somatostatin, a 14-amino-acid peptide, is found in the hypothalamus and other
parts of the central nervous system. It has been sequenced (Figure 37–1) and
synthesized. It inhibits growth hormone release in normal individuals.
Somatostatin has also been identified in the pancreas and other sites in the
gastrointestinal tract. It has been shown to inhibit the release of glucagon,
insulin, and gastrin.
Figure 37–1. Exogenously administered
somatostatin is rapidly cleared from the circulation, with an initial halflife
of 1–3 minutes. The kidney appears to play an important role in its metabolism
and excretion. Peptides have been synthesized that partially separate the
various properties of somatostatin. A 7- aminoheptanoic acid derivative
containing only four of the 14 amino acids of somatostatin has been found to
block the effect of somatostatin.
Clinical
Pharmacology of Octreotide (Somatostatin Analog)
Somatostatin
has limited therapeutic usefulness because of its short duration of action and
its multiple effects on many secretory systems. Octreotide is 45 times more
potent than somatostatin in inhibiting growth hormone release but only twice as
potent in reducing insulin secretion. Because of this relatively reduced effect
on pancreatic B cells, hyperglycemia rarely occurs during treatment.
The greater
potency of octreotide as compared with somatostatin is not due to differences
in affinity for somatostatin receptors. Rather, it appears to be due to
octreotide's much lower clearance and longer half-life. The plasma elimination
half-life of octreotide is about 80 minutes, 30 times longer in humans than the
half-life of somatostatin. Octreotide, in doses of 50–200 g given subcutaneously
every 8 hours, reduces symptoms caused by a variety of hormone-secreting
tumors: acromegaly; the carcinoid syndrome; gastrinoma; glucagonoma; nesidioblastosis; the watery
diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome; and "diabetic
diarrhea." Somatostatin receptor scintigraphy, using radiolabeled
octreotide, is useful in localizing neuroendocrine tumors having somatostatin
receptors and helps predict the response to octreotide therapy. Octreotide is
also useful for the acute control of bleeding from esophageal varices.
Octreotide acetate injectable suspension (octreotide long-acting release; Sandostatin LAR) is a
slow-release formulation in which octreotide is incorporated into microspheres.
It is instituted only after a brief course of shorter-acting octreotide has
been demonstrated to be effective and tolerated. The microspheres must be
carefully put into suspension and immediately injected into a gluteal muscle.
Injections into alternate gluteal muscles are repeated at 4-week intervals in doses
of 20–40 mg.
Octreotide is
extremely costly. Adverse effects of therapy include nausea with or without
vomiting, abdominal cramps, flatulence, and steatorrhea with bulky bowel
movements. Biliary sludge and gallstones may occur after 6 months of use in 20–30%
of patients. However, the yearly incidence of symptomatic gallstones is about
1%. Cardiac effects include sinus bradycardia (25%) and conduction disturbances
(10%). Pain at the site of injection is common, especially with the long-acting
octreotide suspension. Vitamin B12 deficiency may occur with long-term use of
octreotide.
Pegvisomant (Growth Hormone Receptor Antagonist)
Pegvisomant
is a new GH receptor antagonist that is proving useful for the treatment of
acromegaly.
Pegvisomant
is the polyethylene glycol (PEG) derivative of a mutant growth hormone (B2036)
that has increased affinity for one site of the GH receptor but a reduced
affinity at its second binding site. This allows dimerization of the receptor
but blocks the conformational changes required for signal transduction.
Pegvisomant has less GH receptor antagonism than does B2036, but pegylation
reduces its clearance rate and improves its overall clinical effectiveness.
When pegvisomant was administered to 160 acromegalic patients subcutaneously
daily for 12 months or more, serum levels of IGF-I fell into the normal range
in 97% while serum levels of GH rose during treatment; two patients experienced
growth of their GH-secreting pituitary tumors, and two patients developed
increases in liver enzymes.
Growth Hormone (Somatotropin, GH)
Growth
hormone is a peptide hormone produced by the anterior pituitary. It produces
growth at open epiphyses via stimulation of insulin-like growth factor I
(IGF-I, somatomedin C). It also causes lipolysis in adipose tissue and growth
of skeletal muscle.
Absorption, Metabolism, and Excretion
Circulating endogenous growth hormone has a
half-life of 20–25 minutes and is predominantly cleared by the liver. Human
growth hormone can be administered subcutaneously, with peak levels occurring
in 2–4 hours and active blood levels persisting for 36 hours. Somatropin
injectable suspension (Nutropin Depot) is a long-acting preparation of rhGH
enclosed within biodegradable microspheres. These microspheres degrade slowly
after subcutaneous injection such that the rhGH is released over about 1 month.
Clinical Pharmacology
Growth Hormone Deficiency
Genetic GH
deficiency may present in the newborn with hypoglycemic seizures. Acquired GH
deficiency is caused by damage to the pituitary or hypothalamus. In childhood,
GH deficiency presents as short stature and adiposity. Criteria for diagnosis
of growth hormone deficiency usually include (1) a growth rate below
tolerance, and an improved sense of well-being.
Adverse effects often include arthralgias and fluid retention.
Growth Hormone-Responsive States
Some
non-growth hormone-deficient short children with a delayed bone age and a slow
growth rate achieve increased growth with short-term growth hormone therapy.
Selected "normal variant short stature" children can be offered a
trial of growth hormone following a baseline period of measurement to confirm a
subnormal growth rate. During the first 6 months of treatment, the height
velocity must increase by
In 1993, the
FDA approved the use of recombinant bovine growth hormone (rbGH) in dairy
cattle to increase milk production. Although milk and meat from rbGH-treated
cows appears to be safe, these cows have a higher frequency of mastitis, which
could increase antibiotic use and result in greater antibiotic residues in milk
and meat.
Experimental Uses
Therapy with
rhGH appears to be effective for infants with intrauterine growth retardation.
Children with growth retardation following renal transplantation also appear to
respond to rhGH therapy. Hypophosphatemia due to hyperphosphaturia (eg,
X-linked hypophosphatemic vitamin D-resistant rickets) has been improved by
adding rhGH to the treatment regimen. Serum levels of growth hormone normally
decline with aging. Elderly men treated with rhGH for 6 months had an increase
in muscle mass and bone density and a drop of 13% in fat mass, but functional
abilities remained unchanged. Available data do not support the use of rhGH to
reverse the manifestations of normal aging.
Dosage
The
therapeutic dosage of recombinant human growth hormone must be individualized.
It is usually given in the evening by subcutaneous injection in the thighs,
rotating the sites of injections. One milligram of standard rhGH preparations
is equivalent to 3 units.
Children
Treatment is
begun with 0.025 mg/kg daily and may be increased to a maximum of 0.045 mg/kg
daily. Somatropin injectable suspension (Nutropin Depot) is a long-acting
preparation of rhGH that is administered subcutaneously in doses of 1.5 mg/kg
monthly or 0.75 mg/kg twice monthly. Children must be observed closely for
slowing of growth velocity, which could indicate a need to increase the dosage
or the possibility of epiphysial fusion or intercurrent problems such as
hypothyroidism or malnutrition. Children with Turner's syndrome or chronic
renal insufficiency require somewhat higher doses. The injection should be
given at least 3 hours after dialysis to
reduce the risk of hematoma formation due to
residual heparin effect.
Adults
The required
dosage for adults is lower than that for children. Treatment is begun at about
0.2 mg three times weekly and titrated upward gradually at intervals of 2–4
weeks to a maximum of 0.025 mg/kg/d (adults under age 35) or 0.0125 mg/kg/d
(adults over age 35) given three to seven times weekly according to clinical
response. Somatropin injectable suspension is administered subcutaneously to
adult men in doses of 0.2–0.4 mg/kg every 2 weeks; it is administered to adult
women taking oral estrogen in doses of 0.4–0.6 mg/kg every 2 weeks. Women
usually require higher dosages than men, perhaps because of concomitant use of
oral estrogens. Clinical response and adverse effects best determine the final
therapeutic dosage. Serum IGF-I levels (age- and sexadjusted) can also be used.
Thyrotropin-Releasing Hormone (Protirelin, TRH)
Thyrotropin-releasing
hormone, or protirelin, is a tripeptide hormone found in the paraventricular
nuclei of the hypothalamus as well as in other parts of the brain. TRH is
secreted into the portal venous system and stimulates the pituitary to produce
thyroid-stimulating hormone (TSH, thyrotropin), which in turn stimulates the
thyroid to produce thyroxine (T4) and triiodothyronine (T3). TRH stimulation of
thyrotropin is blocked by thyroxine and potentiated by lack of thyroxine.
Chemistry & Pharmacokinetics
TRH is
(pyro)Glu-His-Pro-NH2. It is administered intravenously over 1 minute. Rapid
plasma nactivation occurs, with a half-life of 4–5 minutes.
Clinical Pharmacology
TRH testing
(see above) is now rarely used to diagnose hyperthyroidism or hypothyroidism,
having been supplanted by sensitive assays for serum thyrotropin (see below).
Dosage
The
dose of protirelin for diagnostic use is
Toxicity
Most patients
given intravenous TRH note adverse effects lasting for a few minutes: an urge
to urinate, a metallic taste, nausea, flushing, or light-headedness. Transient
hypertension or hypotension may occur, and marked blood pressure fluctuations
have been reported in a few patients.
Thyroid-Stimulating Hormone (Thyrotropin, TSH) & Thyrotropin Alpha
(rhTSH)
Thyrotropin
is an anterior pituitary hormone that stimulates the thyroid to produce and
synthesize thyroxine (T4), triiodothyronine (T3), and thyroglobulin.
Thyrotropin
alpha is a commercially available analog of TSH that is used to help detection
of metastatic differentiated thyroid carcinoma; it is also known as recombinant
human TSH (rhTSH).
Pharmacodynamics
Thyrotropin
alpha has the biologic properties of pituitary TSH. It binds to TSH receptors
on both normal thyroid and differentiated thyroid cancer cells. The
TSH-activated receptor stimulates intracellular adenylyl cyclase activity.
Increased cAMP production causes increased iodine uptake and increased
production of thyroid hormones and thyroglobulin.
Clinical Pharmacology
Diagnostic Uses
Patients with
well-differentiated (papillary or follicular) thyroid carcinoma are treated
with surgical resection of the cancer along with total or near-total
thyroidectomy.
Total
thyroidectomy normally reduces the serum levels of thyroid hormones and
thyroglobulin to undetectable levels. Postoperatively, these patients must take
oral thyroid hormone in order to maintain clinical euthyroidism and to suppress
pituitary TSH secretion, thereby preventing any stimulation of tumor growth by
TSH. Since thyroid cancer can recur years after apparent cure, such patients
should have follow-up TSH-stimulated whole-body 131I scans and serum
thyroglobulin determinations. However, the aggressiveness of follow-up
surveillance must be individualized according to each patient's risk of
recurrence. Traditionally, patients have had to endure prolonged withdrawal of
thyroid hormone replacement for many weeks before these tests in order to allow
their TSH levels to rise high enough to stimulate any remaining tumor cells to
resume their uptake of 131I and their secretion of thyroglobulin. The use of
thyrotropin alpha can obviate the need for cessation of
thyroid hormone replacement prior to the
diagnostic whole-body 131I scan and serum thyroglobulin determination.
Therapeutic Uses
Treatment of
metastatic differentiated thyroid cancer requires the administration of large
doses of 131I (30–200 mCi) in the presence of persistently high serum levels of
TSH. Patients must withdraw from thyroid hormone replacement in order to
achieve this. For treatment purposes, thyrotropin alpha administration cannot
substitute for thyroid hormone withdrawal.
Dosage
Thyrotropin
alpha injections can stimulate uptake of 131I by thyroid cancer or residual
thyroid. The preparation is stored as a lyophilized powder that must be
reconstituted before use. The dosage is 0.9 mg intragluteally (not
intravenously) every 24 hours for two doses (eg, Monday and Tuesday).
Twenty-four hours after the final thyrotropin injection (eg, Wednesday), 131I
is administered in a dosage of at least 4 mCi (a larger dose than in
hypothyroid patients, since iodine clearance is faster in euthyroid patients).
Then, 48 hours after the 131I administration (eg, Friday), a serum thyroglobulin
is drawn and a scan is obtained using a gamma camera, with neck, anterior whole
body, and posterior whole-body imaging. If the scan shows probable metastases
or if the serum thyroglobulin level (using a sensitive assay) is > 2.5
ng/mL, further evaluation and treatment are indicated.
Toxicity
Side effects
of thyrotropin injections include nausea (11%), headache (7%), and asthenia
(3%). Hyperthyroidism can occur in patients with significant metastases or
residual normal thyroid. Thyrotropin has caused neurologic deterioration in 7%
of patients with brain metastases.
Corticotropin-Releasing Hormone (CRH)
CRH
is a hypothalamic hormone that stimulates release of ACTH and -endorphin from
the pituitary.
Absorption, Metabolism, and Excretion
CRH is
administered intravenously. The first-phase half-lives of human and sheep CRH
are 9 minutes and 18 minutes, respectively. The peptide is metabolized in
various tissues, and less than 1% is excreted in the urine.
Pharmacodynamics
ACTH
released by CRH stimulation of the pituitary subsequently stimulates the
adrenal cortex to produce cortisol and androgens.
Ovine CRH is
more potent than human CRH.
Clinical Pharmacology
CRH
is used only for diagnostic purposes. In Cushing's syndrome, CRH has been used
to distinguish Cushing's disease from ectopic ACTH secretion.
CRH generally
elicits an increase in ACTH and cortisol secretion in Cushing's disease but
usually not in the ectopic ACTH syndrome. However, exceptions occur frequently,
making this test unreliable. A more reliable test depends on differential
concentrations of ACTH. In patients with Cushing's disease, ACTH levels in blood
drawn from the inferior petrosal sinuses draining the pituitary are more than
2.5 times higher than levels in simultaneously drawn peripheral venous blood.
When tumors are associated with ectopic ACTH production, no such difference is
observed. Concurrent administration of CRH (ovine) further improves the
distinction between blood levels of ACTH when Cushing's disease is present.
Preparations & Dosage
Synthetic
human and ovine CRH are available. Sheep CRH is used more frequently because of
its longer half-life and slightly greater potency. CRH may be dissolved in
water or dilute acid but not in saline. A dose of 1 mg/kg is used for
diagnostic testing.
Toxicity
Intravenous
bolus doses of 1 mg/kg produce transient facial flushing and, rarely, dyspnea.
Adrenocorticotropin (Corticotropin, ACTH, ACTH1–24)
Adrenocorticotropin
is a peptide hormone produced in the anterior pituitary. Its primary endocrine
function is to stimulate synthesis and release of cortisol by the adrenal
cortex. Corticotropin can be used therapeutically, but a synthetic derivative
is more commonly—and almost exclusively—used to assess adrenocortical
responsiveness. A substandard adrenocortical response to exogenous
corticotropin administration indicates adrenocortical insufficiency.
Chemistry & Pharmacokinetics
Structure
Human ACTH is
a single peptide chain of 39 amino acids. The amino terminal portion containing
amino acids 1–24 is necessary for full biologic activity. The remaining amino
acids (25–39) confer species specificity. Synthetic human ACTH1–24 is known as
cosyntropin. The amino terminal amino acids 1–13 are identical to
melanocyte-stimulating hormone ( -MSH), which has been found in animals but not
in humans. In states of excessive pituitary ACTH secretion (Addison's disease
or an
ACTH-secreting pituitary tumor),
hyperpigmentation—caused by the -MSH activity intrinsic to ACTH—may be noted.
ACTH from animal sources is assayed biologically by measuring the depletion of
adrenocortical ascorbic acid that follows subcutaneous administration of the
ACTH.
Absorption, Metabolism, and Excretion
Both porcine
and synthetic corticotropin are given parenterally. Corticotropin cannot be
administered orally because of gastrointestinal proteolysis. The biologic
half-lives of ACTH1–39 and ACTH1–24 are under 20 minutes. Tissue uptake occurs
in the liver and kidneys. ACTH1–39 is transformed into a biologically inactive
substance, probably by modification of a side chain. ACTH is not excreted in
the urine in significant amounts. The effects of long-acting repository forms
of porcine corticotropin persist for up to 18 hours with a gelatin complex of
the peptide and up to several days with a zinc hydroxide complex.
Pharmacodynamics
ACTH
stimulates the adrenal cortex to produce glucocorticoids, mineralocorticoids,
and androgens. ACTH increases the activity of cholesterol esterase, the enzyme
that catalyzes the rate-limiting step of steroid hormone production:
cholesterol pregnenolone. ACTH also stimulates adrenal hypertrophy and
hyperplasia. When given chronically in pharmacologic doses, corticotropin
causes increased skin pigmentation.
Clinical Pharmacology
Diagnostic Uses
ACTH
stimulation of the adrenals will fail to elicit an appropriate response in
states of adrenal insufficiency. A rapid test for ruling out adrenal
insufficiency employs cosyntropin (see below). Plasma cortisol levels are
measured before and either 30 minutes or 60 minutes following an intramuscular
or intravenous injection of 0.25 mg of cosyntropin. A normal plasma cortisol
response is a stimulated peak level exceeding 20 g/dL. A subnormal response
indicates primary or secondary adrenocortical insufficiency that can be
differentiated using endogenous plasma ACTH levels (which are increased in
primary adrenal insufficiency and decreased in the secondary form). An
incremental rise in plasma aldosterone generally occurs in secondary but not
primary adrenal insufficiency after cosyntropin stimulation. ACTH stimulation
may distinguish three forms of "late-onset" (nonclassic) congenital
adrenal hyperplasia from states of ovarian hyperandrogenism, all of which may
be associated with hirsutism. In patients with deficiency of 21-hydroxylase,
ACTH stimulation results in an incremental rise in plasma
17-hydroxyprogesterone, the substrate for the deficient enzyme. Patients with
11-hydroxylase deficiency manifest a rise in 11-deoxycortisol, while those with
3 -hydroxy- 5 steroid dehydrogenase deficiency show an increase of 17-hydroxypregnenolone
in response to ACTH stimulation.
Therapeutic Uses
Corticotropin
therapy has been virtually abandoned since it has no therapeutic advantage over
directadministration of glucocorticoids.
Dosage
Cosyntropin
is the preferred preparation for diagnostic use. The standard diagnostic test
dose of 0.25 mg is equivalent to 25 units of porcine corticotropin. ACTH is
rarely indicated but is available for use in doses of 10–20 units four times
daily. Repository ACTH, 40–80 units, may be administered every 24–72 hours.
Gonadotropin-Releasing Hormone (GnRH; Luteinizing Hormone-Releasing
Hormone [LHRH];
Gonadorelin Hydrochloride)
GnRH is
produced in the arcuate nucleus of the hypothalamus. GnRH is secreted into the
hypothalamic-pituitary venous plexus and binds to cell surface receptors of the
anterior pituitary gonadotroph cells. Pulsatile GnRH secretion is required to
stimulate the gonadotroph cell to produce and release luteinizing hormone (LH)
and follicle stimulating hormone (FSH). Divergent production of the two
gonadotropins is controlled by the frequency of GnRH pulses. In women,
increasing levels of estradiol at midcycle have a positive feedback upon the
hypothalamus that increases GnRH secretion, resulting in a sudden increase in
LH secretion. This LH-surge induces the ovulation of the dominant ovarian
follicle, with subsequent luteinization in the ovary that secretes
progesterone; this changes the uterine proliferative endometrium to a secretory
endometrium that is receptive to a fertilized ovum. Ironically, sustained
non-pulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both
women and men, resulting in hypogonadism.
Clinical Pharmacology
Diagnostic Uses
Delayed
puberty in a hypogonadotropic adolescent may be due to a constitutional delay
or to hypogonadotropic hypogonadism. The LH response (but not the FSH response)
to GnRH can distinguish between these two conditions. Serum LH levels are
measured before and then 15, 30, 45, 60, and 120 minutes after a 100 mg
intravenous or subcutaneous bolus of GnRH. A peak LH response exceeding 15.6
mIU/mL is normal and suggests impending puberty, whereas an impaired LH
response suggests hypogonadotropic hypogonadism due to either pituitary or
hypothalamic disease (but may also be seen in constitutional delay of
adolescence).
Therapeutic Uses
Stimulation
GnRH can
stimulate pituitary function and is used to treat infertility caused by
hypothalamic hypogonadotropic hypogonadism in both sexes. A portable
battery-powered programmable pump and intravenous tubing allows pulsatile GnRH
therapy every 90 minutes. Suppression Leuprolide, nafarelin, goserelin, and
histrelin are GnRH analog agonists that induce hypogonadism when given
continuously. Such GnRH agonists are used to treat prostate cancer, uterine
fibroids, endometriosis, polycystic ovary syndrome, and precocious puberty.
Many in vitro fertilization programs sequentially use a GnRH analog to suppress
endogenous gonadotropin release, along with exogenous gonadotropins to achieve
synchronous follicular development. GnRH analog therapy for the purpose of
producing pituitary suppression leads to a transient rise in sex hormone
concentration during the first 2 weeks of treatment. This can be deleterious
during treatment of prostate cancer, precocious puberty, and infertility. Dosage:
Gonadorelin (GnRH, Factrel)
Gonadorelin hydrochloride is available in a
lyophilized powder that is reconstituted and injected either subcutaneously or
intravenously.
Diagnostic Use
Gonadorelin
has been used to test pituitary luteinizing hormone (LH) responsiveness.
Administered as a
Female
Infertility
Gonadorelin
is administered intravenously,
Male
Infertility
For male
infertility caused by hypothalamic GnRH deficiency, gonadorelin treatment is
begun only after preparatory hCG injections continued for up to 1 year in men
with prepubertal hypogonadotropic hypogonadism. A portable pump infuses
gonadorelin intravenously every 90 minutes. Serum testosterone levels and semen
analyses must be done regularly. At least 3–6 months of bolus infusions are
required before significant numbers of sperm are seen. The preferable alternative
to intravenous gonadorelin treatment is subcutaneously administered
gonadotropins.
Dosage:
Leuprolide (GnRH Analog, Lupron)
Leuprolide is
available in solution for daily subcutaneous injection and in slow-release
depot preparations in which leuprolide is lyophilized in microspheres given by
intramuscular injection.
Endometriosis
and Uterine Fibroids
Women with endometriosis receive treatment
courses of 6 months' duration. Concomitant low-dose hormone replacement therapy
has been reported to diminish bone loss without significantly decreasing
clinical effectiveness. Women with uterine fibroids that are symptomatic
(menorrhagia, anemia, pain) receive treatment courses of 3 months, by which
time women have amenorrhea or reduced menorrhagia; uterine fibroids are reduced
in size an average of 37%. Intramuscular depot preparations containing 3.75 mg
(monthly) or 11.5 mg (every 3 months) are used. Prostate Cancer
Leuprolide is usually used in depot form, 7.5 mg
intramuscularly monthly, 22.5 mg intramuscularly at 84-day intervals, or 30 mg
intramuscularly at 4-month intervals.
Central
Precocious Puberty
Leuprolide aqueous solution is started at a
dosage of 0.05 mg/kg body weight injected
subcutaneously daily. If the clinical response is
inadequate, the dose can be increased by increments of 0.01 mg/kg body weight.
Pediatric depot preparations are also available. The dose can be titrated
upward according to the endocrine response. Leuprolide is indicated for
treatment of central precocious puberty (onset of secondary sex characteristics
before 8 years in girls or 9 years in boys). Prior to use, central precocious
puberty must be confirmed by a puberty gonadotropin response to GnRH and a bone
age at least 1 year beyond chronologic age. Pretreatment evaluation must also
include sex steroid levels compatible with precocious puberty and not
congenital adrenal hyperplasia; a hCG level to exclude a chronic
gonadotropin-secreting tumor; an MRI of the brain to exclude an intracranial
tumor; and an ultrasound examination of the adrenals and ovaries or testes to
exclude a steroid-secreting tumor.
Prostate
Cancer
Implants containing 10.8 mg goserelin are
injected subcutaneously every 12 weeks.
Toxicity
GnRH
(gonadorelin) may cause headache, light-headedness, nausea, and flushing. Local
swelling often occurs at subcutaneous injection sites. Generalized
hypersensitivity dermatitis has occurred after long-term subcutaneous
administration. Rare acute hypersensitivity reactions include
bronchospasm and anaphylaxis. Sudden pituitary
apoplexy and blindness has been reported following administration of GnRH to a
patient with a gonadotropin-secreting pituitary tumor. GnRH analog (leuprolide,
nafarelin, goserelin) treatment of women may cause hot flushes and sweats (89%)
and headaches (29%). Depression, diminished libido, generalized pain, vaginal
dryness, and breast atrophy may also occur. Ovarian cysts may develop within
the first 2 months of therapy and generally resolve by 6 weeks, but may persist
and require discontinuation of therapy. Osteoporosis may occur with prolonged
use, so patients may be monitored with bone densitometry prior to repeated
treatment courses. Cholesterol and triglyceride levels may rise.
Contraindications include pregnancy and breast-feeding. GnRH analog
(leuprolide, goserelin) treatment in men causes serum testosterone levels to
rise for about 1 week; this can precipitate pain in men with bone metastases.
In men with vertebral metastases, initial growth of tumor can produce
neurologic symptoms. It can also temporarily worsen symptoms of urinary
obstruction. Within about 2 weeks, serum testosterone levels fall to the
hypogonadal range. Other adverse effects in men include hot flushes and sweats
(59%), edema (13%), gynecomastia, decreased libido, decreased hematocrit, and
asthenia. For men with prostate cancer, GnRH agonists are often given together
with an antiandrogen, which may exacerbate hypogonadal symptoms while reducing
the risk of exacerbation of bone pain.
GnRH analog
(leuprolide, nafarelin) treatment of children is generally well tolerated.
However, temporary exacerbation of precocious puberty may occur during the
first few weeks of therapy. Injection site reactions occur in about 5%.
Nafarelin nasal spray may cause or aggravate sinusitis.
Dosage:
Cetrorelix Acetate for Injection (GnRH Antagonist)
Cetrorelix is
a synthetic decapeptide that reversibly binds to pituitary GnRH receptors
without activating them. Cetrorelix thus inhibits the secretion of FSH and LH
in a dose-dependent manner by competing with natural hypothalamic GnRH for
pituitary cell surface receptors. At the doses used for in vitro fertilization,
cetrorelix produces an immediate suppression of LH; this delays the LH surge
and thus delays ovulation. At higher doses, cetrorelix also suppresses FSH
secretion, thus inhibiting the secretion of estradiol from the ovaries.
Cetrorelix is absorbed rapidly following subcutaneous injection, with maximum
plasma concentrations occurring 1–2 hours after administration. Following a
subcutaneous dose of 3 mg, the duration of action is at least 4 days; daily
administration of 0.25 mg maintains GnRH antagonism. in VItro Fertilization
(IVf) GnRH antagonists produce less ovarian hyperstimulation during IVF than do
GnRH analogs. Cetrorelix suppresses endogenous FSH and LH while recombinant FSH
(rFSH) is being given to prepare the ova for ovulation-induction by hCG
administration. Ovarian stimulation is commenced with rFSH on the second or
third day of the menstrual cycle. When serum estradiol rises to levels that
indicate sufficient ovarian stimulation (requiring 5–9 days), cetrorelix is
administered subcutaneously in order to prevent a natural LH that could cause
premature spontaneous ovulation, obviating laparoscopic harvest of the ova.
Cetrorelix may be administered subcutaneously in a dose of 3 mg, followed by
0.25 mg daily if hCG stimulation has not been given within the next 4 days.
Alternatively, cetrorelix may be given
subcutaneously in doses of 0.25 mg subcutaneously daily, beginning on the fifth
or sixth day of FSH stimulation and continued daily until hCG is administered.
Follicle-Stimulating Hormone (FSH)
Follicle-stimulating
hormone is a glycoprotein hormone consisting of two chains and, like LH, is
produced by gonadotroph cells in the anterior pituitary. FSH and LH regulate
gonadal function by increasing cAMP in the target gonadal tissue. FSH, like
other pituitary glycoproteins, is composed of a common alpha subunit that
promotes hormone action and a unique beta subunit that confers specificity. The
principal function of FSH is to stimulate gametogenesis and follicular
development in women and spermatogenesis in men. FSH acts on the immature
follicular cells of the ovary and induces development of the mature follicle
and oocyte. Both LH and FSH are needed for proper ovarian steroidogenesis. LH
stimulates androgen production by these cells, and FSH stimulates androgen
conversion into estrogens by the granulosa cells. In the testes, FSH acts on
the Sertoli cells and stimulates their production of androgen-binding protein.
FSH has been commercially available since the 1960s. It was first extracted
from the urine of postmenopausal women, which contains a substance with
FSH-like properties (but with 4% of the potency) and an LH-like substance. This
purified extract of FSH and LH, derived from the urine of postmenopausal women,
remains available and is known as menotropins, or human menopausal
gonadotropins (hMG). A purified preparation of human FSH, also extracted from
the urine of postmenopausal women, contains virtually no LH and is know as
urofollitropin, or urinary FSH (uFSH). In
These
preparations are used in states of infertility to stimulate ovarian follicle
development in women and spermatogenesis in men. In both sexes, they must be
used in conjunction with a luteinizing hormone, ie, human chorionic
gonadotropin (hCG), to permit ovulation and implantation in women and
testosterone production and full masculinization in men.
Clinical Pharmacology
FSH or hMG
are indicated for pituitary or hypothalamic hypogonadism with infertility.
Anovulatory women with the following conditions may benefit from hMG: primary
amenorrhea, secondary amenorrhea, polycystic ovary syndrome, and anovulatory
cycles. Both hMG and FSH are used by in vitro fertilization programs for
controlled ovarian hyperstimulation. Over 50% of men with hypogonadotropic
hypogonadism become fertile after hMG or hCG/FSH administration.
Dosage
An ampule of
menotropins contains 75 IU or 150 IU of FSH and an equal amount of LH. One
international unit of LH is approximately equivalent to 0.5 IU of hCG. An
ampule of urofollitropin contains 75 IU of FSH and less than 1 IU of LH. Human
menopausal gonadotropins, FSH, and hCG are
administered intramuscularly.
Women
In hypothalamic hypogonadism and for in vitro
fertilization, one or two ampules are administered daily for 5–12 days until
evidence of adequate follicular maturation is present. Serum estradiol levels
should be measured and a cervical examination performed every 1 or 2 days. When
appropriate follicular maturation has occurred, hMG or FSH is discontinued; the
following day, hCG (5000–10,000 IU) is administered intramuscularly to induce
ovulation.
Men
Following pretreatment with 5000 IU of hCG three
times weekly for up to 12 months to achieve masculinization and a normal serum
testosterone level, menotropins is administered as one ampule (75 units) three
times weekly in combination with hCG, 2000 IU twice weekly. At least 4 months
of combined treatment are usually necessary before spermatozoa appear in the
ejaculate. If there is no response, the menotropins dose may be doubled. When
adding menotropins to hCG therapy, the dose of hCG must be reduced to keep
serum testosterone in the high normal range and avoid hyperandrogenism.
Luteinizing Hormone (LH) & Human Chorionic Gonadotropin (hCG)
Luteinizing
hormone is a glycoprotein hormone consisting of two chains and, like FSH, is
produced by gonadotroph cells in the anterior pituitary. LH is primarily
responsible for regulation of gonadal steroid hormone production. In men, LH
acts on testicular Leydig cells to stimulate testosterone production. In the
ovary, LH acts in concert with FSH to stimulate follicular development. LH acts
on the mature follicle to induce ovulation, and it stimulates the corpus luteum
in the luteal phase of the menstrual cycle to produce progesterone and
androgens.
There is no
LH preparation presently available for clinical use.
Human
chorionic gonadotropin—with an almost identical
structure—is available and can be used as a luteinizing hormone substitute.
Human chorionic gonadotropin is a hormone produced by the human placenta and
excreted into the urine, whence it can be extracted and purified. Human chorionic
gonadotropin is a glycoprotein consisting of a 92-amino-acid alpha chain
virtually identical to that of FSH, LH, and TSH and a
beta chain of 145 amino acids that resembles that
of LH except for the presence of a carboxyl terminal sequence of 30 amino acids
not present in LH.
The function of hCG is to stimulate the ovarian
corpus luteum to produce progesterone and maintain the placenta. It is very
similar to LH in structure and is used to treat both men and women with LH
deficiency.
Clinical Pharmacology
Diagnostic Uses
In
prepubertal boys with undescended gonads, hCG can be used to distinguish a
truly retained (cryptorchid) testis from a retracted (pseudocryptorchid) one.
Testicular descent during a course of hCG
administration usually foretells permanent testicular descent at puberty, when
circulating LH levels rise. Lack of descent usually means that orchiopexy will
be necessary to preserve spermatogenesis. Patients with constitutional delay in
onset of puberty can be distinguished from those with hypogonadotropic
hypogonadism using repeated hCG stimulation. Serum testosterone and estradiol
levels rise in the former but not in the latter group.
Therapeutic Uses
As described
above, hCG can be used in combination with hMG, uFSH, or rFSH to induce
ovulation in women with hypogonadotropic hypogonadism or as part of an in vitro
fertilization program. hCG stimulates testosterone secretion by the testes of
men with hypogonadotropic hypogonadism. In such men, the increased
intratesticular testosterone levels promote spermatogenesis, but FSH is often
needed for fertility.
In patients with AIDS-related Kaposi's sarcoma,
injection of hCG into the lesions has been reported to cause regression in a
dose-related manner.
Dosage
The dosages
for female and male infertility are described under hMG dosage. For prepubertal
cryptorchidism, a dosage of 500–4000 units three times weekly for up to 6 weeks
has been advocated.
Prolactin
Prolactin is a 198-amino-acid peptide hormone produced in the anterior
pituitary. Its structure resembles that of growth hormone.
Prolactin is the principal hormone responsible for lactation. Milk production
is stimulated by prolactin when appropriate circulating levels of estrogens,
progestins, corticosteroids, and insulin are present. A deficiency of
prolactin—which can occur in states of pituitary deficiency—is manifested by
failure to lactate or by a luteal phase defect. In hypothalamic destruction,
prolactin levels may be elevated as a result of impaired transport of
prolactin-inhibiting hormone (dopamine) to the pituitary. Hyperprolactinemia
can produce galactorrhea and hypogonadism and may be associated with symptoms
of a pituitary mass. No preparation is available for use in prolactin-deficient
patients. For patients with symptomatic hyperprolactinemia, inhibition of
prolactin secretion can be achieved with cabergoline and other dopamine
agonists.
Dopamine
Agonists
Dopamine is
released by the hypothalamus to inhibit prolactin release from the anterior
pituitary.
Bromocriptine,
cabergoline, and pergolide are ergot derivatives with a
very high affinity for dopamine D2 receptors in the pituitary. Quinagolide is
a nonergot drug with similar D2 receptor affinity. These drugs lower
circulating prolactin levels and shrink pituitary prolactin-secreting tumors.
Dopamine
agonists decrease pituitary prolactin secretion through a dopamine-mimetic
action on the pituitary at two central nervous system loci: (1) they decrease
dopamine turnover in the tuberoinfundibular neurons of the arcuate nucleus,
generating increased hypothalamic dopamine; and (2) they act directly on
pituitary dopamine receptors to inhibit prolactin release. These agents, like
L-dopa, stimulate pituitary growth hormone release in normal subjects and—
paradoxically—suppress growth hormone release in acromegalics.
Clinical Pharmacology
Prolactin-Secreting
Adenomas A dopamine agonist is the usual initial treatment for prolactinomas.
Significant reduction in both tumor size and serum prolactin levels occurs in
about 85% of those receiving these drugs for 6 months or longer.
Amenorrhea-Galactorrhea
Dopamine
agonists are useful for treating problems induced by hyperprolactinemia:
amenorrhea, galactorrhea, breast tenderness (mastodynia), infertility, and
hypogonadism.
Physiologic
Lactation
Dopamine
agonists can prevent breast engorgement when breast feeding is not desired.
Their use for this purpose has been discouraged because of toxicity (see
below).
Acromegaly
A dopamine
agonist alone or in combination with pituitary surgery, irradiation, or
octreotide may be used to treat acromegaly. Acromegalic patients seldom respond
adequately to bromocriptine unless the pituitary tumor secretes prolactin as
well as growth hormone.
Preparations & Dosage
Cabergoline
is initiated at 0.25 mg orally or vaginally twice weekly. It may be increased
gradually according to serum prolactin determinations, up to a maximum of 1 mg
twice weekly. Bromocriptine is generally taken after the evening meal at the
initial dose of 1.25 mg; the dose is then increased as tolerated. Most patients
require 2.5–7.5 mg daily; acromegalics require higher doses, up to 20 mg/d.
Bromocriptine tablets may be administered intravaginally to reduce nausea.
Long-acting oral bromocriptine formulations (Parlodel SRO) and intramuscular
formulations (Parlodel L.A.R.) are available outside the
Posterior Pituitary Hormones
Two posterior
pituitary hormones are known: vasopressin and oxytocin. Their structures are
very similar. Posterior pituitary hormones are synthesized in the hypothalamus
and then transported to the posterior pituitary, where they are stored and then
released into the circulation.
Oxytocin
Oxytocin
is a peptide hormone secreted by the posterior pituitary that elicits milk
ejection in lactating women. It may contribute to the initiation of labor.
Oxytocin is released during sexual orgasm.
Clinical Pharmacology
Diagnostic Uses
Oxytocin
infusion near term will produce uterine contractions that decrease the fetal
blood supply. The fetal heart rate response to a standardized oxytocin
challenge test provides information about placental circulatory reserve. An
abnormal response suggests intrauterine growth retardation and may warrant
immediate cesarean delivery.
Therapeutic Uses
Oxytocin is
used to induce labor and augment dysfunctional labor for (1) conditions requiring
early vaginal delivery (eg, Rh problems, maternal diabetes, or preeclampsia),
(2) uterine inertia, and (3) incomplete abortion. Oxytocin can also be used for
control of postpartum uterine hemorrhage. Impaired milk ejection may respond to
nasal oxytocin. Synthetic peptide and nonpeptide oxytocin antagonists that can
prevent premature labor are being investigated.
Dosage
Oxytocin is
frequently given to induce and maintain labor after the cervix has ripened
naturally or with the aid of misoprostol. For induction of labor, oxytocin
should be administered intravenously via an infusion pump with appropriate
fetal and maternal monitoring. An initial infusion rate of 1 mU/min is
increased every 15–30 minutes until a physiologic contraction pattern is
established. The maximum infusion rate is 20 mU/min. For postpartum uterine
bleeding, 10–40 units is added to
Vasopressin (Antidiuretic Hormone, ADH)
Vasopressin
is a peptide hormone released by the posterior pituitary in response to rising
plasma tonicity or falling blood pressure.
Vasopressin possesses antidiuretic and
vasopressor properties.
Clinical Pharmacology
Vasopressin
and desmopressin are the alternative treatments of choice for pituitary
diabetes insipidus. Bedtime desmopressin therapy ameliorates nocturnal enuresis
by decreasing nocturnal urine production. Vasopressin infusion is effective in
some cases of esophageal variceal bleeding and colonic diverticular bleeding.
Dosage
Aqueous
Vasopressin
Synthetic
aqueous vasopressin is a short-acting preparation for intramuscular,
subcutaneous, or intravenous administration. The dose is 5–10 units
subcutaneously or intramuscularly every 3–6 hours for transient diabetes
insipidus and 0.1–0.5 units/min intravenously for gastrointestinal bleeding.
Desmopressin
Acetate
This is the
preferred treatment for most patients with central diabetes insipidus.
Desmopressin may be administered intranasally, intravenously, subcutaneously,
or orally. The typical nasal dosage is 10–40 g (0.1–0.4 mL) daily in one to
three divided doses. Nasal desmopressin is available as a unit dose spray that
delivers 0.1 mL per spray; it is also available with a calibrated nasal tube
that can be made to deliver a more precise dose. Injectable desmopressin is
approximately ten times more bioavailable than intranasal desmopressin. The
dosage by injection is 1–4 g (0.25–1 mL) daily every 12–24 hours as needed for
polyuria, polydipsia, or hypernatremia. For nocturnal enuresis, desmopressin,
10–20 g (0.1–0.2 mL) intranasally at bedtime, is used.
Desmopressin
is also available as an oral preparation. The usual dose is 0.1–0.2 mg every
12–24 hours. Desmopressin is also used for the treatment of coagulopathy in
hemophilia A and von Willebrand's disease (see Chapter 34: Drugs Used in
Disorders of Coagulation).
Parenteral: 0.25, 3.0 mg/vial with diluent for
subcutaneous injection
Thyroid & Antithyroid Drugs
Thyroid
& Antithyroid Drugs: Introduction
The
normal thyroid gland secretes sufficient amounts of the thyroid
hormones—triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine)—to
normalize growth and development, body temperature, and energy levels. These
hormones contain 59% and 65% (respectively) of iodine as an essential part of
the molecule. Calcitonin, the second type of thyroid hormone, is important in
the regulation of calcium metabolism
Homeostasis.
Iodide
Metabolism
The
recommended daily adult iodide (I–)* intake is
Biosynthesis of Thyroid Hormones
Once taken up
by the thyroid gland, iodide undergoes a series of enzymatic reactions that
convert it into active thyroid hormone (Figure 38–1). The first step is the
transport of iodide into the thyroid gland by an intrinsic follicle cell
basement membrane protein called the sodium/iodide symporter (
Iodide
is then oxidized by thyroidal peroxidase to iodine, in which form it rapidly
iodinates tyrosine residues within the thyroglobulin molecule to form
monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is called iodide
organification.
Thyroidal
peroxidase is transiently blocked by high levels of intrathyroidal iodide and
blocked more persistently by thioamide drugs. Two molecules of DIT combine
within the thyroglobulin molecule to form L-thyroxine (T4). One molecule of MIT
and one
molecule of DIT combine to form T3. In addition
to thyroglobulin, other proteins within the gland may be iodinated, but these
iodoproteins do not have hormonal activity. Thyroxine, T3, MIT, and DIT are
released from thyroglobulin by exocytosis and proteolysis of
thyroglobulin at the apical colloid border. The MIT and DIT are deiodinated
within the gland, and the iodine is reutilized. This process of proteolysis is
also blocked by high levels of intrathyroidal iodide. The ratio of T4 to T3
within thyroglobulin is approximately 5:1, so that most of the hormone released
is thyroxine. Most of the T3 circulating in the blood is derived from
peripheral metabolism of thyroxine (see below).
Transport of Thyroid Hormones
T4 and T3 in
plasma are reversibly bound to protein, primarily thyroxine-binding globulin
(TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form. Many
physiologic and pathologic states and drugs affect T4, T3, and thyroid
transport. However, the actual levels of free hormone generally remain normal,
reflecting feedback control.
Peripheral Metabolism of Thyroid Hormones
The primary pathway for the peripheral metabolism
of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodination
of the outer ring, producing 3,5,3'-triiodothyronine (T3), which is three to
four times more potent than T4. Alternatively, deiodination may occur in the
inner ring, producing 3,3',5'-triiodothyronine (reverse T3, or rT3), which is
metabolically inactive (Figure 38– 2). Drugs such as ipodate, -blockers, and
corticosteroids, and severe illness or starvation inhibit the 5'-deiodinase
necessary for the conversion of T4 to T3, resulting in low T3 and high rT3
levels in the serum. Normal levels of thyroid hormone in the serum are
Figure 38–1.
listed in Table 38–1. The low serum levels of T3 and rT3 in normal individuals
are due to the high metabolic clearances of these two compounds.
Thyroid-Pituitary Relationships
Hypothalamic & Pituitary
Hormones. Briefly, hypothalamic cells secrete
thyrotropin-releasing hormone (TRH) (Figure 38–3). TRH is secreted into
capillaries of the pituitary portal venous system, and in the pituitary gland,
TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH).
TSH in turn stimulates an adenylyl cyclase–mediated mechanism in the thyroid
cell to increase the synthesis and release of T4 and T3. These thyroid hormones
act in a negative feedback fashion in the pituitary to block the action of TRH
and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other
hormones or drugs may also affect the release of TRH or TSH.
Autoregulation of the Thyroid Gland
The
thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis
by intrathyroidal mechanisms that are independent of TSH.
These
mechanisms are primarily related to the level of iodine in the blood. Large
doses of iodine inhibit iodide organification (Figure 38–1). In certain disease
states (eg, Hashimoto's thyroiditis), this can result in inhibition of thyroid
hormone synthesis and hypothyroidism.
Abnormal Thyroid Stimulators
In Graves'
disease (see below), lymphocytes secrete a TSH receptor-stimulating antibody
(TSH-R Ab [stim]), also known as thyroid-stimulating immunoglobulin (TSI). This
immunoglobulin binds to the TSH receptor and turns on the gland in the same
fashion as TSH itself. The duration of its effect, however, is much longer than
that of TSH. TSH receptors are also found in orbital fibrocytes, which may be
stimulated by high levels of TSH-R Ab [stim].
Thyroid Hormones
Chemistry
The
structural formulas of thyroxine and triiodothyronine as well as reverse
triiodothyronine (rT3) are shown in Figure 38–2. All of these naturally
occurring molecules are levo (L) isomers. The synthetic dextro (D) isomer of
thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of
the L isomer as evidenced by its lesser ability to suppress TSH secretion and
correct hypothyroidism.
Pharmacokinetics
Thyroxine
is absorbed best in the duodenum and ileum; absorption is modified by
intraluminal factors such as food, drugs, and intestinal flora. Oral
bioavailability of current preparations of Lthyroxine averages 80% (Table
38–1). In contrast, T3 is almost completely absorbed (95%). T4 and T3
absorption appears not to be affected by mild hypothyroidism but may be
impaired in severe myxedema with ileus. These factors are important in
switching from oral to parenteral therapy. For parenteral use, the intravenous
route is preferred for both hormones. In patients with hyperthyroidism, the
metabolic clearances of T4 and T3 are increased and the halflives decreased;
the opposite is true in patients with hypothyroidism. Drugs that induce hepatic
microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin) increase the metabolism of both T4 and T3.
Despite this change in clearance, the normal hormone concentration is
maintained in euthyroid patients as a result of compensatory hyperfunction of
the thyroid. However, patients receiving T4 replacement medication may require
increased dosages to maintain clinical effectiveness. A similar compensation
occurs if binding sites are altered. If TBG sites are increased by pregnancy,
estrogens, or oral contraceptives, there is an initial shift of hormone from
the free to the bound state and a decrease in its rate of elimination until the
normal hormone concentration is restored. Thus, the concentration of total and
bound hormone will increase, but the concentration of free hormone and the steady
state elimination will remain normal. The reverse occurs when thyroid binding
sites are decreased.
Mechanism of Action
A model of thyroid hormone action is depicted in
Figure 38–4, which shows the free forms of thyroid hormones, T4 and T3,
dissociated from thyroid-binding proteins, entering the cell by diffusion or
possibly by active transport. Within the cell, T4 is converted to T3 by
5'-deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3
receptor protein, a member of the c-erboncogene
family, which also includes the steroid hormone receptors and receptors for
vitamins A and D. The T3 receptor exists in two forms, and .
Differing concentrations of receptor forms in different tissues may account for
variations in T3 effect on different tissues. Most of the effects of thyroid on
metabolic processes appear to be mediated by activation of nuclear receptors
that lead to increased formation of RNA and subsequent protein synthesis, eg,
increased formation of Na+/K+ ATPase. This is consistent with the observation
that the action of thyroid is manifested in vivo with a time lag of hours or
days after its administration. Large numbers of thyroid hormone receptors are
found in the most hormone-responsive tissues (pituitary, liver, kidney, heart,
skeletal muscle, lung, and intestine), while few receptor sites occur in
hormone-unresponsive tissues (spleen, testes).
The brain,
which lacks an anabolic response to T3, contains an intermediate number of
receptors. In congruence with their biologic potencies, the affinity of the
receptor site for T4 is about ten times lower than that for T3. The number of
nuclear receptors may be altered to preserve body homeostasis. For example,
starvation lowers both circulating T3 hormone and cellular T3 receptors.
Effects of Thyroid Hormones
The
thyroid hormones are responsible for optimal growth, development, function, and
maintenance of all body tissues.
Excess or
inadequate amounts result in the signs and symptoms of thyrotoxicosis or
hypothyroidism (Table 38–4). Since T3 and T4 are qualitatively similar, they
may be considered as one hormone in the discussion that follows. Thyroid
hormone is critical for nervous, skeletal, and reproductive tissues. Its
effects depend on protein synthesis as well as potentiation of the secretion
and action of growth hormone. Thyroid deprivation in early
life results in irreversible mental retardation and dwarfism—symptoms typical
of congenital cretinism. Effects on growth and calorigenesis are
accompanied by a pervasive influence on metabolism of drugs as well as
carbohydrates, fats, proteins, and vitamins.
Many of these changes are dependent upon or
modified by activity of other hormones. Conversely, the secretion and
degradation rates of virtually all other hormones, including catecholamines,
cortisol, estrogens, testosterone, and insulin, are affected by thyroid status.
Many of the manifestations of thyroid hyperactivity resemble sympathetic
nervous system overactivity (especially in the cardiovascular system), although
catecholamine levels are not increased. Changes in catecholamine-stimulated
adenylyl cyclase activity as measured by cAMP are found with changes in thyroid
activity. Possible explanations include increased numbers of receptors or
enhanced amplification of the receptor signal. Other clinical symptoms
reminiscent of excessive epinephrine activity (and partially alleviated by
adrenoceptor antagonists) include lid lag and retraction, tremor, excessive
sweating, anxiety, and nervousness. The opposite constellation of symptoms is
seen in hypothyroidism.
Thyroid Preparations
See the
Preparations Available section at the end of this chapter for a list of
available preparations. These preparations may be synthetic (levothyroxine,
liothyronine, liotrix) or of animal origin (desiccated thyroid). Synthetic
levothyroxine is the preparation of choice for thyroid replacement and
suppression therapy because of its stability, content uniformity, low cost,
lack of allergenic foreign protein, easy laboratory measurement of serum levels,
and long half-life (7 days), which permits once-daily administration. In
addition, T4 is converted to T3 intracellularly; thus, administration of T4
produces both hormones. Generic levothyroxine preparations can be used because
they provide comparable efficacy and are more cost-effective than branded
preparations. Although liothyronine is three to four times more potent than
levothyroxine, it is not recommended for routine replacement therapy because of
its shorter half-life (24 hours), which requires multiple daily doses; its
higher cost; and the greater difficulty of monitoring its adequacy of replacement by conventional laboratory tests. Furthermore,
because of its greater hormone activity and consequent greater risk of
cardiotoxicity, T3 should be avoided in patients with cardiac disease. It is
best used for short-term suppression of TSH. Because oral administration of T3
is unnecessary, use of the more expensive mixture of thyroxine and liothyronine
(liotrix) instead of levothyroxine is never required. The use of desiccated
thyroid rather than synthetic preparations is never justified, since the
disadvantages of protein antigenicity, product instability, variable hormone
concentrations, and difficulty in laboratory monitoring far outweigh the advantage
of low cost. Significant amounts of T3 found in some thyroid extracts and
liotrix may produce significant elevations in T3 levels and toxicity.
Equivalent doses are 100 mg (
Antithyroid Agents
Reduction
of thyroid activity and hormone effects can be accomplished by agents that
interfere with the production of thyroid hormones; by agents that modify the
tissue response to thyroid hormones; or by glandular destruction with radiation
or surgery. "Goitrogens" are agents that suppress secretion of T3 and
T4 to subnormal levels and thereby increase TSH, which in turn produces
glandular enlargement (goiter). The antithyroid compounds used clinically
include the thioamides, iodides, and radioactive iodine.
Thioamides
The
thioamides methimazole and propylthiouracil are major drugs for treatment of
thyrotoxicosis.
Pharmacodynamics
The
thioamides act by multiple mechanisms.
The major action is to prevent hormone synthesis by
inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine
organification. In addition, they block coupling of the iodotyrosines. They do
not block uptake of iodide by the gland.
Propylthiouracil
and (to a much lesser extent) methimazole inhibit the peripheral deiodination
of T4 and T3 (Figure 38–1). Since the synthesis rather than the release of
hormones is affected, the onset of these agents is slow, often requiring 3–4
weeks before stores of T4 are depleted.
Anion Inhibitors
Monovalent
anions such as perchlorate (ClO4 –), pertechnetate (TcO4–), and thiocyanate
(SCN–) can block uptake of iodide by the gland through competitive inhibition
of the iodide transport mechanism. Since these effects can be overcome by large
doses of iodides, their effectiveness is somewhat unpredictable.
The
major clinical use for potassium perchlorate is to block thyroidal reuptake of
I– in patients with iodide-induced hyperthyroidism (eg, amiodarone-induced
hyperthyroidism).
However,
potassium perchlorate is rarely used clinically because it has been shown to
cause aplastic anemia. Iodides Prior
to the introduction of the thioamides in the 1940s, iodides were the major antithyroid agents; today they are
rarely used as sole therapy.
Pharmacodynamics
Iodides have
several actions on the thyroid. They inhibit organification and hormone release
and decrease the size and vascularity of the hyperplastic gland. In susceptible
individuals, iodides can induce hyperthyroidism (jodbasedow phenomenon) or
precipitate hypothyroidism. In pharmacologic doses (> 6 mg daily), the major
action of iodides is to inhibit hormone release, possibly through inhibition of
thyroglobulin proteolysis. Rapid improvement in thyrotoxic symptoms occurs
within 2–7 days—hence the value of iodide therapy in thyroid storm. In
addition, iodides decrease the vascularity, size, and fragility of a
hyperplastic gland, making the drugs valuable as preoperative preparation for
surgery.
Clinical Use of Iodide
Disadvantages
of iodide therapy include an increase in intraglandular stores of iodine, which
may delay onset of thioamide therapy or prevent use of radioactive iodine
therapy for several weeks. Thus, iodides should be initiated after onset of
thioamide therapy and avoided if treatment with radioactive iodine seems
likely. Iodide should not be used alone, because the gland will escape from the
iodide block in 2–8 weeks, and its withdrawal may produce severe exacerbation
of thyrotoxicosis in an iodine-enriched gland. Chronic use of iodides in
pregnancy should be avoided, since they cross the placenta and can cause fetal
goiter. In radiation emergencies, the thyroidblocking effects of potassium
iodide can protect the gland from subsequent damage if administered before
radiation exposure.
Toxicity
Adverse
reactions to iodine (iodism) are uncommon and in most cases reversible upon
discontinuance. They include acneiform rash (similar to that of bromism),
swollen salivary glands, mucous membrane ulcerations, conjunctivitis,
rhinorrhea, drug fever, metallic taste, bleeding disorders and, rarely,
anaphylactoid reactions.
Radioactive Iodine
131I
is the only isotope used for treatment of thyrotoxicosis (others are used in
diagnosis).
Administered orally
in solution as sodium 131I, it is rapidly absorbed, concentrated by the
thyroid, and incorporated into storage follicles. Its therapeutic effect
depends on emission of rays with an effective half-life of 5 days and a
penetration range of 400–2000 m. Within a few weeks after administration,
destruction of the thyroid parenchyma is evidenced by epithelial swelling and
necrosis, follicular disruption, edema, and leukocyte infiltration. Advantages
of radioiodine include easy administration, effectiveness, low expense, and
absence of pain. Fears of radiation-induced genetic damage, leukemia, and
neoplasia have not been realized after more than 30 years of clinical
experience with radioiodine. Radioactive iodine should not be administered to
pregnant women or nursing mothers, since it crosses the placenta and is
excreted in breast milk.
Adrenoceptor-Blocking
Agents
Beta blockers
without intrinsic sympathomimetic activity are effective therapeutic adjuncts
in the management of thyrotoxicosis since many of these symptoms mimic those
associated with sympathetic stimulation. Propranolol has been the -blocker most
widely studied and used in the therapy of thyrotoxicosis.
Hypothyroidism
Hypothyroidism
is a syndrome resulting from deficiency of thyroid hormones and is manifested
largely by a reversible slowing down of all body functions
In infants
and children, there is striking retardation of growth and development that
results in dwarfism and irreversible mental retardation.The etiology and
pathogenesis of hypothyroidism are outlined in Table 38–5. Hypothyroidism can
occur with or without thyroid enlargement (goiter). The laboratory diagnosis of
hypothyroidism in the adult is easily made by the combination of a low free
thyroxine (or low free thyroxine index) and elevated serum TSH (Table 38–2).
The most common cause of hypothyroidism in the
Management of Hypothyroidism
Except for hypothyroidism caused by drugs, which
can be treated by simply removing the depressant agent, the general strategy of
replacement therapy is appropriate. The most satisfactory preparation is
levothyroxine. Infants and children require more T4 per kilogram of body weight
than adults. The average dosage for an infant 1–6 months of age is 10–15
g/kg/d, whereas the average dosage for an adult is about 1.7 g/kg/d. There is
some variability in the absorption of thyroxine, so this dosage may vary from
patient to patient. Because of the long half-life of thyroxine, the dose can be
given once daily. Children should be monitored for normal growth and
development. Serum TSH and free thyroxine should be measured at regular
intervals and maintained within the normal range. It takes 6–8 weeks after
starting a given dose of thyroxine to reach steady state levels in the
bloodstream. Thus, dosage changes should be made slowly. In long-standing
hypothyroidism, in older patients, and in patients with underlying cardiac
disease, it is imperative to start treatment with reduced dosage.
In such adult
patients, levothyroxine is given in a dosage of 12.5–25 g/d for 2 weeks,
increasing the daily dose by
Special Problems in Management of Hypothyroidism
Myxedema and
Coronary Artery Disease
Since
myxedema frequently occurs in older persons, it is often associated with
underlying coronary artery disease. In this situation, the low levels of
circulating thyroid hormone actually protect the heart against increasing
demands that could result in angina pectoris or myocardial infarction. Correction
of myxedema must be done cautiously to avoid provoking arrhythmia, angina, or
acute myocardial infarction.
Antithyroid Drug Therapy
Drug
therapy is most useful in young patients with small glands and mild disease.
Methimazole or propylthiouracil is administered until the disease undergoes
spontaneous remission. This is the only therapy that leaves an intact thyroid
gland, but it does require a long period of treatment and observation (1–2
years), and there is a 60–70% incidence of relapse. Antithyroid drug therapy is
usually begun with large divided doses, shifting to maintenance therapy with
single daily doses when the patient becomes clinically euthyroid. However, mild
to moderately severe thyrotoxicosis can often be controlled with methimazole
given in a single morning dose of 30–40 mg; once-daily dosing may enhance
adherence. Maintenance therapy requires 5–15 mg once daily. Alternatively,
therapy is started with propylthiouracil, 100–150 mg every 6 or 8 hours,
followed after 4–8 weeks by gradual reduction of the dose to the maintenance
level of 50–150 mg once daily. In addition to inhibiting iodine organification,
propylthiouracil also inhibits the conversion of T4 to T3, so it brings the
level of activated thyroid hormone down more quickly than does methimazole. The
best clinical guide to remission is reduction in the size of the goiter.
Laboratory tests most useful in monitoring the course of therapy are serum T3
by RIA, FT4 or FT4I, and serum TSH.
Reactivation
of the autoimmune process may occur when the dosage of antithyroid drug is
lowered during maintenance therapy and TSH begins to drive the gland. TSH
release can be prevented by the daily administration of 50–150 g of
levothyroxine with 5–15 mg of methimazole or 50–150 mg of propylthiouracil for
the second year of therapy. The relapse rate with this program is probably
comparable to the rate with antithyroid therapy alone, but the risk of
hypothyroidism and overtreatment is avoided.
Thyroidectomy
A near-total thyroidectomy is the treatment of
choice for patients with very large glands or multinodular goiters. Patients
are treated with antithyroid drugs until euthyroid (about 6 weeks). In
addition, for 2 weeks prior to surgery, they receive saturated solution of
potassium iodide, 5 drops twice daily, to diminish vascularity of the gland and
simplify surgery. About 80–90% of patients will require thyroid supplementation
following near-total thyroidectomy.
Radioactive
Iodine
Radioiodine
therapy utilizing 131I is the preferred treatment for most patients over 21
years of age. In patients without heart disease, the therapeutic dose may be
given immediately in a range of 80–120 Ci/g of estimated thyroid weight
corrected for uptake. In patients with underlying heart disease or severe
thyrotoxicosis and in elderly patients, it is desirable to treat with
antithyroid drugs (preferably methimazole) until the patient is euthyroid. The
medication is then stopped for 5–7 days before the appropriate dose of 131I is
administered. Iodides should be avoided to ensure maximal 131I uptake. Six to
12 weeks following the administration of radioiodine, the gland will shrink in
size and the patient will usually become euthyroid or hypothyroid. A second
dose may be required in some patients. Hypothyroidism occurs in about 80% of
patients following radioiodine therapy.
Serum FT4 and
TSH levels should be monitored. When hypothyroidism develops, prompt
replacement with oral levothyroxine, 50–150 g daily, should be instituted.
Adjuncts to Antithyroid Therapy
During the
acute phase of thyrotoxicosis, -adrenoceptor-blocking agents without intrinsic
sympathomimetic activity are extremely helpful. Propranolol, 20–40 mg orally
every 6 hours, will control tachycardia, hypertension, and atrial fibrillation.
Propranolol is gradually withdrawn as serum thyroxine levels return to normal.
Diltiazem, 90–120 mg three or four times daily, can be used to control
tachycardia in patients in whom -blockers are contraindicated, eg, those with
asthma. Other calcium channel blockers may not be as effective as diltiazem. Adequate
nutrition and vitamin supplements are essential. Barbiturates accelerate T4
breakdown (by hepatic enzyme induction) and may be helpful both as sedatives
and to lower T4 levels.
Pancreatic Hormones & Antidiabetic Drugs
The
endocrine pancreas in the adult human consists of approximately 1 million
islets of Langerhans interspersed throughout the pancreatic gland. Within the
islets, at least four hormone-producing cells are present (Table 41–1). Their
hormone products include insulin, the storage and anabolic hormone of
the body; islet amyloid polypeptide (IAPP, or amylin), whose metabolic
function remains undefined; glucagon, the hyperglycemic factor that
mobilizes glycogen stores; somatostatin, a universal inhibitor of
secretory cells; and pancreatic peptide, a small protein that
facilitates digestive processes by a mechanism not yet clarified. The elevated
blood glucose associated with diabetes mellitus results from absent or
inadequate pancreatic insulin secretion, with or without concurrent impairment
of insulin action. The disease states underlying the diagnosis of diabetes
mellitus are now classified into four categories: type 1,
"insulin-dependent diabetes," type 2, "noninsulin-dependent
diabetes," type 3, "other," and type 4, "gestational
diabetes mellitus". The hallmark of type 1 diabetes is selective B cell
destruction and severe or absolute insulin deficiency. Administration of
insulin is essential in patients with type 1 diabetes. Type 1 diabetes is
further subdivided into immune and idiopathic causes. The immune form is the
most common form of type 1 diabetes. In the
Type 2 Diabetes Mellitus
Type 2 diabetes is characterized by tissue resistance to the
action of insulin combined with a relative deficiency in insulin secretion. A
given individual may have more resistance or more B cell deficiency, and the
abnormalities may be mild or severe. Although insulin is
Type 1 Diabetes Mellitus produced by the B cells
in these patients, it is inadequate to overcome the resistance, and the blood
glucose rises. The impaired insulin action also affects fat metabolism,
resulting in increased free fatty acid flux and triglyceride levels, and
reciprocally low high-density lipoprotein (HDL) levels.
Individuals
with type 2 diabetes may not require insulin to
survive, but 30% or more will benefit from insulin therapy to control the blood
glucose. It is likely that 10–20% of individuals in whom type 2 diabetes was
initially diagnosed actually have both type 1 and type 2, or have a slowly progressing
type 1, and ultimately will require full insulin replacement. Although persons
with type 2 diabetes ordinarily will not develop ketosis, ketoacidosis may
occur as the result of stress such as infection or use of medication that
enhances resistance, eg, corticosteroids.
Dehydration
in untreated and poorly controlled individuals with type 2 diabetes can lead to
a life-threatening condition called "non-ketotic hyperosmolar coma".
In this condition, the blood glucose may rise to 6–20 times the normal range
and an altered mental state develops or the person loses consciousness.
Urgent medical care and rehydration is required.
Type
3 Diabetes Mellitus
The type 3
designation refers to multiple other specific causes of an elevated
blood glucose: nonpancreatic diseases, drug therapy, etc.
Type
4 Diabetes Mellitus
Gestational
Diabetes (GDM) is defined as any abnormality in glucose levels
noted for the first time during pregnancy. Gestational diabetes is diagnosed in
approximately 4% of all pregnancies in the
Insulin
Chemistry
Insulin is a
small protein with a molecular weight in humans of 5808. It contains 51 amino acids
arranged in two chains (A and B) linked by disulfide bridges; there are species
differences in the amino acids of both chains. Proinsulin, a long single-chain
protein molecule, is processed within the Golgi apparatus and packaged into
granules, where it is hydrolyzed into insulin and a residual connecting segment
called C-peptide by removal of four amino acids .
Insulin and C-peptide are secreted in equimolar
amounts in response to all insulin secretagogues; a small quantity of
unprocessed or partially hydrolyzed proinsulin is released as well. While
proinsulin may have some mild hypoglycemic action, C-peptide has no known
physiologic function. Granules within the B cells store the insulin in the form
of crystals consisting of two atoms of zinc and six molecules of insulin. The
entire human pancreas contains up to 8 mg of insulin, representing
approximately 200 biologic units. Originally, the unit was defined on the basis
of the hypoglycemic activity of insulin in rabbits. With improved purification
techniques, the unit is presently defined on the basis of weight, and present
insulin standards used for assay purposes contain 28 units per milligram.
Insulin Secretion
Insulin is released from pancreatic B cells at a low
basal rate and at a much higher stimulated rate in response to a variety of
stimuli, especially glucose.
Other stimulants such as other sugars (eg,
mannose), certain amino acids (eg, leucine, arginine), and vagal activity are
recognized. One mechanism of stimulated insulin release is diagrammed in Figure
41–2. As shown in the figure, hyperglycemia results in increased intracellular
ATP levels, which close the ATP-dependent potassium channels. Decreased outward
potassium efflux results in depolarization of the B cell and opening of
voltage-gated calcium channels.
The resulting
increased intracellular calcium triggers secretion of the hormone. As noted
below, the insulin secretagogue drug group (sulfonylureas, meglitinides, and
D-phenylalanine) exploits parts of this mechanism.
The liver and kidney are the two main organs that
remove insulin from the circulation. The liver normally clears the blood of
approximately 60% of the insulin released from the pancreas by virtue of its
location as the terminal site of portal vein blood flow, with the kidney
removing 35–40% of the endogenous hormone. However, in insulin-treated
diabetics receiving subcutaneous insulin injections, this ratio is reversed,
with as much as 60% of exogenous insulin being cleared by the kidney and the
liver removing no more than 30–40%. The half-life of circulating insulin is 3–5
minutes.
The
Insulin Receptor
Once insulin has entered the circulation, it is
bound by specialized receptors that are found on the membranes of most tissues.
The biologic responses promoted by these insulin-receptor complexes have been
identified in the primary target tissues, ie, liver, muscle, and adipose
tissue. The receptors bind insulin with high specificity and affinity in the
picomolar range. The full insulin receptor consists of two covalently linked
heterodimers, each containing an subunit, which is entirely extracellular and
constitutes the recognition site, and a subunit that spans the membrane (Figure
41–3). The subunit contains a tyrosine kinase. The binding of an insulin
molecule to the subunits at the outside surface of the cell activates the
receptor and through a conformational change brings the catalytic loops of the
opposing cytoplasmic subunits into closer proximity thereby facilitating
phosphorylation of tyrosine residues and tyrosine kinase activity. The first
proteins to be phosphorylated by the activated receptor tyrosine kinases are
the docking proteins, insulin receptor substrate-1 and -2 (IRS-1, IRS-2).
Insulin Degradation
After tyrosine phosphorylation at several
critical sites, IRS-1 and IRS-2 bind to and activate other kinases—most
importantly phosphatidylinositol-3-kinase—that produce further phosphorylations
or to an adaptor protein such as growth factor receptor-binding protein 2 that
translates the insulin signal to a guanine nucleotidereleasing factor that
ultimately activates the GTP binding protein ras, and the mitogen activated
protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine
kinases have binding specificity with downstream molecules based on their
surrounding 4–5 amino acid sequences or motifs that recognize specific Src
homology 2 (SH2) domains on the other protein. This network of phosphorylations
within the cell represents insulin's second message and results in multiple
effects including translocation of glucose transporters (especially GLUT-4,
Table 41–2) to the cell membrane with a resultant increase in glucose uptake;
glycogen synthase activity and increased glycogen formation; multiple effects
on protein synthesis, lipolysis, and lipogenesis; and activation of
transcription factors that enhance DNA synthesis and cell growth and division. Figure 41–3. Various hormonal agents (eg, glucocorticoids)
lower the affinity of insulin receptors for insulin; growth hormone in excess
increases this affinity slightly. Aberrant serine and threonine phosphorylation
of the insulin receptor subunits or IRS molecules may result in insulin
resistance and functional receptor down-regulation.
Effects
of Insulin on Its Targets
Insulin
promotes the storage of fat as well as glucose (both sources of energy) within
specialized target cells (Figure 41–4) and influences cell growth and the
metabolic functions of a wide variety of tissues (Table 41–3).
Characteristics of Available Insulin Preparations
Commercial insulin preparations differ in a
number of ways, including differences in the recombinant DNA production techniques,
amino acid sequence, concentration, solubility, and the time of onset and
duration of their biologic action. In 2003, seventeen insulin formulations were
available in the
Principal Types and Duration of Action of Insulin Preparations
Four principal types of insulins are available:
(1) rapid-acting, with very fast onset and short duration; (2) short-acting,
with rapid onset of action; (3) intermediate-acting; and (4) long-acting, with
slow onset of action (Figure 41–5, Table 41–4). Rapid-acting and short-acting
insulins are dispensed as clear solutions at neutral pH and contain small
amounts of zinc to improve their stability and shelf-life. All other commercial
insulins have been modified to provide prolonged action and are, with the exception
of insulin glargine, dispensed as turbid suspensions at neutral pH with either
protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin) or
varying concentrations of zinc in acetate buffer (ultralente and lente
insulins). Insulin glargine is the only soluble long-acting insulin. The goal
of subcutaneous insulin therapy is to replace the normal basal (overnight,
fasting, and between meal) as well as prandial (mealtime) insulin. Current
regimens generally use intermediate- or long-acting insulins to provide basal
or background coverage, and rapid-acting or short-acting insulin to meet the
mealtime requirements. The latter insulins are given as supplemental doses to
correct high blood sugars. Intensive therapy ("tight control") attempts
to restore near-normal glucose patterns throughout the day while minimizing the
risk of hypoglycemia. An exact reproduction of the normal glycemic profile is
technically not possible because of the limitations inherent in subcutaneous
administration of insulin. The most sophisticated insulin regimen delivers
rapid-acting insulin through a continuous subcutaneous insulin infusion device;
alternative intensive regimens referred to as multiple daily injections (MDI)
use long-acting or intermediate-acting insulins with multiple boluses of
rapid-acting or short-acting insulin. Conventional therapy presently consists
of split-dose injections of mixtures of rapid- or short-acting and
intermediate-acting insulins.
Rapid-Acting Insulin
Two rapid-acting insulin analogs are commercially
available: insulin lispro and insulin aspart.
The
rapid-acting insulins permit more physiologic prandial insulin replacement
because their rapid onset and early peak action more closely mimics normal
endogenous prandial insulin secretion than does regular insulin, and they have
the additional benefit of allowing insulin to be taken immediately before the
meal without sacrificing glucose control. Their duration of action is rarely
more than 3–5 hours, which decreases the risk of late postmeal hypoglycemia.
They have the lowest variability of absorption of all available insulin
formulations.
Insulin
lispro, the first monomeric insulin analog to be marketed, is produced by
recombinant technology wherein two amino acids near the carboxyl terminal of
the B chain have been reversed in position: proline at position B28 has been
moved to B29 and lysine at position B29 has been moved to B28 (Figure 41–1).
Reversing these two amino acids does not interfere in any way with insulin
lispro's binding to the insulin receptor, its circulating half-life, or with
its immunogenicity, all of which are identical with those of human regular
insulin. However, the advantage of this analog is its very low propensity—in
contrast to human insulin—to self-associate in antiparallel fashion and form
dimers. To enhance the shelf-life of insulin in vials, insulin lispro is
stabilized into hexamers by a cresol preservative. When injected
subcutaneously, the drug quickly dissociates into monomers and is rapidly
absorbed with onset of action within 5–15 minutes, and reaching peak activity
as early as 1 hour. The time to peak action is relatively constant, regardless
of the dose. Its duration is seldom more than 3–5 hours.
Insulin
lispro has a low variability of absorption (5%) of all the commercial insulin
preparations— compared with 25% for regular insulin and 25–50% or more for
intermediate-acting and long-acting insulins. Although not specifically
approved for use in continuous subcutaneous insulin infusion (CSII) pumps, when
used in these devices or in intensive insulin regimens, insulin lispro is
associated with significantly improved glycemic control compared with regular
insulin, without increased incidence of hypoglycemia. Insulin aspart is created
by the substitution of the B28 proline with a negatively charged aspartic acid
(Figure 41–1). This modification reduces the normal ProB28 and GlyB23
monomer-monomer interaction, thereby inhibiting insulin self-aggregation.
Insulin aspart rapidly breaks into monomers after subcutaneous injection,
displays an onset of action within 10–20 minutes, and exerts a peak effect
within 1 hour, with an average duration of action of no longer than 3–5 hours.
Its absorption and activity profile is similar to insulin lispro and more
reproducible than regular insulin, but it has similar binding, activity, and
mitogenicity characteristics to regular insulin and equivalent immunogenicity.
Insulin aspart is approved for subcutaneous administration by injection as well
as through CSII devices.
Short-Acting Insulin
Regular insulin is a short-acting soluble
crystalline zinc insulin made by recombinant DNA techniques to produce a
molecule identical to human insulin. Its effect appears within 30 minutes and
peaks between 2 and 3 hours after subcutaneous injection and generally lasts
5–8 hours. In high concentrations, eg, in the vial, regular insulin molecules
self-aggregate in antiparallel fashion to form dimers that stabilize around
zinc ions to create insulin hexamers. The hexameric nature of regular insulin
causes a delayed onset and prolongs the time to peak action. After subcutaneous
injection, the insulin hexamers are too large and bulky to be transported
across the vascular endothelium into the bloodstream.
As the
insulin depot is diluted by interstitial fluid and the concentration begins to
fall, the hexamers break down into dimers and finally monomers. This results in
three different rates of absorption of the injected insulin, with the final
monomeric phase having the fastest uptake out of the injection site. As with
all older insulin formulations, the duration of action as well as the time of
onset and the intensity of peak action increase with the size of the dose.
Clinically, this is a critical issue because the pharmacokinetics and
pharmacodynamics of small doses of regular, NPH, lente, and ultralente,
insulins differ greatly from those of large doses. Short-acting soluble insulin
is the only type that should be administered intravenously as the dilution
causes the hexameric insulin to immediately dissociate into monomers. It is
particularly useful for intravenous therapy in the management of diabetic
ketoacidosis and when the insulin requirement is changing rapidly, such as
after surgery or during acute infections.
Intermediate-Acting and Long-Acting Insulins
Lente
Insulin
Lente insulin
is a mixture of 30% semilente (an amorphous precipitate of insulin with zinc
ions in acetate buffer that has a relatively rapid onset of action) with 70%
ultralente insulin (a poorly soluble crystal of zinc insulin that has a delayed
onset and prolonged duration of action). These two components provide a
combination of relatively rapid absorption with sustained long action, making
lente insulin a useful therapeutic agent. As with regular insulin, the time of
onset, time to peak, and duration of action are dose-dependent. NPH (Neutral
Protamine Hagedorn, or Isophane) Insulin NPH insulin is an intermediate-acting insulin wherein absorption and the
onset of action is delayed by combining appropriate amounts of insulin and
protamine so that neither is present in an uncomplexed form
("isophane"). Protamine is a mixture of six major and some minor
compounds of similar structure isolated from the sperm of rainbow trout. They
appear to be basic, arginine-rich peptides with an average molecular weight of
approximately 4400. To form an isophane complex (one in which neither component
retains any free binding sites), approximately a 1:10 ratio by weight of
protamine to insulin is required, representing approximately six molecules of
insulin per molecule of protamine. After subcutaneous injection, proteolytic
tissue enzymes degrade the protamine to permit absorption of insulin. The onset
and duration of action of NPH insulin are similar to those of lente insulin
(Figure 41–5); it is usually mixed with regular, lispro, or aspart insulin and
given two to four times daily for insulin replacement in patients with type 1
diabetes. The dose regulates the action profile, specifically, small doses have
lower, earlier peaks and a short duration of action with the converse true for
large doses.
Ultralente Insulin
There has
recently been a resurgence in the use of ultralente insulin, in combination
with multiple injections of rapid-acting insulin, as a means of attempting
optimal control in patients with type 1 diabetes. Human insulin (Humulin U
[Lilly]) is the only ultralente insulin available in the
Insulin
Glargine
Insulin
glargine is a soluble, "peakless" (ie, having a broad plasma
concentration plateau), ultralong- acting insulin analog. This product was
designed to provide reproducible, convenient, background insulin replacement.
The attachment of two arginine molecules to the B chain carboxyl terminal and
substitution of a glycine for asparagine at the A21 position created an analog
that is soluble in solution but precipitates in the more neutral body pH after
subcutaneous injection. Individual insulin molecules slowly dissolve away from
the crystalline depot and provide a low, continuous level of circulating
insulin. Insulin glargine has a slow onset of action (1–1.5 hours) and achieves
a maximum effect after 4–5 hours. This maximum activity is maintained for 11–24
hours or longer. Glargine is usually given once daily, although some very
insulin-sensitive individuals will benefit from split (twice a day) dosing. To
maintain solubility, the formulation is unusually acidic (pH 4.0) and insulin
glargine should not be mixed with other insulin. Separate syringes must be used
to minimize the risk of contamination and subsequent loss of efficacy. The
absorption pattern of insulin glargine appears to be independent of the
anatomic site of injection, and this drug is associated with less
immunogenicity than human insulin in animal studies. Glargine's interaction
with the insulin receptor is similar to that of native insulin and shows no
increase in mitogenic activity in vitro. It has sixfold to sevenfold greater
binding than native insulin to the IGF1 receptor, but the clinical significance
of this is unclear.
Mixtures
of Insulins
Since
intermediate-acting insulins require several hours to reach adequate
therapeutic levels, their use in type 1 diabetic patients
requires supplements of lispro, aspart, or regular insulin before meals. For
convenience, these are often mixed together in the same syringe before
injection. When regular insulin is used, NPH is preferred to lente insulin as
the intermediate-acting component in these mixtures because increased
proportions of lente to regular insulin may retard the rapid action of admixed
regular insulin, particularly if not injected immediately after mixing. This is
due to precipitation of the regular insulin by excess zinc. Premixed
formulations of 70%/30% NPH and regular and 50%/50% NPH and regular are
available in the
Species
of Insulin
Beef
and Pork Insulins
Historically,
commercial insulin in the
Human
Insulins
Mass
production of human insulin by recombinant DNA techniques is now carried out by
inserting the human proinsulin gene into Escherichia coli or yeast and
treating the extracted proinsulin to form the human insulin molecule.
Human insulin from E coli is available for
clinical use as Humulin (Lilly) and dispensed as either regular, NPH, lente, or
ultralente Humulin. Human insulin prepared biosynthetically in yeast is
marketed by Novo Nordisk as human insulin injection in regular, lente, and NPH
forms: Novolin R, Monotard Human Insulin (Novolin L), and Novolin N. The same
company also produces a human insulin marketed as Velosulin (regular) that
contains a phosphate buffer. This reduces aggregation of regular insulin
molecules when used in infusion pumps. However, because of the tendency of
phosphate to precipitate zinc ions, Velosulin should not be mixed with any of
the lente insulins.
Human
insulins appear to be as effective as—and considerably less immunogenic in
diabetic patients than—beef-pork insulin mixtures and slightly less immunogenic
than pork insulin.
Portable Pen Injectors
To facilitate multiple subcutaneous injections of
insulin, particularly during intensive insulin therapy, portable pen-sized
injectors have been developed. These contain cartridges of insulin and
replaceable needles. Disposable insulin pens are also available for selected
formulations. These include regular insulin, insulin lispro, insulin aspart,
NPH insulin, and premixed 70%/30% and 50%/50% NPH/regular, 75% NPL/25% lispro,
50% NPL/50% lispro, and 70% NPA/30% aspart insulin. They have been well
accepted by patients because they eliminate the need to carry syringes and
bottles of insulin to the workplace and while traveling. Continuous
Subcutaneous Insulin Infusion Devices (Csii, Insulin Pumps) Continuous
subcutaneous insulin infusion devices are external open-loop pumps for insulin
delivery. The devices have a user-programmable pump that delivers
individualized basal and bolus insulin replacement doses based on blood glucose
self-monitoring results. Normally, the 24-hour background basal rates are
relatively constant from day to day, although temporarily altered rates can be
superimposed to adjust for a short-term change in requirement. For example, the
basal delivery rate might need to be decreased for several hours because of the
increased insulin sensitivity associated with strenuous activity. In contrast,
the bolus amounts frequently vary and are used to correct high blood glucose
levels and to cover mealtime insulin requirements based on the carbohydrate
content of the food and concurrent activity. The pump—which contains an insulin
reservoir, the program chip, the keypad, and the display screen—is about the
size of a pager. It is usually placed on a belt or in a pocket, and the insulin
is infused through thin plastic tubing that is connected to the subcutaneously
inserted infusion set. The abdomen is the favored site for the infusion set,
although flanks and thighs are also used. The insulin reservoir, tubing, and
infusion set need to be changed using sterile techniques every 2 or 3 days.
CSII delivery is regarded as the most physiologic method of insulin
replacement.
The use of
these devices is encouraged for individuals who are unable to obtain target
control while on multiple injection regimens and in circumstances where
excellent glycemic control is desired, such as during pregnancy. Their optimal
use requires responsible involvement and commitment by the patient. Velosulin
(a regular insulin) and insulin aspart are the only insulins specifically
approved for pump use. Although not formally approved for pump use, insulin
lispro has been successfully delivered through CSII devices since it became
commercially available. Insulins aspart and lispro are preferred pump insulins
because their favorable pharmacokinetic attributes allow glycemic control
without increasing the risk of hypoglycemia.
Inhaled
Insulin
Clinical
trials are in progress to evaluate the safety and efficacy of finely powdered
and aerosolized insulin formulations delivered by inhalation. Insulin is
readily absorbed into the bloodstream through alveolar walls, but the challenge
has been to create particles that are small enough to pass through the
bronchial tree without being trapped and still enter the alveoli in sufficient
amounts to have a clinical effect. Insulin delivered by the inhaled route
should have a rapid onset and a relatively short duration of action and could
be used to cover mealtime insulin requirements or to correct high glucose
levels, but not to provide background or basal insulin coverage. Safety
concerns regarding pulmonary fibrosis or hypertension and excessive antibody
formation may preclude or delay approval.
Treatment with Insulin
The current classification
of diabetes mellitus identifies a group of patients who have virtually no
insulin secretion and whose survival depends on administration of exogenous
insulin. This insulindependent group (type 1) represents 5–10% of the diabetic
population in the
Benefit of Glycemic Control in Diabetes Mellitus
The consensus
of the American Diabetes Association is that intensive insulin therapy
associated with comprehensive self-management training should become standard
therapy in most type 1 patients after puberty (see Benefits of Tight Glycemic
Control in Type 1 Diabetes). Exceptions include patients with advanced renal
disease and the elderly, since the risks of hypoglycemia outweigh the benefit
of tight glycemic control in these groups. In children under the age of 7
years, the extreme susceptibility of the developing brain to damage from
hypoglycemia contraindicates attempts at intensive glycemic control,
particularly since diabetic complications do not seem to occur until some years
after the onset of puberty. A similar conclusion regarding the benefits oftight
control in type 2 diabetes was reached as the result of a large study in the
Complications of Insulin Therapy
Hypoglycemia
Mechanisms and Diagnosis
Hypoglycemic reactions are the most common
complication of insulin therapy. They may result from a delay in taking a meal,
inadequate carbohydrate consumed, unusual physical exertion, or a dose of
insulin that is too large for immediate needs. Rapid development of
hypoglycemia in individuals with intact hypoglycemic awareness causes signs of
autonomic hyperactivity, both sympathetic (tachycardia, palpitations, sweating,
tremulousness) and parasympathetic (nausea, hunger) and may progress to
convulsions and coma if untreated. In individuals exposed to frequent
hypoglycemic episodes during tight glycemic control, autonomic warning signals
of hypoglycemia are less frequent or even absent. This dangerous acquired
condition is termed "hypoglycemic unawareness." When patients lack
the early warning signs of low blood glucose, they may not take corrective
measures in time. In patients with persistent, untreated hypoglycemia, the
manifestations of insulin excess may develop—confusion, weakness, bizarre
behavior, coma, seizures—at which point they may not be able to procure or
safely swallow glucose-containing foods. Hypoglycemic awareness may be restored
by preventing frequent hypoglycemic episodes. An identification bracelet,
necklace, or card in the wallet or purse, as well as some form of rapidly
absorbed glucose, should be carried by every diabetic who is receiving
hypoglycemic drug therapy.
Treatment of Hypoglycemia
All of the
manifestations of hypoglycemia are relieved by glucose administration. To
expedite absorption, simple sugar or glucose should be given, preferably in a
liquid form. To treat mild hypoglycemia in a patient who is conscious and able
to swallow, orange juice, glucose gel, or any sugar-containing beverage or food
may be given. If more severe hypoglycemia has produced unconsciousness or
stupor, the treatment of choice is to give 20–50 mL of 50% glucose solution by
intravenous infusion over a period of 2–3 minutes. If intravenous therapy is
not available, 1 mg of glucagon injected either subcutaneously or
intramuscularly will usually restore consciousness within 15 minutes to permit
ingestion of sugar. If the patient is stuporous and glucagon is not available,
small amounts of honey or syrup can be inserted into the buccal pouch. In
general, however, oral feeding is contraindicated in unconscious patients.
Emergency medical services should be called for all episodes of severely
impaired consciousness.
Immunopathology of Insulin Therapy
At least five
molecular classes of insulin antibodies may be produced during the course of
insulin therapy in diabetes: IgA, IgD, IgE, IgG, and IgM. There are two major
types of immune disorders in these patients:
Insulin Allergy
Insulin
allergy, an immediate type hypersensitivity, is a rare condition in which local
or systemic urticaria results from histamine release from tissue mast cells
sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis
results. Because sensitivity is often to noninsulin protein contaminants, the
highly purified and human insulins have markedly reduced the incidence of
insulin allergy, especially local reactions.
Immune Insulin Resistance
A low titer
of circulating IgG anti-insulin antibodies that neutralize the action of
insulin to a negligable extent develops in most insulin-treated patients.
Rarely, the titer of insulin antibodies will lead to insulin resistance and may
be associated with other systemic autoimmune processes such as lupus
erythematosus.
Lipodystrophy at Injection Sites
Injection of
older insulin preparations sometimes led to atrophy of subcutaneous fatty
tissue at the site of injection. This type of immune complication is almost
never seen since the development of human insulin preparations of neutral pH.
Injection of these newer preparations directly into the atrophic area often
results in restoration of normal contours. Hypertrophy of subcutaneous fatty
tissue remains a problem, even with the purified insulins, if injected
repeatedly at the same site. However, this may be corrected by avoidance of
that specific injection site or with liposuction.
Oral Antidiabetic Agents
Four categories of oral antidiabetic agents are now
available in the
The
thiazolidinediones, under development since the early 1980s, are very effective
agents that reduce insulin resistance. -Glucosidase inhibitors have a
relatively weak antidiabetic effect and significant adverse effects, and they
are used primarily as adjunctive therapy in individuals who cannot achieve
their glycemic goals with other medications.
Insulin
Secretagogues: Sulfonylureas
Mechanism of Action
The major
action of sulfonylureas is to increase insulin release from the pancreas (Table
41–5). Two additional mechanisms of action have been proposed—a reduction of
serum glucagon levels and closure of potassium channels in extrapancreatic
tissues. The latter is of unknown clinical significance.
Insulin
Release from Pancreatic B Cells
Sulfonylureas bind to a 140 kDa high-affinity
sulfonyl-urea receptor that is associated with a B cell inward rectifier
ATP-sensitive potassium channel. Binding of a sulfonylurea inhibits the efflux
of potassium ions through the channel (Figure 41–2) and results in
depolarization. Depolarization, in turn, opens a voltage-gated calcium channel
and results in calcium influx and the release of preformed insulin.
Reduction
of Serum Glucagon Concentrations
Chronic administration of sulfonylureas to type 2
diabetics reduces serum glucagon levels, which may contribute to the hypoglycemic
effect of the drugs. The mechanism for this suppressive effect of sulfonylureas
on glucagon levels is unclear but appears to involve indirect inhibition due to
enhanced release of both insulin and somatostatin, which inhibit A cell
secretion.
Potassium
Channel Closure in Extrapancreatic Tissues
Insulin
secretagogues bind to sulfonylurea receptors in potassium channels in
extrapancreatic tissues but the binding affinity varies among the drug classes
and is much less avid than for the B cell receptors. The clinical significance
of extrapancreatic binding is not known.
Table 41–6. Sulfonureas.
First-Generation
Sulfonylureas Tolbutamide is well absorbed but rapidly metabolized in
the liver. Its duration of effect is relatively short, with an elimination half-life
of 4–5 hours, and it is best administered in divided doses. Because of its
short half-life, it is the safest sulfonylurea for use in elderly diabetics.
Prolonged hypoglycemia has been reported rarely,
mostly in patients receiving certain drugs (eg, dicumarol, phenylbutazone, some
sulfonamides) that inhibit the metabolism of tolbutamide. Chlorpropamide has
a half-life of 32 hours and is slowly metabolized in the liver toproducts that
retain some biologic activity; approximately 20–30% is excreted unchanged in
the urine. Chlorpropamide also interacts with the drugs mentioned above that
depend on hepatic oxidative catabolism, and it is contraindicated in patients
with hepatic or renal insufficiency. Dosages in excess of 500 mg daily increase
the risk of jaundice. The average maintenance dosage is 250 mg daily, given as
a single dose in the morning. Prolonged hypoglycemic reactions are more common
in elderly patients, and the drug is contraindicated in this group. Other side
effects include a hyperemic flush after alcohol ingestion in genetically
predisposed patients and dilutional hyponatremia. Hematologic toxicity
(transient leukopenia, thrombocytopenia) occurs in less than 1% of patients.
Tolazamide is
comparable to chlorpropamide in potency but has a shorter duration of action.
Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect
on blood glucose does not appear for several hours. Its half-life is about 7
hours. Tolazamide is metabolized to several compounds that retain hypoglycemic
effects. If more than 500 mg/d is required, the dose should be divided and
given twice daily. Dosages larger than 1000 mg daily do not further improve the
degree of blood glucose control.
Second-Generation
Sulfonylureas
The
second-generation sulfonylureas are more frequently prescribed in the
Glyburide is
metabolized in the liver into products with very low hypoglycemic activity. The
usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage
is 5–10 mg/d given as a single morning dose; maintenance dosages higher than 20
mg/d are not recommended. A formulation of "micronized" glyburide
(Glynase PresTab) is available in a variety of tablet sizes. However, there is
some question as to its bioequivalence with nonmicronized formulations, and the
FDA recommends careful monitoring to retitrate dosage when switching from
standard glyburide doses or from other sulfonylurea drugs.
Glyburide has
few adverse effects other than its potential for causing hypoglycemia.
renal
insufficiency.
Glipizide has the shortest half-life (2–4 hours) of the more potent agents. For
maximum effect in reducing postprandial hyperglycemia, this agent should be
ingested 30 minutes before breakfast, since absorption is delayed when the drug
is taken with food. The recommended starting dosage is 5 mg/d, with up to 15
mg/d given as a single dose. When higher daily dosages are required, they
should be divided and given before meals. The maximum total daily dosage
recommended by the manufacturer is 40 mg/d, although some studies indicate that
the maximum therapeutic effect is achieved by 15–20 mg of the drug.
An
extended-release preparation (Glucotrol XL) provides 24- hour action after a
once-daily morning dose (maximum of 20 mg/d). However, this formulation appears
to have sacrificed its lower propensity for severe hypoglycemia compared with
longeracting glyburide without showing any demonstrable therapeutic advantages
over the latter (which can be obtained as a generic drug).
Because of
its shorter half-life, glipizide is much less likely than glyburide to produce
serious hypoglycemia. At least 90% of glipizide is metabolized in the liver to
inactive products, and 10% is excreted unchanged in the urine. Glipizide
therapy is therefore contraindicated in patients with significant hepatic or
renal impairment, who would therefore be at high risk for hypoglycemia.
Glimepiride is
approved for once-daily use as monotherapy or in combination with insulin.
Glimepiride achieves blood glucose lowering with the lowest dose of any
sulfonylurea compound. A single daily dose of 1 mg has been shown to be
effective, and the recommended maximal daily dose is 8 mg. It has a long
duration of effect with a half-life of 5 hours, allowing once-daily dosing and
thereby improving compliance. It is completely metabolized by the liver to
inactive products.
Secondary
Failure & Tachyphylaxis to Sulfonylureas
Secondary
failure, ie, failure to maintain a good response to sulfonylurea therapy over the
long term—remains a disconcerting problem in the management of type 2 diabetes.
A progressive decrease in B cell mass, reduction in physical activity, decline
in lean body mass, or increase in ectopic fat deposition in chronic type 2
diabetes also may contribute to secondary failure.
Insulin
Secretagogues: Meglitinides
The
meglitinides are a relatively new class of insulin secretagogues. Repaglinide,
the first member of the group, was approved for clinical use in 1998 (Table
41–7). These drugs modulate B cell insulin release by regulating potassium
efflux through the potassium channels previously discussed. There is overlap
with the sulfonylureas in their molecular sites of action since the
meglitinides have two binding sites in common with the sulfonylureas and one
unique binding site. Unlike the sulfonylureas, they have no direct effect on
insulin exocytosis.
Repaglinide has a very fast onset of action,
with a peak concentration and peak effect within approximately 1 hour after
ingestion, but the duration of action is 5–8 hours. It is hepatically cleared
by CYP3A4 with a plasma half-life of 1 hour. Because of its rapid onset,
repaglinide is indicated for use in controlling postprandial glucose
excursions. The drug should be taken just before each meal in doses of 0.25–4
mg (maximum, 16 mg/d); hypoglycemia is a risk if the meal is delayed or skipped
or contains inadequate carbohydrate. This drug should be used cautiously in
individuals with renal and hepatic impairment. Repaglinide is approved as
monotherapy or in combination with biguanides. There is no sulfur in its
structure, so repaglinide may be used in type 2 diabetic individuals with
sulfur or sulfonylurea allergy.
Biguanides
The structure
of metformin is shown below. Phenformin (an older biguanide) was discontinued
in the
Mechanisms of Action
A full explanation of the biguanides' mechanism
of action remains elusive. Their blood glucoselowering action does not depend
on the presence of functioning pancreatic B cells. Patients with type 2 diabetes
have considerably less fasting hyperglycemia as well as lower postprandial
hyperglycemia after biguanides; however, hypoglycemia during biguanide therapy
is essentially unknown. These agents are therefore more appropriately termed
"euglycemic" agents. Currently proposed mechanisms of action include
(1) direct stimulation of glycolysis in tissues, with increased glucose removal
from blood; (2) reduced hepatic and renal gluconeogenesis; (3) slowing of
glucose absorption from the gastrointestinal tract, with increased glucose to
lactate conversion by enterocytes; and (4) reduction of plasma glucagon levels.
Metabolism & Excretion
Metformin has
a half-life of 1.5–3 hours, is not bound to plasma proteins, is not
metabolized, and is excreted by the kidneys as the active compound. As a
consequence of metformin's blockade of gluconeogenesis, the drug may impair the
hepatic metabolism of lactic acid. In patients with renal insufficiency,
biguanides accumulate and thereby increase the risk of lactic acidosis, which
appears to be a dose-related complication.
Biguanides
have been most often prescribed for patients whose hyperglycemia is due to
ineffective insulin action, ie, insulin resistance syndrome. Because metformin
is an insulin-sparing agent and does not increase weight or provoke
hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in
treating hyperglycemia in such individuals.
The dosage of
metformin is from 500 mg to a maximum of
Toxicities
The most
frequent toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting,
abdominal discomfort, diarrhea) and occur in up to 20% of patients. They are
dose related, tend to occur at the onset of therapy, and are often transient.
However,
metformin may have to be discontinued in 3–5% of patients because of persistent
diarrhea. Absorption of vitamin B12 appears to be reduced during long-term
metformin therapy, and annual screening of serum vitamin B12 levels and red
blood cell parameters has been encouraged by the manufacturer to determine the
need for vitamin B12 injections. In the absence of hypoxia or renal or hepatic
insufficiency, lactic acidosis is less common with metformin therapy than with
phenformin therapy.
Biguanides
are contraindicated in patients with renal disease, alcoholism, hepatic
disease, or conditions predisposing to tissue anoxia (eg, chronic
cardiopulmonary dysfunction), because of an increased risk of lactic acidosis
induced by biguanide drugs in the presence of these diseases.
Thiazolidinediones
Thiazolidinediones
(Tzds) act to decrease insulin resistance. Their primary action is the nuclear
regulation of genes involved in glucose and lipid metabolism and adipocyte
differentiation. Tzds are ligands of peroxisome proliferator-activated
receptor-gamma (PPAR- ), part of the steroid and thyroid superfamily of
nuclear receptors. These PPAR receptors are found in muscle, fat, and liver.
PPAR- receptors are complex and modulate the expression of the genes involved
in lipid and glucose metabolism, insulin signal transduction, and adipocyte and
other tissue differentiation. The available Tzds do not have identical clinical
effects and new drug development will focus on defining PPAR effects and
designing ligands that have selective action—much like the selective estrogen
receptor ligands (see Chapter 40: The Gonadal Hormones & Inhibitors).
In persons
with diabetes, a major site of Tzd action is adipose tissue, where the drug
promotes glucose uptake and utilization and modulates synthesis of lipid
hormones or cytokines and other proteins involved in energy regulation. Tzds
also regulate adipocyte apoptosis and differentiation. Numerous other effects
have been documented in animal studies but applicability to human tissues has
yet to be determined.
Two
thiazolidinediones are currently available: pioglitazone and rosiglitazone
(Table 41–8). Their distinct side chains create differences in therapeutic
action, metabolism, metabolite profile, and adverse effects. A third compound,
troglitazone, was withdrawn from the market because of hepatic toxicity thought
to be related to its side chain.
Pioglitazone
may have PPAR- as well as PPAR- activity. It is absorbed within 2 hours of
ingestion; although food may delay uptake, total bioavailability is not
affected. Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites.
The bioavailability of numerous other drugs also degraded by these enzymes may
be affected by pioglitazone therapy, including estrogencontaining oral
contraceptives; additional methods of contraception are advised. Pioglitazone
may be taken once daily; the usual starting dose is 15–30 mg. The triglyceride
lowering effect is more significant than that observed with rosiglitazone.
Pioglitazone is approved as a monotherapy and in combination with metformin,
sulfonylureas, and insulin for the treatment of type 2 diabetes.
Rosiglitazone
is rapidly absorbed and highly protein bound. It is
metabolized in the liver to minimally active metabolites, predominantly by
CYP2C8 and to a lesser extent by CYP2C9. It is administered once or twice
daily; 4–8 mg is the usual total dose. Rosiglitazone shares the common Tzd
adverse effects but does not seem to have any significant drug interactions.
The drug is approved for use in type 2 diabetes as monotherapy or in
combination with a biguanide or sulfonylurea. Tzds are considered
"euglycemics" and are efficacious in about 70% of new users. The
overall response is similar to sulfonylurea and biguanide monotherapy.
Individuals experiencing secondary failure to other oral agents should benefit
from the addition (rather than substitution) of a Tzd.
Because their
mechanism of action involves gene regulation, the Tzds have a slow onset and
offset of activity over weeks or even months. Combination therapy with
sulfonylureas and insulin can lead to hypoglycemia and may require dosage
adjustment. Long-term therapy is associated with a drop in triglyceride levels
and a slight rise in HDL and low-density lipoprotein (LDL) cholesterol values.
An adverse
effect common to both Tzds is fluid retention, which presents as a mild anemia
and peripheral edema especially when used in combination with insulin or
insulin secretagogues. Many users have a dose-related weight gain (average 1–3
kg), which may be fluid-related. These agents should not be used during
pregnancy, in the presence of significant liver disease, or if there is a
concurrent diagnosis of heart failure. Anovulatory women may resume ovulation
and should be counseled on the increased risk of pregnancy. Because of the
hepatotoxicity observed with troglitazone, the FDA continues to require regular
monitoring of liver function tests for the first year after initiation of Tzd
therapy. To date, hepatotoxicity has not been associated with rosiglitazone or
pioglitazone. Thiazolidinediones have a theoretical benefit in the prevention of
type 2 diabetes. One study reported that troglitazone therapy significantly
decreased the recurrence of diabetes mellitus in high risk Hispanic women with
a prior history of gestational diabetes. Other trials using clinically
available Tzds are in progress. Alpha Glucosidase Inhibitors Only
monosaccharides, such as glucose and fructose, can be transported out of the
intestinal lumen and into the bloodstream. Complex starches, oligosaccharides,
and disaccharides must be broken down into individual monosaccharides before
being absorbed in the duodenum and upper jejunum.
This
digestion is facilitated by enteric enzymes, including pancreatic -amylase, and
–glucosidases that are attached to the brush border of the intestinal cells. Acarbose
and miglitol (Table 41–9) are competitive inhibitors of the
intestinal -glucosidases and reduce the postprandial digestion and absorption
of starch and disaccharides. Miglitol differs structurally from acarbose and is
six times more potent in inhibiting sucrase. Although the binding affinity of
the two compounds differs, acarbose and miglitol both target the -glucosidases:
sucrase, maltase, glycoamylase, dextranase. Miglitol alone has effects on
isomaltase and on -glucosidases, which split -linked sugars such as lactose.
Acarbose alone has a small effect on -amylase. The consequence of enzyme
inhibition is to minimize upper intestinal digestion and defer digestion (and
thus absorption) of the ingested starch and disaccharides to the distal small
intestine, thereby lowering postmeal glycemic excursions as much as 45–60 mg/dL
and creating an insulin-sparing effect. Monotherapy with these drugs is
associated with a modest drop (0.5–1%) in glycohemoglobin levels and a 20–25
mg/dL fall in fasting glucose levels. They are FDA-approved for use in
individuals with type 2 diabetes as monotherapy and in combination with
sulfonylureas, where the glycemic effect is additive. Both acarbose and
miglitol are taken in doses of 25–100 mg just prior to ingesting the first
portion of each meal; therapy should be initiated with the lowest dose and
slowly titrated upward.
to carbohydrate induces the expression of -glucosidase in
the jejunum and ileum, increasing distal small intestine glucose absorption and
minimizing the passage of carbohydrate into the colon. Although not a problem
with monotherapy or combination therapy with a biguanide, hypoglycemia may
occur with concurrent sulfonylurea treatment. Hypoglycemia should be treated
with glucose (dextrose) and not sucrose, whose breakdown may be blocked. These
drugs are contraindicated in patients with inflammatory bowel disease or any
intestinal condition that could be worsened by gas and distention. Because both
miglitol and acarbose are absorbed from the gut, these medications should not
be prescribed in individuals with renal impairment. Acarbose has been
associated with reversible hepatic enzyme elevation and should be used with
caution in the presence of hepatic disease.
The
STOP-NIDDM trial demonstrated that -glucosidase therapy in prediabetic individuals
successfully prevented a significant number of new cases of type 2 diabetes and
helped restore cell function. Diabetes prevention may become a further
indication for this class of medications. Combination Therapy with Oral
Antidiabetic Agents & Insulin
Combination Therapy in Type 2 Diabetes Mellitus
Bedtime insulin has been suggested as an adjunct
to oral antidiabetic therapy in patients with type 2 diabetes patients who have
not responded to maximal oral therapy. Clinical practice has evolved to include
sulfonylureas, meglitinides, D-phenylalanine derivatives, biguanides,
thiazolidinediones, or -glucosidase inhibitors given in conjunction with
insulin. Individuals unable to achieve glycemic control with bedtime insulin as
described above generally require full insulin replacement and multiple daily
injections of insulin. Insulin secretagogues are redundant when an individual
is receiving multiple daily insulin injections, but cases of severe insulin
resistance may benefit from the addition of one of the biguanides,
thiazolidinediones, or - glucosidase inhibitors. In some cases, multiple oral
agents have been required together with insulin.
When oral
agents are added to the regimen of someone already taking insulin, the blood
glucose should be closely monitored and the insulin dosage decreased as needed
to avoid hypoglycemia.
Combination
Therapy in Type 1 Diabetes Mellitus
There is no
indication for combining insulin with insulin secretagogues (sulfonylureas, meglitinides,
or D-phenylalanine derivatives) in individuals with type 1 diabetes. Type 1
diabetics with diets very high in starch may benefit from the addition of
-glucosidase inhibitors, but this is
not typically practiced in the
Glucagon is a peptide—identical
in all mammals—consisting of a single chain of 29 amino acids, with a molecular
weight of 3485. Selective proteolytic cleavage converts a large
precursor molecule of approximately 18,000 MW to glucagon. One of the precursor
intermediates consists of a 69 - amino-acid peptide called glicentin, which
contains the glucagon sequence interposed between peptide extensions. Glucagon
is extensively degraded in the liver and kidney as well as in plasma, and at
its tissue receptor sites. Because of its rapid inactivation by plasma,
chilling of the collecting tubes and addition of inhibitors of proteolytic
enzymes are necessary when samples of blood are collected for immunoassay of
circulating glucagon. Its half-life in plasma is between 3 and 6 minutes, which
is similar to that of insulin.
"Gut
Glucagon"
Glicentin immunoreactivity has been found in
cells of the small intestine as well as in pancreatic A cells and in effluents
of perfused pancreas. The intestinal cells secrete enteroglucagon, a
family of glucagon-like peptides, of which glicentin is a member, along with
glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). Unlike the pancreatic A cell,
these intestinal cells lack the enzymes to convert glucagon precursors to true
glucagon by removing the carboxyl terminal extension from the molecule.
The function
of the enteroglucagons has not been clarified, although smaller peptides can
bind hepatic glucagon receptors where they exert partial activity. A derivative
of the 37-amino-acid form of GLP-1 that lacks the first six amino acids
(GLP-1[7–37]) is a potent stimulant of insulin release.
It represents
the predominant form of GLP in the human intestine and has been termed
"insulinotropin." It has been considered as a potential therapeutic
agent in type 2 diabetes. However, it requires continuous subcutaneous infusion
to produce a sustained lowering of both fasting and postprandial hyperglycemia
in type 2 diabetic patients; therefore, its clinical usefulness is limited.
Pharmacologic
Effects of Glucagon
Clinical
Uses
Severe
Hypoglycemia
The major use
of glucagon is for emergency treatment of severe hypoglycemic reactions in
patients with type 1 diabetes when unconsciousness precludes oral feedings and
use of intravenous glucose is not possible. Recombinant glucagon is currently
available in 1 mg vials for parenteral use (Glucagon Emergency Kit). Nasal
sprays have been developed for this purpose but have not yet received FDA
approval.
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