Handbook of clinical drug data - part 9 pps

Lidocaine concentrations in milk dur- ing continuous IV infusion and epidural administration and in high doses as a local anesthetic are low and poorly absorbed by the infant, so it pose

ANTINEOPLASTICS AND IMMUNOSUPPRESSANTS

CARDIOVASCULAR DRUGS

ANTIARRHYTHMIC DRUGS

Some antiarrhythmics reach near-therapeutic serum concentrations in breastfed infants darone is excreted in amounts that might pose a hazard to the infant and it should not be used during nursing 1,53 Data on disopyramide indicate that infants can receive relatively large amounts of the drug and its active metabolite, with serum concentrations near the therapeutic range Disopyramide can be used cautiously while breastfeeding older infants when other alterna- tives are unacceptable Observe the infant for anticholinergic symptoms, and monitor infant serum concentrations if there is a concern The anticholinergic activity of disopyramide might suppress

Amio-lactation (See Anticholinergics.) Sparse data from one patient indicate that tocainide should be

used with caution during nursing Because of its low oral bioavailability, maternal bretylium is unlikely to harm nursing infants; 400 mg q 8 hr was taken orally by one mother while nursing, with

CARDIOVASCULAR DRUGS

no apparent effects on her infant Infants receive trivial doses of digoxin via breastmilk Amounts of flecainide in milk are small and unlikely to affect the infant Lidocaine concentrations in milk dur- ing continuous IV infusion and epidural administration and in high doses as a local anesthetic are low and poorly absorbed by the infant, so it poses no hazard to the infant 54–56 Amounts of mexile- tine in milk are too low to be detected in the serum of breastfed infants Procainamide and its ac- tive metabolite, N-acetylprocainamide, are found in milk in fairly small concentrations; pro- cainamide may be used with caution in nursing mothers Propafenone milk concentrations are very low, but no clinical experience has been reported 57 Quinidine excretion seems inconsequential.

ANTIHYPERTENSIVE DRUGS

Certain antihypertensives are less desirable than others during nursing Breastfed infants have serum clonidine concentrations approaching those of the mother 1,58 Clonidine and guanfacine also can decrease prolactin secretion These drugs must be used with caution during breastfeed- ing and avoided if possible Avoid reserpine because it can cause nasal stuffiness and increased tracheobronchial secretions in the infant The angiotensin-converting enzyme (ACE) inhibitors, benazepril, captopril, and enalapril, are found in small amounts and no adverse effects have occurred in breastfed infants 1,59 In addition, milk ACE activity was in the normal range after a dose of enalapril These ACE inhibitors are good choices during lactation; others have not been studied Limited data indicate that low-dose, short-term use of hydralazine (ie, a few days post- partum) is safe There is limited information on oral minoxidil in milk, but amounts are small However, use minoxidil with caution, particularly when therapy involves large dosages and long- term use Several studies indicate that methyldopa is excreted in unimportant amounts.

β-ADRENERGIC BLOCKING DRUGS

The excretion of -blockers into breastmilk has been studied extensively The infant’s dosage fers greatly among the different compounds, allowing a range of choices The most water-soluble drugs reach the infant in the greatest amounts because of low serum protein binding Water- soluble agents also have the longest half-lives, are renally eliminated, and therefore are more likely to accumulate in infants Maternal therapy with atenolol and acebutolol have resulted in adverse effects (eg, bradycardia, hypotension, tachypnea, and cyanosis) in breastfed infants These two drugs, as well as betaxolol, nadolol, sotalol, and timolol, should be avoided in moth- ers of newborn infants or when high dosage is required Oxprenolol and mepindolol excretions are intermediate and should be avoided in neonates Propranolol, metoprolol, and labetalol are excreted in low enough quantities to allow nursing even in the neonatal period.

dif-CALCIUM-CHANNEL BLOCKING DRUGS

Case reports indicate that only small amounts of diltiazem, nifedipine, nimodipine, and trendipine are excreted into milk 1,60 Several case reports indicate that the amounts of verapamil and norverapamil in milk and infant serum are low Verapamil appears to be safe during nursing.

ni-CENTRAL NERVOUS SYSTEM DRUGS

ANTICONVULSANTS

Breastfed infants can achieve serum anticonvulsant concentrations that produce pharmacologic effects Mild drowsiness, irritability, and feeding difficulties are common in the infants of mothers taking sedating anticonvulsants, especially during the early neonatal period 1,61 Breastfeeding can

CENTRAL NERVOUS SYSTEM DRUGS

mitigate withdrawal symptoms in infants whose mothers took sedating anticonvulsants during nancy, and withdrawal symptoms have been observed after abrupt weaning Serum concentration monitoring in breastfed infants might be indicated, particularly in infants who are excessively drowsy, feed poorly, or gain weight inadequately Long-term effects of exposure are not well studied Infants

preg-of mothers taking anticonvulsants might have more difficulty nursing and breastfed for a shorter ration, possibly because of negative or equivocal safety advice given by health professionals 62–64

du-No data are available for some of the newer anticonvulsants such as felbamate, gabapentin, levetiracetam, oxcarbazepine, tiagabine, and topiramate Breastfeeding is not recommended during felbamate use 65–67

Carbamazepine

Carbamazepine and its major active metabolite are excreted into milk and can be detected in nursing infants’ serum; concentrations are usually low but near the therapeutic range in some in- fants Two cases of hepatic dysfunction in breastfed neonates have been reported Poor feeding also has been reported Carbamazepine can be used during lactation, but close observation of the infant for jaundice and other signs of possible adverse idiosyncratic effects is advisable 67 Mea- surement of infant serum concentration might be indicated if symptoms occur.

Clonazepam

Serum concentrations of clonazepam were low in two nursing infants, and no effects were noted 1

In another infant, breastfeeding increased serum concentrations over those present at birth 68 Clonazepam has been detected in the serum of a breastfed neonate whose mother was receiving the drug before and after delivery but was undetectable in 4 others 69 Observation of the infant for drowsiness and monitoring of the infant’s serum concentration might be indicated.

Ethosuximide

Breastfed infants can attain ethosuximide serum concentrations near the therapeutic range, and some infants might become drowsy or fussy Breastfeed with caution and keep the mother’s serum concentrations as low as possible while remaining in the therapeutic range Infant serum drug concentration monitoring is indicated.

Lamotrigine

Lamotrigine concentrations in infants breastfed during maternal lamotrigine therapy have ranged from 22 to 85% of the maternal serum concentration, but no adverse effects have been reported with these relatively high levels 67,70,71 Infants can be allowed to nurse, but close monitoring for side effects such as rash (which can be life-threatening), drowsiness, or poor sucking is essential Obtain an infant serum concentration if adverse effects are suspected and discontinue breastfeed- ing if rash occurs.

Phenobarbital

The effect of phenobarbital is unpredictable: drowsiness leading to feeding difficulties can occur; breastfeeding can prevent withdrawal symptoms in infants whose mothers took phenobarbital dur- ing pregnancy; and withdrawal symptoms have been observed after abrupt weaning Phenobarbi- tal can be used in low to moderate dosages but monitor infant behavior, weight gain, and, if there

is concern, serum concentrations Sometimes breastfeeding must be discontinued because of cessive drowsiness and poor weight gain.

ex-Phenytoin

Only small amounts of phenytoin are excreted into milk Rarely, infants might experience cratic reactions such as cyanosis and methemoglobinemia, but infants generally tolerate phenytoin

idiosyn-in milk well.

CENTRAL NERVOUS SYSTEM DRUGS

as a single dose at bedtime and skipping nighttime feeding(s) can further minimize infant exposure A dose of 250 mg/day of amoxapine or 100–150 mg/day of maprotiline produces low drug concen- trations in milk, but effects of these drugs on infants have not been well studied.

Selective Serotonin Reuptake Inhibitors

Although the average daily dosages of fluoxetine and norfluoxetine in milk are about 7% of the mother’s weight-adjusted dosages, some mothers excrete as much as 12% of a dosage and the drugs’ half-lives are very long 81 One case of colic (increased crying, decreased sleep, watery stools, and vomiting) and unexplained high serum concentrations were reported in a breastfed 6-week-old infant The infant improved after switching to formula and colic reappeared with rechallenge Other case reports include seizure-like activity, irritability, hyperglycemia and

CENTRAL NERVOUS SYSTEM DRUGS

glycosuria, and withdrawal symptoms 81 Norfluoxetine is often detectable in infants’ serum 69,81,82 Fluoxetine in breastmilk had no effect on neurologic development in 4 infants, 83 but a larger retro- spective study found that fluoxetine can reduce the growth rate of infants who are exposed via breastmilk from birth 84 Fluoxetine should be avoided during breastfeeding if possible, although older infants might be less susceptible to fluoxetine’s effects than newborns Monitor infants care- fully for behavioral symptoms and adequate weight gain Citalopram reaches the infant in dosages of about 5% of the mother’s mg/kg dosage 85–87 The manufacturer states that drowsi- ness and weight loss in breastfed infants have occurred, and uneasy sleep occurred in the infant

of a mother taking citalopram 88 Citalopram is not a good choice while breastfeeding a newborn Infants receive a dose <1% of the maternal fluvoxamine dose Several infants grew and devel- oped normally with maternal fluvoxamine use 89,90 With paroxetine, infants receive about 1.5% of the maternal dosage Of 23 infants studied, only 1 had detectable serum concentrations of parox- etine No adverse behavioral or growth effects have been observed in studies, but one case of in- fant agitation and feeding difficulties has been reported 91–93 Sertraline dosage to the breastfed infant is <2% of the maternal dosage; concentrations in infant serum are usually low to unde- tectable, platelet serotonin is unaffected, and no adverse effects on growth have been seen in controlled follow-up 94–97 One case of infant agitation and one of somnolence and developmental difficulties have been reported spontaneously to Australian authorities 97 Sertraline and paroxetine are considered the SSRIs of choice during breastfeeding, especially with a neonate.

Monoamine Oxidase Inhibitors

There are no data on the amounts of older nonselective MAOIs excreted into milk Because of their potential for toxicity and lactation inhibition, avoid MAOIs during nursing With moclobemide, a reversible MAO-A inhibitor not available in the United States, infants receive a dose <1% of the mother’s dose and no side effects have been reported in a small number of infants studied 98,99

Other Antidepressants

Bupropion and its metabolites were undetectable in one 14-month-old infant whose mother was taking 300 mg/day and nursing twice daily 99,100 Nefazodone and trazodone dosages in the in- fant are <1% of the mother’s mg/kg dosage, but only a few cases have been reported 1,101 One case of drowsiness, lethargy, poor feeding, and inability to maintain normal body temperature was reported in a small preterm breastfed infant whose mother was taking nefazodone 300 mg/day 102 Infants receive venlafaxine doses of up to 9.2% of the mother’s mg/kg dosage and the active metabolite is detectable in the infant’s serum Although adverse effects were not seen in 3 breast- fed infants, caution should be used with venlafaxine until more experience is gained 99

ANTIPSYCHOTIC DRUGS

Data on the use of antipsychotics during lactation are sparse 103–105 Phenothiazines and anthenes pass into milk somewhat unpredictably but usually in small amounts Drowsiness can occur with the more sedating agents, such as chlorpromazine Other effects, such as extrapyra- midal symptoms, are possible but have not been reported Limited follow-up, ranging from 15 months to 6 yr, indicates no long-term effects on infant development in most infants However,

thiox-3 infants whose mothers were taking large dosages of chlorpromazine (200–600 mg/day) and haloperidol (20–40 mg/day) in combination showed deterioration of mental and psychomotor de- velopmental scores over the first 12–18 months of life 106 Nine other infants whose mothers were taking lower dosages of a single antipsychotic (including haloperidol up to 20 mg/day) showed normal development It appears that maternal phenothiazines, thioxanthenes, and haloperidol

CENTRAL NERVOUS SYSTEM DRUGS

cause no problems for nursing infants unless dosages are at the high end of the range or nations of drugs are used 104,105 Breastfeeding during clozapine use in 4 infants resulted in seda- tion in 1 and agranulocytosis in another, which resolved with discontinuation; nursing is not rec- ommended during clozapine use 100,107 Exposure of 2 infants to olanzapine in breastmilk for a few days each caused no untoward events, but more experience is needed 108 One mother taking risperidone excreted about 4% of her mg/kg dosage into breastmilk; no infant side effects were noted 109

combi-ANXIOLYTICS, SEDATIVES, AND HYPNOTICS

Many sedatives and hypnotics pass into breastmilk in measurable and potentially important amounts Minimize sedative and hypnotic intake during lactation.

Anesthetics, General

Compared with epidural anesthesia, general anesthesia used during cesarean delivery can crease the frequency and duration of breastfeeding 19 Excretion of most inhalation anesthetics in breastmilk has not been well studied Blood levels of anesthetic gases such as desflurane, enflu- rane, halothane, isoflurane, nitrous oxide, and sevoflurane drop rapidly after termination of anesthesia, are predicted to pass poorly into milk, and are probably poorly absorbed by the in- fant 19,20 Etomidate milk levels drop rapidly after a dose and should pose little risk to the infant 110 Amounts of propofol in milk are small and do not have good oral bioavailability in the infant Typi- cal IV doses of methohexital or thiopental for induction of anesthesia produce low concentra- tions in milk that do not cause effects in the infant 1,18,110 Current opinion suggests that breast- feeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia

de-to nurse 19,20

Barbiturates

These drugs can stimulate metabolism of endogenous compounds in the infant when small amounts pass into milk Short-acting agents are preferable to long-acting agents because smaller amounts are excreted into milk Large single doses might have more potential for causing infant

drowsiness than multiple small doses (See also Anesthetics, General; Anticonvulsants.) Benzodiazepines

Long-acting benzodiazepines and those with active metabolites (eg, diazepam) can accumulate and cause adverse effects in infants, especially with repeated doses, and in neonates because of their immature excretory mechanisms Bromazepam taken by the mother might have contributed

to the death of her 4-week-old breastfed infant with a 5-day history of apneic episodes 111 A gle dose of diazepam for short dental, surgical, or diagnostic procedures is not likely to cause se- dation in infants past the neonatal period 18 Milk alprazolam concentrations are low, 112 but infant drowsiness and withdrawal symptoms have been reported with alprazolam use during nursing 1,5 When oral therapy is essential, the short-acting agents, oxazepam or lorazepam, are preferred; temazepam also might be acceptable 103,113 Midazolam concentrations in milk are low and un- likely to affect the infant after a single dose or short course of therapy 19,114

sin-Chloral Hydrate

Chloral hydrate and its active metabolite, trichloroethanol, appear in milk in dosages that imate an infant sedative dosage and are detectable for up to 24 hr after a single dose Using an- other hypnotic is advisable during nursing.

Lithium in milk can adversely affect the infant when its elimination is impaired, as in dehydration

or in neonates or premature infants Neonates also can have transplacentally acquired serum lithium levels The long-term effects of lithium on infants are not known; many investigators con- sider lithium therapy a contraindication to breastfeeding, but others do not Lithium may be used cautiously in mothers who are carefully selected for their ability to monitor their full-term infants Discontinue breastfeeding immediately if the infant appears restless or looks ill Measurement of serum lithium concentrations in the infant can help rule out lithium toxicity 1,67,80

PARKINSONISM DRUGS

Dopamine Agonists

Some ergot alkaloids have dopaminergic activity that can suppress prolactin release and lactation Bromocriptine was used therapeutically for this purpose but has lost this indication in the United States because of potentially serious maternal toxicity (ie, stroke, death).

Levodopa

Levodopa decreases serum prolactin in non-nursing women with hyperprolactinemia and rhea in a dose-dependent fashion and inhibits lactation in animals at high dosages 1 One mother taking sustained-release levodopa/carbidopa 200 mg/50 mg qid successfully breastfed her infant whose development was normal at age 2 yr 117

galactor-GASTROINTESTINAL DRUGS

ACID-PEPTIC THERAPY

Antacids

Although aluminum, calcium, and magnesium antacids are partially absorbed, they are unlikely

to appreciably increase concentrations of these ions in milk and are safe to use.

Histamine H 2 -Blockers

Cimetidine is concentrated in milk because of ion trapping and possibly active secretion; 118 tidine doses in milk are lower Famotidine and nizatidine have the lowest concentrations in milk and are preferred during nursing.

rani-Proton Pump Inhibitors

Omeprazole and lansoprazole have not been adequately studied In one mother, omeprazole milk levels were low and her newborn infant was breastfed without harm 119

loper-GASTROINTESTINAL DRUGS

Diphenoxylate excretion into milk has not been studied One or two small doses of loperamide or diphenoxylate daily should pose little risk to the nursing infant Avoid bismuth subsalicylate be- cause salicylate is absorbable.

Cathartics and Laxatives

Some anthraquinone derivatives, such as aloe and cascara, and other stimulant cathartics (eg, phenolphthalein) should be avoided during nursing because of a laxative effect in breastfed in- fants Laxatives that are nonabsorbable or poorly absorbed, such as bulk-forming (eg, psyllium), osmotic (eg, magnesium or phosphate salts), or stool-softening (eg, docusate) types, are pre- ferred during lactation Senna in moderate dosages is acceptable if other measures fail Bisacodyl is virtually unabsorbed from the GI tract and should be safe.

Gastrokinetic Agents

Metoclopramide elevates serum prolactin via central dopaminergic antagonism and results in creased milk production and a more rapid transition from colostrum to mature milk It can be used therapeutically in mothers who are producing insufficient quantities of milk, such as the mothers

in-of premature or sick infants or adoptive mothers Although infant dosages in-of metoclopramide from milk are low, the infant’s serum prolactin concentrations can become elevated Metoclopramide can induce depression, so caution is warranted Limiting the duration of metoclopramide therapy

to 14 days is essential, and it should not be used in mothers with a history of depression peridone (not available in the U.S.) also has been used to increase milk supply and results in lower milk drug levels than metoclopramide 120,121

Dom-MISCELLANEOUS GASTROINTESTINAL DRUGS

Mesalamine Derivatives

Small amounts of sulfasalazine and sulfapyridine have been found in milk and infants’ sera after oral sulfasalazine use The small amount of sulfapyridine released should cause no bilirubin displace-

ment Olsalazine is not detectable in milk, but its metabolite, N-acetyl-5-ASA, is found in small

amounts 122 Small amounts of mesalamine and larger amounts of its metabolite are found in milk after oral administration 123 Diarrhea has been reported in infants of mothers using mesalamine deriva- tives, but a controlled study found the frequency of diarrhea to be no greater than that in infants of un- treated mothers 124 Sulfasalazine and mesalamine and its derivatives may be used during nursing.

Ursodiol

Ursodiol was undetectable in the milk of 1 lactating mother, and her nursing infant developed mally during therapy 125 Maternal ursodiol therapy decreased the bile acid concentration in colostrum and was found in trivial amounts in breastmilk in 16 mothers with intrahepatic cholesta- sis of pregnancy 126 Their infants showed no adverse effects.

HEMATOLOGIC DRUGS

Heparins

Although minimal documentation exists, it is unlikely that heparin or low-molecular-weight arins (eg, enoxaparin, dalteparin) pass into milk or are absorbed orally by the infant; anti- coagulant activity was undetectable in 1 breastfed infant whose mother received 20–40 mg/day

hep-of enoxaparin 128 Hirudin was not detectable in milk 129

Indandiones

Anisindione and phenindione are contraindicated because infant hemorrhage has occurred 127

HORMONES AND SYNTHETIC SUBSTITUTES

ADRENAL HORMONES

Corticosteroids

Prednisone and prednisolone excretions into milk are minimal even with large oral doses 130 The infant dosage can be reduced even further by using prednisolone rather than prednisone and avoiding nursing for 3–4 hr after a dose Three infants have been breastfed during long-term ma- ternal use of methylprednisolone 6–8 mg/day with apparent safety Large IV doses of cortico- steroids or use of long-acting agents such as dexamethasone have not been studied, and cau- tion is warranted Depot injections, inhaled corticosteroids (eg, beclomethasone, fluticasone), or topical corticosteroids should present little or no risk to the infant because of low maternal serum concentrations However, topical application to the nipple has caused adverse effects in the infant because of direct ingestion 131

ANTIDIABETIC DRUGS

Insulin

Diabetic mothers using insulin may nurse their infants However, it has been found empirically that the mother might need to reduce her insulin dosage to 55–75% of the prepregnancy dosage Close monitoring is required postpartum because the return to prepregnancy insulin dosage has been variably reported to take 1–6 weeks 132,133

Sulfonylureas

Tolbutamide is excreted in milk in small amounts that should cause no harm The manufacturer reports that chlorpropamide concentrations in milk are low, but no published clinical data are available on this or other sulfonylureas.

CONTRACEPTIVES

Estrogen–Progestin Combinations

Although present in milk in small amounts, estrogens and progestins are readily metabolized by nursing infants Rare case reports of breast enlargement in infants have been attributed to estrogen-containing oral contraceptives These effects occur primarily with products containing

>50 g of estrogen These high-estrogen contraceptives also markedly suppress lactation, especially when administered immediately postpartum When currently available low-dose estrogen–progestin combination contraceptives are begun ≥6 weeks postpartum, a dramatic immediate effect on milk supply is usually not seen, but long-term negative effects on milk yield lead to early feeding supplementation and discontinuation of breastfeeding and decreased infant growth An 8-year follow-up of breastfed infants of mothers taking contraceptives containing ethinyl estradiol 50 g found no adverse effects on the infants’ development or behavior Progestin-only contraceptives are preferred during lactation.

HORMONES AND SYNTHETIC SUBSTITUTES

Progestin Only

No immediate effects have been reported with progestin-only contraceptives such as norgestrel implants, depot medroxyprogesterone acetate, or oral norethindrone or norgestrel Progestin-only contraceptives generally have no effect on, or enhance, milk supply and might ex- tend the duration of lactation Although infant growth might undergo a slight, transient depres- sion after insertion of levonorgestrel implants, large multicenter studies have found no effect

levo-of progestin-only contraceptives on growth and development levo-of infants and children up to berty 134–137 Early (ie, immediately postpartum) initiation of these agents is controversial Because physiologic postpartum progesterone withdrawal is a primary stimulus for lactation, it appears best

pu-to wait for at least 3 days postpartum before starting a progestin-only contraceptive 138 One small study found no adverse effects on lactation or infant growth when depot medroxyprogesterone was given immediately postpartum, 139 but anecdotal reports of lactation suppression with immedi- ate postpartum administration exist Progestin-only contraceptives started 6 weeks postpartum are the preferred hormonal contraceptives during lactation 140,141(See also Progesterone.)

FEMALE SEX HORMONES

Progesterone

Contraceptive use via implants (investigationally) or intrauterine devices transfers little terone to the breastfed infant, and any drug in milk is minimally absorbed by the infant 1,140,141 Milk progesterone concentrations have not been measured after higher doses used to treat pre- menstrual syndrome.

proges-THYROID AND ANTIproges-THYROID DRUGS

Iodides

Inorganic iodide is contraindicated during breastfeeding because of possible thyroid suppression and rash Topical and vaginal povidone–iodine in nursing mothers results in elevated milk iodine concentrations and occasional thyroid suppression in nursing infants Avoid povidone–iodine preparations while nursing and minimize their use during delivery.

Thioamides

Propylthiouracil is the antithyroid drug of choice during lactation; little passes into milk and infant thyroid suppression does not occur Dosages as high as 750 mg/day have been given to nursing mothers with no adverse effects in their infants 142 Methimazole 20 mg/day or carbimazole (a methimazole prodrug) 15 mg/day also can be used, but these drugs pass into milk in greater quantities and have longer half-lives than propylthiouracil 143 Infants of mothers who took 20 mg/day of methimazole while nursing had no decrease in intellectual or physical development at age 1 yr 144 A potential for idiosyncratic reactions (eg, agranulocytosis) and hypothyroidism exists, and measurement of the infant’s serum thyroxine and TSH concentrations at 2–4-week intervals might be prudent during maternal antithyroid drug use.

Thyroid Hormones

Normal lactation requires thyroid hormones Levothyroxine (T 4 ) passes into milk poorly, although liothyronine (T 3 ) might pass in more physiologically relevant amounts Milk concentrations of thy- roid hormones have not been measured after exogenous administration, but a physiologic replace- ment dosage of levothyroxine to a breastfeeding mother is not expected to result in excessive thy- roid administration to the infant Replacement therapy with liothyronine or supraphysiologic maternal levothyroxine dosage might transfer larger amounts of liothyronine to the infant.

HORMONES AND SYNTHETIC SUBSTITUTES

in-Human Growth Hormone

Somatropin can increase milk production in mothers with an insufficient milk supply 148,149

RENAL AND ELECTROLYTES

DIURETICS

Large dosages of short-acting thiazide-type diuretics (eg, hydrochlorothiazide), usual dosages of loop diuretics (eg, furosemide), or long-acting thiazide-type diuretics (eg, chlorthalidone and bendroflumethiazide) can suppress lactation and should be avoided Long-acting agents also can accumulate in infants’ serum Low dosages of short-acting thiazide-type diuretics should pose

no problems to the infant or suppress lactation Acetazolamide appears in milk in small amounts that are unlikely to harm the infant The amounts of spironolactone and its metabolites in milk are inconsequential.

Fluoride supplementation is not recommended during the first 6 months after birth; from 6 months

to 3 yr of age, fluoride supplementation of the breastfed infant is recommended only if the mother’s water supply contains <0.3 ppm fluoride 151

Magnesium Sulfate

When given IV, magnesium sulfate increases milk magnesium concentrations only slightly Oral absorption of magnesium is poor, so maternal magnesium therapy is not a contraindication to breastfeeding.

RENAL AND ELECTROLYTES

ANTIGOUT AGENTS

Allopurinol

This drug and its active metabolite, oxypurinol, are excreted into milk in nearly therapeutic amounts, and oxypurinol is detectable in the nursing infant’s serum in near-therapeutic levels 152 Although one infant breastfed without harm during maternal allopurinol therapy, observe infants for side effects, especially hypersensitivity reactions If possible, give allopurinol to the mother in a single dose after the last nursing of the day.

Colchicine

Several infants have been breast-fed safely during long-term, low-dose administration of colchicine to the mother for familial Mediterranean fever 153,154 The amount excreted in milk indi- cates that toxicity might occur with higher dosages 153 Colchicine decreases milk production and alters milk composition in animals when infused into the udder Use it with great caution and in low dosages when breastfeeding, especially with a neonate.

ab-Terbutaline

Oral administration results in low milk terbutaline concentrations, causes no symptoms in breastfed infants, and is not expected to decrease milk supply Other  2 -receptor agonists (eg, albuterol) ap- pear safe to use orally, but inhaler products should transfer less drug to the infant and are preferred.

Theophylline

Maternal theophylline use occasionally can cause irritability and fretful sleep in infants Newborn infants are most likely to be affected because of their slow elimination and low serum protein binding of theophylline There is no need to avoid theophylline products; however, keep maternal serum concentrations in the lower part of the therapeutic range and measure infant serum con- centrations if side effects occur The related drug dyphylline is excreted into milk in greater amounts and is best avoided.

ANTIHISTAMINES

There are few studies on antihistamine use during lactation One study found drowsiness or tability in 12% of breastfed infants whose mothers took antihistamines 5 Older sedating (and more anticholinergic) antihistamines are more problematic because they can affect the infant and might

irri-suppress lactation (See Anticholinergics.) Nonsedating antihistamines are preferred agents for

long-term therapy However, single bedtime doses of a sedating antihistamine after the last feeding

of the day might be adequate and minimize the amount the infant receives Avoid sedating tamines in high dosages, in SR formulations, or in combinations with sympathomimetic agents.

Only small amounts of triprolidine are found in breastmilk.

COUGH AND COLD

-Adrenergic sympathomimetics decrease milk flow in animals by central inhibition of secretion and release of oxytocin and by peripheral vasoconstriction, which limits the access of oxytocin to myoepithelial cells in the mammary glands Norepinephrine also might decrease prolactin re- lease Although these effects are not well documented in humans, lactation inhibition seems to occur with oral decongestant (eg, pseudoephedrine) use; therefore, sympathomimetic nasal sprays (eg, oxymetazoline) are recommended over oral decongestant products Pseudoephedrine also can cause irritability in some infants 5

MISCELLANEOUS DRUGS

CHOLINERGIC DRUGS

Six infants of mothers treated with neostigmine for myasthenia gravis were reportedly breastfed successfully Neostigmine was not found in milk, but 1 infant appeared to have abdominal cramps after each breastfeeding Pyridostigmine has been used safely during breastfeeding in 3 patients with myasthenia gravis.

MISCELLANEOUS DRUGS

Radiopharmaceuticals

Exposure of the infant to excessive amounts of radioactivity is usually the primary concern raised

by administration of radiopharmaceuticals to nursing mothers, rather than any pharmacologic city of the agent Some, but not all, radiopharmaceuticals require discontinuation of breastfeeding,

toxi-at least temporarily, after administrtoxi-ation to a nursing mother Radioactive iodine compounds are the most dangerous and might require complete cessation of breastfeeding The period needed for milk radioactivity to decline (by means of radioactive decay and maternal excretion) to a safe expo- sure level depends on several factors: dosage, biological half-life, radionuclide half-life, and “con- tamination” with other isotopes The age of the infant, potential for oral absorption of the radionu- clide from the infant’s GI tract, and threshold level that is considered safe are also important factors Measurement of milk radioactivity can aid in determining when breastfeeding can resume Consult specialty sources for more detailed information 159,160

Retinoids

Acitretin passes into breastmilk in a quantity sufficient to merit avoidance of nursing while taking

it Although there is no information on use during lactation, the manufacturers of oral isotretinoin and topical tretinoin state that they are not compatible with nursing Based on the systemic bioavailability of tretinoin applied topically to a small area such as the face, it is unlikely that harm- ful amounts reach the infant via breastmilk Avoid contact of the infant’s skin with treated areas of the mother’s skin.

Vaccines

Breastfeeding is not a contraindication to the use of any vaccine (live or inactivated) in the nursing mother 161

DIAGNOSTIC AGENTS

Iodinated Contrast Media

Iopanoic acid contains free iodide that can be detected in milk (See Iodides.) Diatrizoate,

io-damide, iohexol, metrizoate, and metrizamide are detectable in milk after IV administration though no adverse effects have been reported in infants, breastfeeding probably should be with- held for a period after administration of most iodinated contrast media, the period depending on its rate of elimination A few hours is probably adequate after an IV pyelogram Large amounts of io- dine are excreted into milk for weeks after lymphangiography with ethiodized oil, and nursing should be discontinued after this procedure.

Al-Fluorescein

Fluorescein is detectable in milk after IV or topical administration After IV administration, it had a milk half-life of 62 hr in one mother The drug might present a risk to neonates who are undergo- ing phototherapy Temporarily withholding nursing after fluorescein use (especially IV) seems ap- propriate in this situation.

Gadolinium

Gadodiamide and gadopentetate, used in magnetic resonance imaging, are detectable in milk but have poor oral absorption and are rapidly excreted renally Suspension of breastfeeding is not necessary after use of these agents 162

DRUGS FOR NONMEDICAL USE

Alcohol

Alcohol equilibrates rapidly between blood and milk, resulting in milk concentrations equivalent to simultaneous blood concentrations Peak maternal serum alcohol levels occur later (1 hr after the drink) in nursing mothers than in non-nursing women; 163 alteration in milk odor parallels milk alco- hol levels 164,165 Potential effects on infants depend on the pattern of use Drunkenness (deep, unarousable sleep with snoring, deep respiration, no reaction to pain, inability to suck, excessive perspiration, and a feeble pulse) was reported after maternal binge drinking Pseudo-Cushing syn- drome was reported in the infant of a chronic alcoholic mother One prospective study suggests that as little as 1 drink daily can cause slight impairment of the infant’s motor development; the impairment increases in a dose-dependent fashion 166 Infants suck more but consume less milk after maternal alcohol ingestion 164 Alcohol also affects lactation; it inhibits the milk ejection reflex

in a dose-dependent fashion, with single doses >2 g/kg completely blocking suckling-induced oxytocin release Animal studies show that alcohol consumption results in a reduced suckling- induced prolactin release and reduced milk yield An unknown substance in beer increases mater- nal serum prolactin; this effect also occurs with nonalcoholic beer 1,167 Use alcohol in moderation during lactation and withhold nursing temporarily after alcohol consumption, with the duration de- pendent on the amount consumed—at least 2 hr per drink is suggested 168

Amphetamine

In a mother taking amphetamine 20 mg/day therapeutically, amphetamine concentrations in milk were less than those in serum and no adverse effects on the infant were noted However, there is likely to be substantial intersubject variation in excretion, and concentrations in milk have not been measured during high-dose abuse of amphetamines Anecdotally, infants breastfed by ampheta- mine abusers seem to experience drug-induced behavioral abnormalities such as agitation and cry- ing Amphetamine also inhibits prolactin release and, in high dosages, can interfere with lactation.

Caffeine

Anecdotal reports of infant jitteriness and difficulty sleeping have been reported with very high ternal intake of caffeine, but infant serum caffeine concentrations were not measured Systematic studies have indicated that caffeine and its metabolites are excreted into milk in relatively small amounts with usual maternal intake and infants are usually not affected, even with high maternal intake 1,169,170 Effects are more likely in premature and newborn infants because of their greatly diminished ability to metabolize caffeine.

ma-Cocaine

Although not well studied in humans, the chemical nature of cocaine and results from animal studies indicate that it probably appears in milk in amounts that affect the infant Cocaine was detectable in milk for 24–36 hr after use In addition, serum cholinesterase, which is needed to metabolize the drug, is low in newborns Cocaine and its toxic metabolite can be detected in milk and can cause adverse effects (vomiting, diarrhea, irritability, and dilated pupils) in breastfed in- fants Convulsions occurred in an infant whose mother used topical cocaine to treat sore nipples Breastfeeding is not recommended when the mother is a chronic cocaine user, and even occa- sional use of cocaine is discouraged during breastfeeding Withhold breastfeeding for at least

24 hr after occasional cocaine use 1,171

Heroin

Abuse can result in high enough concentrations in milk to cause addiction or alleviate withdrawal symptoms in infants; however, breastfeeding is not a reliable method of preventing withdrawal

DRUGS FOR NONMEDICAL USE

Most authorities consider breastfeeding safe during methadone maintenance in doses up to 80 mg/day 1,172

Marijuana

Marijuana excretion into milk is not well studied, but dronabinol (tetrahydrocannabinol) can reach high concentrations in milk and be detected in the infant, particularly with heavy maternal use Short-term effects in infants have not been reported, but a decrement in motor development at age 1 yr in the infants of marijuana-smoking mothers was reported in one study Marijuana lowers serum prolactin slightly in nonlactating women and oxytocin release in rodents One survey indi- cated that women who smoke marijuana breastfed for a shorter duration than nonusers and that the effect appears to be dose related 173 Avoid breastfeeding in heavy marijuana users and during therapeutic dronabinol use Withhold breastfeeding for several hours after occasional marijuana use and use caution to avoid exposing the infant to marijuana smoke.

of respiratory illness by half that of formula-fed infants 177 In nonsmokers, breastfeeding reduces the risk of sudden infant death syndrome compared with formula feeding, but smoking negates this advantage 178 Advise nursing mothers to (1) stop or decrease smoking to the greatest degree possible, (2) not breastfeed right after smoking, and (3) not smoke in the same room with the in- fant 179 The use of nicotine chewing gum, topical patches, or nasal spray has not been studied during lactation Although they are not recommended by the manufacturer during nursing, these products are likely to be less hazardous to the nursing infant than maternal smoking.

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Pediatric Drug Therapy

William E Murray

Pediatric drug therapy presents a challenge to the practitioner in many respects.The pediatric population is comprised of a range of patient weights and organ ma-turity Often there are no pediatric-specific data in the literature from which to de-rive appropriate dosage regimens At times, medications must be used for whichdata are extrapolated on the basis of limited pharmacokinetic knowledge about thepediatric population It must be remembered that children should not be treated as

“little adults” when designing dosage regimens Dosage administration grams derived from adult data should not be used in the pediatric population.Pharmacodynamic responses for the majority of medications used in children areeven less well known Children often react much differently from adults to certainmedications Examples are the use of stimulants such as methylphenidate to con-trol hyperactivity common with attention deficit disorders and paradoxical hyper-activity, which can be observed in children taking phenobarbital With therapeuti-cally monitored medications, the standard adult therapeutic range is typically usedbecause age-specific, concentration-effect information is scarce Because of pro-tein binding differences, infants might respond to lower total drug concentrationsthan those used in adults for certain medications (eg, phenytoin, theophylline).One of the problems facing the clinician and caregiver of small children isthe administration of medications Dosage forms are usually designed with theadult population in mind, and the dosage cannot easily be individualized in smallpatients This is especially true for most sustained-release products Most youngchildren cannot swallow tablets and capsules; thus, liquid preparations are gener-ally preferred in this age group For many drugs, liquid forms are not commer-cially available and must be extemporaneously compounded Stability of thesepreparations is often unknown or of limited duration Even when appropriatedosage forms suitable for young children are available, palatability, resistance totaking medications, and compliance issues can hinder optimal therapy

nomo-■ PHARMACOKINETICS

ABSORPTION

At birth, gastric pH is neutral but falls to values of 1–3 in the first day of life sequently, gastric pH returns toward neutrality because gastric acid secretion islow in the first several weeks to months Adult values are usually achieved afterthe age of 2 yr.1,2Medications that require gastric acidity for absorption can havepoor bioavailability in this age group, rendering them ineffective or requiringmuch higher doses than normal for therapeutic serum concentrations to bereached Examples of medications in this group are phenytoin, ketoconazole, anditraconazole.1,3Alternative agents might have to be used if adequate serum levelscannot be documented when these drugs are administered orally Certain medica-tions that are acid labile actually might have increased bioavailability in infants,and these are antibiotics such as penicillin G and ampicillin.4

Gastric emptying time can be delayed in infants, especially premature fants.1,3,5Peak drug concentrations can occur much later in infants than in olderchildren and adults Other factors that can influence overall bioavailability of aparticular medication in infants are the relatively high frequencies of gastro-esophageal reflux, which can cause the dose to be spit up or vomited, and acutegastroenteritis (diarrhea), which can considerably shorten intestinal transit time.The oral route must be used with caution in these instances, especially in criticallyill patients.

in-Other routes of administration can pose difficulties in the pediatric ulation Overall muscle mass is decreased, and intramuscular administrationmight not be practical and certainly is not appreciated by most children Mostadults still remember their first injections in the doctor’s office when they werechildren Also, the dose of drug to be administered might require multiple in-jections

pop-Rectal administration may be used in situations where the oral route is notpractical or available; however, absorption might be incomplete and/or erratic.Topical administration of medications can lead to undesired systemic absorption,especially in infants in whom the skin thickness is less and the total skin surfacearea is proportionally greater than in adults.1,2,4

Hy-Protein binding is an important determinant of the Vdfor drugs that arebound by albumin and other plasma proteins In the neonatal period, the bindingaffinity of albumin is decreased compared with that in older children and adults(because of the persistence of fetal albumin).1–3Highly protein-bound drugs such

as phenytoin have higher free fractions in neonates, and there might be an creased pharmacodynamic response at lower concentrations of total drug The Vd

in-of these drugs is inversely related to the degree in-of protein binding

In addition, the clinician must be aware of the potential for highly bound substances to displace bilirubin from binding sites on albumin, particularly

protein-in the newborn.1–3,7The blood–brain barrier in newborns is more permeable than

in older patients, and free bilirubin can readily cross into the CNS and cause nicterus

ker-Tissue binding for many medications is unknown but can differ dramaticallyfrom that in adults One example is digoxin, which binds to erythrocytes in pedi-atric patients to a much greater extent than in adult patients.2,4Digoxin has a muchlarger Vdin pediatric patients, and recommended loading doses in this age groupare much larger on a mg/kg basis than in adult patients In general, drug distribu-tion volumes are larger in neonates and gradually approach adult values (in L/kg)

by the first year of life

Metabolic processes show dramatic changes in the first weeks to months of life

At birth, most hepatic enzymes are immature and drug metabolizing capacity isgreatly reduced Phase I reactions (ie, oxidation) are controlled largely by themixed-function oxidase system, of which the cytochrome P450 enzymes are themajor determinant These enzymes are largely undeveloped in newborns, espe-cially premature infants, but maturation can take place quickly in the first weeks

to months of life Phase II reactions (ie, conjugation) include glucuronidation, fation, and acetylation These reactions also are immature at birth, and drug toxic-ity has resulted (eg, with chloramphenicol) because of the absence of knowledgeabout reduced dosage requirements in newborns.1–3,6

sul-The liver size relative to body weight in newborns is much larger than that inadults.1Rapid weight gain, with subsequent increases in liver size and metabolic ca-pacity, might require many dosage adjustments to prevent newborns from growingout of their dosages for many medications When full metabolic capacity is reached

in the pediatric patient, the hepatic clearance can greatly exceed that observed inadult patients on a weight-adjusted basis Pediatric dosages of many medications on amg/kg basis are often much greater than adult dosages Figure 2–2 illustrates thechange in clearance with age for theophylline.6Most medications have similar curvesbut can be shifted to the left or have different relative peaks compared with adult val-ues A decrease in hepatic clearance relative to body weight typically begins after achild weighs approximately 30 kg.8Thereafter, the increase in total body weight inproportion to liver size becomes greater Thus, in adolescence, drug dosages typicallybegin to approach adult values Drug toxicity can be observed in the adolescent pa-tient if drug dosages on a mg/kg basis (designed for younger patients) are used.RENAL ELIMINATION

The kidneys are the major route of drug elimination for many drugs The kidneysare functionally immature at birth with regard to glomerular filtration and tubularsecretion Glomerular filtration at birth adjusted for body surface area is only

Figure 2–2 Maturation of theophylline metabolism

30 to 40% of values in older infants and healthy young adults.1–3Premature infantsoften have even lower values during the first few weeks of life Dosages of manymedications (eg, aminoglycosides, vancomycin) that are eliminated largely byglomerular filtration must be decreased on the basis of the relative immaturity ofthe kidneys at birth Maturation of glomerular filtration occurs over the first severalweeks to months of life The dosages of most medications are similar to those inolder children by age 4–6 months Although the frequency of renal disease in chil-dren is much lower than in the adult population, factors that can alter renal func-tion, such as shock, nonsteroidal anti-inflammatory drugs, or hypoxia, must be con-sidered when evaluating dosage regimens Serum creatinine, the usual marker forrenal function, is usually lower in young children than in adults because of chil-dren’s lower muscle mass Thus, a serum creatinine that indicates normal renalfunction in an adult might indicate renal impairment in a young child.

Tubular secretion also is diminished in the newborn Drugs that have a ponent of tubular secretion (eg, penicillin) are typically administered at reduceddosages in the newborn Maturation of tubular secretion occurs somewhat moreslowly than glomerular filtration, but approaches adult values by age 8–12months.1–3

com-EVALUATING DRUG DATA IN CHILDREN

With the numerous maturational changes observed in children from birth throughadolescence, results of pediatric drug studies must be used with caution in childrenwhose ages differ from those in the study Dosages extrapolated only on a weightbasis have the potential to underdose or overdose other age groups, depending onthe population studied Body surface area might correlate better than body weightwith total body water and extracellular water and can be useful in certain instances

in calculating dosage regimens With the exception of cancer chemotherapeuticagents, information on drug dosage is more widely available in mg/kg than by bodysurface area.5Medications with narrow therapeutic ranges should have serum con-centrations measured to aid in individualizing drug therapy, especially in criticallyill children or those with known decreased renal or hepatic function

Pharmacodynamic changes are poorly studied in the pediatric population,and responses to specific drug concentrations might be much different from those

in the adult population Diseases of childhood often differ from those in adults.Medications tolerated by adult patients might be inappropriate for the pediatricpopulation (eg, aspirin for fever)

Caution must be used in the interpretation of drug levels because there might

be much greater fluctuation in serum concentrations because of shorter drug lives in children than in adults Further, the total volume of blood needed for druglevel monitoring in small children can limit monitoring

half-Detailed information on specific drugs can be found in the Pediatric Dosagesections of the individual drug monographs

■ REFERENCES

1 Stewart CF, Hampton EM Effect of maturation on drug disposition in pediatric patients Clin Pharm

2 Besunder JB et al Principles of drug biodisposition in the neonate A critical evaluation of the

pharmacokinetic-pharmacodynamic interface (part I) Clin Pharmacokinet 1988;14:189–216.

3 Milsap RL et al Special pharmacokinetic considerations in children In, Evans WE et al, eds Applied netics Principles of therapeutic drug monitoring 3rd ed Vancouver, WA: Applied Therapeutics; 1992:10-1–32.

pharmacoki-4 Morselli PL et al Clinical pharmacokinetics in newborns and infants Age-related differences and therapeutic

im-plications In, Gibaldi M, Prescott LF, eds Handbook of clinical pharmacokinetics Section II Balgowlah, NSW,

Australia: ADIS Health Science Press; 1983:98–141.

5 Maxwell GM Paediatric drug dosing Bodyweight versus surface area Drugs 1989;37:113–5.

6 McLeod HL, Evans WE Pediatric pharmacokinetics and therapeutic drug monitoring Pediatr Rev

1992;13:413–21.

7 Morselli PL Clinical pharmacokinetics in neonates In, Gibaldi M, Prescott LF, eds Handbook of clinical macokinetics Section II Balgowlah, NSW, Australia: ADIS Health Science Press; 1983:79–97.

phar-8 Rane A, Wilson JT Clinical pharmacokinetics in infants and children In, Gibaldi M, Prescott LF, eds Handbook

of clinical pharmacokinetics Section II Balgowlah, NSW, Australia: ADIS Health Science Press; 1983:142–68.

Geriatric Drug Therapy

Dianne E Tobias

Geriatric drug therapy is an important area of therapeutics and research, because

of the growing elderly population, their disproportionately high use of tions, and their increased risk of drug misadventures Although they represent ap-proximately 12% of the U.S population, the elderly consume more than 30% ofall medications.1Trends include increasing numbers of the extreme elderly (overage 80) and elderly with functional disabilities It is estimated that the number ofelderly who are dependent in their activities of daily living will triple from 1985 to

medica-2060 Ethical considerations, such as a patient’s right to exercise decisions ing treatment, are particularly relevant to the elderly population.2,3As the number

regard-of elderly increases and health care resources diminish, cost–benefit tions will become increasingly important.4

considera-The elderly are the most physiologically heterogeneous category of the adultpopulation The rate of normal aging varies considerably, and comparing datafrom persons of chronologically similar age can be misleading; health status isprobably as important as age Optimization of drug therapy in the elderly requires

an understanding of how aging and concomitant pathology affect the netics and pharmacodynamics of drugs, the need to assess elderly patients individ-ually, and elderly patients’ expectations of therapy.5

pharmacoki-Compliance issues leading to misuse and medication errors can be important

in the elderly.6The cost of medications, physical difficulty in opening medicationcontainers, swallowing large tablets, reading the prescription label, and the pres-ence of depression or cognitive impairment can contribute to compliance prob-lems.7–9

Adverse drug reactions are more common in the elderly,10–13although thecorrelation with age alone is debatable.1,14Increased medication use, especiallymedications with greater potential for toxicity, and chronic pathology with in-termittent acute exacerbations are thought to contribute to the higher frequencyand severity of adverse drug reactions Most reactions in the elderly are doserelated rather than idiosyncratic as a result of changes in pharmacokineticsand/or pharmacodynamics Given the wide physiologic variability in the el-derly population, the contribution of pharmacokinetic and pharmacodynamicchanges can vary considerably Additionally, the elderly are more sensitive tospecific adverse reactions For example, they have an increased sensitivity toanticholinergic side effects, especially central effects such as disorientation andmemory impairment These effects can be additive because many drugs com-monly taken by the elderly are centrally active.15–17Varying degrees of cogni-tive impairment or even delirium can be induced by drugs in several classesincluding benzodiazepines, centrally acting antihypertensive agents, and anti-depressants.15,18The onset can be insidious and mistakenly attributed solely tothe aging process

■ PHARMACOKINETICS

ABSORPTION

With aging there is some decrease in gastric secretions, acidity, gastric emptying,peristalsis, absorptive surface area, and splanchnic blood flow,9,19although the ef-fect on gastric pH may not be as pronounced as once believed.20,21Taken together,the changes predict an altered extent or rate of absorption of orally administereddrugs, yet most formal studies show no difference in oral bioavailability Somefactors might counterbalance each other (eg, acidity and gastric emptying; de-creased absorptive surface and longer transit time) Some drugs (eg, digoxin) haveshown a clinically unimportant slowed rate of absorption with equivalent quanti-ties absorbed Drugs with high extraction ratios may have increased bioavailabil-ity in the elderly compared with young patients, because of a decreased first-passeffect secondary to reduced hepatic blood flow Decreased first-pass metabolism

in the elderly has been shown for labetalol, propranolol, lidocaine, and amil.22It is known that the elderly have drier skin with lower lipid content, which

verap-is expected to be less permeable to hydrophilic compounds Although neitherconclusively nor well studied, percutaneous drug absorption appears to decreasewith age.23

The proportion of albumin among total plasma proteins decreases with frailty,catabolic disease states, and immobility seen in many elderly,28but it is no longerbelieved that serum albumin decreases with age alone.23Serum albumin determi-nations should be performed to aid monitoring and dosage adjustment of drugs

that are highly protein bound in the chronically immobile or ill elderly A decrease

in serum albumin can increase the percentage of free drug available for logic effect and elimination Changes in albumin binding are more important withhighly bound (greater than 90%) acidic drugs such as salicylates, phenytoin, andwarfarin.9Conversely, basic drugs, including lidocaine, propranolol, and meperi-dine, have affinity for 1-acid-glycoprotein, which may increase with age, espe-cially when associated with conditions such as inflammatory diseases and malig-nancies.9Protein binding theoretically may be increased and result in less freedrug available, although the clinical relevance of this is unclear.23With both types

pharmaco-of binding, the net effect on clearance varies, depending on metabolism and nation Although not always available, free drug concentration measurements areoften desirable in the elderly There is also some evidence that the elderly mayhave a greater potential for protein displacement drug interactions.29,30

elimi-METABOLISM

Liver size and hepatic blood flow decrease with age and especially with disease.Studies show hepatic blood flow decreases by 35%, and liver volume by 44% and28% in elderly women and men, respectively, when compared to younger counter-parts.13Such a decrease in hepatic blood flow can limit the first-pass effect ofdrugs with high extraction ratios and markedly reduce their systemic clearance.Studies on phase I drug metabolism (ie, oxidation) do not consistently show a cor-relation with age,23although most show that the elderly, especially men, have pro-longed elimination Differences may be explained by environmental factors such

as smoking habits and genetics Phase II metabolism (ie, conjugation) does not pear to be influenced as much by age, although there has been less study in thisarea.9,13,23The effect of aging on drug acetylation is inconsistent and the impor-tance unclear.9,23There does not appear to be any age difference in the degree ofinhibition or induction of cytochrome P450 isozymes.13,31Monitoring and man-agement of interactions with drugs such as cimetidine should be handled in thesame manner as in younger patients The changes described in liver size and meta-bolic function help to explain why certain drugs may have prolonged elimination;however, the variability of data cautions against generalizing about the effect ofage alone The initial dosage of metabolized drugs should be conservative andsubsequent dosage adjustments based on careful monitoring of therapeutic andtoxic parameters

ap-RENAL ELIMINATION

The effect of aging on the renal elimination of drugs is probably the most pletely understood and important aspect affecting geriatric drug therapy.Glomerular filtration, tubular secretion, and renal blood flow all decrease withage Creatinine clearance decreases approximately 1% per year after age 40,32theeffect is variable, and volume depletion, CHF, and renal disease can further de-crease organ function Because creatinine production also decreases with age,serum creatinine may be normal despite a substantial decrease in renal function It

com-is therefore recommended that Cl be measured or estimated using a method that

incorporates age and weight.33,34The dosage of renally excreted drugs with lowtherapeutic indices should be conservative initially, with subsequent dosagetitrated by close clinical and serum drug level monitoring, if applicable.

■ PHARMACODYNAMICS

Heightened drug effects that cannot be explained by altered pharmacokinetic ables alone have been hypothesized to be caused by changes in compensatoryhomeostasis, drug receptor sensitivity, or complications of chronic diseases thatoccur in the elderly There is a gradual decrease in homeostatic reserve withaging Postural control and orthostatic circulatory response are examples of com-pensatory mechanisms that are slowed in aging Adequate postural blood pressurecontrol relies on several factors, including central coordination, muscle tone, andproprioception, all of which can be blunted in the elderly.15As a result, side ef-fects that are minimal or absent in a young patient with normal compensatory re-sponse can be marked in the elderly The administration of long-acting anxiolyt-ics, hypnotics, or antipsychotics can further alter these mechanisms and lead to anincreased risk of falls in the elderly.9,35Similarly, symptomatic postural hypoten-sion can result from the administration of a variety of antihypertensive agents (es-pecially calcium-channel blockers and ACE inhibitors) and other drugs (eg, an-tipsychotics, antidepressants) that affect vasomotor tone Physiologic mechanismssuch as vasoconstriction and tachycardia cannot fully compensate for posturalhypotension in the elderly.15Temperature regulation and intestinal motility areother homeostatic mechanisms that change with aging and can explain heightenedeffects of certain drugs

vari-The number and characteristics of drug receptors can change with aging andproduce altered, often heightened, drug response Research has shown age-relateddecreases in several autonomic receptors There is some evidence of increasedsensitivity to oral anticoagulants and digoxin, apart from the alterations in phar-macokinetics, which might contribute to the higher frequency of adverse reactions

to these two agents in the elderly.15

Preliminary data indicate a possible increase in brain sensitivity to certaindrugs with aging It is unknown whether this effect is caused by changes in blood-brain permeability or tissue receptor sensitivity.9More research into drug pharma-codynamics in the elderly is needed, especially the interrelationship with pharma-cokinetic alterations The presence and impact of multiple concurrent pathologiesand their treatments cannot be overemphasized in their contribution to the variousdrug effects seen in the elderly

■ OTHER FACTORS

Cigarette smoking can cause clinically important induction of the metabolism ofsome drugs to a similar degree in both the elderly and the young.23,36This, and thefact that many published studies do not indicate smoking history, could explainsome interpatient variability of pharmacokinetic data

Nutritional intake is sometimes diminished in the elderly and can lead to tritional and vitamin deficiencies Nutritional status of the elderly can impact theoutcome of drug therapy, and, conversely, drug therapy can affect nutritional sta-tus.19,36,37

nu-■ EVALUATING DRUG DATA FOR THE ELDERLY

Because of age-related changes that may impact the outcome of drug therapy asoutlined in this chapter, the results of drug studies using young subjects cannot al-ways be extrapolated accurately to the elderly Studies on diseases and drugs inthe elderly do not always include sufficient numbers of elderly, especially ex-tremely aged subjects, to draw appropriate conclusions.38Studies that include theelderly do not always separate results by decade of age and health status, two cri-teria that are helpful in assessing applicability of data in this heterogeneous popu-lation Many studies also do not mention data on nutrition, alcohol, and smoking,which might explain some variability of results.19Although single-dose studies inhealthy volunteers can be useful, long-term studies in afflicted elderly patientsoften yield data more applicable to therapeutics Drugs are often not studied over awide dosage range, so a minimal effective dosage in the elderly cannot be deter-mined.39

When reviewing studies that include the elderly, one should consider the lowing potential problems: numbers of subjects must be sufficient to allow forhigh attrition rates and the typically wide variation in this population; studylengths must be sufficient for a chronic disease; concomitant diseases and medica-tions must be acknowledged and their impact assessed; and “normal” values can

fol-be different from those of a younger population.40–42

■ CONCLUSION

The effects of aging as related to drug therapy illustrate the challenges in caringfor the elderly Clinical practice guidelines that have been developed for condi-tions commonly afflicting the elderly, such as those published by the Agency forHealth Care Research and Quality, can be a helpful guide.43Conservative dosage,especially initially, with close clinical monitoring for dose-dependent effects iscritical and should be emphasized by all health care practitioners caring for the el-derly For detailed information on specific drugs in the elderly, refer to the Geri-atric Dosage section of the individual drug monographs

■ REFERENCES

1 Gerety MB et al Adverse events related to drugs and drug withdrawal in nursing home residents J Am Geriatr Soc 1993;41:1326–32.

2 Faden R, German PS Quality of life Considerations in geriatrics Clin Geriatr Med 1994;10:541–55.

3 Goldstein MK Ethical considerations in pharmacotherapy of the aged Drugs Aging 1991;1:91–7.

4 Livesley B Cost-benefit considerations in the treatment of elderly people Drugs Aging 1991;1:249–53.

5 Tobias DE Ensuring and documenting the quality of drug therapy in the elderly Generations 1994;18:40–2.

6 Burns JMA et al Elderly patients and their medication: a post-discharge follow-up study Age Aging 1992;21:

7 Honig PK, Cantilena LR Polypharmacy Pharmacokinetic perspectives Clin Pharmacokinet 1994;26:85–90.

8 Botelho RJ, Dudrak R Home assessment of adherence to long-term medication in the elderly J Fam Pract

1992;35:61–5.

9 Tregaskis BF, Stevenson IH Pharmacokinetics in old age Br Med Bull 1990;46:9–21.

10 Denham MJ Adverse drug reactions Br Med Bull 1990;46:53–62.

11 Beard K Adverse reactions as a cause of hospital admission in the aged Drugs Aging 1992;2:356–67.

12 Owens NJ et al Distinguishing between the fit and frail elderly, and optimising pharmacotherapy Drugs Aging

1994;4:47–55.

13 Woodhouse KW, James OFW Hepatic drug metabolism and ageing Br Med Bull 1990;46:22–35.

14 Walker J, Wynne H Review: the frequency and severity of adverse drug reactions in elderly people Age Ageing

1994;23:255–9.

15 Hämmerlein A et al Pharmacokinetic and pharmacodynamic changes in the elderly Clinical implications Clin Pharmacokinet 1998;35:49–64.

16 Feinberg M The problems of anticholinergic adverse effects in older patients Drugs Aging 1993;3:335–48.

17 Nolan L, O’Malley K Adverse effects of antidepressants in the elderly Drugs Aging 1992;2:450–8.

18 Bowen JD, Larson EB Drug-induced cognitive impairment Defining the problem and finding solutions Drugs Aging 1993;3:349–57.

19 Iber FL et al Age-related changes in the gastrointestinal system Effects on drug therapy Drugs Aging

1994;5:34–48.

20 Gainsborough N et al The association of age with gastric emptying Age Aging 1993;22:37–40.

21 Russell TL et al Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women.

Pharm Res 1993;10:187–96.

22 Durnas C et al Hepatic drug metabolism and aging Clin Pharmacokinet 1990;19:359–89.

23 Roskos KV, Maibach HI Percutaneous absorption and age Implications for therapy Drugs Aging

Phar-26 Rodeheffer RJ et al Exercise cardiac output is maintained with advancing age in healthy human subjects:

cardiac dilatation and increased stroke volume compensate for a diminished heart rate Circulation 1984;

69:208–13.

27 Schumacher GE Using pharmacokinetics in drug therapy VII: pharmacokinetic factors influencing drug

ther-apy in the aged Am J Hosp Pharm 1980;37:559–62.

28 Woo J et al Effect of age and disease on two drug binding proteins: albumin and -1-acid glycoprotein Clin Biochem 1994;27:289–92.

29 Wallace S et al Factors affecting drug binding in plasma of elderly patients Br J Clin Pharmacol

32 Lindeman RD Changes in renal function with aging Implications for treatment Drugs Aging 1992;2:423–31.

33 Siersbaek-Nielsen K et al Rapid evaluation of creatinine clearance Lancet 1971;1:1133–4.

34 Cockcroft DW, Gault MH Prediction of creatinine clearance from serum creatinine Nephron 1976;16:31–41.

35 Campbell AJ Drug treatment as a cause of falls in old age A review of the offending agents Drugs Aging

1991;1:289–302.

36 O’Mahony MS, Woodhouse KW Age, environmental factors and drug metabolism Pharmacol Ther

1994;61:279–87.

37 Roe DA Medications and nutrition in the elderly Prim Care 1994;21:135–47.

38 Gurwitz JH et al The exclusion of the elderly and women from clinical trials in acute myocardial infarction.

JAMA 1992;268:1417–22.

39 Kitler ME Clinical trials and clinical practice in the elderly A focus on hypertension Drugs Aging

1992;2:86–94.

40 Zimmer AW et al Conducting clinical research in geriatric populations Ann Intern Med 1985;103:276–83.

41 Butler RN The importance of basic research in gerontology Age Aging 1993;22:S53–4.

42 Fraser CG Age-related changes in laboratory test results Clinical implications Drugs Aging 1993;3:246–57.

43 Agency for Health Care Policy and Research Guidelines for pressure ulcer prevention: improving practice and a

Renal Disease

Gary R Matzke

■ DOSAGE REGIMEN OPTIMIZATION FOR PATIENTS

WITH RENAL INSUFFICIENCY

Eleven million Americans have early renal insufficiency, defined as a Crs

≥1.5 mg/dL or Clcr<70 mL/min; approximately 1 million have concentrations

>2 mg/dL.1The number of individuals with end-stage renal disease (ESRD) hasbeen increasing at a rate of about 7–9% annually during the past decade.2Reduced renal function can be associated with drug effects, age, or chronicdisease states.3–5Medical problems can contribute to the development of a pa-tient’s initial renal injury, enhance the rate of their progressive decline in renalfunction, or develop as sequelae of chronic renal disease.6Hypertension, diabetesmellitus, infection, bone disease, neurological dysfunction, GI disturbances, andbleeding abnormalities are but a few of the medical conditions frequently encoun-tered in renal failure patients.7These patients are often given medications early inthe course of their disease in an attempt to slow the rate of decline in renal func-tion and prevent cardiovascular complications Surveys of dialysis patients havefound that they average more than eight scheduled prescription drugs and two ormore “prn” drugs.8–10Thus, patients with early renal insufficiency and those withESRD are at increased risk for adverse reactions because of the number of drugsreceived, concurrent medical problems, and impaired drug excretion.11–12Renal insufficiency in any patient requires that the clinician understand theaspects of drug disposition that are altered and the appropriate methods to individ-ualize drug therapy.3,5Complications of drug administration can be minimized bythe application of pharmacokinetic and pharmacodynamic principles.13The ad-vent of specific and sensitive methods for measuring drug concentrations in bio-logical fluids has resulted in a voluminous literature on drug disposition in renaldisease and evaluations of the effects of dialysis.14–17

This section provides a conceptual discussion of how renal disease altersdrug disposition with selected literature examples It also describes an approachfor determining the individual dosage adjustment necessary to achieve the optimaltherapeutic effect with minimal toxicity for a patient with a given degree of renalfunction The subsequent section, Dialysis of Drugs, presents the concepts of drugremoval by hemodialysis, peritoneal dialysis, and continuous renal replacementtherapies that are now frequently used in critically ill patients Data on the amount

of drug removed by dialysis are tabulated and dosage modification schemes for anumber of drugs during dialysis are presented

FOUR BASIC QUESTIONS

A practical approach to drug therapy in patients with renal insufficiency can be rived at if one considers the following questions:

ar-1 What is the patient’s renal function status?

2 What is the degree of alteration in the pharmacokinetics or namics of the patient’s drug(s) in the presence of renal insufficiency?

pharmacody-3 What approaches to dosage modification are useful for a specific drug?

4 What is the impact of dialysis on drug disposition, and is dosage cation or supplementation necessary?

modifi-QUANTIFYING RENAL FUNCTION

Several common laboratory tests provide an assessment of a patient’s renal tion: blood urea nitrogen (BUN), serum creatinine (Crs), the ratio of BUN to Crs,and creatinine clearance (Clcr).18The BUN concentration can change because ofmany factors in addition to changes in renal function Urea is filtered and reab-sorbed by the nephron, and its renal excretion is a function of urine flow Diureticuse, dehydration, and bleeding can increase the BUN concentration without a de-cline in renal function.18These conditions usually result in an increased BUN/Crsratio to values above the normal range of 10–15 Creatinine production and elimi-nation in adults are usually constant at approximately 20 mg/kg/day under steady-state conditions.18Creatinine is filtered predominantly by the glomerulus with lit-tle renal tubular secretion (about 10%) in those with normal renal function.However, secretion becomes an important excretory pathway for patients with a

func-Clcr<50 mL/min In these individuals, accurate measurement of Clcrcan be tained by giving cimetidine before initiating the urine collection because cimeti-dine inhibits the tubular secretion of creatinine.19,20

ob-Because the nonrenal factors that can affect BUN do not alter serum or urinecreatinine concentrations, Crsand Clcrserve as better markers of changing renalfunction The relationship between Crsand Clcris a hyperbolic one, as is shown inFigure 2–3 Small increases in Crsrepresent a larger absolute decrease in renalfunction in subjects with normal renal function than do similar increases in Crsinindividuals with moderate to severe renal insufficiency For example, doubling the

Crsis associated with a halving in Clcr(ie, as Crschanges from 1 to 2 mg/dL, the

Clcrdeclines from 120 to 60 mL/min, whereas an increase from 2 to 4 mg/dL resents a decrease in Clcrof 60 to 30 mL/min)

rep-Although Crsis easy to determine, requiring collection of only a single bloodsample, measurement of Clcris more difficult The standard method consists of acontinuous 24-hr urine collection for urine creatinine with a single blood samplefor Crsat approximately the middle of the urine collection period The most diffi-cult problem from a practical standpoint is obtaining a complete urine collection.Almost invariably, the urine collection is incomplete and consequently the Clcrisunderestimated However, the accuracy of the Clcrand urine collection can be as-sessed by determining the daily creatinine excretion rate—the amount of creatinine(in mg/day) excreted in the urine during the 24-hr collection period This can becompared with the expected amount of creatinine to be excreted, which is approxi-mately 20–25 mg/day/kg ideal body weight in males and 15–20 mg/day/kg in fe-males who are age 18–50 yr Urinary creatinine excretion declines in males and fe-males who are >50 yr.21For example, in a 70-kg man, the expected creatinineproduction and excretion in the urine is approximately 1.4 g/day If his total creati-nine excretion is less than this value, it is likely he did not collect all his urine and

the calculated Clcris an underestimate The use of this approach is valid only understeady-state conditions when creatinine production and excretion are equivalent.

If it is impractical to measure a patient’s Clcr, it can be estimated from equationsbased on the patient’s age, height, and weight.18The most frequently used equationfor adults with stable renal function was derived by Cockcroft and Gault.21Equationsare given for men, women, and children in Appendix 2, Anthropometrics Theseequations assume steady-state serum creatinine values and do not provide valid Clcrestimates in patients with fluctuating renal function or those receiving dialysis of anytype The advantages and disadvantages of the several methods for Clcrestimation inpatients with changing renal function have been reviewed recently.18

■ PHARMACOKINETIC/PHARMACODYNAMIC ALTERATIONS

OF DRUGS IN RENAL FAILURE

Decreased renal function can alter the absorption, distribution, protein binding, tabolism, or excretion of drugs.3,22Furthermore, the pharmacodynamic effects of adrug can be different in patients with renal insufficiency because of biochemical orpathophysiologic changes associated with renal disease The bioavailability ofdrugs can be altered in symptomatic (uremic) patients because of GI disturbancessuch as nausea, vomiting, and diarrhea, increased gastric pH because of the inges-tion of histamine H2-receptor antagonists, or increased salivary urea concentration

me-as a result of markedly increme-ased BUN (>100–120 mg/dL).23This can decrease the

Creatinine clearance (mL/min)

Figure 2–3 Relationship between serum creatinine concentration and creatinine

clearance (Reproduced with permission from DiPiro J et al, eds

Pharmacother-apy: a pathophysiologic approach, 4th ed New York: McGraw-Hill; 1999.)

absorption of ferrous sulfate and other drugs that are best absorbed from an acidicenvironment In addition, patients who routinely take aluminum or calciumantacids might have reduced bioavailability of some drugs because of complexa-tion in the GI tract Propoxyphene, dihydrocodeine, and some -blockers mighthave increased bioavailability because of reduced first-pass metabolism.24–26The plasma protein binding of some drugs is altered in patients with severerenal insufficiency This might be secondary to hypoalbuminemia; accumulation

of acidic byproducts of uremia resulting in competitive displacement of drugsfrom binding sites; or changes in the structure of albumin resulting in a decreasednumber of effective binding sites.3,22,27Most weak organic acid drugs, such ascefazolin, phenytoin, salicylate, valproic acid, and warfarin, exhibit decreasedplasma protein binding (increased free fraction) Weak organic basic drugs mighthave decreased or unchanged binding The protein binding of carbamazepine,dapsone, diazepam, and morphine is decreased, whereas the binding of propran-olol, quinidine, verapamil, and trimethoprim is unchanged Propranolol and lido-caine are bound primarily to 1-acid glycoprotein from which little displacementoccurs in renal disease or hypoalbuminemia If the protein binding of a drug is de-creased, the patient can experience an increased pharmacodynamic effect, an in-creased Vd, and increased or unchanged total body clearance depending onwhether it is a high or low extraction ratio drug

Phenytoin has altered protein binding and disposition in ESRD patients that results in important differences in dosage.28The percentage of unboundphenytoin in plasma is normally 10% but increases to 20 to 35% in ESRD pa-tients This results in an increase in the Vdfrom 0.65 L/kg in those with normalkidney function to 1–1.8 L/kg in ESRD patients Further, the terminal half-life isdecreased from 11–16 hr to 6–10 hr and the apparent plasma clearance increasesfrom 28–41 mL/hr/kg to 64–225 mL/hr/kg in ESRD patients compared withthose with normal renal function These changes in the pharmacokinetics ofphenytoin result in a change in its therapeutic concentration range In patientswith normal kidney function, the usual therapeutic plasma concentration rangefor total phenytoin (unbound plus bound) is 10–20 mg/L; in those with ESRD,the range is approximately 4–8 mg/L Both ranges of total drug represent thesame concentration of unbound drug, 1–2 mg/L

The Vdof drugs can be increased, decreased, or unchanged in renal failure tients.3,22,27An increase in Vdcould be due to decreased protein binding, fluid over-load secondary to reduced renal excretion, or increased tissue binding A decrease in

pa-Vdcould be due to decreased tissue binding or increased protein binding Examples

of drugs with increased Vdare cefazolin, furosemide, gentamicin, naproxen, toin, and vancomycin Digoxin exhibits a decreased Vdin renal impairment, whereasminoxidil and procainamide are drugs whose Vddoes not change markedly in ESRD.Drugs are eliminated from the body by two primary pathways: renal andnonrenal elimination (predominantly hepatic metabolism).29The degree of reduc-tion in renal clearance depends on the percentage of drug excreted unchanged bythe kidney The influence of renal function is very important for aminoglycosides,cephalosporins, penicillins, vancomycin, acyclovir, lithium, and ranitidine, all ofwhich are extensively (>80%) eliminated unchanged renally For many of thesedrugs, linear correlations have been established between the drug’s plasma and

renal clearance and Clcr.17,27These correlations can be used as guides to projectthe drug dosage requirement for those with a given degree of renal insufficiency.For example, the linear correlation between gentamicin plasma clearance and Clcrdemonstrates that the clearance of gentamicin can change from 120 mL/min withnormal renal function to as little as 2 mL/min in ESRD The half-life of gentam-icin in ESRD is markedly prolonged (range 40–60 hr) compared with the 1–2 hrvalues of patients with normal renal function This relationship then can be used todetermine the desired maintenance dosage of gentamicin in patients with differentdegrees of renal insufficiency, as outlined later in this chapter.

Drug metabolism typically involves enzymatic conversion of drugs to morewater-soluble compounds These metabolites are formed through the processes ofoxidation, reduction, synthesis (eg, conjugation), or hydrolysis Once formed,these metabolites often are excreted predominantly by the kidney.27,29 Mostmetabolites are inactive or have minimal pharmacologic activity However, someactive metabolites might accumulate, especially in ESRD patients, and lead to ex-aggerated pharmacodynamic responses that warrant dosage reduction Activemetabolites that are excreted by the kidney include oxypurinol from allopurinol,which is an active inhibitor of xanthine oxidase; desacetylcefotaxime from cefo-taxime, which is microbiologically active; normeperidine from meperidine, which

can cause seizures; and N-acetylprocainamide from procainamide, which has its

own unique antiarrhythmic properties.27

Renal insufficiency also can lead to alterations in drug metabolism.30,31mal experiments indicate that the activity of many drug metabolic pathways is re-duced in the presence of renal insufficiency by up to 70%.32,33The decrement inenzyme activity is larger in the animals with the most severe renal dysfunction.The nonrenal clearance of several drugs is decreased in ESRD.3,27For example,the antiviral agent acyclovir and the antihypertensive agent captopril demonstrate50% decreases in nonrenal clearance in patients with ESRD.34,35 As a conse-quence, the elimination half-life for both drugs is increased 6-fold in the presence

Ani-of renal failure This shows that predictions Ani-of the disposition Ani-of drugs in renalfailure based on general principles and nomograms are subject to considerableerror if one assumes that nonrenal clearance is unaffected by renal disease.The pharmacodynamics of a drug also can be altered in ESRD and result in thepharmacologic effects being different from those one would expect in patients withnormal renal function One well-defined example is that of nifedipine, where markeddifferences in Emax(maximal change in diastolic blood pressure) were observed Theaverage Emaxvalues were 12 and 29% in healthy controls and ESRD patients, respec-tively.36,37Thus, at the same plasma concentration of unbound nifedipine, a greaterblood pressure reduction occurs in patients with renal insufficiency

■ DOSAGE ADJUSTMENT APPROACHES THAT ARE USEFUL

AND PRACTICAL FOR SPECIFIC DRUGS

The general approaches for dosage adjustments of drugs in renal insufficiency are

to (1) decrease the dose and maintain the usual dosage interval, (2) lengthen thedosage interval and maintain the usual dose, or (3) modify the dose and interval.The primary goal of these approaches is to provide average steady-state plasma

concentrations or AUCs in renal insufficiency similar to those in normal kidneyfunction The choice of approach depends on the type of drug and the desirability,from a therapeutic or toxic standpoint, of having small or large peak-to-troughfluctuations.38,39Other considerations are that the dosage regimen adjustmentshould be practical and the reduced dose or prolonged dosage interval should berelatively easy to implement.14,27

When presented with a patient with renal insufficiency for whom drugdosage regimen decisions must be made, the most practical and efficient approach

is to first consult published tables or guidelines that provide a quick referencesource for drug dosage in renal failure.14Additional sources are the appendices of

Handbook of Drug Therapy in Liver and Kidney Disease29and “Use of Drugs in

Renal Failure” in Diseases of the Kidney,40which describe specific netic alterations of drugs in kidney disease, recommended dosage regimens, andtabulate the effects of dialysis The reader also is advised to refer to specific drug

pharmacoki-monographs in this book and in AHFS Drug Information,41which briefly describethe effect of renal failure on drug disposition and provide initial dosage recom-mendations These sources allow the user to determine whether dosage adjust-ments are necessary and if there are any important toxicities or precautions inusing a particular drug These sources, however, provide only general guidelines.For drugs requiring marked dosage adjustment in renal insufficiency or forwhich the achievement of specific therapeutic plasma concentrations is critical, thereader should consult the original publications, which provide specific data on indi-vidual drugs Consulting the original publications or authoritative reviews will pro-vide details regarding the relationship of renal function to drug elimination and canprovide a dosage nomogram or specific dosage recommendations and precautionsfor the use of the drug in patients with various degrees of renal insufficiency.17

If drug-specific data or guidelines are not available, one can use generaldosage equations such as those developed by Rowland and Tozer.42Only basicpharmacokinetic information about the drug is needed—primarily the fraction ofthe available dose that is normally excreted unchanged in the urine, fe The frac-tion of normal renal function (KF) in a given patient is determined as the ratio ofthe patient’s Clcrto the accepted normal value of 120 mL/min The patient’s Clcrcan be determined from Crsvalues at steady state with the method of Cockcroftand Gault.21

The following equation, which takes into consideration the renal clearanceand extrarenal clearance of unbound drug, can be used to determine the dosage ad-justment factor, Q:42

Q is analogous to the ratio of the unbound drug clearance of the patient to that served in those with a Clcr≥120 mL/min, or [Clu(failure)/Clu(normal)] If a drug

ob-is minimally protein bound (<25%) and not extensively metabolized (fe≥70%),this equation can be simplified to:5

Once the value of Q is obtained, the dosage regimen adjustment can be made withthe following equations and scenarios:

where DRIis the maintenance dose in the renally insufficient patient that is to begiven at the normal dosage interval and DNis the normal dose for those with Clcr

An example will clarify the use of this approach An 80-kg, 45-yr-old man with a

Crsof 5.4 mg/dL requires treatment with ceftazidime for a pseudomonal infection.This drug is 70% excreted unchanged in the urine, and the usual dosage is 1 g q 8

hr IV With the equation of Cockcroft and Gault, the patient’s Clcr, KF, and Q arecalculated as follows:

If the maintenance dose for this patient was reduced and the dosage intervalmaintained every 8 hr, the DRIwould be:

This regimen will result in reduced peak and increased trough concentrationsrelative to subjects with normal renal function receiving the standard dose Theaverage concentration would, however, be the same

=

DRI= ×Q DN

Alternatively, one might extend the dosage interval and maintain the dard dose size (DN) This will produce the same peak and trough concentrationsfor the renal patient that one would expect in a patient with Clcr≥120 mL/min.Unfortunately, the use of nonstandard dosage intervals often has been associatedwith drug administration errors.

stan-In this example and many patient scenarios, the best dosage adjustment strategymight be to select a feasible prolonged dosage interval (“RI”), eg, 12 hr, and thencalculate the DRI

This general approach provides a reasonable initial method for adjusting drugdosage regimens in patients with renal insufficiency until more specific guidelinescan be consulted or serum concentrations are measured This method is based onseveral assumptions: (1) bioavailability is unchanged in renal failure; (2) metabo-lites are not therapeutically active or toxic; (3) decreased renal function does notalter metabolism of the drug; (4) metabolism or renal excretion does not exhibitconcentration-dependent pharmacokinetics; (5) renal function is constant withtime; and (6) the renal clearance of the drug is directly proportional to the renalclearance of the compound used to measure renal function If any of these assump-tions is invalid, the accuracy of the projected dosage regimen will be reduced.The time to reach steady state is longer for a patient with renal insufficiencythan one with normal renal function Consequently, it is common to initiate ther-apy for many drugs with a loading dose (ie, at least the DNand in some cases aneven greater dose) to achieve the desired concentration in the expanded Vdand/orshorten the time to reach a therapeutic plasma concentration The amount of theloading dose depends on the particular drug being used and the desired therapeuticobjectives

It should be noted that any dosage regimen modification for renally cient patients might require plasma concentration determinations of the drug, ifavailable, and close clinical observation for assessment of toxicity and verification

insuffi-of achievement insuffi-of the desired therapeutic serum concentrations or effects

■ REFERENCES

1 Jones CA et al Serum creatinine levels in the US population: Third National Health and Nutrition Examination

Survey Am J Kidney Dis 1998; 32:992–9.

2 US Renal Data System 1998 Annual data report Bethesda: National Institutes of Diabetes and Digestive and

τRI τN