Aminophylline
Theophylline can alter the results of some common laboratory tests. Serum concentrations levels of glucose, uric acid, free fatty acids (cholesterol, HDL), and urinary free cortisol excretion may all be reportedly increased. Also, transient decreases in triiodothyronine levels have been reported. The clinician should be aware of these alterations and should weigh the clinical importance of these changes to the benefits of theophylline therapy.
Patients with cardiac disease should be monitored more closely for adverse reactions to theophylline. Lower doses may be necessary for patients with congestive heart failure, including cor pulmonale, due to decreased theophylline clearance (>= 50% decrease). Also, theophylline can exacerbate existing cardiac arrhythmias and should be used with caution in patients at risk. Similarly, because theophylline can increase oxygen demand, it should be prescribed carefully in patients with coronary artery disease, especially those with a history of myocardial infarction.
Patients with hypothyroidism, acute pulmonary edema, sepsis with multiple organ failure, or shock may have decreased theophylline clearance. Any patients with any of the above conditions should be monitored carefully while receiving theophylline.
Increased theophylline clearance may occur in patients with hyperthyroidism or cystic fibrosis. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations. Any patients with cystic fibrosis or conditions affecting the thyroid should be monitored carefully while receiving theophylline.
Patients with uncorrected acidemia can have an increase in the volume of distribution of theophylline due to a decrease in plasma protein binding. Unbound serum theophylline concentrations should be monitored in these patients to avoid toxicity.
Since theophylline is metabolized hepatically, doses may need to be lower in patients with moderate to severe hepatic disease such as cirrhosis, acute hepatitis, cholestasis, or alcoholic liver disease. Patients who regularly consume ethanol but do not exhibit overt hepatic dysfunction may actually require larger doses than normal. The elderly may also have reduced hepatic metabolism, and their doses should generally be lower with cautious titration. Doses should be decreased in in infants under 1 year of age, especially premature neonates due to a less developed hepatic metabolism. Also, since neonates and young infants have a higher percentage of unchanged theophylline excreted via the kidneys (approximately 50% in newborns as compared to 10% in those older than 3 months), neonates and infants less than 3 months with renal impairment require lower doses.
Tobacco smoking has been shown to increase the clearance of theophylline by about 50% in young adult tobacco smokers and about 80% in elderly tobacco smokers. Also, passive smoke exposure may cause a an increase in theophylline clearance by up to 50%. Because the effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component, sudden smoking cessation may result in a reduced clearance of theophylline, despite the initiation of nicotine replacement products. Following 1 week of abstinence from chronic tobacco smoking, theophylline clearance may decrease by roughly 40%, leading to an increase in serum theophylline concentrations. Theophylline serum concentrations should be monitored carefully when changes in smoking status occur.
Prolonged fever has been reported to reduce theophylline clearance. Lower doses should be considered in these conditions. Theophylline also should be used cautiously in patients with respiratory infection or severe hypoxemia.
Since theophylline can stimulate gastric secretions, it should be used with caution in patients with gastritis or active peptic ulcer disease. Theophylline may aggravate symptoms related to hiatal hernia or gastroesophageal reflux disease (GERD).
Theophylline relaxes smooth muscle and can increase urinary retention, so it should be used with caution in patients with prostatic hypertrophy. Use of theophylline initially can cause a diuretic effect.
Theophylline and aminophylline have not been proven to be teratogenic in humans; however, there are no adequate controlled trials of the drugs during pregnancy. Decreased theophylline clearance has been reported during the third trimester of pregnancy. Theophylline is considered an alternative therapy for mild persistent asthma and adjunctive treatment for moderate to severe persistent asthma during pregnancy according to the Guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. Inhaled corticosteroids are the preferred asthma maintenance treatment during pregnancy due to the potential toxicities of theophylline and the propensity for drug interactions that can reduce theophylline clearance. If theophylline or aminophylline must be used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5 to 12 mcg/mL. Use during pregnancy may lead to potentially dangerous serum theophylline and caffeine concentrations and/or symptoms of theophylline toxicity in newborns; an exposed infant should be closely monitored at birth. The selection of any pharmacologic treatment for asthma control during pregnancy should include the specific needs of the patient, based on an individual evaluation, and consideration of the potential benefits or risks to the fetus. In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects.
Use theophylline with caution during breast-feeding. Theophylline is excreted in breast milk in concentrations similar to the serum concentration of the mother. Breastfed infants whose mothers are taking theophylline may experience irritability or other mild signs of toxicity; however, serious adverse events are unlikely unless the mother has toxic serum concentrations. Close monitoring is recommended, particularly in a newborn. Theophylline or aminophylline are not preferred therapy for asthma in the lactating woman; these drugs are considered alternative therapy to inhaled corticosteroids for mild persistent asthma and an adjunctive medication for moderate to severe asthma during lactation according to the Guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. If used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5 to 12 mcg/mL.
Theophylline is contraindicated in patients who have demonstrated a hypersensitivity reaction to theophylline or any component in the commercial product. Some pre-mixed theophylline in dextrose intravenous infusions may be manufactured using corn or corn products and may be contraindicated in patients with corn hypersensitivity.
Theophylline should be used cautiously in patients with a history of seizure disorder due to the risk of exacerbating their condition.
Careful consideration must be given to the benefits and risks of theophylline or aminophylline use and the need for more intensive monitoring of serum theophylline concentrations in older adult and geriatric patients more than 60 years of age. The clearance of theophylline is decreased by an average of 30% in healthy geriatric adults vs younger adults; clearance may be further significantly decreased if concomitant disease states or other factors for reduced clearance are present. If the total daily dose is not appropriately reduced, severe and potentially fatal theophylline toxicity can occur. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, periodic monitoring of serum theophylline concentrations helps identify or verify toxicity, as well as monitoring the clinical status of the patient for signs and symptoms of toxicity, such as arrhythmias, seizures, GI upset, diarrhea, nausea/vomiting, abdominal pain, nervousness, headache, insomnia, distress, dizziness, muscle cramps, and tremor. There are potentially significant interactions with many other medications, particularly antibiotics, anticonvulsants, and cardiac medications.
7-Keto DHEA
7-keto-DHEA may increase T3 levels. People interested in starting 7-keto-DHEA supplementation, particularly those who have a thyroid disorder or who are taking thyroid hormone, should consult a physician.
7-keto-DHEA may lower blood pressure. Individuals with low blood pressure should consult with a physician prior to use of this supplement.
At the time of writing, there were no other reported contraindications/precautions for 7-keto-DHEA. Individuals with known allergy to any of the capsule components or DHEA should not use this product.
Phenylephrine
Phenylephrine injection therapy requires an experienced clinician. The manufacturer includes a black box warning for phenylephrine injection advising that prescribers should become familiar with the product label information before prescribing phenylephrine.
Systemic phenylephrine should not be combined with MAOI therapy or used within 2 weeks of such therapy; use caution with ophthalmic, nasal, and topical rectal products, which may be absorbed systemically.
Some formulations of injectable phenylephrine are contraindicated in patients with severe hypertension or ventricular tachycardia. Because of its increasing blood pressure effects, phenylephrine can cause severe bradycardia and decrease cardiac output, precipitate angina in patients with severe arteriosclerosis or a history of angina, and exacerbate underlying heart failure or pulmonary hypertension. Excessive peripheral and visceral vasoconstriction and ischemia to vital organs may occur, especially in patients with significant peripheral vascular disease. The phenylephrine 10% ophthalmic solution is contraindicated in patients with hypertension; use the 2.5% solution in patients with hypertension or preexisting cardiac disease. In addition, use orally or nasally administered phenylephrine with caution in patients with known or suspected cardiac disease or high blood pressure.
Phenylephrine should be avoided in patients with cerebrovascular disease such as cerebral arteriosclerosis, aneurysm, intracranial bleeding, history or stroke or organic brain syndrome because of the potential sympathomimetic (presumably alpha) effects in the CNS and the potential for cerebrovascular hemorrhage, especially with intravenous use.
Avoid phenylephrine in patients with sulfite hypersensitivity unless the patient is being treated for an emergent condition such as anaphylaxis or cardiac arrest. Phenylephrine formulations contain sodium metabisulfite, a sulfite that can cause severe allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes in susceptible patients. The overall presence of sulfite hypersensitivity in the general population is unknown but presumed to be low. Sulfite hypersensitivity is seen most often in asthmatic patients compared to non-asthmatic patients.
Systemic phenylephrine products should be used with caution in men with symptomatic, benign prostatic hypertrophy, due to the potential for urinary retention.
The phenylephrine 10% ophthalmic solution is contraindicated in patients with thyrotoxicosis, including hyperthyroidism; the 2.5% solution should be used with caution in these patients. All dosage forms of phenylephrine should be used with caution in patients with hyperthyroidism as these patients can be more sensitive to catecholamines; thyrotoxic or cardiotoxic symptoms can occur.
Because phenylephrine is an adrenergic agent, it should be given with caution to patients with diabetes mellitus.
Avoid extravasation of phenylephrine injection by checking infusion site for free flow. Extravasation of phenylephrine can cause necrosis and tissue sloughing.
The 10% ophthalmic phenylephrine solution is contraindicated in neonates and infants younger than 1 year due to the potential for adverse cardiac effects. Infants and children are more susceptible than adults to systemic absorption from intranasal or ophthalmic use, especially with use of the 10% ophthalmic solution, increasing the risk of adverse events. Consider avoiding the use of the 10% solution in patients younger than 5 years. The adverse effects of systemically absorbed sympathomimetics, such as phenylephrine, can be severe, especially in infants and toddlers; CNS stimulation, hypertension and tachycardia may occur. Do not use oral nonprescription phenylephrine products in children and infants younger than 4 years; use any systemic decongestant sympathomimetic amine with caution in children 6 years and younger. Administration of cough and cold products to children and infants younger than 2 years is associated with a risk for serious injury or fatal overdose. Over a 2-year period, 1,519 children younger than 2 years were treated in emergency departments for adverse events related to cough and cold medications; some of these events were due to inadvertent inappropriate use and some fatalities occurred. Nonprescription cough and cold products containing phenylephrine are not recommended for use in children younger than 6 years. Over-the-counter cough and cold products are not recommended for use in infants and children younger than 2 years. Advise parents and caregivers to read labels carefully, to use caution when administering multiple products, and to use only measuring devices specifically designed for use with medications if using cough and cold products in children. Thoroughly assess each patient’s use of similar products, both prescription and nonprescription, to avoid duplication of therapy and the potential for inadvertent overdose.
There are no data on the use of phenylephrine injection during the first or second trimester of human pregnancy. Data from randomized controlled trials and meta-analyses with phenylephrine injection use in pregnant women during labor and obstetric delivery (i.e., Cesarean section) have not established a drug-associated risk of major birth defects and miscarriage. These studies have not identified an adverse effect on maternal outcomes of infant Apgar scores. At recommended doses, phenylephrine does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Untreated hypotension associated with spinal anesthesia for Cesarean section is associated with an increase in maternal nausea and vomiting. A sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis. In animal studies, evidence of fetal malformation was noted when phenylephrine was administered during organogenesis via a 1-hour infusion at 1.2 times the human daily dose (HDD) of 10 mg/60 kg/day. Decreased pup weights were noted in the offspring of pregnant rats treated with 2.9 times the HDD. A study in rabbits indicated that continued moderate overexposure to oral phenylephrine (3 mg/day) during the second half of pregnancy may contribute to perinatal wastage, prematurity, premature labor, and possibly fetal anomalies; when phenylephrine (3 mg/day) was given to rabbits during the first half of pregnancy, a significant number gave birth to litters of low birth weight. Another study showed that phenylephrine was associated with anomalies of aortic arch and with ventricular septal defect in the chick embryo. It is not known whether phenylephrine ophthalmic solution can cause fetal harm or affect reproduction capacity. Use phenylephrine ophthalmic solution during pregnancy only if clearly needed. Under the direction of a health care professional, topical or nasal phenylephrine may be used during pregnancy.
There are no data on the presence of phenylephrine or its metabolite in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for phenylephrine and any potential adverse effects on the breast-fed infant from phenylephrine or from the underlying maternal condition. Use caution when administering ophthalmic phenylephrine to a pregnant woman. Under the direction of a health care professional, topical or nasal phenylephrine may be used by a breast-feeding woman.
The ophthalmic use of phenylephrine while wearing contact lenses is not recommended.
Ophthalmic application of phenylephrine to eyes or adnexa that are diseased, traumatized or following ocular surgery, or to patients with suppressed lacrimation (e.g., during anesthesia) may result in sufficient absorption of phenylephrine to produce a systemic vasopressor effect.
In general, use caution in administering phenylephrine to geriatric patients. In general, elderly patients are more susceptible than younger adults to the drug’s effects. The baroreceptor reflex response to phenylephrine may decrease with age. Elderly patients, especially those with pre-existing cardiac disease, may be more likely to experience adverse cardiovascular reactions including increased blood pressure, cardiac arrhythmias, or ischemia with systemic use. Phenylephrine, when administered by ophthalmic routes, should be also used with caution. The use of the 2.5% ophthalmic solution is preferred for elderly patients when using ophthalmic formulas; avoid use of the 10% ophthalmic solution. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, use of cough, cold, and allergy medications should be limited to less than 14 days unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected. OBRA guidelines also state that oral decongestants, such as phenylephrine, should be used cautiously in patients who have insomnia or hypertension. Oral decongestants may cause dizziness, nervousness, insomnia, palpitations, urinary retention, and elevated blood pressure. During use of phenylephrine to manage urinary incontinence, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after initiating treatment. Medications for urinary incontinence have specific and limited indications based on the cause and categorization of incontinence. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability.
Some oral chewable formulations of phenylephrine contain aspartame and such products should be avoided or restricted in patients who have phenylketonuria or who must restrict intake of phenylalanine, an amino acid used in the synthesis of aspartame.
Phenylephrine injection should be used cautiously during cyclopropane anesthesia or halothane anesthesia since these agents may sensitize the heart to the arrhythmic action of phenylephrine.
Monitor renal function closely in patients with septic shock; phenylephrine can increase the need for renal replacement therapy.
Dose-response data indicate decreased responsiveness to injectable phenylephrine in patients with cirrhosis or hepatic disease (Child-Pugh Class B and C). Initiate treatment in the recommended range; more phenylephrine may be required in this population.
Dose-response data indicate increased responsiveness to injectable phenylephrine in patients with end-stage renal disease (ESRD) or renal failure. Consider initiating treatment at the lower end of the recommended dosage range, and adjust the dose based on the target blood pressure goal.
Use phenylephrine with caution in patients with autonomic neuropathy. Patients with autonomic dysfunction, such as those with spinal cord injury, may have an increased blood pressure response to adrenergic drugs.
Yohimbine HCl
NOTE: Limited information about precautions and contraindications to yohimbine therapy exists.
Yohimbine is contraindicated in patients with a hypersensitivity to yohimbine. Yohimbine should not be used in patients with a history of rauwolfia alkaloid hypersensitivity. Rauwolfia alkaloids include deserpidine, rauwolfia serpentina, or reserpine. Patients sensitive to these agents may also be sensitive to yohimbine.
Yohimbine may worsen renal impairment, therefore administration of this drug in patients with renal disease or renal failure is contraindicated. Serious renal effects, including renal failure, have been reported to the FDA after the use of products containing yohimbe.
Yohimbine should not be used concurrently with MAOI therapy (see Drug Interactions).
Yohimbine should not be used in patients with angina pectoris, cardiac disease, or hypertension because these conditions may be aggravated or worsened by yohimbine. It is also recommended that this drug not be used in cardio-renal patients with history of peptic ulcer disease, children, and geriatric patients. Further, because yohimbine may enhance anxiety or other CNS symptoms, it should be used cautiously in patients with depression or other psychiatric illness.
According to the German E Commission monographs, the use of yohimbine in those with hepatic disease is contraindicated. In theory, patients with hepatic impairment may exhibit impaired metabolism of yohimbine. Although recommendations on the use of yohimbine in those with hepatic disease are not available from the manufacturer, it should be noted that patients with hepatic disease have generally been excluded from participation in clinical trials that assess safety and efficacy of the drug. Therefore, it is advisable to avoid the use of yohimbine in those with hepatic disease, including biliary cirrhosis or hepatic failure.
In general, yohimbine is not for use in females and must certainly not be used during pregnancy. A FDA pregnancy risk category has not been assigned to this drug. However, given yohimbine’s similarity to other rauwolfia alkaloids, it is suggested that yohimbine most closely corresponds to an FDA pregnancy risk category D (see Reserpine monograph). There is no known indication at this time for the use of yohimbine in pregnancy which would justify the potential risks to the fetus.
Generally, this drug is not for use in females, and therefore should not be used during breastfeeding. Many of the rauwolfia alkaloids are excreted in human breast milk. A decision should be made to discontinue the medication or discontinue breastfeeding.
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