Scream Cream

Theophylline is a methylxanthine bronchodilator. FDA-approved products include oral extended-release tablets and capsules (for example Theo-24), oral solution, and theophylline in 5% dextrose injection; aminophylline is its ethylenediamine salt. Systemic theophylline has a narrow therapeutic index. There is no FDA-approved topical theophylline product; compounded topical preparations, such as genital creams, use theophylline off-label, and their systemic absorption has not been characterized.

• Oral and intravenous theophylline: treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases such as emphysema and chronic bronchitis. Intravenous theophylline is also labeled as an adjunct for acute exacerbations of asthma and chronic lung disease.
• Prescribers use compounded topical preparations containing theophylline, alone or with other vasoactive agents, for local application; no FDA-labeled indication or dose exists for topical use.

Theophylline relaxes bronchial and vascular smooth muscle. Its actions include nonselective inhibition of phosphodiesterase types III and IV, which raises intracellular cyclic AMP, and antagonism of adenosine receptors. It also increases diaphragmatic contractility, stimulates the central respiratory drive, and has mild diuretic and cardiac stimulant effects.

Oral theophylline is completely absorbed from immediate-release forms; extended-release forms vary in rate of absorption. Volume of distribution is about 0.45 L/kg and protein binding about 40%. Theophylline crosses the placenta and enters breast milk.

Theophylline is metabolized in the liver, mainly by CYP1A2, with contributions from CYP2E1 and CYP3A4; only about 10% is excreted unchanged in adults. Clearance varies widely: mean half-life is about 8 hours in healthy nonsmoking adults, shorter in smokers, and longer in neonates, adults over 60, and patients with heart failure, liver disease, hypothyroidism, sustained fever or sepsis. Elimination becomes nonlinear at higher concentrations, so small dose changes can produce large changes in serum concentration. Labeling generally targets peak serum concentrations of 10 to 15 mcg/mL.

• Known hypersensitivity to theophylline or any component of the product.

• Narrow therapeutic index: serious toxicity, including cardiac arrhythmias and seizures, can occur above about 20 mcg/mL and may appear without preceding minor symptoms. Persistent vomiting is a sign of toxicity, and the dose should not be increased for symptoms without checking a serum concentration.
• Use with caution in active peptic ulcer disease, seizure disorders and cardiac tachyarrhythmias, all of which theophylline can worsen.
• Reduced clearance and higher risk of toxicity occur with age over 60, acute pulmonary edema, heart failure, cor pulmonale, fever of 102 F or higher for 24 hours or more, hypothyroidism, liver disease, sepsis with multi-organ failure, shock, and in neonates and infants under 1 year. Stopping smoking lowers clearance.
• Topical use: systemic exposure from compounded topical preparations has not been characterized. Absorption across mucosal or irritated skin, use of large amounts, or concurrent systemic theophylline could add to serum concentrations. Accidental ingestion of a topical preparation by a child can cause serious toxicity.

• Drugs that raise theophylline concentrations include cimetidine, ciprofloxacin, enoxacin, fluvoxamine, erythromycin, clarithromycin, high-dose allopurinol, disulfiram, estrogen-containing oral contraceptives, interferon alfa, methotrexate, mexiletine, pentoxifylline, propafenone, propranolol, ticlopidine and zileuton. Fluvoxamine and ciprofloxacin can cause large increases.
• Drugs and exposures that lower theophylline concentrations include carbamazepine, phenobarbital, phenytoin, rifampin, ritonavir, St. John's wort, and tobacco or marijuana smoking.
• Theophylline lowers lithium concentrations, antagonizes adenosine and the sedation of benzodiazepines, and may antagonize nondepolarizing neuromuscular blockers. Ketamine may lower the seizure threshold, and halothane increases arrhythmia risk. Sympathomimetics and caffeine add to central and cardiac stimulation.

• Common at therapeutic concentrations: nausea, vomiting, headache, insomnia, irritability, restlessness, tremor, diarrhea and transient diuresis, often caffeine-like and more frequent when therapy starts.
• At elevated concentrations: persistent vomiting, sinus tachycardia, supraventricular and ventricular arrhythmias, hypokalemia, hyperglycemia and seizures.
• Topical preparations: local burning, tingling, erythema or irritation; systemic effects are possible if absorption is significant.

Theophylline crosses the placenta, and adequate controlled studies in pregnancy are lacking. Clearance can fall in the third trimester, so serum concentrations are monitored when systemic theophylline is used for asthma in pregnancy. Theophylline is excreted into breast milk and can cause irritability in nursing infants. Safety of topical genital theophylline preparations in pregnancy or breastfeeding has not been established.

For systemic therapy: serum theophylline concentrations at initiation, after dose changes, with new interacting drugs, changes in smoking status, or illness that affects clearance, and when toxicity is suspected; heart rate and rhythm; symptoms such as nausea, vomiting or tremor. For topical preparations: local skin reactions, and signs of systemic effects such as palpitations, tremor or nausea, especially in patients who also take oral theophylline or interacting drugs.

• Theo-24 (theophylline anhydrous) Extended-Release Capsules Prescribing Information.
• Theophylline in 5% Dextrose Injection Prescribing Information.
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw Hill.

L-arginine is a conditionally essential amino acid obtained from the diet and synthesized endogenously from citrulline. It is the substrate for nitric oxide synthase and a precursor of urea, ornithine, creatine, polyamines and agmatine.

The only FDA-approved arginine drug product is arginine hydrochloride injection 10% (R-Gene 10), for intravenous use. No FDA-approved oral arginine drug product exists; oral L-arginine is otherwise sold as a dietary supplement.

R-Gene 10 (arginine hydrochloride injection) is FDA-labeled as an intravenous stimulant of pituitary growth hormone release, for use as a diagnostic aid when measuring pituitary growth hormone reserve.

There is no FDA-labeled indication or dose for oral L-arginine. Prescribers use compounded oral preparations when they determine a patient-specific need; dosing is individualized by the prescriber.

Nitric oxide synthase converts L-arginine to nitric oxide and citrulline; nitric oxide activates soluble guanylate cyclase, raising cGMP and relaxing vascular smooth muscle. Arginase converts arginine to ornithine and urea in the urea cycle. Arginine decarboxylase yields agmatine, and peptidyl-arginine deiminases convert protein arginine residues to citrulline.

Given intravenously, arginine stimulates release of growth hormone, prolactin, insulin and glucagon. This secretagogue response is the basis of the labeled diagnostic use.

Oral absorption occurs in the small intestine by cationic amino acid transporters. Oral bioavailability is low and variable, roughly 20% in pharmacokinetic studies, because of extensive first-pass metabolism by intestinal and hepatic arginase. Peak plasma concentrations occur about 1 hour after an oral dose.

The plasma half-life is about 1 to 2 hours. Arginine is metabolized mainly by arginase and nitric oxide synthase; it is filtered by the kidney and largely reabsorbed, with urinary loss rising at high plasma concentrations.

• Hypersensitivity to arginine or any component of the preparation. R-Gene 10 labeling also contraindicates use in patients with highly allergic tendencies.
• Avoid after a recent or acute myocardial infarction (see Warnings & Precautions).

• Post-myocardial infarction: a randomized trial of oral L-arginine added to standard care after acute myocardial infarction was stopped early because of excess deaths in the arginine group. Avoid after recent MI.
• Hyperkalemia: arginine shifts potassium out of cells; life-threatening hyperkalemia has been reported with arginine hydrochloride, particularly in renal or hepatic impairment.
• Acid–base: arginine hydrochloride carries a chloride load and can cause hyperchloremic metabolic acidosis. Pediatric overdosage of the injection has caused cerebral edema and death.
• Hypotension: additive vasodilation with nitrates, PDE5 inhibitors and antihypertensives.
• Herpes simplex: arginine supports herpesvirus replication in vitro; use caution in patients with frequent recurrences.
• Glucose: arginine stimulates insulin and glucagon release; monitor glucose in patients with diabetes.

• Nitrates and riociguat: additive hypotension; avoid unless the prescriber determines otherwise.
• PDE5 inhibitors, alpha-blockers and antihypertensives: additive blood-pressure lowering.
• Potassium-sparing diuretics, ACE inhibitors, ARBs and potassium supplements: increased risk of hyperkalemia.
• Insulin and other antidiabetic agents: possible changes in glucose; monitor.
• Anticoagulants and antiplatelets: a theoretical additive effect on platelet function; monitor in combination.

Oral: nausea, abdominal pain or cramping, bloating and diarrhea are reported, mostly dose-related. Hypotension, flushing and headache can occur. Hypersensitivity, including airway reactions, is uncommon.

Intravenous (arginine hydrochloride): flushing, nausea, vomiting, headache, numbness, local irritation and extravasation injury at the infusion site, hyperkalemia and metabolic acidosis.

Arginine is a normal dietary amino acid, but the safety of supplemental or compounded doses in pregnancy has not been established, and animal reproduction studies of R-Gene 10 have not been conducted. Use in pregnancy is at the prescriber's discretion after weighing risk and benefit.

Arginine is a normal component of human milk. The effect of supplemental maternal doses on the breastfed infant has not been studied.

Blood pressure and symptoms of hypotension, especially with vasodilators or antihypertensives. Serum potassium and renal function in renal or hepatic impairment or with potassium-raising drugs. Blood glucose in patients with diabetes. Gastrointestinal tolerance.

• R-Gene 10 (arginine hydrochloride injection) Prescribing Information, Pfizer.
• Natural Medicines Comprehensive Database, L-Arginine monograph.
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw Hill.

Sildenafil citrate is an oral and intravenous phosphodiesterase type 5 (PDE5) inhibitor. FDA-approved products include Viagra (sildenafil citrate) tablets and Revatio (sildenafil) tablets, oral suspension and injection, with generic equivalents. Doses in FDA labeling are expressed as sildenafil base. Compounded forms include oral capsules, rapid dissolve tablets and topical creams; topical use has no FDA labeling.

• Viagra (oral): treatment of erectile dysfunction in men.
• Revatio (oral and intravenous): treatment of pulmonary arterial hypertension (WHO Group I) in adults, and in pediatric patients 1 to 17 years old.
• Prescribers also use compounded sildenafil preparations for erectile dysfunction when a commercial strength or dosage form does not fit, and topically in women, which is off-label; Viagra labeling states it is not indicated for use in women.

During sexual stimulation, nitric oxide released in the corpus cavernosum activates guanylate cyclase and raises cyclic guanosine monophosphate (cGMP), relaxing smooth muscle and increasing inflow of blood. Sildenafil inhibits PDE5, the enzyme that degrades cGMP, enhancing the effect of nitric oxide; it has no effect without sexual stimulation. PDE5 inhibition in the pulmonary vascular smooth muscle causes pulmonary vasodilation. Weaker inhibition of retinal PDE6 accounts for color-vision changes at higher exposures.

Oral sildenafil is rapidly absorbed (bioavailability about 41%), peaking at a median of 60 minutes fasting; a high-fat meal delays the peak by about 60 minutes and lowers it by about 29%. Protein binding is about 96%.

Sildenafil is cleared mainly by CYP3A4 (major) and CYP2C9 (minor); the N-desmethyl metabolite has about half the parent's PDE5 potency. Terminal half-life is about 4 hours, and metabolites are excreted mostly in feces. Exposure is higher in adults over 65 (free AUC about 40% higher), with hepatic cirrhosis (AUC about 84% higher) and with creatinine clearance below 30 mL/min (AUC about doubled).

• Concomitant use of organic nitrates or nitric oxide donors in any form, regularly or intermittently, including nitroglycerin, isosorbide mononitrate and dinitrate, and amyl or butyl nitrite; sildenafil potentiates their hypotensive effect.
• Concomitant use of guanylate cyclase stimulators such as riociguat, because of the risk of hypotension.
• Known hypersensitivity to sildenafil or any component of the product.

• Cardiovascular: evaluate cardiovascular status before treating erectile dysfunction, since sexual activity carries cardiac risk. Left ventricular outflow obstruction and severely impaired autonomic control of blood pressure increase sensitivity to vasodilators. Recent myocardial infarction, stroke or life-threatening arrhythmia, resting hypotension, uncontrolled hypertension and unstable angina were not studied. ACC/AHA guidance advises at least 24 hours after the last sildenafil dose before an emergency nitrate.
• Priapism: erections lasting more than 4 hours need emergency treatment. Use caution with penile anatomic deformity or conditions predisposing to priapism such as sickle cell anemia, multiple myeloma or leukemia.
• Vision and hearing: sudden vision loss from non-arteritic anterior ischemic optic neuropathy (NAION) and sudden hearing loss have been reported; stop the drug and evaluate promptly. Prior NAION raises recurrence risk. Retinitis pigmentosa has not been studied; use with caution.
• Hypotension with alpha-blockers and other antihypertensives (see Drug Interactions). Combination with other PDE5 inhibitors, including Viagra with Revatio, or with other erectile dysfunction treatments has not been studied and is not recommended.
• Safety in bleeding disorders or active peptic ulcer disease is not known. PAH (Revatio labeling): pulmonary edema may signal pulmonary veno-occlusive disease, where vasodilators are not recommended; vaso-occlusive crises were more frequent in pulmonary hypertension from sickle cell disease; in a long-term pediatric trial, mortality rose with increasing dose.

• Nitrates, nitric oxide donors and riociguat: contraindicated (see Contraindications).
• Alpha-blockers: symptomatic hypotension has occurred; patients should be stable on the alpha-blocker before sildenafil is started at the lowest dose. Other antihypertensives and heavy alcohol use add to blood-pressure lowering.
• CYP3A4 inhibitors: ritonavir raised sildenafil AUC about 11-fold; with ritonavir, Viagra labeling gives 25 mg before sexual activity and a maximum of 25 mg in 48 hours, and Revatio labeling does not recommend strong CYP3A inhibitors. Saquinavir and erythromycin raised AUC about 3-fold, and ketoconazole or itraconazole are expected to raise it more; a 25 mg starting dose is considered. Cimetidine raised concentrations about 56%.
• CYP3A4 inducers such as bosentan, rifampin, carbamazepine and phenytoin lower sildenafil concentrations.

• Erectile dysfunction trials (Viagra): headache and flushing were most common, followed by dyspepsia, abnormal vision (color tinge, light sensitivity, blurring), nasal congestion, back pain, myalgia, nausea, dizziness and rash.
• Pulmonary arterial hypertension trials (Revatio): epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea and rhinitis.
• Postmarketing: serious cardiovascular events (myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage), NAION, sudden hearing loss, priapism, seizure and transient global amnesia; many patients had pre-existing risk factors.

Viagra is not indicated for use in women. Revatio labeling notes that limited data in pregnancy have not shown a clear drug-associated risk of major birth defects or miscarriage, and that untreated pulmonary arterial hypertension in pregnancy carries serious maternal and fetal risk. Limited data show sildenafil and its active metabolite in breast milk at low levels.

Cardiovascular status before treatment; blood pressure and orthostatic symptoms, especially with alpha-blockers; visual or hearing changes; prolonged erection. Review medications for nitrates, riociguat, other PDE5 inhibitors and CYP3A4 inhibitors or inducers. Consider age and hepatic and renal function when selecting a dose.

• Viagra (sildenafil citrate) Tablets Prescribing Information, Viatris Specialty LLC.
• Revatio (sildenafil) Tablets, Oral Suspension and Injection Prescribing Information, Viatris Specialty LLC.
• Cheitlin MD, et al. ACC/AHA Expert Consensus Document: Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology and American Heart Association, 1999.