UPDATE ON PHOSPHODIESTERASE(VIAGRA/potential)TOXICITY.Today, Theophylline
a previously commonly used PDE for asthma /emphysema but now coming under greater scrutiny because of noted rising incidence of toxicity.
As BigKNY3 noted in his now famous post # 4756 on reviewing medical pharmacology and PDEs
"Nonselective phosphodiesterase (PDE) inhibitors such as the
theophylline have been extensively used since 1958."
Here is the...low on Theophylline, ANOTHER, " SAFE ", PDE, just like the cardiac PDE 3s I described in above post: ( Big KNY3, I included the references as a special touch for you because I know how demanding you are, gg:
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PS: this post,, and above post # 4775,
Message 3203236
conclude the review of ALL phophodiesterases currently on the market. I have not reviewd Persantine because it is a bland drug of hardly any usefullness, except some surgeons use it after open heart surgery to prevent blood clotting ( like aspirin ).
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The Pharmacologic Approach
to the
Critically Ill Patient
SECOND EDITION
EDITOR
Bart Chernow, M.D., F.A.C.P.,
F.C.C.P.
Associate Professor of Anesthesia (Critical Care)
Harvard Medical School
Associate Director, Respiratory-Surgical Intensive Care Unit
Co-Director, Henry K. Beecher Anesthesia Research Laboratories
Massachusetts General Hospital
Boston, Massachusetts
Associate Editors:
John W. Holaday, Ph. D., Washington, D.C.
Gary P. Zaloga, M.D., Winston-Salem, North Carolina
Arno L. Zaritsky, M.D., Chapel Hill, North Carolina
Editorial Assistants:
Robert M. Burke
Donia M. Goss
Anne L. Macaulay
WILLIAMS & WILKINS
Baltimore , Hong Kong , London , Sydney
Theophylline
The incidence of theophylline poisoning is on the rise (45). Some cases are a result of intentional overdoses, but many others are the result of physician-prescribing errors (110). The availability of slow-release preparations has also contributed to the increased incidence of theophylline poisonings. Available forms of theophylline include aminophylline, oxtriphylline, dyphylline, slow-release theophylline, and slow-release aminophylline. Theophylline is a methylxanthine similar in structure to caffeine. Short-acting preparations are rapidly absorbed from the gastrointestinal tract, and peak blood levels occur within 2 hours. Slow-release preparations have delayed absorption and peak serum levels may not occur for 8-12 hours depending on the preparation. Once absorbed, approximately 60% of theophylline is protein bound. Only free theophylline is pharmacologically active. Serum levels measure both bound and unbound theophylline. Theophylline is metabolized in the liver, and diseases or drugs affecting the liver's ability to metabolize theophylline may result in higher blood levels.
At therapeutic levels, theophylline is metabolized by first order kinetics. However, at blood levels of 10 mcg/ml or above, metabolizing enzymes become saturated and zero-order kinetics ensues. Thus, patients with therapeutic blood levels of theophylline, may become toxic if doses are increased or liver function is decreased. Medical
problems that may predispose patients to theophylline toxicity include age over 60 years, liver disease ,cirrhosis, hepatitis, cholestasis, OPD, cor pulmonale, congestive heart failure, viral illnesses, febrile illnesses and influenza vaccine. Mediicationsthat can prdispose to toxicity include cimetidine , erythromycin and noncardioselective beta-blockers.
Serum theophylline levels are best determined by high-pressure liquid chromotography. Both symptoms of toxicity and clinical response to therapy correlate well with peak serum levels. Therapeutic serum concentrations range from 10 to 20 mcg/ml. Acute single ingestion-, (in a patient not on maintenance therapy) of less than 10 mg/Kg are unlikely to produce symptoms of toxixity. Acutely toxic patients can tolerate much higher theophylline levels than patients on chronic therapy who become toxic.
Mild levels of toxicity usually occur with serum levels between 20 and 35 mcg/ml. These signs and symptoms include nausea and vomiting, tremors, irritability, polyuria, tachycardia, tachypnea, and headache. Severe toxic manifestations occur above serum levels of 80mcg/ml in acute toxicity and above 50 mcg/ml in chronic toxicity. Severe toxicity includes su raventricular arrhythmias, ventricular ararrhythmias, hypotension, seizures,coma and cardiopulmonary arrest. Metabolic abnormalities of toxicity include hypokalemia,hyperglycemia, leukocytosis, respiratory alcalosis, metabolic acidosis,hypomagnesemia,and hyperphosphatemia (72). The presence of seizures carries up to a 50 % mortality in some series.
The hypotension seen in severe toxicity is usually mediated by a decrease in systemic vascular resistance. It is proposed that this decrease in systemic vascular resistance is secondary to an increase in G-adrenergic activity causing vasodilation in skeletal muscle (36). This has led some authorities to advocate the use of beta-blockers or pure a-agonists (methoxamine) for the treatment of hypotension. In one limited series, beta-blockers did indeed raise blood pressure (17). Manv of the metabolic abnormalities may also result from a hyperadrenergic state.
Treatment includes general supportive measures,institution of gastrointestinal dialysis with repeated doses of activated charcoal, and careful selection of patients for charcoal or resin hemoperfusion. Theophylline levels should be drawn every 2 hours until a trend is established and efficacy of therapeutic measures is proven. Once,theophylline toxicity is established, anticipation of life-threatening dysrhythmias or seizures is paramount.
Early and repeated doses of activated charcoal can decrease ongoing absorption of theophylline and increase elimination because of theophylline's enterohepatic circulation (144, 96 ).Initial doses of activated charcoal range from 50-100 g and are followpd by 30-50 g every 2-4 hours until levels are below the toxic range. Sorbitol ( 100 ml of 70% solution) may be given as a cathartic along with the charcoal (160).
Treatment of arrhythmias from theophylline toxicity follows conventional guidelines .(Seizures associated
with theophylline overdose may be prolonged and intractable. They carry a high mortality and survivors may show permanent neurologic sequelae. Diazepam should be used as a first-line drug. If Diazepam (or one of its benzodiazepine analogues) is given to a total dose of 20-30 mg and the seizures persist beyond 15-20 minutes, phenobarbital should be added. Phenobarbital can be given at a dose of 10 mg/kg intravenously. A repeat dose of 10 mg/kg may be given in l5 minutes. If seizure activity persists beyond 4-5 minutes, thiopental general anesthesia is recommended ( 103 ).
Hemoperfusion may be useful in removing theophylline and minimazing life-threatening complications of toxicity.Criteria for selecting patients for hemoperfusion are poorly defined. Some recommend hemoperfusionl in the setting of a rising serum concentration greater than 60 mcg/ml (17). Others recommend it when levels exceed 80 mcg/ml (61).. In chronic toxicity, hemoperfusion may be instituted when levels exceed 50 mcg/ml in a patient who is over 60 years of age and has heart or liver failure. Hemoperfusion may also be useful in the elderly patient who is unable to tolerate oral activated charcoal. While decisions are being made about hernoperfusion, all patients should have oral charcoal therapy started.
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Zebra, are these the guys you see in ER? < GG>.
TA |
