Al - this one says about all of it: My brother ended up with Parkinson's (non-classical - whatever that means - but is connected with peripheral neuropathy part of this this medicine effect. Takes LOOONG time to exit body - half-life very long)
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amiodarone / CordaroneTM
ANTIARRHYTHMIC:
Cardiovascular
Description: Amiodarone is a class III antiarrhythmic agent approved for the treatment of life threatening ventricular arrhythmias which are refractory to treatment with other antiarrhythmics. Amiodarone was discovered in 1961, and was originally marketed as an anti-anginal agent in 1967. Despite its efficacy as an antiarrhythmic, the use of amiodarone is associated with a multitude of adverse effects, some of which are severe and potentially fatal. Therefore, clinical use of amiodarone is often reserved for patients in whom conventional therapy has failed, and when the potential benefits of its use outweigh the risks. Adverse reactions, however, may be less of a problem with lower doses (i.e., 200-400 mg/day). Oral amiodarone was approved by the FDA for clinical use as an antiarrhythmic agent December 1985. The FDA approved an intravenous formulation for life-threatening arrhythmias in August 1995. Intravenous amiodarone is currently in use in 99 countries worldwide.
Mechanism of Action: Amiodarone is a "broad spectrum" antiarrhythmic structurally similar to thyroxine with multiple and complex electrophysiologic effects. Although its exact mechanism of action is not completely known, using the traditional Vaughn-Williams classification scheme for antiarrhythmic compounds, amiodarone is considered a class III compound. Like the other class III antiarrhythmic agents, bretylium and sotalol, amiodarone acts directly on the myocardium to delay repolarization and increase the duration of the action potential. This results in prolongation of the effective refractory period in the atria, ventricles, AV node, and His-Purkinje system. Amiodarone exerts these electrophysiologic effects without significantly altering the myocardial membrane potential.
By definition, class III agents act only on the repolarization phase of the action potential and therefore should leave conduction unchanged. However, sinus node automaticity (and function) is depressed, AV conduction in prolonged, and conduction is slowed in the His-Purkinje system, primarily as a result of the class II and IV effects of amiodarone. The drug also exhibits significant class I properties including inhibition of "fast" sodium channels, with subsequent impaired recovery of the myocardium due to its membrane stabilizing properties. Conduction in the accessory pathway of patients with Wolff-Parkinson-White syndrome is prolonged by amiodarone. Amiodarone also noncompetitively inhibits ?- and ?-receptors, and possesses both vagolytic and calcium-channel blocking properties. The drug relaxes both smooth and cardiac muscle, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload. Transient, dose-related increases in coronary blood flow may occur following intravenous amiodarone administration, and is thought to be due to direct relaxation of coronary arteries, reductions in myocardial contractility and LVEDP. This activity may result in a decrease in myocardial oxygen demand (MVOA), and decrease the potential for myocardial ischemia.
Pharmacokinetics: Amiodarone is administered orally and intravenously. Following oral administration, amiodarone is absorbed incompletely and slowly from the GI tract, with the absolute bioavailability ranging from 20-86%, but averages approximately 50%. Amiodarone may undergo metabolism in the intestinal lumen and GI mucosa and first pass metabolism in the liver, all of which occur to a variable degree, possibly explaining the variability in bioavailability. A single oral dose of 400 mg of amiodarone achieves peak plasma levels within 3-7 hours. Steady state plasma levels are generally not reached for 1-5 months following continuous oral administration, with the onset of action delayed for as long as 2-3 months, unless aggressive loading doses are utilized. The therapeutic range for amiodarone is generally considered to be roughly 1-2.5 æg/mL, although an absolute relationship between serum concentration and pharmacodynamic effect has not been established.
Once in the systemic circulation, amiodarone distributes extensively throughout the body including into adipose, hepatic, myocardial, pulmonary, kidney, thyroid, skin, ocular, splenic and pancreatic tissues, and concentrates in fluids including bile, semen and saliva. As a reflection of its extensive distribution in the body, the volume of distribution of amiodarone averages approximately 70 L/kg. It is the extensive accumulation of amiodarone (especially in adipose tissue) which accounts for its prolonged elimination, as well as the persistence of adverse effects after discontinuation of therapy. Amiodarone is extensively metabolized in the liver, and the pharmacologically active and principle metabolite of amiodarone, N-desethylaminodarone (DEA) appears in the plasma in concentrations 0.5-2 times that of the unchanged drug following chronic therapy, and distributes into the same tissues, albeit to a lesser extent in adipose tissue. Both amiodarone and DEA distribute into and concentrate in breast milk. Amiodarone and DEA are extensively bound (> 99%)to plasma proteins, primarily albumin and ?-1 acid glycoprotein.¥
Amiodarone and DEA are virtually exclusively eliminated hepatically, although biliary excretion may play a small role in the excretion of amiodarone. As a consequence of its distribution characteristics, the elimination of amiodarone occurs in a biphasic fashion, with an initial reduction of plasma concentrations of 50% occurring within 10 days. The terminal elimination ranges from 26-107 days, and averages around 53 days.
CONTRAINDICATIONS/PRECAUTIONS: Amiodarone is contraindicated in patients with severe sinus node dysfunction or sick sinus syndrome and advanced AV block not concomitantly treated with artificial pacing.
Amiodarone is contraindicated in patients with known iodine hypersensitivity.
Amiodarone may cause potentially fatal pulmonary toxicity (pneumonitis and/or pulmonary fibrosis), and therefore should be used with extreme caution, if ever, in patients with preexisting pulmonary disease (i.e. chronic obstructive disease or reduced diffusion capacity). Thorough pulmonary function testing including diffusion capacity, radiographic and clinical evaluation should be performed prior to and throughout the course of amiodarone therapy to assess the potential development of pulmonary toxicity.
Amiodarone is should be used cautiously in patients with congestive heart failure because amiodarone has mild negative inotropic effects.
Amiodarone is should be used cautiously in patients with preexisting structurally degenerative hepatic disease (i.e. cirrhosis), as the metabolism and/or elimination of amiodarone could be altered potentially increasing the possibility of hepatoxicity, which, in rare cases may be fatal. Baseline and periodic evaluation of hepatic enzymes is recommended for all patients undergoing amiodarone therapy.
Amiodarone is should be used cautiously in patients with uncorrected electrolyte imbalances, particularly hypokalemia and/or hypomagnesemia as these conditions may predispose the patient to the development of proarrhythmias as well as potentially decrease the efficacy of amiodarone.
Amiodarone is should be used cautiously in patients with preexisting thyroid disease, as the drug may exacerbate or cause either hypothyroidism or hyperthyroidism. Appropriate baseline and periodic evaluation of thyroid function tests is recommended for all patients treated with amiodarone.
The safe use of amiodarone in pregnancy and in women who are breast-feeding during amiodarone therapy has not been established and appropriate consideration of risk/benefit ratio is essential.
DRUG INTERACTIONS: Drug interactions associated with amiodarone are pharmacodynamic and/or pharmacokinetic in nature. The pharmacodynamic interactions associated with amiodarone occur primarily with other antiarrhythmics and are a consequence of additive or synergistic electrophysiologic effects. As the pharmacologic effects of amiodarone are delayed by several days even with adequate loading doses, concomitant use of another antiarrhythmic is often necessary. Should this be the case, the dose of the secondary antiarrhythmic should, in general, be decreased by 30-50% after the first few days of initiating amiodarone therapy. Discontinuation of the second antiarrhythmic agent should be attempted as soon as the therapeutic effects of amiodarone are observed. Conversely, in patients requiring combination therapy, the dose of the second antiarrhythmic should, in general, be decreased by 50% until amiodarone eliminated from the body. Proarrhythmia, including torsade de pointes and monomorphic ventricular tachycardia can and has occurred when amiodarone was administered in combination with any number of antiarrhythmic compounds including class Ia agents, mexilitine and propafenone. Caution should be exercised when amiodarone is administered with any drug with electrophysiologic effects.
Flecainide concentrations increase by an average of 60% with concomitant amiodarone therapy. Although the exact mechanism of the interaction is unknown, it is postulated that the hepatic metabolism and/or renal clearance of flecainide may be decreased. Careful clinical observation of the patient as well as close monitoring of the ECG and plasma flecainde concentrations is essential with adjustment of the flecainide dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the flecainide dose by 50% is suggested 2-3 days following initiation of amiodarone therapy.
Quinidine serum concentrations generally increase by about 33% in patients receiving concomitant amiodarone therapy. Although the mechanism is unclear, it appears that hepatic and/or renal clearance may be diminished and quinidine may also be displaced from tissue and protein binding sites. Prolongation of the QT interval is well documented with quinidine, and the addition of amiodarone may dramatically increase this effect, placing the patient at an increased risk for the development of torsade de pointes. Careful clinical observation of the patient as well as close monitoring of the ECG and serum quinidine concentrations is essential with adjustment of the quinidine dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the quinidine dose by 50% is suggested within 2 days following initiation of amiodarone therapy with consideration given to immediately discontinuing quinidine once amiodarone therapy is begun.
Procainamide and N-acetylprocainamide or NAPA (a pharmacologically active metabolite) concentrations increase by approximately 55 and 33%, respectively, during the first 7 days of concomitant amiodarone therapy. The precise pharmacokinetic mechanism of this interaction has not been elucidated, although a reduction the renal clearance of both parent and metabolite, as well as a reduction in hepatic metabolism seem likely. Additive electrophysiologic activity occurs with combination therapy and prolonged QT and QRS intervals or acceleration of preexisting ventricular tachycardia may result. Careful clinical observation of the patient as well as close monitoring of the ECG and serum procainamide and NAPA concentrations is essential with adjustment of the procainamide dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. In general, it is recommended to discontinue completely or reduce the procainamide daily dose by 25% during the first week of initiating amiodarone therapy.
Concomitant administration of ?-blockers, or calcium-channel blockers with amiodarone may result in additive electrophysiologic effects including bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting sinus node dysfunction. In general these drugs should only be continued in patients at risk of significant bradycardia if a permanent artificial pacemaker is in place. In addition, amiodarone can decrease the clearance of drugs eliminated by hepatic metabolism. Severe cardiovascular reactions were observed when amiodarone was coadministered with metoprolol and propranolol.
Amiodarone increases serum levels of digoxin when given concomitantly, and an empiric 50% dosage reduction is advised upon initiation of amiodarone therapy. The degree to which digoxin serum concentrations will increase is not predictable and reassessment of the need for both drugs is prudent. As always, careful clinical observation of the patient, and close monitoring of the ECG and serum digoxin concentrations is essential to ensure efficacy and to avoid enhanced toxicity with adjustment of the digoxin dose performed as necessary. The mechanism of the increase in digoxin serum concentration is complex and not well understood, but is thought to result from an amiodarone-induced displacement of digoxin from tissue binding sites, an increase in bioavailability, and/or a decrease in renal or nonrenal clearance. Furthermore, amiodarone may induce changes in thyroid function and alter sensitivity to cardiac glycosides, and thyroid function should be monitored closely in patients receiving both drugs simultaneously.
Concurrent administration of amiodarone with coumarin or indandione anticoagulants, (warfarin) results in at least a doubling of prothrombin time, significantly increasing the INR in virtually all patients receiving this drug combination and can cause serious or potentially fatal hemorrhagic complications. This effect can occur as early as 4-6 days following the initial administration of the drugs in combination but can be delayed for weeks in some cases. Given the extremely long half-life of amiodarone, the interaction may persist for weeks or even months after discontinuance of amiodarone. A fifty percent reduction in the dosage of warfarin is recommended if amiodarone therapy is initiated with intensive clinical observation and frequent determination of PT and INR values to evaluate the extent of the interaction and guide further adjustments in therapy.
Concomitant administration of amiodarone and phenytoin may result in phenytoin toxicity, secondary to a two- or three-fold increase in total, steady-state serum phenytoin concentrations likely due to a amiodarone-induced decrease in phenytoin metabolism. Close monitoring for symptoms of phenytoin toxicity including nystagmus, lethargy and ataxia; and evaluation of serum phenytoin concentrations with appropriate dosage reduction as necessary, is essential in patients receiving these medications.
Amiodarone may enhance cardiovascular adverse effects such as hypotension and atropine-resistant bradycardia in patients receiving inhalation anesthetics, possibly due to a drug interaction.
Concomitant use of amiodarone with tricyclic antidepressants, phenothiazines or any drug with the potential to prolong the QT interval may cause additive prolongation of the QT interval, and, rarely, torsades de pointes.
Although limited data exists, anecdotal reports have demonstrated a cholestyramine induced reduction in amiodarone elimination half-life and subsequently serum concentrations. This interaction may be of benefit in temporally reducing the serum amiodarone, and presumably DEA concentrations prior to surgery in an attempt to limit the cardiac depressant effects of the drug in the immediate post-surgical period.
ADVERSE REACTIONS: Despite its superior efficacy as an antiarrhythmic agent, the use of amiodarone is limited by its multitude of adverse effects. Overall, approximately 70% of patients taking amiodarone will experience some type of adverse reaction, with 5-20% being of sufficient severity to warrant discontinuation of the drug. In general, the major adverse effects of amiodarone are cumulative and dose related, and therefore, tend to occur with long-term therapy and/or with higher doses.
The most severe potential adverse effects of amiodarone therapy are pulmonary reactions. These reactions can be fatal (10% of cases), and may result from amiodarone-induced pulmonary interstitial pneumonitis, hypersensitivity pneumonitis or pulmonary fibrosis. Patients should be warned to report any symptoms of cough or progressive dyspnea. Pulmonary diffusion capacity may be abnormal in a high percentage of patients receiving amiodarone therapy, but pulmonary fibrosis and interstitial pneumonitis alveolitis are clinically significant in 2-15% of the patients receiving the drug. Pulmonary fibrosis is dose related and has not been reported in patients receiving less than 300 mg/day.D Hypersensitivity pneumonitis occurs in about 30% of amiodarone treated individuals, and generally requires treatment with corticosteroids and discontinuation of amiodarone therapy. Hypersensitivity pneumonitis appears to be unique from other pulmonary toxicities in that it is not dose related and has an earlier onset than either fibrosis or interstitial pnemonitis. Patients with underlying pulmonary disease do not appear to be at increased risk for the development of pulmonary toxicity, although their prognosis is worse should adverse effects develop.
Although quite rare, fatal hepatotoxicity (cirrhosis, hepatitis) has occured secondary to amiodarone therapy and is accompanied by severely elevated hepatic enzymes. Elevations in SGOT, SGPT, and alkaline phosphatase concentrations occur commonly in patients receiving amiodarone. These effects are mild, asymptomatic and usually return to normal following dosage reduction. Rarely, clinically significant hepatic dysfunction may occur, manifest as weight loss, hepatomegaly, ascites, abdominal pain, anorexia, or hepatitis. Amiodarone dosage may be reduced, or the drug may be discontinued.
Cardiovascular effects of amiodarone are difficult to differentiate from extensions of its normal pharmacologic activity. Amiodarone may cause AV block, sinoatrial block, and/or intraventricular block, precipitating serious new cardiac arrhythmias. Existing arrhythmias may be exacerbated. Symptomatic sinus bradycardia may occur as a result of depression of sinus node function. QT prolongation and torsade de pointes have also been associated with amiodarone therapy however, a review of published reports revealed that proarrhythmic events only occurred in 2% of patients receiving amiodarone and torsade de pointes only occurred in one-third of these patients (overall incidence of 0.7%).¥¥ Congestive heart failure has been worsened or induced by amiodarone in about 3% of the patients receiving the drug, but rarely requires discontinuance of the drug. Hypotension may occur secondary to either a proarrhythmic event or worsening heart failure.
Patients receiving amiodarone therapy may experience neurotoxicity, manifested as peripheral neuropathy. Symptoms include: ataxia, tremor, uncontrolled movements of the body, numbness in the fingers or toes, dizziness, muscle weakness, fatigue or malaise, gait disturbances or loss of coordination. Although relatively common as a group (20-40% incidence), these symptoms usually do not warrant discontinuance of the drug, and may be alleviated simply by a reduction in dosage.
Amiodarone has a complex effect on thyroid hormone metabolism and therefore alters thyroid function tests in approximately 10% of patients receiving amiodarone. Despite these biochemical changes, clinically significant alterations in thyroid function only occur in 3-5% of patients. Amiodarone-induced hypothyroidism appears to be slightly more common than hyperthyroidism. In some, but not all cases of thyroid disease, discontinuation of amiodarone is necessary. In any case, periodic monitoring of thyroid function tests may be prudent, particularly in the face of clinical signs or symptoms of hyper- or hypothyroidism. Symptoms of hyperthyroidism include sweating, weight loss, trouble sleeping, sensitivity to heat, and nervousness. Symptoms of hypothyroidism include cold intolerance, dry skin, weight gain, and unusual fatigue.
Photosensitivity, the most common dermatologic adverse effect of amiodarone, may occur in 10% of patients. Individuals who experience this effect seem to be particularly sensitive to long- wave ultraviolet-A (UVA) light, and may experience this symptom even through glass windows and/or cotton clothing. Sunscreens do not prevent this effect unless they also absorb UVA light. Opaquing screens such as zinc oxide or titanium dioxide provide adequate protection. Avoidance of exposure and protective clothing should be used to help prevent this adverse reaction. Long-term administration of amiodarone may infrequently result in blue-gray skin discoloration which may be more likely to occur in patients with fair skin, or those with frequent, unprotected exposure to sunlight. This effect may reverse slowly (and sometimes incompletely) upon discontinuance of the drug.
Gastrointestinal disturbances are quite common during amiodarone therapy, particularly during the loading phase, but usually do not warrant discontinuance of the drug. These effects are generally alleviated by dose reduction or division and administration with food and plenty of fluids. Reported adverse GI symptoms occur in about 25% of patients receiving amiodarone and include nausea/vomiting, anorexia, constipation, and abdominal pain.
Visual impairment or disturbances, including halo vision, blurred vision, photophobia, and dry eyes, occur in up to 10% of the patients receiving amiodarone therapy. Asymptomatic corneal deposits (microdeposits) and occur in virtually all patients who receive amiodarone for at least 6 months, but may occur sooner, and are not usually related to adverse ocular disturbances. Withdrawal of the drug can reverse corneal microdeposits, but this process may take as long as 7 months. Lens opacities have been reported. The opacities are minute, white-yellow punctate deposits within the pupillary aperture. Optic nerve changes have also been reported and are described as papillopathy or optic neuropathy.
Amiodarone has also been reported to cause sexual dysfunction, specifically libido decrease.
PATIENT INFORMATION:
What do amiodarone tablets do?
Amiodarone (CordaroneTM ) is an antiarrhythmic agent. This is a medicine that can help your heart to beat regularly when irregular heartbeats have not responded to other medicines. Amiodarone is not effective against other heart rhythm problems and may make them worse. Generic amiodarone tablets are not yet available.
What should my doctor, dentist, or pharmacist know before I take amiodarone?
They need to know if you have any of these conditions:
other heart problems
liver disease
thyroid disease
lung disease
low blood potassium or magnesium levels
an unusual or allergic reaction to amiodarone, iodine, other medicines, foods, dyes, or preservatives
pregnant or trying to get pregnant
breast-feeding
How should I take this medicine?
Take amiodarone tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Take your doses at regular intervals. Do not take your medicine more often than directed. Keep taking your medicine even if you feel better; do not stop taking except on your doctor's advice.
What if I miss a dose?
If you miss a dose, only take it if you remember within an hour, otherwise wait until your next dose is due. Do no take double or extra doses.
What other medicines can interact with amiodarone?
beta-blockers, often used for high blood pressure or heart problems
cimetidine
cyclosporine
dextromethorphan
digoxin
medicines for angina or high blood pressure
medicines for mental depression
medicines for mental problems or psychotic disturbances
medicines to control heart rhythm
phenytoin
warfarin
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking amiodarone?
Serious side effects with amiodarone include:
appetite increase or decrease
blue-gray coloring of the skin
blurred vision, seeing blue-green halos, increased sensitivity of the eyes to light
cough, or difficulty breathing
difficulty walking
dry or puffy skin or eyes
intolerance to heat or cold
nervousness
numbness or tingling in hands or feet pain and swelling of the scrotum
skin rash
trembling or shaking hands
sleep difficulties
sweating
unusual or uncontrolled movements of body
unusual tiredness or weakness
weight gain or loss
yellowing of the eyes or skin
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with amiodarone include:
bitter or metallic taste in the mouth
constipation
decreased sexual ability or desire in men
dizziness
flushing of the face
headache
nausea
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take amiodarone?
Visit your doctor for regular checks on your progress. Check with your doctor if you develop a cough or have any difficulty breathing. Because your condition and use of this medicine carry some risk, it is a good idea to carry an identification card, necklace or bracelet with details of your condition, medications, and doctor.
If you are going to have surgery tell your doctor or dentist that you are taking amiodarone.
Amiodarone can make your skin more sensitive to the sun. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen. Do not use sun lamps or sun tanning beds or booths.
Your eyes may get dry while you are using amiodarone. Use artificial tears (eye-drops containing methylcellulose) and check with your doctor.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature, approximately 25C (77F). Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date.
The P-I-E-N-O Parkinsn's List Drug Database Index
