Quinidine

CARDIOVASCULARAGENTSPutri Ramadhani1111012012Class :C

DIGOXIN

IntroductionDigoxin is the primary cardiac glycoside in clinical use.Digoxin is used for the treatment of congestive heart failure (CHF) because of its inotropic effects on the myocardium.The positive inotropic effect of digoxin is caused by binding to sodium and potassium-activated adenosine triphosphatase.

THERAPEUTIC AND TOXIC CONCENTRATIONSWhen given as oral or intravenous doses,the serum digoxin concentration/time curve follows a two-compartment model.Exhibits a long and large distribution phase of 8-12 hours.When a digoxin serum concentration is very high but the patient is not exhibiting signs or symptoms of digitalis overdose.

Clinically beneficial inotropic effects of digoxin are generally achieved at steady-state serum concentrations of 0,5-1 ng/ml.Increasing steady-state serum concentrations to 1,2-1,5 ng/ml may provide some minor, additional inotropic effect.Chronotropic effects usually require higher digoxin steady-state serum concentrations of 0,8-1,5 ng/ml.

Steady state digoxin serum concentrations above 2 ng/ml are associated with an increased incidence of adverse drug reactions.At digoxin concentrations of 2,5 ng/ml or above, ~50% of all patients will exhibit some form of digoxin toxicity.Most digoxin side effects involve the gastrointestinal tract, central nervous system, or cardiovascular system.

Plasma protein binding is ~25% for digoxin.The primary route of digoxin elimination from the body is by the kidney via glomerular filtration and active tubular secretion as unchanged drug (~75%).The remainder of a digoxin dose (~25%) is removed by hepatic metabolism or biliary excretion.

Usual digoxin doses for adults are 250 g/d (range 125-500 g/d)In patient with good renal function (creatinine clearance 80 ml/minAnd 125 g every 2-3 days in patients with renal dysfunction (creatinine clearance 15 ml/min).

DRUG INTERACTIONSQuinidine decreases both the renal and non- renal clearance of digoxin and also decreases the volume of distriboution of digoxin.Verapamil, diltiazem, and bepridil inhibit digoxin clearance and increase mean digoxin steady-state concentrations by various degrees.Amiodarone decreases digoxin clearance.

LIDOCAINE

IntroductionLidocaine is a local anesthetic agent that also has antiarrhythmic effects.It is classified as a type IB antiarrhythmic agent.Used for the treatment of ventricular tachycardia or ventricular fibrilation.

THERAPEUTIC AND TOXIC CONCENTRATIONSWhen lidocaine is given intravenously, the serum lidocaine concentration/time curve follow a two-compartment model.When initial loading doses of lidocaine are given as rapid intravenous injections over 1-5 minutes (maximum rate 25-50 mg/min)Distributions phase of 30-40 minutes is observed after drug administration.

The generally accepted therapeutic range for lidocaine is 1,5-5 g/minIn the upper end of the therapeutic range (>3g/ml)Lidocaine half-life varies from 1-1,5 hours in normal adults.5 hours or more in adult patients with liver failureIf lidocaine is given a continuous intravenous infusion, it can take a considerable amount of time (3-5 half-lives or 7,5-25 hours).

BASIC CLINICAL PHARMACOKINETIC PARAMETERLidocaine is almost completely eliminated by hepatic metabolism (>95%)Oral absorption of lidocaine is nearly 100%Plasma protein binding in normal individuals is about 70%.

DRUG INTERACTIONSPropanolol, metoprolol, and nadolol have been reported to reduce lidocaine clearance due to the decrease in cardiac output caused by -blocker agents.Cimetidine also decreases lidocaine clearance.Lidocaine clearance may be accelerated by contamitant use of phenobarbital or phenytoin.

PROCAINAMIDE/N-ACETYLPROCAINAMIDE

IntroductionProcainamide is an antiarrhythmic agent that is used intravenously and orally.It is classified as a type IA antiarrhythmic agent and can be used for the treatment of supraventricular or ventricular arrhythmiasIt is a drug of choice for the treatment of stable sustained monomorphic ventricular tachycardia with coronary heart diseaseProcainamide can be used as an antiarrhythmic for patients that are not converted using electrical shock and intravenous epinephrine or vasopressin.

THERAPEUTIC AND TOXIC CONCENTRATIONSThe generally accepted therapeutic range for procainamide is 410 g/mL.Serum concentrations in the upper end of the therapeutic range (8 g/mL) may result in minor side effects such as gastrointestinal disturbances (anorexia, nausea, vomiting, diarrhea), weakness, malaise, decreased mean arterial pressure (less than 20%), and a 1030% prolongation of electrocardiogram intervals (PR and QT intervals, QRS complex)

Procainamide serum concentrations initially drop rapidly after an intravenous bolus as drug distributes from blood into the tissues during the distribution phase. During the distribution phase, drug leaves the blood due to tissue distribution and elimination. After 2030 minutes, an equilibrium is established between the blood and tissues, and serum concentrations drop more slowly since elimination is the primary process removing drug from the blood. This type of serum concentration/time profile is described by a two-compartment model.

To maintain therapeutic procainamide concentrations, an intravenous loading dose (over 2530 minutes) of procainamide is followed by a continuous intravenous infusion of the drug. A distribution phase is still seen due to the administration of the loading dose. Note that the administration of a loading dose may not establish steady-state conditions immediately, and the infusion needs to run 35 half-lives until steady-state concentrations are attained.

Serum concentration/time profile for rapid-release procainamide (solid line, givenevery 3 hours) or sustained-release procainamide (dashed line, given every 6 hours) oral dosage Forms after multiple doses until steady state is achieved. The curves shown would be typical for an adult with normal renal and hepatic function.

Because many procainamide therapeutic and side effects are not correlated with its serum concentration, it is often not necessary to obtain serum procainamide concentrations in patients receiving appropriate doses who currently have no arrhythmia or adverse drug effects.Procainamide serum concentrations should be obtained in patients who have a recurrence of tachyarrhythmias, are experiencing possible procainamide side effects, or are receiving procainamide doses not consistent with disease states and conditions known to alter procainamide pharmacokinetics

BASIC CLINICAL PHARMACOKINETIC PARAMETERSProcainamide is eliminated by both hepatic metabolism (~50%) and renal elimination of unchanged drug (~50%).Hepatic metabolism is mainly via N-acetyltransferase II (NAT-II)N-acetyl procainamide is the primary active metabolite resulting from procainamide metabolism by N-acetyltransferase II

EFFECTS OF DISEASE STATES AND CONDITIONS ONPROCAINAMIDE PHARMACOKINETICS AND DOSINGNormal adults without the disease states and conditions given later in this section and with normal liver and renal function have an average procainamide half-life of 3.3 hours (range: 2.54.6 hours) and a volume of distribution for the entire body of 2.7 L/kg (V =23.8 L/kg)Because about 50% of a procainamide dose is eliminated unchanged by the kidney, renal dysfunction is the most important disease state that effects procainamide pharmacokinetics

Uncompensated heart failure reduces procainamide clearance because of decreased hepatic blood flow secondary to compromised cardiac output.Volume of distribution (V = 1.6 L/kg) is decreased in uncompensated heart failure patients as wellThe majority of N-acetyltransferase II responsible for the conversion of procainamide to NAPA is thought to reside in the liver. Because of this, most clinicians recommend a decrease in initial doses for procainamide in patients with liver disease

DRUG INTERACTIONSCimetidine, trimethoprim, ofloxacin, levofloxacin, and ciprofloxacin are all drugs that compete for tubular secretion with procainamide and NAPAAmiodarone increases the steady-state concentrations of procainamide and NAPA by 57% and 32%, respectively

Quinidine

IntroductionQuinidine was one of the rst agents used for its antiarrhythmic effects. It is classied as a type IA antiarrhythmic agent and can be used for the treatment of supraventricular or ventricular arrhythmias.Because of its side effect prole, quinidine is considered by many clinicians to be a second-line antiarrhythmic choice. Quinidine inhibits transmembrane sodium inux into the conduction system of the heart thereby decreasing conduction velocity.

Therapeutic and Toxic ConcentrationWhen given intravenously, the serum quinidine concentration/time curve follows a two-compartment model. When oral quinidine is given as a rapidly absorbed dosage form such as quinidine sulfate tablets, a similar distribution phase is also observed with a duration of 2030 minutes. If extended-release oral dosage forms are given, absorption occurs more slowly than distribution so a distribution phase is not seen.

The generally accepted therapeutic range for quinidine is 26 g/mL. Quinidine serum concentrations above the therapeutic range can cause increased QT interval or QRS complex widening (>3550%) on the electrocardiogram, cinchonism, hypotension, high-degree atrioventricular block, and ventricular arrhythmias.

For dose adjustment purposes, quinidine serum concentrations are best measured as a predose or trough level at steady state after the patient has received a consistent dosage regimen for 35 drug half-lives. Quinidine half-life varies from 68 hours in normal adults to 910 hours or more in adult patients with liver failure. If quinidine is given orally or intravenously on a stable schedule, steady-state serum concentrations will beachieved in about 2 days (5 8 h = 40 h)

Basic Clinical Pharmacokinetic ParametersQuinidine is almost completely eliminated by hepatic metabolism (~80%). Hepatic metabolism is mainly via the CYP3A enzyme system. 3-Hydroxyquinidine is the primary active metabolite resulting from quinidine metabolism while dihydroquinidine is an a ctive compound that is found as an impurity in most quinidine dosage forms. The hepatic extraction ratio of quinidine is about 30%, so quinidine is typically classied asan intermediate extraction ratio drug.

Plasma protein binding of quinidine in normal individuals is about 8090%. The drug binds to both albumin and 1-acid glycoprotein (AGP). AGP is classied as an acute phase reactant protein that is present in lower amounts in all individuals but is secreted in large amounts in response to certain stresses and disease states such as trauma, heart failure, and myocardial infarction.The recommended dose of quinidine is based on the concurrent disease states and conditions present in the patient that can inuence quinidine pharmacokinetics.

EFFECTS OF DISEASE STATES AND CONDITIONS ON QUINIDINEPHARMACOKINETICS AND DOSINGNormal adults without the disease states and conditions given later in this section and with normal liver function have an average quinidine half-life of 7 hours (range: 68 hours) and a volume of distribution for the entire body of 2.4 L/kg (V = 23 L/kg).Patients with liver cirrhosis have increased quinidine clearance and volume of distribution which results in a prolonged average quinidine half-life of 9 hours.

Clearance and volume of distribution are larger in patients with liver disease because albumin and AGP concentrations are lower in these patients and result in reduced quinidine plasma protein binding (average V = 3.8 L/kg).The increased unbo raction in the plasma allows more quinidine to enter the liver parenchyma where hepatic drug metabolizing enzymes are present and leads to increased drug clearance. Decreased plasma protein binding also leads to higher unbound levels for a given total quinidine serum concentration.

Heart failure reduces quinidine clearance because of decreased hepatic blood ow secondary to compromised cardiac output.After a myocardial infarction, serum AAG concentrations increase up to 50% over a 1272 hour time period. As AAG serum concentrations increase, plasma protein binding of quinidine increases and the unbound fraction of quinidine decreases.

Patient age has an effect on quinidine clearance and half-life. For elderly patients over the age of 65, studies indicate that quinidine clearance is reduced, the volume of distribution is unchanged, and half-life is longer (average half-life = 10 hours) compared to younger subjects. A confounding factor found in quinidine pharmacokinetic studies conducted in older adults is the possible accidental inclusion of subjects that have subclinical or mild cases of the disease states associated with reduced quinidine clearance (heart failure, liver disease, etc.).

DRUG INTERACTIONSQuinidine has serious drug interactions with other drugs that are capable of inhibiting the CYP3A enzyme system.Because this isozyme is present in the intestinal wall and liver,quinidine serum concentrations may increase due to decreased clearance, decreased rstpass metabolism, or a combination of both.P-glycoprotein is also inhibited by quinidine so drug transport may be decreased and cause drug interactions.

Erythromycin, ketoconazole, and verapamil have been reported to increase quinidine serum concentrations or area under the concentration/time curve (AUC) by >3050%.Drugs that induce CYP3A (phenytoin, phenobarbital, rifampin, rifabutin) decrease quinidine serum concentrations by increasing quinidine clearance and rst-pass metabolism.Propranolol, metoprolol, and timolol have decreased clearance due to quinidine coadministration.

When quinidine is given concomitantly with codeine, the conversion from codeine to morphine does not take place, and patients do not experience analgesia.Quinidine increases digoxin serum concentrations 3050% by decreasing digoxin renal and nonrenal clearance as well as digoxin volume of distribution.Antacids can increase urinary pH leading to increased renal tubular reabsorption of unionized quinidine and decreased quinidine renal clearance.

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