Fandi Harmiki

111012003

• Digoxin is used for the treatment of congestive heart failure (CHF) because of its inotropic effects on the myocardium and for the treatment of atrial fibrillation because of its chronotropic effects on the electrophysiological system of the heart.

• Digoxin is used for the control of ventricular rate in patients with atrial fibrilation with no accessory pathway and can be an excellent choice if the patient is sedentary or has heart failure or left ventricular dysfunction.

DIGOXIN

• In oral or intravenous dose, the serum digoxin concentration-time curve follows a two-compartement model and exhibits a long and large distribution phase of 8-12 hours

• During the distribution phase, digoxin in the serum is not in equilibrium with digoxin in the tissues, so digoxin serum concentrations should not be measured until the distribution phase is finished

THERAPEUTIC AND TOXIC CONCENTRATIONS

• When digoxin serum concentration is very high but the patient is not signs or symptoms of digitalis overdose, clinicians should consider the possibility that the blood sample for the determination of a digoxin serum concentration was obtained during the distribution phase, is too high because digoxin has not had the opportunity to diffuse out of the bloodstream into the myocardium, and is not reflective of myocardial tissue concentrations

• 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 inotropiceffect

• Chronotropic effects usually require higher digoxin steady-state serum concentrations of 0.8–1.5 ng/mL

• 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 gastointestinal tract, central nervous system, or cardiovascular system

In patients receiving digoxin for heart failure, the common signs and symptoms of CHF should be routinuely monitored; left-sided failure-dyspnea on exertion, paroxymal nocturnal dyspnea, orthopnea, tachypnea, cough, hemoptysis, pulmonary rales/edema, s3 gallop, pleural effusion, cheyne-strokes respiration; right-sided failure-abdominal pain, anorexia, nausea, bloating, constipation, ascites, peripheral edema, jugular venous Distention, hepatojugular reflux, hepatomegaly, general symptoms-fatigue, weakness, nocturia, CNS symptoms, tachycardia, paloor, digital ctanosis, cardiomegaly.

Clinical Monitoring Parameters

• When used for the treatment of atrial fibrilation, digoxin will not stop the atrial arrhytmia but is used to decrease or contol the ventricular rate should be monitored and an electrocardiogram can also be useful to clinician able to interpret the output

• The patient’s pulse or ventricular rate should be monitored, and an electrocardiogram can also be useful to clinicians able to interpret the output.

• Atrial fibrillation is characterized by 400–600 nonuniform atrial beats/min.

• Patients with severe heart disease such as cornary artery disease can have increased pharmacodynamic sensitivity to cardiac glycosides and patients receiving these drugs should be monitored closely for adverse drug effects

• Augmented pharmacologic responses to digitalis derivates occur with serum electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypercalcemia even tough steady state digoxin serum concentrations are in the therapeutic range

• As an adjunct to the patient’s clinical response, postdistribution (8-12 hours postdose) staedy-state digoxin serum concentrations can be measured 3-5 half-lives after a stable dose is initiated. Digoxin is primarily eliminated unchanged by the kidney (75%) so its clearance is predominately influenced by renal function.

• The primary route of digoxin elimination from the body is by the kidney via glomerular filtration and active tubular secretion of unchanged drug (~75%).

• The remainder of a digoxin dose (~25%) is removed by hepatic metabolism or biliary excretion.

• The primary transporter involved in active tubular secretion and biliary excretion is p-glycoprotein (PGP)

• Enterohepatic recirculaton (reabsorption of drug from the gastrointestinal tract after elimination in the bile) of digoxin occurs

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

• Digoxin is given as an intravenous injection or orally as a tablet, capsule, or elixir. When given intravenously, doses should be infused over at least 5–10 minutes. Average bioavailability constants (F) for the tablet, capsule, and elixir are 0.7, 0.9, and 0.8.

• Digoxin is not usually administered intramuscularly due to erratic absorption and severe pain at the injection site.

• Plasma protein binding is ~25% for digoxin.• Usual digoxin doses for adults are 250 μg/d (range: 125–500

μg/d) in patients with good renal function (creatinine clearance ≥80 mL/min) and 125 μg every 2–3 days in patients with renal dysfunction (creatinine clearnace ≤15 mL/min)

• Adults with normal renal function (creatinine clearance ≥80 mL/min, Table 6-2) have an average digoxin half-life of 36 hours (range: 24–48 hours) and volume of distribution of 7 L/kg (range: 5–9 L/kg).

Effect of Disease States and Conditions on Digoxin Pharmacokinetics and Dosing

Because digoxin is principally eliminated by the kidney, renal dysfunction is the most important disease state that effects digoxin pharmacokinetics. The digoxin clearance rate decreases in proportion to creatinine clearance, and this relationship will be utilized to aid in the computation of initial doses later. The equation that estimates digoxin clearance from creatinine clearance is:

Cl= 1,303(CrCl)+ClNR

Cl= digoxin clearance (mL/min)

ClNR= digoxin clearance by nonreal routes of elimination

CrCl= creatinine clearance (mL/min)

Unbound digoxin molecules displaced from tissue binding sites move into the blood causing the decreased volume of distribution [↓V = Vb + (fb / ↑ft) Vt,where V is digoxin volume of distribution, Vb is blood volume, Vt is tissue volume, fb is the unbound fraction of digoxin in the blood, and ft is the unbound fraction of digoxin in the tissues.

• The equation that estimates digoxin volume of distribution using creatinine clearance is:

V=(226 + ((298 x CrCl) : 29,1 + CrCl))) (Wt/70)V= volume distribution (L/70 kg)Wt=body weight (kg)CrCl=creatinine clearance (mL/min)

Digoxin is not significantly eliminated by hemodialysis or peritoneal dialysis.28,29 Hemofiltration does remove digoxin with a typical sieving coefficient of 0.7Heart failure decreases cardiac output which in turn decreases liver blood flow. Liver blood flow is an important factor in the determination of hepatic clearance for drugs because it is the vehicle that delivers drug molecules to the liver for possible elimination.

• Moderate-severe heart failure decreases the hepatic clearance of digoxin by this mechanism.

• hepatic clearance of digoxin by this mechanism. When estimating digoxin clearance for the purpose of computing initial drug doses, it is necessary to decrease the nonrenal clearance (ClNR) factor to 20 mL/min in the equation to compansate for decreased hepatic clearance: Cl = 1.303 (CrCl) + 20, where Cl is digoxin clearance in mL/min, CrCl is creatinine clearance in mL/min, and 20 is digoxin nonrenal clearance ClNR in mL/min.

• digoxin clearance is lower in neonates and premature infants because renal and hepatic function are not completely developed. Premature infants and neonates have average digoxin half-lives equal to 60 hours and 45 hours, respectively.

• In older babies and young children (6 months to 8 years old) renal and hepatic function are fully developed and half-lives can be as short as 18 hours.

• Older children (≥12 years old) have mean digoxin half-lives (t1/2 = 36 hours) that are similar to those found in adults. Also, volume of distribution is larger in infants and children compared to adults as is found with many other drugs.

• Malabsorption of oral digoxin has been reported in patients with severe diarrhea, radiation treatments to the abdomen and gastrointestinal hypermotility. In these cases, steady-state digoxin serum concentrations decrease due to poor bioavailability of the drug.

INITIAL DOSAGE DETERMINATION METHODS

• The pharmacokinetic dosing method• The Jelliffe method• Nomograms that use the dosing concepts in the Jelliffe dosing

method are available. But, in order to make calculations easier, they make simplifying assumptions. The nomograms are for adults only, and separate versions are needed for intravenous injection (Table 6-4A), tablet (Table 6-4B), and capsule (Table 6-4C) because of bioavailability differences among dosage forms. All three nomograms assume that digoxin total body stores of 10 μg/kg are adequate, so are limited to heart failure patients requiring this dose. Recommended initial doses for pediatric patients are given in Table 6-3.

Pharmacokinetic Dosing MethodThe goal of initial dosing of digoxin is to compute the best dose possible for the patient given their set of disease and condition that influence digoxin pharmacokinetic paramenters for the patient will be estimated using averange parameters measured in order patients with similiar disease and condition profiles.

- Jusko-Koup method- Jelliffe Method

THERAPEUTIC AND TOXIC CONCENTRATIONS

• When given intravenously, the serum lidocaine concentration/time curve follows a two compartment model.

• This is especially apparent when initial loading doses of lidocaine are given as rapid intravenous injections over 1–5 minutes (maximum rate: 25–50 mg/min) and a distribution phase of 30–40 minutes is observed after drug administration (Figure 7-1).

• The generally accepted therapeutic range for lidocaine is 1.5–5 μg/mL. In the upper end of the therapeutic range (>3 μg/mL), some patients will experience minor side effects including drowsiness, dizziness, paresthesias, or euphoria.

• Lidocaine serum concentrations above the therapeutic range can cause muscle twitching, confusion, agitation, dysarthria, psychosis, seizures, or coma.

• Cardiovascular adverse effects such as atrioventricular block, hypotension, and circulatory collapse have been reported at lidocaine concentrations above 6 μg/mL, but are not strongly correlated with specific serum levels.

• Clinicians should understand that all patients with “toxic” lidocaine serum concentrations in the listed ranges will not exhibit signs or symptoms of lidocaine toxicity. Rather, lidocaine concentrations in the given ranges increase the likelihood that an adverse effect will occur

• For dose adjustment purposes, lidocaine serum concentrations are best measured at steady state after the patient has received a consistent dosage regimen for 3–5 drug halflives. Lidocaine half-life varies from 1–1.5 hours in normal adults to 5 hours or more in adult patients with liver failure.

• If lidocaine is given as a continuous intravenous infusion, it can take a considerable amount of time (3–5 half-lives or 7.5–25 hours) for patients to achieve effective concentrations so an intravenous loading dose is commonly administered to patients

Pharmacology of Lidocaine

• Steady State - Bolus 1-1.5 mg/kg plus - Infusion >1.0 mg/kg/hr

• Lightheadedness -5 mcg/ml serum levels• Unconsciousness -10 mcg/ml• Seizures -(12-18)mcg/ml• Respiratory and Cardiac Depression

-(20-24)mcg/ml

• CD100 – HUMANS -(5-7)mg/kg rapid bolus• CD 50 - HUMANS -(2-4)mg/kg rapid bolus

Dose and Toxicity

Evidence for intravenous lidocaine use

• Use in chronic neuropathic pain

• Major abdominal surgery

• Radical prostatectomy

Clinical Monitoring Parameters• The electrocardiogram (ECG or EKG) should be

monitored to determine the response to lidocaine in patients with ventricular tachycardia or fibrilation.

• The goal of therapy is suppression of ventricular arrhytmias and avoidance of adverse drug reactions

• Lidocaine therapy is often discontinued after 6-42hr of treatment so the need for long term antiarrhytmic drug use can be reassessd, although longer infusion may be used in patients with presistent tachyarrhytmias

• Lidocaine usually given for short duration (<24hr), its often not necessary to obtain serum lidocaine concentrations in patients receiving appropriate dose who curretly have no ventricular arrhytmia or adverse drug effects

• Lidocaine serum concentration should be obtained in patients who have a recurrence of ventricular tachyarrhytmias, are experiencing possible lidocaine side effects, or are receiving lidocaine does not consistent with disease states and conditions known to alter lidocaine pharmacokinetics

Initial Dosage Determination Methods

• The pharmacokinetic dosing method is the most flexible of the techniques.

• Literaturebased recommended dosing is a very commonly used method to prescribe initial doses of lidocaine.

Linear Pharmacokinetics MethodBecause lidocaine follows linear, dose-proportional

pharmacokinetics in most patients during short-term infusions (<24 hours), steady-state serum concentrations change in proportion to dose according to the following equation: Dnew / Css,new = Dold / Css,old or Dnew =(Css,new / Css,old)Dold, where D is the dose, Css is the steady-state concentration, old indicates the dose that produced the steady-state concentration that the patient is currently receiving, and new denotes the dose necessary to produce the desired steady-state concentration. The advantages of this method are that it is quick and simple. The disadvantages are steady-state concentrations are required, and accumulation of serum lidocaine concentrations can occur with long-term (>24 hours) infusions.

Pharmacokinetic Parameter Method• The pharmacokinetic parameter method of adjusting drug

doses was among the first techniques available to change doses using serum concentrations. It allows the computation of an individual’s own, unique pharmacokinetic constants and uses those to calculate a dose that achieves desired lidocaine concentrations. The pharmacokinetic parameter method requires that steady state has been achieved and uses only a steady-state lidocaine concentration (Css in mg/L or μg/mL). During a continuous intravenous infusion, the following equation is used to compute lidocaine clearance (Cl in L/min): Cl = k0/Css, where k0 is the dose of lidocaine in mg/min.

• The clearance measured using this technique is the patient’s own, unique lidocaine pharmacokinetic constant and can be used in the intravenouscontinuous infusion equation to compute the required dose (k0 in mg/min) to achieve any desired steady-state serum concentration (Css in mg/L or μg/mL): k0 = CssCl, where Cl is lidocaine clearance in L/min. Because this method also assumes linear pharmacokinetics, lidocaine doses computed using the pharmacokinetic parameter method and the linear pharmacokinetic method should be identical

Summary

• Digoxin and Lidocain have narrow therapeutic window so the range between MIC and MTC is very little so the dose must be given correctly

• For the patients with renal failure and liver disease the elimination and metabolism of drug is abnormal so we mush calculate the appropriate dose.