CARDIOVASCULAR AGENTS FARKLIN

8/7/2019 CARDIOVASCULAR AGENTS FARKLIN

1/66

CARDIOVASCULAR

AGENTSPUTRI HASANAH RAHMIN

0811012051

FACULTY OF PHARMACY

ANDALAS UNIVERSITY


2/66

DIGOXIN


3/66

Digoxin is used for the treatment of congestive heart failure (CHF)because of its inotropic effects onthe myocardiumDigoxin is used too for thetreatment of atrial fibrillation

because of its chronotropic effectson the electrophysiological systemof the heart


4/66


5/66

THERAPEUTIC AND TOXICCONCENTRATIONS

W hen given as oral or intravenous doses,the serum digoxin concentrationtimecurve follows a two-compartment modeland exhibits a long and large distributionphase of

812 hours


6/66

Digoxin serum concentrations after 250- g doses given intravenously(circles andsolid line) and orally as a tablet (squares with dashed line)


7/66

During the distribution phase, digoxin inthe serum is not in equilibrium withdigoxin in the tissues, so digoxin serumconcentrations should not be measured

until the distribution phase is finished.W hen drug distribution is complete,digoxin serum and tissue concentrations

will be proportional to each other so thatdigoxin serum concentrations reflectconcentrations at the site of action


8/66

Clinically beneficial inotropic effects of digoxinare generally achieved at steady-state serumconcentrations of 0.51 ng/mL.Increasing steady-state serum concentrations

to 1.21.5 ng/mL may provide some minor,additional inotropic effect.Chronotropic effects usually require higher

digoxin steady-state serum concentrationsof 0.81.5 ng/mL.

Additional chronotropic effects may beobserved at digoxin steady-state serumconcentrations as high as 2 ng/mL.


9/66

S IDE EFFEC T

M ost digoxin side effectsinvolvegastointestinal tractcentral nervous systemcardiovascular system


10/66

GA S T

OINT

ES T

INALTR

ACT S

IDE EFFECT

anorexia

nauseavomiting

diarrheaabdominal painconstipation.


11/66

CEN TR AL NE RV OU SSYS T E M S IDE EFFEC T

Headache

fatigueInsomniaconfusionvertigo


12/66

CA R DIAC S IDE EFFEC Tsecond or third degree atrioventricularblock

atrioventricular dissociationbradycardiapremature ventricular contractions

ventricular tachycardia


13/66

CLINICAL MONITORING PARAMETERS

In patients receving digoxin for heart failure,the common signs and symptoms of CHFshould be routinuely monitoredW hen used for the treatment of atrialfibrillation, digoxin is used to decrease, orcontrol, the ventricular rate. T he patients

pulse or ventricular rate should be monitored,and an electrocardiogram can also be useful toclinicians able to interpret the output .


14/66

P atients with severe heart diseasesuch as cornary artery can haveincreased pharmacodynamicsensitivity to cardiac glycosides, andpatients receiving these drugsshould be monitored closely for

adverse drug effects.


15/66

B ASIC CLINICAL PHARMACOKINETICPARAMETERS

T he primary route of digoxin elimination fromthe body is by the kidney via glomerularfiltration and active tubular secretion of unchanged drug (~75%).T he remainder of adigoxin dose (~25%) isremoved by hepatic metabolism or biliaryexcretion.T he primary transporter involved in active

tubular secretion and biliary excretion is p-glycoprotein ( P GP ).


16/66

Digoxin is given as an intravenous injection or orallyas a tablet, capsule, or elixir.

W hen given intravenously, doses should be infusedover at least 510 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 theinjection site.P lasma protein binding is ~25% for digoxin.Usual digoxin doses for adults are 250 g/d (range:

125500 g/d) in patients with good renal function(creatinine clearance 80 mL/min) and 125 g every 2 3 days in patients with renal dysfunction (creatinineclearnace 15 mL/min).


17/66

EFFECTS OF DISEASE STATES ANDCONDITIONS ON DIGOXINPHARMACOKINETICS AND DOSING

Adults with normal renal functionhave an average digoxin half-life of 36 hours (range: 2448 hours) andvolume of distribution of 7 L/kg(range: 59 L/kg)T he volume of distribution is largedue to the extensive tissue binding of digoxin in the body.


18/66

T he digoxin clearance rate decreases inproportion to creatinine clearance.

T he equation that estimates digoxin clearancefrom creatinine clearance is:

Cl = 1.303 (CrCl) + ClN Rwhere

Cl : digoxin clearance in mL/min,CrCl :creatinine clearance in mL/min

ClN R : digoxin clearance by nonrenal routes of elimination which equals 40 mL/mininpatients with no or mild heart failure


19/66

Digoxin clearance is proportional to creatinine clearance for patientswith [ circles withsolid line: Cl = 1.303(CrCl) + 20] and without [squares with dashed line:Cl = 1.303(CrCl) + 40] moderate-severe (N Y HA class III or I V ) heart

failure


20/66

T he equation that estimates digoxin volume of distribution using creatinine clearance is:

298.CrClV = 226 + ( W t/70)

29.1+CrCl

V is digoxin volume of distribution in L/70 kg, W t isbody weight in kilogram (use ideal body weight if >30%overweight) and CrCl is creatinine clearance inmL/min


21/66

digoxin clearance is lower inneonates and premature infantsbecause renal and hepatic functionare not completely developedM alabsorption of oral digoxin hasbeen reported in patients withsevere diarrhea, radiationtreatments to the abdomen andgastrointestinal hypermotility


22/66

DRUG INTERACTIONS

Inhibition of P -glycoprotein, a drugefflux pump which is found in thekidney, liver, and intestine, appears tobe involved in the majority of digoxininteractionsQuinidine decreases both the renal andnonrenal clearance of digoxin and alsodecreases the volume of distribution of digoxin


23/66

V erapamil, diltiazem, and bepridilinhibit digoxin clearance andincrease mean digoxin steady-stateconcentrations by various degreesAmiodarone and propafenone areantiarrhythmic agents that decreasedigoxin clearanceCyclosporine therapy has beenreported to increase average steady-state digoxin concentrations up to50%


24/66

INITIAL DOSAGEDETERMINATION METHODS

p harmacokinetic dosing methodJelliffe method


25/66

LIDOCAINE


26/66

Lidocaine is a local anesthetic agent that

also has antiarrhythmic effects. It isclassified as a type IB antiarrhythmicagent and is a treatment for ventriculartachycardia or ventricular fibrillation

For episodes of sustained ventriculartachycardia with signs or symptoms of hemodynamic instability ,electricalcardioversion is the treatment of choice.


27/66

Lidocaine inhibits transmembrane

sodium influx into the His- P urkinje fiberconduction system thereby decreasingconduction velocity

It also decreases the duration of theaction potential and as a result decreasesthe duration of the absolute refractoryperiod in P urkinje fibers and bundle of His.


28/66


W hen given intravenously, the serumlidocaine concentration/time curvefollows a twocompartment modelT his is especially apparent when initialloading doses of lidocaineare given asrapid intravenous injections over 15minutes (maximum rate: 2550 mg/min)and a distribution phase of 3040minutes is observed after drug

administration


29/66

Lidocaine serum concentrations initially drop rapidly after anintravenous bolus as drug distributes from blood into the tissuesduring the distribution phase


30/66

accepted therapeutic range for lidocaineis 1.55 g/mL. In the upper end of thetherapeutic range (>3 g/mL), somepatients will experience minor sideeffects including drowsiness, dizziness,

paresthesias, or euphoriaLidocaine serum concentrations abovethe therapeutic range can cause muscle

twitching, confusion, agitation,dysarthria, psychosis, seizures, or coma.


31/66

CLINICAL MONITORINGPARAMETERS

T he electrocardiogram (ECG or EKG) should bemonitored to determine the response to lidocainein patients with ventricular tachycardia orfibrillation.T he goal of therapy is suppression of ventriculararrhythmias and avoidance of adverse drugreactions.

Lidocaine therapy is often discontinued after 6 24 hours of treatment so the need for longtermantiarrhythmic drug use can be reassessed,although longer infusions may be used in patients

with persistent tachyarrhythmias.


32/66

P atients receiving lidocaine infusions forlonger than 24 hours are prone tounexpected accumulation of lidocaineconcentrations in the serum and should beclosely monitored for lidocaine side effectsW

hile receiving lidocaine, patients shouldbe monitored for the following adverse drugeffects: drowsiness, dizziness, paresthesias,euphoria, muscle twitching, confusion,

agitation, dysarthria, psychosis, seizures,coma, atrioventricular block, orhypotension .


33/66


Lidocaine is almost completely eliminated by hepaticmetabolism (>95%).Hepatic metabolism is mainly via the C Y P 3A enzyme

system.M onoethylglycinexylidide ( M EGX) is the primarymetabolite resulting from lidocaine metabolismIntramuscular administration of medications canincrease creatine kinase (CK) concentrations due tominor skeletal muscle trauma inflicted by the injection,and this enzyme is monitored in patients who may havehad a myocardial infarction


34/66

P lasma protein binding in normalindividuals is about 70%.Of this value, approximately 30% is due

to drug binding to albumin while 70% isdue to lidocaine bound to 1-acidglycoprotein (AG P )T he recommended dose of lidocaine isbased on the concurrent disease states

and conditions present in the patientthat can influence lidocaineconcentrations.


35/66

EFFECTS OF DISEASE STATES ANDCONDITIONS ON LIDOCAINEPHARMACOKINETICS AND DOSING

Normal adults without the disease statesand conditions given later in this section

with normal liver function have anaverage lidocaine half-life of 1.5 hours(range: 12 hours), a central volume of distribution of 0.5 L/kg ( V c = 0.40.6L/kg) and the volume of distribution forthe entire body of 1.5 L/kg ( V area = 12L/kg


36/66

P atients with liver cirrhosis or acutehepatitis have reduced lidocaineclearance which results in a prolongedaverage lidocaine half-life of 5 hoursHeart failure causes reduced lidocaineclearance because of decreased hepaticblood flow secondary to compromisedcardiac output.

P atients with cardiogenic shockexperience extreme declines in lidocaineclearance due to severe decreases incardiac output and liver blood flow


37/66

P atient age has an effect onlidocaine volumes of distributionand half-lifeLidocaine serum concentrationsaccumulate in patients receiving

long-term (>24 hours) infusionseven if the patient did not have amyocardial infarction


38/66

DRUG INTERACTIONS

Lidocaine has serious drug interactions with -adrenergic receptor blockers and cimetidine thatdecrease lidocaine clearance 30% or more.P ropranolol, metoprolol, and nadolol have been

reported to reduce lidocaine clearance due to thedecrease in cardiac output caused by -blocker agents.Decreased cardiac output results in reduced liver bloodflow which explains the decline in lidocaine clearancecaused by these drugs.Cimetidine also decreases lidocaine clearance, but themechanism of the interaction is different. Because cimetidine does not change liver blood flow, it isbelieved that cimetidine decreases lidocaine clearanceby inhibiting hepatic microsomal enzymes


39/66


p harmacokinetic dosing methodLiterature based

recommended dosing


40/66

PR OCAINA M IDE/ N-ACETYL PR OCAINA M IDE


41/66

P rocainamide is an antiarrhythmicagent that is used intravenously and

orally. It is classified as a type IA antiarrhythmic agent and can be usedfor the treatment of supraventricular orventricular arrhythmiasIt is a drug of choice for the treatment of stable sustained monomorphicventricular tachycardia.P

rocainamide is a useful agent in thetreatment of idiopathic repetitivepolymorphic ventricular tachycardia inpatients with coronary heart disease .


42/66

P rocainamide can be administered forthe long-term prevention of chronicsupraventricular arrhythmias such assupraventricular tachycardia, atrialflutter, and atrial fibrillation.N- acetyl procainamide is an activemetabolite of procainamide that has type

III antiarrhythmic effects.


43/66


W hen given intravenously, the serumprocainamide concentration/time curve follows atwo-compartment mode

T he generally accepted therapeutic range forprocainamide is 410 g/mL.S erum 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 (lessthan 20%), and a 1030% prolongation of

electrocardiogram intervals


44/66

P rocainamide serum concentrations initially drop rapidlyafter an intravenous bolusas drug distributes from blood into the tissues during thedistribution phase.


45/66

Nondose or concentration related side effectsto procainamide include rash, agranulocytosis,

and a systemic lupus-like syndrome.An active procainamide metabolite, known asN- acetyl p rocainamide ( NAPA ) or acecainide,also possesses antiarrhythmic effects.For dose adjustment purposes, procainamideserum concentrations during oraladministration are best measured as a predoseor trough level at steady state after the patienthas received a consistent dosage regimen for35 drug half-lives.


46/66


T he electrocardiogram (ECG or EKG) should bemonitored to determine the response toprocainamide.

T he goal of therapy is suppression of arrhythmiasand avoidance of adverse drug reactions.if a possible concentration-related procainamideadverse drug reaction is noted in a patient and the

procainamide serum concentration is


47/66


P rocainamide is eliminated by both hepatic metabolism(~50%) and renal elimination of unchanged drug (~50%).1Hepatic metabolism is mainly via N- acetyltransferase II (NA T -II).N- acetyl p rocainamide is the primary active metaboliteresulting from procainamide metabolism by N-acetyltransferase II.N- acetyltransferase II exhibits a bimodal genetic

polymorphism that results in slow acetylator and rapidacetylator phenotypes.If the patient has normal renal function, acetylator statuscan be estimated using the ratio of NA P A and procainamide(P A) steady-state concentrations: acetylator ratio =NA P A/P A.


48/66

If this ratio is 1.2 or greater, it is likely the patient is arapid acetylator.If the ratio is 0.8 or less, it is likely the patient is aslow acetylator.

T he ratio of procainamide renal clearance andcreatinine clearance is 23 implying that net renaltubular secretion is taking place in the kidney.T he average oral bioavailability of procainamide forboth immediate-release and sustained-release dosageforms is 83%.P lasma protein binding of procainamide in normalindividuals is only about 15%.


49/66

EFFECTS OF DISEASE STATES ANDCONDITIONS ONPROCAINAMIDE PHARMACOKINETICSAND DOSING

Normal adults without the disease

states and conditions given later inthis section and with normal liverand renal function have an averageprocainamide half-life of 3.3 hours(range: 2.54.6 hours) and a volumeof distribution for the entire body of 2.7 L/kg ( V = 23.8 L/kg


50/66

Because about 50% of a procainamide dose is

eliminated unchanged by the kidney, renal dysfunctionis the most important disease state that effectsprocainamide pharmacokinetics.Uncompensated heart failure reduces procainamideclearance because of decreased hepatic blood flowsecondary to compromised cardiac outputS tudies investigating the impact of obesity (30% overideal body weight) on procainamide pharmacokineticshave found that volume of distribution correlates best

with ideal body weight, but clearance correlates bestwith total body weigh


51/66

DRUG INTERACTIONS

P rocainamide has serious druginteractions with other drugs that are

capable of inhibiting its renal tubularsecretion.Cimetidine, trimethoprim, ofloxacin,

levofloxacin, and ciprofloxacin are alldrugs that compete for tubular secretionwith procainamide and NA P A.


52/66


53/66

QUINIDINE


54/66

Quinidine was one of the first agents used for

its antiarrhythmic effects. It is classified as atype IA antiarrhythmic agent and can be usedfor the treatment of supraventricular orventricular arrhythmias

quinidine therapy can be used to chemicallyconvert atrial fibrillation to normal sinusrhythm for a patient.Quinidine inhibits transmembrane sodiuminflux into the conduction system of the heartthereby decreasing conduction velocity


55/66


W hen given intravenously, the serumquinidine concentration/time curvefollows a twocompartment model.W hen oral quinidine is given as a rapidlyabsorbed dosage form such as quinidinesulfate tablets, a similar distribution

phase is also observed with a duration of 2030 minutes


56/66

T he generally accepted therapeutic range forquinidine is 26 g/mL.

Quinidine serum concentrations above thetherapeutic range can cause increased Q T interval or Q R S complex widening (>3550%)on the electrocardiogram, cinchonism,hypotension, high degree atrioventricularblock, and ventricular arrhythmias symptomsthat includes tinnitus, blurred vision,lightheadedness, tremor, giddiness, andaltered hearing which decreases in severitywith lower quinidine concentrations


57/66

Quinidine metabolites (3-hydroxyquinidine, 2 -

quinidinone, quinidine -N- oxide , O-desmethylquinidine) all have antiarrhythmiceffects in animal modelsOf these compounds, 3-hydroxyquinidine is themost potent (6080% compared to the parentdrug) and achieves high enough serumconcentrations in humans that itsantiarrhythmic effects probably contribute tothe clinical effects observed during quinidinetreatment


58/66


T he electrocardiogram (ECG orEKG) should be monitored todetermine the response to quinidine.T he goal of therapy is suppression of

arrhythmias and avoidance of adverse drug reactions.S erum concentration monitoring canaid in the decision to increase ordecrease the quinidine dose.


59/66

W hile receiving quinidine, patients should bemonitored for the following adverse drug

effects: anorexia, nausea, vomiting, diarrhea,cinchonism, syncope, increased Q T interval orQR S complex widening (>3550%) on theelectrocardiogram, hypotension, high-degree

atrioventricular block, ventriculararrhythmias, and hypersensitivity reactions(rash, drug fever, thrombocytopenia, hemolyticanemia, asthma, respiratory depression, a

lupus-like syndrome, hepatitis, anaphylacticshock).


60/66


Quinidine is almost completely eliminatedby hepatic metabolism (~80%).Hepatic metabolism is mainly via the

CY P 3A enzyme system.3-Hydroxyquinidine is the primary active

metabolite resulting from quinidinemetabolism while dihydroquinidine is anactive compound that is found as animpurity in most quinidine dosage forms.


61/66

After oral administration, quinidine is subject to

moderate first-pass metabolism by C Y P 3A contained in the liver and intestinal wall.Quinidine is also a substrate for P -glycoprotein.Approximately 20% of a quinidine dose iseliminated unchanged in the urineT hree different salt forms of quinidine areavailable. Quinidine sulfate contains 83%

quinidine base, quinidine gluconate contains62% quinidine base, and quinidinepolygalacturonate contains 60% quinidine base.


62/66

P lasma protein binding of quinidine in normalindividuals is about 8090%.T he drug binds to both albumin and 1-acid

glycoprotein (AG P ).AG P is classified as an acute phase reactantprotein that is present in lower amounts in allindividuals but is secreted in large amounts inresponse to certain stresses and disease statessuch as trauma, heart failure, and myocardialinfarction.In patients with these disease states,quinidine binding to AG P can be even largerresulting in an unbound fraction as low as 8%.


63/66

DRUG INTERACTIONS

Quinidine has serious drug interactions with other drugsthat are capable of inhibiting the C Y P 3A enzyme system.Because this isozyme is present in the intestinal wall andliver, quinidine serum concentrations may increase due

to decreased clearance, decreased firstpass metabolism,or a combination of both.P -glycoprotein is also inhibited by quinidine so drugtransport may be decreased and cause drug interactions.

Erythromycin, ketoconazole, and verapamil have beenreported to increase quinidine serum concentrations orarea under the concentration/time curve (AUC) by >30 50%.


64/66

Other macrolide antibiotics (such as clarithromycin) orazole antifungals (such as fluconazole, miconazole, anditraconazole) that inhibit C Y P 3A probably cause similardrug interactions with quinidine Quinidine increasesdigoxin serum concentrations 3050% by decreasingdigoxin renal and nonrenal clearance as well as digoxin

volume of distribution.T he probable mechanisms of this drug interaction are

inhibition of digoxin renal and hepatic P -glycoprotein(P GP ) elimination and tissue binding displacement of digoxin by quinidine.Antacids can increase urinary pH leading to increasedrenal tubular reabsorption of unionized quinidine anddecreased quinidine renal clearance.


65/66


pharmacokinetic dosing methodLiterature based recommendeddosing


66/66

THANK YOU

Documents

CARDIOVASCULAR AGENTS FARKLIN