clinical pharmacokinetics of procainamide

05/02/2023

Clinical Pharmacokinetics of procainamide by Behailu & Bezie 1

CLINICAL PHARMACOKINETICS OF PROCAINAMIDE/N-ACETYL

PROCAINAMIDE

JU School Of PharmacyJimma, Ethiopia

By Behailu Terefe (BPharm, PGY1 clinical pharmacy student)

[email protected] / [email protected]

Phar 611

mailto:[email protected]

mailto:[email protected],[email protected]

05/02/2023Clinical Pharmacokinetics of procainamide by Behailu & Bezie

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Contents

Introduction Therapeutic And Toxic Concentrations Adverse Events

Basic Clinical Pharmacokinetic Parameters Disease States And Conditions Affecting Pk And Dosing Initial Dosage Determination Methods Use of Serum Conc. to Alter Doses


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INTRODUCTION

Procainamide type IA antiarrhythmic agent that is used

I.V and PO. used for the treatment of SV or ventricular

arrhythmias.MOA:-

inhibits trans-membrane Na+ influx thereby ↓

conduction velocity. Increases

the duration of the action potential, threshold potential toward zero, and


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decreases the slope of phase 4 of the action potential and

Automaticitynet effect

↑ refractoriness and ↓conduction in heart conduction tissue, which establishes a bidirectional block in reentrant pathways.


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THERAPEUTIC AND TOXIC CONCENTRATIONS

therapeutic range for procainamide is 4-10 μg/ml.

When given intravenously, the serum PDC-time curve follows a two-compartment model (see figure below).

Date of download: 12/5/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.

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 20-30 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. A two-compartment model describes this type of serum concentration/time profile.

Legend:

From: Cardiovascular AgentsApplied Clinical Pharmacokinetics, 3e, 2015


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To maintain therapeutic procainamide concentrations, an I.V LD (over 25-30 minutes) is followed by a CII. distribution phase is still seen due to the adm. of

LD. administration of a LD may not establish steady-

state conditions immediately, and the infusion needs to run 3-5 t1/2 until Css are attained


To maintain therapeutic procainamide concentrations, an intravenous loading dose (over 25-30 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 3-5 half-lives until steady-state concentrations are attained.

Legend:

From: Procainamide/N-acetyl ProcainamideApplied Clinical Pharmacokinetics, 3e, 2015


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When oral dosage forms are given, absorption occurs more slowly than distribution so a distribution phase is not seen.


Serum concentration-time profile for rapid-release procainamide (solid line, given every 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.

Legend:

From: Procainamide/N-acetyl Procainamide Applied Clinical Pharmacokinetics, 3e, 2015


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ADVERSE EVENTS

can be concentration dependent or independent.


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Recommendations during I.V procainamide therapy, Continuous monitoring of B.P Ensuring availability or actual giving of phenylephrine or NE Constant ECG monitoring equipment to treat ventricular a systole, fibrillation, or both.

RX of Procainamide toxicity Have desirable attributes for extracorporeal drug removal. peritoneal dialysis, hemodialysis, hemoperfusion, and

continuous arteriovenous hemofiltration/hemodiafiltration.


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NAPA or acecainide, has type III antiarrhythmic effects. Prolongs action potential via K+ channel

blockade. effective concentration is 10-30 μg/mL. Conc. dependent A/Es , similar to procainamide. does not appear to cause a SLS.


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BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Absorption and distribution of procainamide average oral F`(both IR and SR DFs) is 83%. lag time of 20-30 minutes occurs in some patients Plasma protein binding is only about 15%. Vd 2.7 L/kg (V = 2-3.8 L/kg)


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Elimination half-life is 3.3 hours (range: 2.5-4.6 hours) both hepatic metabolism (~50%) and renal

elimination of unchanged drug (~50%).Hepatic metabolism

by N-acetyltransferase II (NAT-II) and CYP2D6.

“slow acetylator” and “rapid acetylator” phenotypes.

Mainly via NAT-II.NAPA is 10 active metabolite.t1/2 =6 hr and Vd of 1.4 L/kg.


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Renal clearance procainamide CLR /CLcr is 2 to 3 NAPA

primarily eliminated unchanged in the urine via GF and renal tubular secretion.

When given orally, 85% of the administered dose is recovered in the urine as unchanged drug.

Implies that net renal tubular secretion is taking place in the kidney. Probably in PCT.


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EFFECTS OF DISEASE STATES AND CONDITIONS ON THE PK AND DOSING OF PROCAINAMIDE

Renal dysfunction clearance rate ↓ as Clcr ↓ But it is not as reliable parameter to aid in the

estimation of procainamide clearance. Why????

the major route of CLR for procainamide is via proximal tubular secretion


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In patients with RF, the average procainamide t1/2 is 13.9 hours and Vd is 1.7 L/kg

NAPA t1/2 ↑ to 41 hours on the average NAPA/Procainamide Css exceeds 1. Reason:-NAPA elimination is much more

dependent on renal function.

Thus, in patients with RF, NAPA may be the predominant antiarrhythmic agent present in the serum.


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Uncompensated heart failure Reduces both procainamide CL and Vd (V = 1.6 L/kg) Proca. t1/2 equal to 5.5 hours (t1/2 = [0.693• ↓V]/↓Cl). the effect on procainamide pharmacokinetics is

highly variable and difficult to accurately predict. ↓ initial procainamide doses by 25%-50%.


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Liver cirrhosis or hepatitis have not been adequately studied But recommended to ↓ the initial doses by applying

the Child-Pugh classification system normal liver function is 5 15 is grossly abnormal ≥8 is grounds for a ↓ of 25% in the initial daily drug

dose while a score >10 suggests a ↓ of 50%.


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Test/Symptom Score 1 Point Score 2 Points

Score 3 Points

Total bilirubin (mg/dL)

<2.0 2.0-3.0 >3.0

Serum albumin (g/dL)

>3.5 2.8-3.5 <2.8

PT (seconds prolonged overcontrol)

<4 4-6 >6

Ascites Absent Slight ModerateHE None Moderate Severe

TABLE 8-4Child-Pugh Scores for Patients With Liver Disease


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Obesity 30% above the IBW. Studies investigating the impact of obesity on

PK of procainamide shows best correlation of, Vd-IBW and, CL-TBW(0.52 L/h/kg TBW for normal renal

function)


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DRUG INTERACTIONS Cimetidine, trimethoprim, ofloxacin, levofloxacin,

and ciprofloxacin-compete for tubular secretion. procainamide CLR ↓ses by 30%-50% and NAPA renal clearance ↓ses by 10%-30%.

Amiodarone ↑ses the Css of procainamide and NAPA by 57% and 32%, respectively.


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INITIAL DOSAGE DETERMINATION METHODS

Goal: to compute the best dose possible dose.

Several methods to initiate procainamide therapy are available.

Pharmacokinetic Dosing MethodLiterature-based recommended dosing


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Pharmacokinetic Dosing Method most flexible of the techniques. allows individualized target serum

concentrations each pharmacokinetic parameter can be

customized to reflect specific disease states and conditions


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Half-Life and Elimination Rate Constant Estimate

procainamide half-life moderate HF (NYHA CHF class III), 5.5 hours, renal failure, 3.9 hours. adjusted t1/2 (hrs)= CrCl is adjusted for body SA (ml/min/1.73m2).


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multiple concurrent disease states or conditions.disease state or condition with the longest t1/2 should be used to compute doses.

avoid accidental over dosage as much as currently possible.

k = 0.693/t1/2


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Volume of Distribution Estimate

chosen according to the disease states and conditions

help to compute procainamide clearance 1.7 L/kg for RF, 1.6 L/kg for uncompensated HF and 2.7 L/kg for all other patients.

for obese patients, IBW is used to compute Vd.

E.g., for a non obese 80-kg patient without HF or liver disease, procainamide Vd is 2.7L/Kg* 80 kg = 216 L


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Selection of Appropriate Pharmacokinetic Model and Equations

some reports that procainamide follows nonlinear pharmacokinetics, for the purposes of clinical drug dosing in patients, linear pharmacokinetic concepts and equations can be effectively used to compute doses and estimate serum concentrations.


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Oral administration of procainamide follows a one-compartment pharmacokinetic model or clearance in L/h is computed: For example, what is the estimated clearance of

procainamide for a patient with an estimated KE of 0.210 h−1 and an estimated Vd equal to 189 L:

Cl = 0.210 h−1 • 189 L =39.7 L/h= 39.7 L/h


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When intravenous therapy is required, similar equation is widely used and allows dosage calculation for a continuous

infusion: or . Loading dose (LD in mg), Intravenous procainamide loading doses should be

infused no faster than 25-50 mg/min.


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Methods to administer procainamide LD.1) administers 100 mg q5` to a maximum of 500

mg; a 10 minute waiting period to allow drug distribution to tissues is utilized if more than 500 mg is needed to abate the arrhythmia.

2) administers the loading dose as a short-term infusion at a rate of 20 mg/min over 25-30 minutes, not to exceed a total dose of 17 mg/kg.


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Steady-State Concentration Selection therapeutic range

procainamide is 4-10 μg/ml. + NAPA “total procainamide” is 10-30 μg/mL.

but, are not equipotent anti-arrhythmics. individualized for each patient in order to

achieve optimal responses and minimal S/Es.


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USE OF PROCAINAMIDE AND NAPA SERUM CONC. TO ALTER DOSES

Because procainamide follows linear, dose-proportional pharmacokinetics in most patients, serum Css (procainamide and NAPA) change in proportion to dose according to the following equation:

Css, new = (Dnew/Dold)Css, old


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Example 1 LK is a 50-year-old, 75-kg (height = 5 ft 10 in) male with VT who requires therapy with oral procainamide SR tablets. He has normal liver and cardiac function. Suggest an initial oral procainamide dosage regimen designed to achieve a steady-state procainamide concentration equal to 4 μg/mL.


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a) Estimate t1/2 and KE according to disease states and

conditions present in the patient.t1/2 is 3.3 hours. So,

KE = 0.693/t1/2 = 0.693/3.3 h =0.210 h−1.

b) Estimate the Vd and CL

V = 2.7 L/kg • 75 kg = 203 L. Cl = kV = 0.210 h−1 • 203 L = 42.6 L/h.

c) Compute dosage regimen


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Oral SR procainamide tablets will be prescribed to this patient (F = 0.83). Because the patient has a rapid procainamide CL and short t1/2 , the initial dosage interval (τ) will be set to 6 hours. The dosage equation for oral procainamide is: 𝐷=( ∗ ∗ )/ = (4 mg/L • 42.6 L/h • 6 𝐶𝑠𝑠 𝐶𝐿 𝜏 𝐹

h)/0.83 = 1231 mg, rounded to 1250 mg every 6 hours.


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Literature-Based Recommended Dosing

very commonly used method Doses are based on those that commonly produce

Css in the lower end of the therapeutic range. procainamide Css expected from the lower end of

the dosage range is 4-6 μg/mL and 6-10 μg/mL for the upper end of the dosage range. Seetable on next sld.


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Half-Life and Elimination Rate Constant Estimate

Disease state/Condition Procainamide,

oral tablets Procainamide

Continuous Intravenous Infusion

Adult, normal RF (clcr >50 mL/min)

50 mg/kg/d 2-6 mg/min

Adult, renal dysfunction

Clcr=10-50 mL/min: 25-50% ↓<10 mL/min: 50%-75% ↓

Clcr=10-50 mL/min: 25-50% ↓<10 mL/min: 50%-75% ↓

Adult, uncompensated HF

CHF NYHA class II: 25% dosage ↓, class III or IV: 50% dosage ↓

CHF NYHA class II: 25% dosage ↓, class III or IV: 50% dosage ↓

Adult, liver disease Child/Pugh score = 8-10: 25% dosage ↓>10: 50% dosage ↓

Child/Pugh score = 8-10: 25% dosage ↓>10: 50% dosage ↓

Adult, obese Base dose on TBW according to other disease states/conditions

Base dose on TBW according to other disease states/conditions


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Pediatric doses

similar to those given to adults when adjusted for differences in body weight.

The recommended I.V LD is 2-6 mg/kg over 5 minutes (maximum dose 100 mg), repeating as necessary every 5-10 minutes to a maximum dose of 15 mg/kg (no > 500 mg should be given within a 30`).


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For patients with VT and poor perfusion 15 mg/kg infused over 30-60 minutes as a

single dose can be considered if cardio version is ineffective.

I.V maintenance infusion rates equal 20-80 μg/kg/min (max. dose 2 g/d).

Oral maintenance doses are 15-50 mg/kg/d.


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The dosage interval chosen should be appropriate for dosage form administered to the patient.

For the example given on slide no. 34.procainamide maintenance dose of 50 mg/kg/d is suggested. The suggested initial dose would be 3750 mg/d (50 mg/kg/d • 75 kg = 3750 mg/d), rounded to 4000 mg/d or 1000 mg every 6 hours.


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IV TO PO CONVERSION OF PROCAINAMIDE DOSE

Assuming that equal procainamide serum Css are desired,

Intravenous [] and oral [] corrected for procainamide salt form are

prescribed: or Dpo is equivalent oral dose in mg,


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1) Bauer, Larry A.. "Chapter 8. Procainamide/N-Acetyl Procainamide." Applied Clinical Pharmacokinetics, 2e. Ed. Larry A. Bauer. New York, NY: McGraw-Hill, 2008,http://accesspharmacy.mhmedical.com/content.

2) Lange RA, Hillis LD. Cardiovascular testing. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy. New York, NY: McGraw-Hill; 2011:55–81.


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Thanks!!!!!!

clinical pharmacokinetics of procainamide

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