Presented by: Rabab Abdullah
I.D
:9860352
Supervised by: DR. Rafiq Abou Shabaan
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Contents
 Chemical structure
 Brand name
 Introduction
Dosage
Drug-Disease Contra- indication
Adverse Effect
Warning
Overdose
Drug-Drug interaction
 Pharmacokinetic
Absorption
Distribution
Elimination
Toxic and therapeutic Plasma concentration
Bioavailability
Volume of distribution
Clearance
Half-Life
Key parameter
 N-acetylprocainamide:
 Time of sample
 Cases
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PROCAINAMIDE HCL
Chemical structure:-
COMMON BRAND NAME (S): Pronestyl-SR
Introduction: Procainamide is used to treat ventricular arryhthmias,
supraventricular arryhthmias and Malignant hyperthermia, and is
administered orally, I.M, I.V. The short plasma half of
procainamide dictates the use of three to four –hour dosing
intervals unless sustained –release drug products are used. long –
term administration has been associated with immunologic
reactions.
Dosage:
Dosage of procainamide must be carefully adjusted according to
individual requirements and response, age, renal function, and
the general condition and cardiovascular status of the patient.
Dosage should be reduced in patients with renal insufficiency
and/or congestive heart failure.
A loading dose of 1000mg(15mg/kg) is generally followed by a
mainteanace dose of 250to500mg every three to four hours
Malignant HyperthermiaVarious dosages of procainamide
hydrochloride have been given in the treatment of malignant
hypertheThe IV dosage has ranged from 200—900 mg and has
generally been followed by a maintenance infusion.
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Dosage:
Disease
Ventricular
Arrhythmias.
Parentral
Adult: I.M: 50 mg/kg every
3—6 hours
During surgery : 100-500 mg
IV: 100 mg every 5
minutes
Maintenance IV infusion : 2-6
mg/minute
children: IV dose of of 15
mg/kg
over 30—60 minutes
maintenance IV infusion of
0.02—0.08 mg/kg per minute
I.M: 20—30 mg/kg
daily
Every 4—6 hour
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Oral
Adult : 50 mg/kg daily
every 3 hours
Children: tablets or
capsules of 15—50
mg/kg in 3—6 divided
doses.
Disease contra-indication:
The most significant diseaes are:



COMPLETE ATRIOVENTRICULAR BLOCK
HX OF LUPUS ERYTHEMATOSUS
TORSADES DE POINTs
The significant diseaes are:





AV BLOCK
BUNDLE BRANCH BLOCK
CONGESTIVE HEART FAILURE
DIGITALIS TOXICITY
MYASTHENIA GRAVIS
Procainamide lead to increase
muscle weakness
 RENAL FUNCTION IMPAIRMENT
The possible significant diseases are:
BRONCHIAL ASTHMA, HEPATIC FUNCTION
IMPAIRMENT
Adverse Effects
appetite loss ,diarrhea ,itching , skin rash , systemic lupus ,
dizziness lightheadedness , agranulocytosis/neutropenia (Fatal)
confusion, drug induced depression , hallucinations , leukopenia
and thrombocytopenia.
WARNING:
Prolonged procainamide use may result in testing positive (ANA
test) for a serious skin problem (lupus erythematosus-like
syndrome).
. Procainamide must be used only in cases of life-threatening
heart arrhythmias.
OVERDOSE:
. Symptoms of overdose include weakness, fatigue,dizziness, fast
heartbeat, confusion, and decreased urination.: If you miss a
dose, take it as soon as remembered; do not take it if it is near the
time for the next dose, instead, skip the missed dose and resume
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your usual dosing schedule. Do not "double-up" the dose to catch
up.
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Drug - Drug interaction:
Type of drug
H2-Receptor Antagonists
(cimitidine)
Cardiovascular Drugs
Anticholinesterase and
Anticholinergic Agents
The action
Cimitidine will lead to increase in
plasma concentration of
procainamide (decrease Clrenal)
Procainamide may reduce blood
pressure
Procainamide and amiodarone will
increase the plasma concentration
procainamide and NAPAtoxic
effect
Amiodarone will decrease clrenal
of procainamide/or it inhibit
hepatic metabolism
Use with caution.
(neostigmine and
pyridostigmine )
Neuromuscular Blocking Agents Procainamide may potentiate
(succinylcholine chloride, and
the effects of both
tubocurarine chloride etc)
nondepolarizing and
depolarizing skeletal muscle
relaxants
Other drugs
Procainamide and trimethoprim
may increase plasma
concentration of procainamide
and NAPA
Alcoholreduce t1/2
Pharmacokinetic
Absorption:
Approximately 75—95% of a dose of procainamide
hydrochloride is usually absorbed from the intestine, but a few
patients may absorb less than 50% of an oral dose. Oral
absorption of procainamide is slowed by delayed gastric
emptying, decreased intestinal motility, presence of food in the
GI tract, decreases in intestinal pH, or decreased sphlanchnic
blood flow. Extended-release tablets containing procainamide
are formulated to provide a sustained and relatively constant
rate of release and absorption of the drug throughout the small
intestine.
 Plasma procainamide concentrations of approximately
4—8 µg/mL are required to suppress ventricular
arrhythmias. Toxicity is usually associated with plasma
procainamide concentrations greater than 12 µg/mL.
 Absorption of procainamide after IM administration is
rapid, and the drug appears in the plasma in 2 minutes.
Peak plasma procainamide concentrations after IM
administration of the drug average 30% higher than after
oral administration of the same dose
 If renal excretion of procainamide is prolonged and
conversion to NAPA is rapid, plasma concentrations of
 NAPA exceed procainamide concentrations at steadystate.
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Distribution:
 Procainamide is rapidly distributed into the CSF, liver,
spleen, kidneys, lungs, muscles, brain, and heart.
 The apparent volume of distribution of the drug at steady
state is approximately 2 L/kg.
 The apparent volume of distribution of procainamide is
decrease in patients with heart failure.
 14—23% of the drug is bound to plasma proteins at
therapeutic plasma concentration.
Procainamide and NAPA are distributed into milk and can be
absorbed by a nursing infant.
 Procainamide does cross the placenta, but the extent to
which it does so has not been well characterized .
Elimination:
 After IV administration, procainamide has an initial halflife of 4—5 minutes and a terminal half-life of 2.5—4.7
hours in individuals with normal renal function.
 The elimination half-life of procainamide may be
increased in patients with renal impairment and in geriatric
patients.
 In general, dosage should be titrated carefully in geriatric
patients, usually initiating therapy at the low end of the
dosage range.
 The total amount of unchanged procainamide excreted in
urine varies from 40—70% of a dose due to differences in
acetylator phenotype and in renal excretion.
 Procainamide and NAPA are excreted by active tubular
secretion and glomerular filtration.
 The rate of renal excretion of procainamide and NAPA is
not affected by changes in urine pH nor by acetylator
phenotype.
 Rapid and slow acetylators excrete approximately the
same
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amount of procainamide as unchanged drug .
Therapeutic and toxic Plasma concentration:
 Procainamide plasma concentration of 4-8mg/L are
usually considered therapeutic.Minor toxicities such as
G.I.T disturbances ,weakness , mild hypotension ,and
changes in the electrocardiogram usually don’t occur at
plasma concentration <8mg/L.
 Toxicities may develop in as many 30% of patients when
plasma concentration exceed 12 to 13mg/L.
 Bioavailability:
 The bioavailability of orally administered
procainamide is approximately85%(F=0.85)
 Absorption is usually rapid ,and plasma concentration
peak one to two hours after administration .
 Absorption can very slow and possibly incomplete in
patients with congestive heart failure.
The sustained – release Procainamide products appear to be
completely absorbed over 3-4 hours so it will limits the dose
interval for the sustained – release drugs for about 6 hours.
 Volume of distribution:
 The of distributon of procainamide is~2L/kg .
 The volume is unchanged by renal failure , but by about
25%in patients with decreased cardiac output .
 In obese patients ,the volume of distribution appears to
correlate best with ideal body weight (IBW).
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 Clearance
The clearance of procainamide in an average 70kg patient
with reasonably good renal function is~550mg.clearance of
procainamide can be broken into Cllrenal which is
approximately three times clcr and also there is clother which is
not renal or creatinine clearance .The clearance of
procainamide in obese is increase with IBW(Ideal body
weight).
Half –life (t1/2):
 The apparent volume of distribution t 1/2 (α t 1/2) is
about 5min ,In another hand the Elimination t1/2(β t 1/2) is
a function of it’s volume of distribution and clearance.
The elimination t1/2 is approximately 3hrs calculated by this
equation:
T1/2 = (0.693)(vd) = (0.693)(140L) =3hrs
Cpss ave
33L/hr
So frequent dosing will be unless a continous I.V
infusion or a sustained –release oral product is produced.
 The dosing interval chosen for the sustained release drug
product ,is calculated by this equation :
 Cpss2=(S)(F)(dose/tin)(1-e-kdt) (e-kdt)
1-e-kdt *cl
cpss ave= (S)(F)(dose/τ)
cl
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Key parameter
Therapeutic Plasma concentration
F
S
Vd
CL
Clrenal
4-8mg/L
0.85
0.87
2L/kg
Clacetylation (average)
Fast
Slow
T1/2
0.13L/kg/hr
0.19L/kg/hr
0.07L/kg/hr
Α
5min
3hr
0.87
ß
S(HCLsalt)
[3][clcr]
N.B:
 Volume of distribution decrease by 25% in patients
with low cardiac output.
 Clearance decreases by 25% to50% in patients with low
cardiac output.
 Units of clcr must be appropriate when clrenal is added
to clacetylation and other (i.eL/hr or L/kg /hr)
 T1/2 increases in patients with renal and/ or cardiac
dysfunction.
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N – acetylprocainamide (NAPA):
The therapeutic plasma concentration:
NAPA’s activity is similar to that of procainamide when equal
plasma concentration are compared , however , other have found
that approximately 10 to 20 mg/L are required for partial
suppression of ventricular concentration .
Plasma concentration of NAPA of approximately equal to
procainamide in many patients.
Animal studies have been suggest that NAPA may be less toxic
than Procainamide NAPA may resulted in serious cardiac
toxicity in isolated individual when NAPA level exceeded 30
mg/L .In addition , systemic lupus erythematous (SLE) may less
likely to be associated with NAPA than with procainamide.
NAPA production : The rate of NAPA production depends on
the plasma concentration and it’s clearance by acetylation , which
is genetically determined .About 50% of Black and Causians are
rapid acetylators , and approximately 80% to 90% of Asians are
rapid acetylators . Rapid acetylators convert ~30% of an
administered dose of Procainamide to NAPA, while slow
acetylators convert ~15%. This based upon the acetylation
clearance .The percentage conversion increases in patients
suffering from renal failure because a greater percentage of
procainamide is cleared by the acetylation pathway .
Volume of distribution: vd for NAPA is about 1.5L/kg
Clearance (Cl): Clrenal ~1.6 times of Clcreatinine and a metabolic
clearance that is ~.0.25l/hr/kg
Half –life(t1/2): about 6hrs
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Time of sample:
Since Procainamide has short half – life (three hours) steadystate concentrations are achieved within 12 to 24 hours after
therapy has begun . Although steady state is achieved quickly ,
the sampling time must be selected carefully within the dosing
interval When standard dosage forms of Procainamide are
administered on regular , intermittent basis, trough plasma
concentrations are probably more reproducible than the peak
concentrations.The half life of NAPA is twice as long as that for
Procainamide and steady –state will not be achieved for at least
24hours with patients with good renal function ; as long as one
week may be required for patients with decreased renal function
CASE #1:
A.L , 62 years – old , 70 kg male, was admitted to the
coronary care unit with a diagnosis of acute
myocardial infarction .A.L has a history of mild
chronic renal failure ,
serum creatinine of 1.3 mg/dL , and a creatinine
clearance of ~50 ml / min . A.L developed premature
ventricular contractions ( PVCs) which were
unresponsive to Lidocaine .Calculate a parenteral
loading dose of procainamide designed to active a
plasma of ~ 8 mg /L.
ANS:
Loading dose = (vd)(Cp)
(s)(F)
=(140L)(8mg/L)
(0.87)(1)
=1287mg~1300mg
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If the patient suffers from CHF,the volume of distribution
and the Loading would have beeen dereased by about
25%.
CASE # 2:
If the loading dose of 1300 mg is to be given I.V , how
should it be administered ?
ANS:
Since Procainamide is administered into initial volume of
distribution and the myocardium responds as though it
were located in this initial volume, it should be given in
divided dose ,because if the entire loading dose is given
as a single bolus the initial plasma concentration will
exceed the desired 8mg/L and toxicity may occur. In this
case , 300 mg to 400 mg could be administered initially as
a slow infusion, followed by doses of 150 mg/5min.
(Every 5 minutes to avoid the accumulation of the drug)
CASE #3:
Calculate an infusion rate in mg/min that will maintain
an average plasma Procainamide concentration of
6mg/L for A.L ,the patient described in question #1.
ANS:
Determine clearance : Clrenal = (3)(cl)
= (3)(3L/hr)
= 9L/hr
Clacetylation = (0.13L/kg/hr) (70kg)
= 9.1L/hr
Clother = (0.1L/kg/hr)(70kg)
=7L/hr
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Cltotal=
Clrenal + Clacetylation + Clother
= 9L/hr
+9.1L/hr +7L/hr = 25.1L/hr
calculate a maintenace dose
= (CL)(Cpss ave)( τ)
(S)(F)
=(25.1L/hr)(6mg/hr)(1hr)
(0.87)(1)
= 172mg
This infusion rate of 172mg/hr is~2.9mg/min and
within the guidline of Procainamide infusion (1-3
mg/min).
CASE # 4 :
plasma A.B., a70 kg male with a clcr , of 30 mL /min,
has been receviving a constant procainamide infusion
of 100 mg/hr. This infusion rate has resulted in a
steadly –state procainamide concentration of 5 mg/L .
Calculate an oral dosing regimen that will maintain
his plasma procainamide concentration between 4and 8
mg/L
ANS:
CL = (s) (F) (dose/ τ )
Cpss ave
= (0.87)(1)(100mg/hr)
5mg/L
= 17.4 L/hr
To calculate A.B half – life:
t 1/2 = (0.693)(Vd)
CL
= (0.693)(Vd)
17.4L/hr
16
= 5.6 hr
A dosing interval of four to six hours should be used
Maintenance oral dose = (cl)(Cpss ave)( τ)
(S) (F)
= (17.4 L hr)(6mg L) (4hr)
=565 mg Q 4
Procainamide is available in 250,375and 500mg
therefore ,a dose of 500mg every 4 hours
To calculate the peak and trough concentrations :
Cpss max
Kd = 0.693
T1/2
= 0.693
5.6
=0.124hr
= (S)(F)(Dose)
Vd(1- e-kdt)
=(0.87)((0.85)(500mg)
(140L)(1 – e-(0.124hr-1)(4hr)
= 2.64mg/L
1 – 0.61
=2.64mg/L
0.39
=6.8 mg/L
(Cpss min) = Cpss max(e-kdt)
=6.8mg/L(e-(0.124hr-1)(4hr)
=4.1mg/hr
if the sustained release Procainamide is used ,first the
daily determine dose of the infusion:
Amount of Drug Absorbed = (S)(F)(Dose)
= (0.87)(1)(100mg/hr) (24hr/day)
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=2088mg/day
CASE #5:
Using A.B’s pharmacokinetic parameters , calculate the
expected peak and trough concentrations from a sustained –
release procainamide product when dosed 1000mg Q 8hr
ANS:
Cpss ave = (S)(F)(Dose/)
Cl
=
(0.87)(0.85)(1000mg/8hr)
17.4L/hr
=92mg/hr
17.4L/hr
= 5.3mg/hr
An alternative Equation can be used:
Cpss 2
= (S)(F)(Dose/tin)(1 – e –kdtin)
(1 – e-kd) Cl
(e-kdt2)
=(0.87)(0.85)(1000mg/4hr)(1 – e-(0.124hr(4hr) ) [e-(0.124)(4)]
17.4L/hr
(1 – e-(0.124hr)(8hr)
= (10.6mg/hr)(1 –0.61)
(1 –0.37)
=6.6mg/L
Cpss2 = [6.6mg/hr][e-kdt2]
= (6.6mg/L)(e-(0.124hr-1(4)
= 4.0 mg /L
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CASE #6:
A.B, the patient described in CASE #5, has steady – state
procainamide concentration of 5mg/L.Estimate his plasma
NAPA concentration.
ANS:
Rate of conversion to NAPA
= [Cpss ave(procainamide)] [Clacetylation]
= (5mg/L)(13.3L/hr)
=66.5mg/hr
NAPA Clrenal = (1.6)(Clcr /hr)
NAPA Clmetabolite = (0.025L/kg/hr)(wt in kg)
NAPA Cltotal
=(1.6)(Clcr inL/hr)+ (0.025L/kg/hr) (wt –kg)
=
(1.6)(1.8L/hr) + (0.025)(70kg)
=2.88L/hr + 1.75L/hr
=4.63L/hr
Cpss ave
= (S)(F)(dose/)
Cl
=66.5mg/hr = 14.4mg/L
4.63L/hr
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CASE # 7:
I.C,a 45- year-old,100kg, 5 foot 9 inch man with a serum
creatinine of 1.5 mg /dl,has sever CHF and ventricular
arrhythmias which are to be treated with oral procainamide .
Recomand a dose of procainamide for this obese patient to an
average procainamide concentration of 5 mg/L.
ANS:
Because the patient is obese we should estimate IBW:
IBW = 50 +2.3(height in Inches>60)
=50 + 2.3
= 70.7kg
Cl cr for male =(140-Age)
(72)(SrCrss)
=(140 – 45)
(72)(1.5 mg/dl)
= 0.88 ml/kg/min
Clcr = [cl cr(ml/kg/min]60min/hr
1000 ml/L
=[0.88 ml/kg/min] 60min/hr
1000 ml/L
= 0.0528 L/kg/hr
Clrenal = (3)(Clcr)
= 15.84 L/hr
Clacetylation= (0.13L/kg/hr)(70.7kg)
= 9.19 L/hr
Cl other = (0.1L/kg/hr)(70.7kg)
=7.07 L/hr
Cl total
= Clrenal + Clother + Clacetylation
= 15.84L/hr + 9.19 L/hr = 7.07 L/hr
=32.1 L/hr
Reducing the total Clearance By 0.5 for CHF: =32.1 L/hr *0.5
= 16.05 L/h
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Vd = (1.5 L/kg)(70.7kg)
= 106 L
t1/2 = (0.693)(Vd)
Cl
=(0.693)(106L)
16 L/hr
= 4.59 hr
Maintenace Dose = (Cl)(Cpss ave)( )
(S)(F)
= (16 L/hr)(5 mg/L)(6 hr)
(0.87)(0.85)
= 694 mg (Q 6 hr )
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