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Journal

Does Loperamide Have a Role To


Induce Torsades de Pointes?
dr. Willis Kwandou
Supervisor : dr. Bambang Budiono Sp. JP (K) FIHA
FSCAI FAPSIC

Etiology

Etiology

DEFINITION

o Torsade de pointes is a french language that


means twisting of the point
described by
dessertenne in 1966
o Torsade de pointes is an uncommon and
distinctive form of polymorphic ventricular
tachycardia (VT) characterized by a gradual
change in the amplitude and twisting of the

DEFINITION
o Torsade de pointes, often referred to as torsade,
is associated with a prolonged QT interval,
which may be congenital or acquired. Torsade
usually terminates spontaneously but frequently
recurs and may degenerate into ventricular
fibrillation.

Normal QTc Interval - Criteria

QTc (msec)
Normal
Borderline
Prolonged

Male
<430
431-450
>450

Female
<450
451-470
>470

QT Correction Formulae
Formula

Mathematical
Expression for QTc

Original Cohort
Mean Age
(Range) (years)
N

Log-Linear
Bazett

QT / (RR)

0.5

39

26 (<14-53)

Fridericia

QT / (RR)

0.33

50

26 (2-81)

Baseline correction

QT / (RR)

0.37

NA

NA

Linear
Framingham

QT + 0.154 (1 RR)

5,018

44 (28-62)

Hodges

QT + 1.75 (HR 60)

607

(20s-80s)

Bazzet Formula QTc

Patophysiology

o A prolonged QT reflects prolonged myocyte


repolarisation due to ion channel malfunction.
o This prolonged repolarisation period also gives
rise to early after-depolarisations (EADs).
o TdP is initiated when a PVC occurs during the
preceeding T wave, known as R on T

Torsades De Pointes

Prolonged
QT

Short Run of Polymorphic VT

QTc Using Bazzet Formula = 0.53 sec

PVC R on T initiated TdP

Clinical Presentation
o Patients with torsade usually present with
recurrent episodes of palpitations, dizziness, and
syncope; however, sudden cardiac death can
occur with the first episode. Nausea, cold sweats,
shortness of breath, and chest pain also may
occur but are nonspecific and can be produced
by any form of tachyarrhythmia.

Etiology
o Congenital Prolonged QT
o Acquired Prolonged QT :
o Electrolyte Abnormalities : Hipokalemia,
Hipomagnesemia,
o Anty Arythmic Drugs : Quinidine, Procainamide,
Amiodarone, Sotalol
o Antibiotics : Eryhtromicin, Azythromicin, Levofloxacin,
Cotrimoxazole
o Antifungal : Ketoconazole, Itraconazole
o Anti Psychotic : Haloperidol, phenothiazines,
thioridazine
o Anticonvulsants : phenytoin, carbamazepine
(possible)
o Tricyclic and tetracyclic antidepressants

In This Case, Does Loperamide Really


Induce Torsades de Pointes?? Or
anyelse factor who contribute into
this arrhythmia??

We calculated all condition who can


contribute into Torsades de Pointes
include :
Loperamide given to the patient
Hipomagnesemia or Hipocalcemia
in this patient ??
Underlying Coronary Artery Disease

Patient Were Taking Loperamide 8mg


/ day for 2 days before TdP
Unfortunately, We Cant Check
Magnesium and Calcium Serum of
this patient
Patient Have CAD with history PTCA
13 years ago

Loperamide

o Loperamide is an opioid-receptor agonist and


acts on the -opioid receptors in the myenteric
plexus of the large intestine. Loperamide works
similarly to morphine, decreasing the activity of
the myenteric plexus, which decreases the tone
of the longitudinal and circular smooth muscles
of the intestinal wall

Use of Loperamide

o Loperamide is effective for the treatment of a


number of types of diarrhea.[This includes control
of acute nonspecific diarrhea, mild traveler's
diarrhea, irritable bowel syndrome, chronic
diarrhea due to bowel resection, and chronic
diarrhea secondary to inflammatory bowel
disease. It is also useful for reducing ileostomy
output

Mechanism of Loperamide
o Loperamide binds to the opiate receptor in gut
wall,
reducing
propulsive
peristalsis
and
increasing intenstinal transit time
o Half Life Loperamide 9-14 hours, well absorbed
from the gut but almost completely extracted
and metabolized by liver and excreted to bile
ducts
o Due to its high affinity fot gut wall and its high
first pass metabolism, very little loperamide
reachs the systemic circulation

How Loperamide affect QT


Interval
o The mechanism of QTc prolongation due to
loperamide is unknown.
o However, QTc prolongation related to other
synthetic opioids has been recognized to be due
to blockade of the cardiac human ether-a-go-go
(hERG) potassium channel. It is possible
loperamide blocks hERG, though this has not
been completely investigated.
o Using with cimetidine, will increase the chance of
side effect of overdosing loperamide.

Etiology

Discussion
So What was the cause of Torsades de
Pointes in this patient??
Does 8mg/day loperamide can contribute in
this arrhythmia ??
Or Possible Hipomagnesemia / Hipocalcemia
is the reason of this arrhythmia due to his
diarrhea??
Or Possible Drug Interaction from
Loperamide and Amiodarone who contribute
to this TdP??
Or Possible Underlying CAD is the cause?

Loperamide
Loperamide is a derivative of
phenylpiperidine with a chemical
structure similar to the opiate
receptor agonist
Loperamide is a substrate for Pglycoprotein transporter
membranes in the blood and a
highly lipophilic

Pharmacodynamic
Loperamide is an opioid receptor
agonist and act on the -opioid
receptors in the myenteric plexus large
intestines.
On low doses, it does not affect the CNS
like other opioids
It work by decreasing the activity of the
myenteric plexus which decreased
motility smooth muscles

This increased the amount of time


substances stay in the intestine,
allowing for more water absorbed out
of the fecal matter.
Loperamid also decreased colonic mass
movement and suppresses the
gastrocolic reflex
Loperamide reduces the secretion of
water from the intestines and
elektrolite stimulated with PGE2

Pharmacokinetic
loperamide metabolized by
cytochrome P450 (CYP) system and a
substrate for CYP3A4 isoenzyme.
Onset of action : 1 hour, maximum effect
16-24 hours
time to peak plasma concentration of 2
hour
plasma half-life: 11 hours
duration: up to 3 days half-life of 7-14
hours, bioavailability <2%

ADME (Absorption, Distribution,


Metabolism, Excretion)

Absorption
following oral dosing, loperamide is
absorbed rapidly with plasma
concentrations in 4 hours
metabolism first to loperamide has
biovabilitas only 0.3%

Distribution,metabo
lism, and excretion
Distribution: loperamide is a substrate that
penetrates the P-glycoprotein that is in the
blood brain barrier and the wall of the
gastrointestinal tract
Metabolism: Loperamide extensively
metabolism in the liver by N-desmethyl
loperamide which is the main metabolic
not yet active through N-demethylation
excretion: loperamide mainly excreted
through the feces but drugs or metabolism
has not changed

Dose
The recommended initial dose is 4mg
(two capsules) followed by 2 mg (one
capsule) after each unformed stool.
Daily dose should not exceed 16mg
(eight capsules).

Loperamide unique opioid in that it usually only demonstrates peripheral


activity, slowing gastrointestinal motility w/o the central nervous system
(CNS) effects seen w/ other opiates.
It has a very low bioavailability: reportedly 0.3%. Therefore, when a patient
takes a 2-mg dose, only 0.006 mg of loperamide reaches systemic
circulation.
Loperamide is metabolized primarily by CYP3A4, w/ some contribution from
CYP2C8. The reported plasma concentrations following usual doses of
loperamide range from 0.2 to 1.2 ng/mL. CNS exposure to loperamide is
further limited by P-glycoprotein (P-gp) efflux at the blood-brain barrier.

Patients self-treating diarrhea & loperamide abusers report taking daily


doses of 25 to more than 200 mg. At these doses, the plasma
loperamide concentration can exceed 100 ng/mL.
In addition to decreasing gut motility, these large doses can cause
sedation,

urinary

retention,

respiratory

depression,

cardiac

arrhythmias & death.


At supratherapeutic plasma concentrations, loperamide prolongs the
QRS complex & slows repolarization of the ventricle. This can lead
to ventricular arrhythmias, which can be fatal.

Drug interaction data on loperamide are rather limited.


CYP3A4 & CYP2C8 inhibitors have been reported to increase the plasma concentration of
loperamide by about 2- & 4-fold, respectively, and by over 12-fold when both enzymes
are inhibited concurrently.
Inhibitors of P-gp also increase the plasma concentration of loperamide (2- to 3-fold) and
may increase the loperamide CNS concentration by reducing the effectiveness of the
blood-brain barrier (P-gp mediated) efflux.
Amiodarone & lapatinib have been reported to inhibit the activity of CYP2C8, CYP3A4 &
P-gp. Due to the potential for serious adverse outcomes, it would be prudent to avoid the
use of loperamide in patients taking amiodarone or lapatinib, or combinations of drugs
that inhibit multiple loperamide elimination pathways.

Summary
Patient male 72 years old with
palpitation and diagnosed atrial
fibrillation with hipovolemic shock
due to acute gastroenteritis and
treated with loperamide and
digoxin
At 3rd day patient developed
decrease of conciusness with ecg :
Multiple VES leading to VT with

Summary
VT and Torsade de Pointes treated
with amiodarone IV
After that ECG become junctional
bradycardia with CRBBB
Next day ECG become Sinus
Bradycardia

Conclusion
We Cant Exclude cause of Torsade
de Pointes between Loperamide
and Acute Coronary Syndrome
Loperamide may contribute in to
this arryhtmia, but we cant also
exclude acute coronary syndrome
because the history and risk factor

Planning

We Want to do Coronary Angiography

Thank You