Cardiac effects of different tricyclic antidepressant drugs GD Burrows, J Vohra, D Hunt, JG Sloman, BA Scoggins and B Davies The British Journal of Psychiatry 1976 129: 335-341 Access the most recent version at doi:10.1192/bjp.129.4.335
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Brit.J. Psychiat. (5976), 129, 335—4!
Cardiac Effects of Different Tricyclic Antidepressant
Drugs
By G. D. BURROWS, J. VOHRA, D. HUNT, J. G. SLOMAN, B. A. SCOGGINS and BRIAN DAVIES Summary.
The
effects
of tricydlic
antidepressants
on
the
heart
are
reviewed.
Statistically significant increases in heart rate and in atrioventricular conduction times were found following the administration of tricyclic drugs to 32 depressed patients. The method of His bundle electrocardiography was used to study atrioventricular conduction in ambulant patients and in patients admitted after
an overdose
of tricycic
antidepressant
drugs.
Distal
conduction
defects
were frequently found in patients following tricycic overdosage, but these were not seen
with
occasional
doxepin
patients
overdosage.
Impaired
on therapeutic
distal
conduction
doses of tricyclic
drugs.
was also found
Some animal
in
experi
ments giving similar results to the above clinical findings are also described. The clinical implications of these findings are discussed.
Collaborative
h@rRoDucmoN
Tricydic antidepressant pharmacological treatment
drugs are the first for most depressed
patients in general and psychiatric practice. In recent years psychiatrists have tended to use larger
@
daily
doses of these drugs
and often give
the whole daily dose at night. The diagnosis of depression is being in creasingly made in patients with ischaemic heart disease, and tricyclic drugs are widely used in helping to rehabilitate such patients. Self-poisoning
with
tricyclics
has become
an
1972,
which
Drug found
Surveillance no increase
Committee in sudden
in
deaths
among 8o patients with cardiovascular disease receiving
antidepressants.
The
Aberdeen
group
have since expanded their original findings and have found 13 sudden deaths in 119 patients with heart disease being treated with amitripty line, compared with in a matched control group. In 87 cardiac patients on imipramine there were 4 sudden deaths compared with 2 in the control group (Moir ci al, 1972). These clinical problems led us to study the
increasingly important problem in general hospitals (Vohra and Burrows, ig74). Such patients are usually admitted to intensive care units for continuous monitoring of the level of
cardiac effects of different some detail, and the aim
consciousness and Dangerous cardiac defects occasionally
A complete review of the cardiovascular effects and toxicity of tricycics has recently appeared (Jefferson, 1975). The cardiac and pharmacological effects of tricydic drugs can be summarized as follows:
and fatalities
of cardiovascular function. arrhythmias and conduction develop in these patients,
have been recorded.
In a hospital-based drug information system in Aberdeen (Coull ci al, 1970), 6 of 53 patients with cardiac disease receiving amitriptyline died
suddenly
as compared
with
none
of 53
review these investigations for psychiatrists and to discuss
the
in a similar
survey
by the
usual
their
clinical
sequential
implications.
electrocardiographic
find
ings in patients who die from overdosage of tricydics are sinus tachycardia, conduction
controls matched for age, sex and cardiac state. Sudden death did not occur in patients on imipramine. However, these findings were not confirmed
tricycic drugs in of this paper is to
defects,
supraventricular
T wave abnormalities,
tachycardia,
ventricular
ST
and
arrhythmias,
profound bradycardia and finally asystole. The pharmacological actions of tricyclic antidepres
Boston 335
CARDIAC EFFECTS OF DIFFERENT TRICYCLIC ANTIDEPRESSANT DRUGS 336 sants include an anticholinergic action which is PR interval. Nortniptyline was found to have apparent at low drug concentrations. The tn a significantly greatereffect on thePR interval cyclic drugsblockthere-uptake ofnoradrenaline than doxepin. Usually the PR interval decreases and so raise the levels of circulating catechol with increasing heart rates; tricyclic drugs amines. At higher concentrations myocardial appear to prevent this phenomenon by an contractibility and heart rate are depressed. effect on atrioventnicular conduction. Metabolic acidosis and respiratory depression, which may occur especially in unconscious Si'urw II: patients, may also affect the cardiac state. THE EFFECTS OF TRICYCLIC DRUGS ON Three separate investigations on ambulant INTRACARDIAC CoNDucnoN AS ASSESSED BY and unconscious patients will now be described. His
[email protected]@ EzlcrriwcIoGlIAP}w Our next studies looked more closely at S@nm@I: atrioventricular conduction using the method of His bundle electrocardiography (HBE). THE EFFECTS OF Tiucwcuc DRUGS ON CARDIAC FUNCTION IN DEPRESSED PAn@rs In this method an electrode catheter is put across the tricuspid valve, via the femoral vein, WITH Noiu@i@ HEARTS (Vohra et a!, 1975) while another electrode is put into the right These ambulant patients were being treated as in-patients of the University Department for atrium (Hunt and Vohra, 1973). Recordings are a primary depressive illness. A cardiologist made at ordinary heart rate and after atnial pacing with the second electrode. Informed examined each patient both clinically and with was obtained from the ambulant electrocardiography before tricycic drugs were consent patients, while relatives gave consent for the started. The drugs included nortriptyline, unconscious patients. doxepin, imipramine and amitriptyline. Dosage Fig I shows the records obtained by this was usually 150 mg/day given as 50 mg at 6 am, 2 pm and 10 pm. Plasma levels of method of study.
nortriptyline
were
assayed
by
the
method
described elsewhere(Burrowscial,1972). The cardiac function of 32 depressed patients with normal hearts was studied before and again two weeks after starting treatment with tricydic drugs (Vohra ci a!, 1975). Patients were studied in the afternoons.
SAN
The 2 pm dose was omitted
on the day of the study, and a full ECG, supine and standing blood pressure and a pulse rated exercise on a bicycle with monitoring were performed. summary,
were
continuous ECG The results, in
HBE@
as follows:
(i) Heart rate increased
H
in 26 of 32 patients
by 9@I±I4@2beats/mini. (Mean ±2 SD.) (2) PR interval increase O@0I5±O.024/sec
in all subjects
by
(3) QT interval—no change. (4) Incomplete right bundle branch block developed in3 patients in the resting ECG.
P
(@)No anrhythmiasor ventricularectopic beats occurred with exercise. There was no relationship between increased resting
heart
rate
and
increase
in PR
NormalAH 50—120 msec.
interval,
and no correlation between the plasma levels of nortniptyline and the heart rate or increase in
HY 35— 55 msec. Fio i.—Conduction
system of heart, HBE and ECG.
G. D. BURROWS,
The
J. VOHRA,
D. HUNT,
top part of the diagram
conduction
system
of the heart,
J. G. SLOMAN,
shows the
the sinus
(SAN)
and theatrioventricular (AVN) nodes,theHis bundle (HB) and the right and left bundle branches (RB and LB). The HBE is shown, together
with
the
conventional
electrocardio
1.4
measured,
overdoses
the
normal
values
and 35—55m/sec. respectively. reflects
the
time
taken
are
50—120
The AH interval
for the
impulse
to pass
through the atrioventricular node. The HV interval reflects the time taken for the impulse to travel through the His bundle, the bundle branches and the Purkinje fibres. The AH and HV intervals thus represent proximal and distal conduction respectively. The AH interval is
AND
B. DAVIES
337
with the method of HBE (Vohra et a!, 1975). The AH interval was normal in all 14 patients. The HV interval was abnormal and the QRS complex wide in 7 of the 8 patients with overdoses of nortriptyline, imipramine or amitriptyline, the mean amount taken was
gram. The AH and HV time intervals are and
B. A. SCOGGINS
grams
per patient. of doxepin
(the mean patient).
shown
The
All
had
6 patients
normal
HV
with
intervals
amount taken was i.3 graI@@/ findings
in
in Fig 2, where
the
14
the shaded
patients
area
are
shows
thenormal HV interval range. STUDY IIb:
His BUNDLE ELECTROCARDIOGRAPHY IN 12
altered by autonomic factors, heart rate and many drugs. Distal conduction is prolonged by the drugs quinidine and procainamide but is
DEPRESSED PATIENTS RECEIVING TRICYCLIC DRUGS Patients were studied on two occasions, once before being started and later while on nortripty
independent
line treatment.
rate.
of autonomic
The
effect
conduction
of
function
tricyclic
will be emphasized
or heart
drugs
on
distal
AMBULANT
resulted
In 5 of the 12 patients the drug
in a significant
prolongation
(10
in this paper.
msec
or more) of the HV interval, and there was a correlation between prolongation of the HV STUDY ha: interval and plasma levels of nortriptyline over His Bur@mr@ELECTROCARDIOGRAPHY IN 200 ng/ml. Impairment of distal intracardiac TRICYCLIC DRUG OVERDOSAGE conduction as measured by the HV interval, Fourteen patientswho had been admitted following treatment with 200 mg nortriptyline
after
tricyclic
drug
overdosage
were
studied
per
day,
is shown
in one
patient
100
81
60
H-V
msec. 40
20
a, .@.!
,
,@0
b°2/74
.q@ .@c..%c. Fio 2.—Effect of overdosage 3A
(>500
mg) of tricyclics on distal conduction.
in Fig
3.
CARDIAC EFFECTS OF DIFFERENT 338' Fig 4 shows the three separate His bundle electrocardiograms of the same depressed patient, who was studied before starting nortriptyline, after two weeks
on
TRICYCLIC
(150 mg/day).
Following
an overdose
with 2 g
the HV shows marked
STUDY III: OF THE Emci's
COMPARISON
pro
oi@ DImREN'r
CONDUCTION
A study involving a crossovertrial of nortripty line and doxepin is in progress at present. Fig 5 shows the HBE of such a patient; it can be seen that the HV interval became abnormal on nortriptyline but is normal on doxepin. As we have shown a correlation between changes in the QRS width with changes in HV high
(Vohra
speed
ci a!,
surface
1975)
we
an attempt to measure QRS width more accurately. It is hoped that this technique may avoid the need for invasive HBE.
are
using
electrocardiography
SnijnyIV: AMMAI. STumas
Thirty guinea pigs infused with one of three tricyclic drugs (imipramine (IMI), amitripty-. line (AMIT), and doxepin (DOX)) at a constant infusion rate showed statistically significant differences in their time of death (Fig 6).
The ECG abnormalities seen in these animals were very similar to those seen in tricycic overdose patients. Studies are continuing with different tricyclic agents using isolated hearts and individual heart muscle fibres (Dumovic,
TRICYCLICDRUGS ON
[email protected]
interval
in
1975). DISCUSSION
The results of these studies show that tricyclic drugs in overdosage frequently, and in thera peutic doses occasionally, prolong intracardiac conduction. It is possible that the reported increasein sudden deathsin cardiacpatients receiving
OFF DRUG )
DRUGS
150 mg/day
and finally after she was admitted to hospital following an overdosage of the same drug. Note the increase in the HV interval by 12 msec while on therapeutic doses of nortriptyline of nortriptyline longation.
ANTIDEPRESSANT
therapeutic
doses
of these
ON DRUG
( E.C.G.'2 S.c.
_
H.B.E.
@
AHV
AH,V
AHV
__
@(/\
—¿ ‘¿-I..---,
H 202 A-H -80 ms.c. H-V-48 msec. 63/Mm.
H253 A-H a 90 msec. H-V80 msec. 63/Mj@.
Fio 3.—HBE in a patient before taking and while taking 150 mg of nortriptyline/day.
drugs
could
@
—¿@4@
G. D. BURROWS,J. VOHRA, D. HUNT, J. 0. SLOMAN,B. A. SCOGG@NS AND B. DAVIES
OFF DRUG
THERAPEUTIC.
DOSE
339
OVERDOSE EC.G.
@
E.C.G.
—¿v@
0-4 Sec.
*
H.B.E.
0'4Se@
@-)
0-4Sec.
@fT@@f
AHV
@—¿â€˜-----
@
-
—¿@-@
—¿
A—H - 65 msec. H—V-40msec.
—¿@.‘-..‘-
-
H246 A—H - 95 msec. H-V - 52 moec.
H192
H236
A—H-90 msec. H—V - 90 msec. JULY ‘¿73
Fio 4.—HBEof a patient before drugs, on therapeutic dosage of nortriptyline and after an overdosage
OFF
DRUG
of nortriptyline.
NORTRIPTYLINE 1111111 liii
@
200mg
I
I .11 t
[email protected].
daily
I I II
DOXEPIN II
II
II
1111111111 II
_%@_____@
I
___
•¿â€¢4 Sac.
AH@ @
200mg daily
AHV
-@--—v,—@
II_1_1..LIi..iIIIllIlllIIIllIIIl Ill II 111111111111 111111111 lililIllIll H2$O H1$4
A-H - 75 msec. H-V .45 ms•c.
HEART
H216
A-H-
120
mssc.
HV-
$0
msc.
RATE
$5/mm.
II III I I I!
A-H- 7$ msec. WV- 50 msic.
2/74
Fio @.—HBE of patient before starting tricydlicdrugs, while taking nortriptyline and later doxepin.
CARDIAC
34°
EFFECTS
OF DIFFERENT
TRICYCLIC
ANTIDEPRESSANT
If the ECG is abnormal and shows evidence of bundle branch block, special consideration should be given before starting tricyclic drugs, since they can—though rarely—lead to a com plete heart block and cardiac syncope. In these
TIME OF DEATH 100guinea-pig infusion 1@Omg/kg/min
patients,
p(.O1
the use of doxepin
gradually
and the
seen at regular intervals.
Our results also suggest an association be tween high plasma nortriptyline levels and
mins.
impairment of distal conduction. The same may apply with amitriptyline and imipramine.
Measurement
60-
of plasma levels of tricycic
drugs
may be helpful, as it has been mentioned that nortriptyline levelsabove 200 ng/ml are asso
ciated with cardiac disturbances. Because of the variation in plasma levels produced by the same oral dose of tricycic drugs in different individuals such plasma levels may be reached, even with oral doses as low as ioo mg/day. In this respect, too, phenothiazines should be used with caution in association with tricydic drugs, since they raise tricyclic levels (Gram and Fredricson Overö, 1972). As regards prevention of overdosage, the foil
40'
20
wrapping
10
10
10
IMI
AMIT
DOX
Fio 6.—Effectsof infusions of imipramine, amitriptyline
and doxepinon time of death in guinea pigs.
symptoms,
the
benefits
of
anti
depressant response s/zozddnot be withheld, since the ricks are small. A cardiological assessment should be made, starting with a clinical history and followed by a physical examination and an ECG. Patients with heart failure and/or angina may be made because
of
the
increase
in
heart
of tablets
may
already
have
lowered
the occurrence of tricycic overdosage in children. Doctors should be cautious in pre scribing tricydlic drugs to young patients, who are more likely to take an impulsive
overdose.
In the treatment of patients admitted with
overdosage theuseofprocainamide and quini
be related to this drug-induced prolongation of distal conduction time. We believe that our studies and other reports from the literature provide enough evidence to make psychiatrists cautious in treating depressed patients with heart disease with tricydic drugs. For the moderately depressed patients with
worse
may be preferable.
Dosage should be increased patients
80-
persistent
DRUGS
rate
produced by tricydic drugs. Certainly cardiac failure should be treated before tricycic drugs are used.
dine which have similar action to tricyclic drugs in prolonging distal intracardiac conduction should be avoided. Finally these cardiovascular problems should stimulate
the pharmaceutical
industry
to pro
duce betterantidepressants—drugs that act more quiddy,withfewersubjective sideeffects and fewer cardiovascular effects both in thera peutic and over-dosage than the tricyclic and without the interactional problems
monoamine
group of the
oxidase inhibitors. AcIwowz.xDoassnN'rs
Some of the contents of this paper have been published in the Ewopean Journal of Cardiology. We are grateful to the
Editor of this journal for permission to to reproduce Figs 2, 3, 4 and 5. We are grateful to Dr Warren Gunner of Pfizer Australia for his help in providing funds for this research.
G. D. BURROWS, J. VOHRA, D. HUNT, J. G. SLOMAN, B. A. SCOGGINSAND B. DAVIES HuN'r, D. & VoISRA, J. (m97@) Clinical
REPERENCES
bundle
BICKEL, M. H. (1975) Poisoning by tricycic antidepressant drugs. International Journal of Clinical Pharmacology, ii, 145—76.
electrocardiography.
application
34! of His
Medical Journal
of
Australia, i, 373—5. JEFFERSON,
J.
W.
(‘975) A
review
of
cardiovascular
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MOWBRAY,
R.
M.
&
DAvIEs,
B.
(1972)
A
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sequential
complications of tricyclic Drugs, 8, 432—7.
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364-6.
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D.
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DuMovic, P. Effects of different heart. (In press). GRAss, L
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Inhibiting
effect
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neuroleptics
Drug on
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SLoMAN,
J.
G.
(i975)
Assessment
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overdosage. of
cardio
doses of tricyclic
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and
Xew
Zealand
Journal of Medicine, 5,7-11. —¿
Hwrr,
D.,
Busutows,
G.
D.
&
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F. & FREDRICS0N OVERO, K. (1972)
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—¿
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—¿
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conduction.
G. D. Burrows, M.D., B.&., M.A.N.Z.C.P.,M.R.C.P@ch., First Assistant, Departmentof Psychiatty, University of Melbourne, Royal Melbourne Hospital, Victoria 3050
J. Vohra, M.D., M.R.C.P.,P.R.A.C.P.,Physician,Departmentof Cardiology,Royal MelbourneHospital, Victoria 3050 D. Hunt, M.D., F.R.A.C.P., F.A.C.C., Deputy Director, Depart@nent of Cardiology,Royal Melbourne Hospital, Victoria 3050
J. G. Sloman, B.Sc.,F.R.C.P.(ECI), F.R.A.C.P.,F.A.C.C.,Director,Departmentof Cardiology, RoyalMelbourne Hospital, Victoria 3050 B. A. Scoggins, B.Sc., Ph.D., Howard Florey Institute of Experimental Physiology and Medical Research, University of Melbourne, Parkville, Victoria 3052 Brian Davies, M.D., F.R.C.P., F.R.A.C.P., F.A.N.Z.C.P., Professor of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Victoria 3050, Australia. (Received 2 October; revised 24 November 5975)