Cardiac effects of different tricyclic antidepressant drugs

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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

effects and toxicity of tricyclic antidepressants. BOSTONCou@noita@rivn DRUG SURV 1@ANCE PROGRAMME. Posomatic Medicine, 37, 160-79. REPORT (1972) Adverse reactions to the tricycic antidepressant drugs. Lancet, i, 529-31. Mont, D. C., CRooKS, J., CORNwELI.., W. B., O'MALLEY, M., DINGWALL-FORDYcE, I., TUItNnuu., M. J. & Bujuwws, G. D., DAViES,B. & Scoooins, B. A. (1972) WEnt, R. D. (1972) Cardiotoxicity of amitriptyline. Plasma concentrations of nortriptyline and clinical Lancet, U, 561—4. response in depressiveillness.Lancet,ii, 619—23. —¿

MOWBRAY,

R.

M.

&

DAvIEs,

B.

(1972)

A

Voint@,J. & BuERows,G. D. (i@7@)Cardiovascular

sequential

complications of tricyclic Drugs, 8, 432—7.

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patients.

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i, —¿

364-6.

COULL,

D.

Scorr,

C.,

Caooxs,

J.,

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I.,

A. & Wr.m, R. D. (1970) Amitriptyline

monitoring

system. Lancet, U, 590.

DuMovic, P. Effects of different heart. (In press). GRAss, L

tricyclic

drugs

Inhibiting

effect

of

neuroleptics

Drug on

metabolism of tricydlic antidepressants in man. British Medical Journal, i, 463-5.

SLoMAN,

J.

G.

(i975)

Assessment

side effects of therapeutic drugs.

overdosage. of

cardio

doses of tricyclic

Australia

and

Xew

Zealand

Journal of Medicine, 5,7-11. —¿

Hwrr,

D.,

Busutows,

G.

D.

&

Sw@tar@i,

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on the

F. & FREDRICS0N OVERO, K. (1972)

interaction.

&

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cardiac disease. Risk of sudden death identified by

—¿

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—¿

Buanows,

G.

D.,

HuN'r,

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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)