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Tricyclic antidepressant drugs and cardiac conduction
Prog.
Nemo-Pe~chophar.
Vol.
1, pp. 329-334,
1977.
Pergamon Press.
Printed
in Great
Britain.
TRICYCLIC ANTIDEPRESSANT DRUGS AND CARDIAC CONDUCTION G.D. BURROWS,* J. VOliRA,** P. DDMOVIC,* K. MAGUIRR,* B.A. SCOGGINS,t and B. DAVIES* *Department of Psychiatry, University of Melbourne, **Cardiac Department, Royal Melbourne Hospital, tlloward Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Australia (Final
form,
July
1977)
Abstract 1. Distal intracardiac conduction defects were observed in patients ingesting both toxic and therapeutic doses of tricyclic antidepressants (TCA). 2. In a crossover comparative study of doxepin-nortriptyline (150 mg/day for 3 weeks) six out of seventeen patients on nortriptyline and only one patient on doxepin showed significant prolongation of the QRS interval. 3. Plasma levels of doxepin (52 2 6 rig/ml) were lower than those of nortriptyline (196 f 29 nghl). 4. An in vitro study of TCA has shown that the isolated perfused guinea pig heart could provide a toxicological model for studying the arrhythmogenic effects of TCA in man. Keywords:
Tricyclics,
cardiac
conduction,
plasma
levels
Introduction Several clinical and experimental studies have cyclic antidepressants. In this paper, we shall effect of tricyclic antidepressants respectively and in vitro on the isolated perfused guinea pig Clinical The tricyclic Burrows, 1974).
antidepressants These effects
have complex are not always
been made on the cardiovascular action of tripresent clinical and experimental data on the in uivo on the intracardiac conduction in man, heart. Studies
actions detected
on the cardiovascular system by routine electrocardiography.
(Vohra and Eis
; Fig.
1.
His bundle electrogram (HBE) with the corresponding standard ECG. An anatomical model of the conduction system at the top of the figure is orientated to show the sites of origin of the electrical The A-H and H-V intervals represent proximal and distal waves. intracardiac conduction respectively. 129
330
/
G.D. Burrows
et al.
sensitive recording technique (Hunt and Vohra, bundle electrocardiography (Fig. 1) , an invasive 19731, demonstrated impaired distal intracardiac conduction (H-Vinterval) in seven of eight , imipramine or amipatients admitted to hospital following overdosage of either nortriptyline triptyline (Fig. 2). There was no impaired conduction in the six patients with doxepin overdosage (Vohra et at., 1975).
Fig.
2.
Effect of overdosage (< 500 mg) of tricyclic distal intracardiac conduction (H-V interval). represents normal H-V conduction time.
antidepressants The shaded
on area
In a therapeutic dose study, four of five patients who showed an increase in the H-V interval by more than 10 ms had plasma nortriptyline levels of over 200 rig/ml (Vohra et aZ., 1975). A significant correlation has been shown between changes in the QRS width with changes in the H-V interval (r = 0.82). High fidelity rapid recording surface electrocardiography, a non200 or 500 mm/s invasive technique, allows for accurate measurement of the QRS width at either (Pig. 3).
Fig.
3.
Rapid recording surface electrocardiograms showing the QRS complex at 200 mm/s (left of figure) and 500 mm/s (right of figure).
Tricyclics
and cardiac
conduction
331
In an ongoing double-blind crossover comparative study of nortriptyline and doxepin in dethis latter technique was applied. After 3 weeks on 150 mg/day of either trs pressed patients, cyclic, six out of seventeen patients on nortriptyline showed more than 25% prolongation of the QRS complex. Only one of the patients had significant prolongation while receiving doxepin (Table 1).
Table The
Patient
relationship
Age
Sex
between
QRS width
Mean QRS Width Pre-drug -Lead 320 I B 280 III 315 I1 # III 317 280 I 230 II # III 200 270 I # 226 III
1
49
F
2
50
M
3
42
F
4
58
F
5
45
M
360 406 340 I60 I60 140 178 IS2 II7
and plasma
Mean QRS Width NT
1 levels
X change QRS NT
of
doxepin
(DOX)
Mean QRS Width 00X
and nortriptyline
X change .QRS 00X
(NT)
Plast&¶ NT (nglml)
Plasma 00X (nglml)
425 518 442 385 250 280 270 336 340
+33* +a5* +40* +21 -I I +22 +35* +24 +50*
315 317 330 300 244 278 280 232 213
+2 +13 +5 -5 -13 +21 +40* -14 -6
#
500
+39*
370
+3
I # III I 11 0 III I II 0 III
428 411 193 170 155 200 221 I62
+5 +21 +21 +6 +I1 +12 +21 +38.5*
380 362 192 I61 140 190 198 143
-6 + 6.5 +20 + 0.6 0 +7 +9 +22
305
287
62
0
I96
0
153
-22
416
a0
I III
0
140 137
+4 +13
122 135
-10 +12
29
58
I
0
175
+14
165
+a
210
c30
“2 “4
0
173 148
+22 +4
I60 I33
+13 -6
325
47
127.5 132 128
+9 +10 -3
130 133 II5
+I1 +I1 -13
325
a9
130 I30
-15 -15
130 130
-15 -15
31
32
I
251
c30
la3
<30
III
30
225
42
174
<30
34
47
6
57
M
7
42
M
a
45
F
9
53
M
I96
38
F
135 I21
II
67
M
153
12
32
F
142 142
13
67
F
II7 120 132
I4
63
F
153 153
I5
42
F
158 142 142
160 147 148
+ I + 3.5 +4
155 158 145
-2 +I1 +2
140
46
I6
62
F
130 150
135 125
+4 -17
133 I25
+2 -17
248
60
+2 -2
137 128
- 3.5 +4
40
58
IO
I7
46
NT levels (mean f * 25% or more QRS 0 ECG recorded at # EC’S recorded at
F
142 123
I
z2 0 4 “6 “2 “4
0
145 120
00X levels S.E.M.) 196.1 2 28.8 nglml; prolongation considered significant. 200 m/s 500 mn/s
(mean f
S.B.Y.)
52.3
f
5.9
og/ml.
lia
and Hinsvark, and Raskind, 1976* study
et al., 1975 1976”
1976
et al., 1975 et al., l976b
et al.,
1975”
1973
1975
NT NT NT NT NT NT NT NT
MAP MAP
IMI IMI IMI IMI IMI
DOX DOX DOX
DOX
75-225 150 150 150 150 80-200 150 I50
150 150
150 150 150 3.5 mgfkg 225
75-200 150 150 150
150 150 150
AT AT
AT
tricyclic Dose (mg/day)
of
Drug Studied
levels
2.
DES = Desmethyldoxepin; GLC = Gas liquid TLC-D = Thin-layer assay.
plasma
* Pers. Comm. AT = Amitriptyline; DOX = Doxepin; MAP = Maprotiline; NT = Nortriptyline; spectrometry; Fluor = Fluorimetry; tive assay; D.1 = Double-isotope
Asberg et al., 1971 Burrows et al., 1972 Kragh-Sdrensen et al., Burrows et al., 1974 Lyle et al., 1974 Braithwaite, 1975” Burrows et al., 1977 Present study
Riess Maguire
Perel, Gram
1975” 1975
1972
Moody et al., 1967 Nagy and Treiber, 1973 Olivier-Martin et al.,
O’Brien Friedel Hobbs, Present
Braithwaite Jdrgensen, Braithwaite,
Author
Steady-state
Table
of
1.D 1.D GLC 1.D GLC GLC D.1 D.1
D.1 D.1
Fluor. TLC-D Fluor. Fluor. TLC-D
GLC GC-MS GLC GLC
GLC GLC GLC
Method analysis NT 65 NT Ill NT 67
110, 60, 129, IMI 81,
NT NT NT NT NT NT NT NT
90 I71 I41 I71 170 166 174 196
MAP 200-250 MAP 181
IMI IMI II41 Total IMI
DKI 190 DMI 68 DMI 130 + DMI 210 DMI 141
81
(rig/ml)
DOX 55, DES 27 Total DOX + DES DOX 50 DOX 52
AT 60, AT 76, AT 69.5,
Mean steady-state plasma levels
DMI = Desmethylimipramine; IMI = Imipramine; chromatography; GC-MS = Gas chromatography-mass chromatography-densitometry; 1.D = Isotope-deriva-
32 30 65 I4 IO 19 I7
29
48 8
5 7 24 29 21
I7
7 8
I5 9 22
No. patients
antidepressants
Tricyclics
and cardiac
conduction5
333
Plasma level5 of doxepin were measured by gas-liquid chromatography with protriptyline as an internal standard. Nortriptyline and maprotiline, both secondary amines, were analyeed by double-isotope derivative dilution procedures (Maguire et al., 1976a). These assays are sensitive, specific, accurate and precise. The precision at 100 rig/ml for doxepin is 8X, nortriptyline 7% and maprotiline 441, and the sensitivity is IO rig/ml for nortriptyline and maprotiline , and 30 rig/ml for doxepin. The group of patients when receiving nortriptyline had a mean plasma level of 196 f 29 rig/ml, but while on doxepin a mean plasma level of 52 f 6 rig/ml, was obtained (Table 1). The plasma levels of doxepin were therefore much lower than those of nortriptyline. This may explain the difference in the effect on intracardiac conduction between these two tricyclic compounds. This level of doxepin compare5 with the mean of 81 rig/ml reported by Friedel and Raekind (1975) and that of 55 rig/ml of O'Brien and Hinsvark (1975, Pers. comm.). Hobbs (1976, Pers. comm.) also reported that therapeutic dose5 of doxepin reach peaks of around 50 rig/ml. Plasma levels of other tricyclic antidepressants, as reported by a number of authors, show tricyclic studied, dose (mg/day), number of patients, method of analysis with mean steady-state plasma level5 level for nortriptyline at 150 s&day, apart from one study bghl) . The mean steady-state (Asberg et at., 1971) appear5 reasonably constant (Table 2). Experimental
Study
Our unit has found that the isolated perfused guinea pig heart is a good model for studying the arrhythmogenic effects of tricyclics (Dumovic et al., 1976b). A cardiograph was recorded on a conventional ECG machine at 50 mm/s. A trace was also recorded on a cathode ray oscilloscope at 450 mm/s. Tricyclic drugs in a range of concentration5 from 10w6M to 10m4Mwere introduced directly into the aorta and myocardial contractile force and cardiac electrogram were simultaneously recorded. At the concentration of 4~10'~M the tricyclics for six experiments of each drug - imipramine, amitriptyline, imipramine, nortriptyline, doxepin, protriptyline and desmethylimipramine - all decreased the force of contraction of the heart in comparison to control injections of a buffer solution (McEwans solution - Dumovic et al., 1976a) (n = 12). Doxepin showed a significantly greater negative inotropic effect (decreased force of contraction of the heart) than either amitriptyline, imipramine, nortriptyline, protriptyline or desmethylimipramine (p c 0.05). The electrogram of the isolated perfused guinea pig heart at the drug concentration 4~10~~1 included non-specific ST-T wave abnormalities, prolongation of the PR interval and widening of QRS complex. No significant difference between the drug5 was observed in the increase in the PR interval and QRS width (p > 0.05). With higher concentration5 of these six tricyclics, disturbance5 in excitability and conduction included: decreased heart rates, partial or complete atrioventricular block, and bizarre QRS complexes revealing right and left bundle branch blocks. Conclusions Clinical studies have shown that both toxic and therapeutic dose5 of tricyclics may cause significant prolongation of distal atrioventricular conduction. This prolongation may explain the sudden'deaths reported with tricyclic antidepressants. The experimental study has shown that the isolated perfused guinea pig heart can be used a5 a toxicological model for testing and treating drug-induced cardiac arrhythmias. Inquiries znd reprint requests should Dr. G.D. Burrows, Department of Psychiatry, University of Melbourne, Parkville, Vie., 3052, Australia.
be addressed
to:
Reference5 ASBERG, M., CRONEOLM, B., SJOQVIST, F. and TUCK, D. (-1971). Relationship between plasma level and therapeutic effect in nortriptyline. BP. Med. J. 3: 331-334. BRAITRWAITE, R.A., GOULDING, R., TREANO, G., BAILEY, J. and COPPEN, A. (1972). Plasma concentration of amitriptyline and clinical response. Luxoet i: 1297-1300.
334
G.D. Burrows
et al.
of nortriptyline and BURROWS, G.D., DAVIES, B. and SCOGGINS, B.A. (1972). Plasma concentration clinical response in depressive illness. Lancet ii: 619-623: BURROWS, G.D., MAGUIRE, K.P., SCOGGINS, B.A., STEVEEON, J. and DAVIES, B. (1977). Plasma nortriptyline and clinical response - a study using changing plasma levels. Peychol. med. 7: 87-91. BU&tOWS, G.D., SCOGGINS, B.A., TURECEK, L.R. and DAVIES, B. (1974). Plasma nortriptyline and clinical response. Clin. Pharmac. Ther. 16: 639-644. ,DUMOVIC, P., BURROWS, G.D., VOHRA, J., DAVIE, B. and SCOGGINS, B.A. (1976a). The effect of tricyclic antidepressant drugs on the heart. Arch. Toxicol. 35: 255-262. DUMOVIC, P., BURROWS, G.D., VOHRA, J., MAGUIRE, K., SCOGGINS, B.A. and DAVIES, B. (1976b). Tricyclic antidepressant drugs and the heart. Presented at the South-East Asian/Western Pacific Regional Meeting of Pharmacologists. Singapore Nay 11-14, 1976. FRIEDEL, R.O. and RASKIND, M.A. (1975). Relationship of blood levels of Sinequan to clinical effects in the treatment of depression in aged patients. In: Sinequan {cioxepin HCZI. A MonoJ. Mendels (ed.), pp. 51-53, Excerpta Medica International graph of Recent Clinical Studies, Congress Series No. 385. GRAM, L.F., REISBY, N., IBSEN, I., NAGY, A., DENCKER, S.J., BECH, P., PETERSEN, G.P. and CHRISTIANSEN, J. (1976). Plasma levels and antidepressive effect of imipramine. Chin. Phczrmat. Ther. 19: 318-324. HUNT, D. and ?@lRA, J. (1973). Clinical applications of His bundle electrography. Med. J. Auet. 1: 373-378. JORGENSEN; A. (1975). A gas chromatographic method for the determination of amitriptyline and nortriptyline in human serum. Acta pharmac. 36: 79-90. KRAGH-SORENSEN, P., ASBERG, M. and EGGERT-HANS=, C. (1973). Plasma nortriptyline levels in endogenous depression. Lancet i: 113-115. LYLE, W.H., BRAITHWAITE, R.A., BROOKS, P.W., CUTHILL, J.M., EARLY, D.F., GOULDING, R., LEGGETT, W.P., PEARSON, I.B., SILVERMAN, G., SNAITH, R.P. and STRANG, G.E. (1974). Plasma concentration of nortriptyline as a guide to treatment. Postgrad. med. J. 50: 282-287. MAGUIRE, K.P., BURROWS, G.D., COGHLAN, J.P. and SCOGGINS, B.A. (197G). A rapid radioisotopic procedure for the determination of plasma nortriptyline. CZin. Chem. 22: 761-764. MAGUIRE, K.P., BURROWS, G.D. and SCOGGINS, B.A. (1976b). The value of sasma tricyclic antidepressant measurements. Presented at the South-East Asian/Western Pacific Regional Meeting of Pharmacologists. Singapore May 11-14, 1976. MOODY, J.P., TAIT, A.C. and TODRICK, A. (1967). Plasma levels of imipramine and desmethylimipramine during therapy. BP. J. Psych&d. 113: 183-193. NAGY, A. and TBEIBER, L. (1973). QuantitatiTdetermination of imipramine and desipramine in human blood plasma by direct densitometry of thin-layer chromatograms. J. Pharm. Phanwc. 25: 599-603. OL~IER-MARTIN, R., MARXN, D., BUSCHSENSCHUTZ, E., PICHOT, P. and BOISSIER, J. (1975). Concentrations plasmatiques de l'imipramine et de la desmethylimipramine et effet anti-depresseur au tours d'un traitement controle. Psychophanac. 41: 187-195. RIESS, W., DUBEY, L., FUNFGELD, E.W., IMHOF, P., HUREELERFH., MATUSSEK, N., RAJAGOPALAN, T.G., RASCHDORF, F. and SCHMID, K. (1975). The pharmacokinetic properties of maprotiline (Ludiomil) in man. J. Int. med. Res. 3: 16-41. VOHRA, J. and BURROWS, G.D. (1974): Cardiovascular complications of tricyclic antidepressant overdosage. Drugs 8: 432-437. VOHRA, J., BURROWS, G., HUNT, D. and SLOMAN, G. (1975). The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction. Eur. J. Cardiol. 3: 219-227.
Nemo-Pe~chophar.
Vol.
1, pp. 329-334,
1977.
Pergamon Press.
Printed
in Great
Britain.
TRICYCLIC ANTIDEPRESSANT DRUGS AND CARDIAC CONDUCTION G.D. BURROWS,* J. VOliRA,** P. DDMOVIC,* K. MAGUIRR,* B.A. SCOGGINS,t and B. DAVIES* *Department of Psychiatry, University of Melbourne, **Cardiac Department, Royal Melbourne Hospital, tlloward Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Australia (Final
form,
July
1977)
Abstract 1. Distal intracardiac conduction defects were observed in patients ingesting both toxic and therapeutic doses of tricyclic antidepressants (TCA). 2. In a crossover comparative study of doxepin-nortriptyline (150 mg/day for 3 weeks) six out of seventeen patients on nortriptyline and only one patient on doxepin showed significant prolongation of the QRS interval. 3. Plasma levels of doxepin (52 2 6 rig/ml) were lower than those of nortriptyline (196 f 29 nghl). 4. An in vitro study of TCA has shown that the isolated perfused guinea pig heart could provide a toxicological model for studying the arrhythmogenic effects of TCA in man. Keywords:
Tricyclics,
cardiac
conduction,
plasma
levels
Introduction Several clinical and experimental studies have cyclic antidepressants. In this paper, we shall effect of tricyclic antidepressants respectively and in vitro on the isolated perfused guinea pig Clinical The tricyclic Burrows, 1974).
antidepressants These effects
have complex are not always
been made on the cardiovascular action of tripresent clinical and experimental data on the in uivo on the intracardiac conduction in man, heart. Studies
actions detected
on the cardiovascular system by routine electrocardiography.
(Vohra and Eis
; Fig.
1.
His bundle electrogram (HBE) with the corresponding standard ECG. An anatomical model of the conduction system at the top of the figure is orientated to show the sites of origin of the electrical The A-H and H-V intervals represent proximal and distal waves. intracardiac conduction respectively. 129
330
/
G.D. Burrows
et al.
sensitive recording technique (Hunt and Vohra, bundle electrocardiography (Fig. 1) , an invasive 19731, demonstrated impaired distal intracardiac conduction (H-Vinterval) in seven of eight , imipramine or amipatients admitted to hospital following overdosage of either nortriptyline triptyline (Fig. 2). There was no impaired conduction in the six patients with doxepin overdosage (Vohra et at., 1975).
Fig.
2.
Effect of overdosage (< 500 mg) of tricyclic distal intracardiac conduction (H-V interval). represents normal H-V conduction time.
antidepressants The shaded
on area
In a therapeutic dose study, four of five patients who showed an increase in the H-V interval by more than 10 ms had plasma nortriptyline levels of over 200 rig/ml (Vohra et aZ., 1975). A significant correlation has been shown between changes in the QRS width with changes in the H-V interval (r = 0.82). High fidelity rapid recording surface electrocardiography, a non200 or 500 mm/s invasive technique, allows for accurate measurement of the QRS width at either (Pig. 3).
Fig.
3.
Rapid recording surface electrocardiograms showing the QRS complex at 200 mm/s (left of figure) and 500 mm/s (right of figure).
Tricyclics
and cardiac
conduction
331
In an ongoing double-blind crossover comparative study of nortriptyline and doxepin in dethis latter technique was applied. After 3 weeks on 150 mg/day of either trs pressed patients, cyclic, six out of seventeen patients on nortriptyline showed more than 25% prolongation of the QRS complex. Only one of the patients had significant prolongation while receiving doxepin (Table 1).
Table The
Patient
relationship
Age
Sex
between
QRS width
Mean QRS Width Pre-drug -Lead 320 I B 280 III 315 I1 # III 317 280 I 230 II # III 200 270 I # 226 III
1
49
F
2
50
M
3
42
F
4
58
F
5
45
M
360 406 340 I60 I60 140 178 IS2 II7
and plasma
Mean QRS Width NT
1 levels
X change QRS NT
of
doxepin
(DOX)
Mean QRS Width 00X
and nortriptyline
X change .QRS 00X
(NT)
Plast&¶ NT (nglml)
Plasma 00X (nglml)
425 518 442 385 250 280 270 336 340
+33* +a5* +40* +21 -I I +22 +35* +24 +50*
315 317 330 300 244 278 280 232 213
+2 +13 +5 -5 -13 +21 +40* -14 -6
#
500
+39*
370
+3
I # III I 11 0 III I II 0 III
428 411 193 170 155 200 221 I62
+5 +21 +21 +6 +I1 +12 +21 +38.5*
380 362 192 I61 140 190 198 143
-6 + 6.5 +20 + 0.6 0 +7 +9 +22
305
287
62
0
I96
0
153
-22
416
a0
I III
0
140 137
+4 +13
122 135
-10 +12
29
58
I
0
175
+14
165
+a
210
c30
“2 “4
0
173 148
+22 +4
I60 I33
+13 -6
325
47
127.5 132 128
+9 +10 -3
130 133 II5
+I1 +I1 -13
325
a9
130 I30
-15 -15
130 130
-15 -15
31
32
I
251
c30
la3
<30
III
30
225
42
174
<30
34
47
6
57
M
7
42
M
a
45
F
9
53
M
I96
38
F
135 I21
II
67
M
153
12
32
F
142 142
13
67
F
II7 120 132
I4
63
F
153 153
I5
42
F
158 142 142
160 147 148
+ I + 3.5 +4
155 158 145
-2 +I1 +2
140
46
I6
62
F
130 150
135 125
+4 -17
133 I25
+2 -17
248
60
+2 -2
137 128
- 3.5 +4
40
58
IO
I7
46
NT levels (mean f * 25% or more QRS 0 ECG recorded at # EC’S recorded at
F
142 123
I
z2 0 4 “6 “2 “4
0
145 120
00X levels S.E.M.) 196.1 2 28.8 nglml; prolongation considered significant. 200 m/s 500 mn/s
(mean f
S.B.Y.)
52.3
f
5.9
og/ml.
lia
and Hinsvark, and Raskind, 1976* study
et al., 1975 1976”
1976
et al., 1975 et al., l976b
et al.,
1975”
1973
1975
NT NT NT NT NT NT NT NT
MAP MAP
IMI IMI IMI IMI IMI
DOX DOX DOX
DOX
75-225 150 150 150 150 80-200 150 I50
150 150
150 150 150 3.5 mgfkg 225
75-200 150 150 150
150 150 150
AT AT
AT
tricyclic Dose (mg/day)
of
Drug Studied
levels
2.
DES = Desmethyldoxepin; GLC = Gas liquid TLC-D = Thin-layer assay.
plasma
* Pers. Comm. AT = Amitriptyline; DOX = Doxepin; MAP = Maprotiline; NT = Nortriptyline; spectrometry; Fluor = Fluorimetry; tive assay; D.1 = Double-isotope
Asberg et al., 1971 Burrows et al., 1972 Kragh-Sdrensen et al., Burrows et al., 1974 Lyle et al., 1974 Braithwaite, 1975” Burrows et al., 1977 Present study
Riess Maguire
Perel, Gram
1975” 1975
1972
Moody et al., 1967 Nagy and Treiber, 1973 Olivier-Martin et al.,
O’Brien Friedel Hobbs, Present
Braithwaite Jdrgensen, Braithwaite,
Author
Steady-state
Table
of
1.D 1.D GLC 1.D GLC GLC D.1 D.1
D.1 D.1
Fluor. TLC-D Fluor. Fluor. TLC-D
GLC GC-MS GLC GLC
GLC GLC GLC
Method analysis NT 65 NT Ill NT 67
110, 60, 129, IMI 81,
NT NT NT NT NT NT NT NT
90 I71 I41 I71 170 166 174 196
MAP 200-250 MAP 181
IMI IMI II41 Total IMI
DKI 190 DMI 68 DMI 130 + DMI 210 DMI 141
81
(rig/ml)
DOX 55, DES 27 Total DOX + DES DOX 50 DOX 52
AT 60, AT 76, AT 69.5,
Mean steady-state plasma levels
DMI = Desmethylimipramine; IMI = Imipramine; chromatography; GC-MS = Gas chromatography-mass chromatography-densitometry; 1.D = Isotope-deriva-
32 30 65 I4 IO 19 I7
29
48 8
5 7 24 29 21
I7
7 8
I5 9 22
No. patients
antidepressants
Tricyclics
and cardiac
conduction5
333
Plasma level5 of doxepin were measured by gas-liquid chromatography with protriptyline as an internal standard. Nortriptyline and maprotiline, both secondary amines, were analyeed by double-isotope derivative dilution procedures (Maguire et al., 1976a). These assays are sensitive, specific, accurate and precise. The precision at 100 rig/ml for doxepin is 8X, nortriptyline 7% and maprotiline 441, and the sensitivity is IO rig/ml for nortriptyline and maprotiline , and 30 rig/ml for doxepin. The group of patients when receiving nortriptyline had a mean plasma level of 196 f 29 rig/ml, but while on doxepin a mean plasma level of 52 f 6 rig/ml, was obtained (Table 1). The plasma levels of doxepin were therefore much lower than those of nortriptyline. This may explain the difference in the effect on intracardiac conduction between these two tricyclic compounds. This level of doxepin compare5 with the mean of 81 rig/ml reported by Friedel and Raekind (1975) and that of 55 rig/ml of O'Brien and Hinsvark (1975, Pers. comm.). Hobbs (1976, Pers. comm.) also reported that therapeutic dose5 of doxepin reach peaks of around 50 rig/ml. Plasma levels of other tricyclic antidepressants, as reported by a number of authors, show tricyclic studied, dose (mg/day), number of patients, method of analysis with mean steady-state plasma level5 level for nortriptyline at 150 s&day, apart from one study bghl) . The mean steady-state (Asberg et at., 1971) appear5 reasonably constant (Table 2). Experimental
Study
Our unit has found that the isolated perfused guinea pig heart is a good model for studying the arrhythmogenic effects of tricyclics (Dumovic et al., 1976b). A cardiograph was recorded on a conventional ECG machine at 50 mm/s. A trace was also recorded on a cathode ray oscilloscope at 450 mm/s. Tricyclic drugs in a range of concentration5 from 10w6M to 10m4Mwere introduced directly into the aorta and myocardial contractile force and cardiac electrogram were simultaneously recorded. At the concentration of 4~10'~M the tricyclics for six experiments of each drug - imipramine, amitriptyline, imipramine, nortriptyline, doxepin, protriptyline and desmethylimipramine - all decreased the force of contraction of the heart in comparison to control injections of a buffer solution (McEwans solution - Dumovic et al., 1976a) (n = 12). Doxepin showed a significantly greater negative inotropic effect (decreased force of contraction of the heart) than either amitriptyline, imipramine, nortriptyline, protriptyline or desmethylimipramine (p c 0.05). The electrogram of the isolated perfused guinea pig heart at the drug concentration 4~10~~1 included non-specific ST-T wave abnormalities, prolongation of the PR interval and widening of QRS complex. No significant difference between the drug5 was observed in the increase in the PR interval and QRS width (p > 0.05). With higher concentration5 of these six tricyclics, disturbance5 in excitability and conduction included: decreased heart rates, partial or complete atrioventricular block, and bizarre QRS complexes revealing right and left bundle branch blocks. Conclusions Clinical studies have shown that both toxic and therapeutic dose5 of tricyclics may cause significant prolongation of distal atrioventricular conduction. This prolongation may explain the sudden'deaths reported with tricyclic antidepressants. The experimental study has shown that the isolated perfused guinea pig heart can be used a5 a toxicological model for testing and treating drug-induced cardiac arrhythmias. Inquiries znd reprint requests should Dr. G.D. Burrows, Department of Psychiatry, University of Melbourne, Parkville, Vie., 3052, Australia.
be addressed
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