H U M A N PSYCHOPHAKMACOLOGY, VOL. 3, 47-52 (1988)

Hypotension and Bradycardia Induced by Amitriptyline in Healthy Volunteers STEPHEN H. CURRY PhD,:* Professor and Director, Division of Clinical Pharmacokinetics, C. LINDSAY DEVANE PharmD, Associate Professor of Pharmacy Practice, M. MICHAEL WOLFE MD, Assistant Professor of Medicine Colleges of Pharmacy and Medicine, Univer,sity of Florida, Gainesville, Florida 32610

Seventeen healthy volunters in three groups received no treatment, or 25 or SO mg doses of amitriptyline. Maximal measured concentrations of amitriptyline occurred at 4 h post-dosage. There was a dose-dependent change i n performance of a digit symbol substitution test. Visual analogue scales measuring drowsiness, speed of thinking, and lethargy were sensitive to the drug. The low dose induced no blood pressure changes, but tachycardia occurred. The higher dose induced hypotension with bradycardia, a hitherto undocumented reaction to the drug.

KEY WORDS-Amitriptyhne, nortriptyhe, hypotension, digit-symbol substitution, visual analogue scales, bradycardia.

INTRODUCTION

The acute effects of therapeutic doses of tricyclic antidepressants are poorly documented, probably because the primary use of these drugs is in long-term treatment. Initial doses of amitriptyline (10-50 mg) and related compounds are generally balieved to cause sedation, postural hypotension and tachycardia (Melmon and Morelli, 1978; Gilman et al., 1980). In contrast, much has been written about effects following overdoses (for reviews see Hong et al . , 1974 and Ross and Sharp, 1984). Generally speaking, single doses in volun- teers have not been considered relevant to overdoses in patients. However, in recent years. concern has been expressed that the effects of initial doses may, in fact, be similar to those of overdoses, and potentially severe (Glassman and Bigger, 1981; Glassman et a l . , 1983). A direct depressant effect on the heart has been proposed, and a decreased inotropic effect following deple- tion of catecholamines from the myocardium has been observed (Raisfeld, 1972). Plasma nore- pinephrine levels have been shown to be changed by tricyclic antidepressants (Veith et a l . , 1983).

T h e pharmacokinetic properties of tricyclic antidepressants have been the subject of numer- ous investigations (Gram, 1983). There is agree- ment, for example, that amitriptyline demons- trates multi-compartment kinetics and undergoes

*Author to whom correspondence should be addrcssed.

0885-62221881010047-06$05 .OO 0 1988 by John Wiley & Sons, Ltd.

presystemic elimination, and that peak concentra- tions following oral doses occur 1-2 h after dosing (Mellstrom et al . , 1982). The terminal phase half-life of amitriptyline is within the range 10-20 h (Rogers et al . , 1983). Demethylation and hydroxylation are the major metabolic reactions (Bush and Harrier, 1983) and both amitriptyline and its first demethylation product, nortriptyline, accumulate in plasma during long-term treat- ment. However, only one published study has involved more than one dose level (Schulz et a l . , 1983).

In the present study we measured plasma concentrations of amitriptyline and nortriptyline after 25 and 50 mg doses, with blood pressure and pulse rate measured in the standing posture. Sedation was also assessed. An unexpected combination of hypotension and bradycardia was noted after the higher doses.

METHODS

Seventeen healthy male volunteers (age range 20-40; weight range 120-160 Ib - 54-72 kg) were initially screened by means of physical examina- tion, medical history, blood chemistry and haematology. On the day of the investigation they reported to the Clinical Research Center of the University of Florida at 8 a . m . after an overnight fast. Six of them received no medication (control

Accepted 20 Murch 1087

48 S. H. CURRY, C . L. DEVANE AND M. M. WOLFE

subjects). Five received a single 25mg dose of amitriptyline, five received a single 50 mg dose, and one received both doses (50mg first; 3 months apart), so that 18 sets of data were obtained and analysed. Doses were SK brand amitriptyline tablets (Smith Kline and French). Blood was collected for plasma analysis of amitriptyline and nortriptyline content before dosing, and at 1, 2, 3 , 4, 5 , 6, 8, 10, 12, 24, 30 (25 mg doses only), 36 and 48 h and at 72 and 96 h (50 mg doses only) post-dosage.

Blood pressure and pulse rate were measured twice before dosage, and then 5 min before the collection of each post-dosage blood sample. The subjects were standing (with a 2-min equilibration period) for readings up until the time of maximum blood pressure and pulse rate change, after which they were studied supine until the 12-h point. Measurements from this point on- wards were again standing. A digit symbol substitution test, a battery of visual analogue scales, and a questionnaire relating to blurred vision and dry mouth were applied at 30 and 15 min pre-dosage, and at 1.5, 3.5, 6-5 and 24h post-dosage. The digit symbol substitution test sheet presented the subjects with a 10-item number-symbol code. The subjects then ex- amined a series of 100 items consisting of numbers from 0 to 9 inclusive, presented in random order, and were required to indicate in a designated space the symbo1 for each number. The numbers were ‘decoded’ sequentially. The time limit for the test was 1.5 min. The score was the number of correct substitutions in this time. A different symbol-number code was used at each test time.

The battery of visual analogue scales was presented on a test sheet as five 100mm lines. Lines A-E were marked respectively at their left and right ends as foll3ws: drowsyhlert; mentally slowiquick-witted; wellicoordinatediclumsy; leth- argicienergetic; and tensekelaxed. The subjects first set their own baselines by marking the scales with a clear cross or perpendicular line in a position appropriate to their pre-dosage subjec- tive state, and the scales were evaluated from the lengths (mm) from the left-hand ends to the subjects’ marks. Thus, for example, the length recorded was 50mm for ‘normality’, and it lessened if the subject became more drowsy, mentally slow, well-coordinated, lethargic or tense.

In regard to blurred vision and dry mouth, the subjects were asked to place a circle around a

number from 1 to 5 in each case, with 1 representing normality and 5 representing the most extreme abnormality imaginable.

Amitriptyline and nortiptyline concentrations were measured by high-pressure liquid chroma- tography (HPLC) using standard approaches. Analysis was carried out on a microparticulate silica column with a mobile phase consisting of acetonitrile containing methanol (7 per cent) ammonium hydroxide (0.4 per cent) and butyla- mine (0.012 per cent). Linear calibration curves ranging to > 60 ngiml were obtained for both compounds using UV absorbance detection at 254nm. The lower limit of detection was 1 ngiml for both amitriptyline and nortriptyline when extracting 5 ml of plasma. The metabolites 10-hydroxy-arnitriptyline and 10-hydroxy- nortriptyline were determined not to coelute with the compounds of interest. Coefficient of varia- tion figures for replicate amitriptyline assays ranged from 1.0 to 7.2 per cent. Standardization was conducted daily.

Statistical methods involved analysis of variance, and t-testing. A probability of 0-05 or less was taken as indicating statistical significance. Where no statistical comment is included in this report, no significance was found.

RESULTS

Blood pressure and pulse rate were stable throughout the investigation in the control subjects, shown by the mean values differing by no more than 5mmHg (blood pressure) or four beats per minute (pulse rate) from pretreatment values at any time point. The digit symbol substitution and visual analogue scale tests similarly showed no clinically or statistically significant differences from pretreatment scores at any time point in the control subjects. These results were in agreement with observations made in other projects in which preliminary studies have shown inactive medication to be associated with no changes in blood pressure and pulse rate, or with changes in the psychomotor tests, in subjects examined in our conditions of study (Curry and Smith, 1979; Curry et al., 1984a, b).

Figure 1 shows amitriptyline and nortriptyline concentrations over 96 h following 50 mg dosage. The time of mean observed maximum amitripty- line concentrations was 4 h post-dosage. The time of mean observed maximum nortriptyline concen- tration was 5-6 h post-dosage. Mean nortriptyline concentrations exceeded amitriptyline concentra-

AM ITRl PTY LI NE PHARMACOLOGY 49

SYSTOLIC B.P. mm Hg

Figure 1. Concentrations (Mean and S.E.M.) of amitriptyline (AT) and nortriptyline (NT) in plasma of six healthy male volunteers after 50 mg doses.

I 1

12 24

Time h DIASTOLIC B.P. mm Hg

95 -

24 48 72 96 TIME H

t., 2 5 m g - 5 0 m g

10

5

24 48 TIME H

Figure 2. Concentrations (Mean and S.E.M.) of amitriptyline (AT) and nortriptyline ( N T ) in plasma of six healthy male volunteers after 25 mg doses.

tions from 36 h onwards. Figure 2 shows analo- gous data for 2.5 mg dosage. Data are not reported beyond 48 h at this dose level because of the low concentrations which occurred (< 1 ng/ml).

Figure 3 shows mean systolic and diastolic blood pressures after 50 and 25mg doses. The lower dose caused no clinically or statistically significant change in either measurement, but the

1 2 24

Time h

Figure 3. Systolic and diastolic blood pressures (Mean and S.E.M.) in the two groups of volunteers of Figs. 1 and 2.

higher dose caused a clear fall in both systolic and diastolic pressures, especially in the first 6 h post-dosage. Analysis of variance applied to the higher dose data confirmed significant effects of time and subject. Application of t-tests for independent samples to data from the two doses showed significant differences at 2, 3 , 4, 5 , 8 and 9 h post-dosage (systolic) and 2, 3, 4, 5 , 7, 8 and 9 h post-dosage (diastolic). Differences beyond the 9-h point were neither clinically nor statistical- ly significant.

Figure 4 shows the mean pulse rate after 50 and 2.5 mg doses. The 25 mg dose caused the expected rise in pulse rate. This had subsided by the 6h time point post-dosage. The 50mg dose caused an unexpected fall in pulse rate, especially during the first 4h post-dosage. This fall was initiated with the subjects standing, but it persisted for several hours with the subjects lying down. Thus the 50mg dose, in healthy volunteers in the standing position, caused hypotension and brady- cardia at the same time, a hitherto unreported phenomenon with this drug. Analysis of variance

50 S . H. CL’RRY. C. L. DE\’ASE AND M. M. WOLFE

95 E 8 v)

75

5 5

1 I B i 1 A

1.5 3.5 6.5 24

Time h

Figure 5 . Digit symbol substitution scores (Mean and S.E.M.) in the two groups of volunteers of Figs. 1 and 2.

12 24 Time h

Figure 4. Pulse rate (Mean and S.E.M.) in the two groups of volunteers of Figs. 1 and 2. score as time elapsed (Figure 5 ) . Against this

trend, there was a dose-dependent depression of the score which was especially prominent at 3.5 h post-dosage. This depression was statistically significant, using the mathematical approach applied to pulse rate data. The visual analogue scales indicated a mixed pattern of effects (Figure 6). The drowsyialert, mentally slowiquick-witted, and lethargicienergetic scales showed drug effects

again confirmed significant differences between times and subjects, and t-tests for unrelated samples indicated highly significant differences between the two dose levels at all points from 1 to 6 h post-dosage.

After the 25 mg dose the digit symbol substitu- tion test showed a tendency towards a higher

D E I r

Figure 6. Visual analogue scale scores (Mean and S.E.M.) in the two groups of volunteers of Figs. 1 and 2. Designations A-E identify the scales used (see methods). Designations a-f, which apply to all five scales, indicate first pretreatment time, second pretreatment time, 1.5, 3.5, 6.5 and 24 h respectively.

AMITRIPTYLINE PHARMACOLOGY 51

(drowsy, mentally slow and lethargic designa- tions) while the other two scales showed no significant effects. The three responsive scales showed a weak dose-dependence, in that only at 3.5h on scales B and D was the larger change from baseline occurring with the higher dose significantly different from the change occurring with the lower dose.

There were occasional positive reports of blurred vision and/or dry mouth. However, no consistent time or dose-related pattern was observed.

DISCUSSION The results reported herein emerged from an unblinded, exploratory, dose-ranging study, in groups matched for size, age, sex and weight distribution. Allocation of subjects to treatment groups was random. Duplicate blood pressure, pulse rate and psychomotor testing took place before amitriptyline dosing and no significant changes were observed between first and second occasions or between the different groups.

The important comparisons in this study are those between results following the two different doses. The work demonstrated the anticipated dose-dependency of plasma concentrations of amitriptyline and nortriptyline. It also characte- rized the time course of plasma concentrations, as well as the effect of amitriptyline, exerted either by the parent drug or by its metabolite, nortripty- line, as assessed by the digit symbol substitution test and visual analogue scales evaluating central nervous system depression. It is not surprising, given established knowledge of amitriptyline, that the coordination and tension scales proved unresponsive.

The lower dose of amitriptyline, as expected, caused no blood pressure changes, but induced tachycardia. This is in keeping with established knowledge that amitriptyline is both anti- adrenergic and anticholinergic, with any tendency to a blood pressure reduction induced by anti- adrenergic mechanisms being offset by reflex tachycardia, which enhanced any tachycardia induced by the anticholinergic effect. The effect of the higher dose was a surprise. Bradycardia and hypotension presumably arose as the result of direct anticholinergic effects on the heart pre- dominating at the higher dose, such that reflex tachycardia and tachycardia induced by anticho- linergic effects were both masked. This appears to

occur only if the subject is standing, in that other workers have failed to report it in subjects in other postural configurations. However, it per- sisted for 4-6h in our subjects when they lay down, so was more than simple inhibition of a reflex. It was necessary for safety reasons to permit the postural change at the time of maximum amitriptyline effect. However, while this weakened the experimental design, i t did replicate the likely situation in a new amitripty- line patient experiencing dizziness.

These observations may have considerable clinical significance, to naive patients, even though they were made in healthy volunteers, given single doses, and at subtherapeutic plasma levels. It has been reported that many patients experience fainting or some analogous response when treatment with tricyclic antidepressants at 25 or 50mg doses is initiated. This could be the result of postural hypotension with reflex tachy- cardia masked. This probably does not persist beyond the first two or three doses, as plasma levels become higher and tolerance apparently develops. In contrast, these observations prob- ably have little or no significance to overdose patients, except in that they demonstrate that bradycardia and hypotension can occur together; there is one report in the literature of bradycardia following overdose of amitriptyline, showing that, in a single patient, death occurred ‘by slowing of the heart to effective standstill’ (Williams and Shirter, 1971).

ACKNOWLEDGEMENTS

We are grateful to our experimental subjects, to Mrs Sandy Sundlof and to the staff of the Clinical Research Center of the University of Florida for their skilled participation in this work.

REFERENCES

Busch, J. E. and Herrier, D. G. (1983) The demethylation of amitriptyline administered by oral and intramuscular routes (1983). Psychopharmacolo- gy 80, 249-253.

Curry, S. H., Chu, P. I., Baumgartner, T. G. and Stacpoole, P. W. (1985) Plasma concentrations and metabolic effects of intravenous sodium dichloroace- tate. Clinical Pharmacology and Therapeutics 37,

Curry, S. H., DeVane, C. L. and Wolfe, M. M. (1985). Cimetidine interaction with amitriptyline. European Journal of Clinical Pharmacology 29, 429433.

89-93.

52 S. H . CURRY, C . L. DEVANE AND M. M. WOLFE

Curry, S. H. and Smith, C. M. (1979). Diazepam- ethanol interaction in humans: addition or potentia- tion? Communications in Psychopharmacology 3.

Gilman, A. G., Goodman, L. S. and Gilman, A. (1980) (eds) Goodman and Gilman’s The Pharmaco- logical Basis of Therapeutics (6th edition) New York, Macmillan (1980), pp 421-422.

Glassman, A. H. and Bigger, J. T. (1981) Cardiovascu- lar effects of therapeutic doses of tricyclic antide- pressants. Archives of Generid Psychiatry 38, 815- 820.

Glassman, A. H., Johnson, L. L., Giardina, E-G. V., Walsh, B. T., Roose, S. P . , Cooper, T. B. and Bigger, J. T. (1983) The use of imipramine in depressed patients with congestive heart failure. Journal of the American Medical Association 250,

Gram, L. F. (1983) Plasma level monitoring of tricyclic antidepressant therapy. In Handbook of Clinical Pharmacokinetics (Gibaldi, M. and Prescott, L. F., eds) Sydney, Adis Health Science Press, Section IV,

Hong, W. K. , Mauer, P., Hockman, R., Caslowitz, J. G. and Paraskos, J. A. (1974) Amitriptyline Toxic- ity. Chest 66, 304-306.

Mellstrom, B., Alvan, G. , Bertilsson, L.. Potter, W. Z. , Sawe, J. and Sjoqvist, F. (1982) Nortriptyline formation after single oral and intramuscular doses of amitriptyline. Clinical Phurmacolog~ Therapeutics

101-113.

1197-2001.

pp 63-80,

32, 664-667. Melmon, K. L. and Morelli, H. F. (1978) (eds) Clinical

Pharmacology (2nd edition) New York, Macmillan, pp 851-852.

Raisfeld, I . €I. (1972) Cardiovascular complications of antidepressant therapy; interactions at the adrenergic neuron. American Heart Journal 83,

Rogers, H. J., Morrison, P. J. and Bradbrook, I. D. (1983) The half-life of amitriptyline. British Journal of Clinical Pharmacology 6, 181-183.

Ross, J. C. and Sharp, D. J. (1984) Antidepressant drugs and cardiovascular side effects. A comparison of fluvoxaniine and the tricyclic antidepressant drugs. In Biological Psychiatry: Recent Studies G . D. Burrows, T. R. Norman, and K. P. Maguire (eds.) London, J. Libbey and Co., Ltd. pp. 146158.

Schulz, P . , Balart-Gorgia, A. E., Kubli, A, , Gertsch- Geret, C. and Garrone. G . (1983) Elimination and pharmacological effects following single oral doses of 50 and 75mg of amitriptyline in man. Archiv des Psychiatrie urid Nervenkrankheiten 233, 449-455.

Veith, R. C., Raskind, M. A,, Barnes, R. F., Gumbrecht, G., Ritchie, J. L. and Halter, J. B. (1983) Tricyclic antidepressants and supine, standing and exercise plasma norepinephrine levels. Clinical Pharmacology and Therapeutics 33, 763-769.

Williams, R. B. and Shirter, C. (1971) Cardiac complications of antidepressant therapy. Annals of Internal Medicine 74, 395-398.

129-133.