Kanazirev, B.

Ruseva, T.

Tzekov, H.

English

Varna Medical University Press: Journals

S E R U M DIGOXIN CONCENTRATIONS DURING CHRONIC COR P U L M O N A L E T R E A T M E N T H. Tzekov, B. Kanazirev, T. Ruseva Key-words: cor pulmonale — serum digoxin level — digoxin intoxication —serum electrolytes — electrocardiography At present, there s t i l l exists certain reservation concerning digitalis glyco-sides treatment of decompensated cor pulmonale. Th i s reservation is based mainly on the known unwanted hemodynamic effect of glycosides related to the increase of pulmonary arterial pressure and to a less extent — of pulmonary vascular re-sistance (1—5). Some authors contrast the r isk of rapid advancing digitalis intoxication induced by progressed respiratory insufficiency wi th the increased myocardial contract i l i ty by digitalis giycosides (6—8). T h e determination of the serum levels of cardiac glycosides wi th small cu-mulative effect such as of digoxin enables a more profound evaluation of the side effects and r isk from overdosage. The purpose of the present work consists in : I . Es t imat ion of serum digoxin levels in case of moderately rapid and slow saturation during advanced respiratory and right-side heart insufficiency. 2. Ascertaining of the maximal levels of serum digoxin and of c l in ica l symp-toms of toxic doses. 3. Follow-up of the risk factors of the digitalis intoxication. Material and methods A total of 35 patients (32 males and 3 females) at an average age of 5 9 = 8 years wi th chronic obstructive lung disease ( C O L D ) and chronic cor pulmonale at the stage of decompensation were studied. A t ly ing position, serum levels of digoxin, potassium, sodium, calcium and chlorides were estimated prior to digo-x i n therapy as wel l as on the 1st, 5th and 10th day after beginning of treatment. Serum levels were assessed on the 5th and on the 10th day 8 hours after the last taking of the drug. A l l the patients were administered the rest adequate therapy including chemotherapeutics, bronchodilatators, and mucolytics. Diuretics were commonly administered intermittently observing the rule to exclude aldosterone antagonists. C l in ica l characteristics was based on the physical , functional, roent-genological, and electrocardiographical examination as well as on the follow-up of both objective and subjective symptomatics of digitalis preparation overdo-sage. Patients were divided into 3 groups in the course of treatment and investi-gation: 1 s t group of 19 patients treated wi th digoxin (Richter , G D R ) at dosis of 1 tablet thrice dai ly for 5 days up to total dosis of 3.75 mg followed by main-tenance dosage of one tablet (a dosis of 0.25 mg) dai ly. 2 n d group consisted in 8 patients in which a maintenance dosage was started. Blood gases were examined at the onset as well as on the 10 t h day after beginning of treatment. I n the 3 r d group consisting in 8 patients wi th chronic respiratory failure and cor pulmonale maintenance dosage of one digoxin tablet dai ly was of 3 month duration prior to investigation. Serum digoxin concentrations during chronic cor. 53 T a b l e 1 Serum d i g o x i n levels ( S D L ) Indexes Patients'groups first second third before th th before 5 t h 5 t h th 3 r d treatment 5 day 10 day treatment hour day 10 day month 0.99== 3 . 0 2 ± 2.51=1= 0.19==: 0.68=1= 1.1=1= 2.14=1= 1.56== 0.56 1.35 1.46 0.07 0.09 0.21 0.25 0.39 146=s=ll 146:== 9 143=1=13 136=1=8 — 133=1=5 — 4.76=!= 4.99=1= 4.44==: 4.86=1= 4.78=1= 0.23 0.19 0.36 0.68 0.74 106== 18 119=±=24 114=1=21 101=±= 11 — — 105=1=13 — 2.44== 2.62=1= 2.39=1= — — — — — 0.31 0.56 0.33 104^=8 102=1=11 103=1=9 — — — — — S D L nmol/1 Sodium mmol/1 Pot assium mmol/1 Creatinin mkmol/1 Calcium mmol/1 Chlorides mmol/1 pO a kPa mm Hg pC0 2 k P a mm Hg 7.42==0.1 56==0,8 8.64=1= 1.57 67=±=12 8.21: 62== = 0.21 1,2 7.01== 0.96 53==7.2 We considered reference values of therapeutic digoxin concentrations for adults these given by the firm between 1.5 and 1.8 nmol/1 but toxic ones — over 2,6 nmol/1. Results and discussion Digoxin levels were studied after a 5-day interrution in order to achieve disappearance of its effect in the patients of the first group. The serum concentra-tions (presented on table 1) — 0.99===0.56 nmol/1 — showed that excretion was delayed despite the absence of renal failure. Digoxin administration at a dosis of 0.75 mg dai ly for 5 days elevated the concentrations up to 3.02=+= 1.35 nmol/1. I n two patients wi th chronic pulmonary failure, 1 s t stage, the levels reached up to 5 nmol/1 without any electrolyte changes. Electrocardiographically, 6 patients demonstrated diffuse S T - T changes due to digitalis but one patient — due to sinusoidal bradycardia. Maintenance dosage administration during the next 5 days resulted in serum digoxin level reduction down to 2.51 =+=1.46 nmol/1. Heart frequency decreased stat ist ically significantly (p<0.001) on the 5 t h day as compar-ed wi th that of the in i t ia l rate and then increased insignificantly on the 10 t h day after beginning of the study (fig. 1). Patients of the 2 n d group had not received digoxin 3 months long before treat-ment and investigation. I t was confirmed by the levels established prior to inve-s t i ga t i on—namely 0.19=r=0.07 nmol/1. F i v e hours after the first taking of the drug a considerable change of serum digoxin level occurred — 0.68=±=0.09 nmol/1 reaching up to 1.1 =±=0.21 nmol/1, i . e. nearly to the therapeutic one on the 5 t h day but then insignificantly prevail ing over it on the 10 t h day (2.14=±=0.25 nmol/1) (fig. 2) . The rates of partial pressure of C 0 2 — p C 0 2 and of oxygen — p 0 2 were prior to treatment 8.64=== 1.57 k P a (67=== 12 mm Hg) and 7.42=±=0.1 k P a (56===0.8 mm H g ) , respectively. Therefore, we considered the respiratory failure an ad-H . Tzekov, В . Kanazirev, Т. Ruseva vanced one. After a 10-day treatment both hypoxemia and hypercapny persisted but they were considerably reduced down to the following rates: p0 9 —8.21 ± 0 . 2 1 k P a ( 6 2 ± 1 . 6 mm Hg) and p C 0 2 — 7.01 ± 0 . 9 6 k P a ( 5 3 ^ 7 . 2 mm Hg) . Concerning the patients of the 3 r d group who were on maintenance therapy for more than 3 U I I О 5ibday Wtrrdag F i g . 1. months prior to study it could be noted that stabile therapeutic concentrations (1.56=±:0.39 nmol/1) were warranted (fig. 3) . We established high residual levels inspite of 5-day long digoxin therapy interruption. When we related this fact to the early therapeutic levels during maintenance treatment of the patients of the 2 n d group we could realize that di­goxin resorption was much higher than the presumed one but excretion quota was lower, on the contrary. The absence of severe phenomena of digitalis intoxi­cation made rather doubtful the known fact that myocardium was more sensible in hypoxemic patients. P . Souich and J . P . Clozel (9) proved that hypoxemia prolonged plasma half-life of digoxin from 25 up to 33 hours but digoxin concen­trations increased in the brain and diaphragm musculature and did not in the heart muscle despite high serum levels. A . Nanj i i and D . Greenway (10) rendered Serum digoxin concentrations during chronic cor. 55 count of the presence of digoxin-like immuno-reactive substances in hepatic and nal lesions as well as in premature newborns. 0 70 t h day 5 t h ftour 6 t h day 10 th'day 6,ra'month F i g . 3. The lack of any digitalis intoxication inspite of the high digoxin levels should be explained by the absence of electrolyte disturbances in our patients. L . Green and T . Smi th (11) point out that hypokaliemia and renal lesions cause digital is intoxication in 53 per cent of cor pulmonale patients. J . Morrison and T . K i l l i p (12) find out a digitalis intoxication at 1.2 ng/ml in 8 patients wi th p 0 2 of 39 mm H g . G . Koren and R. Parker (13) investigate 47 children aged between 2 and 16 H . Tzekov, В. Kanazirev, Т. Ruseva years and emphasize that the very high serum digoxin concentrations exert not always a toxic effect. R . Goldmann and D . Harrison (14) report that while hypo-xemia possesses an indirect effect hypercapny acts directly on sympathico-adrenal st imulation. The fact that we have not investigated blood-gas parameters in most of our patients does not enable us to associate ourselves wi th this concept, s t i l l more, that heart frequency reduction is best experessed in cases wi th the highest serum digoxin concentration. We can draw the following conclusions: 1. Digoxin has a good enteral resorption in patients wi th chronic respiratory insufficiency and cor pulmonale. 2. Both^ moderately rapid saturation and continuous maintenance therapy together wi th missing electrolyte balance disturbances does not create any r isk of intoxication. 3. Excessive elevation of serum digoxin levels is c l in ica l ly manifested as a bradycardic effect and ST-T-changes of the electrocardiogram. R E F E R E N C E S | N I U - i , 1. Т о м о в , Л . , И. Т о м о в . Хронично белодробно сърце. С., Мед. и физк. , 1973. — 2. Т о м о в, И. Хронично белодробно сърце. — В: Ръководство по вътрешни болести. Том 3. С., Мед. и физк., 1986. — 3. Т о м о в, И. Лечение на болестите на сърцето. С., Мед. и физк. , 1982. — 4. Ч а з о в, Е. И. Руководство по кардиологии. Том 3. М., Медицина, 1982. — 5. М с F a d е 1 е n, S. R е g i s, Е. В r a u n w a 1 d. I n : Textbook of cardiovas-cular medicine. E d . E . Braunwald, 1984. — 6. H a 1 f о r d, F . D . , J . С. M i t h о е f е r . Аmer. Rev. Respir. Dis., 108, 1973, 879. - 7. S i d е r i s, D . Amer. Heart. J . , 89, 1975,, N 1, 32—35. — 8. T h o m a s , A . J . B r i t . Heart J . , 31 , 1969, 491—495. — 9. S о u i с h, P . , J . P . С 1 о z е 1, е t а 1. Amer. Rev. Respir. Dis . , 132, 1985, 504—509. — 10. N а n j i i , A . , D . G r е е n w а y . B r i t . Med. J . , 290, 1984, 432—433. — 11. G г е е n, L . , Т. S m i t h . Ann . In tern. Med., 87, 1977, 459—465. — 12. M о r r i s о n, J . , Т. К i 1 1 i p. Circulation, 93, 94, 1971, Suppl . 2, 4 1 . — 13. К о r е n, G . , R . P a r k e r . Amer. J . Cardiol., 255, 1985, 1210—1214. — 14. G о 1 d m а n n, R . , D . H а r r i s o n . J . Pharmacol. Exper im. Ther., 174, 1970, N 2, 307—314. СЫВОРОТОЧНЫЕ (КОНЦЕНТРАЦИИ ДИГОКСИНА ПРИ [ЛЕЧЕНИИ ХРОНИЧЕСКОГО ЛЕГОЧНОГО СЕРДЦА . X. Цеков, Б. Каназирев, Т. Русева I Р Е З Ю М Е ! I При помощи радиоиммунологической методики прослеживался сывороточный уровень дигоксина у 35 больных хронической обструктивной легочной болезнью и хроническим ле­гочным сердцем. Установлено, что умеренно быстрое насыщение и непрерывное поддержи­вающее лечение не создают риска интоксикации. Эксцессивно повышенный уровень дигок­сина вызвал брадикардию у одного больного. У шести больных наблюдались S T - T изме­нения дигиталисового типа. Получение терапевтических сыровоточных концентраций к пятому дню умеренно быстрого насыщения (3.02—1.35 нмол/л) и к десятому дню (2.14=^0.25 нмол/л) свидетельствует о хорошей энтеральной резорбции дигоксина. Умерено быстрое насыщение статистически достоверно замедляет сердечную деятельность ( Р < 0 . 0 0 1 ) . Н и з к и й исходный уровень, установленный у больных, не получающих дигоксина до исследования (0 .19^0.07 нмол/л), доказывает отсутствие дигоксиноподобных субстанций и определяет высокую специфичность радиоиммунологического метода. Определение сывороточных кон­центраций дигоксина дает представлението некоторых особенностях его фармакокинетики . Это подчеркивает также, что страх интоксикации дигиталисом у больных хронической об­структивной легочной болезнью и хроническим легочным сердцем неоснователен. 

SERUM DIGOXIN CONCENTRATIONS DURING CHRONIC COR PULMONALE TREATMENT

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SERUM DIGOXIN CONCENTRATIONS DURING CHRONIC COR PULMONALE TREATMENT

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