Reprint from******International Journal of

******************clinical pharmacology

******************therapy and toxicology

******************

******************Dustri-Verlag Dr. Karl Feistle

******************München-Deisenhofen

 __________________________________________________________________________________________________

International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 19 No. 8 -1981 (pp. 377-378)

Propranolol treatment in chronic alcoholic

outpatients

C. CARLSSON

Nordhemspolikliniken, Goteborg, Sweden

Abstract. In a double-blind cross-over study on chronic alcoholic outpatients propranolol was determined to positively influence their number of visits to the clinic. The study is of theoretical as well as practical interest.

Key Words: propranolol - chronic alcoholic outpatients

A study during the abstinence phase in chronic alcoholics showed that propranolol could limit the frequently occurring hyperkinetic circulatory condition [Carlsson 1969]. Also, it was found that propranolol seemed to decrease psychic tension, which was later confirmed in a double-blind study [Carlsson and Johansson 1971]. Propranolol was seen to be significantly more effective than placebo in reducing the tension symptoms of the alcoholics. A comparison between propranolol and diazepam in a larger and more extensive study proved that all significant differences in various psychic symptoms were in propranolol's favor [Carlsson and Fasth 1976]. Thus, it is obvious that propranolol could have an effect on the psychic symptoms in chronic alcoholism. However, one question remained - do these effects on psychic symptoms also help the patient to cope with his alcohol problem? Therefore, a new study was planned. Its purpose was to determine whether the chronic alcoholic would come to the clinic more frequently if given propranolol instead of placebo. Method The study was made at a clinic that specialized in outpatient care of alcoholics. The clinic had 200 visits per day, which were mainly handled by the nurses. The patients usually came 5 times a week for consultation and to receive different medicines. Also at their disposal were psychologists, sociometrists, and doctors. Disulfiram or similar drugs such as benzodiazepines, barbiturates, or other addictive drugs, were hardly ever used. The clinic also provided group therapy and hypnotic treatment, and maintained close ties with organizations such as Alcoholics Anonymous, religious groups, etc. The majority of the patients at the clinic are chronic alcoholics in the medical sense, or gamma alcoholics, according to Jellinek [1960], or alcohol addicts, who if they start drinking again lose control and then, as a rule, fail to appear at the clinic. However, they usually return when the alcoholic period has passed after a few weeks.

Patients suitable for studies are those who can cope with the alcohol problem well enough to come to the clinic at least several weeks in a row without any signs of drinking. However, the information given by alcoholics on their consumption is very unreliable. It was considered impossible to check by interviews or laboratory tests how the patients had managed. The only firm data available were their appearance at the clinic or their absence. Whether or not the patient comes to the clinic is also very much dependent on the person they contact. For our study a special nurse was employed who along with her therapeutic skills easily established contact with the patients and influenced them to come to her. Patients included in this study were not permitted to receive other medications, e. g., for epilepsy. The only drugs allowed in the study were hexapropymate (0.4 g) and, if absolutely necessary for sleeping, one tablet was given in the evening (Modirax). Before the study the patients were examined for heart disease, obstructive lung disease, or other contraindications for D blockade. Pretrial propranolol (80 mg x 2) was given to all patients to note whether they had any acute side effects from the drug. The majority of chronic alcoholics tolerate such medication very well. Each day when the patient arrives at the clinic, he is asked in accordance with the questionnaire how he feels as regards tension, depression, sleep, and how he has managed with his alcohol problem. Eventual side effects are also noted. On Mondays the patient is also asked how he felt on Saturday and Sunday when he was not at the clinic. Subjects A total of 52 male and 4 female chronic alcoholics, in the medical sense, entered the study. Their mean age was 43.1 (range 26-64). All patients had attended the clinic for several weeks before the study and had apparently been alcohol-free. The patients were allocated in a double-blind, randomized manner to propranolol (80 mg x 2) or placebo for 14 days and thereafter received the other for another 14 days.

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378 ***************************************************************************** Carlsson 

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Comment ********************************************************************************379

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SHORT COMMENT TO: "Pharmacokinetics of prostaglandins: prediction of steady-state concentrations during i. v. infusions" by M. Weiss and W. Forster. Int. J. Clin. Pharmacol. 18: 344, 1980. Systemic clearance of prostaglandins in man M. WEISS and W. FÖSTER Department of Pharmacology and Toxicology, Martin Luther University Halle-Wittenberg, Halle, German Democratic Republic Recently we reported a pharmacokinetic model useful for compounds with high pulmonary clearance [Weiss and Forster 1980]. Here we wish to correct an apparently erroneous conclusion drawn in this article on the systemic clearance of prostaglandins (PGs) F2,l and El. As shown by Bito and Barody [1975] rabbit erythrocytes are impermeable to E and F PGs. This finding strongly suggests the use of plasma flow instead of blood flow when PG plasma concentrations are predicted with the recirculation model. Assuming a hematocrit Hct = 0.44 [Qplasma = (I-Hct)Q], a mean systemic extraction ratio Esys = 0.59 is predicted by the model for PGF2, from the data of Jose et al. (Patient V. B.). But since the pulmonary first-pass effect is of great importance in determining the plasma concentrations of PGs after intravenous infusion, the latter are only little affected by changes in systemic extraction. On the other hand, very exact values of plasma flow and PG concentrations would be needed for an estimation of Fsys = I-Esys using Equation 22 [Weiss and Forster 1980]. Whereas direct experimental data on the systemic clearance of PGF21, are currently not available, a systemic extraction ratio of about 50% seems compatible with the model predictions based on the clinical data cited in our previous publication. This is in good agreement with the value 54.1 + 15.2% reported by Bukhave and Hansen [1977] for PGEI in the rat. A hepatic extraction ratio Ehep = 0.72 was determined for PGF2a by Anderson et al. [1976] in dogs (io = 15 ug/min). This value would lead to a systemic extraction ratio of 16%, indicating a substantial extrahepatic elimination of PGF2O in the systemic circulation (the data suggest a value of 36% in

the lower organs and extremities, i. e., Esys ³ 3 0.36). If Equation 23 is corrected (Q replaced by Qplasma and Fpul multiplied by Fsys), an endogeneous PGFQ synthesis of about 30 m g/day in female human subjects is predicted, which is still in agreement with the reported experimental value. In conclusion, assuming that the membranes of red blood cells are impermeable to E and F PGs, a significant systemic clearance is in accordance with the predictions of our model. The total plasma clearance becomes Cltot = Qplasma x (1-FsysFpul)> but the plasma concentration is mainly determined by the presystemic elimination of PGs (intravenous bioavailability Fpul). Acknowledgment The authors wish to thank Dr. H. S. Hansen for his helpful criticism. For the authors: Dr. M. Weiss Institut fur Pharmakologie und Toxikologie Martin-Luther-Universitat DDR-402 Halle REFERENCES Anderson FL, Jubiz W. Tsagaris TJ 1976 Degradation of prostaglandins E2 and F2a , by the canine liver. Amer. J. Physiol. 231:426 Bito LZ, Barody RA 1975 Impermeability of rabbit erythrocytes to prostaglandins. Amer. J. Physiol. 229: 1580 Bukhave K, Hansen HS 1977 Elimination of low steady-state concentrations of (5,6-^3H2) prostaglandin El in the pulmonary and the systemic circulations of anesthetized rats. Biochim. Biophys. Acta 489:403 Weiss M, Förster W 1980 Pharmacokinetics of prostaglandins: prediction of steady-state concentrations during intravenous infusion. Int. J. Clin. Pharmacol. 18:344

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