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Disulfiram-induced reversible hypertension: a prospective case series and review of the literature.
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PMID:  25336781     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
Disulfiram (DSF) is one of the recommended aids in the management of selected patients with alcohol dependence. Hypertension (HTN) as an adverse effect of DSF therapy is less understood. In our prospective case series of 7 subjects with co-morbid alcohol and nicotine dependence, a temporal, dose-dependent, and reversible grade 1-3 HTN within 1-6 weeks of initiation of DSF therapy (125-500 mg/day) with no other detectable causes of HTN was noted. Challenges and strategies surrounding diagnosis and treatment along with mean change and percentage rise in blood pressure are described. Literature review and clinical description of case series may suggest neurobiological role in its causation. HTN may be a clinically significant, dose-dependent, and reversible adverse effect of DSF therapy, especially in co-morbid alcohol and nicotine-dependent patients. Awareness amongst clinicians may render better health care delivery to subjects with alcohol dependence.
Authors:
Ranganath R Kulkarni; Santosh I Ramdurg; Bhavya K Bairy
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Indian journal of psychological medicine     Volume:  36     ISSN:  0253-7176     ISO Abbreviation:  Indian J Psychol Med     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-22     Completed Date:  2014-10-22     Revised Date:  2014-10-24    
Medline Journal Info:
Nlm Unique ID:  7910727     Medline TA:  Indian J Psychol Med     Country:  India    
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Languages:  eng     Pagination:  434-8     Citation Subset:  -    
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Journal Information
Journal ID (nlm-ta): Indian J Psychol Med
Journal ID (iso-abbrev): Indian J Psychol Med
Journal ID (publisher-id): IJPsyM
ISSN: 0253-7176
ISSN: 0975-1564
Publisher: Medknow Publications & Media Pvt Ltd, India
Article Information
Copyright: © Indian Journal of Psychological Medicine
open-access:
Print publication date: Season: Oct-Dec Year: 2014
Volume: 36 Issue: 4
First Page: 434 Last Page: 438
PubMed Id: 25336781
ID: 4201801
Publisher Id: IJPsyM-36-434
DOI: 10.4103/0253-7176.140744

Disulfiram-Induced Reversible Hypertension: A Prospective Case Series and Review of The Literature
Ranganath R. Kulkarniaff1
Santosh I. Ramdurgaff1
Bhavya K. Bairyaff1
Department of Psychiatry, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India
Correspondence: Address for correspondence: Dr. Ranganath R. Kulkarni Department of Psychiatry, SDM College of Medical Sciences and Hospital, Dharwad-580009, Karnataka, India. E-mail: dranant007@rediffmail.com

INTRODUCTION

Disulfiram (DSF) is one of the USFDA-approved recommended aids in the management of selected cases of alcohol dependence for over 6 decades, that relies on “psychological threat” to avoid DSF-ethanol reactions.[1] Its toxicity may present different clinical aspects, though the mechanism (direct or idiosyncratic) remains unclear.[2] DSF (125-500 mg/day)-related hypertension (HTN) has been documented in very few earlier reports to cause reversible, dose-dependent grade 1-2 HTN within 2-3 weeks of administration,[3, 4, 5, 6, 7] while a systematic review observed no change in blood pressure (BP) with 6 weeks of DSF (250 mg/day) therapy.[8] Surprisingly, most of the related articles were during the period between 1950s and 1980s. This shows the need for research, especially in the Indian context, when alcohol population and wide use of DSF (sometimes surreptitiously) in de-addiction centers are considered.[3] We report prospective series of 7 subjects with alcohol dependence that developed reversible grade 1-3 HTN within 1-6 weeks of DSF therapy. A PubMed search was done using the keywords; ‘disulfiram,’ ‘hypertension,’ ‘blood pressure,’ and relevant articles were retrieved supplemented with a manual search of cross-references to compile the information on possible mechanisms of DSF-induced HTN.


CASE REPORT

Detection of a case with DSF-induced HTN[3] led us to monitor BP in patients on DSF therapy as a matter of therapeutic concern, which revealed a temporal association of HTN within 6 weeks of initiation of DSF therapy in another 7 subjects with alcohol dependence syndrome diagnosed as per ICD-10 criteria.[9] All had sought inpatient treatment at the Alcohol and Drug De-addiction Clinic, Department of Psychiatry of our Medical Institution. All were males with age range from 31 to 55 years. Six of 7 (85.71%) subjects had uncomplicated alcohol withdrawal state as also co-morbid tobacco dependence syndrome. Only one case had co-morbid diabetes mellitus (with normal BP) since 2 years with euglycemic control on oral hypoglycemic agents. BP was recorded manually by sphygmomanometer, with baseline BP defined as that measured after completion of alcohol detoxification but before initiation of DSF therapy. Severity of HTN was graded as per the European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for management of arterial HTN.[10] None of the subjects had high-normal BP or HTN during baseline assessment. DSF was started after written informed consent from patient and spouse/caregiver. The daily dose of DSF ranged from 250-500 mg (mean 428.57 ± 121.99 mg). Compliance with medications was supervised, and abstinence from alcohol was ensured by caregivers. None of the cases had prior medical history of HTN, diabetes, renal problems, neurological deficits, or any drug intake. Family history of alcoholism was noted in 4 subjects and HTN in 2 subjects. Liver function tests revealed marginally elevated liver enzymes. Ultrasonography of abdomen showed mildly enlarged liver with grade-2 fatty infiltration. Renal parameters were within normal limits in all subjects. Upon detection, initial DSF dose was continued in 3 subjects, while dose was reduced (125-250 mg/day) in another 3 subjects based on patient preference and severity of HTN. DSF was discontinued in one subject who had diabetes mellitus with accelerated HTN (200/100 mm Hg), chest pain, and left ventricular strain on electrocardiograph. All subjects were encouraged for life style modifications (LSM) like regular exercises and dietary measures like low salt diet (LSD). Considering the severity of possible DSF-induced HTN, physician initiated anti-hypertensives in 3 subjects. Table 1 shows the socio-demographic and clinical profile, while Table 2 presents the prospective BP monitoring with management strategies of 7 subjects with DSF-induced HTN. Figures 1 and 2 show the changes in systolic BP (SBP) and diastolic BP (DBP) from baseline, respectively, in our series.


DISCUSSION

DSF is relatively non-toxic substance when administered alone that markedly alters the intermediary metabolism of alcohol. It acts by inhibiting aldehyde dehydrogenase, alcohol dehydrogenase, and dopamine beta-hydroxylase (DBH).[11] DSF along with its two metabolites, diethyldithiocarbamate, and carbon disulphide inhibit DBH activity, a norepinephrine (NE) biosynthetic enzyme, which normally catalyzes the formation of NE from dopamine.[12] This increases urinary excretion of the main dopamine metabolite homovanillic acid and decreases urinary excretion of NE and its major metabolite vanillylmandelic acid.[7] Furthermore, side-effects of DSF such as fatigue, tremor, reduced sexual potency, headache, and dizziness can be mediated by sympathetic nervous system where NE is the neurotransmitter.[13]

Mechanism of DSF-induced HTN in humans is unclear. Central nervous system alpha-adrenergic receptors modulate peripheral autonomic activities both, which regulate BP.[7] Possibly, changes in central or peripheral NE activity are responsible for the increase in BP. Peripheral synthesis of NE is probably not affected by the DSF as it is noted to have no effect on the pressor effect of tyramine and NE,[7] as also plasma levels of NE increase following long-term high-dose (> 500 mg/day) DSF therapy.[5] DSF limits NE synthesis in sympathetic nerves but not in the adrenal medulla, possibly due to large reserve of DBH in adrenals rendering DSF incapable of making DBH activity rate limiting and also due to limited access of drug to the adrenal DBH.[7] As DBH enzyme doesn’t cross the blood brain barrier and DSF does not inhibit plasma DBH levels, there remains possibility of central inhibition of DBH in brain and possibly deplete brain NE levels, thereby increase in BP.[6] Thus, it might be speculated that reduced DBH activity, due to either genetic factors or to effects of DSF, might reduce NE concentrations in critical areas of the brain and thereby increase BP.[7] DSF also inhibits uptake of monoamines by chromaffin granules,[14] which may result in increased amounts of catecholamine reaching the plasma. However, DSF increases the nitroglycerine-induced postural hypotension while decreasing the accompanying tachycardia.[7] This implies that DSF impairs the BP regulation through central nervous system by inhibition of the central DBH activity resulting in decreased central NE synthesis, which may interfere with the central alpha-adrenergic activity at the bulbar sympathetic cardio-accelerator and vasomotor centers, resulting in increased BP,[4] opposite of which is noted with anti-hypertensive agents like central alpha agonists (clonidine, methyldopa, reserpine, and guanfacine).

In our series, the temporal association of DSF initiation and HTN (1-6 weeks), absence of prior history of HTN, diabetes, renal illness or drug intake suggestive or contributing to HTN, reduction in BP with DSF dose-reduction, and appearance of hypotension upon discontinuation of DSF during anti-hypertensive therapy, all led to the suspicion of possible DSF-induced HTN. In our subjects who had fatty liver, the dose of DSF was 250-500 mg/day. However, even low-doses of DSF (125 mg/day) in subjects with cirrhosis of liver have been quoted to induce HTN due to reduced DSF metabolism.[4] Reduction of dose in 3 cases showed mild reduction in BP, although LSM and LSD helped in 2 cases possibly suggests dose-dependent vascular adverse effect of DSF with some beneficial effect of LSM/LSD. In 3 subjects managed with anti-hypertensives, 2 cases showed a significant fall in BP upon discontinuation of DSF necessitating discontinuation of anti-hypertensives with subsequent return to normal BP; while another case showed an adequate control of HTN upon anti-hypertensives being continued with reduced DSF dose (125 mg/day). This may imply that DSF-induced HTN can be controlled with anti-hypertensive agents, which needs to be discontinued upon stopping DSF.

In a small, randomized, double-blind, placebo-controlled trial on DSF therapy (250 mg/day), a significant increase in SBP with mean change in BP of 8.35 ± 1.3 mm Hg (P < 0.001) in those on DSF therapy was noted, although discontinuation of DSF was not advised.[6] However, in our study, mean rise in SBP was 48.86 ± 13.7 mm Hg and that of DBP was 24.0 ± 5.77 mm Hg with mean duration of its detection being 3.29 ± 2.06 weeks. This may be due to usage of relatively higher DSF dose (428.57 ± 121.99 mg) in our sample or due to comorbid nicotine dependence (85.71%) as nicotine may alter blood levels of DSF through cytochrome P450 enzyme inhibition.[3, 11] Mean percentage change in BP from baseline of 40.08 ± 10.69% rise in SBP and 31.22 ± 8.60% rise in DBP in our series may implicate the severity of this adverse effect in patients on DSF therapy. Paradoxically, DSF-ethanol reaction may produce a hypertensive reaction in some cases.[15] However, this was not the case in our patients whose compliance was ensured by supervised medication as also the findings of temporal causation of side-effect, gradual persistent increase in BP, and a dose-dependent reduction in the BP with a return to normal values following the discontinuation of DSF and/or anti-hypertensives may support it to be drug-related HTN. These findings reflect DSF-induced HTN as a significant vascular adverse effect that needs early detection and management.


CONCLUSION

DSF can be viewed as a drug with a moderate record of adverse effects. Alcohol dependence, for which it can be a helpful treatment, is associated with a high morbidity and mortality.[2] HTN may be a clinically significant, dose-dependent, and usually reversible adverse effect of DSF therapy.[16, 17] Its awareness amongst physicians and psychiatrists in the holistic management of alcohol-dependent patients is worthwhile to keep a follow-up and sustain patient compliance with the drug, as also prevent misdiagnosis of essential HTN.[3, 18] In our opinion, an index of suspicion for DSF-induced HTN is needed, especially in cases with co-morbid alcohol and tobacco dependence. In detected individuals, reduction of DSF dose may be advised along with LSM, LSD, and anti-hypertensives. However, DSF may be discontinued if significant HTN persists. Regular BP monitoring for at least fortnightly for initial 3 months, followed by monthly for next 3 months, and later once in 3 months during DSF therapy may appear prudent to detect the ‘silent’ neurovascular adverse effect of DSF.[3]


Notes

Source of Support: Nil

Conflict of Interest: None.

REFERENCES
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2. Chick J. Safety issues concerning the use of disulfiram in treating alcohol dependenceDrug SafYear: 1999204273510348093
3. Kulkarni RR,Bairy BK. Disulfiram induced reversible hypertension: A prospective case study and brief reviewIndian J Psychol MedYear: 201335217924049238
4. Volicer L,Nelson KL. Development of reversible hypertension during disulfiram therapyArch Intern MedYear: 1984144129466732388
5. Lake CR,Major LF,Ziegler MG,Kopin IJ. Increased sympathetic nervous system activity in alcoholic patients treated with disulfiramAm J PsychiatryYear: 197713414114920841
6. Silver DF,Ewing JA,Rouse BA,Mueller RA. Responses to disulfiram in healthy young men: A double-blind studyJ Stud AlcoholYear: 197940100313
7. Rogers WK,Benowitz NL,Wilson KM,Abbott JA. Effect of disulfiram on adrenergic functionClin Pharmacol TherYear: 19792546977106999
8. Peachey JE,Brien JF,Roach CA,Loomis CW. A comparative review of the pharmacological and toxicological properties of disulfiram and calcium carbimideJ Clin PsychopharmacolYear: 198112167028794
9. World Health OrganizationThe ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic GuidelinesYear: 199210th edGenevaWorld Health Organization
10. Mancia G,Fagard R,Narkiewicz K,Redón J,Zanchetti A,Böhm M,et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)J HypertensYear: 201331128135723817082
11. DisulfiramLast Accessed on 2012 Dec 9 Available from: http://www.pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?q=all&cid=3117#ec.
12. Weinshenker D,Schroeder JP. There and back again: A tale of norepinephrine and drug addictionNeuropsychopharmacologyYear: 20073214335117164822
13. Ritchie JM. Goodman LS,Gilman AThe aliphatic alcoholsThe Pharmacological Basis of TherapeuticsYear: 19705thedNew YorkMacMillan Publishing Co13751
14. Schlichter D,DaPrada M,Pletscher A. Interference of inhibitors of dopamine-β-hydroxylase with uptake of monoamines by chromaffin granular membranesEur J PharmacolYear: 1975342237187432
15. Zapata E,Orwin A. Severe hypertension and bronchospasm during disulfiram-ethanol test reactionBMJYear: 19923058701422404
16. Huffman JC,Stern TA. Disulfiram use in an elderly man with alcoholism and heart disease: A discussionPrim Care Companion J Clin PsychiatryYear: 2003541415156245
17. Grover S,Bhateja G,Basu D. Pharmacoprophylaxis of alcohol dependence: Review and update Part 1: PharmacologyIndian J PsychiatryYear: 200749192520640061
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Figures

[Figure ID: F1]
Figure 1 

Changes in systolic blood pressure from baseline during disulfiram (DSF) therapy (N = 7)



[Figure ID: F2]
Figure 2 

Changes in diastolic blood pressure from baseline during disulfiram (DSF) therapy (N = 7)



Tables
[TableWrap ID: T1] Table 1 

Socio-demographic and clinical profile of subjects with disulfiram-induced hypertension (N = 7)



[TableWrap ID: T2] Table 2 

Prospective monitoring of blood pressure and management of subjects with disulfiram — induced hypertension (N = 7)




Article Categories:
  • Case Report

Keywords: Adverse effect, alcoholism, disulfiram, hypertension.

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