Download RESPONSES TO CARDIOVASCULAR DRUGS DURING ALCOHOL

Alcohol & Alcoholism Vol. 41, No. 1, pp. 11–13, 2006
Advance Access publication 31 October 2005
doi:10.1093/alcalc/agh228
COMMENTARY
RESPONSES TO CARDIOVASCULAR DRUGS DURING ALCOHOL WITHDRAWAL
SEPPO KÄHKÖNEN*
BioMag Laboratory, Helsinki University Central Hospital; Cognitive Brain Research Unit, University of Helsinki, Finland
(Received 11 May 2005; first review notified 6 July 2005; in revised form 23 August 2005; accepted 7 October 2005;
advance access publication 31 October 2005)
Abstract — Aim: To present findings on the kinetics and dynamics of cardiovascular drugs during alcohol withdrawal (AW), compared
with that observed in remission. Method: Studies were reviewed and summarized. Results: A single-dose study in alcoholic patients
with propranolol, a b-adrenergic antagonist, showed that the negative inotropic effect was decreased and the bradycardiac effect
increased during AW as compared with during early remission. The hypotensive effect of isosorbid dinitrate, commonly used as a
vasodilatator, was weaker at the onset of AW, being associated with the decreased bioavailability of the drug. Verapamil, which is a
2+
L-type Ca
channel antagonist, produced a bradycardiac effect at the onset of AW, but no effect was observed in early remission.
The effect was probably due to changes in L-type Ca2+ channels because no differences in verapamil concentrations between AW
and early remission were observed. Conclusion: Taken together, AW modifies the dynamics and kinetics of cardiac drugs, which
may have an impact on the treatment of alcoholic patients with cardiac diseases.
INTRODUCTION
after one month of abstinence some alcoholics with transitory
hypertension during AW continued to show high systolic
blood pressure in response to isometric handgrip test, higher
total peripheral resistance and heart rate, and lower stroke
volume than patients without hypertension (King et al.,
1991, 1996). Cardiovascular changes in AW are mediated by
several central and peripheral mechanisms. The level of
the activation of the sympathetic nervous system is the most
important factor regulating the functioning of the cardiovascular system in AW directly and indirectly with the
renin-angiotensin-aldosterone system, vasopressin, cortisol,
and sodium sensitivity (for review, see Kähkönen, 2004).
Alcohol-dependent subjects undergo different phases of their
disorder including acute intoxication, withdrawal and remission, all of which may affect drug kinetics and dynamics.
Acute and long-term alcohol intake is known to modify the
pharmacokinetics of many drugs. When administered simultaneously, alcohol can potentiate effects of several drugs,
whereas long-term alcohol abuse may have an inhibitory
effect due to pharmacokinetic interactions (for review, see
Fraser, 1997; Lieber and Abittan, 1999). In this overview,
recent findings will be discussed showing that alcohol
withdrawal (AW) also modifies drug kinetics and dynamics
producing drug responses different from those observed in
early remission.
EFFECTS OF BETA BLOCKING DRUGS
Kähkönen (2003) reported a study in six male alcoholics. On
Day 1 following AW, 80 mg of propranolol reduced the heart
rate by 25 ± 3.8 beats/min, whereas the reduction on Day 10
was 19 ± 2.1 beats/min (P = 0.05). Resting heart rate was
82 ± 6.2 and 73 ± 3.4 beat/min, respectively (P = 0.05). The
higher heart rate on day one reflects increased sympathetic
activity, associated with initial AW (see above). The blood
level reached on Day 1 was 70 ± 13.8 mg/ml and on Day 10
was 50 ± 9.5 mg/ml, thus more pronounced bradycardiac
effect on Day 1 is hardly unexpected. Another factor explaining the greater bradycardiac effect on Day 1 is higher initial
heart rate. It is evident that if an increase in heart rate is due
to strong adrenergic stimulation, it is easier for an adrenoreceptor antagonist to reveal its anti-adrenergic effect. In the
same study, the extent of the negative inotropic effect did
not differ between Days 1 and 10. However, when the
inotropic effect based on changes in cardiac output was plotted
against changes in propranolol concentration, the curve was
shifted to the left on Day 10. This may indicate that sensitization to the inotropic effect of propranolol occurs at early
remission.
The different cardiovascular responses to propranolol in
AW compared with early remission may arise partly from
altered central and peripheral adrenergic nervous activity
CARDIOVASCULAR CHANGES DURING ALCOHOL
WITHDRAWAL
Alcohol withdrawal is a severe complication of alcohol dependence that develops after cessation of alcohol intake in
alcohol-dependent patients. It is characterized by increased
anxiety, tremulousness, paroxysmal sweating, and reduced
sleep (American Psychiatric Association, 1994). In severe
forms, AW may precede the development of delirium tremens,
seizures, and complications such as arrhythmias which can
lead to sudden death (Puddey et al., 1999). Cardiovascular
changes that occur in AW, as a result of over-activity of the
sympathetic nervous system are tachycardia, arterial hypertension, elevated cardiac output, and increased total peripheral
resistance (Beckman et al., 1981; Saunclers et al., 1981;
Clark and Friedman, 1985; Kähkönen and Bondarenko,
2000). These changes are mostly transitory abnormalities
soon subsiding if abstinence is continued (Saunders et al.,
1981; Clark and Friedman, 1985; Kähkönen, 1997). However,
*Correspondence: Tel.: +358 9 47175579; Fax: +358 9 47175781; E-mail:
[email protected]
11
The Author 2005. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved
12
S. KÄHKÖNEN
during AW. Evidence suggests that AW is associated with
rebound b-adrenergic hypersensitivity (Sellers et al., 1976).
Further, the level of dihydroxyphenylalanine, dopamine,
noradrenaline, adrenaline, and homovanillic acid in alcoholic
patients are much higher than those in healthy subjects. With
the development of AW symptoms, urinary excretion of
catecholamines increases further, returning to normal levels
after AW reduction (Mendelson, 1970). On the first day of
AW, lymphocyte b-adrenoceptor levels have been found
to be reduced and associated with high noradrenaline and
adrenaline levels. Catecholamine levels rapidly subsided
over the next 3 days and lymphocyte b-receptors were
restored to normal levels within the same period (Mäki et al.,
1990). High-catecholamine levels have been established to
lead to a reduced b-receptor population (Cruickhank and
Prichard, 1994).
AW. On Day 1, verapamil caused a bradycardiac response,
which was absent on Day 10. The relative hypotensive effect
of verapamil was concomitantly weakened (Kähkönen and
Bondarenko, 2003). These results on Ca2+ channel modulation
of cardiovascular symptoms of AW are in line with those
obtained in animal experiments. Administration of antagonists
of L-type Ca2+ channels decreases withdrawal signs and
mortality in alcohol-dependent rats deprived of ethanol
(Little et al., 1986; Bone et al., 1989; Colombo et al., 1995;
Watson and Little, 2002). Further, long-term alcohol exposure
in rats has been reported to increase the number of dihydropyridine binding sites of cardiac L-type Ca2+ channels (Guppy
et al., 1995) and enhance their activity (Solem et al., 2000).
EFFECTS OF NITRATES
Propranolol concentrations on Day 1 of AW were compared
with concentrations on Day 10, being significantly higher on
Day 1 for the entire 2 h investigation (Kähkönen, 2003). These
findings are in line with those of Sandor et al. (1983), who
found elevated concentrations of free propranolol in plasma
during AW. Furthermore, alcohol consumed during the evening is capable of increasing the plasma clearance rate of
propranolol in non-alcoholic subjects 12 h later (Sotaniemi
et al., 1981), indicating that the enzymes responsible for
metabolism of propranolol in the liver, recover by early remission. On Day 10, the AUC0–1.5 h, Cmax and t1/2 of ISDN were
increased compared with those on Day 1 suggesting an
increase in bioavailability in early remission. Concentrations
of ISDN metabolites did not differ between the two periods
of investigation (Kähkönen and Zvartau, 2003). The reason
for increased bioavailability of ISDN in early remission is
uncertain. ISDN is metabolized by glutathione-S-transferase
to nitrite (Hill et al., 1989). Chronic ethanol treatment in
rats may activate glutathione-S-transferase (Antonenkov
et al., 1988; Ribiere et al., 1992). Thus, changes in drug metabolism induced by AW may underlie the observed alteration
in ISDN pharmacokinetics. AW did not affect verapamil
and norverapamil plasma concentrations (Kähkönen and
Bondarenko, 2004).
In conclusion, AW seems to be an important factor modifying responses to cardiac drugs. More studies are needed to
establish the relevance of altered drug responses in alcoholic
patients with cardiac diseases.
Cardiovascular effects after isosorbide dinitrate (ISDN; 20 mg
sublingually) were studied in nine alcoholic patients on Days 1
and 10 of AW (Kähkönen and Zvartau, 2003). No significant
difference was observed in the absolute decrease in systolic
blood pressure after ISDN administration. However, when
the decrease in systolic blood pressure was plotted against
changes in concentrations of ISDN and its metabolites, a
more marked effect was observed on Day 10. At the same
time, the tachycardiac response to ISDN was more pronounced on Day 1 of AW. Increased vasodilatation in
response to ISDN in early remission might be associated
with changes in nitric oxide (NO) function during AW.
ISDN has been suggested to induce vasodilatation through
NO function (Bennett and Marks, 1984; Brien et al., 1987).
ISDN undergoes bioformation to NO and S-nitrosothiol,
resulting in activation of guanylate cyclase to produce cyclic
GMP, which initiates relaxation of vascular smooth muscle
(Gruetter et al., 1981). Some evidence also indicates that
ISDN given to rats undergoing withdrawal from ethanol worsens withdrawal signs, suggesting that NO is involved in AW
(Adams et al., 1995). This was confirmed by findings of the
same authors that administration to rats, of an NO synthase
inhibitor, NG-nitro-L-arginine methyl ester, decreases the
severity of AW (Adams et al., 1995).
Although ISDN-induced vasodilatation was increased in
early remission, the effect was accompanied by a smaller
rise in heart rate than during AW. Tachycardia is a sympathetic reflex-mediated response to vasodilatation induced
by ISDN to maintain the cardiac output at a constant level
(Murad, 1990). Sympathetic activity is increased in alcoholic
patients undergoing withdrawal (Linnoila et al., 1987), which
may also result in a higher heart rate response to administration of ISDN. When sympathetic activity decreases after
resolution of AW, a lower heart rate response to ISDN can
be expected.
EFFECTS OF CALCIUM CHANNEL ANTAGONISTS
Cardiovascular effects of verapamil (5 mg intravenously)
were studied in seven alcoholic subjects on Days 1 and 10 of
CARDIOVASCULAR DRUG KINETICS AND
CONCENTRATIONS
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