Liver beta-blocker effects

Drug interactions Proleukin may affect central nervous system function. Therefore interactions could occur following concomitant administration of psychotropic drugs. Concurrent administration of drugs possessing nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic effects with Proleukin may increase toxicity in these organ systems. Reduced kidney and liver function secondary to Proleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs. Beta-blockers and other antihypertensives may potentiate the hypotension seen with Proleukin. 

Many beta-adrenoceptor antagonists undergo substantial first-pass hepatic metabolism these include alprenolol, metoprolol, oxprenolol, and propranolol. Hepatic cirrhosis, with consequent portosystemic shunting, can therefore result in increased systemic availability and higher plasma concentrations, perhaps resulting in adverse effects. Beta-blockers may also reduce liver blood flow and cause interactions with drugs with flow-dependent hepatic clearance. 

C. Toxicity Cardiovascular adverse effects, which are extensions of the beta blockade induced by these agents, include bradycardia, atrioventricular blockade, and congestive heart failure. Patients with airway disease may suffer severe asthma attacks. Premonitory symptoms of hypoglycemia from insulin overdosage, eg, tachycardia, tremor, and anxiety, may be masked, and mobilization of glucose from the liver may be impaired. CNS adverse effects include sedation, fatigue, and sleep alterations. Atenolol, nadolol, and several other less lipid-soluble beta-blockers are claimed to have less marked CNS action because they do not enter the CNS as readily as other members of this group. 

A PO/sublingual. Rapid, complete absorption of sublingual dose. 98% protein bound. Metabolites are inactive, half-life = 3 hrs. Hypotension. Beta blockers increase risk of severe hypotension, heart failure, and angina. Nifedipine increases effects of oral anticoagulants. Cimetidine elevates nifedipine levels. Inttiai doses may exacerbate angina. Reduce dose in patients with liver dysfunction. 

One of the normal physiological responses to a fall in blood sugar levels is the mobilisation of glucose from the liver under the stimulation of adrenaline from the adrenals. This sugar mobilisation is blocked by non-selective beta blockers (such as propranolol) so that recovery from hypoglycaemia is delayed and may even proceed into a full-scale episode in a hypoglycaemia-prone diabetic. Normally the adrenaline would also increase the heart rate, but with the beta-receptors in the heart already blocked this fails to occur. A rise in blood pressure occurs because the stimulant effects of adrenaline on the beta-2 receptors (vasodilation) are blocked leaving the alpha (vasoconstriction) effects unopposed. 

The plasma levels and the effects of beta blockers that are mainly metabolised by the liver (e.g. alprenolol, metoprolol, timolol) are reduced by the barbiturates. Alprenolol concentrations are halved, but the other beta blockers are possibly not affected as much. Beta blockers that are mainly excreted unchanged in the urine (e.g. atenolol, sotalol, nadolol) would not be expected to be affected by the barbiturates. 

Not understood. Where pharmaeokinetie ehanges are seen, a possible reason is that the metabolism of the beta bloekers is altered by changes in blood flow through the liver. The pharmacodynamic changes with nifedipine may be explained by the fact that nifedipine reduces the contractility of the heart muscle. This is counteracted by a sympathetic reflex increase in heart rate due to nifedipine-induced peripheral vasodilation, so that the ventricular output stays the same or is even improved. The presence of a beta blocker may oppose this to some extent by slowing the heart rate, which allows the negative inotropic effects of nifedipine to go unchecked. 

Pharmacokinetic evidence and animal studies suggest that propranolol and chlorpromazine mutually inhibit the liver metabolism of the other drug so that both accumulate within the body. The mechanism of the interaction between propranolol and thioridazine is prohahly similar. Both beta blockers and phenothiazines can cause hypotension, and these effects could be additive. 

The interaction between propranolol and chlorpromazine appears to he established although information is limited. Concurrent use should be well monitored and the dosages reduced if necessary. The same precautions apply with propranolol and thioridazine. There seems to be no information about any interaction between other beta blockers and phenothiazines, but if the mechanism of interaction suggested above is true, it seems possible that other beta blockers that are mainly cleared from the body by liver metabolism might interact similarly with chlorpromazine, whereas those mainly cleared unchanged in the urine are less likely to have a pharmacokinetic interaction, although additive hypotensive effects would still be expected. See Table 22.1 , (p.833), for information on the metabolism of the commonly used systemic beta blockers. 

Information is limited but the interaetion would seem to be established. Concurrent use need not be avoided but antieipate the need to reduce the dosage of metoprolol and propranolol. Monitor closely because some patients may experience adverse effects. If the suggested mechanism of interaction is correct it is possible (but not confirmed) that other beta blockers that undergo liver metabolism will interact similarly but not those largely excreted unchanged in the urine. See Table 22.1 , (p.833) for the metabolism of some commonly used beta blockers. Also note that propafenone and the beta blockers have negative inotropic effects, which could be additive and result in unwanted cardiodepression. 

Fluoxetine and paroxetine inhibit the cytochrome P450 isoenzyme CYP2D6 thus inhibiting the metabolism of some beta blockers (e.g. propranolol, metoprolol, carvedilol) so that they accumulate, the result being that their effects, such as bradycardia, may be increased. Citalopram and escitalopram may also inhibit CYP2D6. In vitro studies with human liver microsomes found that fluoxetine and paroxetine are potent inhibitors of metoprolol metabolism and fluvoxamine, sertraline and citalopram less potent. However, fluvoxamine also potently inhibits the metabolism of propranolol by CYP1A2. Beta blockers that are not extensively me-... 

Smoking tobaeco increases heart rate, blood pressure and the severity of myocardial ischaemia, probably as a direct effect of the nicotine and due to the reduced oxygen-carrying capacity of the blood. - These actions oppose and may even totally abolish the beneficial actions of the beta blockers. In addition, smoking stimulates the liver enzymes concerned with the metabolism of some beta blockers (e.g. propranolol) so that their serum levels are reduced. 

In kidney, diltiazem and the atrial natriuretic peptide act together with Mn(II) in controlling haemodynamics [621,622]. In liver, ethanol alters the levels of a number of trace metals, including Mn(II) [623], while Mn(II) itself reduces the effects of aflatoxin and enhances the cytochrome P-450 mediated metabolism of hexabarbitol-type drugs [624,625]. In the nervous system, the effects of ischaemia are modulated by Ca-channel blockers such as Mn(II) [626]. Mn(II) ions have also been reported to modulate or inhibit the transient outward current in cultured sensory neurons or in taste nerve responses [627,628]. In pancreas beta-cells, interactions between the fluxes of Mn(II) and Ca(II) have also been observed [629]. 

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