Liquorice

Spanish and Italian liquorice is Glycyrrhiza glabra var typica Reg. et Herd. Persian or Turkish liquorice is Glycyrrhiza glabra L var violacea Boiss. Russian liquorice is Glycyrrhiza glabra L var glandulifera.

Constituents

• Liquorice has a great number of active compounds of different classes that act in different ways.

• The most important constituents are usually considered to be the oleanane-type triterpenes, mainly glycyrrhizin (glycyrrhizic or glycyrrhizinic acid), to which it is usually standardised, and its aglycone glycyrrhetinic acid.

• There are also numerous phenolics and flavonoids of the chalcone and isoflavone type, and many natural coumarins such as liqcoumarin, umbelliferone, glabrocoumarones A and B, herniarin and glycyrin.

• It also contains polysaccharides such as glycyrrhizin GA, and a small amount of volatile oil.

Use and indications

• The dried root and stolons of liquorice are used as an expectorant, antispasmodic and anti-inflammatory, and to treat peptic and duodenal ulcers.

• Liquorice is widely used in traditional oriental systems of medicine, and as a flavouring ingredient in food.

• It has mineralocorticoid and oestrogenic activity in large doses, as a result of glycyrrhetinic acid, and has many other reputed pharmacological effects.

Liquorice + Antihypertensives

Liquorice may cause fluid retention and therefore reduce the effects of antihypertensives. Additive hypokalaemia may also occur with loop and thiazide diuretics.

Mechanism

• Ingestion of liquorice inhibits 11β-hydroxysteroid dehydrogenase type 2, thereby preventing the inactivation of cortisol to cortisone.

• This results in mineralocorticoid effects including sodium and water retention (leading to hypertension) and hypokalaemia.

• This effect would oppose the effects of drugs used to lower blood pressure. In addition, the potassium-depleting effect of liquorice would be expected to be additive with loop and thiazide diuretics.

• The mineralocorticoid effect of liquorice is due to the content of glycyrrhetinic acid (a metabolite of glycyrrhizic acid), and therefore deglycyrrhizinated liquorice would not have this effect.

Liquorice + Corticosteroids

Liquorice, if given in large quantities with corticosteroids, may cause additive hypokalaemia.

Mechanism

• Inhibition of 11β-hydroxysteroid dehydrogenase by glycyrrhetinic acid may slightly delay the clearance of hydrocortisone and prednisolone and thereby enhance their effects.

• However, note that whether a mineralocorticoid or glucocorticoid is a substrate for this enzyme system depends on its chemical structure.

• Therefore, it cannot be assumed that liquorice will inhibit the inactivation of all corticosteroids.

• Dexamethasone appears to attenuate the mineralocorticoid effects of glycyrrhizin because it suppresses endogenous cortisol secretion (causes adrenal suppression).

• Other corticosteroids would be expected to interact similarly if given in adrenal-suppressant doses. Deglycyrrhizinated liquorice would not have these effects.

Liquorice + Digitalis glycosides

An isolated case of digoxin toxicity has been reported in an elderly patient attributed to the use of a herbal laxative containing kanzo (liquorice).

Mechanism

• The reason for the increase in digoxin levels is unclear. Digoxin inhibits the sodium–potassium ATPase pump, which is concerned with the transport of sodium and potassium ions across the membranes of the myocardial cells.

• Potassium loss caused by a combination of the liquorice, rhubarb and diuretics exacerbated the potassium m thereby enhancing the bradycardia, already caused by an elevated digoxin level. Hypokalaemia

Also promotes the binding of digoxin to myocardial cells. The patient’s pre-existing cardiovascular disease may have also predisposed the patient to enhanced digoxin effects.

Liquorice + Laxatives

Liquorice may cause additive hypokalaemia if given in large quantities with laxatives.

(a) Additive potassium depletion

• Liquorice root may cause water retention and potassium depletion.

• Chronic diarrhoea caused by the long-term use or abuse of stimulant laxatives such as aloes and senna may lead to excessive loss of water and potassium, and can also lead to potassium deficiency.

• Theoretically, concurrent use of these herbs might have additive effects on potassium loss.

• One report describes four cases of pseudohyperaldosteronism (hypertension, hypokalaemia and suppression of the renin–aldosterone axis) in patients taking liquorice-containing laxatives for chronic constipation.

• The possible additive potassium depletion in patients given liquorice and anthraquinone-containing laxatives (such as senna and rhubarb) is a theoretical interaction, but bear it in mind in patients who are taking liquorice and who are regular users/abusers of anthraquinonecontaining substances.

• However, note that, if anthraquinone laxatives are used as recommended (at a dose producing a comfortable soft-formed motion), this interaction is unlikely to be important.

• It is unclear if sodium picosulfate affects the efficacy of liquorice as a laxative, and combination products are common.

References

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Sigurjonsdottir HA, Franzson L, Manhem K, Ragnarsson J, Sigurdsson G, Wallerstedt S. Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens (2001) 15, 549–52.

Walker BR, Edwards CRW. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am (1994) 23, 359–77.

Hammer F, Stewart PM. Cortisol metabolism in hypertension. Best Pract Res Clin Endocrinol Metab (2006) 20, 337–53.

Kageyama Y, Suzuki H, Saruta T. Glycyrrhizin induces mineralocorticoid activity through alterations in cortisol metabolism in the human kidney. J Endocrinol (1992) 135, 147–52.

Ojima M, Satoh K, Gomibuchi T, Itoh N, Kin S, Fukuchi S, Miyachi Y. The inhibitory effects of glycyrrhizin and glycyrrhetinic acid on the metabolism of cortisol and prednisolone – in vivo and in vitro studies. Nippon Naibunpi Gakkai Zasshi (1990) 66,584–96.

Teelucksingh S, Mackie ADR, Burt D, McIntyre MA, Brett L, Edwards CRW. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet (1990) 335, 1060–3.

Chen M-F, Shimada F, Kato H, Yano S, Kanaoka M. Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn (1991) 38, 167– 74.

Chen M-F, Shimada F, Kato H, Yano S, Kanaoka M. Effect of glycyrrhizin on the pharmacokinetics of prednisolone following low dosage of prednisolone hemisuccinate. Endocrinol Jpn (1990) 37, 331–41.

Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11β-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology (1993) 132, 2287–92.

Harada T, Ohtaki E, Misu K, Sumiyoshi T, Hosoda S. Congestive heart failure caused by digitalis toxicity in an elderly man taking a licorice-containing chinese herbal laxative. Cardiology (2002) 98, 218.

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Scali M, Pratesi C, Zennaro MC, Zampollo V, Armanini D. Pseudohyperaldosteronism from liquorice-containing laxatives. J Endocrinol Invest (1990) 10, 847–8.

Mizuhara Y, Takizawa Y, Ishihara K, Asano T, Kushida H, Morota T, Kase Y, Takeda S, Aburada M, Nomura M, Yokogawa K. The influence of the sennosides on absorption of glycyrrhetic acid in rats. Biol Pharm Bull (2005) 28, 1897–902.

Goto E, He J-X, Akao T, Tani T. Bioavailability of glycyrrhizin from Shaoyao-Gancao- Tang in laxative-treated rats. J Pharm Pharmacol (2005) 57, 1359–63.