a) Hypertension may be a complication of long term abuse of glycyrrhetenic acid, the hydrolyzed metabolite of glycrrhizic acid (the active component of liquorice) which causes exogenously induced hypermineralcorticoidism (hypertension, retention of sodium and water, potassium loss and suppression of the renin-aldosterone system) (Morgan et al, 2011; Yorgun et al, 2010; Caubet-Kamar et al, 2010; Johns, 2009; Kurisu et al, 2008; Breidthardt et al, 2006; Nielsen & Pedersen, 1984; Heikens et al, 1995; de Klerk et al, 1997).
b) CASE REPORT: Hypertension and hypokalemia were reported in a 21-year-old woman with a history of chewing gum (2 packs daily) which contained 585 mg liquorice in each 15 gram packet with a daily intake calculated as 120 mg of glycyrrhizinic acid (de Klerk et al, 1997). Blood pressure and serum potassium returned to normal with 3 weeks after stopping the product.
c) CASE REPORT: A 40-year-old woman developed severe hypertension (mean blood pressure 170/110 mmHg) following chronic large ingestions (estimated at 100 to 200 grams/day) of liquorice daily. Based on cortisol levels and metabolic clearance of cortisol, the patient had developed an inhibited cortisol-cortisone shuttle, which resulted in a mineralocorticoid excess syndrome (Heikens et al, 1995).
d) CASE REPORT: A 67-year-old man with hypertension (diagnosed a month prior to admission) and benign prostatic hypertrophy, developed progressive muscular weakness following chronic (4 months) ingestion of a powdered Chinese herbal formula (approximately 50 g/day) containing a large amount of glycyrrhizic acid (0.56 mg/mL herbal solution; 336 mg/day) mixed in 600 mL of water. Laboratory tests revealed hypokalemia (potassium 2.2 mmol/L), and metabolic alkalosis (HCO3 30 mmol/L), a very high urinary excretion of potassium (urine potassium 18 mmol/L, 24-hour potassium excretion 42 mmol), and transtubular potassium concentrating gradient (TTKG) of 7. A week after starting treatment with oral potassium chloride (48 mmol/day), he had low levels of plasma renin (0.03 ng/L [0.11-0.69]) and aldosterone (36 pmol/L [111-860]). Approximately two weeks after starting treatment with 100 mg/day of spironolactone, his plasma potassium level and blood pressure returned to normal (Lin & Chau, 2002).
e) CASE REPORT: A 59-year-old man developed muscular weakness, hypokalemic paralysis (potassium 1.8 mmol/L), severe rhabdomyolysis (CK 35,063 Units/L), metabolic alkalosis (HCO3 40 mmol/L), and hypertension (BP 187/87 mmHg) after taking approximately 200 g of liquorice a day for 4 weeks. A symmetric flaccid paralysis with areflexia in the lower and upper extremities was observed. Urinary excretion of potassium was low and plasma renin activity and aldosterone levels were far below the plasma level of normal. Following supportive therapy, he recovered without further sequelae (van den Bosch et al, 2005).

a) CASE REPORT: A 59-year-old diabetic woman developed torsades de pointes after drinking 5 to 6 glasses of liquorice tea for 2 days prior to admission for constipation. Immediately after arrival to the ED, resuscitation efforts were started for polymorphic ventricular tachycardia. The patient was converted to normal sinus rhythm. However, a recurrence of polymorphic VT developed and she was admitted to the ICU after receiving several electrical shocks. An ECG also showed a prolonged QT interval (QT 580 msn). Laboratory studies revealed a normal potassium (3.7 mmol/L) and slightly elevated glucose (155 mg/dL); all other laboratory studies including cardiac enzymes were within normal limits. Her potassium remained normal throughout her hospital course. High rate pacing was needed to control recurring episodes of torsades de pointes. Coronary angiography showed no acute changes and an echocardiogram showed mild septal hypertrophy and left ventricular diastolic dysfunction. By day 4, the patient was stable with no further dysrhythmias and by day 8 her QT interval and ECG were normal and the patient was discharged to home (Ozturk et al, 2013).

a) CASE REPORT: A 50-year-old woman presented with palpitations, syncope, weakness and chest pain, evaluation revealed profound hypokalemia (1.77 mEq/L). An initial ECG revealed sinus rhythm, a ventricular rate of 112 beats/min and right bundle branch block, with a corrected QT interval of 0.45 s, a J point elevation of 2 mm, and a PR interval of 0.22 s. At this time, it was found that she had been drinking 2 cups of liquorice extract daily for 3 months. She later developed ventricular fibrillation and was successfully converted to sinus rhythm. Intravenous potassium was started and a repeat ECG on day 2 was consistent with Brugada syndrome, sinus rhythm with a coved-type ST segment elevation on precordial leads V1-V2 followed by a deep T-wave inversion, and a corrected QT interval of 0.44 s. At this time, laboratory results revealed higher potassium levels (3.19 mEq/L). She was discharged home after her potassium level normalized, and at that time ECG showed a QTc of 0.44 msec, J point elevation of 1 mm and a PR interval of 0.22 sec. Three months after the initial admission, she received an IV ajmaline challenge (1 mg/kg over 5 min) which showed a coved-type ST segment elevation in V1-V2. A cardioverter defibrillator was implanted after the diagnosis of Brugada syndrome was confirmed (Yorgun et al, 2010).

a) CHRONIC USE: Dyspnea developed in two patients with hypokalemia and ECG changes after using medications containing glycyrrhizin (daily doses: 75 to 240 mg PO or 34 to 120 mg IV) (Kurisu et al, 2008).

a) CASE REPORT: A 28-year-old woman developed hypokalemia (2.07 mmol/L) and neuromuscular paralysis after ingesting 40 to 60 grams of liquorice daily for over three years. Symptoms included: severe weakness of proximal muscles of the arms and shoulder girdles, moderate weakness of the muscles of forearms, hands, and proximal muscles of the legs (unable to raise legs) and mild weakness of the posterior and anterior neck muscles. Almost complete neuromuscular paralysis occurred as the patient's potassium level declined to 1.3 mmol/L. Following intravenous potassium replacement (in a glucose-free solution) over a 48 hour period, paralysis completely resolved within 72 hours (Famularo et al, 1999).
b) Paralysis developed in two patients with hypokalemia after using medications containing glycyrrhizin (daily doses: 75 to 240 mg PO or 34 to 120 mg IV) (Kurisu et al, 2008).

a) CASE REPORT: A 65-year-old woman presented with sudden onset confusion, disorientation, and slurred speech after binging on black liquorice for several days. On admission, he had a blood pressure of 160/95 mmHg, pulse rate of 88 beats/min, and temperature of 36.4 degrees C. All laboratory results, including standard blood tests, lumbar puncture, head CT, and EEG were normal. He developed severe occipital headache, loss of vision and bilateral fine resting tremor of upper limbs 4 days after admission. At this time, her systolic blood pressure was above 220 mmHg and another blood test revealed plasma sodium of 144 mmol/L, potassium of 3.5 mmol/L, and creatinine of 284 mcmol/L. A CT scan of the head showed hypodensities in the cortical and subcortical regions of the occipital, parietal and posterior frontal lobes and no signs of intracranial hemorrhage or infarction. She was diagnosed with posterior reversible encephalopathy syndrome and severe hypertension. Following supportive care, she recovered gradually and was discharged after 3 days. No irreversible cerebral damage was noted on a follow-up MRI of the brain 2 months later (Morgan et al, 2011).

a) Nausea developed in 2 patients with hypokalemia after using medications containing glycyrrhizin (daily doses: 75 to 240 mg PO or 34 to 120 mg IV) (Kurisu et al, 2008).

a) Changes in the sodium/potassium ratios may result in pH changes (Salassa et al, 1962). A hypochloremic, hypokalemic alkalosis may be seen in severe cases (Roussak, 1952).
b) CASE REPORT: In one case, the patient's potassium was 0.8 mmol/liter, the chloride 0.63 mmol/liter, the sodium within normal limits, and the pH 7.60 (Nielsen & Pedersen, 1984).
c) CASE REPORT: A 59-year-old man developed muscular weakness, hypokalemic paralysis (potassium 1.8 mmol/L), severe rhabdomyolysis (CK 35,063 Units/L), metabolic alkalosis (HCO3 40 mmol/L), and hypertension (BP 187/87 mmHg) after taking approximately 200 g of liquorice a day for 4 weeks. Urinary excretion of potassium was low and plasma renin activity and aldosterone levels were far below the plasma level of normal. Following supportive therapy, he recovered without further sequelae (van den Bosch et al, 2005).
d) CASE REPORT: A 67-year-old man with hypertension (diagnosed a month prior to admission) and benign prostatic hypertrophy, developed progressive muscular weakness following chronic (4 months) ingestion of a powdered Chinese herbal formula (approximately 50 g/day) containing a large amount of glycyrrhizic acid (0.56 mg/mL herbal solution; 336 mg/day) mixed in 600 mL of water. Laboratory tests revealed hypokalemia (potassium 2.2 mmol/L), and metabolic alkalosis (HCO3 30 mmol/L), a very high urinary excretion of potassium (urine potassium 18 mmol/L, 24-hour potassium excretion 42 mmol), and transtubular potassium concentrating gradient (TTKG) of 7. A week after starting treatment with oral potassium chloride (48 mmol/day), he had low levels of plasma renin (0.03 ng/L [0.11-0.69]) and aldosterone (36 pmol/L [111-860]). Approximately two weeks after starting treatment with 100 mg/day of spironolactone, his plasma potassium level and blood pressure returned to normal (Lin & Chau, 2002).

a) CASE REPORT: One patient with severe hypokalemia was paralyzed from the waist down on admission (Nielsen & Pedersen, 1984).
b) Muscle weakness resolved in as little as 12 hours after administration of potassium both orally and intravenously (Bannister et al, 1977).

a) CASE REPORT: A 28-year-old woman regularly ingested (over a 3 year period) three or four bags (40 to 60 grams) of pure liquorice daily and took furosemide (25 to 50 mg 3 times per week) over the previous month for weight loss developed severe hypokalemia (2.97 mmol/L {serum}) and muscle weakness. Creatine kinase on admission was 19,109. The patient was treated symptomatically and within 72 hours had recovered complete muscle strength (Famularo et al, 1999).
b) CASE REPORT: Rhabdomyolysis was noted in a 62-year-old who had ingested 100 grams of liquorice per day for 30 days. Symptoms developed after 20 days (Achar et al, 1989). Rhabdomyolysis has been noted in other patients as well (Piette et al, 1984).
c) CASE REPORT: A 59-year-old man developed muscular weakness, hypokalemic paralysis (potassium 1.8 mmol/L), severe rhabdomyolysis (CK 35,063 Units/L), metabolic alkalosis (HCO3 40 mmol/L), and hypertension (BP 187/87 mmHg) after taking approximately 200 g of liquorice a day for 4 weeks. Urinary excretion of potassium was low and plasma renin activity and aldosterone levels were far below the plasma level of normal. Following supportive therapy, he recovered without further sequelae (van den Bosch et al, 2005).

a) Avoid intravenous solutions containing dextrose in patients with severe hypokalemia as they may precipitate worsening hypokalemia.
b) CASE REPORT: Neuromuscular weakness and hypokalemia were reported in an adult following chronic exposure to liquorice. Initial treatment with intravenous potassium in a dextrose solution led to worsening neuromuscular paralysis and a further decline in serum potassium. Clinical and laboratory improvement was seen when potassium was added to a normal saline solution. The authors cited other cases of worsening hypokalemia following potassium administration in a dextrose solution and suggested that the resulting enhanced insulin secretion is triggered by glucose which results in increased uptake of potassium into cells further depleting serum potassium levels (Famularo et al, 1999).

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

a) LIDOCAINE/INDICATIONS
b) LIDOCAINE/DOSE
c) LIDOCAINE/MAJOR ADVERSE REACTIONS
d) LIDOCAINE/MONITORING PARAMETERS

a) AMIODARONE/INDICATIONS
b) AMIODARONE/ADULT DOSE
c) AMIODARONE/PEDIATRIC DOSE
d) ADVERSE EFFECTS

1) SUMMARY: Differences in glycyrrhizic acid content in liquorice preparations, the duration of use, and individual variation are likely to play a role in producing toxicity (Famularo et al, 1999).
2) 55 g of liquorice/day produced alkalotic hypokalemia within 2 months (Salassa et al, 1962).
3) 100 to 200 g of liquorice daily (time unspecified) produced severe hypokalemia, dysrhythmias, and paralysis in a patient (Nielsen & Pedersen, 1984).
4) Hypokalemic myopathy developed in a 66-year-old man who presented with muscular weakness, myalgia, difficulty walking, and hypertension after ingesting 4 L of a licorice beverage daily (1.6 g/day) for 2 months. He developed pulmonary edema and worsening hypertension 20 hours after receiving IV normal saline with 4 g/L of potassium chloride (1 L every 8 hours). Following supportive care, he recovered completely (Caubet-Kamar et al, 2010).
5) CASE SERIES: Fourteen patients (mean age 74 +/- 10) with a history of hypertension developed symptomatic hypokalemia (serum potassium levels of 1.5 to 3.1 mmol/L) and ECG changes after using medications containing glycyrrhizin (daily doses: 75 to 240 mg PO or 34 to 120 mg IV). Seven patients were also using diuretics (furosemide (4), azosemide, indapamide, and hydrochlorothiazide) for hypertension or edema. Following supportive therapy, all patients gradually recovered (Kurisu et al, 2008).
6) Severe muscle weakness, dysrhythmias, hypokalemia, and hypertension were seen in a 63-year-old man who ingested 3.5 pounds of liquorice per week for 15 to 20 years (Holmes et al, 1979).
7) Severe muscle weakness, hypokalemia (1.5 mEq/L), and myoglobinuria was seen in a 45-year-old who ingested 30 to 40 g of liquorice/day for 9 months while also on hydrochlorothiazide 50 mg 3 times per week (Gross et al, 1966). A similar case was reported in a woman who chronically ingested liquorice and took furosemide 3 to 4 times per week (Famularo et al, 1999).
8) A 59-year-old who ate 2 to 7 g of glycyrrhizinic acid per day for "several months" developed hypokalemic alkalosis and hypertension (Jenny et al, 1961).
9) A total dose of 595 mL of ext glycyrrh liq. B.P. was administered over 4 months to a 15-year-old as a flavoring agent for P.A.S.. Muscle stiffness, tetany, carpopedal and facial spasms, generalized seizures, and hypokalemia were noted. She was shown to have hypokalemic, hypochloremic alkalosis just before she died (Roussak, 1952).
10) Ingestion of 1.8 kg of liquorice per week (duration unspecified) produced myopathy, hypokalemia, and cardiac arrest (Bannister et al, 1977).
11) Hypertension, hypokalemia, aldosteronopenia, and suppressed plasma renin activity were signs and symptoms reported in a 58-year-old man who had ingested 2 to 3 36-g liquorice candy bars a day for 6 to 7 years (Conn et al, 1968).
12) A 33-year-old ingested approximately 500 g of liquorice a week for many years (duration not specified). Shortly after being given bendrofluazide 5 mg/day, she developed severe myopathy and hypokalemia (Sudaram & Swaminathan, 1981).