Cimetidine and ranitidine can reduce or abolish effects of tolazoline used as a pulmonary vasodilator in children
A newborn infant with persistent foetal circulation was given a continuous infusion of tolazoline to reduce pulmonary hypertension. The oxygenation improved but gastrointestinal bleeding occurred. When cimetidine was given, condition of child deteriorated with a decrease in oxygen saturation and arterial pO2 values (See reference number 1). A second case report describes a similar outcome in a 2-day-old neonate,who had an initial improvement with tolazoline alone, but then developed worsening hypoxaemia when cimetidine was given (See reference number 2).
These reports are similar to another, in which tolazoline-induced reduction in pulmonary arterial pressure in a child was reversed when cimetidine was given, for acute gastrointestinal haemorrhage (See reference number 3). Another study in 12 children found that intravenous ranitidine 3 mg/kg abolished tolazoline-induced reduction in pulmonary and systemic vascular (See reference number 4).
Tolazoline dilates pulmonary vascular system by stimulating both H1and H2-receptors. Cimetidine and ranitidine block H2-receptors so that at least part of effects of tolazoline are abolished
Cimetidine and ranitidine are not suitable drugs for prophylaxis of gastrointestinal adverse effects of tolazoline in children
Roll C,Hanssler L. Interaktion von Tolazolin und Cimetidin bei persistierender fetaler Zirkulation des Neugeborenen. Monatsschr Kinderheilkd (1993) 141, 297–9.
Huang C-B,Huang S-C. Caution with use of cimetidine in tolazoline induced upper gastrointestinal bleeding. Changgeng Yi Xue Za Zhi. (1996) 19, 268–71.
Jones ODH,Shore DF, Rigby ML. The use of tolazoline hydrochloride as a pulmonary vasodilator in potentially fatal episodes of pulmonary vasoconstriction after cardiac surgery in children. Circulation (1981) 64 (Suppl II), 134–9.
Bush A,Busst CM, Knight WB, Shinebourne EA. Cardiovascular effects of tolazoline and ranitidine. Arch Dis Child (1987) 62, 241–6.
Plant extracts containing cardiac glycosides have been in use for thousands of years. The ancient Egyptians were familiar with squill (a source of proscillaridin), as were Romans who used it as a heart tonic and diuretic. The foxglove was mentioned in writings of Welsh physicians in thirteenth century and features in An Account of Foxglove and some of its Medical Uses, published by William Withering in 1785, in which he described its application in treatment of dropsy or oedema that results from heart failure.
The most commonly used cardiac glycosides are those obtained from members of foxglove family, Digitalis purpurea and Digitalis lanata. The leaves of D. lanata are source of a number of purified glycosides including digoxin, digitoxin, acetyldigoxin, acetyldigitoxin, lanatoside C, deslanoside, of gitalin (an amorphous mixture largely composed of digitoxin and digoxin), and of powdered whole leaf digitalis lanata leaf.
D. purpurea is source of digitoxin, digitalis leaf, and standardised preparation digitalin. Metildigoxin is a semi-synthetic digitalis glycoside. Occasionally ouabain or strophanthin-K (also of plant origin) are used for particular situations, while for a number of years Russians have exploited cardiac glycosides from lily of valley (convallaria). Bufalin is a related cardioactive compound obtained from toads,and is found in a number of Chinese medicines.
The cardiac glycosides have two main actions and two main applications. They reduce conductivity within atrioventricular (AV) node, hence are used for treating supraventricular tachycardias (especially atrial fibrillation), and they have a positive inotropic effect (i.e. increase force of contraction), hence are used for congestive heart failure, although this use has declined.
Because most commonly used glycosides are derived from digitalis, achievement of desired therapeutic serum concentration of any cardiac glycoside is usually referred to as digitalisation. Treatment may be started with a large loading dose so that therapeutic concentrations are achieved reasonably quickly, but once these have been reached amount is reduced to a maintenance dose. This has to be done carefully because there is a relatively narrow gap between therapeutic and toxic serum concentrations. Normal therapeutic levels are about one-third of those that are fatal, and serious toxic arrhythmias begin at about two-thirds of fatal levels. The normal range for digoxin levels is 0.8 to 2 nanograms/mL (or
1.02 to 2.56 nanomol/L). To convert nanograms/mL to nanomol/L multiply by 1.28,or to convert nanomol/L to nanograms/mL multiply by 0.781. Note that micrograms/L is same as nanograms/mL.
If a patient is over-digitalised,signs of toxicity will occur, which may include loss of appetite, nausea and vomiting, and bradycardia. These symptoms are often used as clinical indicators of toxicity,and a pulse rate of less than 60 bpm is usually considered to be an indication of over-treatment. Note that paroxysmal atrial tachycardia with AV block and junctional tachycardia can also occur as a result of digitalis toxicity. Other symptoms include visual disturbances,headache, drowsiness and occasionally diarrhoea. Death may result from cardiac arrhythmias. Patients treated for cardiac arrhythmias can therefore demonstrate arrhythmias when they are both under- as well as over-digitalised.
Interactions of cardiac glycosides
The pharmacological actions of these glycosides are very similar,but their rates and degree of absorption, metabolism and clearance are different. For example, digoxin is mainly renally cleared whereas digitoxin undergoes a degree of metabolism by liver. It is therefore most important not to extrapolate an interaction seen with one glycoside and apply it uncritically to any other. Because therapeutic ratio of cardiac glycosides is low, a quite small change in serum levels may lead to inadequate digitalisation or to toxicity. For this reason interactions that have a relatively modest effect on serum levels may sometimes have serious consequences.
Many interactions between digoxin and other drugs are mediated by Pglycoprotein. Drugs that inhibit activity of P-glycoprotein in renal tubules may reduce elimination of digoxin in urine and this may result in toxic serum levels. Further, induction or inhibition of P-glycoprotein in gut may affect oral absorption of digoxin. See also Drug transporter proteins,.