A drug interaction is the (potentiating or antagonising) influence of one drug on the effects or side effects of another drug. The interaction may be pharmacokinetic or pharmacodynamic. For example, the increased duration of epidural block from inhibition of the absorption of local anaesthetics (LA) produced by addition of epinephrine is a pharmacokinetic interaction; the same increase obtained by the addition of an opiate (due to the effect on the receptors in the spinal cord) is a pharmacodynamic interaction.
Interactions:
1. Epinephrine: Maximum enhancement of a LA block by epinephrine is obtained by the addition of a dose of 5 mcg/ml (its ceiling effect). In obstetrics, if epinephrine is unintentionally injected intra-vascularly the main side effect is vasoconstriction of the uterine arteries, which could be harmful for the fetus (5).
2. Opiates: Opioids added to LAs also exhibit a ceiling effect. For fentanyl this occurs at 50 mcg epidurally and 10 mcg subarachnoidally (6) even though higher doses are recommended. For sufentanil the corresponding ceiling doses are 25 mcg and 10 mcg respectively (3) and for morphine it is 0.1 mg subarachnoidally (7). These amounts are safe for both mother and fetus (1, 2, 9). Morphine, a hydrophilic drug, in a dose up to 3mg epidurally, as an additive to the LAs, is also safe as far as late respiratory depression is concerned. This 3mg epidural dose is significantly lower than the morphine ceiling effect dose.
3. Clonidine: The pharmacodynamic potentiation of LA effects can also be obtained with clonidine, but its use in pregnancy is controversial because of its haemodynamic side effects.
4. Bicarbonate: Since penetration of LAs is dependent upon their ionization, the addition of bicarbonate (4) or CO2 (8) may shorten the onset and increase the intensity of the block (a pharmacokinetic interaction). With bupivacaine, however, this effect is limited because the drug precipitates at a specific pH.
5. H2 antagonists: Repeated intake of cimetidine (but not ranitidine) may enhance bupivacaine toxicity by inhibiting bupivacaine metabolism (5).
6. Others: All drugs with high protein binding may increase toxicity of bupivacaine (Table 36.6) and ropivacaine (Chapter 4) (a pharmacokinetic interaction). This is especially so in the fetus where decreased protein binding produces higher serum and tissue free drug levels (Chapter 77 and Chapter 50).
References:
1. Benlabed M et al Anesthesiology 1990 73:1110
2. Capogna G et al Reg Anesth 1989 14:S24.
3. Courtney MA et al Reg. Anesth 1992 17:274
4. DiFazio CA et al. Anesth Analg 1986 65:760
5. Janowski EC. Anesthesiology Clinics of North America 1990 8:1
6. Naulty JS. Anesthesiology 1985; 63:694
7. Schaer H et al Anaesthesist 1992 41:689
8. Sukhani R, Winnie AP. Anesth Analg 1987 66:739
9. Youngstrom P. Anesthesiology 1984 61 :A414