4 Drug Interactions and Obstetric Anesthesia ᭢ Drugs Used for Maternal and Fetal Indications Drugs Used for Maternal Indications Antibiotics Antiepileptic Drugs Enzyme Induction Sympathomimetic Drugs Sympathetic nervous system agonist drugs Antiasthmatic Drugs Xanthine derivatives Sympathomimetic drugs Corticosteroids Histamine H2 Receptor Blockers Psychotropic Agents Phenothiazine, thioxanthenes, and butyrophenones Tricyclic antidepressants Monoamine oxidase inhibitors Lithium carbonate The serotonin syndrome Anesthetic implications Tocolytic Drugs Magnesium sulfate b-Mimetic drugs Calcium channel blockers Prostaglandin inhibitors Hypotensive Drugs Hydralazine Nitroglycerin Nitroprusside Trimethaphan Uterotonic Agents Oxytocin Ergot alkaloids Prostaglandin Local Anesthetics Narcotics Anti-fungal drugs Drugs Used for Fetal Indications DRUG INTERACTIONS AND OBSTETRIC INTERACTIONS 39 Drugs Used for Maternal and Fetal Indications Newer pharmacological agents are being used more fre- quently for the treatment of maternal and fetal pathological states. Obstetric anesthesiologists should be aware of the inter- actions of maternally administered drugs with anesthetic agents and techniques. Drugs Used for Maternal Indications Antibiotics Rarely, parturients may receive antibiotics for various disease processes. Most of the antibiotics will prolong the effect of nondepolarizing muscle relaxants, but prolongation of depolarizing muscle relaxants has also been observed (Table 4-1).1 The mechanism of this phenomenon is unknown. Antagonism of this action by neostigmine and pyridostigmine is found to be unpredictable; however, neuromuscular block- ade from antibiotics could be reversed predictably by 4- aminopyridine.2 Interestingly, the neuromuscular blocking action of the local anesthetic lidocaine is found to be exag- gerated in the presence of neuromuscular blocking drugs and aminoglycoside antibiotics.3 Antiepileptic Drugs Parturients may be taking antiepileptic drugs when they arrive in the hospital for labor and delivery. The common antiepileptic drugs at the present time include phenytoin, phe- nobarbital, benzodiazepines, and valproic acid. The pharma- cokinetics of most of the antiepileptic drugs are altered during pregnancy. Parturients need higher amounts of antiepileptic drugs because of increased volume of distribution; hence mea- surement of the plasma concentration is important. Most of these drugs are metabolized in the liver and thus can interfere with the biotransformation of other drugs. The duration of action of the drugs, which are mainly metabolized by the liver, can be prolonged in parturients who are receiving antiepileptic drugs. These drugs also cross the placenta and can thus 40 D Table 4-1. Interaction of Antibiotics, Muscle Relaxants, Neostigmine, and Calcium RUG Neuromuscular Block Neuromuscular Block Increase in From Antibiotic and I From Antibiotic Alone Neuromuscular d-Tubocurarine NTERACTIONS AND Antagonized by Block of Antagonized by Neostigmine Calcium d-Tubocurarine Succinylcholine Neostigmine Calcium Neomycin Sometimes Sometimes Yes Yes Usually Usually Streptomycin Sometimes Sometimes Yes Yes Usually Usually Gentamicin Sometimes Yes† Yes ‡ Sometimes Yes† Kanamycin Sometimes Sometimes Yes Yes Sometimes Sometimes Paromomycin Yes† Yes† Yes ‡ Yes† Yes† † † ‡ † † O Viomycin Yes Yes Yes Yes Yes BSTETRIC Polymyxin A No No Yes ‡ No No Polymyxin B No§ No Yes Yes No§ No Colistin No Sometimes Yes Yes No Sometimes Tetracycline No ‡ Yes No Partially Partially Lincomycin Partially Partially Yes ‡ Partially Partially A NESTHESIA Clindamycin Partially Partially Yes ‡ Partially Partially From Smith NT, Corbascio AN (eds): Drug Interactions in Anesthesia. Philadelphia, Lea & Febiger, 1986. Used by permission. † In spite of this, difficulty with antagonizing the block from these antibiotics is still likely to occur. ‡ Not studied. §Block augmented by neostigmine. DRUG INTERACTIONS AND OBSTETRIC INTERACTIONS 41 interfere with the synthesis of vitamin K-dependent clotting factors in the fetal liver. Hence, careful observation of the neonate is absolutely essential. Regional anesthesia should be the anesthetic technique of choice because there is evidence that a local anesthetic like lidocaine can be an effective anti- convulsant in therapeutic doses.4 If general anesthesia is indi- cated, the use of enflurane should be avoided because of its epileptogenic property.5 Enzyme Induction Enzyme induction is an adaptive response associated with accumulation of specific mRNAs and increased expression of the associated enzyme system. Oxidative metabolism is cat- alyzed by the P450 enzyme system. P450 enzymes have been grouped into three families: CYP1, CYP2, and CYP3. Several medications selectively induce specific families of the P450 enzyme system. Rifampicin decreased concentration of mida- zolam; its elimination half-life was also reduced.6 Sympathomimetic Drugs Pregnant women may use both sympathetic nervous system agonist and antagonist drugs for either therapeutic or recre- ational reasons. Sympathetic nervous system antagonists are used for the treatment of hypertension; a-Methyldopa, reser- pine, and guanethidine have been used in parturients. Deple- tion of norepinephrine is possible6a in such a situation, and indirect-acting agonists like ephedrine may be ineffective fol- lowing hypotension. Direct-acting agonists like phenylephrine may be indicated in such a situation. Besides these antagonist agents, b-receptor antagonist drugs like propranolol can be used for therapeutic reasons. If the parturient is taking pro- pranolol, medications that increase airway resistance, such as large doses of morphine or prostaglandin F2a (PCF2a) (Prostin), should be used cautiously. Calcium channel block- ers with negative inotropic effects can exaggerate the depres- sant effect of propranolol. Propranolol will cross the placenta and can cause fetal bradycardia and hypoglycemia. Auto- 42 DRUG INTERACTIONS AND OBSTETRIC ANESTHESIA nomic ganglionic blocking drugs like trimethaphan camsylate (Arfonad) are used occasionally to treat hypertension. Because this drug is destroyed by cholinesterase, which is also respon- sible for the metabolism of succinylcholine, a prolonged neu- romuscular block has been described following the use of Arfonad and succinylcholine.7 A few words of caution must be mentioned in using beta blockers such as esmolol. Severe fetal bradycardia has been described when esmolol was given to the mother. The proposed mechanisms include (1) large pla- cental transfer and (2) more beta-specific medications have unrestricted alpha constriction of the uterine blood vessels. Sympathetic Nervous System Agonist Drugs Two drugs in this group that are used recreationally are worth mentioning: 1. Amphetamine is a central nervous system (CNS) stimulant. A new smoked form, “ice,” that produces a “high” of long duration is popular in Hawaii and on the West Coast of the United States. The minimum alveolar concentration is increased in parturients who are addicted to ampheta- mines. Higher doses of narcotics and inhalational anesthetics may be needed for general anesthesia.8 Vaso- pressors, both direct and indirect acting, should be used carefully for the treatment of hypotension. 2. Cocaine is one of the commonly used recreational agents at the present time. It blocks the presynaptic uptake of nor- epinephrine, serotonin, and dopamine. Chronic use will a decrease 2-adrenergic- and presynaptic cholinergic medi- ated norepinephrine release.9 Cocaine is metabolized by cholinesterase and can affect the metabolism of 2-chloro- procaine. Ketamine or excessive catecholamines can cause severe hypertension and myocardial infarction. Tachycar- dia following cocaine use should be treated with labetalol because pure b-adrenergic agents will have unopposed a-adrenergic activity with associated hypertension.10 Calcium channel blockers will also have unopposed action. Decreased pseudocholinesterase levels may prolong the duration of action of succinylcholine. DRUG INTERACTIONS AND OBSTETRIC INTERACTIONS 43 Antiasthmatic Drugs Xanthine Derivatives Xanthine derivatives such as theophylline and amino- phylline may be associated with different drug interactions. Cimetidine has been observed to slow down the elimination of theophylline.11 If general anesthesia is indicated, ketamine should be used carefully because the combination of ketamine and aminophylline can cause significant lowering of the seizure threshold.12 Methylxanthines are associated with the release of endogenous catecholamines; hence halothane can induce dysrhythmias. This problem can be exaggerated if the parturient receives ephedrine13 or epinephrine at the same time. Theophylline can antagonize a nondepolarizing muscle- relaxant block.14 The mechanism is unknown. Pancuronium should be used cautiously because of the possibility of supraventricular tachycardia.15 Sympathomimetic Drugs See the later section “Sympathomimetic Amines.” Corticosteroids Corticosteroids have been observed to alter the disposition of theophylline. The intravenous administration of large doses of corticosteroids was associated with a twofold increase in serum levels of theophylline in patients who were receiving a theophylline infusion.16 Histamine H2 Receptor Blockers The use of H2 receptor blockers has become a common practice before cesarean section. Both cimetidine and raniti- dine have been used as premedicant agents. Cimetidine binds to the hepatic microsomal cytochrome P-450 system. Cimeti- dine as well