Drug Interactions and Obstetric Anesthesia
䉲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 H
2Receptor 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
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).
1The 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.
2Interestingly, 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.
3Antiepileptic 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
Table 4-1. Interaction of Antibiotics, Muscle Relaxants, Neostigmine, and Calcium
Neuromuscular Block Neuromuscular BlockIncrease inFrom Antibiotic and From Antibiotic AloneNeuromusculard-Tubocurarine Antagonized by Block ofAntagonized by Neostigmine Calciumd-TubocurarineSuccinylcholineNeostigmineCalciumNeomycin 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
†Viomycin Yes
†Yes
†Yes
‡Yes
†Yes
†Polymyxin A N o N o Yes
‡No No Polymyxin B N o
§No Yes Yes No
§No Colistin No Sometimes Yes Yes No Sometimes Tetracycline No
‡Yes No Partially Partially Lincomycin Partially Partially Yes
‡Partially Partially 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.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.
4If general anesthesia is indi- cated, the use of enflurane should be avoided because of its epileptogenic property.
5Enzyme 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: CYP
1, CYP
2, and CYP
3. Several medications selectively induce specific families of the P450 enzyme system. Rifampicin decreased concentration of mida- zolam; its elimination half-life was also reduced.
6Sympathomimetic 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 possible
6ain 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 F
2a(PCF
2a)
(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-
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.
7A 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.
8Vaso- 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
decrease a
2-adrenergic- and presynaptic cholinergic medi-
ated norepinephrine release.
9Cocaine 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.
10Calcium channel blockers will also have unopposed
action. Decreased pseudocholinesterase levels may
prolong the duration of action of succinylcholine.
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.
11If general anesthesia is indicated, ketamine should be used carefully because the combination of ketamine and aminophylline can cause significant lowering of the seizure threshold.
12Methylxanthines are associated with the release of endogenous catecholamines; hence halothane can induce dysrhythmias. This problem can be exaggerated if the parturient receives ephedrine
13or epinephrine at the same time. Theophylline can antagonize a nondepolarizing muscle- relaxant block.
14The mechanism is unknown. Pancuronium should be used cautiously because of the possibility of supraventricular tachycardia.
15Sympathomimetic 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.
16Histamine H
2Receptor Blockers
The use of H
2receptor 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 as ranitidine significantly decrease hepatic blood flow and thus can decrease hepatic clearance of various drugs.
Chronic cimetidine use will decrease clearance as well as
the metabolism of drugs like theophylline, benzodiazepines,
morphine, lidocaine, and propranolol.
17-20Ranitidine does not
bind with cytochrome P-450 and is more potent than cimeti- dine; hence drug interactions with ranitidine are extremely rare.
Psychotropic Agents
A broad range of antipsychotic drugs are available at the present time, and these drugs may be associated with multiple complex drug interactions. Three commonly used groups of drugs include phenothiazine, and butyrophenones. Antipsy- chotic drugs are associated with elevation of serum prolactin levels and blocking of dopaminergic receptors.
21Phenothiazine, Thioxanthenes, and Butyrophenones
Narcotic Analgesics. Most of the antipsychotic drugs will enhance the effect of narcotic analgesics. This might have additive and/or synergistic effects.
22One has to reduce the dose of narcotics if the patient is taking antipsychotic drugs.
Central Nervous System Depressants. Antipsychotic drugs also exert an increased effect on sedative and hypnotic drugs. A study showed that chlorpromazine reduced the thiopental requirement as well as prolonged postoperative recovery following thiopental use.
23Sympathomimetic Drugs. Antipsychotic drugs can block the pressor effects of norepinephrine and other a-adrenergic agonist drugs.
24Hence, higher doses of vasopressors may be necessary to treat hypotension in these cases. Selective a- adrenergic-blocking effects of these drugs may exaggerate the effects of drugs with b-agonist activity (propranolol).
25Anticholinergic Drugs. Some antipsychotic drugs like chlorpromazine and thioridazine do exert active anticholiner- gic effects: hence one has to be careful while administering anticholinergic premedications.
26Inhalation Anesthetics. Because of the higher incidence
of hypotension when inhalational anesthetics are used in
women taking antipsychotic drugs, one has to be careful when
using general anesthesia in this population.
Regional Anesthesia. A higher incidence of hypotension has been described in women receiving chlorpromazine.
Proper volume replacement and active treatment of hypoten- sion are important.
27Direct-acting a-agonists like phenyle- phrine (NeoSynephrine) may be necessary for the treatment of hypotension.
Other popular psychotropic drugs outside the three main groups (phenothiazine, thioxanthenes, and butyrophenones) are tricyclic antidepressants monoamine oxidase inhibitors (MAOIs), lithium, and serotonin reuptake inhibitors (SSRIs).
Tricyclic Antidepressants
This group of drugs has become very popular recently for the treatment of severe depression. Their mechanisms of action include blocking the uptake of norepinephrine, sero- tonin, or dopamine into presynaptic nerve endings, thus increasing central and peripheral adrenergic tone. Tricyclic antidepressants also possess a strong anticholinergic effect.
Drug interactions with tricyclic antidepressants are complex, and the obstetric anesthesiologist must be aware of the prob- lems. Tricyclic antidepressants heighten the pressor response of direct-acting vasoactive drugs such as norepinephrine, epi- nephrine, or Neo-Synephrine.
28Hence, local anesthetic solu- tion containing epinephrine should be used very carefully.
Ephedrine may not be effective for treating hypotension in this group of women following regional anesthesia.
NeoSynephrine, in small doses, may be necessary in such a situation. Tricyclic antidepressants will also exaggerate the response of anticholinergics and narcotics as well as other sedative and hypnotic drugs (Table 4-2).
Monoamine Oxidase Inhibitors
These drugs work by inhibiting the enzyme monoamine
oxidase. Monoamine oxidase is responsible for the oxidative
deamination of serotonin, norepinephrine, and dopamine
(Table 4-3); thus their metabolism is disturbed by this group
of drugs (MAOIs). These drugs can also inhibit other hepatic
microsomal enzymes. Three important drug interactions to
consider for parturients receiving MAOI agents are sympa- thetic amine interactions, narcotic analgesic interactions, and muscle-relaxant interactions.
Sympathomimetic Amines. Indirect-acting sympath- omimetic drugs such as amphetamine, methamphetamine, mephentermine, metaraminol, and ephedrine can release excessive amounts of catecholamine and can be associated with severe hypertension in parturients receiving MAOI agents.
29Direct-acting sympathomimetic amines have fewer problems,
28so in women receiving MAOI agents, a very small amount of a direct-acting vasopressor may be the drug of choice to treat hypotension following regional anesthesia.
Narcotic Analgesics. Meperidine’s interaction with MAOI agents is complex and can precipitate a hypertensive crisis.
Severe respiratory depression, hypotension, and coma have also been described.
30,31The mechanisms are not com- pletely clear; however, the hypertensive crisis may be explained by the presence of elevated brain serotonin con- centrations in the presence of an MAOI and meperidine because of the inhibition of enzyme metabolism by MAOI agents. Because meperidine is still one of the most common analgesics used for obstetric cases, one has to be very careful if the population is receiving an MAOI. Metoclo- pramide has been observed to potentiate opiate analgesia. The administration of metoclopramide was associated with a
Table 4-2. Some Interactions Between Tricyclic Antidepressants and Drugs Used in Anesthesia
Tricyclic Antidepressants Interaction
Narcotics ≠Analgesia
≠Respiratory depression
Barbiturates ≠Sleep time
Anticholinergics ≠Central acitvity
≠Peripheral activity
Sympathomimetics ≠Effect of direct-acting agents
From Janowsky EC, Craig Risch S, Janowsky DS: Psychotropic agents, in Smith NT, Corbascio AN (eds): Drug Interactions in Anesthesia.Philadelphia, Lea & Febiger, 1986, chap 19. Used by permission.
reduction in demand of analgesic requirements and a signifi- cant reduction in pain scores.
31aMuscle Relaxants. Prolonged apnea following succinyl- choline administration has been described in patients receiv- ing MAOI agents.
32A decrease in plasma cholinesterase content may be responsible for this interaction; since preg- nancy also reduces the plasma cholinesterase activity, this drug effect may be heightened in obstetric population.
Table 4-3. Biosynthesis and Metabolism of Catecholamines
Enzyme Catecholamine Enzyme Inhibitors Phenylalanine
Ø ¨ Hydroxylase
Tyrosine
Ø ¨ Hydroxylase ¨a-methyl-
p-tyrosine
DOPA Rate
limiting
Ø ¨ Decarboxylase ¨a-methyldopa
(Aldomet) Dopamine
Ø ¨ b-hydroxylase ¨Disulfiram
(Antabuse) Norepinephrine Rate
limiting
Ø ¨ N-methyltrans-
ferase Epinephrine
Ø ¨ COMT† ¨Pyrogallol,
Tropolone Metanephrine
Ø ¨ MAO ¨MAO inhibitor
(Pargyline) Vanillylmandelic
acid
From Wona KC, Everett JD: Sympathomimetic drugs, in Smith NT, Corbascio AN (eds): Drug Interactions in Anesthesia. Philadelphia, Lea & Febiger, 1986, chap 7.
Used by permission.
†COMT = catechol-O-methyltransferase.