Clinical experience with camphor overdose is very limited and no specific antidote is available. Therefore, the nonspecific antidote regimen should be given and supportive therapy provided. Even limited experience with gravid women who have ingested camphor is sufficient to begin antiseizure medication as a component of the antidote regimen in antic.i.p.ation that seizures may ensue.

Turpentine and ammonia No details of the course of pregnancy following poisoning with these nondrug chemicals have been reported. No specific antidote to these poisons is available and nonspecific antidote regimens and supportive therapy should be given.

Quinine overdose An attempt to induce abortion should be suspected when quinine overdose is encountered in pregnant women. Quinine has not been used in suicide attempts based upon published experience. Among 70 published cases of pregnant women taking quinine at Summary Summary 273.

high doses in an attempt to induce abortion suggest the drug may be teratogenic (Dannenberg et al et al., 1983). At least 11 women died as a result of quinine overdose and many who did not expire experienced toxic effects of the drug. No fewer than 41 infants with major congenital anomalies were born to women who took large doses of quinine during pregnancy. Causality cannot be proven using these data because the information comprised of only case reports. Nonetheless, large doses of quinine appear to pose an increased risk of some specific abnormalities that parallel toxicity from the drug often seen in adults. Eighteen of 60 infants (30 percent) born to women who ingested large amounts of quinine during pregnancy were congenitally deaf (Dannenberg et al et al., 1983).

Ototoxicity is a common and well-doc.u.mented complication of quinine therapy in adults.

Large doses of quinine during the first trimester of pregnancy are anecdotally a.s.sociated with major congenital anomalies, including central nervous system anomalies (especially hydrocephalus or otolithic damage), limb defects, cardiac defects, and gastrointestinal tract anomalies (Nishimura and Tanimura, 1976). No characteristic pattern of anomalies or syndrome was identified, and the a.s.sociation of these anomalies with maternal quinine ingestion remains empirically uncertain, but seems plausible.

Nonspecific antidote treatment and supportive therapy should be given because no specific antidote for quinine overdose is available.

Ergotamine overdose Overdose of ergotamine during pregnancy was published in a case report of a woman at 35 weeks' gestation who took 10 tablets of ergotamine tartrate in a suicide gesture.

Two hours later uterine contractions began with no relaxation between contractions.

Fetal death occurred approximately 8 h after the overdose. Two weeks after the overdose, a macerated stillbirth with no gross abnormality was delivered. Impaired placental perfusion and fetal anoxia a.s.sociated with ergotamine was speculated to have caused the fetal death (Au et al et al., 1985).

Spontaneous onset of preterm labor following ingestion of ergot also occurred with therapeutic levels of the drugs, but at usual therapeutic levels prematurity was the only complication, and there were no fetal deaths. Two antidotes to ergot alkaloid overdose (prazosin and nitroprusside) are now available that were unavailable to patients described above (Au et al et al., 1985). Nitroprusside should be avoided during pregnancy because it conjugates to cyanide and acc.u.mulates in the fetal liver. Therefore, prazosin is the preferred antidote for use during pregnancy.

SUMMARY.

Early aggressive treatment of attempted suicide during pregnancy is a.s.sociated with better outcomes than late or pa.s.sive treatment. Fetal monitoring should begin as early as possible. If a specific antidote exists, it should be given as soon as possible. If there is no specific antidote, a nonspecific aggressive treatment should be inst.i.tuted as early as possible (see Appendix).

274.

Drug overdoses during pregnancy Key References Anonymous. Nalmefene, a long-acting injectiable opioid antagonist. Med Lett Drugs Ther 1995; 37 37: 97.

Brost BC, Scardo JA, Newman RB. Diphenhydramine overdose during pregnancy. Lessons from the past. Am J Obstet Gynecol 1996; 175 175: 1376.

Dannenberg AL, Carter DM, Lawson HW, Ashton DM, Dorfman SF, Graham EH. Homicide and other injuries as causes of maternal death in New York City, 1987 through 1991. Am J Obstet Gynecol 1995; 172 172: 1557.

Flint C, La.r.s.en H, Nielsen GL, Olsen J, Srensen HT. Pregnancy outcome after suicide attempt by drug use. A Danish population-based study. Acta Obstet Gynecol Scand 2002; 81 81: 516.

Kamanyire R. Aspirin overdose. Emerg Nurse 2002; 10 10: 17.

Kozer E, Koren G. Management of paracetamol overdose. current controversies. Drug Safety 2001; 24 24: 503.

Sancewicz-Pach K, Chmiest W, Lichota E. Suicidal paracetamol poisoning of a pregnant woman just before a delivery. Przegl Lek 1999; 56 56: 459.

Tran T, Wax JR, Philput C, Steinfeld JD, Ingardia CJ. Intentional iron overdose in pregnancy management and outcome. J Emerg Med 2000; 18 18: 225.

Tran T, Wax JR, Steinfeld JD, Ingardia CJ. Acute intentional iron overdose in pregnancy.

Obstet Gynecol 1998; 92 92: 678.

w.a.n.g PH, Yang MJ, Lee WL, Chao HT, Yang ML, Hung JH. Acetaminophen poisoning in late pregnancy. A case report. J Reprod Med 1997; 42 42: 367.

Wilkes JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. South Med J 2005; 98 98: 1118.

Zimmerman HJ. Acetaminophen toxicity. Clin Liver Dis 1998; 2 2: 529.

Further references are available on the book's website at http://www.drugsandpregnancy.com Appendix to Chapter 14: 2005 List of antidotes available Antidote 2005 List of antidotes available Antidote Used for drug overdose, poison, or toxin N-Acetylcysteine (Mucomystreg;, Acetaminophen Acetadoltereg;) Carbon tetrachloride Other hepatotoxins Amyl nitrite, sodium nitrite, and Acetonitrile sodium thiosulfate (Cyanide Acrylonitrile antidote kit) Bromates (thiosulfate only) Chlorates (thiosulfate only) Cyanide (e.g., HCN, KCN, and NaCN) Cyanogen chloride Cyanogenic glycoside natural sources (e.g., apricot pits and peach pits) Hydrogen sulfide (nitrites only) Laetrile Mustard agents (thiosulfate only) Nitroprusside (thiosulfate only) Smoke inhalation (combustion of synthetic materials) Appendix to chapter 14 275.

Appendix to Chapter 14: 2005 List of antidotes available continued Antidote 2005 List of antidotes available continued Antidote Used for drug overdose, poison, or toxin Antivenin, Crotalidae Polyvalent Pit viper envenomation (e.g., rattlesnakes, (equine origin) cottonmouths, timber rattlers, and copperheads) Antivenin, Crotalidae Polyvalent Pit viper envenomation (e.g., rattlesnakes, Immune Fab Ovine (CroFab) cottonmouths, timber rattlers, and copperheads) Antivenin, Latrodectus mactans Black widow spider envenomation (Black widow spider) Atropine sulfate Alpha agonists (e.g., clonidine, guanabenz, and 2.guanfacine) Alzheimer drugs (e.g., donepezil, galantamine, rivastigmine, tacrine) Antimyesthenic agents Bradyarrhythmia-producing agents (e.g., beta blockers, (e.g. pyridostigmine) calcium channel blockers, and digitalis glycosides) Cholinergic agonists (e.g., bethanechol) Muscarine-containing mushrooms (e.g., c.l.i.tocybe and Inocybe) Nerve agents (e.g., sarin, soman, tabun, and VX) Organophosphate and carbamate insecticides Calcium disodium Lead EDTA (Versenate) Zinc salts (e.g., zinc chloride) Calcium chloride and Calcium gluconate Beta blockers Calcium channel blockers Fluoride salts (e.g., NaF) Hydrofluoric acid (HF) Hyperkalemia (not digoxin-induced) Hypermagnesemia Deferoxamine mesylate (Desferal) Iron Digoxin immune Fab (Digibind, Cardiac glycoside-containing plants (e.g., foxglove Digifab) and oleander) Digitoxin Digoxin Dimercaprol (BAL in oil) a.r.s.enic Copper Gold Lead Lewsite Mercury Ethanol Ethylene glycol Methanol Flumazenil (Romazicon) Benzodiazepines Zalepion Zolpidem Folic acid and Folinic acid (Leucovorin) Methanol Methotrexate trimetrexate Pyrimethamine Trimethoprim Fomepizole (Antizol) Ethylene glycol Methanol 276.

Drug overdoses during pregnancy Appendix to Chapter 14: 2005 List of antidotes available continued Antidote 2005 List of antidotes available continued Antidote Used for drug overdose, poison, or toxin Glucagon Beta blockers Calcium channel blockers Hypoglycemia Hypoglycemic agents Hyperbaric oxygen (HBO) Carbon monoxide Carbon tetrachloride Cyanide Hydrogen sulfide Methemoglobinemia Methylene blue Meth.o.m.oglobin-inducing agents including aniline dyes Dapsone Dinitrophenol Local anesthetics (e.g., benzocaine) Metoclopramide Monomethylhydrazine-containing mushrooms (e.g., Gyromitra) Naphthalene Nitrates and nitrites Nitrobenzene Phenazopyridine Nalmefene (Revex) and Naloxone ACE inhibitors (Narcan) Alpha agonists (e.g., clonidine, guanabenz and 2.guanfacine) Coma of unknown cause Imidazoline decongestants (e.g., oxymetazoline and tetrahydrozoline) Loperamide Opioids (e.g., codeine, dextromethorphan, diphenoxylate, fentanyl, heroin, meperidine, morphine, and propoxyphene) D-Penicillamine (Cuprimine) a.r.s.enic Copper Lead Mercury Physostigmine salicylate (Antilirium) Anticholinergic alkaloid-containing plants (e.g., deadly nightshade and jimson weed) Antihistamines Atropine and other anticholinergic agents Intrathecal baclofen Phytonadione Indandione derivatives (Vitamin K ) Long-acting anticoagulant rodenticides (e.g., 1.brodifacoum and bromadiolone) (AquaMEPHYTON, Mephyton) Warfarin Pralidoxime chloride Antimyesthenic agents (e.g., pyridostigmine) (2-PAM).

Nerve agents (e.g., sarin, soman, tabun and VX) (Protopam) Organophosphate insecticides Tacrine Appendix to chapter 14 277.

Appendix to Chapter 14: 2005 List of antidotes available continued Antidote 2005 List of antidotes available continued Antidote Used for drug overdose, poison, or toxin Protamine sulfate Enoxaparin Heparin Pyridoxine hydrochloride Acrylamide (Vitamin B ) Ethylene glycol 6.Hydrazine Isoniazid (INH) Monomethylhydrazine-containing mushrooms (e.g., Gyromitra) Sodium bicarbonate Chlorine gas Hyperkalemia Serum alkalinization: agents producing a quinidine-like effect as noted by widened QRS complex on EKG (e.g., amantadine, carbamazepine, chloroquine, cocaine, diphenhydramine, fecainide, propagenone, propoxyphene, tricyclic antidepressants, quinidine and related agents) Urine alkalinization: Weakly acidic agents (e.g., chlorophenoxy herbicides), chlorpropamide, phen.o.barbital, and salicylates) Succimer (Chemet) a.r.s.enic Lead Lewisite Mercury Benztropine mesylate (Cogentin) Medications causing a dystonic reaction Bromocriptine mesylate (Parlodel) Medications causing neuroleptic malignant syndrome (NMS).

L-Carnitine (Camitor) Valproic acid Cyproheptadine HCL (Periactin) Medications causing serotonin syndrome Dantrolene sodium (Dantrium) Medications causing NMS Medications causing malignant hyperthermia Diazepam (Valium) Chloroquine and related antimalarial drugs NMS.

Serotoninc syndrome Diphenhydramine HCL (Benadryl) Medications causing a dystonic reaction Insulin and dextrose Beta blockers Calcium channel blockers (diltiazem, nifedipine, verapamil) Octreotide acetate (Sandostatin) Sulfonylurea hypoglycemic agents (e.g., glipizide, glyburide) Phentolamine mesylate (Regitine) Catecholamine extravasation Intradigital epinephrine injection Thiamine Ethanol Ethanol glycol 278.

Drug overdoses during pregnancy Appendix to Chapter 14: 2005 List of antidotes available continued Antidote 2005 List of antidotes available continued Antidote Used for drug overdose, poison, or toxin Calcium-diethylenetriamine penaacetic Internal contamination with transuranium elements: acid (Ca-DTPA; Pentetate calcium americium, curium, plutonium trisodium injection) Zinc-diethylenetriamine pentaacetic acid (Zn-DTPA: pentetate zinc trisodium injection) Pota.s.sium Iodide, Kl tablets (Iostate, Prevents thyroid uptake of radioactive iodine (I-131) Thyro-Block, Thyrosafe) Kl liquid (Thyroshield) Prussian blue, ferric hexacyanoferrate Radioactive cesium (Cs-137), radioactive thallium (Radiogardase) (TI-201), and nonradioactive thallium) ACE, angiotensin-converting enzyme; DTPA, diethylenetriaminepentaacetic acid; EDTA, ethylenediaminetetraacetic acid.

Compiled from Illinois Poison Center Antidote List, 2005, with permission.

15.Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants Tocolytics 279.

Special considerations 290.

Immunosuppressants during Summary 294.

pregnancy 287.

Key references 295.

TOCOLYTICS.

Of an estimated 4 million women in the USA who give birth annually, approximately 11 percent of women deliver prematurely (less than 36 weeks). No tocolytic agent is universally effective, although more than 100 000 pregnancies will receive tocolysis therapy. Efficacy of most tocolytic agents is not universally accepted by physicians. Pregnant women treated with tocolytics are at increased risk for serious cardiopulmonary complications that are directly attributed to the tocolytic drug. Tocolytic therapy invariably occurs outside embryogenesis, so congenital anomalies are not an issue. The primary concern is for adverse maternal, fetal, and neonatal effects (Sanchez-Ramos et al et al., 2000).

The three princ.i.p.al indications that guide the use of tocolysis in the treatment of preterm labor are: (1) prophylaxis, (2) acute therapy, and (3) maintenance.

Instances do exist when exposure to tocolytic agents occurs during organogenesis, and is used for other indications: terbutaline (asthma), indomethacin (pain), and nifedipine (hypertension). Use for these indications is discussed in the chapters on antiasthma (Chapter 5), a.n.a.lgesic (Chapter 8), and cardiovascular drugs (Chapter 3), respectively.

Pharmac.o.kinetics of tocolytic drugs Pharmac.o.kinetic data on tocolytic drugs in pregnancy are limited to five studies of four drugs (Table 15.1). Half-life and steady-state concentrations are generally not different between pregnant and nonpregnant states.

Beta-adrenergic receptor agonists Ritodrine and terbutaline are beta-agonist drugs, structurally related to epinephrine, and are used as tocolytics. Fenoterol is another drug in this cla.s.s which has been popular in Europe.

280.

Miscellaneous drugs during pregnancy: Table 15.1 Pharmac.o.kinetics of tocolytic agents during pregnancy Agent Pharmac.o.kinetics of tocolytic agents during pregnancy Agent n EGA.

Route AUC.

V.

C.

C.

t Cl PPB.

Control groupa Authors d max SS.

1/2.

(weeks) Fenoteral 4.3032 IV.

No Mandach et al. (1995) Ritodrine 91.2836 IV, IM, PO.

Yes (1) Van Lierde et al. (1984) tocolytics and immunosuppressants Ritodrine 10.2034 IV.

Yes (1) Caritis et al. (1989) Salbutamol 7.1633 IV, PO.

Yes (3,4) Hutchings et al. (1987) Terbutaline 8.2735 IV.

Yes (4) Berg et al. (1984) Source: Little BB. Obstet Gynecol 1999; 93 93: 858.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , peak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared with nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV = intravenous; IM = intramuscular.

aControl groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female controls combined.

Tocolytics 281.

Box 15.1 Tocolytic agents Beta-sympathomimetic agents Sulindac Fenoterol Calcium channel blockers Hexoprenaline Atosiban Ritodrine Nifedipine Solbutanola Nitric oxide donor drugs Terbutaline Nitroglycerin Magnesium sulfate Oxytocin a.n.a.log Indomethacin Verapamil Prostaglandin synthetase inhibitors aNot available in the USA.

There are several other beta-agonists that have been utilized for tocolysis that are currently either not approved for tocolysis or not available in the USA (Box 15.1). This type of tocolytic binds to beta-adrenergic receptors on the outer myometrial cell membrane and activates adenylate cyclase. Adenylate cyclase catalyzes conversion of ATP to cAMP. Increased intracellular cAMP activates cAMPase-dependent protein kinase, decreasing intracellular calcium, resulting in reduced myometrial contractility (Caritis et al et al., 1988; Roberts, 1984).

Another pathway is the phosphorylation of myosin light chain kinase which inactivates the enzyme, thus inhibiting subsequent phosphorylation of the myosin light chain.

Maternal metabolic abnormalities (gluconeogenesis, hypokalemia, and hyperglycemia), as well as cardiopulmonary complications (tachycardia, hypotension, arrhythmias, myocardial ischemia, pulmonary edema) are a.s.sociated with beta-agonist tocolytics (Box 15.2). Apprehension, electrocardiogram (EKG/ECG) changes (S-T segment depression) and maternal death are also a.s.sociated with this cla.s.s of tocolytic agents.

Every beta-agonist is a.s.sociated with pulmonary edema and occurs among as many as 5 percent of gravidas who took any of these drugs (Boyle, 1995; McCombs, 1995).

Maternal tocolytic therapy has been a.s.sociated with neonatal hypoglycemia and tachycardia. Several fetal and neonatal cardiovascular adverse effects are a.s.sociated with beta-sympathomimetic therapy (Katz and Seeds, 1989) (Box 15.3). Decreases in the systolic/diastolic ratios of the umbilical artery have been reported in patients using either terbutaline or ritodrine (Brar et al et al., 1988; Wright et al et al., 1990).

RITODRINE.

Ritodrine is only drug approved by the US Food and Drug Administration (FDA) for obstetric use for tocolysis. After being developed specifically for tocolysis, it was Box 15.2 Maternal adverse effects of beta-sympathomimetic Box 15.2 Maternal adverse effects of beta-sympathomimetic therapy therapy Cardiac arrhythmia Hypotension Chest pain Pulmonary edema Hyperglycemia Shortness of breath Hypokalemia Tachycardia 282.

Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants Box 15.3 Possible adverse fetal effects of maternal beta-sympathomimetic therapy Box 15.3 Possible adverse fetal effects of maternal beta-sympathomimetic therapy Hypoglycemia Hypotension and tachycardia Other cardiovascular effectsa Cardiac dysrhythmia Decrease in umbilical artery systolic/diastolic ratios Heart failure Myocardial ischemia Neonatal death Ventricular hypertrophy aFrom Brar et al., 1988; Hill, 1995; Katz and Seeds, 1989.

approved in 1980, in the USA. By 1979, ritodrine was available as a tocolytic agent in 23 foreign countries (Barden, et al et al., 1980). Ritodrine hydrochloride is a beta-adrenergic agonist with beta -receptor effects that relax smooth muscle in the arterioles, bronchi, 2 and uterus. Although ritodrine use is in widespread use for the inhibition of preterm labor (Leveno et al et al., 1990), controversy remains concerning its clinical efficacy in prevention of preterm birth (Calder and Patel, 1985; Canadian Preterm Labor Investigation Group, 1992; Casparis et al et al., 1971; King et al et al., 1988; La.r.s.en et al et al., 1980, 1986; Leveno et al et al., 1986; Merkatz et al et al., 1980).

Tocolytic agents may successfully inhibit labor for up to 48 h. No long-term beneficial effect of tocolytic therapy (decreased perinatal mortality or severe neonatal respiratory disorders) was found in meta-a.n.a.lysis of 890 pregnancies in which ritodrine or another beta-mimetic tocolytic agent was used to prevent premature delivery (King et et al al., 1988). Downregulation of beta -adrenergic receptors following the use of these 2 drugs may explain their poor efficacy because uterine-relaxant effects are short lived (Berg et al et al., 1985; Fredholm et al et al., 1982; Harden, 1983; Hausdorff et al et al., 1990; Mickey et al et al., 1975; Ryden et al et al., 1982; Swillens et al et al., 1980; Wolfe et al et al., 1977). Ritodrine is also used to reverse 'fetal distress' and uterine hypertonus. For this indication, a dose of 13 mg is usually given over a 2-min period (Smith, 1991).

In the longer term, preterm labor is not effectively prevented by tocolysis. We a.n.a.lyzed national ritodrine sales over a 7-year period and found no evidence that treatment of preterm labor with ritodrine hydrochloride was a.s.sociated with a decreased incidence of low birth weight (LBW) infants in the USA. Estimates of ritodrine usage suggest a lack of impact, even though as many as 4050 percent of the preterm labors that resulted in LBW infants (approximately 116 000 annually) were probably managed with ritodrine therapy (Leveno et al et al., 1990). It is possible that a weak effect was present and the signal could not be separated from background noise.

Maternal effects Acute maternal pulmonary edema, in addition to hypokalemia and hyperglycemia, has been reported among women given ritodrine. Steroids administered concomitantly to accelerate fetal lung maturity seem to increase the risk for this maternal complication Tocolytics Tocolytics 283.