Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system.

The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure.

Pharmacological Agents Affecting Emesis

Drug abuse's smallest victims: in utero drug exposure.

http://anes-som.ucsd.edu/VP%20Articles/Topic%20C.%20Mellor.pdf

The importance of ‘awareness’ for understanding fetal pain

Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current “gold standard”, and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a µ-opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial µ-opioid receptor agonist and a κ-opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term.

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The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data.

Surveys of drug use in pregnancy demonstrate that a significant proportion of human fetuses are exposed to prescription and non-prescription drugs antenatally or during labor, although recently a decrease in licit drug consumption during pregnancy may have occurred. However, legitimate medical reasons for drug therapy of the mother or fetus remain and there is an increasing problem with illicit drugs. Several approaches are used to examine placental transfer of and fetal exposure to drugs, including studies on pregnant women, the use of chronically catheterized pregnant animals (particularly sheep), acute studies on small animals (e.g. guinea pig and rabbit) and the use of the perfused placenta. Fetal drug exposure is affected by large number of maternal, placental and fetal factors. For long term maternal drug administration, drug binding in maternal and fetal plasma, and fetal drug elimination seem particularly important. Thus, the rate of non-placental clearance of morphine, methadone, acetamionophen, metoclopramide, ritodrine and diphenhydramine in the fetal lamb is comparable to that in the ewe, although the routes of fetal elimination are not fully elucidated. The fetal liver may be of lesser importance in overall drug elimination than in the adult, but conjugated drug metabolites in the fetus may persist because of limited placental transfer. Hence, we have observed that the glucuronide conjugate of ritodrine accumulates in amniotic fluid after intravenous ritodrine administration. Accumulation of intact drugs in amniotic fluid also occurs via fetal renal excretion and perhaps via the fetal membranes. Also, a number of basic amine drugs are also concentrated in fetal tracheal fluid, probably as a consequence of pulmonary uptake, which also takes place in the adult. However, this could result in high fetal lung levels of agents, such as beta 2-adrenergic agonists, that have potent effects on pulmonary function and maturation. When digoxin, metoclopramide and diphenhydramine are injected into amniotic fluid, they are preferentially distributed to the fetus and, for the latter 2 drugs, uptake by the chorioallantoic membranes appears to be important. Thus, there is the possibility of recycling of drugs from amniotic fluid to the fetal circulation and their persistence in the fetus. Many of the therapeutic agents given to pregnant women in late pregnancy have effects on fetal CNS, cardiovascular or metabolic functions. Alterations in fetal behaviour are elicited by prescription sedatives and anesthetics and illicit drugs, and also by the antihistamine, diphenhydramine, present in various nonprescription medications.

Drug disposition and effects in the fetus.

The disposition of metoclopramide was studied on a four-way crossover basis in six healthy non-smoking volunteers. The linearity of kinetic parameters and absolute bioavailability of metoclopramide were examined. In contrast to previous reports, metoclopramide obeyed linear kinetics over oral doses ranging from 5 to 20 mg. The absolute bioavailability of metoclopramide was 0.76 +/- 0.38 (mean +/- s.d.) from the oral dosage forms examined in this study.

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Linearity of metoclopramide kinetics at doses of 5-20 mg

The disposition of the beta-2 adrenoreceptor agonist, ritodrine, has been examined in the fetal lamb during and after constant rate fetal intravenous infusion (8-24 h). Samples were collected from the fetal femoral artery, umbilical vein, maternal femoral artery, uterine vein, fetal trachea and the amniotic activity for ritodrine quantitation. The amniotic fluid was also analyzed for conjugated metabolites of ritodrine. Ritodrine appears to be cleared across the sheep placenta only to a limited extent (placental clearance 9.2 +/- 2 ml/min/kg; mean +/- S.E.M.). There is, however, significant fetal nonplacental clearance of ritodrine (fetal nonplacental clearance 52.8 +/- 8.0 ml/min/kg). At least part of this clearance appears to be due to fetal drug metabolism, as evidenced by the accumulation of glucuronide conjugates of ritodrine in the amniotic fluid. Ritodrine was also shown to accumulate in the amniotic and fetal tracheal fluids and persist after fetal arterial plasma ritodrine concentrations became undetectable. The accumulation of ritodrine in the tracheal fluid may be of pharmacologic significance, given the well documented, potent effects of beta-2 agonists on fetal lung function and development.

Clearance and disposition of ritodrine in the fluid compartments of the fetal lamb during and after constant rate fetal intravenous infusion

The maternal-fetal disposition of labetalol, a combined alpha-1 and beta adrenergic blocker, and its pharmacodynamics in pregnancy are not well understood. This study describes the pharmacokinetics, cardiovascular and metabolic effects of labetalol in the mother and in utero fetus after a 100-mg maternal i.v. bolus administration, in the chronically instrumented pregnant sheep. Labetalol shows a triexponential decline in the mother with a total body clearance of 30.8 +/- 3.83 ml/min/kg, an apparent steady-state volume of distribution (nonparametric) of 3.02 +/- 0.18 liters/kg and terminal elimination half-life of 2.79 +/- 0.66 hr. These estimates are similar to the reported values in pregnant women. Labetalol rapidly crosses the sheep placenta. The peak fetal plasma concentration was 33.7 +/- 5.8 ng/ml, the fetal exposure to labetalol as calculated by the fetal to maternal area under the curve ratio was 14.37 +/- 1.54% and the apparent fetal elimination half-life was 3.71 +/- 0.5 hr. Labetalol persists in the amniotic and fetal tracheal fluids up to 24 hr with concentrations reaching 2- to 4 times the fetal plasma concentration. Whereas there were no significant maternal or fetal cardiovascular effects, some very significant metabolic effects were observed, including fetal and maternal lactic acidosis and hyperglycemia. Lactic acid accumulates in the fetal blood and amniotic fluid with peak concentrations (6.0 +/- 0.31 and 5.5 +/- 0.26 mM, respectively) showing a more than 300% increase over control values. The exact mechanism by which labetalol causes these metabolic effects is not clear, but it may involve its partial beta-2 agonist activity.

Pharmacokinetics and pharmacodynamics of labetalol in the pregnant sheep.

Ritodrine infusion to fetal lambs causes numerous metabolic perturbations including hypoxemia. To investigate these changes further and to elucidate a mechanism for the development of hypoxemia, ritodrine was infused at rate of 2.6 micrograms/min into nine chronically catheterized fetal lambs for 8, 12 or 24 hr. Plasma levels of ritodrine (20.0 +/- 2.7 ng/ml) were within the range of those reported in human fetuses exposed to ritodrine tocolysis. Fetal arterial glucose levels nearly doubled (0.72 +/- 0.07 to 1.29 +/- 0.18 mM), whereas lactate levels rose more than 5-fold (1.54 +/- 0.11 to 8.67 +/- 1.12 mM), with the latter change leading to a decline in fetal arterial pH from 7.370 +/- 0.004 to 7.273 +/- 0.033. Fetal oxygen consumption (VO2) rose from 342 +/- 35 to 407 +/- 30 mumol/min.kg via an increase in fetal fractional O2 extraction (32.0 +/- 1.1 to 49.0 +/- 1.7%). The rise in fetal O2 extraction contributed to concurrent declines in fetal arterial PO2 (21.9 +/- 0.6 to 17.0 +/- 0.5 mm Hg) and O2 content (3.7 +/- 0.2 to 2.1 +/- 0.1 mM). Umbilical venous PO2 and O2 content also fell resulting in a decline in fetal O2 delivery (DO2) from 1115 +/- 97 to 838 +/- 68 mumol/min.kg. The rise in fetal VO2 was reflected by a similar rise uterine VO2 (not significant), with the latter being accompanied by a significant increase in uterine O2 extraction and decrease in uterine venous PO2 and O2 content, perhaps contributing to the fall in fetal DO2. In conclusion, fetal hypoxemia during the infusion of ritodrine results from an increase in fetal VO2 that is not compensated for by a similar increase in umbilical or uterine DO2. These metabolic effects may put the fetus at risk, particularly in situations in which fetal DO2 is already reduced, as may occur in compromised pregnancies.

M R Wright

Papers

Drug disposition and effects in the fetus.

Linearity of metoclopramide kinetics at doses of 5-20 mg

Clearance and disposition of ritodrine in the fluid compartments of the fetal lamb during and after constant rate fetal intravenous infusion

Pharmacokinetics and pharmacodynamics of labetalol in the pregnant sheep.

Metabolic effects of ritodrine in the fetal lamb.