Pharmacology Conference

Abstract I

SEX DIFFERENCES IN PAIN AND ANALGESIA
M. A. Ruda, Ph.D.

Chronic pain problems such as migraine headache facial pain and arthritis disproportionately affect women. The causes of these sex differences in the development of chronic pain are not clearly understood. Pain and analgesia are dynamic and complex events that can be influenced by many biological factors including sex. Study of the biological effects of sex differences in the response to pain and analgesia is in its infancy. However, the science has touched on some of the most important issues in gender-based biology including time of life, hormonal milieu, neuronal mechanisms and socio-cultural issues.

Opioids are one of the main classes of analgesic drugs for the treatment of severe pain. Recent studies have identified sex differences in the analgesic actions of opioid agonists in human studies and in animal research. In studies of postoperative dental pain, different analgesic efficacies in classes of opioid action were found. In human females, there was a greater sensitivity to the analgesic effect of kappa opioid agonists than those seen in males. A recent study has shown that in an animal model of peripheral inflammation and hyperalgesia, the kappa opioid dynorphin is upregulated to a greater level in the spinal cord of female rats in proestrus and diestrus than in male rats. In animal research, it has generally been observed that male rodents are more responsive to opioids than that seen in female rodents. However the mechanisms responsible for these sex differences are unknown. Potential contributing factors include sex-linked inherited determinants, time of day, hormonal status, age, receptor activation and etiology or nociceptive assay of the pain response.

To understand the sex specific pharmacodynamics in the response to pain and analgesia it is important to know the underlying basic mechanisms. Pain and analgesia are multifactorial events involving activity in peripheral tissues and the nervous system. Differences in the biology at each of these sites could contribute to sex differences in the pharmacology of pain and analgesia. It is important to look at the potential mechanisms from a broad perspective. In the nervous system, pain messages can be modified at the level of the dorsal root ganglia, spinal cord, brainstem and higher centers of the neuraxis. Each of these levels has a unique neurochemistry and pharmacology. Action at the different levels of the nervous system may reflect differences in the sensory-discriminative and motivational-affective components of the response to pain and analgesia. Identification of underlying mechanisms for sex differences in pain and analgesia may suggest novel pharmaco-therapies for chronic pain.
Pharmacologic Treatment of Epilepsy in Pregnancy
Katharine D. Wenstrom, M.D.

Epilepsy affects between 0.5 and 2.0% of the population, and occurs in 1 of every 200 pregnancies; it is estimated that as many as 1.1 million American reproductive age women have epilepsy. Epilepsy is thus one of the most common and serious medical conditions complicating pregnancy. The multiple maternal and fetal morbidities associated with antenatal seizure activity mandate pharmacologic therapy during pregnancy for most epileptic women. Unfortunately, despite the best medical efforts, up to 50% of epileptic women experience an increase in seizure frequency during pregnancy. Why seizures are difficult to control during gestation is incompletely understood, but is thought to be due in large part to the normal physiologic changes of pregnancy, as well as minor problems unique to gravid women.

The myriad physiologic changes of pregnancy begin with a dramatic rise in hormone levels. Both estrogen and progesterone have been implicated in seizure induction, with high estrogen levels believed to lower seizure threshold and even to provoke "gestational" epilepsy. High progesterone levels may change the seizure threshold by provoking hyperventilation (which begins as early as the first trimester), leading to a mild compensated respiratory alkalosis. Seizure frequency can also increase when other physiologic changes result in subtherapeutic antiepileptic drug levels. Such changes include a 50% increase in maternal blood volume (volume of distribution), and altered protein binding resulting from a drop in albumin levels and a rise in levels of other plasma proteins. Drug levels are also affected by malabsorption, resulting from the delayed gastric emptying, altered gastric pH, and slowed gastrointestinal passage that typify normal gestation. Cholestasis (resulting from elevated estrogen levels), changes in plasma enzymes, and placental metabolism can all affect maternal drug levels. In addition, induction of the hepatic microsomal enzyme system by elevated hormone levels may degrade many antiseizure medications more rapidly during pregnancy, and a marked increase in both renal plasma flow and glomerular filtration rate may result in more rapid drug clearance. The normal physiologic changes of pregnancy thus lead to a lowered seizure threshold, subtherapeutic drug levels, and more rapid drug clearance than in the pregravid state.

Minor problems unique to pregnancy can also complicate antiepileptic drug therapy. The patient may be unable to ingest medication because of chronic nausea and vomiting, or may self-discontinue her medication in the belief that it is damaging to her fetus. Heartburn resulting from a decrease in gastric tone may prompt the patient to ingest antacids, which significantly reduce drug absorption. Additionally, sleep deprivation and stress during pregnancy and hyperventilation and pain during labor may lower her seizure threshold.

Despite our growing understanding of the physiology of pregnancy and common minor pregnancy-associated problems, pharmacologic management of epilepsy during pregnancy is still an art and not a science. This is thus an area deserving of more intensive and specific research, which could potentially benefit many gravid women and their fetuses.
Sex/Gender Differences in Pharmacokinetics

Leslie Z. Benet, Ph.D., Robert Z. Harris, Ph.D.,
Janice B. Schwartz, M.D. and Shirley M. Tsunoda, Pharm.D.

There are a number of examples of sex differences in drug pharmacokinetics, although some of these disappear when body weight corrections are made. Recent advances in the characterization of specific isoenzymes involved in drug metabolism now allow for the preliminary identification of enzyme systems that are affected by sex. While current data are still limited and not in complete agreement, the majority of studies show that cytochrome P450 (CYP) 3A4 activity is higher in women than in men, whereas activity of other systems involved in drug metabolism may be higher in men than in women. For hepatic metabolized drugs, compounds that are metabolized by CYP3A4 appear to be eliminated faster by women in many cases, where those drugs eliminated by CYP2C19, CYP1A2 and dihydrouracil dehydrogenase may be eliminated faster by men. Conjugation activity appears to be greater in men than in women. Although there is an explosion of interest in the effect of efflux and absorptive transporters on drug pharmacokinetics, no sex differences have yet been identified (or studied) in humans, although a marked gender difference in P-glycoprotein is noted in rats. Female-specific issues such as pregnancy, menopause, oral contraceptive use and menstruation may also have profound effects on drug metabolism. Pregnancy may increase the elimination of anti-epileptic drugs, reducing their efficacy. There is evidence suggesting that CYP3A activity is decreased in menopause to that found in men. Oral contraceptive use can interfere with metabolism of many drug while hormone replacement therapy appears to have less, if any, effect.