HEALTH AND MEDICAL PRODUCTS:PREMENSTRUAL SYNDROME DRUGS.

PREMENSTRUAL SYNDROME DRUGS

During their reproductive years, nonpregnant human females usually experience a cyclical sequence of changes in the ovaries and uterus. Each cycle has a duration of approximately twenty-eight days (one “month”; often between twenty-one and thirty-five days in healthy females of reproductive age) and is controlled principally by various protein-based hormones, including gonadotrophin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, and oxytocin, and steroid-based hormones, including estrogen and progesterone. Hormones in general are chemical messengers released by cells into the extracellular fluids (e.g., blood) that regulate the physiological function of other cells within the body. The general term “female reproductive cycle” encompasses the unique events that occur within the ovarian and uterine cycles, the hormonal changes that regulate these cycles, and the additional cyclical changes in the breasts and cervix. While the ovarian cycle specifically refers to a series of events associated with oogenesis and the maturation of the ovum (egg) in the ovaries, the uterine cycle (also called the menstrual cycle) refers to a series of cyclical changes that occur within the inner tissue lining (endometrium) of the uterus. Each “month,” the endometrium is prepared for the potential arrival and implantation of a fertilized ovum that will develop in the uterus during a nine-month ges- tation (pregnancy) period until birth. If fertilization of the ovum by a sperm cell does not occur, a portion of the endometrium tissue layer (called the “stratum functionalis”) is shed from the female body through the cervix and vagina. Overall, the endometrial changes of the uterine cycle are coordinated with the phases of the ovarian cycle during each twenty-eight-day “monthly” period through changing levels of hormones in the bloodstream.

The events of the three-stage uterine cycle are menses (menstrual flow phase; days one to five), the proliferative phase (days six to fourteen), and the secretory phase (days fifteen to twenty-eight). The menses phase is marked by the degeneration and detachment of the thick functional tissue zone (stratum functionalis) from the endometrium of the inner uterine wall primarily as a result of decreases in progesterone hormone levels in the bloodstream. The deterioration occurs in patches and is caused by the constriction of arteries, which reduces the blood flow to the areas of the endometrium. The weakened arterial walls eventually rupture, and the blood released seeps into nearby connective tissue and destabilized capillary beds, and both the pool of blood cells and the de- generating endometrial tissues then finally break away from the uterine wall and enter the uterine center (lumen) to be eventually shed out of the female body through the cervix and vagina as menstrual flow. The process of endometrial sloughing is called menstruation, a process that is accompanied by bleeding for three to five days, over which time roughly thirty-five to fifty milliliters of blood is lost. The proliferative phase of the menstrual cycle is marked by the regeneration and thickening of the re- maining thin endometrium for a week or two. This event is followed by the secretory phase, which is usually approximately two weeks in duration and is characterized by the continual thickening and vascularization (blood vessel formation) of the endometrium, with associated endometrial gland development and secretion of a glycogen-rich fluid. If a fertilized ovum has not implanted in the uterine lining by the end of the secretory phase, the uterine cycle begins with the onset of menses, mark- ing day one of a new twenty-eight-day cycle.

While many females find this process relatively painless, painful men- struation, or dysmenorrhea, can result from uterine inflammation and contraction or from severe medication conditions involving nearby pelvic organs or tissues. However, many females experience a combination of troublesome physical and psychological symptoms seven to ten days be- fore the start of menses (called the luteal phase in the ovarian cycle and the secretory phase in the uterine cycle) and sometimes overlapping with menses, which is termed premenstrual syndrome (PMS). Signs and symptoms usually increase in severity until the onset of menses and then dramatically disappear. Common symptoms of this mysterious malady, which results from complex physical and physiological changes occurring in the female body days before menses, include fluid retention (swelling), weight gain, skin eruptions (acne), breast engorgement and enlargement, headaches, food cravings (e.g., sweets, salty foods), fatigue, crying, in- somnia, forgetfulness, dizziness, severe pelvic and abdominal pain, and an uncomfortable sensation of bloating. Such symptoms may be combined with associated psychological changes to elicit feelings of irritability, confusion, anxiety, nervous tension, mood swings, and depression, which overall may cause a recurring cycle of symptoms so severe that it affects the lifestyle and work of many females.

While the exact cause and mechanism of PMS has yet to be clearly described, changes in steroid-based sex hormone (e.g., estrogen and progesterone) concentrations in the bloodstream are suspected to be involved. For example, such hormones may be involved directly, by acting on peripheral organ systems, or indirectly, by modifying the release of neurotransmitters (chemical messengers released by nerve cells) in the central nervous system (the brain and spinal cord). However, some symptoms of PMS are not directly related to changes in the levels of these hormones. As there are currently no conclusive laboratory tests or medical procedures to accurately diagnose PMS, retaining records on the emergence of symptoms over a period of two to four months is recommended to reveal characteristic patterns. At present, PMS is simply treated for each individual at the symptom level, which may include recommendations for changes in lifestyle such as exercise, vitamin intake, and specific dietary regimens. Medication is often used for PMS, de- pending on the characteristics of the primary experienced symptom.

Over-the-counter (OTC) oral medications specifically marketed for the treatment of PMS symptoms can contain three active ingredients: an analgesic, a diuretic, and an antihistamine. Analgesics are drugs that re- lieve the feeling of pain. An example of an analgesic found in OTC oral PMS medications is acetaminophen. Acetaminophen is the least toxic member of a class of analgesic (and antipyretic [antifever]) medications known as the p-aminophenols. A major metabolite of phenacetin (the so- called coal tar analgesic) and acetanilide, acetaminophen is an effective and fast-acting analgesic that acts centrally to relieve mild to moderate pain. Acetaminophen acts to alleviate pain by effectively inhibiting the COX enzyme in the body, which normally catalyzes the synthesis of pain-producing chemicals called prostaglandins. Prostaglandins are local- acting chemical messengers that promote the redness, heat, and swelling of tissue inflammation and associated pain. Interestingly, the lining of the uterus releases prostaglandins during menses. Prostaglandins are known to stimulate uterine contractions but are inhibited in the presence of high progesterone levels. If pregnancy does not occur, progesterone levels decrease rapidly and prostaglandin production increases. The re- leased prostaglandins then target the middle smooth muscle layer of the uterus to cause an increase in painful uterine contraction, which assists in the flow of menstrual discharge but may also lead to an increase in uterine blood vessel constriction. Such vascular constriction may cause a de- crease in available oxygen to the uterine muscle, resulting in additional intense pain (e.g., cramping). Acetaminophen also specifically acts to alleviate the pain of headaches associated with PMS fever by effectively inhibiting the COX enzyme and prostaglandin production in the brain, thereby producing a pain-relieving effect by increasing the pain thresh- old (the conscious awareness of pain through nerve transmission at a particular stimulus intensity). Thus, acetaminophen temporarily relieves minor aches and pain attributable to headache, backache, and uterine cramping associated with PMS.

Drugs called diuretics (from the Greek word diouretikos, meaning promoting urine) cause an overall removal of fluid from the body by tar- geting the kidneys and increasing the rate of urine output and sodium excretion from the body. Diuretics such as pamabrom (8-bromo-3,7-di- hydro-1,3-dimethyl-1H-purine-2,6-dione compound with 2-amino-2- methyl-1-propanol [1:1]; C11H18BrN5O3) are often used to combat the symptoms of bloating and fluid retention associated with PMS by causing an increase in fluid loss through urination. Diuretics have many different mechanisms of action, but all affect transport activity or water reabsorption along the nephron and collecting duct system of the kid- neys. Proposed by the Food and Drug Administration as an OTC di- uretic for menstrual drug products in 1988, pamabrom is therapeutically considered a drug combination, meaning a single preparation containing two active ingredients for the purpose of a concurrent administration as a fixed-dose mixture. Chemically, it contains both a propanolamine (amino alcohol) group and a theophylline group. The theophylline chemical group of pamabrom increases renal (kidney) blood flow and glomerular filtration rate (the total amount of filtrate solution formed from the blood per minute by the kidneys) and may also decrease proximal tubular reabsorp- tion of sodium and water, overall causing a mild diuretic (water loss) ef- fect. The amino alcohol group of pamabrom may also function as a diuretic, as alcohols act indirectly as diuretics by suppressing the release of antidiuretic hormone from the posterior pituitary gland located near the human brain. After release from the posterior pituitary gland, antidiuretic hormone normally travels through the bloodstream and targets the distal convoluted tubules and collecting ducts of the kidney nephrons to promote water retention, thus decreasing urine output. The diuretic effect of pamabrom is directly dependent on the amount of drug consumed and the duration of use. Thus, pamabrom temporarily relieves the water weight gain, bloating, swelling, and full feeling associated with PMS. Antihistamines antagonize (inhibit) the activity of a chemical called histamine. Histamine [2-(4-imidazolyl)-ethyl-amine], a vasoactive monoamine formed by the decarboxylation of histidine by the enzyme histidine carboxylase, chemically mediates local immune responses. It is located in most body tissues but is highly concentrated in the lungs, skin, and gas- trointestinal tract. In the CNS, it may serve as a neurotransmitter. Histamine acts by binding to receptors on target cells. Different cell types express different histamine receptor (H) types, which currently include H1, H2, H3, and H4. Overall, histamine contributes to the inflammatory response, acts on the smooth muscles of blood vessels to cause vasodila- tion (increase in blood vessel diameter), causes an increase in the permeability of blood vessel walls, and affects nearby sensory nerves, resulting in itching (also called pruritus). The effects of histamine cause the familiar symptoms of allergy, which include sneezing, inflammation of the nasal passageways, nasal itching, watery nasal discharge, and itchy, in- flamed, tearing eyes. When released in the lungs, histamine causes smooth muscle contraction of the airway bronchioles, which is an attempt by the body to prevent the offensive allergens from entering the lung tissue. Unfortunately, this type of response leads to the symptoms of wheezing and shortness of breath like that experienced by individuals with the life-threatening condition called asthma.

In 1937, D. Bovet and A. Staub discovered the first H1 receptor an- tagonist. This discovery marked the “first generation” of antihistamines. Antihistamines suppress the wheal (swelling) and flare (vasodilation) symptoms, typical of what is called a type I immediate hypersensitivity immune response, by blocking the binding of histamine to its receptors on nerves, vascular smooth muscle, glandular cells, endothelium tissue, and mast cells. Thus, antihistamines antagonize the action of basophils (granular white blood cells) and mast cells, which release vasoactive amines and other chemical mediators of inflammation. Classic first-generation antihistamines block the action of histamine at specific histamine receptors (e.g., H1 receptors). First-generation antihistamines are small lipophilic molecules, so they may cause potentially adverse effects (e.g., sedation, impaired cognition, blurred vision, gastrointestinal symptoms, dryness of mouth, heart palpitations, urinary retention) because their structure closely resembles that of blockers of cholinergic (specifically muscarinic) and a-adrenergic receptors of the autonomic nervous system, and because of their ability to cross the blood-brain barrier to affect the CNS. These H1 receptor antagonists are reversible, competitive inhibitors of the pharmacological actions of histamine on H1 receptors.

An example of a first-generation H1-blocking compound available in OTC oral PMS medications is pyrilamine maleate [also called paramal or mepyramine maleate; 1,2-ethanediamine, N-((4-methoxyphenyl)methyl)- N,N'-dimethyl-N-2-pyridinyl-, (Z )-2-butenedioat; C17H23N3O·C4H4O4)], which belongs to the ethylenediamine-derivative chemical class of first- generation H1 receptor antagonist agents. Thus, because of the blockade of H1 and muscarinic receptors in the nervous system and associated sedative effects, pyrilamine maleate may alleviate such PMS symptoms as insomnia and nervous tension. In addition, this antihistamine may alleviate cramping by inhibiting histamine-induced uterine smooth muscle con- traction during menses. While peak plasma concentrations are usually reached two to three hours after oral administration, adverse gastrointestinal effects and sensitivity are common with ethylenediamine-derivative antihistamines in humans.