Reproductive system pharmacology
Introduction
Several sites in the human reproductive system are either vulnerable to chemicals or can be manipulated by drugs. Within the central nervous system, sensitive sites include the hypothalamus (and adjacent areas of the brain) and the anterior lobe of the pituitary gland. Regions outside the brain that are vulnerable include the gonads (i.e., ovary or testis, the uterus in the female, and the prostate in the male).
The body has anatomical or physiological barriers that tend to protect the system. The so-called placental barrier and the blood-testis barrier impede certain chemicals, although both allow most fat-soluble chemicals to cross. Drugs that are more water soluble and that possess higher molecular weights tend not to cross either the placental or the blood-testis barrier. In addition, if a drug or chemical binds to a large molecule such as a blood-borne protein, it is less likely to be transported into the testes or less likely to come in contact with the fetus. There appears to be little, if any, barrier to chemicals or drugs gaining entry to breast milk or semen.
If the fetus is exposed in the uterus to certain environmental chemicals, infections, or drugs, it may develop abnormalities. The toxic substance is described as teratogenic (literally, "monster-producing"), and the study of this type of toxicity is called teratology. About 3 percent of developmental abnormalities have been proved to be drug-induced. It is wise to avoid all drugs (including nicotine) during pregnancy, unless the medicine is well tried and essential. Drugs taken by male partners may be teratogenic if they damage the genetic material (chromosomes) of the spermatozoa.
Female reproductive system
Oral contraceptives, universally known as "the Pill", constitute a class of steroid hormones. They are capable of suppressing the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior lobe of the pituitary gland. Known collectively as gonadotrophic hormones, FSH and LH are capable of stimulating the release of progesterone and esterogen from the gonads, or ovaries, all of these hormones are responsible for modulating the female menstrual cycle. Ovulation is believed to be related to a midcycle release of LH, which can be effectively suppressed or blocked by the systematic administration of systemic hormones. There are many commercial preparations of oral contraceptives, but most of them contain a combination of an estrogen (usually ethynyl estradiol) and a progestin (commonly norethindrone). In general, oral contraceptives are taken in a monthly regiment that parallels the menstrual cycle. Protection from pregnancy is often unreliable until the second or third drug cycle, and during this time certain side effects such as nausea, breast tenderness, or breakthrough bleeding may be evident. More serious side effects, including venous and arterial thromboembolism and a rise in blood pressure, are possible, especially in women over 34 years of age. Normal ovulation usually commences two to three months after stopping thePill.
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Progestin-only preparations (the so-called Minipill) thicken the mucus lining of the cervix and make it more acidic, thereby rendering it hostile to the male spermatozoa. Progestin-only preparations are somewhat less reliable than the combination preparations, but produce fewer side effects. Under certain circumstances, the progestin may be administered as an intramuscular deposit that gradually releases the hormone over the course of one to three months.
Short courses of a high-dose estrogen (the so-called Morning-After Pill) may be taken after coitus. It increases the activity of the fallopian tubes so that the fertilized egg is expelled into the uterus before the uterus has undergone the modification necessary to receive it. This type of contraceptive produces a great deal of nausea and vomiting.
Apart from oral contraceptives, no other drugs are used therapeutically to affect ovarian function. Some drugs may have undesirable side effectson the ovary, which often culminate in menstrual irregularities. Certain tranquilizers (e.g., reserpine chlorpromazme, narcotics, and anti-cancer drugs) can adversely affect the hormonal secretions of the ovary.
Male reproductive system
The only male reproductive organ that is a target of pharmacologic manipulation is the prostate gland. This accessory sex organ is susceptible to both benign and malignant change that seem to be linked to age. The prostate gland is affected by the general class of hormones called androgens, which comprise the male sex hormones. A chemical class of drugs known as antiandrogens is used therapeutically to treat selected pathologic changes in the prostate, which usually include an increase in growth. Antiandrogens can be subdivided into those drugs that contain inherent hormonal properties (e.g., estrogens such as diethylstilbestrol) and those that possess no hormonal properties (e.g., flutamide). Cyproterone acetate, spironolactone, and Leuprolide are still other examples of antiandrogens or antiandrogen - like agents used in the treatment of prostate disorders.
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In males there is no process comparable to ovulation and no cyclic release of gonadotropins (hormones that stimulate the gonads, or testes). There is, therefore, no need to suppress the release of gonadotropins by anterior pituitary-hypothalamic axis. Alteration of the amount of pituitary gonadotropins released in the male result largely from the undesirable side effects of various antihypertensive medicines, tranquilizers, and morphine or morphine-like substances. Ultimately such alteration may manifest itself as sterility, impotence, or loss of libido.
The male gonad also does not represent a purposeful target for pharmacologic agents. The testes are, however, affected adversely by the side effects of certain drugs (e.g., anticancer agents) or by exposure to certain occupational or environmental hazards. They are most susceptible to damage by chemicals.
Gossypol, an extract obtained from cottonseed oil, is used as a male oral contraceptive in China. While it has only limited success, gossypol is an example of a gonadotoxin that cannot inhibit mitotic activity.
Antiviral drugs
Viruses are among the most common and widespread causes of infectious diseases. They cause such illnesses as influenza, herpes simplex type I (cold sores of the mouth) and type II (genital herpes), shingles, viral hepatitis, encephalitis, infectious mononucleosis, and the common cold. Viruses remain one of the least understood and most difficult of all infectious organisms to control; but this is changing as more is learned about their structure and replication. Viruses consist of nucleic acid, either DNA or RNA., and a protein coat. Because viruses do not have the enzymes that are needed to manufacture cellular components, they are obligate parasites, which means they must enter a cell for replication to occur.
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The nucleic acid of the virus instructs the host cell to produce viral components, which leads to an infectious virus. In some cases, as in herpes infections, the virus nucleic acid may remain in the host cell without causing replication of the virus and damage to the host (viral latency). In other eases, the production of virus by the host cell may cause the death of the cell. A major problem in treating some viral diseases is that latent viruses can become activated, frequently when the host undergoes stress, thereby producing infectious virus and cellular effects.
Many factors account for the difficulty in developing antiviral chemotherapeutic agents. The structure of each virus differs, and specific therapy is often unsuccessful because of periodic changes in the antigenic proteins of the virus. The need for a host cell to support the multiplication of the virus makes treatment difficult because the chemotherapeutic agent must be able to inhibit the virus without seriously affecting the host’s cells.
The greatest success against virus infections has been by increasing immunity through vaccination (influenza, poliomyelitis, measles, mumps, and smallpox) with live attenuated (weakened) or killed viruses. Vaccination has resulted in the total elimination of smallpox. While vaccination has proved to be effective against the specific virus used for smallpox, influenza is caused by viruses that constantly change their antigenic protein, thereby requiring revaccination as the antigenic makeup of the virus changes. Some virus groups contain 50 or more different viruses.
Passive immunization with serum or globulin (antibodies) from immune persons has been used to prevent viral infections. Immune globulins, such as those used against hepatitis, often cause adverse effects, however, and they are effective only for prophylaxis and not for treatment.
An antiviral agent must act at one of five basic steps in the viral replication cycle in order to inhibit the virus. The steps are (1) attachment and penetration of the virus into the host cell; (2) uncoating of virus – e.g., removal of the protein surface and release of the viral DNA or RNA; (3) synthesis of new viral components by the host cell as directed by the virus DNA; (4) assembly of the components into new virus; and (5) release of the virus from the host cell.
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Antiprotozoal drugs
The protozoans, unlike bacteria and fungi, do not have a cell wall. They have a nucleus and a cytoplasm that is surrounded by a selectively permeable cell (plasma) membrane. The cytoplasm contains organelles similar to those found in other animal and plant cells (e.g., mitochondria, Golgi apparatus, and endoplasmic reticulum). Thus, most of the antibiotics effective in inhibiting bacteria are not active against protozoans. Amphotericin B, however, reacts with sterols, which are components of both fungal and protozoal membranes. Most of the drugs used in the chemotherapy of diseases caused by the protozoans are derived from plants or are synthetic chemical compounds.
Metronidazole is usually given orally for the treatment of vaginal infections caused by Trichomonas vaginaliis, and it is effective in treating bacterial infections caused by anaerobes. It affects these organisms by causing nicks in, or breakage of, strands of DNA or by preventing DNA replication.
Iodoquinol inhibits several enzymes of protozoans. It is given orally for treating asymptomatic amebiasis and is giveneither by itself or in combination with metronidazole for intestinal and hepatic amebiasis. Balantidium coli and Dientamoeba fragilis infections also are treated with iodoquinol. Emetine, an alkaloid derived from ipecac syrup, is obtained from the roots of Cephaelis ipecacuanha, a plant native to Brazil. It is used along with iodoquinol or chloroquine phosphate as alternative therapy for treatment of severe intestinal and hepatic amebiasis. Emetine is given by injection and can cause serious toxicity. Dehydroemetine is less toxic than emetine and may be used as an alternative drug.
Quinacrine is the drug of choice for giardiasis, an infection of the intestine caused by a flagellated amoeba. Quinacrine inserts itself into DNA, thereby ultimately preventing the synthesis of nucleic acids. It is given orally and can cause yellow staining of skin and sclera and deposition of blue and black pigment in the nail beds.
Trypanosomes are flagellated protozoans that cause a number of diseases. Trupanosoma cruzi, the agent of Chagas' disease, is treated with nifurtimox, a nitrofuran derivative. It is given orally and results in the production of activated forms of oxygen, which are lethal to the parasite. Other forms of trypanosomiasis (African trypanosomiasis, or sleeping sickness) are caused by T. gambiense or T. rhodesiense. When these parasites invade the blood or lymph, the drug of choice is suramin, a nonmetallic dye that affects glucose utilization and hence energy production. Because suramin is not absorbed from the gastrointestinal tract, it is given by intravenous injection. In the late form oftrypanosomiasis, when the parasites have invaded the central nervous system, melarsoprol and tryparsamide areadministered intravenously. They are used because they can penetrate the central nervous system and affect cellular structures and their functions.
Pneumocystis carinii causes pulmonary disease in immunocompromised patients. These infections are treated with trimethoprim-sulfamethoxazole, which inhibits folic acid synthesis in protozoans. An alternative agent for treatment of these diseases is pentamidine, which probably affects the parasite by binding to DNA. Because the drug is not well absorbed from the gastrointestinal tract it is given by the intramuscular route.
Malaria is one of the more serious protozoal infections. Chloroquine phosphate, given orally, is the drug of choice for prophylaxis and treatment. In regions where chloroquine-resistant Plasmodium falciparum is encountered, however, pyrimethamine, in combination with sulfadoxine, is used for prophylaxis. Both drugs interfere with folic acid synthesis and are well tolerated. Quinine sulfate, along with pyrimethamine and sulfadoxine, are used to treat infections caused by chloroquine-resistant P. falciparum.. A high level of quinine in the plasma frequently is associated with cinchonism, a mild adverse reaction associated with such symptoms as a noise in the ears (tinnitus), headache, nausea, abdominal pain, and visual disturbance. Primaquine phosphate is given orally to prevent attacks after a person has left an area where P. vivax and P. ovale are endemic and to prevent relapses with the same organisms.
Antibacterial agents
Antibacterial agents are categorized as narrow-, broad-, or extended-spectrum agents. Narrow-spectrum agents (e.g., penicillin G) affect primarily gram-positive bacteria. Broad-spectrum antibiotics, such as tetracyclines and chloramphenicol, affect both gram-positive and some gram-negative bacteria. An extended-spectrum antibiotic is one that, as a result of chemical modification, affects additional types of bacteria, usually gram-negative bacteria.
Whether an antimicrobial agent affects a microorganism depends on several factors. The drug must be delivered to a sensitive site in the cell, such as an enzyme that is involved in the synthesis of a cell wall or a protein or enzyme responsible for the synthesis of proteins, nucleic acids, or the cell membrane. Whether the antibiotic enters thecell depends on the ability of the drug to penetrate the outer membrane of the cell, or on the presence or absence of transport systems for the antimicrobial agent, or on the availability of channels in the cell surface. In some cases the microorganism prevents the entry of the antibiotic by producing an enzyme that destroys or modifies the antibiotic by transferring a chemical group. If the aintimicrobial agent does not penetrate the organism or is destroyed or modified, or if the organism does not contain a sensitive site, then the microorganism will not be affected; in such a case it is said to be resistant.
A major problem associated with the use of antibacterial drugs is that an organism that originally was sensitive to a given drug can become resistant. For example, bacteria undergo spontaneous mutations; and exposure of these bacteria to an antimicrobial can eradicate sensitive organisms, thereby selecting a population resistant to that drug and sometimes to related drugs. Bacteria sensitive to anitimicrobial agents can become resistant by acquiring from resistant organisms deoxyribonucleic acid (DNA) containing genes coding for resistance (resistance genes). Bacteria sensitive to an antimicrobial can mate (conjugation) with bacteria containing resistance genes, or they can acquire these resistance genes by transduction. In transduction, a bacterial virus (bacteriophage) incorporates resistance genes into its genome by infecting a resistant bacterium. When the bacterial virus infects another bacterium, the phage DNA (containing resistance genes) can be incorporated into that bacterium and center resistance. Some bacteria may acquire multiple resistance genes simultaneously and become resistant to several antibiotics. This is possible because circular pieces of DNA (plasmids) can, by recombination, acquire several genes, each of which codes for resistance to a different agent. Plasmids containing these multiple resistance genes can transfer to sensitive bacteria and thereby confer multiple resistance. Transfer of genes into the chromosome or into plasmids is facilitated in many cases because the genes are found on transposons, which are sequences of DNA that can excise themselves from plasmids and chromosomes and insert themselves into other plasmids and chromosomes. Bacteria resistant to as many as 10 different antimicrobial agents are known. One of the major problems associated with the transfer of resistance genes is that they can be transferred not only among similar but also to quite different bacteria.
Resistance to antimicrobial agents results from (1) decreased permeability of the organism to the drug; (2) deactivation or modification of the drug by an enzyme; (3) modification of the drug receptor or binding site; (4) increased synthesis of an essential metabolite whose production is blocked by the antimicrobial agent; or (5) production of an enzyme that is altered so that it is not inhibited or affected by the drug.
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