By P. Gorok. Marylhurst University.
As a result water can enter the cell cheap motilium 10 mg mastercard, but the components of the cell cannot pass out of the cell purchase motilium 10 mg without prescription. In the type of diﬀusive motion we have discussed so far, the movement of the molecules is due to their thermal kinetic energy. Some materials, however, are transported through membranes with the aid of electric ﬁelds that are gen- erated by charge diﬀerences across the membrane. We have shown that over distances larger than a few millimeters diﬀusion is a slow process. Therefore, large living organisms must use circulating sys- tems to transport oxygen nutrients and waste products to and from the cells. The evolution of the respiratory system in animals is a direct consequence of the inadequacy of diﬀusive transportation over long distances. At rest, an average 70-kg adult requires about 70 Cal of energy per hour, which implies a consumption of 14. It has been determined that in a person only about 2% of oxygen consumed at rest is obtained by diﬀusion through the skin. The lungs can be thought of as an elastic bag suspended in the chest cav- ity (see Fig. When the diaphragm descends, the volume of the lungs increases, causing a reduction in gas pressure inside the lungs. The trachea branches into smaller and smaller tubes, which ﬁnally terminate at tiny cavities called alveoli. Itis here that gas is exchanged by diﬀusion between the blood and the air in the lungs. The lungs of an adult contain about 300 million alveoli with diameters ranging between 0. The total alveolar area of the lungs is about 100 m2, which is about 50 times larger than the total surface area of the skin. In fact, the full 1 volume of the lungs is about 6 liter, and at rest only about liter is exchanged 2 during each breath. The oxygen requirement, of course, rises with increased physical activity, which results in both faster and deeper breathing. While diﬀusion through the skin can supply only a small fraction of the oxygen required by large animals, the oxygen needs of small animals may be completely satisﬁed through this channel. The energy consumption and, hence, the oxygen requirement of an animal is approximately proportional to its mass. The amount of oxygen diﬀusing through the skin is proportional to the surface area of the skin. Now, if R is a characteristic linear dimension of the animal, the volume is proportional to R3, and the skin surface area is proportional to R2. It is possible to obtain an estimate for the maximum size of the animal that can get its oxygen entirely by skin diﬀusion. A highly simpliﬁed calcula- tion outlined in Exercise 9-7 shows that the maximum linear size of such an animal is about 0. Therefore, only small animals, such as insects, can rely entirely on the diﬀusion transfer to provide them with oxygen. However, during hibernation when the oxygen requirements of the animal are reduced to a very low value, larger animals such as frogs can obtain all the necessary oxygen through their skin. In fact some species of frog hibernate through the winter at the bottom of lakes where the temperature is constant at 4◦C. The inner wall of the alveoli is coated with a thin layer of water that protects the tissue. The surface tension of this water layer tends to minimize the surface thereby shrinking the alveolar cavity. When the diaphragm descends, the incoming air has to enter the alveoli and expand them to their full size. Because the alveoli are embedded in a moist medium, expanding the alveoli is analogous to cre- ating a bubble inside a liquid. Clearly the incoming air at one atmosphere cannot open the small alveoli and can barely begin to expand the larger ones. Breathing is made possible by surfactants that cover the alveolar water layer and greatly reduce its surface tension. These surfactant molecules are a complex mixture of lipids and proteins produced by special cells in the alveoli and they can reduce surface tension by as much as a factor of 70 (to about 1 dyn/cm). The lungs of premature infants often fail to produce adequate amounts of surfactants required for breathing. This life threatening condition called Infant Respiratory Distress Syndrome can now be treated with artiﬁcial lung surfac- tants developed in the 1980s. When introduced into the lungs of the infant these surfactants often stabilize breathing till the alveoli begin to produce sur- factants on their own.
Concomitant use of such drugs will affect the drug disposition of substrate drugs in which the transporters are deeply involved cheap 10mg motilium fast delivery. The possible sites for drug-drug interactions involving transports are summarized in Table 2 safe motilium 10 mg. Drug- drug interactions in the liver, kidney, and small intestine affect the drug exposure in the circulating blood, while those in the peripheral organs affect the tissue concentrations only in the peripheral organs, leading to enhancement/attenuation of pharmacological effect and/or incidence of adverse effect. In most cases, the drug-drug interactions in peripheral tissues hardly affect the drug exposure in the circulating blood because of small contribution of transporters in peripheral tissues to the clearance mechanism and distribution volume. The impact of the drug-drug interaction depends on the pharmacokinetic properties of the substrate drug and the contribution of the transporter to the net membrane transport process in addition to the concentration of the inhibitors. This chapter describes recent advances in the prediction of transporter- mediated drug-drug interactions and methods for their evaluation. Unlike channels, transporters form intermediate complex with its substrate, and thus, the membrane transport involving transporters is charac- terized by saturation, reaching the maximum transport velocity by increasing the substrate concentrations. Competitive inhibition occurs when substrates and inhibitors share a common binding site on the transporter, resulting in an increase in the apparent Km value in the presence of inhibitor (Eq. Noncompetitive inhibition assumes that the inhibitor has an allosteric effect on the transporter, does not inhibit the formation of an (text continues on page 146) Drug-Drug Interactions Involving the Membrane Transport Process 137 138 Kusuhara and Sugiyama Drug-Drug Interactions Involving the Membrane Transport Process 139 140 Kusuhara and Sugiyama Drug-Drug Interactions Involving the Membrane Transport Process 141 142 Kusuhara and Sugiyama Drug-Drug Interactions Involving the Membrane Transport Process 143 144 Kusuhara and Sugiyama Drug-Drug Interactions Involving the Membrane Transport Process 145 146 Kusuhara and Sugiyama Figure 1 The schematic diagram for the prediction of drug-drug interactions involving membrane transport from in vitro transport experiments. When the substrate con- centration is much lower than the Km value (so-called linear condition, this assumption holds true for many drugs at their clinical dosages), the intrinsic membrane transport clearance can be expressed by the following equation, independently of the type of inhibition. Finally, the unbound concentration of inhibitors at clinical dosage and inhibition constant (Ki) for the target transporter are necessary to predict the interaction in vivo. The inhibition constant can be determined by kinetic analysis of the data from an in vitro transport study using isolated or cultured cells, membrane vesicles, and gene expression systems, etc. It is recommended to use human-based experimental systems to obtain kinetic parameters. Although ani- mal-based experimental systems are readily available, species differences in the kinetic parameters and the relative contribution of the transporters cannot be ruled out. When multiple transporters participate in the membrane transport of a drug, not only the degree of inhibition of the target transporter but the contri- bution of the transporter to the net transport process, is taken into consideration for the prediction (Eq. X X X nj Rnet ¼ n Rj j ¼ nj ¼ 1 ð5Þ 1 þ Cu,i,j/Ki,j where Rj represents the degree of inhibition for each transporter and nj represents the contribution of the transporter to the net membrane transport. In the case of hepatobiliary and tubular secretion where transporters are involved both in the uptake and efflux processes, the overall degree of inhibition can be approximated by multiplying the degrees of inhibition at the uptake and efflux processes (Eq. Roverall Ruptake Â Rexcretion ð6Þ Strictly speaking, the calculation of Rexcretion requires the unbound concen- tration in the tissue, which is not available in most of the case. It is recommended to perform sensitivity analysis of Rexcretion by changing the tissue concentration from the plasma unbound concentration to the 10-fold greater values. When even 10-fold greater concentration does not affect Rexcretion significantly, inhibition will not occur. For hepatic transport, when inhibitors are given intravenously, the peak unbound 148 Kusuhara and Sugiyama concentration in the blood will also provide the degree of inhibition of hepatic transport. However, when inhibitors are given orally, the concentration in the inlet to the liver is often higher than the peak concentration in the circulating blood, and thus, maximum inhibition should be predicted using the inlet concentration. To avoid false negative predictions, maximum unbound concentration of inhibitors in the inlet to the liver (Cu,i) can be approximated by the following equation (3,4). It should be noted that this approximation overestimates the Cu,i,and thereby, the degree of inhibition. When the predicted R value is close to unity, the possibility of a drug-drug interaction can be excluded. In other cases, more detailed analysis using physiologically based pharmacokinetic model is required for more precise prediction. Details of the experimental conditions are readily available in the references cited in this section. Isolated/Cultured Hepatocytes Hepatocytes freshly prepared are subjected to the transport study using a cen- trifugal filtration technique. After incubating the hepatocytes with test com- pounds, the reaction was terminated by separating the cells from the medium by passing through the layer of a mixture of silicone and mineral oil (density: 1. The hepatic uptake of peptidic endothelin antagonists by freshly isolated rat hepatocytes was extrapolated to give the in vivo uptake clearance based on the assumption of a well-stirred model; they were very close to those obtained by in vivo integration plot analysis (Fig. Thus, isolated hepatocytes are a good model for evaluating hepatic uptake clearance. Because of progress in cryopreservation techniques, cryopreserved human hepatocytes are now available from several commercial sources for transport studies. Cry- opreserved hepatocytes are now frequently used for the characterization of hepatic uptake of drugs in human.
With these cheap 10 mg motilium mastercard, there is so-called nervous dyspepsia generic 10 mg motilium otc, atonicity, in fact, of the entire gastrointestinal tract. There is heart feebleness with some irregularity; there is cool skin and cool or cold extremities: there is melancholia, irritability, peevishness, vagaries of thought, morbid desires and fancies, usually accompanied with autotoxemia which demands persistent elimination. In sexual neurasthenia it is the remedy par excellence, as it has a selective influence upon the nerve structure of the genito-urinary apparatus. Therapy—It will be found directly serviceable in paralysis and wasting disease of the aged, in nerve tremors, and especially in chorea and in paralysis agitans. In the convalescence of prostrating disease, and during the asthenic or later stages of inflammatory and exanthematous disease and diphtheria, it is as important as quinine and strychnia, and certainly as reliable. The local paralysis of diphtheria, has no better antidote, and if given in Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 72 hot infusion during the course of acute exanthematous disease, it quickly determines the eruption to the surface and promotes convalescence. Because of its selective action upon the nervous structure which supplies the reproductive organs, it will be found to allay nervous excitement, nervous palpitation of the heart, insomnia and mental weakness, or failure and general debility caused by masturbation, over sexual indulgence, or onanism. This writer has had better satisfaction in the use of this agent in the temporary impotence of young newly married men, than from any other single remedy or combination of remedies. If there be prostatic or other local irritation, a combination of this agent with saw palmetto will cover the field. In uterine or ovarian disorders with hysterical manifestations it is of much service. The nervous headaches of the menstrual epoch, especially those accompanied with burning on the top of the head, and sick headaches apparently from disordered stomach at this time, or in fact sick headache at any time if accompanied with nervous weakness, are all promptly benefitted by Avena Sativa, provided gastric acidity is neutralized. In neuralgic and congestive dysmenorrhea, with slow and imperfect circulation and cold skin and extremities, it is an excellent remedy. Simmons of Toledo, Ohio, in the Gleaner, mentioned the use of avena in acute coryza. Those who are subject to colds in the head, he furnishes with a small vial of specific avena. This may be repeated or increased to thirty or forty drops in two hours, but the third close is usually sufficient to remove every evidence of coryza if present, and to prevent its occurence. If twenty drops do not produce a feeling of warmth in the face and flushing of the skin, the next dose is increased. This agent exercises a restorative power in overcoming the habits of alcohol, tobacco, morphine, and opium. In the treatment of the morphine habit, our subsequent experience has not confirmed our early anticipations, and yet it is a useful addition to Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 73 the treatment. It should be used in conjunction with capsicum, strychnine, xanthoxylum, or hyoscyamine hydrochlorate, and sustained in its action by persistent concentrated nutrition. In conjunction with cactus, or apocynum, as these remedies are indicated, it will be found of much service in the treatment of weak heart, and the resulting complications. Webster lays much stress upon its action as a remedy to prevent the recurrence of cardiac rheumatism. This influence would be facilitated by combination with specific alteratives, and remedies that will facilitate the elimination of uric acid, without depressing the action of the heart. The persistent use of this remedy, especially if conjoined with capsicum or minute doses of strychnine, will be found of great assistance in certain cases of paralysis. French used ergot and avena with bromide as an occasional sedative, with satisfactory results. He says: “I also give avena for the symptoms of nervous breakdown and exhaustion, regardless of the name of the special disease from which they may be suffering. Some patients claim to realize almost instantaneous effects on taking it while others are less easily affected. In all well-known cases selected for the indications of paralysis and deficiency of nerve power, it seems to me to be good. It exercises an influence Similar to quinine after prostrating fevers and is similar to coca and phosphorus in its restorative powers. Zanthoxylum will enhance its general stimulant influence, and it may be combined with cimicifuga and scutellaria and gelsemium in chorea. It is antagonized by nerve depressants and nerve sedatives which exercise no stimulant or restorative influence. There is no danger of forming the habit of taking the drug, as it can be suddenly abandoned at any time without evil consequences, even when given in large quantities. Physiological Action—The remedy is disinfectant-antiseptic, and when applied to the skin and to raw surfaces it is stimulant. It promotes healing of wounds and restores impaired and abnormal conditions of the skin.
Finally my doctor prescribed a low dose of birth control pills order motilium 10mg mastercard, which smoothed over my emotional life generic 10mg motilium amex, but did nothing for my migraines (in fact, it probably exacerbated them). In my fifties, as my periods became more erratic and I lumbered on toward menopause, the first sign that something was terribly amiss was my inability to sleep. Finally she suggested I try an acupuncturist at the college where she was studying. Yeah, right, someone’s going to stick me with needles and I’m going to be able to think again? It took a few months, but between weekly sessions of acupuncture and a daily dose of Chinese herbs, I was able to sleep well enough that my brain worked. Charlotte, whom you met previously, in chapter 4, articulates the interconnection of stress and her other hormonal symptoms, including infertility, migraines, unstable emotions, and sleep problems. Stress and Downstream Hormonal Imbalances As you read through my explanation of the common hormonal imbalances I see in my practice, you might notice that most of them have one feature in common: dysregulated cortisol. Left unchecked, unremitting stress has important consequences —including infertility, a “fried” control system (the hypothalamus), fatigue, and moodiness—for women who are largely neglected by mainstream medicine. Your organ reserve gets depleted along with your natal chi, according to Traditional Chinese Medicine, and your telomeres may shorten. You age prematurely, and so do your ovaries (diminished ovarian reserve) and thyroid (thyropause). Recap of Cortisol Interdependence with Other Hormones Let me repeat: cortisol bosses around production of several major and minor hormones. Cortisol regulates blood sugar, immune function, and blood pressure, plus it inhibits or stimulates many other hormones. When stress is excessive or perceived to be excessive, initially cortisol (a member of the glucocorticoid family) rises in the blood, saliva, and urine. High cortisol blocks or lowers the production of thyroid hormones, sex hormones (such as estrogen and progesterone), growth hormone, and melatonin. Over time, if the adrenals can no longer continue the high output, cortisol levels will decrease. I’ve included several hormonal formulas in this chapter to help you understand the interactions among the variables, which are hormones and actions that affect hormones, such as physiological stress. Here’s one applicable to adults to get us started: This simple equation shows that stress goes up when your adrenals are off kilter and make too much cortisol. Stress levels go down with restorative sleep, regular exercise, nutrient-dense food, and contemplative practice, such as meditation. Stress and Dysregulated Adrenals: Common Hormonal Combinations Referring back to the questionnaires in chapter 1, if you answered “yes” to three or more of the questions as in either Part A or Part B (or collectively, more than three in both Part A and Part B), plus three or more in another part, you have a problem with the cross talk between the adrenal glands and either the thyroid or the ovaries. Finally, you’ve got an explanation for the crushing fatigue, poor mood, lack of libido, and climbing weight—you’re not going crazy. You begin taking medication, usually a synthetic T4 such as Synthroid or levothyroxine as a tablet by mouth. There are many women who are properly prescribed thyroid hormone and do not experience the party-crashing adrenal on their thyroid honeymoon. But if your symptoms are atypical, or you feel better but then backslide, or if you answered “yes” to three or more questions in chapter 1, Part A and/or Part B and Part G, I suggest you take into account the important chain reaction between the thyroid and adrenal systems, because an adrenal problem will cause your thyroid issue to be much worse and harder to correct, and vice versa. Cortisol, when it is deficient or excessively high for prolonged periods of time, can slow down thyroid function. Folks with dysregulated cortisol and thyroid problems document this finding, showing that both high and low cortisol can impair thyroid function, although the relationship is not linear. Women who have too much or too little cortisol, plus an underperforming thyroid, get a double dose of fatigue, yet often neither condition is typically recognized in conventional medicine nor believed to be properly documented by existing biomarkers. When cortisol is just right, and in the normal range, the thyroid performs best and generates optimal levels of hormones. Reassess your symptoms six to twelve weeks after you’ve implemented the changes of Step 1. If you are still not feeling that your hormone issues are improved, add in Step 2 from both chapters. If you still are experiencing five or more symptoms from both chapters 4 and 9, see your doctor to consider further testing and a prescription for bioidentical hormones. Keep in mind that your thyroid medication requires adequate cortisol to work best: not too high and not too low. Dysregulated Cortisol and Dysregulated Sex Hormones (Estrogen and Progesterone) High cortisol is the single most common hormonal problem I see in my practice, and high cortisol with low estrogen and/or progesterone is another common combination. This varies by age: low progesterone coupled with high cortisol is the most common hormone combination that I see in women younger than thirty- five years of age. If you answered “yes” to three or more of the questions in chapter 1, Part A and/or Part B (the high and low cortisol questionnaires), together with three or more from Part C, Part D, and Part E, this is your hormone combo.
Tamoxifen and toremifene concentrations¨ in plasma are greatly decreased by rifampin buy cheap motilium 10 mg on-line. A preliminary review of its pharmacodynamic and pharmacokinetic properties motilium 10mg fast delivery, and therapeutic use Role of the Gut Mucosa in Metabolically Based Drug-Drug Interactions 513 as a prokinetic agent in gastrointestinal motility disorders. An investigation of the pharma- cokinetics of ethynylestradiol in women using radioimmunoassay. Effects of grapefruit juice on pharmaco- kinetics of atorvastatin and pravastatin in Japanese. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Effect of grapefruit juice on carbamaze- pine bioavailability in patients with epilepsy. Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride. Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam half-life. Effects of grapefruit juice and smoking on verapamil concentrations in steady state. The most common paradigm in the prediction of in vivo drug interactions has been first to determine the enzyme selectivity of a suspected inhibitor and subsequently to estimate the constant that quantifies the potency of reversible inhibition in vitro. This approach has been successful in identifying clinically important potent competitive inhibitors, such as quinidine, fluoxetine, and itraconazole. Irreversible inhibition is an additional mechanism that may reduce the catalytic activity of an enzyme in vitro and in vivo. A seminal illustration of the importance of an irreversible mechanism of inhibition is provided by erythromycin, the widely used macrolide antibiotic. Thus, the goal of this text is to describe the scope of irreversible inhibition of drug metabolizing enzymes and to indicate how the prediction of in vivo drug interactions can be incorporated into this phenomenon. The latter two modes of inhibition are most commonly displayed by inhibitors that are dependent on the enzyme itself to reveal their inhibition, and they are therefore commonly referred to as mechanism- based inhibitors (5). A mechanism-based inhibitor must first bind and then become catalytically activated by the enzyme. The activated species irreversibly alters the enzyme and removes it permanently from the pool of active enzyme. For a substance to be classified as a direct mechanism-based inhibitor, it should meet the following rigorous criteria proposed by Silverman (5): 1. Under conditions that support catalysis, a time-dependent loss of enzyme activity is observed. The rate of enzyme inactivation is proportional to low inactivator con- centration but is independent at high inactivator concentration [Eq. The rate of inactivation is slower in the presence of a competing substrate than in its absence. A catalytic step for the conversion of inactivator to a reactive intermediate can be proposed. There is no lag time for inactivation; the presence of exogenous nucleo- philes has no effect on the inactivation rate; following inactivation, a second, equal addition of enzyme results in the same rate of inactivation as the first addition in the absence of inactivator and cofactor depletion. Compounds That Covalently Bind to the Protein Examples of xenobiotics that bind to proteins and fall into this class of mechanism- based inhibitor include tienilic acid, cannabidiol, chloramphenicol, secobarbital, some psoralens, spironolactone, mifepristone, and grapefruit juice. Evidence suggests that an electrophilic sulfoxide metabolite of tienilic acid is the reactive species. Chloramphenicol and secobarbital exhibit properties similar to those of tienilic acid, but they have not been studied in humans (11). The mechanism of inhibition by this compound appears to be an initial oxidation to generate an epoxide that reacts with a nucleophilic amino acid at the active site (14). The proposed mechanism of inactivation involved addition of reactive oxygen to the carbon-carbon triple bond of mifepristone to yield a highly reactive ketene intermediate that reacts with a nucleophilic residue at the enzyme active site (16). This coordination can only be displaced under nonphysiological experimental conditions (e. The primary amines are hydroxylated and then further oxidized to a nitroso group that appears to chelate to the heme, which results in a more stable (ferrous) state of iron. This ferrous state exhibits a spectrum with an absorbance maximum of 445–455 nm (17).
Mutations of the α subunit cheap motilium 10 mg mastercard, particularly a leucine for arginine substitution at position 271 order motilium 10 mg online, lead to a very rare neurological disorder termed hyperekplexia. Patients with this disease demonstrate an exaggerated startle response to environmental stimuli, jumping dramatically or even collapsing in response to minor situational stimuli such as a car door shutting. The strychnine-sensitive Cl− channel glycine receptor functions as an anion channel. Permitting chloride anion to enter neu- rons causes neuronal hyperpolarization (increased negative charge within the cell), which in turn decreases neuronal excitability. Therefore, this glycine receptor is inhibitory and, when binding to this receptor, glycine is acting as an inhibitory neuro- transmitter. Autoradiography studies with [3H]strychnine show that these receptors are clustered mainly in the spinal cord and brainstem. On this receptor, unlike the strychnine-sensitive receptor, glycine is linked to neuronal excitation. Both the strychnine-sensitive and insensitive receptors are involved in pathological processes and thus are targets for drug design. The strychnine-sensitive site may be a useful target when designing drugs (as agonists) to treat spasticity. Spasticity is a symp- tom arising from damage to the spinal cord or to the descending corticospinal tract from the brain that is characterized by increased tone, sometimes painful, in the muscles of the arms and legs. The strychnine-insensitive receptor may be a useful target when designing drugs (as antagonists) to treat either epilepsy or stroke. In medicinal chemistry, the strychnine-insensitive receptor has received more attention. In addition, a number of 3-substituted indole-2-carboxylates were shown to be powerful glycine site antagonists. Compounds targeting the glycine receptors have had mixed success as drug candi- dates. This observation calls into question the utility of some of the animal models of stroke that are currently employed. As amino acids, they have many other important biochemical roles; thus their concentration is uniformly high throughout the nervous system. Certain areas in the spinal cord, interneurons of the reflex arc, and a pathway from the cortex to the striatum are presumed sites of activity. Because of the uniform glutamate and aspartate distribution, mapping of the receptors was accomplished only recently. For the same reason, specific nonendogenous natural- product agonists had to be used for receptor characterization, in the same manner as in the differentiation of the nicotinic and muscarinic cholinoceptors. Broadly speaking, the glutamate receptors can be categorized in two major groups: ionotropic and metabotropic. These three receptor types are both functionally distinct and defined by distinct molecular families of recep- tor genes. In 1989, the notion of metabotropic receptors was barely emerg- ing; by 1995, there were three metabotropic receptors; by 1999 there were reportedly eight of them. These ionotropic and metabotropic receptors influence a variety of neuro- chemical and neurophysiological events. They have been implicated in the mechanism of information processing, memory, and learning, through long-term poten- tiation of neuronal pathways. They have also been involved in pathological processes such as epilepsy and stroke. In addition to the anticipated agonist and competi- tive antagonist binding sites, there are a number of other functional subsites on the receptor complex: glycine, polyamine, Zn2+ and Mg2+. Each one of these additional bind- ing sites responds functionally to either endogenous or exogenous ligands and is thus also a reasonable target for drug design. Bioisosteric replacement of a carboxylate group also produces agonists; D,L-(tetrazol-5-yl)glycine (4. Likewise, with appropriate substitutions and replacement, glutamic acid analogs can also be competitive antagonists. In these antagonists, bioisosteric replacement of carboxylates with phosphonates is a frequent design strategy. Introduction of trans-4-methyl substituents into this piperidine derivative yields even greater receptor affinity. Work on glycine subsite antagonists is discussed in the section on glycine (section 4. Designing drugs to uniquely interfere with the biochemistry of a metallic anion in the central nervous system is non- trivial. It can be appreciated, from studies that attempt to design ion-specific chelating agents, that developing drugs to uniquely target one metal ion (e. Nevertheless, tricyclic antidepressants and phenoth- iazines, including desmethylimipramine and ethopropazine, have been suggested to act as zinc site ligands. The relationship between the zinc site and the magnesium site has also been considered. Oxytocin is used to induce labor in childbirth and to promote the expulsion of the pla- centa, although the antidiuretic activity of the native hormone is a disadvantage.