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Ideally a drug should only bind to one receptor type 1 but in reality very few discount clomiphene 25mg free shipping pregnancy over 45, if any buy clomiphene 25mg fast delivery menopause the play, are that specific, especially at high concentrations. DRUG±RECEPTOR INTERACTIONS The effect of an agonist drug whether it is measured as the ability to fire a neuron, inhibit an enzyme or reduce motor function, increases with the concentration of the drug and the number of receptors it occupies. In fact the magnitude of the response, like that of a chemical reaction, is proportional to the product of the concentration of the reactants, in this case the drug and its receptors, and as such obeys the law of Mass Action. Thus the rate at which a drug [D] combines with the receptor [R] to give occupied receptors (or drug receptor complexes [DR]), can be represented by its rate constant K1 so that ‰DŠ‡‰RŠˆK1‰DRŠ Since the drug±receptor interaction is reversible the drug also dissociates from the receptor at a rate K2 when ‰DRŠˆK2‰DŠ‡‰RŠ The equilibrium constant (KA) for the reaction is thus given by Neurotransmitters, Drugs and Brain Function. Webster &2001 John Wiley & Sons Ltd 106 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION K1 ‰DŠ‰RŠ KA ˆ ˆ K2 ‰DRŠ When 50% of the receptors are occupied [R] and [DR], free and occupied receptors, must be equal and cancel out so that KA ˆ D, the concentration of drug required to bind to 50% of the receptors. Thus the lower the concentration of drug required to achieve this occupancy, the greater its affinity. Unfortunately its affinity does not necessarily reflect its potency in producing an effect. The relationship between the dose (concentration) of a drug and the response it produces provides the so-called dose (or concentration) response curve (DRC). This is hyperbolic but is transformed to a sigmoid shape, which is linear over a large dose range, when the dose is plotted on a log scale (Fig. Comparison of the con- centrations of two or more drugs required to produce the same response is a measure of their relative potency. Often the potency of a drug is defined as the dose or concentration of drug required to produce 50% of the maximal response, i. It obviously has agonist activity but since it cannot produce a maximal response it is known as a partial agonist. While such a property may seem unwanted the drug could still produce an adequate effect and avoid the danger of that becoming too great with increasing dose. There are some points about the dose±response curve that justify consideration. When a drug is administered to either humans or animals we obviously know the dose but not the concentration at its site of action. In this instance the relationship between the amount of drug and its effect really is a dose±response curve. If a drug is added to an in vitro system in an organ or tissue bath then, provided the volume of the bathing solution is known, the concentration of drug can be calculated. Concentration is also known if a tissue is superfused with a prepared drug solution. Even then, the actual con- centration of drug at the receptor site is not really known, since there can be a steep gradient between the concentration of drug in the medium and that at the actual receptor, especially if the drug is only in contact with the tissue for a short time. A proportion of most NTs is likely to be metabolised in, or taken up by, the tissue before reaching the receptor, although this is less likely with synthetic drugs. It could be that they are achieving the same response by acting through different receptors and that those targeted by A are either more numerous or better equipped to initiate the response. If they are both acting on the same receptor then obviously A has a more appropriate chemical structure to fit that receptor than B, but whether this has conferred on it a greater ability to combine with the receptor (affinity) or to activate it (efficacy) is unclear. It certainly should not be assumed that the EC50 is a measure of the affinity of the drug for the receptor. All responses are the result of a series of PHARMACOLOGY AND DRUG EFFECTS 107 Figure 5. The curves show that drug A achieves the same responses as drug B but at lower doses. Drugs A and B 50 can both produce the maximal response and are full agonists. Drug C cannot produce a maximal response even at large doses and is known as a partial agonist cellular events and, with the possible exception of studies on single-channel opening, not a direct measure of receptor occupancy. In any case, the efficacy of the drug must also be considered and since antagonists are devoid of that property their affinity and activity cannot be measured directly through a response (see below).

Ventricular repolarization (produc- (ventricular outflow) ing the T wave) initiates ventricular relaxation or ventricu- 0 lar diastole discount clomiphene 25mg online pregnancy exercises. When the ventricular pressure drops below the atrial pressure discount 25mg clomiphene with visa women's health clinic gladstone, the mitral valve opens, allowing the blood 120 accumulated in the atrium during systole to flow rapidly into the ventricle; this is the rapid phase of ventricular fill- ing. Both pressures continue to decrease—the atrial pres- Ventricular volume sure because of emptying into the ventricle and the ven- 85 tricular pressure because of continued ventricular relaxation (which, in turn, draws more blood from the atrium). About midway through ventricular diastole, filling slows as ven- tricular and atrial pressures converge. S S2 S S4 1 3 S4 Pressures, Flows, and Volumes in the Cardiac R P T Electrocardiogram Chambers, Aorta, and Great Veins Can Be Matched With the ECG and Heart Sounds Q S The pressures, flows, and volumes in the cardiac chambers, 0 0. In electrical terms, ventricular systole is de- fined as the period between the QRS complex and the end of the T wave. In mechanical terms, it is the period between ously, blood enters the right atrium from the superior and the closure of the mitral valve and the subsequent closure of inferior vena cavae. In either case, ventricular diastole com- during atrial diastole produces the v wave and reflects its prises the remainder of the cycle. The small pressure oscillation early in atrial dias- The first (S1) and second (S2) heart sounds signal the be- tole, called the c wave, is caused by bulging of the mitral ginning and end of mechanical systole. The first heart sound valve and movements of the heart associated with ven- (usually described as a “lub”) occurs as the ventricle contracts tricular contraction. The relatively low- pitched sound associated with their closure is caused by vi- TABLE 14. Force of contraction tic and pulmonic valves close at the end of ventricular sys- 1. End-diastolic fiber length (Starling’s law, preload) tole, when the ventricles relax and pressures in the ventricles a. Contractility aortic and pulmonic valves produce the second heart sound, a. Sympathetic stimulation via norepinephrine acting on 1 which is relatively high-pitched (typically described as a receptors “dup”). Circulating epinephrine acting on 1 receptors (minor) and nearby structures contribute to these two sounds, espe- c. Intrinsic changes in contractility in response to changes cially S1; these factors include movement of the great vessels in heart rate and afterload and turbulence of the rapidly moving blood. Ventricular radius the rapid phase of ventricular filling and is associated with 2. Heart rate (and pattern of electrical excitation) heard in normal children and adolescents, its appearance in a patient older than age 35 usually signals the presence of a cardiac abnormality. It is caused by blood movement resulting from atrial contraction and, like S , is more com- Stroke Volume Is a Determinant 3 mon in patients with abnormal hearts. The force of contraction is affected by Cardiac output (CO) is defined as the volume of blood end-diastolic fiber length, contractility, and hypertrophy. The usual resting val- Afterload, the force against which the ventricle must con- ues for adults are 5 to 6 L/min, or approximately 8% of tract to eject blood, is affected by the ventricular radius and body weight per minute. When it is neces- across the aortic valve is normally small, aortic pressure is sary to normalize the value to compare the cardiac output often used as a substitute for ventricular pressure in such among individuals of different sizes, either cardiac index or considerations. Car- diac output is the product of heart rate (HR) and stroke Effect of End-Diastolic Fiber Length. The relationship volume (SV), the volume of blood ejected with each beat: between ventricular end-diastolic fiber length and stroke volume is known as Starling’s law of the heart. Within lim- CO SV HR (1) its, increases in the left ventricular end-diastolic fiber Stroke volume is the difference in the volume of blood in length augment the ventricular force of contraction, which the ventricle at the end of diastole—end-diastolic volume— increases the stroke volume. This reflects the relationship and the volume of blood in the ventricle at the end of sys- between the length of a muscle and the force of contraction tole—end-systolic volume. After reaching an optimal diastolic fiber If heart rate remains constant, cardiac output increases in length, stroke volume no longer increases with further proportion to stroke volume, and stroke volume increases stretching of the ventricle. Ejection fraction (EF) is a commonly used measure of End-diastolic pressure is the force that expands the ventri- cardiac performance. In Chapter 10, preload was de- diastolic volume (EDV), expressed as a percentage: fined as the passive force that establishes the muscle fiber length before contraction. For the intact heart, preload can EF (SV/EDV) 100 (2) be defined as end-diastolic pressure. It is de- compliance (change in volume caused by a given change in pendent on heart rate, preload, afterload, and contractility pressure), a higher end-diastolic pressure (preload) in- (all to be discussed below) and provides a nonspecific index creases both diastolic volume and fiber length.

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In the chronic phase order clomiphene 100mg fast delivery women's health center keokuk ia, anticonvulsants such as carbamaze- pine and gabapentin are used generic clomiphene 100 mg amex menstrual pain. Less common is the painful tetanic posturing of an arm or leg, usually on one side of the body. Treatment consists of carbamazepine, clonazepam, tizanidine, and baclofen. Lightning-like extremity pain can be treated with carbamazepine, gabapentin, and phenytoin. Lhermitte’s sign responds to the above medications and also to tricyclic antidepressant medications. Headache has been reported to be causally related to demye- linating lesions. When associated with a relapse, treatment with steroids may cause resolution of headache. Optic neuritis is due to inflammation and demyelination occurring in and around pain-sensitive meninges surrounding the optic nerve. Gabapentin—useful in dysesthetic and paroxysmal pain; better SE profile than phenytoin 3. Accentuation of DTR and clonus occurs, with exaggeration of flexor reflexes C. Spasms and stiffness are common in the quadriceps, hamstrings, and gastrocnemious muscles D. May be heightened during an exacerbation, with underlying infection, and with noxious stimuli E. Reduce muscle hypertonia by stretching spastic muscles and by application of warm or cold packs 4. Develop and improve useful automatic movements and thus promote maximal function 6. Supply supportive aids such as walkers, wheelchairs, crutches, orthoses, and special shoes F. Screening for noxious stimuli will promote prompt treatment and reduction of spasticity. Medications for spasticity may be sedating and excessive doses may result in weakness CHAPTER 11: THE SYMPTOM CHAIN IN MULTIPLE SCLEROSIS 57 1. Surgically implanted pump for intrathecal baclofen delivery no systemic side effects expensive requires surgery reserved for patients in whom other interventions are unsuccessfulTremor, incoordination, and weakness A. Physical and occupational therapy may provide patient with education and assistive devices, but do not correct the underlying problemDysarthria A. Normal speech consists of five systems working together smoothly and rapidly: 1. Articulation—making quick, precise movements of the lips, tongue, mandible, and soft palate 5. Treatment consists of management of spasticity and tremor along with speech and language therapy (SLT) 58 NURSING PRACTICE IN MULTIPLE SCLEROSIS: A CORE CURRICULUM F. Are problematic speech and voice characteristics detracting from the message being communicated? Are speech, voice, and communication problems interfering with the patient’s quality of life? Are speech, voice, and communication problems perceived as troublesome by the patient and family? Normal swallowing involves intricate and rapid coordination of sensory and motor activity in the oral cavity, pharynx, and esophagus. Normal oromotor control for swallowing involves lip closure, facial tone and musculature, rotary lateral jaw motion, and pharyngeal swallow. Assessment includes a careful history (pneumonia, difficulty with liquids and solids, aspiration or choking while eating). Optimal management includes referral to a speech/language pathologist familiar with MS and its related problems. Videofluoroscopic examination or modified barium swallow (MBS) may identify the patient’s swallowing pathology. The resulting report should include a description of the patient’s physiologic or anatomic swallowing abnormalies; any symp- toms associated with the problem; results of any treatment attempted; and recommendations for treatment and dietary intake.

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Note that hypoxia increases the slope of the fort by sensing the discrepancy between tensions of the in- line in addition to changing its location buy 25mg clomiphene with mastercard pregnancy fruit comparison. This mechanism provides in- creased motor excitation when movement is opposed purchase clomiphene 50 mg online breast cancer journal. Evi- dence also shows that chest wall proprioceptors play a intermediate zone in which the activities of the caudal and major role in the perception of breathing effort, but other rostral groups converge and are integrated together with sensory mechanisms may also be involved. Exactly which cells exhibit chemosensitivity is unknown, but they are not the same as those of the DRG/VRG complex. Although specific cells have not been identified, the chemosensitive neurons that CONTROL OF BREATHING BY H , PCO2, and PO2 respond to the H of the surrounding interstitial fluid are Breathing is profoundly influenced by the hydrogen ion referred to as central chemoreceptors. The H concentra- concentration and respiratory gas composition of the arte- tion in the interstitial fluid is a function of PCO2 in the cere- rial blood. The general rule is that breathing activity is in- bral arterial blood and the bicarbonate concentration of versely related to arterial blood PO2 but directly related to cerebrospinal fluid. Responses to carbon dioxide and, to a lesser Concentration and PCO2 extent, blood pH depend on sensors in the brainstem and Cerebrospinal fluid (CSF) is formed mainly by the sensors in the carotid arteries and aorta. In contrast, re- choroid plexuses of the ventricular cavities of the brain. However, choroidal epithelium actively transports several substances, including ions, and this ac- Respond to Local H tive transport participates in determining the composition Ventilatory drive is exquisitely sensitive to PCO2 of blood of CSF. The source of this chemosensitivity has plexuses is exposed to brain interstitial fluid across the been localized to bilaterally paired groups of cells just be- surface of the brain and spinal cord, with the result that low the surface of the ventrolateral medulla immediately the composition of CSF away from the choroid plexuses is caudal to the pontomedullary junction. Each side contains closer to that of interstitial fluid than it is to CSF as first a rostral and a caudal chemosensitive zone, separated by an formed. Brain interstitial fluid is also separated from blood CHAPTER 22 The Control of Ventilation 369 60 50 PACO2 43 mm Hg 40 30 20 30 10 34 37 38 39 20 40 60 80 100 120 140 Movement of H , HCO , and molecular FIGURE 22. If this had not been done (lower curve), hypocapnia secondary to the hypoxic hyper- In healthy people, the PCO2 of CSF is about 6 mm Hg ventilation would have reduced the ventilatory response. The numbers next to the lower curve are PaO values measured at each higher than that of arterial blood, approximating that of 2 point on the curve. The pH of CSF, normally slightly below that des O2-Druckes in der Einatmungsluft auf die Atemtätigkeit des of blood, is held within narrow limits. Cerebrospinal fluid Menschen, geprüft unter Konstanthaltung des alveolaren CO2- pH changes little in states of metabolic acid-base distur- Druckes. Pflugers Arch Gesamte Physiol Menschen Tiere bances (see Chapter 25)—about 10% of that in plasma. During chronic by the blood-brain barrier (capillary endothelium), acid-base disturbances, the bicarbonate concentration of which has its own transport capability. CSF changes in the same direction as in blood, but the Because of the properties of the limiting membranes, changes may be unequal. In metabolic disturbances, the CSF is essentially protein-free, but it is not just a simple CSF bicarbonate changes are about 40% of those in blood ultrafiltrate of plasma. CSF differs most notably from an but, with respiratory disturbances, CSF and blood bicar- ultrafiltrate by its lower bicarbonate and higher sodium bonate changes are essentially the same. Potassium, magnesium, base disturbances are imposed, CSF bicarbonate changes and calcium ion concentrations also differ somewhat from more slowly than does blood bicarbonate, and it may not plasma; moreover they change little in response to reach a new steady state for hours or days. As already marked changes in plasma concentrations of these noted, the mechanism of bicarbonate regulation is unset- cations. Irrespective of how it occurs, the bicarbonate regula- in CSF, but the mechanism that controls bicarbonate con- tion that occurs with acid-base disturbances is important centration is controversial. Because of the relative imperme- Peripheral Chemoreceptors abilities of the choroidal epithelium and capillary endothe- Respond to PO2, PCO2, and pH lium to H , changes in H concentration of blood are poorly reflected in CSF. By contrast, molecular carbon diox- Peripheral chemoreceptors are located in the carotid and ide diffuses readily; therefore, blood PCO2 can influence the aortic bodies and detect changes in arterial blood PO2, PCO2, pH of CSF. Carotid bodies are small ( 2 mm wide) sensory bicarbonate concentration and PCO2. The relative ease of organs located bilaterally near the bifurcations of the com- movement of molecular carbon dioxide in contrast to hy- mon carotid arteries near the base of the skull.

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