By N. Alima. University of Maryland at Baltimore.
The most obvious and important characteristic revealed by these curves is that the dose-response relationship is graded generic plavix 75mg line. Because drug responses are graded buy plavix with a visa, therapeutic effects can be adjusted to fit the needs of each patient by raising or lowering the dosage until a response of the desired intensity is achieved buy 75mg plavix otc. B, The same dose-response relationship shown in A but with the dose plotted on a logarithmic scale. Note the three phases of the dose-response curve: Phase 1, The curve is relatively flat; doses are too low to elicit a significant response. Phase 2, The curve climbs upward as bigger doses elicit correspondingly bigger responses. Phase 3, The curve levels off; bigger doses are unable to elicit a further increase in response. The curve is flat during this phase because doses are too low to elicit a measurable response. During phase 2, an increase in dose elicits a corresponding increase in the response. As the dose goes higher, eventually a point is reached where an increase in dose is unable to elicit a further increase in response. Maximal Efficacy and Relative Potency Dose-response curves reveal two characteristic properties of drugs: maximal efficacy and relative potency. A, Efficacy, or maximal efficacy, is an index of the maximal response a drug can produce. B, Potency is an index of how much drug must be administered to elicit a desired response. In this example, achieving pain relief with meperidine requires higher doses than with morphine. Note that, if administered in sufficiently high doses, meperidine can produce just as much pain relief as morphine. Maximal Efficacy Maximal efficacy is defined as the largest effect that a drug can produce. The concept of maximal efficacy is illustrated by the dose-response curves for meperidine [Demerol] and pentazocine [Talwin], two morphine-like pain relievers (see Fig. As you can see, the curve for pentazocine levels off at a maximal height below that of the curve for meperidine. This tells us that the maximal degree of pain relief we can achieve with pentazocine is smaller than the maximal degree of pain relief we can achieve with meperidine. Put another way, no matter how much pentazocine we administer, we can never produce the degree of pain relief that we can with meperidine. Accordingly, we would say that meperidine has greater maximal efficacy than pentazocine. Despite what intuition might tell us, a drug with very high maximal efficacy is not always more desirable than a drug with lower efficacy. This may be difficult to do with a drug that produces extremely intense responses. If we only want to mobilize a modest volume of water, a diuretic with lower maximal efficacy (e. Similarly, in a patient with a mild headache, we would not select a powerful analgesic (e. Rather, we would select an analgesic with lower maximal efficacy, such as aspirin. Relative Potency The term potency refers to the amount of drug we must give to elicit an effect. Potency is indicated by the relative position of the dose-response curve along the x (dose) axis. These curves plot doses for two analgesics—morphine and meperidine—versus the degree of pain relief achieved. As you can see, for any particular degree of pain relief, the required dose of meperidine is larger than the required dose of morphine. Because morphine produces pain relief at lower doses than meperidine, we would say that morphine is more potent than meperidine. The only consequence of having greater potency is that a drug with greater potency can be given in smaller doses. It is important to note that the potency of a drug implies nothing about its maximal efficacy! In everyday parlance, people tend to use the word potent to express the pharmacologic concept of effectiveness. That is, when most people say, “This drug is very potent,” what they mean is, “This drug produces powerful effects. Drug-Receptor Interactions Introduction to Drug Receptors Drugs produce their effects by interacting with other chemicals. Receptors are the special chemical sites in the body that most drugs interact with to produce effects. We can define a receptor as any functional macromolecule in a cell to which a drug binds to produce its effects. The other macromolecules to which drugs bind, such as enzymes and ribosomes, can be thought of simply as target molecules, rather than as true receptors. Under physiologic conditions, endogenous compounds (neurotransmitters, hormones, other regulatory molecules) are the molecules that bind to receptors to produce a response. When a drug is the molecule that binds to a receptor, all that it can do is mimic or block the actions of endogenous regulatory molecules. By doing so, the drug will either increase or decrease the rate of the physiologic activity normally controlled by that receptor. In other words, drugs cannot make the body do anything that it is not 2 already capable of doing. Receptors and Selectivity of Drug Action Selectivity, the ability to elicit only the response for which a drug is given, is a highly desirable characteristic of a drug, in that the more selective a drug is, the fewer side effects it will produce. Selective drug action is possible in large part because drugs act through specific receptors. As a rule, each type of receptor participates in the regulation of just a few processes (Fig. If a drug interacts with only one type of receptor, and if that receptor type regulates just a few processes, then the effects of the drug will be limited. Conversely, if a drug interacts with several different receptor types, then that drug is likely to elicit a wide variety of responses. In some important ways, a receptor is analogous to a lock and a drug is analogous to a key for that lock: just as only keys with the proper profile can fit a particular lock, only those drugs with the proper size, shape, and physical properties can bind to a particular receptor (Fig. Note also how the positive charges on acetylcholine align with the negative sites on the receptor. Theories of Drug-Receptor Interaction In the discussion that follows, we consider two theories of drug-receptor interaction: (1) the simple occupancy theory and (2) the modified occupancy theory. These theories help explain dose-response relationships and the ability of drugs to mimic or block the actions of endogenous regulatory molecules. Simple Occupancy Theory The simple occupancy theory of drug-receptor interaction states that (1) the intensity of the response to a drug is proportional to the number of receptors occupied by that drug and (2) a maximal response will occur when all available receptors have been occupied.
The husband reveals on the telephone that his wife has not slept since the baby was born and is making bizarre comments about the health of the baby plavix 75mg free shipping. Her psychiatric liaison worker has left a written care plan in her obstetric notes buy cheap plavix 75 mg on line. A Admit immediately to a psychiatric ‘mother and baby’ unit This woman appears to have developed postpartum psychosis and needs inpatient assessment done by an experienced team buy plavix on line amex. If she goes into a specialised unit she can take the baby with her, which is better for bonding as she improves in the long run. If there is a written care plan it is likely that she has previous history and the plan should be accessible to everyone looking after her. She gives a history of postnatal depression that involved several months of in-patient care following her previous delivery. I Routine opinion from a specialist obstetric psychiatric clinic This woman has booked early, which provides the obstetric and psychiatric medi- cal team a great deal of time to look into her history and assess the risk for this pregnancy. The fact that she was looked after as an in-patient previously increases the likelihood of it having been a psychosis rather than an ordinary depression, but this can be investigated to confrm the previous diagnosis to work out her recur- rence risk. Initially there was some minor abdominal pain, but this has settled and there is no uter- ine activity. D Electronic cardiotocograph fetal monitoring Although the diagnosis here could be placenta praevia, therefore an ultrasound is a good idea; it is important to check that the baby is healthy before she goes to scan because another potential diagnosis is placental abruption. At some stage she will also need a speculum examination to exclude a cervical cause of the bleeding – such as chlamydial infection – but this should not be done until after the scan excludes placenta praevia. The uterus is nontender and the baby is well grown but appears to be lying transversely. There are no contractions and the condition of both the mother and the baby is stable. If she were contracting (so you haven’t much time to make the diagnosis) we would consider examining her in theatre, in case doing that makes her bleed torrentially from a low-lying placenta. D Electronic cardiotocograph fetal monitoring Recurrent antepartum haemorrhage is sometimes associated with intrauterine growth restriction. Although a Doppler is indicated here and another growth scan in 2 weeks’ time, it is important to check that the baby is healthy now before plan- ning future management. G Speculum examination of the cervix with microbiology swabs The lack of uterine tenderness rules out abruption as a diagnosis and it is likely that she has had a scan (which would have picked up placenta praevia) even though she booked late. The rate of chlamydial carriage in teenagers is very high and this infection is the most likely cause of her postcoital bleeding. D Electronic cardiotocograph fetal monitoring The diagnosis here is likely to be placental abruption so the frst priority is to check that the baby is healthy. A Candida albicans B Chlamydia trachomatis C Escherichia coli D Gardnerella vaginalis E Gonococcus 154 09:34:02. G Listeria monocytogenes Rubella, toxoplasma, and listeria all cause a mild fu-like illness in pregnancy and all three organisms can cross the placenta and infect the fetus. Listeria monocy- togenes causes suppression of fetal bone marrow and leads to severe fetal anae- mia that causes the classical picture of hydrops fetalis. However, the core knowledge being tested is the risk that listeria poses to the pregnant woman and the dietary advice given to all pregnant women to avoid unpasteurised foods. On examination she is ﬂushed, has a tachycardia of 100 bpm, and has a tem- perature of 38°C. C Escherichia coli This should be a familiar clinical example; the woman clearly has a urinary tract infection and the high pyrexia suggests pyelonephritis. It is tempting to think that the answer is too obvious and look for complexity where there is none, so-called overthinking the question. Not all questions will have complex answers; pyelonephritis is a risk for premature labour and, therefore, this is important core knowledge to be tested. Speculum examination reveals a ﬂorid ectropion with contact bleeding on taking swabs. B Chlamydia trachomatis There are two possible answers to this question, Chlamydia trachomatis and Gonococcus. On speculum examination there is a thick, white discharge adherent to the vaginal walls. A Candida albicans The nature of the discharge and the symptoms suggest thrush infection, which is exceedingly common in pregnancy. Several children in her class have ‘slapped cheek syndrome’ at the start of term and when she comes to hospital for her routine anomaly scan her baby is found to be hydropic. H Parvovirus B19 Children with slapped cheek syndrome due to parvovirus do not feel ill and are therefore sent to school where the parvovirus poses a risk to the pregnancy. It causes fetal anaemia, which is why the baby looks hydropic on the scan – high output cardiac failure. In the last pregnancy she had a very slow ﬁrst stage of labour and got stuck at 9 cm dilatation. Which of these factors increases the chances of rupture of the uterine scar during labour? It is also diffcult to assess maternal condition in terms of scar tenderness if she is in a birthing pool. The risk of uterine rupture is increased if the previous section was complicated by infection because it compromises the healing of the uterine scar. Waterbirth Cord prolapse is an obstetric emergency necessitating immediate delivery and is more likely where the presenting part is either not in the pelvis (e. Undiagnosed antepartum haemorrhage Urinary tract infection is not an indication for induction, and active infection in the pelvis during labour may increase the chances of septic complications. There is no evidence that inducing labour is benefcial to patients with symphysis pubis dysfunction although they usually request induction (or even caesarean). Although antepartum haemorrhage is an indication for induction of labour it is important to exclude placenta praevia before planning induction. Although it is not ideal for a woman who did not manage a normal delivery last time or does not get on well with her midwife to plan a home birth she is still likely to be able to deliver without medical intervention. A grand multip is more likely to have a postpartum haemorrhage and therefore should be advised to plan delivery in a consultant-led unit. A primigravid woman whose baby is in the occipito-posterior position at the start of labour B. A woman with an otherwise uncomplicated pregnancy who has had a successful external cephalic version E. The main issue for the rhesus disease mother is going to be the baby’s haemoglobin and bilirubin levels, and as long as the midwife can obtain blood samples from the cord after delivery, labouring in the birthing pool should be safe. The anaesthetist will check the level of the block and get ready to intubate her should the spinal rise any higher. Previous third-degree tear Mothers who are pushing actively are performing the Valsalva manoeu- vre frequently, which is probably not a good idea if she has cardiac problems. Instrumental delivery is associated with an increased risk of third-degree tear so should only be used if there is failure to progress or fetal compromise in women with a previous third-degree tear. The woman refuses to give consent for the operation and the midwife looking after her thinks that she may be confused on account of her high temperature.
Intrauterine insemination is indicated when a cervi- cal fact or is t h ou gh t t o be the cau se of in fer t ilit y buy plavix 75 mg, su ch as t h ick viscid cer vi- cal mu cu s befor e ovu lat ion generic plavix 75 mg otc. This pr ocedu r e bypasses the u n favor able cer vix using a catheter to inject washed sperm proven 75mg plavix. The patient in this scenario does not present with symptoms consistent with cervical factor infertility. In vitro fer- tilization can be considered if the problem was a tubal factor or male factor. T h e h ist or y of ch lamydial in fect ion st r on gly su ggest s t ubal fact or in fer t il- it y. Laparoscopy would be the next st ep in management and is considered the “g o l d s t a n d a r d ” f o r d i a g n o s i n g tubal and peritoneal disease. The patient does not present with any of the “three Ds” of peritoneal factor, and the semen analysis is normal which excludes male factor as t he cause for infert ilit y. There is no mention of a history of fibroids, and she reports regular menses; this eliminates uterine and ovulatory factors as the etiology of her infertility. This patient’s history of dysmenorrhea and dyspareunia (two out of the three Ds of peritoneal factor symptoms) suggests endometriosis, which is best diagnosed by laparoscopy. A hysterosalpingogram visualizes the inside of the uterus and would not be helpful in the diagnosis of endometriosis, since it manifest s out side t he uterus, tubes, and ovaries. She has menses every month; therefore, her basal body temperature chart should be normal. A progesterone assay may be used to assess whether ovulation occurs, or the adequacy of t he corpus lut eum (a so-called lut eal phase defect ). The hysterosalpingogram (radiologic study in which dye is injected into the uterus) is not specific and should be followed up with laparoscopy; some- times tubal spasm can prevent dye from flowing into the tubes. Laparos- copy can pr ovid e the t r eat ment of t ubal an d p er it on eal d isease t h r ou gh a minimally invasive technique. Clomiphene is not effective in patients with tubal factor, and is indicated with anovulation. Her medical history is significant for diabetes mellitus controlled with an oral hypoglycemic agent. On examination, she weighs 190 lb, her height is 5 ft 3 in, blood pressure is 150/90 mm Hg, and temperature is 99°F (37. The external genitalia appear normal, and the uterus seems to be of normal size without adnexal masses. Understand that postmenopausal bleeding requires endometrial sampling or vagin al u lt r aso u n d assessm en t of the en d om et r ial st r ip e t o assess for en d om e- trial cancer. Co n s i d e r a t i o n s This patient has postmenopausal vaginal bleeding, which should always be inves- tigated, because it can indicate malignant or premalignant conditions. Sh e also h as n u m er ou s r isk fact or s for endomet rial cancer including obesit y, diabet es, hypert ension, prior anovulat ion (irregular menses), late menopause, and nulliparity. The endometrial sampling or biopsy can be performed in the office by placing a thin, flexible catheter through the cervix. Either endometrial biopsy or transvaginal ultrasound is acceptable init ial t est s to assess for endomet rial cancer. This pat ient is not t aking unopposed est rogen-replacement t herapy, wh ich would be anot her risk fact or. If endomet rial can cer were diagn osed, the pat ient would n eed su r gical st agin g. If the en d ome- trial sampling is negative for cancer, another cause for postmenopausal bleed- ing, such as at roph ic endomet rium or endomet rial polyp, is possible. A blind sampling of t he endomet rium, such as with t he endomet rial biopsy device, has 90% to 95% sensitivity for detecting cancer. If this patient, who has so many risk fact ors for endomet rial cancer, were t o h ave a negat ive endomet rial sampling, many practitioners would go to a direct visualization of the endometrial cavity such as hyst eroscopy. If t he clinician were t o elect t o observe this pat ient aft er the endometrial biopsy, any further bleeding episodes would necessitate further invest igat ion. Pipelleisathinflexiblecatheterandplacedthroughthecervix in t o the u t e ru s via sp e cu lu m. Th e st yle t is wit h d rawn cre at in g a su ct io n, a n d the n the ap p arat u s is gently withdrawn while rotating to get a sampling of the entire endometrium. These cancers involve late menopausal women, thin patients, or those with regular menses. Notably,complexhyperplasia with atypia is associated with endometrial carcinoma in 30% to 50% of cases. The most common etiology of postmenopausal bleeding is atrophic endome- tritis or vaginitis. However, since endometrial malignancy can coexist with atrophic changes or in women t aking h ormone-replacement t h erapy, endometrial carcinoma must be ruled out in any patient with postmenopausal bleeding. Possible methods for assessment of the endometrium include endometrial sampling, hysteroscopy, or t ransvaginal sonography. Alt h ough endo- metrial cancer typically affects older women, a woman in her 30s with a history of chronic anovulation, such as polycystic ovarian syndrome, may be affected. Endometrial hyperplasia especially with cellular atypia is strongly associ- at ed wit h t he development of endomet rial cancer. When the endometrial sampling is unrevealing, the patient with persistent postmenopausal bleeding, or with numerous risk factors for endometrial cancer, should undergo furt her evaluat ion, such as by hyst eroscopy. D irect visualizat ion of the intrauterine cavity can identify small lesions that may be missed by the office endomet rial sampling device. More recently, saline infusion sonohysterography has been used to identify endometrial pathology such as polyps. En d o m e t r i a l Ca n c e r Endometrial carcinoma is the most common female genital tract malignancy. Although endometrial cancer is not the most common cause of postmenopausal bleeding, it is the one that is most concerning. Fortunately, because endometrial can cer is associat ed wit h an ear ly sympt om, abn or mal ut er in e bleed in g, it is u su ally detected at an early stage. The subset of women who have grade 1 (well differentiated), endo- metriod carcinoma that is minimally invasive may not necessarily need lymph node sampling. In fact, clear cell car cin oma on ly accou nt s for 10% of ut er in e can cer but is associat ed wit h 40% of deaths. Women with Lynch syndrome are at increased risk of developing colon can- cer, ovarian cancer, and Type I endometrial cancer. T his is an autosomal dominant disorder and associated with mutations of one of the mismatch repair genes. The lifet ime risk of developing endomet rial cancer varies from 16% t o 61% depending on the exact mutation. Em e r g i n g Co n c e p t s Yo u n g w o m e n w i the n d o m e t r i a l c a r c i n o m a m a y s t r o n g l y d e s i r e t o h a v e a c h i l d. St r ict cr it er ia are u sed in t h ese set t in gs: gr ad e 1, n o myom et r ial invasion, n o ext r aut er in e involvement, an d st r on g d esir e for fer t ilit y sparing procedure. Most exper t s recommen d defin it ive surgical man age- ment immediately after childbearing.
In addition buy plavix 75 mg low price, the following conditions must be met: £ Several inattentive or hyperactive-impulsive symptoms were present before age 12 order plavix 75 mg with visa. Alternatively order plavix uk, information can be surmised through narratives or descriptive interviews. Management includes the implementation of a long-term treatment program in collaboration with caregivers and teachers. Behavioral modification can be used alone or in conjunction with pharmacologic therapy. Positive reinforcement (providing rewards or privileges) and negative con- sequences (time-out or withdrawal of privileges) emphasize appropriate behavior. Small class size, structured work, stimulating schoolwork, and appropriate seat- ing arrangements can help decrease disruptive classroom behaviors. Commonly used stimulant medications include methylphenidate and dextroamphetamine. Atomoxetine (Strat- tera) is a nonstimulant, selective norepinephrine reuptake inhibitor approved for use in adults and children. Tricyclic antidepressants, clonidine and bupropion, often prescribed under the direction of a psychiatrist or neurologist, are also used. Approximately 50% of children func- tion well in adulthood; others demonstrate continued inattention and impulsivity symptoms. Thus, in all patients who are considered for the diagnosis of attention deficit disorder other diagnostic possibilities must be considered. At home he is always restless, never seems to pay attention, and is always losing things. His mother notes that he daydreams “all of the time,” and when he is daydreaming he does not respond to her. She describes the episodes as short (lasting several seconds) and occurring many times per day. Obtain further information from his parents and teachers with the Con- ners rating scale. She tries to avoid sustained mental effort, is frequently losing things, and is very forgetful. They are also concerned that she does not smile as often and stays in her room not interested in activities that used to make her happy. A physical examination (with emphasis on the neurologic component) is completed to identify any soft signs of neurologic conditions. Episodes of “daydream- ing,” which last several seconds, may be petit mal or absence seizures; an elec- troencephalogram is needed. Prior to developing a management plan, the child is assessed for coexist- ing psychiatric and learning disorders (psychoeducational testing). Manage- ment can include stimulant medication, behavioral modification, and therapy appropriate for coexisting conditions. While she does fulfill six of the nine inattention criteria, her symptoms can also be better explained by her likely mood disorder (which is an exclusion criteria). Also, while her symptoms have occurred for over 6 months, it is suggested that these are recent changes that were not occurring prior to age 12. Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. During last night’s game, he was tackled from the side, sustaining a blow from the other player against his left shoulder. When he fell, he struck the right side of his head against the ground but did not lose consciousness. Subsequently he has had a dull, throbbing headache (described in intensity as 5 out of 10), located globally. He denies associated visual disturbance, photophobia, phonophobia, nausea, vomiting, and dizziness. He described no exacerbating factor for the headache and it is relieved with ibuprofen. He reports he felt “a little woozy” after the ini- tial hit but feels tired only this morning. His mother says he slept an extra hour today but was not difficult to awaken; he has shown no change in his behav- ior. Examination of his head, neck, cranial nerves, strength, range of motion of all joints, sensation, gait, balance, coordi- nation, and deep tendon reflexes is normal. He is oriented to month, date, day of week, year and time, able to recall five words immediately, but when asked to recall them 5 minutes later he can only remember three of the words. He may then begin a gradu- ated return-to-play protocol in which he must remain asymptomatic before advancing to each subsequent phase. List factors associated with a concussion that warrant further evaluation with imaging. Considerations This boy has a sport-related concussion, an injury which accounts for almost 10% of all athletic injuries during high school. Concussion is a functional injury so imaging is not routinely done nor required for diagnosis. Instead, signs and symptoms indicating a concussion will involve one or more of the following areas: somatic, cognitive, emotional, or sleep (Table 60–1). Some of the symptoms will be immediate, such as his dizziness and the mental “fogginess,” a somatic and a cognitive symptom, respectively, which may worsen, subside, or fully resolve only to be followed by new findings. He now has symptoms from each of the categories: headache (somatic), anterograde amnesia (cognitive), fatigue (emo- tional), and increased sleep. The athlete must remain symptom free for 24 hours at each level without any medication before advancing. These inju- ries can be more significant than in professional athletes because the developing brain is more vulnerable and the cervical and shoulder musculature is less devel- oped. The immediate assessment of the child or adolescent with head injury begins at the time of the trauma. Sideline evaluation tools are available for older children, and assess for the signs and symptoms that define a concussion. The athlete should be removed from play and is not to return to any level of activity on the same day a concussion is sustained. Otherwise the child’s caregiver should be informed of the event, the definition of a concus- sion, and instructed to observe the child for 24 to 48 hours. Emergent care is to be obtained if increasing headache, vomiting, confusion, or unusual behavior develops. Cognitive exertion or physical activity can cause wors- ening of symptoms, so the best management after a concussion is physical and cog- nitive rest. A concussion is more of a functional brain injury than a structural injury so neuroimaging is usually normal. For optimal patient safety, graduated return-to-play protocols have been devel- oped and provide guidelines for a stepwise approach to advance activity while monitoring for symptoms.
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