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Sikic Modern cancer chemotherapy originated in the The mitotic index is the fraction or percentage of 1940s with the demonstration that nitrogen mustard cells in mitosis within a given cell population order prilosec 10mg gastritis diet 3-2-1. The possessed antitumor activity against human lymphomas thymidine labeling index is the fraction of cells incorpo- and leukemias cheap 40 mg prilosec mastercard gastritis diet sheet. They represent cells in M- cer have 40 to 80% “cure” rates using chemotherapy phase and S-phase and define the proliferative charac- alone or chemotherapy plus surgery or radiation (Table teristics of normal and tumor cells discount 40 mg prilosec overnight delivery chronic gastritis low stomach acid. For this purpose cure is defined as the disappear- ance of any evidence of tumor for several years and a The Tumor Cell Cycle high actuarial probability of a normal life span order 10 mg prilosec gastritis zucker. Patients with other types of unresectable cancer also The duration of the S-phase in human tumors is 10 to 20 may benefit from chemotherapy, as evidenced by pro- hours. This period is followed by the G2-phase, or period longation of life, shrinkage of tumor, and improvement of preparation for mitosis, in which cells contain a in symptoms. The G2-phase lasts lial and breast carcinomas, oat cell (small cell undiffer- only 1 to 3 hours for most cell types, with mitosis itself entiated) carcinoma of the lung, and acute myelocytic lasting approximately 1 hour. Cancers that are for the most part resistant to then enter the G1-phase, whose duration varies from today’s agents include melanoma, colorectal and renal several hours to days. The factors that influence daughter cells to enter the G0, or resting The normal cell cycle consists of a definable sequence of stage, are not well understood. The ability to cause such events that characterize the growth and division of cells resting cells to reenter the cell cycle would be quite use- and can be observed by morphological and biochemical ful, since proliferating cells generally are more sensitive means. Age Type of Cancer Unfortunately, many human cancers have a large Childhood Acute lymphocytic leukemia Burkitt’s sarcoma proportion of cells in the resting phase, and these cells Ewing’s sarcoma are also resistant to the class 3 agents, which include cy- Retinoblastoma clophosphamide, dactinomycin, and fluorouracil. For instance, it may be difficult to generalize Adult Hodgkin’s disease Non-Hodgkin’s disease about the phase specificity of a particular drug, since Trophoblastic choriocarcinoma this may vary among cell types. Several techniques are Testicular and ovarian germ cell cancers available to synchronize cell populations in such a way that most cells will be in the same phase of the cell cy- cle. After synchronization, one can treat cells in each phase and determine their relative sensitivity to drugs classification divides the anticancer drugs into three cat- throughout the cell cycle. Such a dosage regimen would increase increasing tumor size is related both to a decrease in the the number of tumor cells exposed to the drug proportion of cancer cells actively proliferating (termed during the sensitive phase of their cell cycle. Class 3 agents kill proliferating cells in prefer- loss due to hypoxic necrosis, poor nutrient supply, im- ence to resting cells. However, the growth fraction, or percentage of cells in the cell cycle, is the most important determinant of overall tumor enlargement. The doubling times of human tumors have been estimated by direct measure- ment of chest radiographs of lesions or palpable masses G2 to be 1 to 6 months. The growth fraction indicates dividing cells that are potentially sensitive to chemotherapy; thus, it is not sur- G1 M (mitosis) prising that tumors with high growth fractions are the G0 ones most easily curable by drugs. Other patients respond mor decreases, and the greater the distance of cells from initially, only to relapse. Tumors of chemotherapy is instituted for a human cancer that has a the same type and size will vary in their responsiveness low growth fraction. For instance, the larger the tumor, to therapy because of the chance occurrences of drug- the more cells will be present in the nonproliferating, rel- resistant mutations during tumor growth. Therefore, the earlier chemother- Assuming the same initial drug sensitivity, smaller apy is instituted, the greater the chance of a favorable re- tumors are generally more curable than larger tumors sponse. Debulking of tumors by surgery or radiation because of the increased probability of drug-resistant therapy may be a means of stimulating the remaining mutations in the larger tumors. Small metastases may re- lier in the course of tumor growth should increase the spond to drugs more dramatically than will large primary chance for cure. Tumors Several cycles of treatment may be necessary to that are resistant to drugs from the outset will always achieve a substantial reduction in tumor size. The have a largely drug-resistant population and will be re- chemotherapeutic regimen, especially when one is deal- fractory to treatment. Amplification of var- killing of a fraction of cells rather than an absolute ious genes may be a relatively frequent event in tumor number per dose is called the log cell kill hypothesis. Tumor cells may become generally resistant to a va- This number reflects the result of at least 30 cycles of riety of cytotoxic drugs on the basis of decreased uptake cell division, or cell doublings, and represents a kineti- or retention of the drugs. Most pa- termed pleiotropic, or multidrug, resistance, and it is the tients actually have tumor burdens that are greater than 9 major form of resistance to anthracyclines, vinca alka- 10. The gene cytotoxicity to normal tissues, only a limited log cell kill that confers multidrug resistance (termed mdr I) en- can be expected with each individual treatment. Alter- 55 The Rational Basis for Cancer Chemotherapy 633 natively, a drug may be metabolically inactivated by re- and thioguanine. Daily treatment with these agents sistant tumors, which is the case with cytarabine (pyrim- rather than high-dose intermittent therapy is the pre- idine nucleoside deaminase) and bleomycin (bleomycin ferred schedule for immune suppression. Leukemias have been shown to develop re- sistance to L-asparaginase because of a drug-related in- duction of the enzyme asparagine synthetase. Rapidly pro- Although manipulation of the host immune response in liferating normal tissues, such as bone marrow, gastroin- animal tumor models has at times yielded impressive testinal tract, and hair follicles, are the major sites of therapeutic results, attempts to extend these results to acute toxicity of these agents. In contrast, the ni- The ability of certain anticancer agents to suppress trosourea drugs exhibit hematological toxicity that is both humoral and cellular immunity has been exploited delayed until 4 to 6 weeks after beginning treatment. In particular, the alkylating agents cy- clophosphamide and chlorambucil have been used in toxicity or hypoplastic state may develop after long-term this context, as have several of the antimetabolites, in- treatment with nitrosoureas, other alkylating agents, and cluding methotrexate, mercaptopurine, azathioprine, mitomycin C. Thus, patients frequently will require a pro- gressive reduction in the dosages of myelosuppressive drugs when they are undergoing long-term therapy, since such treatment may result in chronic pancytopenia. These symptoms are ameliorated by treatment with phenothiazines and other centrally acting Detoxification Tubulins antiemetics. Although this symptom is distressing to patients, it is rarely severe enough to re- quire cessation of therapy. Continuous in- Damage to the normally proliferating mucosa of the fusion or frequent administration of cytarabine hy- gastrointestinal tract may produce stomatitis, dyspha- drochloride is superior to intermittent injection of the gia, and diarrhea several days after treatment. Bleomycin is another drug for which continuous cerations, esophagitis, and proctitis may cause pain and infusion may increase therapeutic efficacy. Administration of some anticancer drugs by contin- uous infusion has been shown to improve their thera- peutic index through selective reduction of toxicity with Hair Follicle Toxicity retained or enhanced antitumor efficacy. Patients should be Routes of Administration warned of this reaction, especially if paclitaxel, cy- clophosphamide, doxorubicin, vincristine, methotrex- In addition to the usual intravenous or oral routes, some ate, or dactinomycin is used. Hair usually regrows nor- anticancer agents have been administered by regional mally after completion of chemotherapy. Pharmacokinetic Sanctuaries Intracavitary administration of various agents has The existence of the blood-brain barrier is an important been used for patients with malignant pleural or peri- consideration in the chemotherapy of neoplastic dis- toneal effusions. The testes also are organs in given intrathecally or intraventricularly to prevent re- which inadequate antitumor drug distribution can be a lapses in the meninges in acute lymphocytic leukemia cause of relapse of an otherwise responsive tumor. Thiotepa and The multidrug transporter P-glycoprotein is ex- bleomycin have been administered by intravesical in- pressed in the endothelial lining of the brain and testis stillation to treat early bladder cancers. Fluorouracil can but not in other organs and is thought to be a major be applied topically for certain skin cancers. Drug Interactions Antineoplastic drugs may participate in several types of Schedules of Administration drug interactions. Methotrexate, for example, is highly Although the effects of various schedules are not al- bound to serum albumin and can be displaced by sali- ways predictable, drugs that are rapidly metabolized, cylates, sulfonamides, phenothiazines, phenytoin, and excreted, or both, especially if they are phase specific other organic acids.
Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia order prilosec 40mg free shipping gastritis urination, or if the patient develops potential signs or symptoms of procainamide toxicity cheap prilosec 40mg otc gastritis symptoms how long do they last. A procainamide dose of 50 mg/kg/d is suggested by Table 8-3 for an adult with normal renal and hepatic function generic prilosec 40 mg free shipping gastritis diet plans. The ini- tial dosage interval will be set to 12 hours: D = procainamide dose ⋅ Wt = 50 mg/kg/d ⋅ 130 kg = 6500 mg cheap prilosec 40 mg visa gastritis nutrition diet, rounded to 6000 or 3000 mg every 12 hours. Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxicity. Because the serum pro- cainamide serum concentration was obtained on the second day of therapy, but two different doses were given on day 1, it is unlikely that the serum concentration was obtained at steady state so the linear pharmacokinetics or pharmacokinetic parameter methods cannot be used. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. The pharmacokinetic parameters computed by the program are a volume of distribu- tion of 235 L, a half-life equal to 5. The one-compartment model first-order absorption equations used by the program to compute doses indicates that a dose of 4000 mg every 12 hours will produce a steady- state procainamide concentration of 4. A steady-state trough procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxicity. Estimate half-life and elimination rate constant according to disease states and con- ditions present in the patient. The patient is not obese, so the estimated procainamide volume of distribution will be based on actual body weight: V = 2. Estimated pro- cainamide clearance is computed by taking the product of the volume of distribution and the elimination rate constant: Cl = kV = 0. Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxicity. A procainamide loading dose of 500 mg over 25–30 minutes would be administered followed by a continuous infusion. A procainamide dose of 2–6 mg/min is suggested by Table 8-3 for an adult with normal hepatic and renal function. A dose of 3 mg/min would be expected to attain a steady-state concentration in the lower end of the therapeutic range. A procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxicity. Using linear pharmacokinetics, the new infusion rate to attain the desired concentration should be proportional to the old infusion rate that produced the measured concentration: Dnew = (Css,new / Css,old)Dold = (8 μg/mL / 4. The booster dose would be given to the patient before the infusion rate was increased to the new value. A steady-state trough procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxicity. Procainamide clearance can be computed using a steady-state procainamide concentra- tion Cl = k0 / Css = (3 mg/min) / (4. Procainamide clearance is used to compute the new procainamide infusion rate: k0 = Css ⋅ Cl = 8 mg/L ⋅ 0. The booster dose would be given to the patient before the infusion rate was increased to the new value. A steady-state trough procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxicity. A procainamide loading dose of 500 mg over 25–30 minutes would be administered followed by a continuous infusion. A procainamide dose of 1–3 mg/min (2–6 mg/min normal dose, reduced by 50%) is suggested by Table 8-3 for an adult with severe liver disease. A dose in the lower end of this range should result in a procainamide steady-state concentration in the lower end of the therapeutic range. Because of this, it is unlikely that the serum concentration was obtained at steady state even though a loading dose was given so the linear pharmacoki- netics or pharmacokinetic parameter methods cannot be used. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program Note: DrugCalc requires procainamide infusion rates to be entered in the units of mg/h (3 mg/min ⋅ 60 min/h = 180 mg/h). The pharmacokinetic parameters computed by the program are a volume of distribu- tion of 139 L, a half-life equal to 8. The one-compartment model infusion equations used by the program to compute doses indicate that a procainamide infusion of 71 mg/h or 1. How- ever, if the patient was experiencing drug side effects, the new infusion rate would be started after holding the infusion for 8 hours (~one half-life) to allow procainamide serum concentrations to decrease by one half. Estimate half-life and elimination rate constant according to disease states and con- ditions present in the patient. Patients with severe heart failure have highly variable procainamide pharmacokinetics and dosage requirements. Heart failure patients have decreased cardiac output which leads to decreased liver blood flow, and the expected procainamide half-life (t1/2) is 5. The patient is not obese, so the estimated procainamide volume of distribution will be based on actual body weight: V = 1. Estimated procainamide clearance is computed by taking the product of the volume of distribution and the elimi- nation rate constant: Cl = kV = 0. A steady-state procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. Procainamide serum concen- trations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxic- ity. If heart failure improves, cardiac output will increase resulting in increased liver blood flow and procainamide clearance. A procainamide loading dose of 500 mg over 25–30 minutes would be administered followed by a continuous infusion. A procainamide dose of 1–3 mg/min (2–6 mg/min normal dose, reduced by 50%) is suggested by Table 8-3 for an adult with severe heart failure. A dose in the lower end of this range should result in a procainamide steady-state concentration in the lower end of the therapeutic range. A steady-state procainamide serum concentration could be measured after steady state is attained in 3–5 half-lives. Procainamide serum concentrations should also be measured if the patient experiences an exacerbation of their arrhythmia, or if the patient develops potential signs or symptoms of procainamide toxicity. If heart failure improves, cardiac output will increase resulting in increased liver blood flow and pro- cainamide clearance. Alternatively, if heart failure worsens, cardiac output will decrease further resulting in decreased liver blood flow and procainamide clearance. Because the serum pro- cainamide serum concentrations were obtained after 4 hours and 8 hours of therapy, it is unlikely that the serum concentrations were obtained at steady state even though a load- ing dose was given so the linear pharmacokinetics or pharmacokinetic parameter methods cannot be used.
Their use in the treatment of effort-induced increased frequency safe 20 mg prilosec gastritis diet karbo, duration discount 10mg prilosec fast delivery gastritis pdf, and intensity and are angina relies on the reduction in myocardial oxygen precipitated by progressively less effort purchase prilosec 20mg without prescription gastritis diet . Ranolazine is indicated by a short-lasting burning buy 20mg prilosec mastercard chronic gastritis management, heavy, or squeezing feeling for the treatment of chronic angina and may be used in the chest. It could be given as a frst- Nitrates inhibit coronary vasoconstriction or spasm, line agent for this patient. Thus, therapy is generally directed adverse effect of nitroglycerin, as well as of the other at preventing future disease sequelae rather than re- nitrates, is headache. The adverse Cardiovascular Pharmacology 107 effects associated with the hypertensive therapy may cause photosensitivity. Of the diuretics listed, only mannitol zine cause an irreversible inhibition of their target and ethacrynic acid do not contain a sulfonamide enzymes. Mannitol should not be used because it is con- the potential for additive interactions with other traindicated in patients with heart failure. Tyramine, found in many foods such as cheeses and beer, causes a release of catecholamines 47 The answer is A: Amiodarone. To prevent can also stimulate b1-adrenergic receptors at the right a recurrence (which may be more severe), antiplatelet concentration. Heparin is an anticoagulant tient with cardiac disease, depletion of potassium is but is not an antiplatelet drug. Although most tis- therapy in a patient suffering from edema associated sues receive dual innervation, some effector organs, with liver disease. If a cles, and sweat glands, receive innervation only from marked volume contraction occurs, the diuretics the sympathetic nervous system. Calcium pressure is also mainly a sympathetic activity, with reabsorption in the proximal tube can become mark- essentially no participation by the parasympathetic edly enhanced under that circumstance. The risk of this side effect is greater in patients with a history of reactive airway 56 The answer is A: Amlodipine. It works to lower blood pressure by many drugs, but acebutolol is not known to cause inhibiting contraction of vascular smooth muscle. This reaction is dose related, so blocks sympathetic stimulation of b1-receptors on the a lower dose may alleviate the edema. Sympathomi- most common side effects of sertraline are headache, metic amines that contain the 3,4-dihydroxybenzene nausea, and diarrhea. Hydralazine is the initial antihypertensive of choice and is given in 5 mg 61 The answer is A: Cocaine. These agents, which include amphetamine, cocaine, This agent will have no effect on cardiac output or and tyramine, may block the uptake of norepineph- renal blood fow but can cause lethargy, fever, head- rine (uptake blockers) or are taken up into the ache, and lupus-like syndrome. As with neuronal stimula- (C) Methyldopa is a b-blocker and can decrease car- tion, the norepinephrine then traverses the synapse diac output and renal blood fow. Examples of increase cardiac output without change in renal blood uptake blockers and agents that cause norepineph- fow. Acebutolol is a b1- or release of the hormone epinephrine from the ad- selective antagonist, but at high doses, its b-selectivity renal medulla. These agents do not trig- is used to increase cardiac output in acute congestive ger refex tachycardia to the same extent as the heart failure as well as for inotropic support after car- nonselective receptor blockers. Dobutamine should be used with cau- and lethargy can result from administration of tion in atrial fbrillation because the drug increases a-blockers. Note: The names of all to dobutamine, it is unlikely to cause cardiac conduc- blockers end in “-olol” except for labetalol and tivity changes. This agent will potentiate the action of other antihyperten- drug is also useful in the chronic management of these sives, and the patient can become hypotensive. This (B) High-dose dopamine causes an increase in heart drug’s action lasts for approximately 4 h after a single rate. The drug can also trigger ar- b-Blockers, such as topically applied timolol, betaxo- rhythmias and anginal pain, and phentolamine is lol, or carteolol, are effective in diminishing intraocu- contraindicated in patients with decreased coronary lar pressure in glaucoma. Many patients with glaucoma have been maintained (C) No change should be observed in myocardial per- with these drugs for years. When Cardiovascular Pharmacology 111 administered to the eye, the onset is about 30 min, bradycardia, will occur as a result of adrenergic stimu- and the effects last for 12 to 24 h. Furosemide, bumetanide, and ethacrynic surgical and other medical procedures, anesthesia acid exert their effects on the ascending limb of the provides these fve important benefts: sedation and loop of Henle. Osmotic diuretics work mostly on reduction of anxiety, lack of awareness and amnesia, the proximal tubule. Atenolol is a b1-antagonist hypertension include sleep apnea, drug induced, and is effective in lowering blood pressure in patients chronic kidney disease, primary aldosteronism, reno- with hypertension. Side effects of blockers include vascular disease, pheochromocytoma, and thyroid fatigue and exercise intolerance. This patient with diabetes Many patients with peripheral vascular disease expe- has been diagnosed with hypertension and diabetic rience an exacerbation of symptoms with smoking. Because of (C) Pulmonary embolism can occur because of hyper- the patient having diabetes with the initial stages coagulable state, but this is unlikely, given the presen- of protein-losing nephropathy, lisinopril is a better tation of this patient. This is associated with tachy- several well-known side effects, including pulmonary cardia, hypertension, pupillary dilation, and peripheral fbrosis, hepatotoxicity, and thyroid imbalances. Recent evidence suggests that the this reason, pulmonary function tests, liver function ability of baroreceptor refexes to buffer the hyper- tests, and thyroid function tests should be monitored tensive effect may be impaired. It would stimulate cholinergic receptors in the Protamine is strongly positively charged and forms a iris and cause miosis, not mydriasis. Vanillylmandelic acid is leads to hyperpolarization and decreased intracellular the end product of catecholamine metabolism. Adenosine is commonly used to treat supraven- important catecholamines in the body are dopamine, tricular tachycardia. Epinephrine is Cardiovascular Pharmacology 113 made from norepinephrine by phenylethanolamine hiccups. It also reduces intracra- norepinephrine can be converted to dihydroxyman- nial pressure mainly because of systemic vasodilation. The -zosin drugs such as that plays an important role in stimulating uterine terazosin, prazosin, and doxazosin are a1-adrenergic contractions. Vanillyl- prostate narrows the prostatic urethra, impeding mandelic acid levels have no connection to levels of urine outfow. Brimonidine is an common side effects is dizziness because of impaired a2-agonist that decreases the synthesis of aqueous vasoconstriction. As an a1-blocker, terazosin impairs vaso- the secretion of aqueous humor by inhibiting car- constriction and can lead to dizziness. Trazodone is a (E) Timolol is a b-blocker that decreases aqueous drug known to be associated with priapism. Dantrolene works by preventing the in the cell membrane by a seven-pass transmembrane release of calcium from the sarcoplasmic reticulum in domain. It prevents sodium-potassium exchange pump on the distal tu- calcium from entering the smooth muscle cell, so bule cells. It such as ethacrynic acid work by inhibiting the Na1/ prevents calcium from entering the smooth muscle K1/2Cl2 transporter on the ascending limb of the cell, so calmodulin cannot be activated. It causes has no major effects on the blood pressure or heart calcium retention by an unknown mechanism but rate except at large doses at which hypotension and does not cause potassium retention.
Normal sexual intercourse with orgasm is accompanied by • Other important steps in secondary prevention transient but brisk physiological changes cheap prilosec 10 mg otc gastritis tratamiento, e order 40mg prilosec fast delivery gastritis differential diagnosis. When the healthy (with hypertension order prilosec 10 mg line gastritis y sus sintomas, angina pectoris or after myo- condition is secondary to hypoxia accompanying chronic cardial infarction) discount prilosec 10 mg without prescription gastritis diet in dogs. Sudden deaths do occur during or obstructive pulmonary disease, long-term oxygen therapy 418 Arterial hypertension, angina pectoris, myocardial infarction and heart failure Chapter | 24 | improves symptoms and prognosis; anticoagulation is es- tremor or sweating) is useful in alerting the physician to sential when the cause is multiple pulmonary emboli. This is because stimulation of the vasodilator The prostanoid formulations have the limitations of a short b2 receptor in resistance arteries attenuates the rise in dia- half-life and a heterogeneous response to therapy. Evidence stolic pressure, and vagal activation is insufficient then to suggests that endothelin, a powerful endogenous vasocon- oppose the chronotropic effect of combined b1 and b2 strictor, may play a pathogenic role; antagonists, bosentan, receptor stimulation in the heart. Only tadalafil has been shown to (from noradrenaline/norepinephrine) and metanephrine improve survival, although in a comparison of the three (from adrenaline/epinephrine) in blood or 24-h urine. Heart cause the enzyme catechol-O-methyltransferase is present and lung transplantation is recommended for younger in phaeochromocytoma but not sympathetic nerve end- patients. The finding of elevated metaphrine se- In about 5% of patients it is possible to identify a single cretion (as well as normetanephrine) indicates an adrenal cause of the hypertension, and some of these can be cured location since only the adrenal tumours are exposed to the by a surgical or endovascular intervention. This is particularly true of adrenal causes of lary circulation from cortex to medulla is progressively hypertension. Either the ganglion-blocking drug pentolinium or centrally acting a2-agonist clonidine This tumour of chromaffin tissue, usually arising in the ad- suppresses physiological elevations of metaphrines, but renal medulla, secretes principally noradrenaline/norepi- not autonomous secretion from a tumour. If the tumour secretes history of hypertensive crisis induced by dopamine antag- only noradrenaline/norepinephrine, which stimulates a- onists (e. The recognition of bradycardia at tumour cannot be removed is achieved by a-adrenoceptor 1 the time of catecholamine-induced symptoms (e. An important function of the a-blockade is not just 39Barst R J, Rubin L J, Long W A et al 1996 A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for 40 primary pulmonary hypertension. New England Journal of Medicine Brown M J, Allison D J, Jenner D A et al 1981 Increased sensitivity and 334:296–302. Consequently patients are usually vol- This refers to benign adenomas of the adrenal cortex, which ume depleted, often severely, and this must be corrected secrete the sodium-retaining hormone aldosterone, and are before it is safe to proceed to surgery. Synonyms Not infrequently, the pressure natriuresis completely include primary hyperaldosteronism, although this term compensates for vasoconstriction, and patients present can extend to a larger number of patients with elevated with features other than hypertension – even hypotension plasma aldosterone to renin ratios but no lateralisation after an episode of fluid depletion. Since adrenaline/epinephrine secretion, as demonstration that the adenoma is responsible for excess explained above, tends to fall as tumours enlarge, tachycar- aldosterone secretion. Prior to surgery, or longer-term is required, once a-blockade is established, in order to treat when surgery is not selected, the hypertension and hypoka- b2-effects (tremor, tachycardia) of an atypical adrenaline/ laemia should be treated by the mineralocorticoid receptor epinephrine-secreting phaeochromoctyoma. Spironolactone sion, but the irreversible a-blocker, phenoxybenzamine 25–100 mg daily is the most effective, but causes gynaeco- 10–80 mg daily, whose blockade cannot be overcome by mastia on chronic dosing. Titration of the dose requires inspection of the 5–10 mg daily, although regular electrolyte monitoring is jugular venous pressure, as index of volume replacement, necessary to avoid hyperkalaemia and hyponatraemia. During surgical removal – which is usually by laparo- scopic adrenalectomy – phentolamine (or sodium nitroprus- Heart failure and its treatment side) should be at hand to control rises in blood pressure when the tumour is handled. When the adrenal veins have Some physiology and been clamped, volume expansion is often required to maintain blood pressure even after adequate preoperative pathophysiology a-blockade. As the preload rises so also do the degree of stimulate renin and noradrenaline/norepinephrine produc- stretch and the length of cardiac muscle fibres. Preload tion through actions at the juxtaglomerular apparatus in the is thus a volume load and can be excessive, e. Chronic heart failure is present when the heart can- stretch but, applied to the whole ventricle, it can explain not provide all organs with the blood supply appropriate to the normal relationship between filling pressure and car- demand. Most patients with heart failure pre- cardiac output may be normal at rest, but secondly, when sent in phase ‘A’ of the relationship, and before the demand is increased, perfusion of the vital organs (brain ‘decompensated’ phase (B), in which there is gross dilata- and kidneys) continues at the expense of other tissues, espe- tion of the ventricle. Overall, systemic arterial pressure is tive symptoms of heart failure, which are due to the sustained until the late stages. These responses follow neuro- increased filling pressure (preload), but actually reduces endocrine activation when the heart begins to fail. Depending on whether The therapeutic importance of recognising this patho- their predominant symptom is dyspnoea (due to physiology is that many of the neuroendocrine abnormali- ties of heart failure – particularly the increased renin output 42 Braunwald E 2008 Biomarkers in heart failure. New England Journal of and sympathetic activity – can be a consequence of drug Medicine 358:2148–2159. Renal perfusion is normal 43Ernest Henry Starling, 1866–1927, Professor of Physiology, University in early heart failure, whereas diuretics and vasodilators College, London. The process is will reduce the filling pressure but the cardiac output generically referred to as ‘cardiac remodelling’ and the aim of will fall. In phase B, lowering the blood volume will reduce much drug therapy in heart failure treatment is to try to place a the filling pressure but the cardiac output will increase brake on this process. Objectives of treatment pulmonary venous congestion) or fatigue (due to reduced As for cardiac arrhythmias, these are to reduce morbidity cardiac output), patients feel better or worse. It is likely that (relief of symptoms, avoid hospital admission) and a principal benefit of using angiotensin-converting enzyme mortality. There is Natural history of chronic a further tension between the needs of treating the features heart failure of forwards failure, or low output, and backwards failure, Injury to the heart, e. The principal symptom of a sion, leads to adaptive (‘compensatory’) molecular, cellu- low cardiac output, fatigue, is difficult to quantify, and pa- lar and interstitial changes that alter its size, shape and tients have tended to have their treatment tailored more to function. With the passage of disease of the myocardium itself, mainly ischaemic, or an time, and with maladaption, the heart ‘decompensates’ excessive load imposed on it by arterial hypertension, val- and heart failure worsens. Many patients with heart failure strongly stimulated to contract by increased sympathetic die from an arrhythmia, rather than from terminal decom- drive that therapeutic efforts to induce it to function yet pensation, and drugs that avoid increasing the heart’s expo- more vigorously are in themselves alone unlikely to be of sure to increased catecholamine concentrations, as do benefit. Despite numerous candidate drugs introduced some vasodilators (but see below), appear best for improv- over recent years, digoxin remains the only inotropic drug ing prognosis. The main hazard of their use is a drastic fall in cardiac output 422 Arterial hypertension, angina pectoris, myocardial infarction and heart failure Chapter | 24 | in those occasional patients whose output is dependent on The reduction in mortality occurred among patients with a high left ventricular filling pressure, e. Mainte- ume and lower excessive venous filling pressure (see nance of blood pressure in such individuals may depend Ch. Such drugs can be initiated nous capacitance vessels, increase the volume of the venous outside hospital in patients who are unlikely to have a vascular bed (which normally may comprise 80% of the high plasma renin (absence of gross oedema or wide- whole vascular system), reduce ventricular filling pressure, spread atherosclerotic disease), although it is prudent to thus decreasingheart wall stretch, and reducemyocardialox- arrange for the first dose to be taken just before going ygen requirements. The realisation that activation of the renin–angiotensin–aldosterone and sympathetic ner- vous systems can adversely affect the course of chronic heart Reduction of afterload failure led to exploration of the possible benefits in heart Hydralazine (see also Ch. Reflex tachy- have, indeed, shown that bisoprolol, carvedilol or metopro- cardia limits its usefulness and lupus erythematosus is a risk lol lower mortality and decrease hospitalisation when added usually only if the dose exceeds 100 mg per day. Early trials were underpowered but a meta-analysis The phosphodiesterase inhibitors enoximone and did suggest a 31% reduction in the mortality rate. The only cautionary note A scheme for the stepwise drug management of chronic is that patients must be b-blocked very gradually from low starting doses (e. In a landmark study, following sub- group analyses of earlier trials, 1050 black patients who hyperaldosteronism in heart failure. New England combination of isosorbide dinitrate 120 mg daily plus hy- Journal of Medicine 351:2049–2057. New England follow-up, the trial terminated prematurely following the demonstration Journal of Medicine 336:525–532).
