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However purchase 100 mg zenegra visa impotence pump medicare, the efficacy of N-acetylcysteine in humans 26 in clinical studies remains unclear buy zenegra 100mg on line erectile dysfunction treatment news, given the high heterogeneity in study protocols and populations order zenegra with a mastercard erectile dysfunction pump medicare. These findings were attributed to a potential reduction in the production of reactive oxygen species in the renal parenchyma. However, recent meta- 27,28 analyses did not show superiority of sodium bicarbonate over saline solution. For this reason, both N- acetylcysteine and sodium bicarbonate have minimal roles in the latest guidelines on prevention (i. Risks Related to Radiation Exposure Coronary catheterization may result in radiation-related injury, which although infrequent may be potentially serious. Stochastic injury can result in cancer, pregnancy complications, and inheritable diseases. However, the most common location of radiation-induced lesions in cardiac catheterization is the skin of the back, and common patterns include erythema, 29 telangiectasia, and plaques. The sensitivity of the skin to radiation exposure is differentiated by site; areas at risk in decreasing order of sensitivity include anterior neck, antecubital and popliteal areas, 30 flexor extremities, chest and abdomen, face, back, extensors, nape of the neck, scalp, palms, and soles. Although uncommon in contemporary practice, early reports from coronary catheterization indicate deep and extensive skin rashes and burns at the site of radiation exposure, some requiring skin grafting. For exposures of absorbed radiation greater than 5 Gy, patients should be advised to watch for areas of erythema; for those greater than 10 Gy, a medical physicist should be consulted to calculate the peak dose in 2 to 4 weeks; greater than 15 Gy is regarded as a hospital risk management event. From the perspective of occupational radiation exposure, operators should be cognizant of the need to wear protective personal equipment during catheterization procedures, including a lead apron, thyroid 33 drape, lead eyeglasses, and dosimeters. Table height and distance from the x-ray source are important, and radiation risk decreases as the inverse square of distance from the source. Operators should also optimally position lead shields and skirts and should be compliant with use of radiation dosimeters for monitoring exposure to the whole body (chest) and eye. Novel dosimeters providing real-time monitoring 34 and alerts can serve to decrease operator radiation exposure. Monitoring, reporting, and audit of radiation exposure can promote improved awareness and practice in the operator and catheterization laboratory staff. Coronary Arteriography Technique Patient Preparation Patients should receive a comprehensive explanation of the diagnostic angiographic procedure and of the coronary intervention potentially required. Risks of angiography should be discussed in-depth and weighed against both the clinical benefit and the risks related to refusal of the procedure. Patients are required to provide written informed consent before coronary angiography. Women of childbearing age should be questioned on their pregnancy status and advised on the additional risks of radiation exposure for pregnant women. A thorough medical history, including comorbidities, current medications, and allergies, needs to be obtained before the procedure. Patients may receive mild sedation with a benzodiazepine before the procedure according to the hospital 35 standard practice. In case of hemodynamic instability or respiratory distress, anesthesiologist support might be necessary. In most patients, however, general anesthesia and deep sedation are unnecessary for coronary angiography. Conscious sedation with short-term agents such as midazolam or fentanyl is most common. A venous access line should be readily available for the infusion of fluids or medications. Local anesthesia with topical anesthetic cream or subcutaneous injection of 1% lidocaine or mepivacaine (0. An adequate local anesthetic will not only make the patient more comfortable but, by reducing the pain during the arterial cannulation, also reduce the risk of peripheral artery spasm. Access Sites Possible access sites for coronary angiography are the femoral artery and the radial artery. Although the radial access approach is associated with fewer vascular and bleeding complications, femoral access remains the most commonly used in the United States. In addition, accessing from the femoral artery usually grants an easier advancement of the catheter to the aortic root due to the lack of tortuosity in the descending aorta. The head of the femur, visualized under fluoroscopy, can be used as a landmark (see Chapter 19, Fig. Puncture should be performed with the needle leveled at half the head of the femur. Multiple punctures should be avoided to reduce the risk of bleeding and vascular damage. The needle is then removed and a sheath advanced around the wire into the artery (see Fig. Once the sheath is fully advanced in the artery, the dilator 37 and wire are removed, and the sheath is flushed with saline. Verification of the correct position of the sheath in the vessel can be ascertained simply by drawing blood from the sheath. Radial access should always be considered first, before resorting to the femoral approach, especially 38 for diagnostic coronary angiography. The procedure for the sheath insertion is similar to that described for the femoral artery. However, when using radial access, a modified Allen test should be performed on both hands (see Chapter 19). The modified Allen test is performed by applying pressure on both the ulnar and the radial artery of one wrist to occlude them while the patient keeps the hand elevated with the fist clenched for approximately 30 seconds. The compression on the ulnar artery is then removed while pressure is maintained on the radial artery. If the ulnar artery supply to the hand is adequate, the color quickly returns to the hand and the test is normal. Conversely, if color does not return, the ulnar artery supply is insufficient, meaning that the radial artery supports the entire circulation of the hand. In this case the radial artery should not be punctured, because this may compromise the blood flow to the hand. This rule may be bypassed if an oximeter is placed in the thumb during radial artery occlusion, and resurgence of pulsation and oxygenation is documented after its initial disappearance (“Barbeau method”). However, the left subclavian artery may be less tortuous than the innominate artery. The ideal puncture site is 1 to 2 cm proximal to the radial styloid with the wrist slightly hyperextended. After removing the needle, a 5F or 6F sheath is inserted in the radial artery over the wire. A small incision 1 mm long can be made on the skin to facilitate advancement of the sheath. Because the radial artery is extremely vasoactive, the risk of spasm is high, especially in women; therefore, as soon as access is obtained, an intra-arterial spasmolytic agent such as nitroglycerin (100 to 200 µg) or 35 verapamil (2. A hydrophilic-coated sheath can further reduce the likelihood of spasm and regional pain. Radial access appears associated with fewer periprocedural events and should be preferred whenever possible.
Echocardiographic evidence of moderate or severe systemic right ventricular dysfunction is present in up to 40% of patients purchase zenegra 100 mg without a prescription erectile dysfunction herbs. More than mild systemic tricuspid regurgitation is present in 10% to 40% order 100mg zenegra fast delivery erectile dysfunction holistic treatment, both reflecting and exacerbating right ventricular dysfunction buy 100 mg zenegra fast delivery erectile dysfunction email newsletter. Palpitations and near-syncope or syncope from rhythm disturbances are fairly common. Atrial flutter occurs in 20% of patients by 20 years of age, and sinus node dysfunction is seen in half of the patients by that time. These rhythm disturbances are a consequence of direct and indirect atrial and sinus node damage at the time of atrial baffle surgery. Sudden cardiac death may occur in these patients and may be related to systemic right ventricular dysfunction, the presence of atrial flutter, and/or pulmonary hypertension. Superior vena cava or inferior vena cava baffle obstruction often goes undetected because collateral drainage through the azygos vein prevents systemic venous congestion. Pulmonary venous baffle obstruction causes elevated pulmonary artery pressure, and patients can present with dyspnea and pulmonary venous congestive 50 features. Physical examination of a patient whose condition is otherwise uncomplicated reveals a right ventricular parasternal lift, a normal S , a loud single S (P is often not heard because of its posterior1 2 2 location), a pansystolic murmur from tricuspid regurgitation (if present, best heard at the left lower sternal border, but not increasing with inspiration), and a right-sided S when severe systemic ventricular3 dysfunction is present. Data on long-term complications in adults who have undergone the arterial switch procedure are 51-54 emerging. The development of progressive neoaortic valve regurgitation from neoaortic root dilation is the most common long-term sequela. The development of ostial coronary artery disease has also been described in some patients. Compared with either the arterial switch or Mustard procedure, the survival rate after the Rastelli procedure is poor, and the need for repeat intervention is high. Progressive right ventricular–to– pulmonary artery conduit obstruction can cause exercise intolerance or right ventricular angina. Left ventricular tunnel obstruction is frequent, and can present as exertional dyspnea or syncope. Conduit replacement or transcatheter stent or stent-valve implantation is inevitably required in surviving 56 patients. Physical examination in uncomplicated patients reveals, in contrast to those after the atrial switch procedure, no right ventricular lift, a systolic ejection murmur from the conduit, and two components to the S. Sinus bradycardia or junctional rhythm (without a right atrial overload pattern) with evidence of marked right ventricular hypertrophy is characteristically present in patients after the atrial switch procedure. On the posteroanterior film, a narrow vascular pedicle with an oblong cardiac silhouette (“egg on side”) is typically seen in patients after the atrial switch procedure. On the lateral view, the anterior aorta may be seen to fill the retrosternal space. After the Rastelli procedure, the chest radiograph may be normal unless the conduit becomes calcified. They are best visualized from a parasternal long axis view (running side by side) or from a parasternal short axis view (seen en face, with the aorta anterior and rightward). Qualitative assessment of systemic right ventricular function, the degree of systemic tricuspid regurgitation, and the presence or absence of subpulmonary left ventricular obstruction (dynamic or fixed) is important. Normal baffle flow should be phasic in nature and vary with respiration, with a peak velocity of less than 1 m/sec. After the arterial switch procedure, neoaortic valve regurgitation, supraneopulmonary valve stenosis, and a segmental wall motion abnormality from ischemia due to coronary ostial stenosis should be sought. In patients who have undergone the Rastelli operation, left ventricular–to–aorta tunnel obstruction, as well as right ventricular–to–pulmonary artery conduit degeneration (stenosis or regurgitation), must be assessed. The angiogram on the right upper panel shows complete obstruction of the inferior limb of the systemic venous baffle, whereas the lower right panel shows the same case after stenting. The lower left panel shows the systemic venous baffle at its left ventricular end. Diagnostic cardiac catheterization may be required for assessing the presence or severity of systemic or pulmonary baffle obstruction, baffle leak, and pulmonary hypertension; coronary ostial stenosis; or tunnel or conduit obstruction when not adequately assessed by noninvasive means. After the atrial switch procedure, severe symptomatic right ventricular dysfunction may warrant surgical treatment in the form of a two-stage arterial switch procedure or cardiac transplantation. Superior vena cava or inferior vena cava pathway obstruction may require intervention (Video 75. Superior vena cava stenosis is usually benign, whereas inferior vena cava stenosis may have greater hemodynamic consequences, depending on the adequacy of alternative routes of venous return, usually via the azygos vein to the superior vena cava. Balloon dilation of superior vena cava or inferior vena cava stenosis is an option in expert hands. Pathway obstruction after the Senning operation is usually more amenable to balloon dilation and stenting (see Video 75. Pulmonary venous obstruction, although usually seen early and reoperated on in childhood, may present in adulthood. Symptomatic bradycardia warrants permanent pacemaker implantation, whereas tachyarrhythmias may require catheter ablation, an antitachycardia pacemaker device, or medical therapy. After an atrial switch procedure, transvenous pacing leads must traverse the upper limb of the baffle to enter the morphologic left ventricle. Active fixation is required because of the tightly packed fine apical trabeculations in the morphologic left ventricle. Transvenous pacing should be avoided in patients with residual intracardiac communications because paradoxical emboli can occur. After an arterial switch procedure, significant right ventricular outflow tract obstruction at any level (gradient > 50 mm Hg or right-to-left ventricular pressure ratio > 0. Myocardial ischemia from coronary artery obstruction may require coronary artery bypass grafting, preferably with arterial conduits. In patients who have had the Rastelli procedure, significant right ventricle–to–pulmonary artery conduit stenosis (> 50 mm Hg withdrawal gradient or mean echocardiography gradient) or significant regurgitation necessitates intervention. Subaortic obstruction across the left ventricle–to–aorta tunnel necessitates left ventricle–to–aorta baffle reconstruction. In patients who have undergone an atrial switch procedure, medical therapy is uncertain. Severe systemic ventricular dysfunction or intractable arrhythmias may be a contraindication to pregnancy, and baffle obstruction should, ideally, be relieved before pregnancy. Women who have undergone an atrial switch procedure usually tolerate pregnancy well, but about 15% will develop 58 worsening right ventricular function or systemic tricuspid regurgitation during the pregnancy. Pregnancy following an arterial switch 59 procedure is better tolerated, assuming there are no significant hemodynamic lesions prior to pregnancy. Serial follow-up surveillance of systemic right ventricular function is warranted.
The practice is common in areas where there are contract pathologists paid by the case cheap zenegra 100 mg amex erectile dysfunction treatment with herbs. For every case that comes into the ofﬁce order line zenegra smoking erectile dysfunction statistics, at least blood order zenegra without prescription what is an erectile dysfunction pump, urine and vitreous should be obtained and retained. Routine drug 18 Forensic Pathology screens on apparent natural deaths have, with regular monotony, revealed deaths from suicidal and accidental overdoses of drugs. Such extensive screen- ing is not possible in most areas of the country because of limitations on the toxicology laboratory. If an autopsy is performed, what specialized tests are done at the time of autopsy are determined by the type of case. Thus, a rape examination may be conducted in a suspected rape case, or hair obtained in a death with blunt- force injuries to the head. For all cases coming to autopsy, it is recommended that, at the minimum, blood, vitreous, urine, and bile be obtained for toxicological analysis. If this is not possible, other sites, in descending order of preference, are the subclavian vessels, the root of the aorta, the pulmonary artery, the superior vena cava and the heart. Blood should never be obtained by incising a vessel or the heart and attempting to capture the ﬂuid as it escapes. When suicidal overdose of oral medications is suspected, the stomach contents should be kept. Some laboratories retain portions of liver and kidney in all suspected drug overdose deaths — whether decomposed or not. With modern instrumentation and analytical methods, however, it is rarely necessary to analyze these materials. The detection of a drug in the urine indicates only that the individual has taken that drug at some time in the past, not that they were under its inﬂuence at time of death. Absence of a drug in the urine also does not necessarily indicate that it will not be found in the blood. Thus, an intravenous injection of heroin could cause death before any metabolites appear in the urine. At the time of autopsy, tissue should be retained for possible micro- scopic examination, although this is not necessary in every case. Thus, in traumatic deaths, such as a shooting or motor vehicle accident, while a medical examiner may elect to do microscopic examination of the tissue, it is rarely necessary. Even if microscopic slides are not made, tissue should still be retained for this possibility. It is the opinion of the authors that toxicologic specimens and tissue removed for possible microscopic exam- ination should be retained for 3–5 years. In homicide cases and cases where extensive civil litigation is expected, photographic documentation of the injuries is recommended. The standards represent minimum standards for an adequate medicolegal system, emphasizing policies and procedures. Evaluated are: The facilities Safety policies, procedures and equipment Personnel Notiﬁcation, acceptance and release Investigations Body handling Postmortem examinations Identiﬁcation Evidence and specimen collection Support services Reports and records Mass disaster plan Quality assurance One area addressed is medical examiner caseload. The rec- ommended annual caseload for a forensic pathologist without administra- tive responsibilities is 250 autopsies. On a short-time basis, one can perform autopsies at an annual rate of 300, perhaps 325. By the time, caseload exceeds 350 autopsies, mistakes are being made and the quality of the autopsy is being sacriﬁced. Deﬁning Death: A Report on the Medical, Legal and Ethical Issues in the Deter- mination of Death. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Hanzlick R and Combs D: Medical examiner and coroner systems: history and trends (special communication). The Ofﬁce of the Medical Examiner of the City of New York: Report by the Committee on Public Health, New York Academy of Medicine. National Medicolegal Review Panel: Death Investigation: A Guide for the Scene Investigator. Time of Death 2 Determination of the time of death is important in both criminal and civil cases. In criminal cases, it can set the time of the murder, eliminate or suggest suspects, conﬁrm or disprove an alibi. In civil cases, the time of death might determine who inherits property or whether an insurance policy was in force. Unfortunately, all methods now in use to determine the time of death are to a degree unreliable and inaccurate. One obvious facet of time of death determination often not considered is that the time the fatal injury is incurred is not necessarily the time of death. One can incur massive fatal injuries, yet linger in an unconscious state for hours prior to death (Figure 2. Postmor- tem lividity is occasionally misinterpreted as bruising by people unfamiliar with this phenomenon. Dependent areas resting against a ﬁrm surface will appear pale in contrast to the surrounding livor mortis due to compression of the vessels in this area, which prevents the accumulation of blood. Thus, areas sup- porting the weight of the body, for example, the shoulder blades, buttocks, 21 22 Forensic Pathology Figure 2. Tight clothing, for example, a brassiere, corset, or belt, which compresses soft tissues, collapsing the vessels, also produces pale areas. Livor mortis usually, but not invariably, has a cherry-red to pinkish color in deaths due to carbon monoxide. Iden- tical coloration may be caused by exposure of a body to cold temperatures, and in deaths due to cyanide. In all three of the aforementioned entities, the coloration is caused by predominance of oxygenated hemoglobin. In indi- viduals dying a slow lingering death with terminal cardiac failure, livor mortis may actually appear antemortem. Livor mortis develops gradually, usually reaching its maximum coloration at 8–12 h. Thus, if an individual dies lying on his back, livor mortis develops posteriorly, i. If one turns the body on its face, blood will 24 Forensic Pathology drain to the anterior surface of the body, now the dependent aspect. Livor mortis becomes “ﬁxed” when shifting or drainage of blood no longer occurs, or when blood leaks out of the vessels into the surrounding soft tissue due to hemolysis and breakdown of the vessels. Fixation can occur before 8–12 h if decomposition is accelerated, or at 24–36 h if delayed by cool tempera- tures. Thus, the statement that livor mortis becomes ﬁxed at 8–12 h is really just a vague generalization.
Treatment of patients with tachyarrhythmias has evolved dramatically over the last 40 years and has become more complex and specialized discount zenegra 100mg mastercard impotence following prostate surgery. This mode in turn was replaced by catheter ablation for better control or even cure of many types of supraventricular tachycardias and ventricular tachycardias in the absence of structural heart disease starting in the 1980s 100 mg zenegra for sale how is erectile dysfunction causes. Drug therapy for arrhythmias buy 100 mg zenegra free shipping impotence back pain, at one time the only option, has largely been replaced as the mainstay of therapy by ablation or implanted devices. Pharmacologic Therapy The principles of clinical pharmacokinetics and pharmacodynamics are discussed in Chapter 8. The commonly used classification (Vaughan Williams) is a useful framework for categorizing drug action but is limited because it is based on the electrophysiologic effects exerted by an arbitrary concentration of the drug, generally on a laboratory preparation of normal cardiac tissue. In practice, the actions of these drugs are complex and depend on tissue type, degree of acute or chronic damage, heart rate, membrane potential, ionic composition of the extracellular milieu, autonomic influences (see Chapter 99), genetics (see Chapter 33), age (Chapter 88), and other factors (Table 36. Many drugs exert more than one type of electrophysiologic effect or operate indirectly, such as by altering hemodynamics, myocardial metabolism, or autonomic neural transmission. Some drugs have active metabolites that exert effects different from those of the parent compound. Relative potency of blockade or extracardiac side effect: ○ = low; = moderate; ● = high; □ = agonist; A = activated state blocker; I = inactivated state blocker. Despite its limitations, the Vaughan Williams classification is widely known and provides a useful communication shorthand, but the reader is cautioned that drug actions are more complex than those depicted by the classification. Reproduced with permission from Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The Sicilian gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Block alpha receptors; enhance vagal Adenosine ↑ 0 ↓ More (−) ↑ 0 0 ↓ ↓ 0 ↓ Vagomimetic Ranolazine ↑ 0 0 ↑ 0 0 0 0 0 0 * With a background of sympathetic activity. The kinetics of onset and offset of these drugs in blocking the sodium channel is rapid (<500 milliseconds). Antiarrhythmic agents appear to cross the cell membrane and interact with receptors in the membrane channels when the channels are in the resting, activated, or inactivated state (see Table 36. Transitions among resting, activated, and inactivated states are time and voltage dependent. When the drug is bound (associated) to a receptor site at or close to the channel pore (the drug may not actually “plug” the channel), the channel cannot conduct, even in the activated state. Some drugs exert greater inhibitory effects on the upstroke of the action potential at more rapid rates of stimulation and after longer periods of stimulation, a characteristic called use dependence. Drugs with this property depress V̇max to a greater extent after the channel has been “used” (i. With increased time spent in diastole (slower rate), a greater proportion of receptors become drug free, and the drug exerts less effect. Some drugs exert greater effects at slow rates than at fast rates, a property known as reverse use dependence. This effect is not an ideal antiarrhythmic property, because prolongation of refractoriness should be increased at fast rates to interrupt or prevent a tachycardia and should be minimal at slow rates to avoid precipitation of torsades de pointes (TdP). Other agents act directly on the sinus node to slow heart rate, whereas drugs that exert vagolytic effects, such as disopyramide and quinidine, can increase the sinus discharge rate. Drugs can also suppress early or delayed afterdepolarizations and eliminate triggered arrhythmias based on these mechanisms. Reentry depends critically on the interrelationships between refractoriness and conduction velocity, the presence of unidirectional block in one of the pathways, and other factors that influence refractoriness and conduction, such as excitability (see Chapter 34). An antiarrhythmic agent can stop ongoing reentry that is already present or can prevent it from starting if the drug depresses or, alternately, improves conduction. For example, improving conduction can (1) eliminate unidirectional block so that reentry cannot begin or (2) facilitate conduction in the reentrant loop so that the returning wavefront reenters too quickly, encounters cells that are still refractory, and is extinguished. A drug that depresses conduction can transform unidirectional block into bidirectional block and thus terminate reentry or prevent it from starting by creating an area of complete block in the reentrant pathway. Conversely, a drug that slows conduction without producing block or significantly lengthening refractoriness can actually promote reentry. If a drug prolongs the refractoriness of fibers in the reentrant pathway, the pathway may not recover excitability in time to be depolarized by the reentering impulse, and reentrant propagation ceases. In considering the properties of a drug, it is important to define carefully the situation or model from which conclusions are drawn. Electrophysiologic, hemodynamic, autonomic, pharmacokinetic, and adverse effects can all differ in normal individuals compared with patients, in normal versus abnormal tissue, in cardiac muscle compared with specialized conduction fibers, and in atrial versus ventricular muscle (Table 36. Pregnancy Class: A, controlled studies show no fetal risk; B, no controlled studies, but no evidence of fetal risk; fetal harm unlikely; C, fetal risk cannot be excluded; drug should be used only if potential benefits outweigh potential risk; D, definite fetal risk; drug should be avoided unless in a life-threatening situation or safer alternatives do not exist; X, contraindicated in pregnancy. Categorization of safety during pregnancy and lactation is currently undergoing revision. Drug metabolites can add to or alter the effects of the parent compound by exerting similar actions, competing with the parent compound, or mediating drug toxicity. Quinidine has at least four active metabolites, but none with a potency exceeding that of the parent drug, and none implicated in causing TdP. A lidocaine metabolite can compete with the parent drug for sodium channels and partially antagonize its blocking effect. Slow acetylator phenotypes appear to be more prone than rapid acetylators to the development of lupus. Lack of this enzyme (in approximately 7% of patients) reduces metabolism of the parent compound and thereby leads to increased plasma concentrations of the parent drug and reduced concentrations of metabolites. Thus, poor metabolizers may experience more heart rate slowing and neurotoxicity than extensive metabolizers do. Many astute clinicians use, and refer their patients to, websites such as Crediblemeds. Interrogation of implanted device memory can also provide an indicator of the success of drug therapy. In some patients, tachycardia episodes are infrequent enough (months between occurrences) and symptoms mild enough that reactive drug administration is more reasonable than chronic daily dosing. Adverse Effects Antiarrhythmic drugs produce one group of adverse effects related to excessive dosage and plasma concentrations that result in both noncardiac (e. This process is underway but 5 until completed, adverse event risk in this setting is characterized using the previous classification. Proarrhythmia Drug-induced or drug-exacerbated cardiac arrhythmias (proarrhythmia) constitute a major clinical 6 problem. Proarrhythmia can manifest as an increase in frequency of a preexisting arrhythmia, sustaining of a previously nonsustained arrhythmia (even making it incessant), or development of arrhythmias that the patient has not previously experienced. Proarrhythmic events can occur in as many as 5% to 10% of patients receiving antiarrhythmic agents; heart failure increases this risk. Deaths were equally distributed throughout the treatment period, indicating that another type of proarrhythmic response can occur sometime after the beginning of drug therapy. Such late proarrhythmic effects may be related to drug-induced exacerbation of the regional myocardial conduction delay caused by ischemia and to heterogeneous drug concentrations that can promote reentry. Although quinidine shares the antimalarial, antipyretic, and vagolytic actions of quinine, only quinidine has direct cellular electrophysiologic effects. The ultimate biologic effect of the drug in a given patient depends on heart rate, drug concentration, and which channels are more prominently affected.