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There are also receptor-operated cation gout (see also Chapter 14) order cheap mestinon spasms of the diaphragm, but it is now appreciated that they have a channels that are important because the entry of cations through them depolarizes the cell purchase genuine mestinon on line muscle spasms youtube, opening voltage-dependent (L-type) Ca2+ chan- fat dose–response curve and the low doses of thiazides currently used nels and causing additional Ca2+ to enter the cell purchase mestinon visa muscle relaxant renal failure. This reduces the peripheral resistance and β-Adrenoceptor antagonists results in a fall in blood pressure buy mestinon line muscle relaxant tv 4096. With continued treatment, the cardiac output returns to common side-effects are caused by excessive vasodilatation and normal, but the blood pressure remains low because, by an unknown include dizziness, hypotension, fushing and ankle oedema. A central mecha- α1-Adrenoceptor antagonists nism has been suggested, but this seems unlikely as some drugs Doxazosin causes vasodilatation by selectively blocking vascular α1- do not readily pass the blood–brain barrier. Unlike non-selective α-blockers, α1-selective drugs are in renal juxtaglomerular granule cells that secrete renin may be not likely to cause tachycardia, but they may cause postural hypoten- involved and such a mechanism could explain why β-blockers are sion. They are used with other antihypertensives in cases of resistant less effective in older patients who may have low renin levels. Disadvantages of β-blockade are the common adverse effects, such as cold hands and fatigue, and the less common, but serious, adverse Other vasodilators effects, such as the provocation of asthma. All of the β-blockers lower blood pressure, but at least headaches and fuid retention (as a result of secondary hyperaldos- some of the side-effects can be reduced by using cardioselective teronism). However, intravenous drugs are rarely necessary, and the trend not seriously impair, aldosterone secretion, and excessive K+ retention is to use oral agents whenever possible (e. With increasing age, oxygen demand, β-blockers may also increase the perfusion of the atheromatous plaques progressively narrow the arteries, and the ischaemic area, because the decrease in heart rate increases the dura- obstruction to blood fow may eventually become so severe that, when tion of diastole and hence the time available for coronary blood fow. The ischaemic muscle β-Blockers are the standard drugs used in angina, but they have then produces the characteristic symptoms of angina pectoris (epi- many side-effects and contraindications (Chapter 15). If β-blockers sodic chest pain that may radiate to the jaw, neck, or arms; shortness cannot be used, e. Calcium- The basic aim of drug treatment of angina is to reduce the work of channel blockers relieve angina mainly by causing peripheral arteri- the heart and hence its oxygen demand. Their main effect is to cause peripheral vasodilata- there is some degree of coronary artery spasm (variant angina). Reduction in the distension of the heart wall decreases should take low-dose aspirin to reduce the probability of platelet oxygen demand and the pain is quickly relieved. Glyceryl trinitrate aggregation, and statins should be considered to lower low-density given sublingually to avoid frst-pass metabolism is used to treat acute lipoprotein cholesterol. This causes platelet aggregation bined therapy is required in which β-adrenoceptor blockers (top left) and the formation of an intracoronary thrombus, which results in a or calcium-channel blockers (middle top) are taken in addition to sudden decrease in blood fow through the artery. Patches containing glycerol ducting tissues of the heart are also affected by calcium-channel block- trinitrate (transdermal administration) have a long duration of action ers, which produce a negative inotropic effect by reducing calcium (up to 24 h). However, the Long-acting nitratesare more stable and may be effective for several dihydropyridines (e. The use of isosorbide mononitrate, vascular muscle because it is relatively more depolarized than cardiac which is the main active metabolite of the dinitrate, avoids the variable muscle (membrane potential 50 mV cf. The arterial dilatation produced by the nitrates tone that causes a mild tachycardia and counteracts the mild negative causes headaches, which frequently limit the dose. Prolonged extent, diltiazem depress the sinus node, causing a mild resting high dosage may cause methaemoglobinaemia as a result of oxidation bradycardia. Smoking is prothrombotic and atherogenic; it of K-channels, causing membrane hyperpolarization that inhibits Ca reduces coronary blood fow, and the nicotine-induced rise in heart infux by switching off voltage-dependent Ca-channels. Generally in bypass operations, the distal end of the internal does not produce tolerance, presumably because the overnight rest mammary artery is inserted at a point beyond the stenosis of the allows tissue sensitivity to return by the next day. Angina is relieved or improved in 90% of is poorly understood, but depletion of sulphydryl group donors may be patients, but returns within 7 years in 50%. Mortality is decreased in involved, because tolerance to nitratesin vitrocan sometimes be reversed some pathological conditions (e. Unfortunately, β-Adrenoceptor antagonists this damages the vessel, often leading to proliferative growth of β-Blockers are used for the prophylaxis of angina. Intrinsic activity might be a disadvantage in angina, signifcantly reduced by the use of stents that elute sirolimus or pacli- and the cardioselective β-blockers such as atenolol and metoprolol taxel from a polymer–drug matrix bound to the stent (less than 10% are probably the drugs of choice. The adverse effects essential with drug-eluting stents because the endothelialization of the and contraindications of β-blockers should be reviewed (Chapters 9 stent (which prevents thrombosis) is delayed by the antiproliferative and 15). Unfortunately the ideal duration of antiplatelet therapy (aspirin Calcium-channel blockers with clopidogrel) with drug eluting stents is unkown but is probably These drugs are widely used in the treatment of angina and have fewer at least 12 months. Calcium-channel blockers inhibit Drugs used in angina 39 17 Antiarrhythmic drugs Sinus Vagal fibres Sympathetic fibres Supraventricular bradycardia adenosine I. Arrhythmias can occur in the An arrhythmia common after acute myocardial infarction is sinus apparently healthy heart, but serious ones (e. The effects of antiarrhythmic agents on the parasympathetic and sympathetic nerves, respectively (upper fgure). Arrhythmias may be caused by an ectopic focus, mias, especially in patients with ischaemic heart disease. Because of the limitations and dangers of antiarrhythmic drugs, muscle fbres which, being no longer refractory, again depolarize, invasive procedures and devices are increasingly being used in serious establishing a loop of depolarization (circus movement). Cardiac action potential These actions decrease the automaticity of pacemaker cells and increase Most cardiac cells have two depolarizing currents, a fast Na+ current the effective refractory period of atrial, ventricular and Purkinje fbres. The 2 those effective in ventricular arrhythmias (bottom left); and long refractory period of cardiac fbres normally protects them from 3 those effective in both types (middle left). As relatively slowly (<5 s) and so, if the frequency is high, drug is still f b the K+ current decreases, the Na+ currents cause increasing depolariza- bound to the channel, which therefore cannot contribute to the action tion until threshold is reached and an action potential is initiated. Thus, the threshold for fring is reached later and the mainly used in the prophylaxis of paroxysmal atrial fbrillation, but it heart beat slows. K+ and inward Na+ current (I ), and so threshold is reached earlier and inactivated Na+ channels) and β-adrenoceptors. Norepinephrine also increases the force of effective when other drugs have failed, but its long-term use is contraction by increasing the infux of calcium during the plateau restricted to patients in whom other drugs are ineffective because it phase (positive inotropic effect). Drugs used in ventricular arrhythmias Adenosine is rapidly inactivated (t = 8–10 s) and so side-effects (e. Intravenous adenosine is Lidocaine given intravenously is used in the treatment of ventricular used to terminate paroxysmal supraventricular tachycardia. By delaying atrioventricular con- mic areas, where anoxia causes depolarization and arrhythmogenic ductance, digoxin increases the degree of block and slows and activity, many Na+ channels are inactivated and therefore susceptible strengthens the ventricular beat. It also inhibits the infux of Ca2+ during the plateau phase of current shock causes reversion to sinus rhythm in most patients with the action potential and therefore has a negative inotropic action. Surgical ablation of the ectopic ment of supraventricular tachycardias because it is safer, especially if focus or bundle of His is a successful method of controlling supraven- the patient really has a ventricular tachycardia, in which case the nega- tricular arrhythmias. Because atrioventricular block is produced, a permanent pacemaker is Verapamil should not be used with β-blockers or quinidine because of required. In those patients at risk of life-threatening tachyarrhythmias, cumulative negative inotropic effects. This leads to and clinical trials have shown that they decrease symptoms, slow a variety of symptoms, e.
Once the correct clearance and volume of distribution estimates are identiﬁed for the patient purchase mestinon amex muscle relaxant usa, they can be converted into the valproic acid half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0 purchase generic mestinon online muscle relaxant orphenadrine. A steady-state trough valproic acid serum concentration should be measured after steady state is attained in 3–5 half-lives order mestinon visa spasms pelvic area. Since the patient is expected to have a half-life equal to 10 hours cheap mestinon 60mg free shipping muscle relaxant 551, the valproic acid steady-state concentration could be obtained any time after the second day of dosing (5 half-lives = 5 ⋅ 10 h = 50 h). Valproic acid serum con- centrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. Estimate clearance and volume of distribution according to disease states and con- ditions present in the patient. The clearance rate for a child who takes other drugs that induce hepatic drug metabo- lism is 20–30 mL/h/kg. Using a value of 25 mL/h/kg, the estimated clearance would equal 1 L/h: Cl = 40 kg ⋅ 25 mL/h/kg = 1000 mL/h or 1 L/h. Once the correct clearance and volume of distribution estimates are identiﬁed for the patient, they can be converted into the valproic acid half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0. A steady-state trough valproic acid serum concentration should be measured after steady state is attained in 3–5 half-lives. Since the patient is expected to have a half-life equal to 6 hours, the valproic acid steady-state concentration could be obtained any time after the ﬁrst day of dosing (5 half-lives = 5 ⋅ 6 h = 30 h). Valproic acid serum concentra- tions should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. Suggest an initial valproic acid dosage regimen designed to achieve a steady-state valproic acid concentration equal to 75 μg/mL. Estimate clearance and volume of distribution according to disease states and con- ditions present in the patient. The clearance rate for an adult patient not taking other drugs that induce hepatic drug metabolism is 7–12 mL/h/kg. Once the correct clearance and volume of distribution estimates are identiﬁed for the patient, they can be converted into the valproic acid half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0. A steady-state trough valproic acid serum concentration should be measured after steady state is attained in 3–5 half-lives. Since the patient is expected to have a half-life equal to 11 hours, the valproic acid steady-state concentration could be obtained any time after the second day of dosing (5 half-lives = 5 ⋅ 11 h = 55 h). Valproic acid serum con- centrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. Literature-Based Recommended Dosing Because of the large amount of variability in valproic acid pharmacokinetics, even when concurrent disease states and conditions are identiﬁed, most clinicians believe that the use of standard valproic acid doses for various situations is warranted. The original computation of these doses were based on the pharmacokinetic dosing methods, and sub- sequently modiﬁed based on clinical experience. In general, the expected valproic acid steady-state serum concentrations used to compute these doses was 50 μg/mL. Usual initial maintenance doses for pediatric patients are 10 mg/kg/d if the child is not taking a hepatic enzyme inducer (phenytoin, phenobarbital, carbamazepine, and rifampin) or 20 mg/kg/d if the child is taking a hepatic enzyme inducer. If the patient has signiﬁcant hepatic dysfunction (Child-Pugh score ≥8), maintenance doses prescribed using this method should be decreased by 25–50% depending on how aggressive therapy is required to be for the individual. To illustrate the similarities and differences between this method of dosage calculation and the pharmacokinetic dosing method, the same examples used in the previous section will be used. This dose would be titrated upward in 5–10 mg/kg/d increments every 1–2 weeks while monitoring for adverse and therapeutic effects. A steady-state trough total valproic acid serum concentration should be measured after steady state is attained in 1–2 weeks. Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. The suggested initial main- tenance dosage rate for valproic acid for a child taking enzyme inducers is 20 mg/kg/d: 40 kg ⋅ 20 mg/kg/d = 800 mg/d or 250 mg every 8 hours. This dose would be titrated upward in 5–10 mg/kg/d increments every 1–2 weeks while monitoring for adverse and therapeutic effects. A steady-state trough total valproic acid serum concentration should be measured after steady state is attained in 1–2 weeks. Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. This dose would be titrated upward in 5–10 mg/kg/d increments every 1–2 weeks while moni- toring for adverse and therapeutic effects. A steady-state trough total valproic acid serum concentration should be measured after steady state is attained in 1–2 weeks. Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. Because of pharmacokinetic vari- ability, the nonlinear pharmacokinetics followed by the drug owing to concentration- dependent plasma protein binding, the narrow therapeutic index of valproic acid, and the desire to avoid adverse side effects of valproic acid, measurement of valproic acid serum concentrations is conducted for most patients to ensure that therapeutic, nontoxic levels are present. In addition to valproic acid serum concentrations, important patient parameters (seizure frequency, potential valproic acid side effects, etc. When val- proic acid serum concentrations are measured in patients and a dosage change is necessary, clinicians should seek to use the simplest, most straightforward method available to deter- mine a dose that will provide safe and effective treatment. In most cases, a simple dosage ratio can be used to change valproic acid doses by temporarily assuming valproic acid fol- lows linear pharmacokinetics (pseudolinear pharmacokinetics method). An empiric adjust- ment is made in the estimated steady-state concentrations to adjust for nonlinear, concentration-dependent plasma protein binding. In some situations, it may be necessary or desirable to compute the valproic acid pharmacokinetic parameters for the patient and uti- lize these to calculate the best drug dose. Computerized methods that incorporate expected population pharmacokinetic characteristics (Bayesian pharmacokinetic computer programs) can be used in difﬁcult cases where renal function is changing, serum concentrations are obtained at suboptimal times, or the patient was not at steady state when serum concentra- tions were measured. An additional beneﬁt of this method is that a complete pharmacoki- netic workup (determination of clearance, volume of distribution, and half-life) can be done with one or more measured concentrations that do not have to be at steady state. Pseudolinear Pharmacokinetics Method A simple, easy way to approximate new total serum concentrations after a dosage adjust- ment with valproic acid is to temporarily assume linear pharmacokinetics, then subtract 10–20% for a dosage increase or add 10–20% for a dosage decrease to account for nonlinear, concentration-dependent plasma protein binding pharmacokinetics: Dnew = (Cssnew/Cssold) Dold, where Cssnew is the expected steady-state concentration from the new valproic acid dose in μg/mL, Cssold is the measured steady-state concentration from the old valproic acid dose in μg/mL, Dnew is the new valproic acid dose to be prescribed in mg/d, and Dold is the cur- rently prescribed valproic acid dose in mg/d. Note: This method is only intended to provide a rough approximation of the resulting valproic acid total steady-state concentration after an appropriate dosage adjustment has been made. Of course, as expected, unbound steady-state concentrations increase or decrease in a linear fashion with dose. After dosage titration, the patient was prescribed 500 mg every 12 hours of enteric-coated divalproex sodium tablets (1000 mg/d) for 1 month, and the steady-state valproic acid total concentration equals 38 μg/mL. Suggest a valproic acid dosage regimen designed to achieve a steady-state valproic acid concentration of 80 μg/mL. Use pseudolinear pharmacokinetics to predict new concentration for a dosage increase, then compute 10–20% factor to account for nonlinear, concentration-dependent plasma protein binding pharmacokinetics. Using pseudolinear pharmacokinetics, the resulting total steady-state valproic acid serum concentration would equal Dnew = (Cssnew/Cssold) Dold = (80 μg/mL / 38 μg/mL) 1000 mg/d = 2105 mg/d, rounded to 2000 mg/d or 1000 mg every 12 hours. Because of nonlinear, concentration-dependent protein binding pharmacokinetics, the total steady-state serum concentration would be expected to be 10% less, or 0. Thus, a dosage rate of 2000 mg/d would be expected to yield a total valproic acid steady-state serum concentration between 64–72 μg/mL.
Effective oral dosages are higher than intravenous dosage because of first-pass metabolism and range from 120 mg to 640 mg daily buy genuine mestinon online spasms during mri, divided into three or four doses purchase discount mestinon on-line muscle relaxant of choice in renal failure. Adenosine or verapamil are preferred over older treatments (propranolol order mestinon on line muscle relaxant drugs side effects, digoxin order mestinon mastercard muscle relaxant tv 4096, edrophonium, vasoconstrictor agents, and cardioversion) for termination. However, intravenous verapamil in a patient with sustained ventricular tachycardia can cause hemodynamic collapse. An intravenous form of diltiazem is available for the latter indication and causes hypotension or bradyarrhythmias relatively infrequently. It is also becoming clear that certain nonantiarrhythmic drugs, such as drugs acting on the renin-angiotensin-aldosterone system, fish oil, and statins, can reduce recurrence of tachycardias and fibrillation in patients with coronary heart disease or congestive heart failure. Its + cardiac mechanism of action involves activation of an inward rectifier K current and inhibition of calcium current. The results of these actions are marked hyperpolarization and suppression of calcium-dependent action potentials. Adenosine is currently the drug of choice for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm because of its high efficacy (90–95%) and very short duration of action. The drug is less effective in the presence of adenosine receptor blockers such as theophylline or caffeine, and its effects are potentiated by adenosine uptake inhibitors such as dipyridamole. The Nonpharmacologic Therapy of Cardiac Arrhythmias It was recognized over 100 years ago that reentry in simple in vitro models (eg, rings of conducting tissues) was permanently interrupted by transecting the reentry circuit. This concept is now applied in cardiac arrhythmias with defined anatomic pathways—eg, atrioventricular reentry using accessory pathways, atrioventricular node reentry, atrial flutter, and some forms of ventricular tachycardia—by treatment with radiofrequency catheter ablation or extreme cold, cryoablation. Mapping of reentrant pathways and ablation can be carried out by means of catheters threaded into the heart from peripheral arteries and veins. Recent studies have shown that paroxysmal and persistent atrial fibrillation may arise from one or more of the pulmonary veins. Both forms of atrial fibrillation can be cured by electrically isolating the pulmonary veins by radiofrequency catheter ablation or during concomitant cardiac surgery. The increasing use of nonpharmacologic antiarrhythmic therapies reflects both advances in the relevant technologies and an increasing appreciation of the dangers of long- term therapy with currently available drugs. Toxicity Adenosine causes flushing in about 20% of patients and shortness of breath or chest burning (perhaps related to bronchospasm) in over 10%. Unlike other heart rate-lowering agents such as β blockers, it reduces heart rate without affecting myocardial contractility, ventricular repolarization, or intracardiac conduction. Elevated heart rate is an important determinant of the ischemic threshold in patients with coronary artery disease and a prognostic indicator in patients with congestive heart failure. Antianginal and anti-ischemic effects of ivabradine have been demonstrated in patients with coronary artery disease and chronic stable angina. In patients with left ventricular dysfunction and heart rates greater than 70 bpm, ivabradine reduced mean heart rate and the composite end points of cardiovascular mortality and hospitalization. Inappropriate sinus tachycardia is an uncommon disorder characterized by multiple symptoms, including palpitations, dizziness, orthostatic intolerance, and elevated heart rates. Recent case reports and one clinical trial have shown that ivabradine provides an effective alternative to slow the heart rate in patients with inappropriate sinus tachycardia. Subsequent studies have demonstrated antiarrhythmic properties that are dependent on the blockade of multiple ion channels. Ranolazine had been shown to have antiarrhythmic properties in both atrial and ventricular arrhythmias. It is currently undergoing clinical trials in combination with dronedarone for the suppression of atrial fibrillation. Ranolazine has been shown to suppress ventricular tachycardia in ischemic models and in a major clinical trial of its effects in coronary artery disease. Magnesium therapy appears to be indicated in patients with digitalis-induced arrhythmias if hypomagnesemia is present; it is also indicated in some patients with torsades de pointes even if serum magnesium is normal. The usual dosage is 1 g (as sulfate) given intravenously over 20 minutes and repeated once if necessary. A full understanding of the action and indications for the use of magnesium as an antiarrhythmic drug awaits further investigation. The effects of increasing serum K can be summarized as (1) a resting potential depolarizing action and (2) a membrane potential stabilizing action, the latter caused by increased potassium permeability. Hypokalemia results in an increased risk of early and delayed afterdepolarizations, and ectopic pacemaker activity, especially in the presence of digitalis. Because both insufficient and excess potassium is potentially arrhythmogenic, potassium therapy is directed toward normalizing potassium gradients and pools in the body. However, the chloride channels involved in cystic fibrosis and other conditions are of great clinical importance and have been the subject of intensive research (see Box: A Cystic Fibrosis Link in the Heart? Risks and benefits must be carefully considered (see Box: Antiarrhythmic Drug-Use Principles Applied to Atrial Fibrillation). Pretreatment Evaluation Several important steps must be taken before initiation of any antiarrhythmic therapy: 1. These include not only abnormalities of internal homeostasis, such as hypoxia or electrolyte abnormalities (especially hypokalemia or hypomagnesemia), but also drug therapy and underlying disease states such as hyperthyroidism or cardiac disease. It is important to separate this abnormal substrate from triggering factors, such as myocardial ischemia or acute cardiac dilation, which may be treatable and reversible by different means. For example, the misuse of verapamil in patients with ventricular tachycardia mistakenly diagnosed as supraventricular tachycardia can lead to catastrophic hypotension and cardiac arrest. As increasingly sophisticated methods to characterize underlying arrhythmia mechanisms become available and are validated, it may be possible to direct certain drugs toward specific arrhythmia mechanisms. Underlying heart disease is a critical determinant of drug selection for a particular arrhythmia in a particular patient. Few antiarrhythmic drugs have documented safety in patients with congestive heart failure or ischemic heart disease. In fact, some drugs pose a documented proarrhythmic risk in certain disease states, eg, class 1C drugs in patients with ischemic heart disease. A reliable baseline should be established against which to judge the efficacy of any subsequent antiarrhythmic intervention. These include prolonged ambulatory monitoring, electrophysiologic studies that reproduce a target arrhythmia, reproduction of a target arrhythmia by treadmill exercise, or the use of transtelephonic monitoring for recording of sporadic but symptomatic arrhythmias. The mere identification of an abnormality of cardiac rhythm does not necessarily require that the arrhythmia be treated. Benefits & Risks The benefits of antiarrhythmic therapy are actually relatively difficult to establish. Two types of benefits can be envisioned: reduction of arrhythmia-related symptoms, such as palpitations, syncope, or cardiac arrest; and reduction in long-term mortality in asymptomatic patients. Among drugs discussed here, only β blockers have been definitely associated with reduction of mortality in relatively asymptomatic patients, and the mechanism underlying this effect is not established (see Chapter 10). Antiarrhythmic Drug-Use Principles Applied to Atrial Fibrillation Atrial fibrillation is the most common sustained arrhythmia observed clinically. Hyperthyroidism is an important treatable cause of atrial fibrillation, and a thyroid panel should be obtained at the time of diagnosis to exclude this possibility.