Drugs Used In Hypertension PDF

30 15 Drugs used in hypertension Medical Pharmacology at a Glance Centrally acting Medulla Initial effect...

30 15 Drugs used in hypertension Medical Pharmacology at a Glance Centrally acting Medulla Initial effect Diuretics α2 + ? – clonidine bendroflumethiazide methyldopa BodyNa + chlortalidone Blood indapamide volume spironolactone others Carotid Precursor sinus Renin Vasodilators β-blockers Angiotensin I ACE β1 -SELECTIVE INHIBITORS Converting bisoprolol Aldosterone enzyme – lisinopril Initial effect metoprolol Cardiac enalapril atenolol Angiotensin II output others others Sympathetic NA+ + ANGIOTENSIN RECEPTOR NA nerves – BLOCKERS – losartan, others – Ca2+- CHANNEL BLOCKERS te β1-receptors – nifedipine odila Arteriolar resistance amlodipine Vas vessels α1-BLOCKERS doxazosin K+-CHANNEL ACTIVATION minoxidil Thiazides (chronic administration) NO FORMATION nitroprusside Venous capacitance vessels UNKNOWN MECHANISM hydralazine S ustained elevation of blood pressure (hypertension) is now its action at the angiotensin II receptor (AT1 subtype). ACE recognized as the largest single cause of death and morbidity inhibitors and ARBs reduce vascular tone because angiotensin II worldwide. Hypertension increases risk of acute events such is a vasoconstrictor and stimulates aldosterone production. ACE as stroke and myocardial infarction and may lead to organ damage inhibitors\ARBs are preferred first‐line treatments in patients such as heart failure and renal failure. The problem is that the risk under 55 years in whom activation of the renin–angiotensin system is graded and so there is no obvious line between patients who is greater than in older subjects. In older patients, calcium channel should be treated and those who should not. In the UK, it is gener- blockers (middle right) that block the entry of calcium into ally accepted that patients without additional risk factors should vascular smooth muscle are preferred. β‐adrenoceptor antagonists be treated if the systolic pressure is greater than 160 mmHg and/ (β‐blockers, centre left) and thiazide diuretics (top right) reduce or the diastolic pressure is greater than 100 mmHg. Additional risk blood pressure by mechanisms that are not fully understood. ACE factors include the presence of established cardiovascular disease inhibitors, angiotensin antagonists, calcium‐channel blockers and (e.g. angina, previous stroke or myocardial infarction), established thiazides significantly reduce the risks of stroke, coronary heart target organ damage, smoking, hyperlipidaemia and diabetes. In disease and cardiovascular death. β‐blockers are equally effective at these patients lower targets for intervention are appropriate. In reducing blood pressure but are associated with a higher incidence some patients hypertension is secondary to renal or endocrine dis- of stroke than other drugs. They are no longer preferred for ease and these patients need specific treatment. Lifestyle modifica- uncomplicated hypertension but may be used if there are additional tions: a healthy diet (in particular, moderation of alcohol and salt indications for example, patients with angina, heart failure, or intake) and increased exercise reduce blood pressure, and smok- following myocardial infarction. Other vasodilators (bottom right) ing cessation reduces concurrent cardiovascular risk. However, have been largely superseded by the ACE inhibitors and calcium many (almost a third of the UK population) need drug treatment. antagonists. Centrally acting drugs (top left) are little used because Several groups of drugs, by different mechanisms, reduce of their adverse effects. blood pressure by decreasing vasoconstrictor tone and Mild‐to‐moderate hypertension may be controlled by a single hence peripheral resistance. The most important of these drug but most patients require combinations of two or even three are the angiotensin converting enzyme (ACE) inhibitors drugs to adequately control the blood pressure. The effectiveness (middle right) and angiotensin receptor blockers (ARBs). of antihypertensive therapy is clear but many, if not most, These decrease synthesis of angiotensin II or antagonize patients do not have their blood pressure adequately controlled. Medical Pharmacology at a Glance, Eighth Edition. Michael J. Neal. © 2016 by John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd. Companion website: www.ataglanceseries.com/pharmacology Thiazide and other diuretics supplements or potassium‐sparing diuretics (aldosterone increases 31 The mechanism by which diuretics reduce arterial blood pressure Na+ reabsorption and K+ excretion, Chapter 14). ARBs (e.g. losartan) lower the blood pressure by blocking Chapter 15 Drugs used in hypertension is not known. Initially, the blood pressure falls because of a decrease in blood volume, venous return and cardiac output. Gradually, angiotensin (AT1) receptors. They have similar properties to the the cardiac output returns to normal, but the hypotensive effect ACE inhibitors, but do not cause cough, perhaps because they do remains because the peripheral resistance has, in the meantime, not prevent bradykinin degradation. decreased. Diuretics have no direct effect on vascular smooth Calcium-channel blockers (see also Chapters 16 muscle and the vasodilatation they cause seems to be associated and 17). with a small but persistent reduction in body Na+. One possible The tone of vascular smooth muscle is determined by the cytosolic mechanism is that a fall in smooth muscle Na+ causes a secondary Ca2+ concentration. This is increased by α1‐adrenoceptor reduction in intracellular Ca2+ so that the muscle becomes less activation (resulting from sympathetic tone) that triggers Ca2+ responsive to endogenous vasoconstrictors. Thiazide diuretics release from the sarcoplasmic reticulum via the second messenger may cause hypokalaemia, diabetes mellitus, and gout (see also inositol‐1,4,5‐trisphosphate (Chapter 1). There are also receptor‐ Chapter 14). Thiazides seem to be particularly effective in operated cation channels that are important because the entry older patients (over 55). Chlortalidone and indapamide are of cations through them depolarizes the cell, opening voltage‐ ‘thiazide‐like diuretics’ with different chemical structure but dependent (L‐type) Ca2+ channels and causing additional Ca2+ similar actions. They may be more effective with fewer adverse to enter the cell. The calcium antagonists (e.g. nifedipine, effects and are currently recommended as first‐line diuretics in amlodipine) bind to the L‐type channels and, by blocking the the UK. Potassium‐retaining diuretics such as spironolactone entry of Ca2+ into the cell, cause relaxation of the arteriolar and amiloride are increasingly being used in patients resistant to smooth muscle. This reduces the peripheral resistance and results conventional drugs, provided hyperkalaemia is not a concern. in a fall in blood pressure. The efficacy of calcium antagonists is β-adrenoceptor antagonists similar to that of the thiazides and ACE inhibitors. Their most common side‐effects are caused by excessive vasodilatation and β-blockers initially produce a fall in blood pressure by decreasing include dizziness, hypotension, flushing and ankle oedema. the cardiac output. With continued treatment, the cardiac output returns to normal, but the blood pressure remains low because, α1-adrenoceptor antagonists by an unknown mechanism, the peripheral vascular resistance is Prazosin and the longer acting doxazosin cause vasodilatation ‘reset’ at a lower level (individual drugs are discussed in Chapter by selectively blocking vascular α1‐adrenoceptors. Unlike non‐ 9). A central mechanism has been suggested, but this seems selective α‐blockers, these drugs are not likely to cause tachycardia, unlikely as some drugs do not readily pass the blood–brain but they may cause postural hypotension. They are used with barrier. Block of β1‐receptors in renal juxtaglomerular granule other antihypertensives in cases of resistant hypertension. cells that secrete renin may be involved and such a mechanism could explain why β‐blockers are less effective in older patients Other vasodilators who may have low renin levels. Disadvantages of β‐blockade Hydralazine is used in combination with a β‐blocker and are the common adverse effects, such as cold hands and fatigue, diuretic. Side‐effects include reflex tachycardia, which may and the less common, but serious, adverse effects, such as the provoke angina, headaches and fluid retention (as a result of provocation of asthma, heart failure or conductance block. β‐ secondary hyperaldosteronism). In slow acetylators in particular, blockers also tend to raise serum triglyceride and decrease high hydralazine may induce a lupus syndrome resulting in fever, density lipoprotein–cholesterol levels. All of the β‐blockers arthralgia, malaise and hepatitis. lower blood pressure, but at least some of the side‐effects can Minoxidil is a potent vasodilator that causes severe fluid be reduced by using cardioselective hydrophilic drugs (i.e. those retention and oedema. However, when given with a β‐blocker without liver metabolism or brain penetration), such as atenolol. and loop diuretic, it is effective in severe hypertension resistant to other drug combinations. Vasodilator drugs ACE inhibitors Centrally acting drugs Angiotensin II is a powerful circulating vasoconstrictor and Methyldopa is converted in adrenergic nerve endings to the inhibition of its synthesis in hypertensive patients results in a fall false transmitter, α‐methylnorepinephrine, which stimulates in peripheral resistance and a lowering of blood pressure. ACE α2‐receptors in the medulla and reduces sympathetic outflow. inhibitors do not impair cardiovascular reflexes and are devoid Drowsiness is common and in 20% of patients it causes a positive of many of the adverse effects of the diuretics and β‐blockers. A antiglobulin (Coombs’) test and, rarely, haemolytic anaemia common unwanted effect of ACE inhibitors is dry cough that (Chapter 45). Clonidine causes rebound hypertension if the may be caused by increased bradykinin (ACE also metabolizes drug is suddenly withdrawn. bradykinin). Rare, but serious, adverse effects of ACE inhibitors include angioedema, proteinuria and neutropenia. The first dose Acute severe hypertension may cause a very steep fall in blood pressure, for example, in patients In hypertensive crisis, drugs may be given by intravenous infusion on diuretics (because they are Na+ depleted). ACE inhibitors may (e.g. hydralazine in hypertension associated with eclampsia cause renal failure in patients with bilateral renal artery stenosis, of pregnancy; nitroprusside in malignant hypertension with because in this condition angiotensin II is apparently required encephalopathy). However, intravenous drugs are rarely to constrict postglomerular arterioles and maintain adequate necessary, and the trend is to use oral agents whenever possible glomerular filtration. Inhibition of angiotensin II formation (e.g. atenolol, amlodipine). Nitroprusside decomposes in the reduces, but does not seriously impair, aldosterone secretion, and blood to release nitric oxide (NO), an unstable compound that excessive K+ retention only occurs in patients taking potassium causes vasodilatation (see Chapter 16 for mechanism). 32 16 Drugs used in angina Medical Pharmacology at a Glance Vascular smooth muscle cell L-type Ca channel -Blockers Calmodulin Reduced Ca 2+ Ca2+ Bisopropolol afterload Calcium-channel others blockers (Chapters 9 and 15) + Systemic nifedipine Ca2+ circulation Myosin Rate diltiazem + light chain Dilate verapamil PMCA kinase (MLCK) Contractility amlodipine Dilate Arteriolar + + Oxygen SERCA Myosin resistance light chain MLC- P demand vessels (MLC) + Low LDL/HDL Dilate Actin ratio, diabetes, Nitrates MLC phosphatase smoking, K+ + hypertension glyceryl trinitrate + Dilate isosorbide dinitrate and Tissue thiols isosorbide PKG abdominal Dilate + Contraction obesity mononitrate Venous cGMP GTP Ischaemic capacitance Reduced Antiplatelet drugs zone vessels RSH Guanylyl cyclase preload NO 3– aspirin + clopidogrel Reduced venous tirofiban NO2– NO return eptifibatide PMCA – plasma membrane Ca2+-ATPase SERCA – smooth endoplasmic reticulum Ca2+-ATPase T he coronary arteries supply blood to the heart. With increas- reduce the oxygen demand, β‐blockers may also increase the ing age, atheromatous plaques progressively narrow the arter- perfusion of the ischaemic area, because the decrease in heart ies, and the obstruction to blood flow may eventually become rate increases the duration of diastole and hence the time so severe that, when exercise increases the oxygen consumption available for coronary blood flow. If necessary, a long‐acting of the heart, not enough blood can pass through the arteries to nitrate is added (middle). supply it. The ischaemic muscle then produces the characteristic β‐Blockers are the standard drugs used in angina, but they symptoms of angina pectoris (episodic chest pain that may radi- have many side‐effects and contraindications (Chapter 15). ate to the jaw, neck, or arms; shortness of breath; dizziness). If β‐blockers cannot be used, e.g. in patients with asthma, The basic aim of drug treatment of angina is to reduce the then a calcium‐channel blocker can be used as an adjunct to work of the heart and hence its oxygen demand. The nitrates short‐acting nitrates. Calcium‐channel blockers relieve angina (middle) are the first‐line drugs. Their main effect is to cause mainly by causing peripheral arteriolar dilatation and afterload peripheral vasodilatation, especially in the veins, by an action on reduction. They are especially useful if there is some degree of the vascular smooth muscle that involves the formation of nitric coronary artery spasm (variant angina). oxide (NO) and an increase in intracellular cyclic guanosine Stable angina occurs when an atheromatous plaque produces monophosphate (cGMP) (right figure). The resulting pooling of a coronary artery stenosis. There is a relatively predictable blood in the capacitance vessels (veins) reduces venous return, pattern to the pain, which is usually relieved by rest and and the end‐diastolic ventricular volume is decreased. Reduction nitrates. Patients with stable angina should change their lifestyle in the distension of the heart wall decreases oxygen demand (e.g. stop smoking, eat healthily, take more exercise) to try to and the pain is quickly relieved. Glyceryl trinitrate given reduce the progression of atheroma. They should take low‐dose sublingually to avoid first‐pass metabolism is used to treat acute aspirin to reduce the probability of platelet aggregation, and anginal attacks. If this is required more than twice a week, then statins should be considered to lower low‐density lipoprotein combined therapy is required in which β‐adrenoceptor blockers cholesterol. Unstable angina results from fissuring or erosion (top left) or calcium‐channel blockers (middle top) are taken in of an atheromatous plaque. This causes platelet aggregation and addition to glyceryl trinitrate, which is retained for acute attacks. the formation of an intracoronary thrombus, which results in a β‐Adrenoceptor blockers depress myocardial contractility sudden decrease in blood flow through the artery. Patients with and reduce the heart rate. In addition to these effects, which unstable angina are at a high risk of myocardial infarction and are Medical Pharmacology at a Glance, Eighth Edition. Michael J. Neal. © 2016 by John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd. Companion website: www.ataglanceseries.com/pharmacology treated as an emergency in hospital. They are given heparin and The adverse effects and contraindications of β‐blockers should 33 antiplatelet drugs to reduce the risk of myocardial infarction. In be reviewed (Chapters 9 and 15). patients at high risk of myocardial infarction or in whom medical Chapter 16 Drugs used in angina treatment is not controlling symptoms, revascularization is considered. In high‐risk patients undergoing revascularization, Calcium-channel blockers GP11b/111a blockade with eptifibratide or tirofiban (Chapter 19) These drugs are widely used in the treatment of angina and have may improve outcomes. fewer serious side‐effects than β‐blockers. Calcium‐channel blockers inhibit L‐type voltage‐sensitive calcium channels in arterial smooth muscle, causing relaxation and vasodilatation Nitrates (Chapter 15). Preload is not significantly affected. Calcium channels Short‐acting nitrates. Glyceryl trinitrate (sublingual tablet in the myocardium and conducting tissues of the heart are also or spray) acts for about 30 min. It is more useful in preventing affected by calcium‐channel blockers, which produce a negative attacks than in stopping them once they have begun. Patches inotropic effect by reducing calcium influx during the plateau containing glycerol trinitrate (transdermal administration) have phase of the action potential. However, the dihydropyridines a long duration of action (up to 24 h). (e.g. nifedipine, amlodipine) have relatively little effect on the Long‐acting nitrates are more stable and may be effective heart because they have a much higher affinity for channels in for several hours, depending on the drug and preparation used the inactivated state. Such channels are more frequent in vascular (sublingual, oral, oral sustained‐release). Isosorbide dinitrate is muscle because it is relatively more depolarized than cardiac widely used, but it is rapidly metabolized by the liver. The use of muscle (membrane potential 50 mV cf. 80 mV). Furthermore, isosorbide mononitrate, which is the main active metabolite of at clinical doses, vasodilatation results in a reflex increase in the dinitrate, avoids the variable absorption and unpredictable sympathetic tone that causes a mild tachycardia and counteracts first‐pass metabolism of the dinitrate. the mild negative inotropic effect. Amlodipine, which has a long Adverse effects. The arterial dilatation produced by the duration of action, produces less tachycardia than nifedipine. nitrates causes headaches, which frequently limit the dose. Verapamil and, to a lesser extent, diltiazem depress the sinus node, More serious side‐effects are hypotension and fainting. Reflex causing a mild resting bradycardia. Verapamil binds preferentially tachycardia often occurs, but this is prevented by combined to open channels and is less affected by the membrane potential. therapy with β‐blockers. Prolonged high dosage may cause Conduction in the atrioventricular node is slowed and, because the methaemoglobinaemia as a result of oxidation of haemoglobin. effect of verapamil (unlike nifedipine) is frequency dependent, it Mechanism of action. Initial metabolism of these drugs effectively slows the ventricular rate in atrial arrhythmias (Chapter releases nitrite ions (NO2−), a process that requires tissue thiols. 17). The negative inotropic effects of verapamil and diltiazem are Within the cell, NO2− is converted to nitric oxide (NO), which partially offset by the reflex increase in adrenergic tone and the then activates guanylyl cyclase, causing an increase in the decrease in afterload. Diltiazem has actions intermediate between intracellular concentration of cGMP in the vascular smooth those of verapamil and nifedipine and is popular in the treatment muscle cells. cGMP activates protein kinase G (PKG), an enzyme of angina because it does not cause tachycardia. that causes the vascular smooth muscle to relax by several Tobacco smoking. Smoking is prothrombotic and atherogenic; mechanisms. These include: (i) activation of Ca pumps that it reduces coronary blood flow, and the nicotine‐induced rise in sequester Ca2+ into the smooth endoplasmic reticulum (SERCA) heart rate and blood pressure increases the oxygen demand of and extrude Ca2+ into the extracellular space (PMCA); and (ii) the heart. In addition, the formation of carboxyhaemoglobin activation of K‐channels, causing membrane hyperpolarization reduces the oxygen‐carrying capacity of the blood. Some patients that inhibits Ca influx by switching off voltage‐dependent improve remarkably on giving up smoking. Ca‐channels. The fall in [Ca2+]i decreases MLCK activity, and relaxation occurs as light‐chain phosphorylation is reduced by MLC‐phosphatase, the activity of which is increased by PKG. Revascularization Tolerance to nitrates may occur. For example, chronic Coronary artery bypass grafting (CABG) or percutaneous pentaery‐thritol tetranitrate has been shown to produce coronary intervention (PCI) may be indicated in patients not tolerance to sublingual glyceryl trinitrate, and moderate doses responding to drugs. Generally in bypass operations, the distal of oral isosorbide dinitrate four times a day produce tolerance end of the internal mammary artery is inserted at a point beyond with loss of the antianginal effect. However, twice daily dosing the stenosis of the affected coronary artery. Angina is relieved of isosorbide dinitrate at 08.00 and 13.00 does not produce or improved in 90% of patients. Mortality is decreased in some tolerance, presumably because the overnight rest allows tissue pathological conditions (e.g. left main coronary artery disease). sensitivity to return by the next day. Tolerance to nitrates is Originally, in PCI, a balloon catheter was used to split and poorly understood, but depletion of sulphydryl group donors compress the atheromatous plaque, but now the dilatation is may be involved, because tolerance to nitrates in vitro can followed by a metal wire‐mesh tube (stent) to scaffold the vessel sometimes be reversed by N‐acetylcysteine. Another possibility segment. Unfortunately, this damages the vessel, often leading to is that peroxynitrite formed from NO inhibits cGMP formation proliferative growth of smooth muscle and restenosis in 20–30% from guanosine triphosphate (GTP). of patients. This problem is significantly reduced by the use of stents that elute everolimus or zotarolimus from a polymer– drug matrix bound to the stent (less than 15% restenosis rate). β-Adrenoceptor antagonists Prolonged and continuous antiplatelet therapy is essential with β‐Blockers are used for the prophylaxis of angina. The choice of drug‐eluting stents because the endothelialization of the stent drug may be important. Intrinsic activity might be a disadvantage (which prevents thrombosis) is delayed by the antiproliferative in angina, and the cardioselective β‐blockers such as bisoprolol and drugs. Unfortunately the ideal duration of antiplatelet therapy metoprolol are probably the drugs of choice. All β‐blockers must (aspirin with clopidogrel) with drug eluting stents is unkown but be avoided in asthmatics as they may precipitate bronchospasm. is probably at least 12 months. 34 17 Antiarrhythmic drugs Medical Pharmacology at a Glance Sinus Vagal fibres Sympathetic fibres Supraventricular bradycardia adenosine I.V. atropine I.V. digoxin verapamil Ventricular and supraventricular ACh + NE – SAN Bundle of His CLASS III NE Stress induced ACh + amiodarone – Sl sotalol AVN – CLASS II ow ph s CLASS IA β-blockers a se propranolol 0 procainamide an atenolol d disopyramide 3 sotalol CLASS IC flecainide propafenone Stress Decrease fast Na + Inhibit 1 current Ca 2+ channel Ventricular 2 Heart norepinephrine CLASS IB gCa rate epinephrine release lidocaine I.V. 0 3 mexiletine gNa gK 4 Pacemaker potential gK (gK decreasing; g Na increasing) Threshold β-receptors gNa Cardiac action potential (AP) Inhibit 4 Most drugs (Composite diagram pacemaker potentials Effective refracetory occur only in the SAN and AVN) period Increase refractory period VS AP duration T he rhythm of the heart is normally determined by pacemaker 2 those effective in ventricular arrhythmias (bottom left); and cells in the sinoatrial node (SAN, top), but it can be disturbed 3 those effective in both types (middle left). in a variety of ways, producing anything from occasional dis- Arrhythmias associated with stress conditions in which there is comfort to the symptoms of heart failure or even sudden death. an increase in adrenergic activity (emotion, exercise, thyrotoxicosis, Arrhythmias can occur in the apparently healthy heart, but seri- myocardial infarction) may be treated with β‐blockers (bottom ous ones (e.g. ventricular tachycardia) are usually associated with right). An arrhythmia common after acute myocardial infarction is heart disease (e.g. myocardial infarction) and a poor prognosis. sinus bradycardia, which can be treated with intravenous atropine The rhythm of the heart is affected by both acetyl‐choline (ACh) if the cardiac output is lowered (top left). Antiarrhythmics have and norepinephrine (NE, noradrenaline), released from para- also been classified on the basis of their electrophysiological effects sympathetic and sympathetic nerves, respectively (upper figure). on Purkinje fibres (roman numerals). The effects of antiarrhythmic Supraventricular arrhythmias arise in the atrial myocardium agents on the cardiac action potential are shown in the lower or atrio‐ventricular node (AVN), whereas ventricular figure, but it is not usually known how these actions relate to the arrhythmias originate in the ventricles. Arrhythmias may be drugs' therapeutic effects. Many antiarrhythmic drugs can actually caused by an ectopic focus, which starts firing at a higher rate induce lethal arrhythmias, especially in patients with ischaemic than the normal pacemaker (SAN). More commonly, a re‐entry heart disease. Except for β‐blockers and perhaps amiodarone in mechanism is involved, where action potentials, delayed for myocardial infarction, there is no evidence that antiarrhythmic some pathological reason, re‐invade nearby muscle fibres which, drugs reduce mortality in any condition. Because of the limitations being no longer refractory, again depolarize, establishing a loop and dangers of antiarrhythmic drugs, invasive procedures and of depolarization (circus movement). devices are increasingly being used in serious arrhythmias as Many antiarrhythmic drugs have local anaesthetic activity alternatives to drugs. (i.e. block voltage‐dependent Na+ channels) or are calcium channel blockers. These actions decrease the automaticity of pacemaker cells and increase the effective refractory period of atrial, ventricular and Purkinje fibres. Cardiac action potential Most cardiac cells have two depolarizing currents, a fast Na+ Antiarrhythmic agents can be classified into: current and a slower Ca2+ current. However, in the SAN and 1 those effective in supraventricular arrhythmias (top right); AVN, there is only a Ca2+ current and, because pure ‘Ca2+ spikes’ Medical Pharmacology at a Glance, Eighth Edition. Michael J. Neal. © 2016 by John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd. Companion website: www.ataglanceseries.com/pharmacology conduct very slowly, there is a delay between atrial and ventricular Drugs effective in supraventricular and 35 contraction. The long refractory period of cardiac fibres normally protects them from re‐excitation during a heart beat. ventricular arrhythmias Chapter 17 Antiarrhythmic drugs Class IA agents act by blocking (open) voltage‐dependent Na+ channels. They slow phase 0 and lengthen the effective Pacemaker cells refractory period. Class IA agents produce a frequency (use)‐ In the SAN and AVN there are no fast channels, and the upswing dependent block. During diastole, when the Na+ channels are (essentially phase 2) of the action potential is slow because the closed, class IA agents dissociate relatively slowly (