ANTIANGINAL AGENTS (Nitroglicerinum, Sustac, Isosorbididinitras, Isosorbidimononitras, Verapamilum, Amlodipinum, Anaprilinum, Atenololum, Metoprololum, Dipiridamolum, Drotaverinum (No-spanum), Validolum, Trimetasidinum, ADP-long)

ANTIARRHYTHMIC AGENTS (Chinidinisulfas, Novocainamidum, Ethmosinum, Ajmalinum, Lidocainum, Trimecainum, Dypheninum, Aethacizinum, Propaphenolum (Rythmilen), Anaprilinum (Propranololum), Atenololum, Talinololum, Metoprololum, Amiodaronum, Verapamilum)

ANTIHYPERTENSIVE AGENTS (Anaprilinum (Propranololum), Atenololum, Talinololum, Metoprololum, Carvediolum, Prasosinum, Doxasosinum, Labetololum, Captoprilum (Capotenum), Enalaprilum, Lisinoprilum, Losartanum, Clopamidum,Fenigidinum, Amlodipinum, Furosemidum, Dichlothiazidum, Spironolactonum, Clophelinum, Reserpinum, Octadinum, Methyldopha, PentoxiphyllinumAgapurinum), Diazoxidum, Natriinitroprussidum, Drotaverinum, (No-spa), Magnesiisulfas, Dibasolum, Papaverinihydrohloridum)

Antianginal agents

Angina pectoris is chest pain due to ischemia (a lack of blood and hence oxygen supply) of the heart muscle, generally due to obstruction or spasm of the coronary arteries (the heart's blood vessels). Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries. The term derives from the Greekankhon ("strangling") and the Latinpectus ("chest"), and can therefore be translated as "a strangling feeling in the chest".

http://www.musc.edu/bmt737/spring2001/Kate/angina2.html

An anginal pain attack signals a transient hypoxia of the myocardium. As a rule, the oxygen deficit results from inadequate myocardial blood flow due to narrowing of larger coronary arteries. The underlying causes are: most commonly, an atherosclerotic change of the vascular wall (coronary sclerosis with exertional angina); very infrequently, a spasmodic constriction of a morphologically healthy coronary artery (coronary spasm with angina at rest; variant angina); or more often, a coronary spasm occurring in an atherosclerotic vascular segment. The goal of treatment is to prevent myocardial hypoxia either by raising blood flow (oxygen supply) or by lowering myocardial blood demand (oxygen demand).

Factors determining oxygen supply. The force driving myocardial blood flow is the pressure difference between the coronary ostia(aortic pressure) and the opening of the coronary sinus (right atrial pressure). Blood flow is opposed by coronary flow resistance, which includes three components. Due to their large caliber, the proximal coronary segments do not normally contribute significantly to flow resistance. However, in coronary sclerosis or spasm, pathological obstruction of flow occurs here. Whereas the more common coronary sclerosis cannot be overcome pharmacologically, the less common coronary spasm can be relieved by appropriate vasodilators (nitrates, nifedipine).

The caliber of arteriolar resistancevesselscontrols blood flow through the coronary bed. Arteriolar caliber is determined by myocardial O2 tension and local concentrations of metabolic products, and is “automatically” adjusted to the required blood flow. This metabolic autoregulationexplains why anginal attacks in coronary sclerosis occur only during exercise. At rest, the pathologically elevated flow resistance is compensated by a corresponding decrease in arteriolar resistance, ensuring adequate myocardial perfusion. During exercise, further dilation of arterioles is impossible. As a result, there is ischemia associated with pain. Pharmacological agents that act to dilate arterioles would thus be inappropriate because at rest they may divert blood from underperfused into healthy vascular regions on account of redundant arteriolar dilation. The resulting “steal effect” could provoke an anginal attack. The intramyocardial pressure, i.e., systolic squeeze, compresses the capillary bed. Myocardial blood flow is halted during systole and occurs almost entirely during diastole. Diastolic wall tension (“preload”) depends on ventricular volume and filling pressure. The organic nitrates reduce preload by decreasing venous return to the heart. Factors determining oxygen demand. The heart muscle cell consumes the most energy to generate contractile force. O2 demand rises with an increase in heart rate, contraction velocity, systolic wall tension (“afterload”). The latter depends on ventricular volume and the systolic pressure needed to empty the ventricle. As peripheral resistance increases, aortic pressure rises, hence the resistance against which ventricular blood is ejected. O2 demand is lowered by в-blockers and Ca-antagonists, as well as by nitrates It is common to equate severity of angina with risk of fatal cardiac events. There is a weak relationship between severity of pain and degree of oxygen deprivation in the heart muscle (i.e. there can be severe pain with little or no risk of a heart attack, and a heart attack can occur without pain). Worsening ("crescendo") angina attacks, sudden-onset angina at rest, and angina lasting more than 15 minutes are symptoms of unstable angina (usually grouped with similar conditions as the acute coronary syndrome). As these may herald myocardial infarction (a heart attack), they require urgent medical attention and are generally treated as a presumed heart attack.

Most patients with angina complain of chest discomfort rather than actual pain: the discomfort is usually described as a pressure, heaviness, tightness, squeezing, burning, or choking sensation. Apart from chest discomfort, anginal pains may also be experienced in the epigastrium (upper central abdomen), back, neck, jaw, or shoulders. Typical locations for radiation of pain are arms (often inner left arm), shoulders, and neck into the jaw. Angina is typically precipitated by exertion or emotional stress. It is exacerbated by having a full stomach and by cold temperatures. Pain may be accompanied by breathlessness, sweating and nausea in some cases. It usually lasts for about 1 to 5 minutes, and is relieved by rest or specific anti-angina medication. Chest pain lasting only a few seconds is normally not angina.

Myocardial ischemia comes about when the myocardia (the heart muscles) fail to take in sufficient blood and oxygen to function correctly. This inadequate perfusion of blood and the resulting reduced delivery of oxygen and nutrients, is directly correlated to blocked or narrowed blood vessels.

Some experience "autonomic symptoms" (related to increased activity of the autonomic nervous system) such as nausea, vomiting and pallor. Major risk factors for angina include cigarette smoking, diabetes, high cholesterol, high blood pressure and family history of premature heart disease. A variant form of angina (Prinzmetal's angina) occurs in patients with normal coronary arteries or insignificant atherosclerosis. It is thought to be caused by spasms of the artery. It occurs more in younger women. Increase in heart rate results in increased oxygen demand by the heart. The heart has a limited ability to increase its oxygen intake during episodes of increased demand. Therefore, an increase in oxygen demand by the heart (eg, during exercise) has to be met by a proportional increase in blood flow to the heart.

Myocardial ischemia can result from:

1. a reduction of blood flow to the heart caused by the stenosis or spasm of the heart's arteries

2. resistance of the blood vessels

3. reduced oxygen-carrying capacity of the blood.

Atherosclerosis is the most common cause of stenosis (narrowing of the blood vessels) of the heart's arteries and, hence, angina pectoris. Some people with chest pain have normal or minimal narrowing of heart arteries; in these patients, vasospasm is a more likely cause for the pain, sometimes in the context of Prinzmetal's angina and syndrome X.

Myocardial ischemia also can be the result of factors affecting blood composition, such as reduced oxygen-carrying capacity of blood, as seen with severe anemia (low number of red blood cells), or long-term smoking. Angina is more often the presenting symptom of coronary artery disease in women than in men. The prevalence of angina rises with an increase in age. All forms of coronary heart disease are much less-common in the Third World, as its risk factors are much more-common in Western and Westernized countries; it could therefore be termed a disease of affluence. The increase of smoking, obesity and other risk factors has already led to an increase in angina and related diseases in countries such as China.

Antianginal Drugs

Antianginal agents derive from three drug groups, the pharmacological properties of which have already been presented in more detail, viz., the organic nitrates, the Ca2+ antagonists, and the в-blockers.

Organic nitrates (A) increase blood flow, hence O2 supply, because diastolic wall tension (preload) declines as venous return to the heart is diminished. Thus, the nitrates enable myocardial flow resistance to be reduced even in the presence of coronary sclerosis with angina pectoris. In angina due to coronary spasm, arterial dilation overcomes the vasospasm and restores myocardial perfusion to normal. O2 demand falls because of the ensuing decrease in the two variables that determine systolic wall tension (afterload): ventricular filling volume and aortic blood pressure.

Nitroglycerin (NG), also known as nitroglycerine, trinitroglycerin, and glyceryltrinitrate, is a chemical compound. It is a heavy, colorless, oily, explosive liquid obtained by nitratingglycerol. It is used in the manufacture of explosives, specifically dynamite, and as such is employed in the construction and demolitionindustries, and as a plasticizer in some solid propellants. It is also used medically as a vasodilator to treat heartconditions.Nitroglycerin was discovered by chemist AscanioSobrero in 1847, working under TJ Pelouze at the University of Torino. The best manufacturing process was developed by Alfred Nobel in the 1860s. His company exported a liquid combination of nitroglycerin and gunpowder as 'Swedish Blasting Oil', but it was extremely dangerous as a result of its extreme instability, as shown in a number of "appalling catastrophes," such as the explosion that destroyed a Wells Fargo office in San Francisco in 1866. The liquid was widely banned, and this led to the development of dynamite (and similar mixtures such as dualine and lithofracteur), by mixing the nitroglycerine with inert (Nobel used kieselguhr) absorption (chemistry)|absorbents]] (e.g., nitrocellulosegel, blasting gelatine).

Nitroglycerin in medicine, where it is generally called glyceryltrinitrate, is used as a heart medication (under the trade names Nitrospan®, Nitrostat®, and Tridil®, amongst others). It is used as a medicine for angina pectoris (ischaemic heart disease) in tablets, ointment, solution for intravenous use, transdermal patches (Transderm Nitro®, Nitro-Dur®), or sprays administered sublingually (Nitrolingual Pump Spray®, Natispray®). The principal action of nitroglycerin is vasodilation — that is, widening of the blood vessels. The main effects of nitroglycerin in episodes of angina pectoris are:

• subsiding of chest pain
• decrease of blood pressure
• increase of heart rate.
• fainting or loss of consciousness (side effect that may occur upon change of posture)

These effects arise because nitroglycerin is converted to nitric oxide in the body (by a mechanism that is not completely understood), and nitric oxide is a vasodilatator).

Infrequent exposure to high doses of nitroglycerin can cause severe headaches known as NG head: these headaches can be severe enough to incapacitate some people; however, humans develop a tolerance and addiction to nitroglycerin after long-term exposure. Withdrawal can (rarely) be fatal; withdrawal symptoms include headaches and heart problems; with re-exposure to nitroglycerin, these symptoms may disappear. For workers in nitroglycerin manufacturing facilities, this can result in a "Monday Morning Headache" phenomenon for those who experience regular nitroglycerin exposure in the workplace; over the weekend they develop symptoms of withdrawal, which are then countered by reexposure on the next work day.

Isosorbitemononitrate

Mechanism of Action

The isosorbidemononitrate extended release tablets product is an oral extended-release formulation of isosorbidemononitrate, the major active metabolite of isosorbidedinitrate; most of the clinical activity of the dinitrate is attributable to the mononitrate. The principal pharmacological action of isosorbidemononitrate and all organic nitrates in general is relaxation of vascularsmooth muscle, producing dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood, decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonarycapillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, and systolic arterial pressure and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Isosorbidemononitrate is the major active metabolite of isosorbidedinitrate, and most of the clinical activity of the dinitrate is attributable to the mononitrate.

Pharmacodynamics

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored.

Immediate Release Tablets

The drug-free interval sufficient to avoid tolerance to isosorbidemononitrate has not been completely defined. In the only regimen of twice-daily isosorbidemononitrate that has been shown to avoid development of tolerance, the two doses of isosorbidemononitrate tablets are given 7 hours apart, so there is a gap of 17 hours between the second dose of each day and the first dose of the next day. Taking account of the relatively long half-life of isosorbidemononitrate this result is consistent with those obtained for other organic nitrates.

The same twice-daily regimen of isosorbidemononitrate tablets successfully avoided significant rebound/withdrawal effects. The incidence and magnitude of such phenomena have appeared, in studies of other nitrates, to be highly dependent upon the schedule of nitrate administration.

Extended Release Tablets

The isosorbidemononitrate extended release tablets during long-term use over 42 days dosed at 120 mg once daily continued to improve exercise performance at 4 hours and at 12 hours after dosing but its effects (although better than placebo) are less than or at best equal to the effects of the first dose of 60 mg.

Pharmacokinetics

Immediate Release Tablets

In humans, isosorbidemononitrate is not subject to first pass metabolism in the liver. The absolute bioavailability of isosorbidemononitrate from isosorbidemononitrate tablets is nearly 100%. Maximum serum concentrations of isosorbidemononitrate are achieved 30 to 60 minutes after ingestion of isosorbidemononitrate.

The volume of distribution of isosorbidemononitrate is approximately 0.6 L/Kg, and less than 4% is bound to plasma proteins. It is cleared from the serum by denitration to isosorbide; glucuronidation to the mononitrateglucuronide; and denitration/hydration to sorbitol. None of these metabolites is vasoactive. Less than 1% of administered isosorbidemononitrate is eliminated in the urine.

The overall elimination half-life of isosorbidemononitrate is about 5 hours; the rate of clearance is the same in healthy young adults, in patients with various degrees of renal, hepatic, or cardiacdysfunction, and in the elderly. In a single-dose study, the pharmacokinetics of isosorbidemononitrate was dose-proportional up to at least 60 mg.

Nitroglycerine Tolerance

• can be avoided in most patients if there is a nitrate- free interval of 10-12 hours per day.
• may be the result of depletion of intracellular suphydryl groups which prevents further nitrate metabolism and nitric oxide release.
• reversed within 18 hours of stopping nitrates.
• if tolerance is supected in the case of modified isosorbidedinitrate (and conventional preparations of isosorbidemononitrate) then the second of two daily doses can be given after about 8 hours rather than after 12 hours.
• there is no relationship to tolerance to adverse and therapeutic effects.
• toleance may develop in less than 48 hours after the initiation of treatment with nitrates.

Calcium antagonists (B) decrease O2 demand by lowering aortic pressure, one of the components contributing to afterload. The dihydropyridinenifedipineis devoid of a cardiodepressant effect, but may give rise to reflex tachycardia and an associated increase in O2 demand. The catamphiphilic drugs verapamil and diltiazemare cardiodepressant. Reduced beat frequency and contractility contribute to a reduction in O2 demand; however, AV-block and mechanical insufficiency can dangerously jeopardize heart function. In coronary spasm, calcium antagonists can induce spasmolysis and improve blood flow.

CCBs exert their clinical effects by blocking the L-class of voltage gated calcium channels. By blocking transmembrane entry of calcium into arteriolar smooth muscle cells and cardiac myocytes, CCBs inhibit the excitation-contraction process. CCBs are a heterogeneous group of drugs. Dihydropyridines are primarily potent vasodilators of peripheral and coronary arteries. Non-dihydropiridines Verapamil and Diltiazem are moderate vasodilators with significant cardiac effects

Adverse effects: Most common side effect of CCBs is ankle edema. This is caused by vasodilatation, which also causes headache, flushing and palpitation, especially with short-acting dihydropyridines. Some of these side effects can be offset by combining a calcium channel blocker with a beta blocker. Verapamil and Diltiazem cause constipation. More seriously, they can cause heart block, especially in those with underlying conduction problems. Verapamil, diltiazem and short-acting dihydropyridines should be avoided in patients with heart failure.

Amlodipine

Amlodipine (prolong acting) is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, Amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassiumepinephrine, serotonin, and thromboxane A₂ analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of NORVASC in vasospastic (Prinzmetal’s or variant) angina.

в-Blockers protect the heart against the O2-wasting effect of sympathetic drive by inhibiting в-receptormediated increases in cardiac rate and speed of contraction.

Beta-blockers act by blocking the action of catecholamines at adrenergic receptors throughout the circulatory system and other organs. BBs major effect is to slow the heart rate and reduce force of contraction. BBs via inhibition of receptors at justaglomerular cells inhibit renin release.

Beta-blockers may be classified based on their ancillary pharmacological properties. Cardioselective agents have high affinity for cardiac β ₁ and less affinity for bronchial and vascular β₂ receptors compared with non-selective agents and this reduces (but does not abolish) β ₂ receptor-mediated side effects. However, with increasing doses cardiac selectivity disappears. Lipid-soluble agents cross the blood-brain barrier more readily and are associated with a higher incidence of central side effects. Some beta-blockers have intrinsic sympathomimetic activity – ISA (i.e., they stimulate β receptors when background sympathetic nervous activity is low and block them when background sympathetic nervous activity is high). Adverse effects: BBs slow the rate of conduction at the atrio-ventricular node and are contraindicated in patients with second- and third-degree heart block. Sinus bradycardia is common and treatment should be stopped if patient is symptomatic or heart rate falls below 40 b/min. Because of blockade of pulmonary ß₂ receptors, even small doses of BBs can cause bronchospasm (less common with cardioselective agents), and all beta-blockers are contraindicated in asthma. Blockade of ß receptors in the peripheral circulation causes vasoconstriction and may induce particularly in patients with peripheral circulatory insufficiency adverse effects such as cold extremities, Raynaud’s phenomenon, and intermittent claudication. Nevertheless, they are reasonably tolerated in patient with mild peripheral vascular disease. Lipid-soluble agents can cause central nervous system side effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced by BBs and patients may experience tiredness and fatigue. BBs can worsen glucose intolerance and hyperlipidemia and in diabetic patients mask signs of hypoglycemia. However, diabetic hypertensive patients with previous MI should not be denied BB because of concerns about metabolic side effects.

Uses of antianginal drugs (D).For relief of the acute anginal attack, rapidly absorbed drugs devoid of cardiodepressant activity are preferred. The drug of choice is nitroglycerin (NTG, 0.8–2.4 mg sublingually; onset of action within 1 to 2 min; duration of effect ~30 min). Isosorbidedinitrate (ISDN) can also be used (5–10 mg sublingually); compared with NTG, its action is somewhat delayed in onset but of longer duration. Finally, nifedipine may be useful in chronic stable, or in variant angina (5–20 mg, capsule to be bitten and the contents swallowed).

For sustained daytime angina prophylaxis, nitrates are of limited value because “nitrate pauses” of about 12 h are appropriate if nitrate tolerance is to be avoided. If attacks occur during the day, ISDN, or its metabolite isosorbidemononitrate, may be given in the morning and at noon (e.g., ISDN 40 mg in extended- release capsules). Because of hepatic presystemic elimination, NTG is not suitable for oral administration. Continuous delivery via a transdermal patch would also not seem advisable because of the potential development of tolerance. With molsidomine, there is less risk of a nitrate tolerance; however, due to its potential carcinogenicity, its clinical use is restricted. The choice between calcium antagonists must take into account the differential effect of nifedipine versus verapamil or diltiazem on cardiac performance. When в-blockers are given, the potential consequences of reducing cardiac contractility (withdrawal of sympathetic drive) must be kept in mind. Since vasodilating в2-receptors are blocked, an increased risk of vasospasm cannot be ruled out. Therefore, monotherapy with в-blockers is recommended only in angina due to coronary

sclerosis, but not in variant angina.

Acute Myocardial Infarction

Myocardial infarction is caused by acute thrombotic occlusion of a coronary artery (A).

Myocardial infraction (MI)is the condition of irreversible necrosis of the heart muscle that results from prolonged ischemia. Nearly 1.5 million people in US sustain an MI each year, and this event proves fatal in approximately one third of patients. Approximately 90% of MI results from formation of an acute thrombus that obstructs an atherosclerotic coronary artery. The thrombus transforms a region of plaque narrowing to one of complete vessel occlusion (top right in pink). The responsible thrombus appears to be generated by interactions between the atherosclerotic plaque, the coronary endothelium, circulating platelets, and dynamic vasomotor tone of the vessel wall, all of which overwhelm natural protective mechanisms. The endogenous protective mechanisms against thrombosis include: 1. Inactivation of thrombin by antithrombin III (ATIII), the effectiveness of which is enhanced by binding of ATIII to heparin sulafate. The antithrombin binding region of commercial heparin consists of sulfated disaccharide units (bottom panel). 2. Inactivation of clotting factors Va and VIIIa by activated protein C (protein C*), an action that is enhanced by protein S. Protein C is activated by the thrombomodulin (TM)-thrombin complex. 3. Inactivation of factor VII/tissue factor complex by tissue factor pathway inhibitor (TFPI). Coumarin drugs (Warfarin) blocks the g-carboxylation of Glu residues in prothrombin and factors VII, IX and X which results in incomplete molecules that are biologically inactive in coagulation (left panel). 4. Lysis of fibrin clots by tissue plasminogen activator (tPA). 5. Inhibition of platelet activation by prostacyclin and EDRF-NO. Platelets adhere to exposed collagen and are activated at the site of endothelial damage in the blood vessel. Activated platelets release adenosine diphosphate (ADP), serotonin (5-HT), and thromboxane A2 (TXA2), which activate additional platelets. Binding of thrombin further activates the platelets. Three adjoining platelets are shown in the process of viscous metamorphosis (top right). Increased cellular Ca2+ facilitates binding of fibrinogen. If the intraluminal thrombus at the site of plaque disruption totally occludes the vessel, blood flow beyond the obstruction will cease, prolonged ischemia will occur and MI (usually Q-wave MI) will likely result (see electrocardiogram on the top left)

Therapeutic interventions aim to restore blood flow in the occluded vessel in order to reduce infarct size or to rescue ischemic myocardial tissue. In the area perfused by the affected vessel, inadequate supply of oxygen and glucose impairs the function of heart muscle: contractile force declines. In the great majority of cases, the left ventricle anterior or posterior wall) is involved. The decreased work capacity of the infarcted myocardium leads to a reduction in stroke volume (SV) and hence cardiac output (CO). The fall in blood pressure (RR) triggers reflex activation of the sympathetic system. The resultant stimulation of cardiac β-adrenoceptors elicits an increase in both heart rate and force of systolic contraction,

which, in conjunction with an β-adrenoceptor- mediated increase in peripheral resistance, leads to a compensatory rise in blood pressure. In ATP-depleted cells in the infarct border zone, resting membrane potential declines with a concomitant increase in excitability that may be further exacerbated by activation of β-adrenoceptors. Together, both processes promote the risk of fatal ventricular arrhythmias. As a consequence of local ischemia, extracellular concentrations of H+ and K+ rise in the affected region, leading to excitation of nociceptive nerve fibers. The resultant sensation of pain, typically experienced by the patient as annihilating, reinforces sympathetic activation. The success of infarct therapy critically depends on the length of time between the onset of the attack and the start of treatment. Whereas some theraputic measures are indicated only after the diagnosis is confirmed, others necessitate prior exclusion of contraindications or can be instituted only in specially equipped facilities. Without exception, however, prompt action is imperative. Thus, a staggered treatment schedule has proven useful. The antiplatelet agent, ASA, is administered at the first suspected signs of infarction. Pain due to ischemia is treated predominantly with antianginal drugs (e.g., nitrates).

In case this treatment fails (no effect within 30 min, administration of morphine, if needed in combination with an antiemetic to prevent morphine-induced vomiting, is indicated. If ECG signs of myocardial infarction are absent, the patient is stabilized by antianginal therapy (nitrates, β- blockers) and given ASA and heparin. When the diagnosis has been confirmed by electrocardiography, attempts are started to dissolve the thrombus pharmacologically (thrombolytic therapy: alteplase or streptokinase) or to remove the obstruction by mechanical means (balloon dilation or angioplasty). Heparin is given to prevent a possible vascular reocclusion, i.e., to safeguard the patency of the affected vessel. Regardless of the outcome of thrombolytic therapy or balloon dilation, a β-blocker is administered to suppress imminent arrhythmias, unless it is contraindicated.

Treatment of life-threatening ventricular arrhythmias calls for an antiarrhythmic of the class of Na+-channel blockers, e.g., lidocaine. To improve long-term prognosis, use is made of a β-blocker ( incidence of reinfarction and acute cardiac mortality) and an ACE inhibitor (prevention of ventricular enlargement after myocardial infarction) (A).

Antiarrhythmic agents

The past two decades have witnessed a rapid growth in understanding of the cellular and molecular basis of both normal andpathological electrophysiology. Elucidation of cardiac ion channelstructure and function has contributed to many of these advances.As a result, we may be on the verge of an era where arrhythmiamanagement will no longer be dominated by trial and error basedobservational treatment. Our aim in this article is to providean overview of antiarrhythmic drug action, linking known actionsat the level of cellular electrophysiology to clinical use. Takingparticular examples, we shall also illustrate how molecular geneticadvances have shown that some rhythm disturbances can result fromspecific defects in genes encoding cardiac ion channels. Makingreference to investigational drugs under study, we will also considerthe issue of whether advances in the understanding of cardiaccellular electrophysiology may improve rational approaches toantiarrhythmic drug design andtreatment.

The mechanism of drug action is central to the process of choosing a drug to treat any particular arrhythmia. Thus it is usefulto consider first impulse generation at the cellular level. Thisin turn demands consideration of the ion channels underpinningimpulse generation in different cardiac muscle cell types. Itis the opening and closing of a range of different ion channelsthat leads to the distinct profiles of membrane potential whichcomprise cardiac action potentials. Therefore, we shall initiallyconsider the electrophysiological characteristics of cardiac actionpotentials, aspects of ion channel function, and ion channelsas sites of antiarrhythmic drugaction.

Membrane and action potentials: conventionsshow schematic representations of action potentials from pacemaker, ventricular, and atrial tissues. Whereas themembrane potential in pacemaker cells (typically from the sinusnode, as this is usually the dominant pacemaker) constantly cycles, cells (myocytes) from ventricular and atrialtissue ( possess true resting potentials, which usuallylie between 70 and 80 mV. The negative value of the restingpotential reflects the dominant effect of a steady net effluxof positively charged K⁺ ions in these cell types by way of an ionic current (I_K1), througha channel type called the inward rectifier.¹ Pacemaker cellsfrom sinoatrial² and atrioventricular nodes³ appear to lacka significant I_K1, and as a result along with other ionic currents theydo not show a true resting membrane potential; rather, a pacemakerpotential precedes each action potential. Action potentials inall cell types result from positive shifts in membrane potential(depolarisation), caused by opening of ion channels, allowingpositively charged sodium and calcium ions to enter the cell throughchannels selective for each ionic type. The rate of depolarisationduring the action potential upstroke in atrial and ventricularcells is faster than in pacemaker cells, owing to the fact thata large and fast sodium current underlies the upstroke in thesecell types, while the upstroke in pacemaker cells is predominantlycarried by a calcium current. After the peak of the action potential,the membrane potential is restored to its original value duringthe repolarisation phase, as channels passing depolarising currentclose and repolarising channels (largely a range of potassiumchannels) open.

Ventricular cells in particular also possess adistinct plateau phase, and the relatively long duration of theventricular action potential helps make the ventricular tissuerefractory to overexcitation which might otherwise tetanise theventricular myocardium. The distinct action potential phases discussedabove are sometimes referred to as phases 0 to 4: phase 0 is theaction potential upstroke, phase 1 is the early repolarisation"notch" (evident immediately after the ventricular action potentialpeak , phases 2 and 3 describe plateau and late repolarisation(pacemaker cell action potentials without a distinct notch orplateau may lack distinct phases 1 and 2), while phase 4 is theperiod after repolarisation is complete (the resting level innon-pacemaker cells, and the pacemaker depolarisation in pacemakercells).

Ion channels: the basics Critical to action potential generation is the combined function of different membrane bound ion channels, together with ionexchange proteins and ATP driven pumps. ATPases for Na/K⁴ andCa⁵ help sustain the normal transmembrane gradients for theseions, and a sodium-calcium exchange protein contributes to calciumand sodium homeostasis and membrane potential generation (forexample, Allen and colleagues,⁶Janvier and Boyett⁷). Tounderstand modifications of ionic currents by antiarrhythmic drugs,some basic properties of ion channel function need to be examined.In simple terms, transmembrane ion channels activated by membranepotential changes can be viewed as proteins comprising a voltagesensor coupled to a pore through which ions flow; the pore incorporatesa "selectivity filter" which determines which types of ions willpass through the openpore.

FLOW OF IONIC CURRENT IN RELATION TO "EQUILIBRIUM POTENTIAL"

The direction of ion flow (and therefore of electrical current generation) is determined by the transmembrane concentrationgradient established by the concentrations C_o outside and C_i insidethe cell of the permeant ion, together with the electrical gradientresulting from the membranepotential.

For a particular ionic species and given values of C_oand C_i, there will be one membrane potential value), at which there is no net driving forcefor ions to flow across the membrane. For example, for sodiumions E_Nalies near +70 mV; at potentials negative to this, sodiumions will flow down their concentration gradient (from outsideto inside the cell) and generate a depolarising or inward currentBeyond E_Na(a situation encountered experimentally,but not physiologically), sodium ions would flow in the oppositedirection Conversely, for potassium ions,E_Klies near -90 mV, and at potentials positive to this potassiumions will flow down their concentration gradient (from insideto outside the cell) and generate repolarising or outward current. If the inside of the cell is made more negativethan E_K the direction of ion flow will be reversed With a knowledge of the normal intracellular and extracellularion concentrations, it is possible to predict the contributionsof sodium, calcium, and potassium channels in generating membranepotential depolarisation or repolarisation.

One further aspect of ion channel function should be covered before considering the roles played by individual ion channeltypes channel gating. Voltage operated channels are usually referredto as voltage gated, as biophysical measurements indicate thatspecific membrane potential regulated processes determine themagnitude and time course of ionic current flow across the rangeof ion channel types. This can be explained by considering anion channel that does not pass current until a depolarising stimulusis applied. At rest, the channel is therefore considered to beclosed . When a depolarising stimulus is applied, themembrane potential change is detected by the voltage sensor thechannel undergoes a conformational change and opens in order toallow ionic current to flow. The process describing thetransition from the closed to open state is termed activation.The probability of channels moving to the open state usually dependson the magnitude of the voltage change (activation is therefore"voltage dependent"), and the speed with which channels move fromthe closed to the open state will determine the rate of activation. Some voltage dependent channels show only a voltage dependent activation process, but for many a second process also influencesionic current flow. If the depolarising stimulus is maintained,a second conformational change occurs in the ion channel. Partof the ion channel protein moves to occlude the channel pore suchthat, while the channel may be fully activated, it becomes poorlyconducting

This process, which, like activation, is voltage and time dependent, is termed inactivation. Experimentally, the propertiesof channel activation, inactivation, voltage sensitivity, andionic selectivity can be studied using voltage or patch clamptechniques. The important points here are as follows:

• Distinct ion channel types generate depolarising and repolarising currents during the actionpotential.
• From the existence of distinct ion channels with distinct roles arises the potential for drug classification anddesign.
• The fact that ion channels undergo voltage dependent state transitions means that, theoretically, drugs could bindto resting/closed (C), activated/open (O) or inactivated (I) states.

Drugs which bind preferentially to open or inactivated channel states may exert effects that vary with stimulation frequency(or in vivo, with heart rate) and as such can show use dependence.For antiarrhythmic agents, an ideal channel blocking agent wouldhave positive use dependence showing a greater inhibitory actionat faster heart rates. Drugs binding preferentially to closedchannels may either exert use independent actions or show "reverseuse dependence," in which the drug dissociates from its bindingsite during channel activation. With reverse use dependent blockade, faster rates of channel stimulation (or indeed heart rate) encouragegreater dissociation than slower rates, resulting in comparativelyless channel inhibition at faster than at slowerrates.

TIARRHYTHMIC DRUGS (Continued) ANTIARRHYTHMIC DRUGS (Continued)CHANNELS INVOLVED IN PACEMAKING

In the sinus node, the T type calcium current (I_Ca,T) and the hyperpolarisation activated current (I_f) both provide inward,depolarising current during the pacemaker depolarisation thatprecedes each action potential upstroke. Agents thatreduce these currents should therefore slow the rate of the pacemakerdepolarisation and thereby have a negative chronotropic effect.Specific inhibitors of I_f produce rate reduction. Mibefradilis a blocker of I_Ca,T which preferentially relaxes coronary vasculatureand slows heart rate without reducing contractility, makingit a potential bradycardic agent. This particular compound wasvoluntarily withdrawn because it was involved in several clinicallyrelevant drug interactions. In general, the use of selectivebradycardic agents is likely to be of limited value except ininappropriate sinustachycardia.

CHANNELS INVOLVED IN ACTION POTENTIAL DEPOLARISATION

L type calcium and sodium channels are of greater importance as antiarrhythmic targets. I_Ca,L appears to be the dominant depolarisingcurrent during action potentials from the sinoatrial and atrioventricular(AV) nodes.The dependence of AV nodal conduction on I_Ca,Lmakes L type channel blockers such as verapamil and diltiazemimportant in the management of supraventricular tachycardias.In paroxysmal atrioventriculartachycardias, either anterogradeor retrograde conduction through the AV node forms part of thecircuit maintaining the arrhythmia; thus blockade of I_Ca,L canbe effective in preventing recurrence ofthe arrhythmia.. Ltype channel blockers can also be effective against AV nodal reentranttachycardias and atrial fibrillation.

The importance of I_Na in generating the fast upstroke phase of both atrial and ventricular action potentials makes I_Na blockerspotentially effective against both supraventricular and ventriculararrhythmias. Sodium channel-drug interactions are usefully consideredwithin the "modulated receptor" model, which takes into considerationthe channel state to which a drug preferentially binds.The action potential upstroke rate can become slowed when I_Nais reduced and as a result I_Na blockers can decrease impulse conductionvelocity. In addition, agents that delay the recovery of I_Na fromchannel inactivation have the effect of prolonging tissuerefractoriness.

Agents such as quinidine,propafenone, and disopyramide preferentially bind to the open (activated) state of thesodium channel, while others including lignocaine (lidocaine)and mexiletine show a preference for the inactivated channel.Open channel blockers are effective in generally reducing electricalexcitability and impulse conduction, while inactivated channelblockers may show a blocking effect influenced by differencesin atrial and ventricular action potential profile. Thecomparatively longer and more depolarised ventricular action potentialplateau results in a more prolonged inactivation of I_Na, withan increased level of block. This property may contribute to theselectivity of drugs such as mexiletine against ventricular arrhythmias;it might also be used in combination treatment by combining aninactivated state sodium channel blocker with a drug that delaysrepolarisation, resulting in enhanced sodium channel inhibitionand thereby prolongedrefractoriness.

The kinetics of recovery from block are also critically important in determining the effects of sodium channel blockers. Agentsassociated with slow recovery from block (for example, flecainide)cause a block that accumulates rapidly on repetitive stimulation,and a stable steady state level of block is attained over a widerange of heart rates. Agents with relatively fast recoveryfrom block (for example, mexiletine) may show little cumulativeblock at slow heart rates, as block is relieved between actionpotentials. At faster rates (tachycardias), block accumulatesbecause there is too little time for unbinding to occur betweenaction potentials. This produces the effect of "positive use dependence,"which is beneficial in that little ECG alteration may be experiencedat normal rates, whereas drug effects become important duringtachyarrhythmias.

It is important to realise, however, that blocking efficiency and recovery can be affected by various factors. Open channelblockers may be less effective in damaged or ischaemic tissue;this is often depolarised, resulting in the inactivation of aproportion of channels, thereby rendering these unavailable forblock. In contrast, inactivated state blockers may be more effectivein conditions where tissue becomes depolarised experimental evidencesuggests that the efficacy of lignocaine and the risk of proarrhythmiaare both enhanced in acutely ischaemic myocardium.In additionto the effects of membrane potential depolarisation on block,the low pH associated with ischaemia can also slow the time constantof drug dissociation, enhancing the cumulative level of channelblock.

POTASSIUM CHANNELS Some sodium channel blocking agents, for example disopyramide and in particular quinidine, are also associated withdelayed repolarisation and QT prolongation on the ECG. For bothdisopyramide and quinidine,his effect results frompotassium channel blocking actions of the drug. Excessive actionpotential and QT prolongation (when the corrected QT interval(QT_c) exceeds ~440² to 460 ms), carries a risk of proarrhythmia.However, potassium channel blockade can also be antiarrhythmic,because moderately delayed action potential repolarisation canenhance the inactivation of depolarising currents (I_Na and I_Ca),thereby prolonging the period between successive action potentials.This can be effective in disrupting arrhythmias caused by reentrantmechanisms. Different potassium channel types, therefore, offerpotential antiarrhythmic drug targets. Major potassium ion channeltypes involved in action potential repolarisation include thetransient outward current, I_TO, responsible for the action potentialnotch in ventricular cells and prominent during atrial repolarisation.The rapid and slow components of delayed rectifier current (I_Krand I_Ks, respectively) are important in plateau repolarisation.The inward rectifier potassium current is important for the finalstage of repolarisation and for maintaining the cell restingpotential. Owing to their roles in plateau repolarisation, I_Krand I_Ks are of particular interest as antiarrhythmictargets.

As in the case of sodium channel blocking agents, the desirable potassium channel blocker is one that shows positive use dependence(that is, the drug effects are greatest at faster action potentialrates). Unfortunately, many potassium channel blocking drugs appearto be associated with a reverse use dependent effect: action potentialprolongation is greater at slower rather than at faster rates.The problem with this is that action potential prolongation atslow rates can be proarrhythmic through the cellular mechanismof early afterdepolarisations. By a mechanism originally investigatedby January and Riddle and recently reviewed by Makielski andJanuary, sufficiently slowed membrane repolarisation duringthe action potential facilitates calcium entry through L typecalcium channels, which can result in early afterdepolarisations.These in turn could give rise to triggered activity and lead totorsade de pointes. Selective block of I_Kr (for example, by thedrug E-4031) can be sufficient to induce early afterdepolarisations.Early afterdepolarisations are relieved at faster rates; thereforeI_Kr block is most likely to be proarrhythmic at slow rates. Theclinical implications of reverse use dependence and specific I_Krblock are exemplified by sotalol which, as the racemic D-L mix,possesses  blocking and I_K blocking actions and is indicatedfor the treatment of life threatening ventricular tachycardia.Racemic sotalol produces some QT prolongation and is bradycardic.D-sotalol lacks the  blocking activity of the racemic mix, butis an I_Krblockerand shows reverse use dependent effectson the action potential. Significantly, D-sotalol is associatedwith an increased risk of death from presumed arrhythmias.

A simple explanation for reverse use dependent drug effects on action potential prolongation involves drug binding to theresting channel (in the interval between action potentials) anddissociating during membrane depolarisation. This would producea greater relief of block at faster rates (at which there wouldbe shorter intervals between action potentials for drug bindingto occur). However, subsequent experiments on cloned channelsare not consistent with this explanation (for example, Syndersand colleagues). Moreover, agents such as almokalant blockI_Kr in a use dependent fashion, while producing reverse usedependent action potential prolongation.In addition, dofetilidehas been reported to produce rate independent effects on I_Kr,but reverse rate dependent effects on the action potential.In the same study, repetitive stimulation was observed toincrease the magnitude of I_Ks but not of I_Kr. It has been proposed,therefore, that reverse use dependence may result from the interactionbetween I_Kr and I_Ks during repolarisation at different heart rates.At slower rates I_Kr may be dominant; at faster heart rates therole of I_Ks increases owing to incomplete deactivation (the transitionof channels from O C, fig 3A) of the current between action potentials.Thus specific I_Kr inhibition would have a greater effect on repolarisationat slower than at fasterrates.

If this mechanism holds, then an agent which blocks I_Ks specifically might be better for treating tachycardias than an I_Krblocker; moreover, an agent that blocks both components of I_Kmight have an improved safety profile over a specific I_Kr blocker.There are few experimental data yet available to support the firstof these possibilities (selective I_Ks blockers are only beginningto appear); the second, however, does seem to hold true. Quinidineand sotalol do not appear to block I_Ks. By contrast amiodarone,which has a much better cardiac safety profile, blocks both I_Krand I_Ks, while also showing a more consistent effect onaction potentials at different rates.

A further potassium channel should be mentioned, as it is likely to mediate the antiarrhythmic actions of adenosine. The extremelyshort half life of adenosine makes intravenous administrationvaluable in terminating tachycardias involving the AV node (eitherAV nodal re-entry or AV re-entry). In bolus form, adenosine hasbeen shown to be highly effective against paroxysmal supraventriculartachycardias that require AV nodal conduction for their maintenance.The cellular basis for the effect of adenosine appears to resemblethat for acetylcholine. Acetylcholine activates a potassium current(I_KACh), which is important in mediating parasympathetic effectson the sinoatrial and AV nodes. When activated, I_KAChproduces membrane potential hyperpolarisation; it thereby decreasesautomaticity and excitability. At the cellular level, adenosineactivates a current (I_KAdo) with properties identical to thoseof I_KACh (for example, Belardinelli and colleagues). Cellularstudies on rabbit AV node suggest that activation of I_KAdo islikely to be predominantly responsible for the action of adenosine,with possible supplementary effects on L type calcium channels.

Molecular insights into arrhythmogenesisSome of the most exciting cardiological developments of the last decade relate to advances in understanding the molecularbiology underlying ion channel function, and the finding thatdefects in individual ion channels can underlie particular arrhythmias.This is no better exemplified than in congenital long QT syndrome.This syndrome illustrates how various different channelopathiescan manifest themselves clinically as virtually identical electrocardiographicendpoints. Congenital long QT syndrome is characterised by abnormallyprolonged ventricular repolarisation leading to QT_C prolongation(as discussed earlier), with an associated risk of malignant ventriculartachyarrhythmias (torsade depointes).

Congenital long QT syndrome has been found to arise from a range of different genetic abnormalities . Thetwo main forms are the autosomal dominant Romano-Ward syndrome(pure cardiac phenotype) and the autosomal recessive Jervell-Lange-Nielsensyndrome (in which cardiac abnormalities coexist with congenitaldeafness). Of the genetic abnormalities identified in theRomano-Ward syndrome, four are associated with identified ionchannels. Most of the mutations causing congenitallong QT (LQT) syndrome are missense mutations. However, substantialphenotypic heterogeneity remains, even with identical gene abnormalities.LQT1, 2, and 3 all result in prolongation of the action potential.The extent of prolongation depends not only upon the gene mutated,but also upon the exact location of the mutation. As discussedearlier, it is the risk of afterdepolarisations associated withQT interval prolongation rather than slowing of action potentialrepolarisation on its own that is arrhythmogenic. The involvementof L type I_Ca in the production of early afterdepolarisationsand the widely known enhancement of I_Ca by  adrenergic stimulationmay, at least in part, explain the clinical effectiveness of blockers in reducing the incidence of syncopal episodes and arrhythmiasin the long QT syndrome.

As shown in alterations in the genes underlying I_Kr and I_Ks are associated with LQT-2 and LQT-1. The channels forboth I_Kr and I_Ks are multimeric,and alleles from both parentscontribute to the channel complexes. Mutant channels expressedin oocytes or cell lines show loss of function. Channel kinetics,as well as reduced overall current, contribute to the loss offunction (that is, a reduction in repolarising outward current).In contrast, mutations of sodium (SCN5A) channels cause a gainof function, in which a late persistent (depolarising)sodium current is produced because of defective inactivation ofI_Na. Owing to the heterogeneous basis for congenital long QT syndrome,identification of the underlying cause is pivotal in decidingupon appropriate treatment. Provocation may distinguish betweenthe different congenital LQT syndromes. While the QT intervalshortens only minimally with exercise in LQT1 and LQT2, in patientswith LQT3 it shortens significantly. Furthermore, torsadede pointes is precipitated by adrenergic stimulation (for example,during exercise) in LQT1, possibly because I_Ks normally predominatesat high rates, and therefore reduced I_Ks would lead to inadequateshortening of the action potential. In contrast, most patientswith LQT 3 experience more events at rest than on exertion.

Another interesting group of patients providing a clear link between cellular abnormalities and clinical treatment are thosewith the Brugada syndrome. These patients have structurallynormal hearts and right precordial ST segment elevation or rightbundle branch block. The ECG abnormalities probably reflectexaggerated transmural differences in action potential configuration,especially within the right ventricular outflow tract. The endresult is an increased risk of ventricular fibrillation withinthese families. One variant of the Brugada syndrome arises froma mutation of the SCN5A gene (the same gene that is implicatedin LQT3), leading to a gain of function; hence drugs targetingthe sodium channel may be clinicallyeffective.

However, while long QT syndrome and the Brugada syndrome may provide a clear route from cell to clinic, some common arrhythmiasare not yet so accommodating. Refractory arrhythmias, for example,may be refractory because of the complex processes involved intheir pathogenesis. These may include both electrical and structuralremodelling. Electrical remodelling may be physiological and unrelatedto cardiac disease (for example, atrial fibrillation may becomeself sustaining), or pathological in origin (alteration inthe distribution of gap junctions between cells in diseased tissue).Structural remodelling may also be either physiological (for example,initial ventricular hypertrophy in response to hypertension) orpathological (cell hypertrophy in peri-infarct zones and cellloss with replacement fibrosis within infarcted regions).Therefore complex arrhythmias with a multifactorial aetiologymay benefit from primary prevention targeted towards alleviationof diseases such as coronary occlusion or ventricular hypertrophy.A second line of attack may then be directed towards the electrophysiologicalsequelae of upstream events. Treatment must be tailored towardsthe aetiology of the arrhythmia, as drug treatment for ventriculartachycardia in one patient may be detrimental in another. Indeed,in the structurally abnormal heart for example, after myocardialinfarction or during congestive cardiac failure drug efficacyhas been limited and in these conditions antiarrhythmic drugscan have a significant proarrhythmic potential.

Re-evaluation of antiarrhythmic drug classificationAnother area that has experienced change owing to the increased information available from cellular cardiology is that ofdrug classification. Early approaches to antiarrhythmic drug developmentinvolved the identification of natural compounds with antiarrhythmicactivity such as cinchona, or identification of antiarrhythmiceffects of drugs licensed for other uses, primarily local anaesthetics,including lignocaine and its derivatives. Clinical studies verifiedthe acceptability as antiarrhythmic agents of synthetic moleculessuch as procainamide. Further attempts were than made to producerelated compounds with increased potency and reduced toxicity(for example, flecainide, lorcainide, and encainide).While this approach has provided many useful drugs for therapeuticuse, the derived compounds have to varying degrees retained theadverse effect profiles of parent drugs. Progress in the developmentof newer antiarrhythmic drugs has not been as great as once anticipated,and the chance discovery of antiarrhythmic properties of drugsdeveloped for other conditions for example, amiodarone (initiallydeveloped as an antianginal drug) has contributed significantlyto the armoury available to theclinician.

In 1970, Vaughan Williams proposed a classification based on possible ways in which abnormal cardiac rhythms could be correctedor prevented.In this early classification, class I drugsact by reducing inward sodium current at concentrations not affectingthe resting membrane potential. Class II drugs act by blockingsympathetic activity of the heart. Although not thought to affectthe action potential of most myocardial cells, these drugs reducethe spontaneous rate of depolarisation of pacemaker cells underadrenergic stimulation and are therefore negatively chronotropic.They are also negatively dromotropic, as the AV node tends tobe under greater sympathetic drive than the sinoatrial node forwhich vagal tone normally predominates. Class III drugs prolongaction potential duration. They do not specifically affect anysingle factor involved in repolarisation (although in realitymost class III drugs exert potassium channel blocking actions).They are able to alter the activity of several different ion channelconductances at a cellular level, making their impact upon theaction potential quite complex. In general, they prolong actionpotential duration and hence prolong the length of the refractoryperiod. In a separate class was placed diphenylhydantoin, a centrallyactingdrug.

In 1974, Singh and Hauswirth modified the classification, with two major changes.First, lignocaine and diphenylhydantoinwere placed in a separate class, because at low concentrationsand at low external potassium concentrations, they had littleeffect upon the action potential or cardiac conduction. Secondly,a separate class (now denoted class IV) was introduced to accommodatecalcium channel blockers, which (as described earlier) predominantlyaffect regions in which action potential depolarisation dependson I_Ca,L. In a further development, class I drugs were subclassifiedby Harrison according to their effect upon action potentialupstroke and duration. Additional studies showed thatthe subclassification separated class I drugs according to therate of recovery of I_Na channels from blockade. Class 1a drugswere intermediate between class Ib drugs, with fast recovery timeconstants less than one second, and class Ic drugs, with relativelyslower recovery time constants of more than 15 seconds.

The "Singh-Hauswirth-Harrison-Vaughan Williams" (S-H-H-VW) classification is summarised. Many antiarrhythmic drugshave more than one class of action (for example, racemic sotalolhas class II and class III activity and amiodarone has class I-IVactions). Moreover, some drugs within a particular class may differin their clinical effects owing to subtle (but significant) differencesin their mechanism of action at the ion channel level. In addition,there are some antiarrhythmic drugs (for example, digoxin andadenosine) which cannot be fitted into the S-H-H-VW I-IV classification.While the S-H-H-VW classification has been valuable, the limitations of inadequate correlations between drug mechanism, arrhythmiamechanism, and therapeutic efficacy gave rise to the "SicilianGambit" approach to antiarrhythmic treatment. This approach toarrhythmia management, formulated by the European Society of Cardiologyworking group seeks the critical mechanisms responsible forarrhythmogenesis) to identify a "vulnerable parameter"or "Achilles heel" of the arrhythmia concerned. This would enablethe clinician to select a drug on the basis of its mechanism ofaction and not empirically. This approach complements well thoserecent advances in our understanding of molecular biology (forexample, cloning and sequencing of ion channels and receptors)that have raised hopes for a "target oriented" approach to antiarrhythmictreatment. There are, however, two fundamental issues that mighthinder this approach to drug selection. First, an Achilles heelis not always (yet) identifiable for many arrhythmias, and insome cases there may be more than one Achilles heel, some of whichare not involved in arrhythmogenesis. In addition, there are drugsclassified within the S-H-H-VW classification that have multipleelectrophysiological targets; this may preclude them from beingselective for any one particular Achilles heel. Second, considerationof drug action based on multiple targets (ion channels, receptors,and second messenger systems) and the "spread sheet" approachadvanced in the Sicilian Gambit⁹⁴ generates a degree of complexityabsent from the S-H-H-VW classification, and which may hinderacceptance of this approach. Against this, however, a majoradvantage of the Sicilian Gambit approach is that it providesa framework within which the ever increasing information on arrhythmogensisand drug action can be readily accommodated and considered.(forexample, Members of the Sicilian Gambit

Our increasing knowledge of the basic electrophysiological and genetic characteristics of ion channels, the cellular actionsof antiarrhythmic agents, their effects on animal models, andthe results of clinical trials should help guide future rationaldrug development and classification. In a recent article,Camm and Yap summarise attributes for future antiarrhythmic agents,including: appropriate modification of the arrhythmia substrate,suppression of arrhythmia triggers, efficacy in pathologic tissuesand states, positive rate/use dependent effects, similar efficacyin oral and parenteral formulations, similar efficacy in arrhythmiasand their surrogates, few side effects, and cardiac selectiveion channelblockade.

One of the central issues will be whether approaches which focus on a single ion channel target offer more promise than approachesbased on compounds with "polypharmacological" (multiple ion channel)effects. Recently discovered ion channels such as the ultrarapiddelayed rectifier (I_K,ur) in atrial tissue may offer new,alternative drug targets. Importantly, the reverse use dependenceassociated with some drugs with class III (predominantly I_Kr)blocking actions might be taken as suggesting that either drugsagainst alternative targets to I_Kr or drugs with multiple effectsmay be superior to selective I_Kr blockersalone.

Unfortunately, the emerging picture is not as clear as this. While the results of the SWORD (survival with oral d-sotalol)trial indicate that d-sotalol increases mortality and is thereforeunsuitable for use, the same does not appear to be true fordofetilide. Dofetilide is a potent and selective blocker of I_Kr,which, although associated with reverse use dependent effectson the action potential at the cellular level,has a profilethat is not clearly reverse use dependent in humans (for example,Bashir and colleagues). The drug appears to be reasonablywell tolerated and at some concentrations is effective at suppressingventricular tachycardia. Moreover, its use does not seem tobe associated with significantly increased mortality, and withonly a low incidence of torsade de pointes. Quite why dofetilideappears to be safer than d-sotalol is not entirely clear, thoughthere is some experimental evidence that the class III effectsof d-sotalol are much more sensitive to extracellular potassiumlevels than those of dofetilide. At this stage, it would appearpremature to rule out selective I_Kr blockade as a viable antiarrhythmicstrategy.

I_Ks blockade may, in principle, offer an attractive alternative or supplementary approach to I_Kr inhibition. Azimilide isa relatively new agent effective at inhibiting both I_Kr and I_Ks.Data from experiments in which I_Ks blocking effects of the drugon the action potential have been estimated suggested that theI_Ks block alone was associated with rate independent action potentialprolongation. The overall drug effect on the action potential(involving combined I_Kr and I_Ks actions) shows some variationsbetween experimental studies, with reports of either some reverseuse dependence or a rate independent action on effectiverefractory period. Azimilide may be effective against bothatrial and ventricular arrhythmiasand, while it is tooearly to comment with certainty on its efficacy and safety inhumans, initial signs appear promising. Several clinical trialsincluding the ALIVE (azimilide post-infarct survival evaluation)study were ongoing at the time ofwriting.

Other investigative agents with polypharmacological effects include ibutilide and tedisamil. Ibutilide has an interestingpharmacological profile in that in addition to affecting I_Kr italso appears to induce a sustained sodium current, an effect thatwould be synergistic in prolonging the action potential. Tedisamilblocks I_Kr and the transient outward potassium current (I_TO)It has been shown to be effective against ventricular fibrillationin a rabbit model and it prolongs the monophasic action potentialin humans. Dronedarone, an investigational drug related toamiodarone, may be an agent of particular interest. Like itsparent compound, dronedarone may be expected to exert multipleS-H-H-VW effects and thereby have wide ranging efficacy. The resultsof trials of this and other agents with polypharmacological effectswill be important in the debate about whether the future developmentof antiarrhythmic agents lies in single or multiple ion channeltargets. As the underlying basis for the generation and maintenanceof particular arrhythmias becomes increasingly understood, sowill our understanding of the nature of any associated Achillesheel or vulnerable parameter. This knowledge, together with ongoingrevision of drug classification according to target/action, islikely to refine pharmacotherapeutic approaches to clinical arrhythmiamanagement.

This work was supported by grants from the British Heart Foundation, the United Bristol Healthcare Trust, and the WellcomeTrust. KCRP was supported by a British Heart Foundation clinicaltraining fellowship, and JCH was supported by a Wellcome Trustresearch fellowship. We thank Kathryn Yuill for providing theionic current record for figure B, and Helen Wallis for commentson themanuscript.

Antihypertensive Drugs

Goal

The goal of this session is to make students familiar with the pharmacology of antihypertensive drugs and with basic principles of rational pharmacotherapy of essential hypertension, hypertensive urgency and hypertensive emergency.

Learning Objectives

After attending this session and reading provided information, student should be able to able to:

1. Discuss the pharmacological properties of various oral antihypertensive drugs

2. List the properties of an “ideal” antihypertensive drug

3. List the first-line drugs for treatment of essential hypertension

4. Discuss the main adverse effects of first-line antihypertensive drugs

5. List target blood pressure and at least two drugs of choice for hypertensive patients with co-existing diseases

6. Discuss the rationale for combining antihypertensive drugs

7. List the drugs for treatment of hypertensive crisis (emergency and urgency)

8. Discuss the treatment algorithm for the hypertensive patient

I. Pharmacology of Oral Antihypertensive Drugs

Algorithm for the treatment of hypertension.

The role of ACE inhibitors

1.1 Diuretics

A. Thiazides: Bendroflumethiazide [NATURETIN]; Benzthiazide [EXNA]; Chlorothiazide [DIURIL]; Hydrochlorothiazide [HYDRODIURIL]; Hydroflumethiazide [SALURON]; Methyclothiazide [ENDURON]; Polythiazide [RENESE]

B. Thiazide-like: Chlorthalidone [HYGROTON]; Indapamide [LOXOL]; Metolazone [MYKROX, ZAROXOLYN]

Mechanism of action: Inhibition of the sodium/chloride symport in distal convoluted tubule and subsequent reduction in sodium and chloride re-absorption. The initial drop in BP is due to increased sodium excretion and water loss and reduced extracellular fluid and plasma volume, whereas the chronic action of TZD diuretics is due to reduction of peripheral vascular resistance. There is evidence that TZDs have some direct vasodilating properties and decreases vasocontrictor response of vascular smooth muscle cells to other vasoconstricting agents.

At low doses TZDs (12.5-25 mg of hydrochlorothiazide [HCTZ] or its equivalent) are relatively well tolerated. Very rarely they cause severe rash, thrombocytopenia and leucopenia. The most common side effect is hypokalemia. Reduction in serum potassium varies with the dose and is between 0.3-1 mmol. Thiazides may increase plasma lipid elevation, and induce glucose intolerance and hyperuricemia. These adverse effects are less frequent with low doses. Importantly, the metabolic side effects of diuretics do not compromise their expected beneficial effects on cardiovascular morbidity and mortality.

As antihypertensive agents TZDs may be particularly useful in elderly patients, African Americans, patients with mild or incipient heart failure, when cost is crucial, and in patients with poor control of salt intake. Low dose TZDs are combined with other first line antihypertensive drugs. The use of TZDs should be avoided in patients with NIDDM, hyperlipidemia or gout.

C. Na Channel Inhibitors (K-Sparing):Amiloride [MIDAMOR]; Triamterene [DYRENIUM, MAXZIDE]

Potassium-sparing diuretics produce little reduction in blood pressure themselves. They may be useful in combination with other diuretics to prevent hypokalemia.

D. Aldosterone Antagonists (K-Sparing):Sironolactone [ALDACTONE]; Eplerenone [INSPRA™]

Spironolactone is a specific aldosterone antagonist, with mild antihypertensive effect. The hypotensive mechanism of spironolactone is unknown. It is possibly due to the ability of the drug to inhibit aldosterone's effect on arteriole smooth muscle. Spironolactone also can alter the extracellular-intracellular sodium gradient across the membrane. Spironolactone inhibits the effects of aldosterone on the distal renal tubules. Unlike amiloride and triamterene, spironolactone exhibits its diuretic effect only in the presence of aldosterone, and these effects are enhanced in patients with hyperaldosteronism. Aldosterone antagonism enhances sodium, chloride, and water excretion, and reduces the excretion of potassium, ammonium, and phosphate. Spironolactone improves survival and reduces hospitalizations in patients with severe heart failure (NYHA Class IV) when added to conventional therapy (ACE inhibitor and a loop diuretic, with or without digoxin).

Eplerenone is approved for treatment of hypertension and for the treatment of post-myocardial infarction patients with heart failure. It is a more selective aldosterone receptor antagonist, similar in action to spironolactone, with lower incidence of side effects (gynecomastia) due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors. It is more expensive than spironolactone.

1.2. Beta Blockers

There are 15 Beta blockers (BB) on the market in the US. All BBs except esmolol and sotalol are approved for treatment of hypertension (13) and one or more of following indications: angina pectoris, myocardial Infarction, ventricular arrhythmia, migraine prophylaxis, heart failure and perioperative hypertension. Only sotalol delays ventricular repolarization and is effective for maintenance of sinus rhythm in patients with chronic atrial fibrilation. Esmolol has short half-life and is given for hypertensive (perioperative) urgency and for atrial arrhythmias after cardiac surgery.

Beta-blockers act by blocking the action of catecholamines at adrenergic receptors throughout the circulatory system and other organs. BBs major effect is to slow the heart rate and reduce force of contraction. BBs via inhibition of receptors at justaglomerular cells inhibit renin release.

Beta-blockers may be classified based on their ancillary pharmacological properties. Cardioselective agents have high affinity for cardiac β ₁ and less affinity for bronchial and vascular β₂ receptors compared with non-selective agents and this reduces (but does not abolish) β ₂ receptor-mediated side effects. However, with increasing doses cardiac selectivity disappears. Lipid-soluble agents cross the blood-brain barrier more readily and are associated with a higher incidence of central side effects. Some beta-blockers have intrinsic sympathomimetic activity – ISA (i.e., they stimulate β receptors when background sympathetic nervous activity is low and block them when background sympathetic nervous activity is high). Therefore, theoretically BBs with ISA are less likely to cause bradycardia, bronchospasm, peripheral vasoconstriction, to reduce cardiac output, and to increase lipids. BBs with ISA are less frequently used in the treatment of hypertension.

Beta Blocker	Relative Cardiac Selectivity	Intrinsic Sympathomimetic Activity	Daily Dosing Frequency	Lipid Solubility	b1 + a1
Acebutolol SECTRAL	++	+	2	Moderate	-
Atenolol TENORMIN	++	-	1	Low	-
Betaxolol KERIONE	++	-	1	Low	-
Bisoprolol ZEBETA	++	-	1	Low	-
Carteolol CARTROL	-	++	1	Low	-
Carvedilol COREG	-	-	2	High	+
Esmolol BREVIBLOC	+	-	i.v.	Moderate	-
Labetalol TRANDATE NORMODYNE	-	-	2	Moderate	+
Metoprolol LOPRESSOR	+	-	1 or 2	Mod. / High	-
Nadolol CORGARD	-	-	1	Low	-
Penbutol LEVATOL	-	+	1	High	-
Pindolol VISKEN		+++	2	Moderate	-
Propranolol INDERAL	-	-	2	High	-
Timolol BLOCADREN	-	-	2	Low / Mod.	-

Lipophilic beta blockers may enter CNS more extensively and readily which may lead to increased CNS side effects. Labetalol and carvedilol have both β₁- and α₁-blocking properties, and decrease heart rate and peripheral vascular resistance. Both agents possess the side effects common for both classes of drug. Beta-blockers tend to be less effective in the elderly and in black hypertensives. To reduce side effects in hypertensive patients it is recommended to use a beta-blocker with high cardioselectivity, low lipid solubility and long half-life that allows once daily dosing.

Adverse effects: BBs slow the rate of conduction at the atrio-ventricular node and are contraindicated in patients with second- and third-degree heart block. Sinus bradycardia is common and treatment should be stopped if patient is symptomatic or heart rate falls below 40 b/min. Because of blockade of pulmonary ß₂ receptors, even small doses of BBs can cause bronchospasm (less common with cardioselective agents), and all beta-blockers are contraindicated in asthma. Blockade of ß receptors in the peripheral circulation causes vasoconstriction and may induce particularly in patients with peripheral circulatory insufficiency adverse affects such as cold extremities, Raynaud’s phenomenon, and intermittent claudication. Nevertheless, they are reasonably tolerated in patient with mild peripheral vascular disease. Lipid-soluble agents can cause central nervous system side effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced by BBs and patients may experience tiredness and fatigue. BBs can worsen glucose intolerance and hyperlipidemia and in diabetic patients mask signs of hypoglycemia. However, diabetic hypertensive patients with previous MI should not be denied BB because of concerns about metabolic side effects.

1.3. Alpha-1 adrenergic receptor blockers ( ….OSIN )

Prazosin [MINIPRESS] Terazosin [HYTRIN] Doxazosin [CARDURA]

Alfuzosin [UROXATRAL] Tamsulosin [FLOMAX]

The β₁-adrenoceptor blockers produce vasodilatation by blocking the action of norepinephrine at post-synaptic β₁ receptors in arteries and veins. This results in a fall in peripheral resistance, without a compensatory rise in cardiac output. Doxazosin, terazosin, and, less commonly, prazosin are used as oral agents in the treatment of hypertension. They are relatively more selective for a_1b - and a_1d-receptors which are involved in vascular smooth muscle contraction. Alfuzosinand tamsulosin are used for symptomatic treatment of begin prostatic hyperplasia (BPH), since compared to other oral α₁-blockers, they have less antihypertensive effects and are relatively more selective as antagonists at the α_1a subtype, the primary subtype located in the prostate.

Based on ALLHAT study data, alpha blockers are not longer considered first-line drug for treatment of hypertension. They are drugs of choice for treatment of hypertensive patient with BPH. Adverse effects include first dose hypotension, dizziness, lethargy, fatigue, palpitation, syncope, peripheral edema and incontinence.

1.4. Angiotensin Converting Enzyme Inhibitors (ACEIs; ... PRIL)

Benazepril [LOTENSIN] Captopril [CAPOTEN] Enalapril [VASOTEC] Fosinopril [MONOPRIL] Lisinopril [PRINIVIL, ZESTRIL] Moexipril [UNIVASC] Perindopril [ACEON] Quinapril [ACCUPRIL] Ramipril [ALTACE] Spirapril [RENOMAX] Trandolapril [MAVIK]

ACEIs block the renin-angiotensin system activity by inhibiting the conversion of the biologically inactive angiotensin I to angiotensin II, a powerful vasoconstrictor and stimulator of release of sodium-retaining hormone aldosterone. These effects result in decreased peripheral vascular resistance and reduction in aldosterone plasma levels. ACE inhibitors also reduce the breakdown of the vasodilator bradykinin, which may enhance their action but is also responsible for their most common side effect, cough. ACE inhibitors reduce central adrenergic tone and influence renal hemodynamics (i.e., reduce intraglomerular hypertension) that may have beneficial effects in proteinuric renal disease.

The ACEIs tend to be less effective as antihypertensives in patients who tend to have lower renin levels (African Americans and elderly). This relative ineffectiveness can be overcome by using high doses of ACEI or by adding a diuretic. Captopril is short acting, sulfhydryl-group containing agent; Beenazepril, enalapril, fosinopril, moexipril, quinapril, ramipril, spirapril are pro-drugs that in the body have to be converted to active metabolites; and lisinopril is active non metabolized ACEI.

In addition to treatment of hypertension, various ACEIs are approved for treatment of heart failure, left ventricular dysfunction, diabetic nephropathy, and acute MI.

Adverse effects include cough (most frequent 3-10%), hypotension (particularly in volume depleted patients), hyperkalemia, angioedema, renal Insufficiency, and fetal injury (2nd & 3rd trimesters).

1.5. Angiotensin II Receptor Antagonists (ARBs; ...SARTAN )

Losartan [COZAAR] Valsartan [DIOVAN] Irbesartan [AVAPRO] Candesartan [ATACAND]

Eprosartan [TEVETEN] Tasosartan [VERDIA] Telmisartan [MICARDIS}

Similar to ACEI, angiotensin II receptor antagonists inhibit the activity of renin-angiotensin-aldosterone system. Sartans act by blocking the angiotensin II type-1 receptors. As they do not inhibit the breakdown of bradykinin, they do not cause cough. However, they may lack the additional physiological benefits that rises in bradykinin levels may bring. ARBs have similar physiological effects to ACE inhibitors, produce similar falls in blood pressure and have same indications and adverse effects profile (except for the cough).

1.6. Calcium Channel Blockers (CCBs)

CCBs exert their clinical effects by blocking the L-class of voltage gated calcium channels. By blocking transmembrane entry of calcium into arteriolar smooth muscle cells and cardiac myocytes, CCBs inhibit the excitation-contraction process. CCBs are a heterogeneous group of drugs. Dihydropyridines are primarily potent vasodilators of peripheral and coronary arteries. Non-dihydropiridines Verapamil and Diltiazem are moderate vasodilators with significant cardiac effects (Table2).

Pharmacologic Effects of Calcium Channel Blockers
Effect	Verapamil CALAN, CALAN SR COVERA-HS, ISOPTIN, ISOPTIN SR VERELAN VERELAN PM	Diltiazem Cardizem, Cardizem CD Cardizem LA, Cardizem Lyo-Ject, Cardizem SR Cartia XT, Dilacor XR Diltia XT, Taztia XT Tiamate, Tiazac®	Dihydropyridines Amlodipine [NORVASC] Felodipine [PLENDIL] Isradipine [DYNACIRC] Nicardipine [CARDENE] Nifedipine PROCARDIA ADALAT]
Peripheral Vasodilation
Heart Rate	¯¯	¯
Cardiac Contractility	¯¯	¯	0 / ¯
SA/AV nodal conduction	¯	¯	0
Coronary Blood Flow

Adverse effects: Most common side effect of CCBs is ankle edema. This is caused by vasodilatation, which also causes headache, flushing and palpitation, especially with short-acting dihydropyridines. Some of these side effects can be offset by combining a calcium channel blocker with a beta blocker. Verapamil and Diltiazem cause constipation. More seriously, they can cause heart block, especially in those with underlying conduction problems. Verapamil, diltiazem and short-acting dihydropyridines should be avoided in patients with heart failure.

Central Alpha-2 Agonist

Methyl-dopa [ALDOMET], Clonidine [CATAPRES]

These drugs stimulate central a₂ adrenergic receptors in rostral ventrolateral medulla which control sympathetic outflow. The resulting decrease in central sympathetic tone leads to a

fall in both cardiac output and peripheral vascular resistance.

The drugs cause sedation, dry mouth and fluid retention. Methyl-dopa requires conversion to alpha-methyl norepinephrine, and clonidine does not.

Methyl-dopa is safe in pregnancy and this is the only indication for its use as a first line agent in hypertension. Clonidine has rapid onset of action (30-60 min) and is used in hypertensive urgency. However, it is short acting agent, and transdermal patch system was developed to provide 7-day constant dose of drug. Abrupt withdrawal of clonidine therapy may result in “rebound hypertension.”

A new centrally acting drug, moxonidine, acts on central imidazoline receptors and is hoped to have less side effects.

Peripheral Vasodilators

Hydralazine [APRESOLINE], Minoxidil [LONITEN]

These agents act directly to relax vascular smooth muscle, thereby reducing peripheral vascular resistance. Within this class of drugs, the oral vasodilatorsHydralazine and Minoxidil are used for long-term outpatient therapy of hypertension. They are second line of drugs for treatment of hypertension and must be combined with first line antihypertensives to offset some of their adverse effects. Decreased arterial resistance and blood pressure elicit compensatory responses, mediated by baroreceptors and the sympathetic nervous system and renin-angiotensin-aldosterone system (reflex tachycardia, fluid and sodium retention). High doses of hydralazine may also induce, particularly in slow acetilators, “lupus-like” syndrome (arthralgia, myalgia, skin rashes, and fever). The effect of minoxidil appears to result from the opening of potassium channels in smooth muscle membranes by its active metabolite minoxidil sulfate. Even more than with hydralazine, the use of minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with a b-blocker and a loop diuretic. Headache, sweating, and hirsutism, are common adverse effects of minoxidil. Topical minoxidil (as Rogaine) is now used as a stimulant to hair growth for correction of baldness.

The parenteral vasodilators (nitroprusside, nitroglycerin, fenoldopam, diazoxide) used for treatment of hypertensive crisis are described below.

1.9. Adrenergic Neural Terminal Inhibitors

Guanethidine [ISMELIN], Guanadrel [HYCOREL], Reserpine

These drugs lower blood pressure by preventing normal physiologic release of nor-epinephrine from postganglionic sympathetic neurons. Because of unacceptable adverse effects profile (“pharmacologic sympathectomy") this old group of antihypertensive drugs is rarely used for treatment of hypertension.

1.10. Ganglionic Blockers (Mecamylamine [INVERSINE])

Ganglion blockers competitively block nicotinic cholinergic receptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. Most of these agents are no longer available clinically because of unacceptable adverse effects related to their primary action. The adverse effects are due to both sympathetic inhibition (excessive orthostatic hypotension, sexual dysfunction) and parasympathetic inhibition (constipation, urinary retention, precipitation of glaucoma, blurred vision, and dry mouth).

II. Antihypertensive Drugs for Treatment of Hypertensive Crisis

1.Definition of Hypertensive Crisis

§ Normal blood pressure: SBP <120, DBP <80 mmHg

§ Prehypertension: SBP 120-139; DBP 80-89 mmHg

§ Hypertension Stage 1: SBP140-159; DBP 90-99 mmHg

§ Hypertension Stage 2: SBP >160; DBP >100 mmHg

§ Hypertensive crisis (Hypertensive Emergency vs. Hypertensive Urgency)

Hypertensive crisis is arbitrarily defined as a severe elevation of BP hypertension (i.e., DBP > 120 mmHg) which, if not treated, promptly will result with high morbidity and mortality. Severe elevation in blood pressurein the presenceof acute or ongoing end-organ damage is classified as hypertensive emergencies, whereas severe elevation of blood pressure in the absence of target-organ involvement is defined as hypertensive urgencies^. Distinguishing hypertensive urgencies from emergenciesis important in formulating a therapeutic plan.

The diagnosis of hypertensive emergency is based more on the clinical state of the patient rather than on the absolute level of blood pressure per se. Sometime (i.e., children with acute GN, women with severe preeclampsia - eclampsia) the absolute level of blood pressure (i.e., >250/150 mm Hg), or the rate of rise of BP may constitute an emergency because of the risk of developing hypertensive encephalopathy, intracerebral hemorrhage, or acute congestive heart failure.

§ CNS Emergencies: Hypertensive encephalopathy; Intracerebral or subarachnoidal hemorrhage; Thrombotic brain infarction with severe HTN

§ Cardiac Emergencies: Acute heart failure; Acute coronary insufficiency; Aortic dissection; Post vascular surgery HTN

§ Renal Emergencies: Severe HTN with rapidly progressive renal failure; Rapidly rising BP with rapidly progressive glomerulonephritis

Therapeutic principles in hypertensive crisis

Be cautions but aggressive - Distinguish from situations where rapid BP reduction is not necessary or may be even hazardous - Treatment may be necessary based on a presumptive diagnosis (i.e., before results of laboratory tests are done) - Select an agent that allows for “precise” control of the blood pressure level (“titration” of BP).

Therapeutic objectives in hypertensive crisis:

· For hypertensive emergency the therapeutic goal is to reduce the blood pressure (i.e., by 30% or to 105 mm Hg DBP) within a matter of minutes to an hour and to prevent further rapid deterioration of the target organs’ function.

· For hypertensive urgency therapeutic goal is to reduce BP during the period of 1-24 hours.

1. Sodium Nitroprusside

Sodium Nitroprusside (SNP) is an extremely potent vasodilator with a rapid onset and a short duration of action (t½ = 1-2 minutes). SNP decreases pre-load (venodilatation) and after-load (arteriolar dilatation) to a similar degree. In hypertensive patients reduces cardiac output (CO) and increases heart rate. However, in patients with heart failure SNP increases cardiac index, CO, and stroke volume and reduces heart rate.

The peripheral vasodilatory effects of SNP are due to a direct action on arterial and venous smooth muscle cells. Other smooth muscle tissue and myocardial contractility are not affected.

SNP is rapidly metabolized into cyanide radicals which are (in the liver) converted to thiocyanate, a metabolite excreted almost entirely in the urine. Therefore, SNP is relatively contraindicated in patients with severe liver or renal disease. Cyanide toxicity is rare unless large doses of SNP are administered to patients with renal insufficiency. Thiocyanate toxicity can also occur in patients with renal insufficiency who receive SNP, but the onset is slower than cyanide toxicity. However, when SNP is administered with a computerized continuous infusion device utilizing continuous intra-arterial blood pressure monitoring, it is probably the safest agent to use for treatment of hypertensive emergency. Adverse effects usually related to the abrupt reduction in blood pressure include nausea, vomiting, tachycardia, hypoxemia and “coronary steal” phenomenon. SNP may not be drug of choice for treatment of hypertensive emergency in patients with acute coronary insufficiency, aortic dissection, severe preeclampsia and eclampsia, and increased intracranial pressure.

2. Nitroglycerin

Nitroglycerin is an organic nitrate available in various dosage forms. It is converted in the vascular smooth muscles cells to nitric oxide, a free radical which activates guanylatecyclase. Subsequent increase in cGMP leads to relaxation of vascular smooth muscle. With the exception of greater effect on veins (venous pooling) and beneficial redistribution of coronary blood flow, nitroglycerin shares the pharmacological profile of sodium nitropruisside.

Nitroglycerin may be considered the drug of choice in hypertensive patients with post coronary bypass hypertension, acute coronary insufficiency, or acute CHF when BP is only slightly increased.

It should not be used in patients with increased intracranial pressure, glaucoma, severe anemia and constrictive pericarditis; should be used with caution in elderly, volume depleted patients and patients with hepatic disease (increased risk of methemoglobinemia).

3. Nicardipine

Nicardipine is a dihydropyridine CCB used intravenously for treatment of postoperative hypertension or hypertension with increased intracranial pressure. Nicardipine has similar pharmacological profile with other CCBs, and is presumably more selective for cerebral and coronary blood vessels.

4. Esmolol

Esmolol is β ₁-selective beta-blocker administered via continuous IV infusion. Because of the extremely short duration of action of esmolol, it is useful for acute control of hypertension or certain supraventricular arrhythmias. Except for short half-life and duration of action, esmolol has similar pharmacological profile to other BBs.

5. Fenoldapam

Fenoldopam is a selective agonist at dopamine DA₁ receptors, used intravenously for acute treatment of severe hypertension. Fenoldopam dilates renal and mesenteric vascular beds via stimulation of postsynaptic DA₁ receptors. Blood pressure and total peripheral resistance are lowered while renal plasma flow is enhanced. Onset of action is >5 min and duration ~ 30 minutes. Adverse effects appeared to be dose-related and include flushing, headache, nausea, vomiting, tachycardia and hypotension.

8. Drugs given by intermittent intravenous infusion:

- Labetalol: combined a+b adrenergic receptor blocker

- Enalaprilat: ACE inhibitor, active metabolite of pro-drug enalapril.

- Diazoxide: prevents vascular smooth muscle contraction by opening potassium channels and stabilizing the membrane potential at the resting level. Diazoxide induces rapid fall in systemic vascular resistance and blood pressure associated with substantial tachycardia and an increase in cardiac output. Diazoxide causes renal salt and water retention, which can be avid if the drug is used for short periods only. Inhibits insulin secretion and induces hyperglycemia (used for treatment hyperinsulinom-related hypoglycemia).

III. Selection of Antihypertensive Drug (s)

Therapeutic objectives in hypertension: For patients with essential hypertension stage 1-2 the therapeutic objective is to lower the high blood pressure and reduced cardiovascular morbidity and mortality. The ultimate goal is to reduce morbidity and mortality, rather than to reduce elevated blood pressure per se. We are using blood pressure as a surrogate end-point to guide therapy. The goal is during the 4-8 week period to bring blood pressure within physiological range (<140/90, or <130/80 mmHg for patients with diabetes or chronic renal disease) by the least intrusive means possible (i.e. no side effects or an acceptable placebo-like side effect profile); in most of the cases this is a life-long treatment of an asymptomatic disease.

· Properties of the “ideal” antihypertensive drug

· Presence of other risk factors for cardiovascular disease & target organ damage

· Coexisting diseases

· JNC VII Therapeutic Algorithm

1. http://www.youtube.com/watch?v=JwB7VG6WaaY&feature=related

2. http://www.youtube.com/watch?v=oHTGtYsEJBo&feature=channel

3. http://www.youtube.com/watch?v=VKxQgjj2yVU&feature=related

4. http://www.youtube.com/watch?v=oHTGtYsEJBo&feature=channel

5. http://www.youtube.com/watch?v=wJKkYGe7a3k&feature=related

6. http://www.youtube.com/watch?v=OT9HhHtQruA&feature=related

7. http://www.youtube.com/watch?v=xw4nDMgTOrw&feature=related

8. http://www.youtube.com/watch?v=x67vRkooZDc&feature=related

9. http://www.youtube.com/watch?v=PwnpEoQDzo0&feature=related