13 Antianginal agents

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

ANTIARRHYTHMIC AGENTS (Chinidini sulfas, 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, Pentoxiphyllinum Agapurinum), Diazoxidum, Natrii nitroprussidum, Drotaverinum, (No–spa), Magnesii sulfas, Dibasolum, Papaverini hydrohloridum)

 

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 Greek ankhon (“strangling”) and the Latin pectus (“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) (A).

 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. (1) 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 byappropriate vasodilators (nitrates, nifedipine). (2)

The caliber of arteriolar resistancevessels controls 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 (B, healthy subject). This metabolic autoregulation explains why anginal attacks in coronary sclerosis occur only during exercise (B, patient). 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. (3) 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 (1) heart rate, (2) contraction velocity, (3) 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. Similar figures apply in the remainder of the Western world. 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.

Angina pectoris—it is a common disease (ischaemic heart disease) affecting the middle aged persons, usually males.

Angina→ pain, Pectoris→ chest.

Definition—it is a clinical condition where there is chest pain due to transient ischaemia resulting due to imbalance in O₂ supply and O₂ demand.

 Causes of pain—

1. Atherosclerotic narrowing of the epicardial arteries (fat deposition in the sub-endothelial region/tunica intima)

2. Prinz metal angina / variant angina—due to spasm of the epicardial arteries.

3. Severe left ventricular hypertrophy where demand of the hypertrophied myocardium is so great that coronary blood supply fails to meet the demand.

4. Thrombosis.

5. Other less important causes are—

a.    Narrowing of the coronary ostea.

b.   Congenital anomaly and so forth.

 *** A transient ischaemia is produced due to underlying disease, as a result myocardial cells suffer from ischaemia and ischaemic pain is felt.

 Precipitating factors—

1. Heavy meal

2. Intense physical exercise

3. Intense emotion

4. Cold exertion

 Risk factors—smoking, HTN, diabetes, hypercholesterolemia

 Basically there are two things to be considered—

1. The requirement that is the O₂ demand of the heart.

2. The O₂ supply via the coronary blood flow.

Obviously fall of O₂ supply or rise of O₂ demand or combination of both can precipitate an anginal attack.

 Preload—venous return to the heart.

Afterload—arterial side of the heart (the aorta and the branches, blood pumped out)

*** the TPR determines the afterload

 Factors determining cardiac output—

1. HR

2. Force of contraction

3. Preload (increases in fluid overload)

4. Afterload (increases in valvular disease and increased PR)

*** if the angina persists for more than 30 min with other sign symptoms such as sweating, palpitation, then it is MI.

*** diabetic patients are sometimes not aware of cardiac pain

 Unstable angina—when anginal pain is felt even at rest without any provocation then it is called unstable angina.

 Basic steps of treatment—

1. To give symptomatic treatment

2. To cure the underlying cause

3. Remove the risk factors

 Pharmacotherapy of atherosclerotic angina / anti-anginal drugs—

These are divided into 3 groups (all drugs basically reduces the O₂ demand of the heart)—

a. Nitrates

b. Calcium channel blockers

c.  β-blockers

Nitrates—reduce the O₂ demand by venodilatation, thus reducing the preload of the heart. They also dilate epicardial arteries and to some extent reduce the after load.

Calcium channel blockers—cause systemic arteriolar dilatation resulting in ↓ PR. So there is fall of BP and after load decreases. They also dilate the epicardial arteries.

 β-blockers—works by reducing the tachycardia and/or contractility—thus work done by the heart is reduced.

 *** epicardial arterial dilatation is well marked with calcium channel blockers, so they are popularly used in prinz metals angina where there is spasm of the epicardial arteries.

 NITRATES (Nitro-vasodilators)—

Theses are simple nitrous or nitric acid esters of poly alcohol. The prototype is nitroglycerine/GTN

 Nitro-vasodilators can be,

 Nitrates and nitrites with their route of administration—

 *** in emergency nitrate spray can be given.

*** we usually do not give nitrate orally as there is extensive first pass metabolism→ ↓ bioavailability→↓ efficacy.

 Nitrates can be used as anti-anginal drug for the following purpose—

1. To abort an attack (when pain already started), for this purpose short acting nitrate given sublingually is very effective.

2. Just before an anticipated but unavoidable stress which is likely to precipitate angina. Ex—physical exertion, heated argument.

3. Long term prophylaxis, drug is routinely given.

 Short acting nitrates—

     i.   GTN

   ii.   Iso-sorbide di-nitrate when given sublingually

iii.   Erithrityl tetra-nitrate when given sublingually

 Long acting—

     i.   Iso-sorbide di-nitrate when given orally

   ii.   Iso-sorbide mono-nitrate when given orally

iii.   Nitroglycerine ointment

 Mechanism of Action of nitrates (gross organ level)—

Nitrates cause relaxation of the vascular smooth muscles particularly venodilatation, thus reduces the pre-load (venous return to the heart). So there is reduction in the ventricular cavity diameter and reduction in the ventricular wall stretching. As a result there is fall of O₂ demand.

Fall of BP due to arteriolar relaxation caused by small or lower dose of nitrates are compensated via sino-aortic reflex which causes tachycardia and vasospasm, thus correcting the BP.

At higher doses the compensatory mechanism cannot prevent fall of BP. So there is fall of afterload.

Nitrates can also dilate epicardial arteries.

 Mechanism of Action of nitrates (at molecular level)—

The di-nitrates taken are converted into mono-nitrates in the body (liver). Mono-nitrates within the vascular wall are converted first into nitrous oxide then into nitric oxide which is a potent vasodilator.

{From the vascular smooth muscle the nitric oxide is released and activates the Guanylil cyclase present in the endothelium. Active G cyclase converts GTP into GMP which is a 2^nd messenger. GMP causes dephosphorilation of the myosin light chain kinase (MLCK) which causes vasodilatation}

Conversion of nitrous oxide into nitric oxide requires the presence of sulph-hydril (SH) group of glutathione. So if nitrites are used for prolong period the SH group will be used up. So further conversion of nitrous oxide to nitric oxide will not be possible and tolerance will develop.

 Because of vasodilatation some adverse effects can be seen—

1. Headache (due to meningeal vasodilatation)

2. Throbbing sensation within the head (intracranial vasodilatation)

3. Flushing of the face

4. Palpitation (due to reflex tachycardia)

5. Orthostatic hypotension (due to peripheral pulling of blood)

 Clinical uses of nitrates—

1. angina pectoris

2. heart failure

3. acute hypertension (IV nitroglycerin)

4. acute myocardial infarction (in this case the drug is used cautiously and by specialist)

5. cardiac arrhythmia

6. migraine

7. hyperthyroidism (T₃ and T₄ increases the number of β₁ receptors in the heart)

 Nitrate tolerance—it is a condition associated with the use of long acting nitrates (mono and di) in which there may be sustained elevation in the blood concentration of the nitrates. If we give drugs at 6-8 hours interval (drug free period) then we can avoid this phenomena. It is mainly associated with the reduction of vascular smooth muscle SH (sulph-hydril) group.

 Individual drugs—

 GTN—

1. Available as tablets (sublingual) 300-600μgm and used as the drug of choice in angina pectoris.

2. Oral (buccal/swallow) formulation of 1-5mg. these are sustained release preparations.

3. Metered oral spray in acute condition (given under the tongue and then mouth is closed).

4. Formulation applied via skin available in patches or ointment, used for prophylaxis.

 Iso-sorbide di-nitrate—

1. Oral formulation (½ life is 20min).

2. Used as prophylaxis for angina.

3. Have extreme first pass metabolism and less systemic availability than mono-nitrates.

(Breaks down into mono-nitrates in the body).

 Iso-sorbide mono-nitrate—

1. Oral formulation (½ life is 4hrs).

2. Has less extensive first pass metabolism but more systemic availability.

3. Used in prophylaxis of angina.

 note:-

Afterload reducers—relaxation of the arterial vascular smooth muscle.

Ex—Hydralazine, Diazoxide, Minoxidin, Ca⁺⁺ channel blockers.

 Preload and afterload reducers—relaxes the vascular smooth muscle of both arteries and veins.

Ex—ACE inhibitors, Nitroprusside, Nitrates (mainly relaxation of the veins)

 Ca⁺⁺-channel blocker—

They are used in—angina, hypertension, supra-ventricular tachycardia.

 Classification—

According to the chemical structure—

1.      Phenyl alk-amines—Verapamil.

2.      Di-hydro pyridines—Nifedipine, Amlodipine, Nicardipine, Felodipine, Nimodipine.

3.      Benzodiazepine—Diltiazem.

 According to the generation—

1.      First generation (older)—Verapamil, Nifedipine, Diltiazem.

2.      Second generation (newer)—

   Amlodipine (ultra long acting, half life is 36 hrs)

 Felodipine and Isradipine (intermediate acting, half life is 8 hrs)

   Nicardipine (short acting, half life is 4 hrs)

 *** they differ in pharmacokinetics—they are absorbed well but suffers hepatic first pass metabolism, thus bioavailability is not good. Bioavailability can increase in two conditions—

i.        hepatic damage

ii.     when used in high doses because degrading enzymes are saturated

usually 2^nd generation drugs have longer plasma half life.

 Pharmacodynamics—

Mechanism of Action—

1.      At gross level calcium channel blockers cause relaxation of the vascular smooth muscle. It may decrease the myocardial contractility. Influences the development of pace making by SA node and AV node.

2.      At molecular level they act on tissue where the development of action potential is largely dependent on entry of calcium from ECF to ICF.

  There are 2 such tissues—vascular smooth muscle and myocardial cells. (in skeletal muscle Na⁺ causes contraction)

 Hence calcium channel blockers will act on the vascular smooth muscles as well as myocardial cells but have no effect on skeletal muscle.

           In the vascular smooth muscle, the calcium ion enters from the ECF via the calcium channel and forms a complex with a protein called calmodulin within the cytosol. This calmodulin-calcium complex now stimulates the enzyme called myosin light chain kinase (MLKC). MLKC causes phosphorylation of myosin light chain. So that myosin-ATP complex is formed, resulting in contraction of the muscle.

            Ca⁺⁺ channel blockers primarily cause dilatation of the arterioles but not the veins, so they are afterload reducers. Because arterioles dilate, there is ↓ in the PR and ↓ in BP. So heart will act against less resistance, workload of the heart will be reduced and O₂ demand will also be reduced. This less O₂ demand will thus relief the ischaemia and angina.

            Ca⁺⁺ channel blockers also relaxation of the epicardial arteries. So they are very effective in vaso-spastic or prinz metal angina. In myocardial cells the events are as follows—calcium enters the myocardial cells through the channels and activates the sarcoplasmic reticulum, causing release of Ca⁺⁺ from the sarcoplasmic reticulum then calcium ion concentration in the cytosol rises causing contraction of the myocardial cells.

            Ca⁺⁺ channel blockers can also cause GIT relaxation producing constipation side effects. Relaxation of the bronchus and the uterus can occur to some extent.

In low therapeutic doses Ca⁺⁺ channel blockers can affect the vascular smooth muscle only, but not the myocardial cells. Therefore at low doses Ca⁺⁺ channel blockers can cause vasodilatation but little or no effect on the heart.

 Note:-Verapamil and diltiazem can reduce myocardial contractility and HR whereas nifedipine produces tachycardia.

 Individual drugs—

 Verapamil—it has effects on heart and arterial tree.

            On heart—

a. Myocardial contractility

b. Produces bradycardia by acting on the SA node and AV node. So verapamine is also used in supra-ventricular tachycardia.

 *** it cause constipation and ankle oedema.

 It is contra-indicated in—

a.   Sick-sinus syndrome

b.   Conduction defect of AV node (heart block)

c.    Myocardial failure

d.  Cannot be used with β-blockers

 Nifedipine—more powerful arteriolar dilator than Verapamil, it also dilates the coronary epicardial arterioles better. It has very little negative ionotropic effect on the heart. It can produce reflex tachycardia due to ↓ BP.

It is very popular in prinz-metal angina, it can be used along with β-blockers (nifedipine ↑ HR and β-blockers ↓ HR)

 Mechanism of reflex tachycardia—

Nifedipine→ arteriolar dilatation→ ↓ PR→ ↓ BP→ sensed by the sino-aortic receptor (baroreceptor) in the arch of the aorta→ send signal to the vasomotor center (VMS) in the medulla→ VMC increases sympathetic outflow→ secretion of adrenalin and nor-adrenalin→ act on the β1 receptor of the heart→ ↑ HR.

 Therapeutic use of Ca⁺⁺ channel blockers—

1.                      Hypertension

2.                      Angina

3.                      Some of them are used in supra-ventricular tachycardia.

4.                      They may be used in Raynaud’s phenomenon

5.                      Cardiac myopathy

6.                      Prevention of the pre-term labour

 As anti-anginal agent they have several advantages—

1.                      They are largely a safe drug

2.                      Drug of choice in prinz metal angina

3.                      Nifedipine can be used along with β-blockers but Verapamil and Diltiazem cannot be used.

4.                      They can be used in diabetes whereas β-blockers are not used.

5.                      They have no bad effects on lipid profile but β-blockers have.

6.                      They do not develop tolerance but nitrates do.

 Side effects—

a. Excessive vasodilatation (nifedipine) can lead to headache, dizziness, flushing of the face, syncopal attack.

b. In some persons anginal attack can be aggravated due to reflex tachycardia (nifedipine) and coronary steal.

 β-blockers—

The objective to use β blockers in angina is to reduce the myocardial O₂ demand by reducing the heart rate, blood pressure and myocardial contractility.

The different β blockers differ in their pharmacokinetic properties. Propranolol (lipid soluble) is the prototype.

2^nd generation drug is Metoprolol.

Very short acting drug is Esmolol and very long acting is Nadelol.

 Classification—

 According to the receptor selectivity—non selective (β₁+β₂) and selective β₁

*** in liver disease water soluble drug is given and in renal disease lipid soluble drug of correct dose is used.

 Mechanism of Action—β-blockers block the β receptor mediated effects of sympathomimetics on the heart. Normally sympathomimetics stimulate the β receptors and increase the cardiac cyclic-AMP. The C-AMP then produces the sympathomimetic effects on the heart. When β blockers are given they block β receptors and decreases the heart rate, cardiac contraction thereby decreasing the myocardial O₂ demand.

 Mode of action—

1. Reduces the O₂ demand of the heart by reducing the sympathetic activity on the heart.

2. Particularly reduces the exercise induced tachycardia, so that chances of angina during exercise reduce.

3. Reduces Renin-Angiotensin axis activity, so Angiotensin-II activity is reduced and ↓ BP.(reducing renin secretion by blocking the β₁ receptors of the myoepithelial cells of the juxtra-glomerular apparatus)

4. β-blockers are anti-hypertensive which results in reduction of afterload causing reduction of myocardial O₂ demands.

 Renin angiotensinogen mechanism—

                                                   Renin ↓                                          ↓ ACE (lung)  

Angiotensinogen (liver)                               Angiotensin I                                          Angiotensin II

 Now angiotensin II increases BP by three mechanisms—

1.     ↑ aldosterone → ↑ Na-retention→ ↑ plasma volume→ ↑ CO→ ↑ BP

2.     direct vasoconstriction→ ↑ BP

3.     sympathetic activity→ ↑ BP

 Indication of β blockers—

Angina

Hypertension

Arrhythmia

Hyperthyroidism

Migraine

 Contraindication—

Bronchospasm (asthma)

Heart failure

A-V block

 Adverse effects—

Bronchospasm

Nightmares

Insomnia

Hypotension

Delayed recovery from hypoglycemia

 Advantages over nitrates—

1. No headache, flushing or syncopal attack. (in contrast to nifedipine and nitrates)

2. Less chance of developing tolerance thaitrates, rather with chronic use dose might have to be reduced.

3. (Ca⁺⁺ channel blockers never develop tolerance)

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 glyceryl trinitrate, is a chemical compound. It is a heavy, colorless, oily, explosive liquid obtained by nitrating glycerol. It is used in the manufacture of explosives, specifically dynamite, and as such is employed in the construction and demolition industries, and as a plasticizer in some solid propellants. It is also used medically as a vasodilator to treat heart conditions.Nitroglycerin was discovered by chemist Ascanio Sobrero 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., nitrocellulose gel, blasting gelatine).

Nitroglycerin in medicine, where it is generally called glyceryl trinitrate, 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 iitroglycerin 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.

Isosorbite mononitrate

Mechanism of Action

The isosorbide mononitrate extended release tablets product is an oral extended-release formulation of isosorbide mononitrate, the major active metabolite of isosorbide dinitrate; most of the clinical activity of the dinitrate is attributable to the mononitrate. The principal pharmacological action of isosorbide mononitrate and all organic nitrates in general is relaxation of vascular smooth 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 pulmonary capillary 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.

Isosorbide mononitrate is the major active metabolite of isosorbide dinitrate, 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 isosorbide mononitrate has not been completely defined. In the only regimen of twice-daily isosorbide mononitrate that has been shown to avoid development of tolerance, the two doses of isosorbide mononitrate 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 isosorbide mononitrate this result is consistent with those obtained for other organic nitrates.

The same twice-daily regimen of isosorbide mononitrate 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 isosorbide mononitrate 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, isosorbide mononitrate is not subject to first pass metabolism in the liver. The absolute bioavailability of isosorbide mononitrate from isosorbide mononitrate tablets is nearly 100%. Maximum serum concentrations of isosorbide mononitrate are achieved 30 to 60 minutes after ingestion of isosorbide mononitrate.

The volume of distribution of isosorbide mononitrate 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 mononitrate glucuronide; and denitration/hydration to sorbitol. None of these metabolites is vasoactive. Less than 1% of administered isosorbide mononitrate is eliminated in the urine.

The overall elimination half-life of isosorbide mononitrate is about 5 hours; the rate of clearance is the same in healthy young adults, in patients with various degrees of renal, hepatic, or cardiac dysfunction, and in the elderly. In a single-dose study, the pharmacokinetics of isosorbide mononitrate were 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 isosorbide dinitrate (and conventional preparations of isosorbide mononitrate) 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 dihydropyridine nifedipine is devoid of a cardiodepressant effect, but may give rise to reflex tachycardia and an associated increase in O2 demand. The catamphiphilic drugs verapamil and diltiazem are 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 muscle 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, potassium epinephrine, 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 (C) 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 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.

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). Isosorbide dinitrate (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 isosorbide mononitrate, 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 result 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. ECG 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 lifethreatening 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).

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Antiarrhythmic agents

The past two decades have witnessed a rapid growth in understanding of the cellular and molecular basis of both normal and pathological electrophysiology. Elucidation of cardiac ion channel structure and function has contributed to many of these advances. As a result, we may be on the verge of an era where arrhythmia management will no longer be dominated by trial and error based observational treatment. Our aim in this article is to provide an overview of antiarrhythmic drug action, linking known actions at the level of cellular electrophysiology to clinical use. Taking particular examples, we shall also illustrate how molecular genetic advances have shown that some rhythm disturbances can result from specific defects in genes encoding cardiac ion channels. Making reference to investigational drugs under study, we will also consider the issue of whether advances in the understanding of cardiac cellular electrophysiology may improve rational approaches to antiarrhythmic drug design and treatment.

The mechanism of drug action is central to the process of choosing a drug to treat any particular arrhythmia. Thus it is useful to consider first impulse generation at the cellular level. This in turn demands consideration of the ion channels underpinning impulse generation in different cardiac muscle cell types. It is the opening and closing of a range of different ion channels that leads to the distinct profiles of membrane potential which comprise cardiac action potentials. Therefore, we shall initially consider the electrophysiological characteristics of cardiac action potentials, aspects of ion channel function, and ion channels as sites of antiarrhythmic drug action.

         Membrane and action potentials: conventions shows schematic representations of action potentials from pacemaker, ventricular, and atrial tissues. Whereas the membrane potential in pacemaker cells (typically from the sinus node, as this is usually the dominant pacemaker) constantly cycles , cells (myocytes) from ventricular  and atrial tissue ( possess true resting potentials, which usually lie between 70 and 80 mV. The negative value of the resting potential reflects the dominant effect of a steady net efflux of positively charged K⁺ ions in these cell types by way of an ionic current (I_K1), through a channel type called the inward rectifier.¹ Pacemaker cells from sinoatrial² and atrioventricular nodes³ appear to lack a significant I_K1, and as a resultalong with other ionic currentsthey do not show a true resting membrane potential; rather, a pacemaker potential precedes each action potential. Action potentials in all cell types result from positive shifts in membrane potential (depolarisation), caused by opening of ion channels, allowing positively charged sodium and calcium ions to enter the cell through channels selective for each ionic type. The rate of depolarisation during the action potential upstroke in atrial and ventricular cells is faster than in pacemaker cells, owing to the fact that a large and fast sodium current underlies the upstroke in these cell types, while the upstroke in pacemaker cells is predominantly carried by a calcium current. After the peak of the action potential, the membrane potential is restored to its original value during the repolarisation phase, as channels passing depolarising current close and repolarising channels (largely a range of potassium channels) open.

Ventricular cells in particular also possess a distinct plateau phase, and the relatively long duration of the ventricular action potential helps make the ventricular tissue refractory to overexcitation which might otherwise tetanise the ventricular myocardium. The distinct action potential phases discussed above are sometimes referred to as phases 0 to 4: phase 0 is the action potential upstroke, phase 1 is the early repolarisation “notch” (evident immediately after the ventricular action potential peak , phases 2 and 3 describe plateau and late repolarisation (pacemaker cell action potentials without a distinct notch or plateau may lack distinct phases 1 and 2), while phase 4 is the period after repolarisation is complete (the resting level in non-pacemaker cells, and the pacemaker depolarisation in pacemaker cells).

Ion channels: the basics Critical to action potential generation is the combined function of different membrane bound ion channels, together with ion exchange proteins and ATP driven pumps. ATPases for Na/K⁴ and Ca⁵ help sustain the normal transmembrane gradients for these ions, and a sodium-calcium exchange protein contributes to calcium and sodium homeostasis and membrane potential generation (for example, Allen and colleagues,⁶ Janvier and Boyett⁷). To understand modifications of ionic currents by antiarrhythmic drugs, some basic properties of ion channel functioeed to be examined. In simple terms, transmembrane ion channels activated by membrane potential changes can be viewed as proteins comprising a voltage sensor coupled to a pore through which ions flow; the pore incorporates a “selectivity filter” which determines which types of ions will pass through the open pore.

Normal QRS complex.

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 concentration gradient established by the concentrations C_o outside and C_i inside the cell of the permeant ion, together with the electrical gradient resulting from the membrane potential.

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

One further aspect of ion channel function should be covered before considering the roles played by individual ion channel typeschannel gating. Voltage operated channels are usually referred to as voltage gated, as biophysical measurements indicate that specific membrane potential regulated processes determine the magnitude and time course of ionic current flow across the range of ion channel types. This can be explained by considering an ion channel that does not pass current until a depolarising stimulus is applied. At rest, the channel is therefore considered to be closed . When a depolarising stimulus is applied, the membrane potential change is detected by the voltage sensorthe channel undergoes a conformational change and opens in order to allow ionic current to flow. The process describing the transition from the closed to open state is termed activation. The probability of channels moving to the open state usually depends on the magnitude of the voltage change (activation is therefore “voltage dependent”), and the speed with which channels move from the 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 influences ionic current flow. If the depolarising stimulus is maintained, a second conformational change occurs in the ion channel. Part of the ion channel protein moves to occlude the channel pore such that, while the channel may be fully activated, it becomes poorly conducting

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

• Distinct ion channel types generate depolarising and repolarising currents during the action potential.
• From the existence of distinct ion channels with distinct roles arises the potential for drug classification and design.
• The fact that ion channels undergo voltage dependent state transitions  means that, theoretically, drugs could bind to resting/closed (C), activated/open (O) or inactivated (I) states.⁸

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 would have positive use dependenceshowing a greater inhibitory action at faster heart rates. Drugs binding preferentially to closed channels may either exert use independent actions or show “reverse use dependence,” in which the drug dissociates from its binding site during channel activation. With reverse use dependent blockade, faster rates of channel stimulation (or indeed heart rate) encourage greater dissociation than slower ates, resulting in comparatively less channel inhibition at faster than at slower rates.ANARHYTHMIC 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 depolarisation² that precedes each action potential upstroke. Agents that reduce these currents should therefore slow the rate of the pacemaker depolarisation and thereby have a negative chronotropic effect. Specific inhibitors of I_f produce rate reduction. Mibefradil is a blocker of I_Ca,T which preferentially relaxes coronary vasculature and slows heart rate without reducing contractility, making it a potential bradycardic agent. This particular compound was voluntarily withdrawn because it was involved in several clinically relevant drug interactions. In general, the use of selective bradycardic agents is likely to be of limited value except in inappropriate sinus tachycardia.

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 depolarising current during action potentials from the sinoatrial² and atrioventricular (AV) nodes. The dependence of AV nodal conduction on I_Ca,L makes L type channel blockers such as verapamil and diltiazem important in the management of supraventricular tachycardias. In paroxysmal atrioventricular tachycardias, either anterograde or retrograde conduction through the AV node forms part of the circuit maintaining the arrhythmia; thus blockade of I_Ca,L can be effective in preventing recurrence ofthe arrhythmia. L type channel blockers can also be effective against AV nodal reentrant tachycardias and atrial fibrillation.

The importance of I_Na in generating the fast upstroke phase of both atrial and ventricular action potentials makes I_Na blockers potentially effective against both supraventricular and ventricular arrhythmias. Sodium channel-drug interactions are usefully considered within the “modulated receptor” model, which takes into consideration the channel state to which a drug preferentially binds. The action potential upstroke rate can become slowed when I_Na is reduced and as a result I_Na blockers can decrease impulse conduction velocity. In addition, agents that delay the recovery of I_Na from channel inactivation have the effect of prolonging tissue refractoriness.

Agents such as quinidine, propafenone,² and disopyramide preferentially bind to the open (activated) state of the sodium channel, while others including lignocaine (lidocaine) and mexiletine show a preference for the inactivated channel. Open channel blockers are effective in generally reducing electrical excitability and impulse conduction, while inactivated channel blockers may show a blocking effect influenced by differences in atrial and ventricular action potential profile (fig 1). The comparatively longer and more depolarised ventricular action potential plateau results in a more prolonged inactivation of I_Na, with an increased level of block. This property may contribute to the selectivity of drugs such as mexiletine against ventricular arrhythmias; it might also be used in combination treatment by combining an inactivated state sodium channel blocker with a drug that delays repolarisation,resulting in enhanced sodium channel inhibition and thereby prolonged refractoriness.

The kinetics of recovery from block are also critically important in determining the effects of sodium channel blockers. Agents associated with slow recovery from block (for example, flecainide²⁵) cause a block that accumulates rapidly on repetitive stimulation, and a stable steady state level of block is attained over a wide range of heart rates.²⁶ Agents with relatively fast recovery from block (for example, mexiletine) may show little cumulative block at slow heart rates, as block is relieved between action potentials. At faster rates (tachycardias), block accumulates because there is too little time for unbinding to occur between action potentials. This produces the effect of “positive use dependence,” which is beneficial in that little ECG alteration may be experienced at normal rates, whereas drug effects become important during tachyarrhythmias.

It is important to realise, however, that blocking efficiency and recovery can be affected by various factors. Open channel blockers may be less effective in damaged or ischaemic tissue; this is often depolarised, resulting in the inactivation of a proportion of channels, thereby rendering these unavailable for block. In contrast, inactivated state blockers may be more effective in conditions where tissue becomes depolarisedexperimental evidence suggests that the efficacy of lignocaine and the risk of proarrhythmia are both enhanced in acutely ischaemic myocardium.²⁷ In addition to the effects of membrane potential depolarisation on block, the low pH associated with ischaemia can also slow the time constant of drug dissociation, enhancing the cumulative level of channel block.²⁶

POTASSIUM CHANNELS Some sodium channel blocking agents, for example disopyramide²⁸ and in particular quinidine,²⁹ are also associated with delayed repolarisation and QT prolongation on the ECG. For both disopyramide³⁰ and quinidine,^31 32 this effect results from potassium channel blocking actions of the drug. Excessive action potential and QT prolongation (when the corrected QT interval (QT_c) exceeds ~440²⁹ to 460³³ ms), carries a risk of proarrhythmia. However, potassium channel blockade can also be antiarrhythmic, because moderately delayed action potential repolarisation can enhance 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 reentrant mechanisms. Different potassium channel types, therefore, offer potential antiarrhythmic drug targets. Major potassium ion channel types involved in action potential repolarisation include the transient outward current, I_TO, responsible for the action potential notch in ventricular cells and prominent during atrial repolarisation.^1 34 The rapid and slow components of delayed rectifier current (I_Kr and I_Ks, respectively³⁵) are important in plateau repolarisation. The inward rectifier potassium current is important for the final stage of repolarisation^37 38 and for maintaining the cell resting potential. Owing to their roles in plateau repolarisation, I_Kr and I_Ks are of particular interest as antiarrhythmic targets.

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 potential rates). Unfortunately, many potassium channel blocking drugs appear to be associated with a reverse use dependent effect: action potential prolongation is greater at slower rather than at faster rates.³⁹ The problem with this is that action potential prolongation at slow rates can be proarrhythmic through the cellular mechanism of early afterdepolarisations. By a mechanism originally investigated by January and Riddle⁴⁰ and recently reviewed by Makielski and January,⁴¹ sufficiently slowed membrane repolarisation during the action potential facilitates calcium entry through L type calcium channels, which can result in early afterdepolarisations. These in turn could give rise to triggered activity and lead to torsade de pointes. Selective block of I_Kr (for example, by the drug E-4031) can be sufficient to induce early afterdepolarisations.⁴² Early afterdepolarisations are relieved at faster rates; therefore I_Kr block is most likely to be proarrhythmic at slow rates. The clinical implications of reverse use dependence and specific I_Kr block are exemplified by sotalol which, as the racemic D-L mix, possesses  blocking and I_K blocking actions and is indicated for the treatment of life threatening ventricular tachycardia. Racemic sotalol produces some QT prolongation and is bradycardic.⁴³ D-sotalol lacks the  blocking activity of the racemic mix, but is an I_Kr blocker³⁵ and shows reverse use dependent effects on the action potential.⁴⁴ Significantly, D-sotalol is associated with an increased risk of death from presumed arrhythmias.⁴⁵

A simple explanation for reverse use dependent drug effects on action potential prolongation involves drug binding to the resting channel (in the interval between action potentials) and dissociating during membrane depolarisation.⁴⁶ This would produce a greater relief of block at faster rates (at which there would be shorter intervals between action potentials for drug binding to occur). However, subsequent experiments on cloned channels are not consistent with this explanation (for example, Synders and colleagues⁴⁷). Moreover, agents such as almokalant block I_Kr in a use dependent fashion,⁴⁸ while producing reverse use dependent action potential prolongation.²⁴ In addition, dofetilide has been reported to produce rate independent effects on I_Kr, but reverse rate dependent effects on the action potential.⁴⁹ In the same study,⁴⁹ repetitive stimulation was observed to increase the magnitude of I_Ks but not of I_Kr. It has been proposed, therefore, that reverse use dependence may result from the interaction between I_Kr and I_Ks during repolarisation at different heart rates.⁴⁹ At slower rates I_Kr may be dominant; at faster heart rates the role of I_Ks increases owing to incomplete deactivation (the transition of channels from OC, fig 3A) of the current between action potentials. Thus specific I_Kr inhibition would have a greater effect on repolarisation at slower than at faster rates.

If this mechanism holds, then an agent which blocks I_Ks specifically might be better for treating tachycardias than an I_Kr blocker; moreover, an agent that blocks both components of I_K might have an improved safety profile over a specific I_Kr blocker. There are few experimental data yet available to support the first of these possibilities (selective I_Ks blockers are only beginning to appear); the second, however, does seem to hold true. Quinidine and sotalol do not appear to block I_Ks.⁵⁰ By contrast amiodarone, which has a much better cardiac safety profile, blocks both I_Kr and I_Ks,^50 51 while also showing a more consistent effect on action potentials at different rates.⁵²

A further potassium channel should be mentioned, as it is likely to mediate the antiarrhythmic actions of adenosine. The extremely short half life of adenosine makes intravenous administration valuable in terminating tachycardias involving the AV node (either AV nodal re-entry or AV re-entry). In bolus form, adenosine has been shown to be highly effective against paroxysmal supraventricular tachycardias that require AV nodal conduction for their maintenance.^53 54 The cellular basis for the effect of adenosine appears to resemble that for acetylcholine. Acetylcholine activates a potassium current (I_KACh), which is important in mediating parasympathetic effects on the sinoatrial² and AV nodes.⁵⁵ When activated, I_KACh produces membrane potential hyperpolarisation; it thereby decreases automaticity and excitability. At the cellular level, adenosine activates a current (I_KAdo) with properties identical to those of I_KACh (for example, Belardinelli and colleagues⁵⁶). Cellular studies on rabbit AV node suggest that activation of I_KAdo is likely to be predominantly responsible for the action of adenosine, with possible supplementary effects on L type calcium channels.^57 58

Congenital long QT syndrome has been found to arise from a range of different genetic abnormalities. The two main forms are the autosomal dominant Romano-Ward syndrome (pure cardiac phenotype) and the autosomal recessive Jervell-Lange-Nielsen syndrome (in which cardiac abnormalities coexist with congenital deafness). Of the genetic abnormalities identified in the Romano-Ward syndrome, four are associated with identified ion channels. Most of the mutations causing congenital long QT (LQT) syndrome are missense mutations. However, substantial phenotypic 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 discussed earlier, it is the risk of afterdepolarisations associated with QT interval prolongationrather than slowing of action potential repolarisation on its ownthat is arrhythmogenic. The involvement of L type I_Ca in the production of early afterdepolarisations and the widely known enhancement of I_Ca by  adrenergic stimulation may, at least in part, explain the clinical effectiveness of  blockers in reducing the incidence of syncopal episodes and arrhythmias in the long QT syndrome.

As shown in table 1, alterations in the genes underlying I_Kr and I_Ks are associated with LQT-2 and LQT-1. The channels for both I_Kr and I_Ks are multimeric, and alleles from both parents contribute to the channel complexes. Mutant channels expressed in oocytes or cell lines show loss of function. Channel kinetics, as well as reduced overall current, contribute to the loss of function (that is, a reduction in repolarising outward current). In contrast, mutations of sodium (SCN5A) channels cause a gain of function,^71 72 in which a late persistent (depolarising) sodium current is produced because of defective inactivation of I_Na. Owing to the heterogeneous basis for congenital long QT syndrome, identification of the underlying cause is pivotal in deciding upon appropriate treatment. Provocation may distinguish between the different congenital LQT syndromes. While the QT interval shortens only minimally with exercise in LQT1 and LQT2, in patients with LQT3 it shortens significantly.^70 73 Furthermore, torsade de pointes is precipitated by adrenergic stimulation (for example, during exercise) in LQT1, possibly because I_Ks normally predominates at high rates, and therefore reduced I_Ks would lead to inadequate shortening of the action potential.⁷⁰ In contrast, most patients with LQT 3 experience more events at rest than on exertion.^70 73

Another interesting group of patients providing a clear link between cellular abnormalities and clinical treatment are those with the Brugada syndrome.^74 75 These patients have structurally normal hearts and right precordial ST segment elevation or right bundle branch block.⁷⁶ The ECG abnormalities probably reflect exaggerated transmural differences in action potential configuration, especially within the right ventricular outflow tract. The end result is an increased risk of ventricular fibrillation within these families. One variant of the Brugada syndrome arises from a mutation of the SCN5A gene (the same gene that is implicated in LQT3),⁷⁷ leading to a gain of function; hence drugs targeting the sodium channel may be clinically effective.

IMPLICATIONS OF GENETIC INSIGHTS In addition to the syndromes described above, our understanding of the role of genes in other conditions has also increased. The reader is referred to a recent and comprehensive review by Priori and colleagues. A clear result of the arrival of molecular biology in the clinical arena is that genetic testing may be available not only for diagnostic purposes in patients presenting with arrhythmias but also possibly for individuals who could benefit from prophylactic treatment to avoid sudden death. Increased genetic knowledge may also influence treatment strategy. For example, sodium channel blockers such as lignocaine and mexiletine may be effective in LQT-3, while LQT-2 would be expected to be respond to a different approach. Cloned channels encoded by HERG (the gene underlying channels for I_Kr) show currents that increase in size as external potassium concentration ([K]_e) is raised and decrease as [K]_e is lowered.⁶⁰ Consistent with this experimental observation, Compton and colleagues have shown that abnormal repolarisation in patients with LQT-2 can be corrected by raising serum potassium.

However, while long QT syndrome and the Brugada syndrome may provide a clear route from cell to clinic, some common arrhythmias are not yet so accommodating. Refractory arrhythmias, for example, may be refractory because of the complex processes involved in their pathogenesis. These may include both electrical and structural remodelling. Electrical remodelling may be physiological and unrelated to cardiac disease (for example, atrial fibrillation may become self sustaining), or pathological in origin (alteration in the 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) or pathological (cell hypertrophy in peri-infarct zones and cell loss with replacement fibrosis within infarcted regions). Therefore complex arrhythmias with a multifactorial aetiology may benefit from primary prevention targeted towards alleviation of diseases such as coronary occlusion or ventricular hypertrophy. A second line of attack may then be directed towards the electrophysiological sequelae of upstream events. Treatment must be tailored towards the aetiology of the arrhythmia, as drug treatment for ventricular tachycardia in one patient may be detrimental in another. Indeed, in the structurally abnormal heartfor example, after myocardial infarction or during congestive cardiac failuredrug efficacy has been limited and in these conditions antiarrhythmic drugs can have a significant proarrhythmic potential.

Re-evaluation of antiarrhythmic drug classification Another area that has experienced change owing to the increased information available from cellular cardiology is that of drug classification. Early approaches to antiarrhythmic drug development involved the identification of natural compounds with antiarrhythmic activity such as cinchona,⁸⁵ or identification of antiarrhythmic effects of drugs licensed for other uses, primarily local anaesthetics, including lignocaine and its derivatives. Clinical studies verified the acceptability as antiarrhythmic agents of synthetic molecules such as procainamide. Further attempts were than made to produce related compounds with increased potency and reduced toxicity (for example, flecainide, lorcainide, and encainide). While this approach has provided many useful drugs for therapeutic use, the derived compounds have to varying degrees retained the adverse effect profiles of parent drugs. Progress in the development of newer antiarrhythmic drugs has not been as great as once anticipated, and the chance discovery of antiarrhythmic properties of drugs developed for other conditionsfor example, amiodarone (initially developed as an antianginal drug)has contributed significantly to the armoury available to the clinician.

In 1970, Vaughan Williams proposed a classification based on possible ways in which abnormal cardiac rhythms could be corrected or prevented. In this early classification, class I drugs act by reducing inward sodium current at concentrations not affecting the resting membrane potential. Class II drugs act by blocking sympathetic activity of the heart. Although not thought to affect the action potential of most myocardial cells, these drugs reduce the spontaneous rate of depolarisation of pacemaker cells under adrenergic stimulation and are therefore negatively chronotropic. They are also negatively dromotropic, as the AV node tends to be under greater sympathetic drive than the sinoatrial node for which vagal tone normally predominates. Class III drugs prolong action potential duration. They do not specifically affect any single factor involved in repolarisation (although in reality most class III drugs exert potassium channel blocking actions). They are able to alter the activity of several different ion channel conductances at a cellular level, making their impact upon the action potential quite complex. In general, they prolong action potential duration and hence prolong the length of the refractory period. In a separate class was placed diphenylhydantoin, a centrally acting drug.

In 1974, Singh and Hauswirth modified the classification, with two major changes. First, lignocaine and diphenylhydantoin were placed in a separate class, because at low concentrations and at low external potassium concentrations, they had little effect upon the action potential or cardiac conduction. Secondly, a separate class (now denoted class IV) was introduced to accommodate calcium channel blockers, which (as described earlier) predominantly affect regions in which action potential depolarisation depends on I_Ca,L. In a further development, class I drugs were subclassified by Harrison according to their effect upon action potential upstroke and duration. Additional studies showed that the subclassification separated class I drugs according to the rate of recovery of I_Na channels from blockade. Class 1a drugs were intermediate between class Ib drugs, with fast recovery time constants less than one second, and class Ic drugs, with relatively slower recovery time constants of more than 15 seconds.

The “Singh-Hauswirth-Harrison-Vaughan Williams” (S-H-H-VW) classification is summarised. Many antiarrhythmic drugs have more than one class of action (for example, racemic sotalol has class II and class III activity and amiodarone has class I-IV actions). Moreover, some drugs within a particular class may differ in their clinical effects owing to subtle (but significant) differences in their mechanism of action at the ion channel level. In addition, there are some antiarrhythmic drugs (for example, digoxin and adenosine) 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, arrhythmia mechanism, and therapeutic efficacy gave rise to the “Sicilian Gambit” approach to antiarrhythmic treatment. This approach to arrhythmia management, formulated by the European Society of Cardiology working group,⁹⁴ seeks the critical mechanisms responsible for arrhythmogenesis to identify a “vulnerable parameter” or “Achilles heel” of the arrhythmia concerned. This would enable the clinician to select a drug on the basis of its mechanism of action and not empirically. This approach complements well those recent advances in our understanding of molecular biology (for example, cloning and sequencing of ion channels and receptors) that have raised hopes for a “target oriented” approach to antiarrhythmic treatment. There are, however, two fundamental issues that might hinder this approach to drug selection. First, an Achilles heel is not always (yet) identifiable for many arrhythmias, and in some cases there may be more than one Achilles heel, some of which are not involved in arrhythmogenesis. In addition, there are drugs classified within the S-H-H-VW classification that have multiple electrophysiological targets; this may preclude them from being selective for any one particular Achilles heel. Second, consideration of drug action based on multiple targets (ion channels, receptors, and second messenger systems) and the “spread sheet” approach advanced in the Sicilian Gambit⁹⁴ generates a degree of complexity absent from the S-H-H-VW classification, and which may hinder acceptance of this approach.⁹⁵ Against this, however, a major advantage of the Sicilian Gambit approach is that it provides a framework within which the ever increasing information on arrhythmogensis and drug action can be readily accommodated and considered.(for example, Members of the Sicilian Gambit⁹⁶)

Our increasing knowledge of the basic electrophysiological and genetic characteristics of ion channels, the cellular actions of antiarrhythmic agents, their effects on animal models, and the results of clinical trials should help guide future rational drug development and classification. In a recent article,⁹⁷ Camm and Yap summarise attributes for future antiarrhythmic agents, including: appropriate modification of the arrhythmia substrate, suppression of arrhythmia triggers, efficacy in pathologic tissues and states, positive rate/use dependent effects, similar efficacy in oral and parenteral formulations, similar efficacy in arrhythmias and their surrogates, few side effects, and cardiac selective ion channel blockade.

One of the central issues will be whether approaches which focus on a single ion channel target offer more promise than approaches based on compounds with “polypharmacological” (multiple ion channel) effects. Recently discovered ion channelssuch as the ultrarapid delayed rectifier (I_K,ur) in atrial tissue⁹⁸may offer new, alternative drug targets. Importantly, the reverse use dependence associated with some drugs with class III (predominantly I_Kr) blocking actions might be taken as suggesting that either drugs against alternative targets to I_Kr or drugs with multiple effects may be superior to selective I_Kr blockers alone.

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 therefore unsuitable for use,⁴⁵ the same does not appear to be true for dofetilide. Dofetilide is a potent and selective blocker of I_Kr, which, although associated with reverse use dependent effects on the action potential at the cellular level,⁴⁹ has a profile that is not clearly reverse use dependent in humans (for example, Bashir and colleagues⁹⁹). The drug appears to be reasonably well tolerated and at some concentrations is effective at suppressing ventricular tachycardia.⁹⁹ Moreover, its use does not seem to be associated with significantly increased mortality, and with only a low incidence of torsade de pointes. Quite why dofetilide appears to be safer than d-sotalol is not entirely clear, though there is some experimental evidence that the class III effects of d-sotalol are much more sensitive to extracellular potassium levels than those of dofetilide.⁴⁴ At this stage, it would appear premature to rule out selective I_Kr blockade as a viable antiarrhythmic strategy.

I_Ks blockade may, in principle, offer an attractive alternative or supplementary approach to I_Kr inhibition. Azimilide is a relatively new agent effective at inhibiting both I_Kr and I_Ks.¹⁰¹ Data from experiments in which I_Ks blocking effects of the drug on the action potential have been estimated suggested that the I_Ks block alone was associated with rate independent action potential prolongation.The overall drug effect on the action potential (involving combined I_Kr and I_Ks actions) shows some variations between experimental studies, with reports of either some reverse use dependence or a rate independent action on effective refractory period.¹⁰⁴ Azimilide may be effective against both atrial and ventricular arrhythmias and, while it is too early to comment with certainty on its efficacy and safety in humans, initial signs appear promising.¹⁰¹ Several clinical trials including the ALIVE (azimilide post-infarct survival evaluation) study were ongoing at the time of writing.

Other investigative agents with polypharmacological effects include ibutilide and tedisamil. Ibutilide has an interesting pharmacological profile in that in addition to affecting I_Kr it also appears to induce a sustained sodium current, an effect that would be synergistic in prolonging the action potential.¹⁰⁶ Tedisamil blocks I_Kr and the transient outward potassium current (I_TO).¹⁰⁷ It has been shown to be effective against ventricular fibrillation in a rabbit model¹⁰⁸ and it prolongs the monophasic action potential in humans.¹⁰⁹ Dronedarone, an investigational drug related to amiodarone, may be an agent of particular interest.⁹⁷ Like its parent compound, dronedarone may be expected to exert multiple S-H-H-VW effects and thereby have wide ranging efficacy. The results of trials of this and other agents with polypharmacological effects will be important in the debate about whether the future development of antiarrhythmic agents lies in single or multiple ion channel targets. As the underlying basis for the generation and maintenance of particular arrhythmias becomes increasingly understood, so will our understanding of the nature of any associated Achilles heel or vulnerable parameter. This knowledge, together with ongoing revision of drug classification according to target/action, is likely to refine pharmacotherapeutic approaches to clinical arrhythmia management.

This work was supported by grants from the British Heart Foundation, the United Bristol Healthcare Trust, and the Wellcome Trust. KCRP was supported by a British Heart Foundation clinical training fellowship, and JCH was supported by a Wellcome Trust research fellowship. We thank Kathryn Yuill for providing the ionic current record for figure 3B, and Helen Wallis for comments on the manuscript.

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

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

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

 

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 patientlood Pressure Levels fr Adults

I.     Pharmacology of Oral Antihypertensive Drugs

 Algorithm for the treatment of hypertension.

  Activity of angiotensinogen in relation to increased blood pressure.

 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.  Alfuzosin and 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).   

 

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 vasodilators Hydralazine 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 pressure in the presence of 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 emergencies is 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

2. 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).

2.1. 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 guanylate cyclase. 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

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