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Sotalol

Sotalol

Sotalol is a drug used in individuals with rhythm disturbances (cardiac arrhythmias) of the heart. It falls into the class of beta blockers (and class II antiarrhythmic agents) because of its primary action on the β-adrenergic receptors in the heart. In addition to its actions on the beta receptors in the heart, sotalol inhibits the inward potassium ion channels of the heart. In so doing, sotalol prolongs repolarization, therefore lengthening the QT interval and decreasing automaticity. It also slows atrioventricular (AV) nodal conduction. Because of these actions on the cardiac action potential, it is also considered a class III antiarrhythmic agent. Sotalol is used to treat ventricular tachycardias as well as atrial fibrillation. It may be taken orally, since its bioavailability is almost 100%. Some evidence suggests that sotalol should be avoided in the setting of decreased ejection fraction due to heart attack.¹

References

1. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet. 1996 Jul 6;348(9019):7-12. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8691967 Medline abstract])

Drug

Drug may refer to:
- Medication
- Psychoactive drug
- substances used for recreational drug use
- substances used in drug abuse
- Hard and soft drugs
- A drug or demon in ancient Vedic Hinduism, from the Vedic Sanskrit root druh = "be hostile"
- The Drûg or Drúedain, a race of Men from Middle-earth in the fiction of J. R. R. Tolkien

Heart

The heart (Latin cor) is a hollow, muscular organ that pumps blood through the blood vessels by repeated, rhythmic contractions. The term cardiac means "related to the heart", from the Greek kardia (καρδια) for "heart".

The human heart

Structure

In the human body, the heart is normally situated slightly to the left of the middle of the thorax, underneath the sternum (breastbone). It is enclosed by a sac known as the pericardium and is surrounded by the lungs. In normal adults, it weighs 250-350 g, but extremely diseased hearts can weigh up to 1000 g. It consists of four chambers, the two upper atria (singular: atrium) and the two lower ventricles. A septum divides the right atrium and ventricle from the left atrium and ventricle, preventing blood from passing between them. Valves between the atria and ventricles (atrioventricular valves) maintain coordinated unidirectional flow of blood from the atria to the ventricles. The function of the right side of the heart (see right heart) is to collect deoxygenated blood from the body and pump it into the lungs so that carbon dioxide can be dropped off and oxygen picked up. this happens through a process called diffusion. The left side (see left heart) collects oxygenated blood from the lungs and pumps it out to the body. On both sides, the lower ventricles are thicker than the upper atria. lung Oxygen-depleted or deoxygenated blood from the body enters the right atrium through two great veins, the superior vena cava which drains the upper part of the body and the inferior vena cava that drains the lower part. The blood then passes through the tricuspid valve to the right ventricle. The right ventricle pumps the deoxygenated blood to the lungs, through the pulmonary artery. In the lungs gaseous exchange takes places and the blood releases carbon dioxide into the lung cavity and picks up oxygen. The oxygenated blood then flows through pulmonary veins to the left atrium. From the left atrium this newly oxygenated blood passes through the mitral valve to enter the left ventricle. The left ventricle then pumps the blood through the aorta to the entire body. Even the lungs take some of the blood supply from the aorta via bronchial arteries. The left ventricle is much more muscular (1.3 - 1.5 cm thick) than the right (0.3 - 0.5 cm thick) as it has to pump blood around the entire body, which involves exerting a considerable force to overcome the vascular pressure. As the right ventricle needs to pump blood only to the lungs, it requires less muscle. Even though the ventricles lie below the atria, the two vessels through which the blood exits the heart (the pulmonary artery and the aorta) leave the heart at its top side. The contractile nature of the heart is due to the presence of cardiac muscle in its wall which can work continuously without fatigue. The heart wall is made of three distinct layers. The first is the outer epicardium which is composed of a layer of flattened epithelial cells and connective tissue. Beneath this is a much thicker myocardium made up of cardiac muscle. The endocardium is a further layer of flattened epithelial cells and connective tissue which lines the chambers of the heart. The blood supply to the heart itself is supplied by the left and right coronary arteries, which branch off from the aorta.

The cardiac cycle

See main page cardiac cycle cardiac cycle cardiac cycle The function of the heart is to pump blood around the body. Every single beat of the heart involves a sequence of events known as the cardiac cycle, which consists of three major stages: atrial systole, ventricular systole and complete cardiac diastole. The atrial systole consists of the contraction of the atria and the corresponding influx of blood into the ventricles. Once the blood has fully left the atria, the atrioventricular valves, which are situated between the atria and ventricular chambers, close. This prevents any backflow into the atria. It is the closing of the valves that produces the familiar beating sounds of the heart, commonly referred to as the "lub-dub" sound. The ventricular systole consists of the contraction of the ventricles and flow of blood into the circulatory system. Again, once all the blood empties from the ventricles, the pulmonary and aortic semilunar valves close. Finally complete cardiac diastole involves relaxation of the atria and ventricles in preparation for refilling with circulating blood.

Regulation of the cardiac cycle

Cardiac muscle is myogenic, which means that it is self-exciting. This is in contrast with skeletal muscle, which requires either conscious or reflex nervous stimuli. The heart's rhythmic contractions occur spontaneously, although the frequency or heart rate can be changed by nervous or hormonal influences such as exercise or the perception of danger. The rhythmic sequence of contractions is coordinated by the sinoatrial and atrioventricular nodes. The sinoatrial node, often known as the cardiac pacemaker, is located in the upper wall of the right atrium and is responsible for the wave of electrical stimulation (See action potential) that initiates atria contraction. Once the wave reaches the atrioventricular node, situated in the lower right atrium, it is conducted through the bundles of His and causes contraction of the ventricles. The time taken for the wave to reach this node from the sinoatrial nerve creates a delay between contraction of the two chambers and ensures that each contraction is coordinated simultaneously throughout all of the heart. In the event of severe pathology, the Purkinje fibers can also act as a pacemaker; this is usually not the case because their rate of spontaneous firing is considerably lower than that of the other pacemakers and hence is overridden.

Other physiological functions

The heart also secretes ANF (atrial natriuretic factor), a powerful peptide hormone, that affects the blood vessels, the adrenal glands, the kidneys and the regulatory regions of the brain to regulate blood pressure and volume.

Diseases and treatments

The study of diseases of the heart is known as cardiology. Important diseases of the heart include:
- Coronary heart disease is the lack of oxygen supply to the heart muscle; it can cause severe pain and discomfort known as Angina.
- A heart attack occurs when heart muscle cells die because blood circulation to a part of the heart is interrupted.
- Congestive heart failure is the gradual loss of pumping power of the heart.
- Endocarditis and myocarditis are inflammations of the heart.
- Cardiac arrhythmia is an irregularity in the heartbeat. It is sometimes treated by implanting an artificial pacemaker
- Congenital heart defects. If a coronary artery is blocked or narrowed, the problem spot can be bypassed with coronary artery bypass surgery or it can be widened with angioplasty. Beta blockers are drugs that lower the heart rate and blood pressure and reduce the heart's oxygen requirements. Nitroglycerin and other compounds that give off nitric oxide are used to treat heart disease as they cause the dilation of coronary vessels. At Groote Schuur Hospital in Cape Town, South Africa, 53-year-old Louis Washkansky on December 3, 1967 became the first human to receive a heart transplant (however he died 18 days later from double pneumonia). The transplant team was headed by Christiaan Barnard. See also: Cardiology diagnostic tests and procedures

First aid

See cardiac arrest for emergencies involving the heart If a person is encountered in cardiac arrest (no heartbeat), cardiopulmonary resuscitation (CPR) should be started, and help called. If an automated external defibrillator is available, this device may automatically administer defibrillation if this is indicated.

The hearts of other animals

Heartbeat

Smaller animals have faster heartbeats. This is evident within a species as well, as the young beat their hearts faster than the adults. The Gray Whale's heart beats 9 times per minute, Harbour Seal 10 when diving, 140 when on land, elephant 25, human 70, sparrow 500, shrew 600, and hummingbird 1,200 when hovering. The earthworm has a series of multiple primitive hearts.

Food use

The hearts of cattle, sheep, pigs and certain fowl are consumed as food in many countries. They are counted among offal, but being a muscle, the taste of heart is much more like regular meat than that of other offal. It resembles venison in structure and taste. Different species have different heart chambers. It can vary from one to four chambers (2 atria and 2 ventricle)

As an icon

The heart may also be illustrated as an icon (♥), symbolizing love. See Heart (symbol).

External links

- [http://www.zygote.com/DF/Heart-Anatomy-Pictures.htm Free 3D Heart Images]
- [http://library.thinkquest.org/C003758/home.htm Very Comprehensive Heart Site]
- [http://www.invisionguide.com/heart The InVision Guide to a Healthy Heart] An interactive website Category:Cardiovascular system Category:Thorax ko:심장 ms:Jantung ja:心臓 simple:Heart

Beta blocker

Beta blockers or beta-adrenergic blocking agents are a class of drugs used to treat a variety of cardiovascular conditions and some other diseases. Beta blockers block the action of epinephrine and norepinephrine on the β-adrenergic receptors in the body (primarily in the heart, peripheral blood vessels, bronchi, pancreas, and liver). The hormones and neurotransmitters stimulate the sympathetic nervous system by acting on these receptors. There are three types of beta receptors: β₁-receptors located mainly in the heart, and β₂-receptors located all over the body, but mainly in the lungs, muscles and arterioles. β₃-receptors are less well characterised, but have a role in fat metabolism. Activation of β₁-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Drugs that block β₂ receptors generally have a calming effect and are prescribed for anxiety, migraine, esophageal varices and alcohol withdrawal syndrome, among others. Many beta blockers affect both type 1 and type 2 receptors; these are termed non-selective blockers. Propranolol and nadolol are examples. Selective beta blockers primarily affect β₁-receptors. Non-selective beta blockers should generally not be used in patients with asthma or any reactive airway disease. Doing so can precipitate bronchospasm by blocking the β₂ mediated relaxation of the bronchiole muscles. Selective beta blockers generally only block the type 1 receptor. They gradually become less selective at higher doses. Examples of selective beta₁ blockers in common use include atenolol and metoprolol. Since they lower heart rate, beta blockers have been used by some Olympic marksmen to provide more aiming time between heart beats. Some musicians use beta blockers to avoid stage fright and tremor during auditions and performances. Beta blockers decrease nocturnal melatonin release.

External links

- [http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2004/10/17/MNGB599PJC1.DTL Musicians using beta blockers]
- [http://www.nytimes.com/2004/10/17/arts/music/17tind.html?ex=1270785600&en=37bef79604f97228&ei=5090&partner=rssuserland Better Playing Through Chemistry] by Blair Tindall, New York Times, October 17, 2004. (Discussing the use of beta-blockers among professional musicians.) Category:Beta blockers

Antiarrhythmic agents

Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress fast rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation. While the use of antiarrhythmic agents to suppress atrial arrhythmias (atrial fibrillation and atrial flutter) is still in practice, it is unclear whether suppression of atrial arrhythmias will prolong life ^1,2. In the past, it was believed that suppression of the potentially dangerous ventricular arrhythmias, ventricular tachycardia and ventricular fibrillation would prolong life, but it was found in large clinical trials that suppression of these arrhythmias would paradoxically increase mortality^3,4, which may happen due to the increased workload these drugs place on the heart. In individuals with atrial fibrillation, antiarrhythmics are still used to suppress arrhythmias. This is often done to relieve the symptoms that may be associated with the loss of the atrial component to ventricular filling (atrial kick) that is due to atrial fibrillation or flutter. In individuals with ventricular arrhythmias, antiarrhythmic agents are often still in use to suppress arrhythmias. In this case, the patient may have frequent arrhythmic events or at high risk for ventricular arrhythmias. Antiarrhythmic agents may be considered the first-line therapy in the prevention of sudden death in certain forms of structural heart disease, and failure of these agents to suppress arrhythmias may lead to implantation of an implantable cardioverter-defibrillator (ICD). The use of antiarrhythmic agents in this population may be in conjunction with an ICD. In this case, the ICD is used to prevent sudden death due to ventricular fibrillation, while the antiarrhythmic agent(s) are used to suppress ventricular tachyarrhythmias so that the ICD doesn't shock the patient frequently. sudden death Many attempts have been made to classify antiarrhythmic agents. The problem arises from the fact that many of the antiarrhythmic agents have multiple modes of action, making any classification imprecise.

Vaughan Williams antiarrhythmic classification

The Vaughan Williams classification is one of the most widely used classification schemes for antiarrhythmic agents. This scheme classifies a drug based on the primary mechanism of its antiarrhythmic effect. However, its dependence on primary mechanism is one of the limitations of the VW classification, since many antiarrhythmic agents have multiple action mechanisms. Amiodarone, for example, has effects consistent with all of the first four classes. Another limitation is the lack of consideration within the VW classification system for the effects of drug metabolites. Procainamide, a class Ia agent whose metabolite – N-acetyl procainamide (NAPA) – has a class III action is one such example. A historical limitation was that drugs such as digoxin and adenosine – important antiarrhythmic agents – had no place at all in the VW classification system. This has since been rectified by the inclusion of class V. There are five main classes in the Vaughan Williams classification of antiarrhythmic agents:
- Class I agents interfere with the sodium (Na⁺) channel.
- Class II agents are anti-sympathetic nervous system agents. All agents in this class are beta blockers.
- Class III agents affect potassium (K⁺) efflux.
- Class IV agents affect the AV node.
- Class V agents work by other or unknown mechanisms.

Class I agents

The class I antiarrhythmic agents interfere with the sodium (Na⁺) channel. Class I agents are grouped by what effect they have on the Na⁺ channel, and what effect they have on cardiac action potentials.

Class Ia agents

action potential Class Ia agents block the fast sodium channel. Blocking this channel depresses the phase 0 depolarization (reduces V_max), which prolongs the action potential duration by slowing conduction. Agents in this class also cause decreased conductivity and increased refractoriness. Indications for Class Ia agents are supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats, and prevention of ventricular fibrillation. Class Ia agents include quinidine, procainamide and disopyramide. Procainamide can be used in the treatment of atrial fibrillation in the setting of Wolff-Parkinson-White syndrome, and in the treatment of wide complex hemodynamically stable tachycardias. While procainamide and quinidine may be used in the conversion of atrial fibrillation to normal sinus rhythm, they should only be used in conjunction with an AV node blocking agent (ie: digoxin, verapamil, or a beta blocker), because procainamide and quinidine can increase the conduction through the AV node and may cause 1:1 conduction of atrial fibrillation, causing an increase in the ventricular rate.

Class Ib agents

beta blocker Class Ib antiarrhythmic agents are sodium channel blockers. Class Ib agents have fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. Class Ib agents shorten the action potential duration and reduce refractoriness. These agents will decrease V_max in partially depolarized cells with fast response action potentials. They either do not change the action potential duration, or they may decrease the action potential duration. Class Ib agents are indicated for the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation. Class Ib agents include lidocaine, mexiletine, tocainide, and phenytoin.

Class Ic agents

phenytoin Class Ic antiarrhythmic agents markedly depress the phase 0 repolarization (decreasing V_max). They decrease conductivity, but have a minimal effect on the action potential duration. Of the sodium channel blocking antiarrhythmic agents (the class I antiarrhythmic agents), the class Ic agents have the most potent sodium channel blocking effects. Class Ic agents are indicated for life-threatening ventricular tachycardia or ventricular fibrillation, and for the treatment of refractory supraventricular tachycardia (ie: atrial fibrillation). Class Ic agents include encainide, flecainide, moricizine, and propafenone.

Class II agents

Class II agents are conventional beta blockers. They act by slowing impulse induction in the Sinus node. Class II agents include esmolol, propranolol, and metoprolol.

Class III agents

metoprolol Class III agents predominantly block the potassium channels, thereby prolonging repolarization⁵. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is more like to interact with tissue that has become refractory). Class III antiarrhythmic agents exhibit reverse use dependent prolongation of the action potential duration (Reverse use-dependence)⁵. This means that the refractoriness of the ventricular myocyte increases at lower heart rates. This increases the susceptibility of the myocardium to early after-depolarizations (EADs) at low heart rates. Antiarrhythmic agents that exhibit reverse use-dependence are more efficacious at preventing a tachyarrhythmia that converting someone into normal sinus rhythm. Because of the reverse use-dependence of class III agents, at low heart rates class III antiarrhythmic agents may paradoxically be more arrhythmogenic. Class III agents include amiodarone, azimilide, bretylium, clofilium, dofetilide, ibutilide, sematilide, and sotalol. Amiodarone is indicated for the treatment of refractory VT or VF, particularly in the setting of acute ischemia. Amiodarone is also safe to use in individuals with cardiomyopathy and atrial fibrillation, to maintain normal sinus rhythm. However, it does not cardiovert individuals from atrial fibrillation to normal sinus rhythm. Sotalol is indicated for the treatment of atrial or ventricular tachyarrhythmias, and AV re-entrant arrhythmias. Ibutilide is the only antiarrhythmic agent currently approved by the FDA for acute conversion of atrial fibrillation to sinus rhythm.

Class IV agents

Class IV agents are slow calcium channel blockers. They decrease conduction through the AV node. Class IV agents include verapamil and diltiazem.

Class V agents

Class V agents include adenosine and digoxin.

References

# Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347(23):1825-33. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=12466506&dopt=Abstract Medline abstract])
# Nichol G, McAlister F, Pham B, Laupacis A, Shea B, Green M, Tang A, Wells G. Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation. Heart. 2002 Jun;87(6):535-43. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12010934 Medline abstract])
# The Cardiac Arrhythmia Suppression Trial (CAST): The CAST investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomised trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989, 321:406–412.
# The Cardiac Arrhythmia Suppression Trial II (CAST II): The CAST II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med. 1992 Jul 23;327(4):227-33. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1377359&dopt=Abstract Medline abstract])
# Lenz TL, Hilleman DE, Department of Cardiology, Creighton University, Omaha, Nebraska. Dofetilide, a New Class III Antiarrhythmic Agent. Pharmacotherapy 20(7):776-786, 2000. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10907968 Medline abstract])
- Category:Cardiac electrophysiology

Adrenergic receptor

The adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors that is the target of catecholamines. Adrenergic receptors specifically bind their endogenous ligands, the catecholamines adrenaline and noradrenaline (also called epinephrine and norepinephrine) and are activated by these. Many cells possess these receptors, and the binding of an agonist will generally cause the cell to respond in a flight-fight manner. For instance, the heart will start beating quicker and the pupils will dilate.

Sub-types of adrenergic receptors

There are several types of adrenergic receptors, but there are five main groups:

Alpha α receptors

Agonist affinity: noradrenaline > adrenaline > phenylephrine > isoprenaline

Type α₁

Acts by phospholipase C activation, which forms IP₃ and DAG, one consequence of which is a rise in intracellular calcium. In blood vessels these cause vasoconstriction. Blood vessels with alpha-1 receptors are present in the skin and the gastrointestinal system, and during the fight-or-flight response there is decreased blood flow to these organs. This is the reason people can appear pale when they've been frightened.

Type α₂

Acts by inactivation of adenylate cyclase, cyclic AMP levels within the cell decrease. These are found on pre-synaptic nerve terminals.

Beta β receptors

Agonist affinity: isoprenaline > adrenaline > noradrenaline All β receptors activate adenylate cyclase, raising the intracellular cAMP concentration.

Type β₁

These are present in heart tissue, and cause an increased heart rate by acting on the cardiac pacemaker cells. Many beta-blockers used for treatment of angina will mainly affect these receptors and the beta-2 receptors to a lesser extent. These are referred to as 'cardio-selective' beta-blockers. Noradrenaline>Adrenaline>Phenyeprhine order of potency for alpha-1

Type β₂

These are in the vessels of skeletal muscle, and cause vasodilation, which allows more blood to flow to the muscles, and reduces total peripheral resistance. These tend to work with adrenaline (epinephrine), but not noradrenaline (norepinephrine). Beta-2 receptors are also in bronchial smooth muscle, and cause bronchodilation when activated. Some Anti-asthma drugs, such as the bronchodilator salbutamol (Ventolin) work by binding to and stimulating the β₂ receptors. Non-selective beta-blocking drugs, such as propranolol (Inderal), can represent a risk to people with asthma by blocking the beta-2 receptors, causing bronchoconstriction.

Type β₃

Beta-3 receptors are present in adipose tissue and are thought to have a role in the regulation of lipid metabolism.

External links

[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109691 Brief overview of functions of the beta-3 receptor] Category:G protein coupled receptors

Ion channel

Another, unrelated ion channeling process is part of ion implantation. Ion channels are pore-forming proteins that help establish the small voltage gradient that exists across the membrane of all living cells (see cell potential), by controlling the flow of ions. They are present in the membranes that surround all biological cells.

Basic features

An ion channel is an integral membrane protein or more typically an assembly of several proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or related proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer. While large-pore channels permit the passage of ions more or less indiscriminately, the archetypal channel pore is just one or two atoms wide at its narrowest point, it conducts a specific species of ion, such as sodium or potassium, and conveys them through the membrane single file--nearly as fast as the ions move through free fluid. In some ion channels, access to the pore is governed by a "gate," which may be opened or closed by chemical or electrical signals, or mechanical force, depending on the variety of channel.

Biological role

Because "voltage-gated" channels underlie the nerve impulse and because "transmitter-gated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, most of the offensive and defensive toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g. the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails and others) work by plugging ion channel pores. But ion channels figure in a wide variety of biological processes that involve rapid changes in cells. In the search for new drugs, ion channels are a favorite target.

Diversity and activation

- Voltage-gated channels open or close, depending on the transmembrane potential. Examples include the sodium and potassium voltage-gated channels of nerve and muscle, that are involved in the propagation of the action potential, and the voltage-gated calcium channels that control neurotransmitter release in pre-synaptic endings.
- Ligand-gated channels open in response to a specific ligand molecule on the external face of the membrane in which the channel resides. Examples include the "nicotinic" Acetylcholine receptor, AMPA receptor and other neurotransmitter-gated channels.
- Cyclic nucleotide-gated channels, Calcium-activated channels and others open in response to internal solutes and mediate cellular responses to second messengers.
- Stretch-activated channels open or close in response to mechanical forces that arise from local stretching or compression of the membrane around them; for example when their cells swell or shrink. Such channels are believed to underlie touch sensation and the transduction of acoustic vibrations into the sensation of sound.
- G-protein-gated channels open in response to G protein-activation via its receptor.
- Inward-rectifier K channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows into the cell but not out of the cell. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in glial cells.
- Light-gated channels like channelrhodopsin are directly opened by the action of light
- Resting channels remain open at all times. Certain channels respond to multiple influences. For instance, the NMDA receptor is partially activated by interaction with its ligand, glutamate, but is also voltage-sensitive and only conducts when the membrane is depolarized. Some calcium-sensitive potassium channels respond to both calcium and depolarization, with an excess of one apparently being sufficient to overcome an absence of the other.

Detailed structure

Channels differ with respect to the ion they let pass (for example, Na⁺, K⁺, Cl⁻), the ways in which they may be regulated, the number of subunits of which they are composed and other aspects of structure. Channels belonging to the largest class, which includes the voltage-gated channels that underlie the nerve impulse, consists of four subunits with six transmembrane helices each. On activation, these helices move about and open the pore. Two of these six helices are separated by a loop that lines the pore and is the primary determinant of ion selectivity and conductance in this channel class and some others. The channel subunits of one such other class, for example, consist of just this "P" loop and two transmembrane helices. The determination of their molecular structure by Roderick MacKinnon using X-ray crystallography won a share of the 2003 Nobel Prize in Chemistry. Because of their small size and the difficulty of crystallizing integral membrane proteins for X-ray analysis, it is only very recently that scientists have been able to directly examine what channels "look like." Particularly in cases where the crystallography required removing channels from their membranes with detergent, many researchers regard images that have been obtained as tentative. An example is the long-awaited crystal structure of a voltage-gated potassium channel, which was reported in May 2003. One inevitable ambiguity about these structures relates to the strong evidence that channels change conformation as they operate (they open and close, for example), such that the structure in the crystal could represent any one of these operational states. Most of what researchers have deduced about channel operation so far they have established through electrophysiology, biochemistry, gene sequence comparison and mutagenesis.

History

The existence of ion channels was hypothesized by the British biophysicists Alan Hodgkin and Andrew Huxley as part of their Nobel Prize-winning theory of the nerve impulse, published in 1952. Channel's existence was confirmed in the 1970s with an electrical recording technique known as the "patch clamp," which led to a Nobel Prize to Erwin Neher and Bert Sakmann, the technique's inventors. Hundreds if not thousands of researchers continue to pursue a more detailed understanding of how these proteins work. In the last years the development of automated patch clamp devices helped to increase the throuput in ion channel screening signigicantly.

References

# Two textboks that discuss ion channels are: Neuroscience (2nd edition) Dale Purves, George J. Augustine, David Fitzpatrick, Lawrence. C. Katz, Anthony-Samuel LaMantia, James O. McNamara, S. Mark Williams, editors. Published by Sinauer Associates, Inc. (2001) [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.227 online textbook] and Basic Neurochemistry: Molecular, Cellular, and Medical Aspects (6th edition) by George J Siegel, Bernard W Agranoff, R. W Albers, Stephen K Fisher and Michael D Uhler published by Lippincott, Williams & Wilkins (1999): [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.chapter.421 online textbook]

External links

- [http://physrev.physiology.org/cgi/content/full/80/2/555 The Voltage Sensor in Voltage-Dependent Ion Channels]
- [http://www.cellbio.wustl.edu/faculty/huettner/69.pdf X-ray crystal structure of a potassium channel]
- [http://www.ionchannels.org Ion Channel, Biophysics and Electrophysiology Resources] Category:membrane biology Category:Biochemistry ja:イオンチャンネル

Repolarization

In neuroscience, repolarization refers to the change in membrane potential that returns the membrane potential to a negative value after the depolarization phase of an action potential has just previously changed the membrane potential to a positive value. Repolarization results from the movement of positively charged potassium ions out of the cell. Typically the repolarization phase of an action potential results in hyperpolarization, attainment of a membrane potential that is more negative than the resting potential.

QT interval

In medicine, specifically cardiology, the study of the heart, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval is dependent of the heart rate as has to be corrected. The standard clinical correction is to use Bazett's formula¹ calculating the heart rate corrected QT interval QTc. Bazett's formula is

QTc = \frac

, where QTc is the QT interval corrected for rate, and RR is the interval from the onset of one QRS complex to the onset of the next QRS complex, measured in seconds. However, this formula tends to not be accurate, and over-corrects at high heart rates and under-corrects at low heart rates. A more accurate method to correct the QT interval for the rate was developed by Rautaharju et al.², who developed the formula

QTp=\frac

. This method is not widely used by clinicians. Normal values for the QT interval are between 0.30 and 0.44 (0.45 for women) seconds. If abnormally prolonged or shortened, there is a risk of developing ventricular arrhythmias. An abnormal prolonged QT interval could be due to Long QT syndrome, whereas an abnormal shortened QT interval could be due to Short QT syndrome.

References

1. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7:353-370 2. Rautaharju PM, Warren JW, Calhoun HP. Estimation of QT prolongation. A persistent, avoidable error in computer electrocardiography. J Electrocardiol. 1990;23 Suppl:111-7. PMID 2090728. Category:Cardiology QT Interval ja:心電図

AV node

The atrioventricular node (abbreviated AV node) is the tissue between the atria and the ventricles of the heart which conducts the normal electrical impulse from the atria to the ventricles. The AV node receives two inputs from the atria: posteriorly via the crista terminalis, and anteriorly via the interatrial septum. An important property that is unique to the AV node is decremental conduction. This is the property of the AV node that prevents rapid conduction to the ventricle in cases of rapid atrial rhythms, such as atrial fibrillation or atrial flutter. The blood supply of the AV node is from a branch of the right coronary artery in 85 to 90 percent of individuals, and from a branch of the left circumflex artery in 10 to 15 percent of individuals. In certain types of supraventricular tachycardia a person could have two AV Nodes, this will cause a loop in electrical current and uncontrollably rapid heart beat. When this electricity catches up with itself, it will dissipate and return to your normal heart beat speed.

References

ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation - Executive Summary ([http://www.acc.org/clinical/guidelines/atrial_fib/exec_summ/exec_afindex.htm Full text]) Category:Cardiac anatomy

Cardiac action potential

The cardiac action potential is the electrical activity of the individual cells of the electrical conduction system of the heart. The cardiac action potential differs significantly in different portions of the heart. This differentiation of the action potentials allows the different electrical characteristics of the different portions of the heart. For instance, the specialized conduction tissue of the heart has the special property of depolarizing without any external influence. This is known as automaticity. The electrical activity of the specialized conduction tissues are not apparent on the surface electrocardiogram (ECG). This is due to the relatively small mass of these tissues compared to the myocardium (muscle of the heart).

Resting membrane potential

Intracellular and extracellular ion concentrations
Ion	Extracellular concentration (mM)	Intracellular concentration	Ratio of extracellular to intracellular concentration
Na⁺	145	15 mmol/L	9.7
K⁺	4	150 mmol/L	0.027
Cl^-	120	5-30 mmol/L	4-24
Ca²⁺	2	10^-7 mmol/L	2 x 10⁴
Although intracellular Ca²⁺ content is about 2 mM, most of this is bound or sequestered in intracellular organelles (mitochondria and sarcoplasmic reticulum).

The resting membrane potential is the difference in ionic charge across the membrane of the cell during phase 4 of the action potential. The normal resting membrane potential in the ventricular myocardium is about -85 to -95 mV. This potential is determined by the selective permeability of the cell membrane to various ions. The resting membrane potential is permeable to K⁺, and is relatively impermeable to other ions. The resting membrane potential is therefore determined by the K⁺ gradient across the cell membrane (the reversal potential for K⁺). The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the Na⁺-K⁺ ion exchange pump and the Na⁺-Ca²⁺ exchange mechanism. Intracellularly (within the cell), K⁺ is the principle cation, and phosphate and the conjugate bases of organic acids are the dominant anions. Extracellularly (outside the cell), Na⁺ and Cl^- predominate.

Phases of the cardiac action potential

Cl^- The standard model used to understand the cardiac action potential is the action potential of the ventricular myocyte. The action potential has 5 phases (numbered 0-4). Phase 4 is the resting membrane potential, and describes the membrane potential when the cell is not being stimulated. Once the cell is electrically stimulated (typically by an electric current from an adjacent cell), it begins a sequence of actions involving the influx and eflux of multiple cations and anions that together produce the action potential of the cell, propogating the electrical stimulation to the cells that lie adjacent to it. In this fashion, an electrical stimulation is conducted from one cell to all the cells that are adjacent to it, to all the cells of the heart.

Phase 4

Phase 4 is the resting membrane potential. This is the period that the cell remains in until it is stimulated by an external electrical stimulus (typically an adjacent cell). This phase of the action potential is associated with diastole of the chamber of the heart. Certain cells of the heart have the ability to undergo spontaneous depolarization, in which an action potential is generated without any influence from nearby cells. This is also known as automaticity. The cells that can undergo spontaneous depolarization the fastest are the primary pacemaker cells of the heart, and set the heart rate. Usually, these are cells in the SA node of the heart. Electrical activity that originates from the SA node is propagated to the rest of the heart. The fastest conduction of the electrical activity is via the electrical conduction system of the heart. In cases of heart block, in which the activity of the primary pacemaker does not propagate to the rest of the heart, a latent pacemaker (also known as an escape pacemaker) will undergo spontaneous depolarization and create an action potential. The mechanism of automaticity is still unclear. Depolarization of SA and AV nodal cells largely depend on a net increase in intracellular positive charge. Mechanisms include a decrease in the net K⁺ outward flow, and a time-dependent increase in flow of Na⁺ and Ca²⁺ ions.

Phase 0

Phase 0 is the rapid depolarization phase. The slope of phase 0 is determined by the maximum rate of depolarization of the cell and is known as V_max. This phase is due to opening of the fast Na⁺ channels and the subsequent rapid increase in the membrane conductance to Na⁺ (g_Na) and a rapid influx of ionic current in the form of Na⁺ ions (I_Na) into the cell. The ability of the cell to open the fast Na⁺ channels during phase 0 is related to the membrane potential at the moment of excitation. If the membrane potential is at its baseline (about -85 mV), all the fast Na⁺ channels are closed, and excitation will open them all, causing a large influx of Na⁺ ions. If, however, the membrane potential is less negative, some of the fast Na⁺ channels will be opened earlier, causing a lesser response to excitation of the cell membrane and a lower V_max. The maximal fast inward Na⁺ current is generated when the membrane potential is at the normal resting potential (-85 to –95 mV). If the resting membrane potential is reduced to a low enough level, the increase in fast inward Na⁺ current may be inadequate to produce a response, making the fiber unexcitable.

The fast Na⁺ channel

The fast sodium channel is made up of two gates, the m gate and the h gate. It is the interaction of these two gates that allows Na⁺ to enter the cell through this channel. In the resting state, the m gate is closed and the h gate is open. Upon electrical stimulation of the cell, the m gate opens quickly while simultaneously the h gate closes slowly. For a brief period of time, both gates are open and Na⁺ can enter the cell across the electrochemical gradient.

Phase 1

Phase 1 of the action potential is due to closure of the fast Na⁺ channels. The transient net outward current is due to the movement of K⁺ and Cl^- ions. Phase 0 and 1 together correspond to the R and S waves of the ECG.

Phase 2

Phase 2 of the action potential corresponds to the ST segment of the ECG. This "plateau" phase of the cardiac action potential is sustained by a balance between inward movement of Ca²⁺ (I_Ca) through L-type calcium channels and outward movement of K⁺ through potasium channels.

Phase 3

During phase 3 of the action potential, the K⁺ channel is still open, allowing more K⁺ to leave the cell and accumulate in the extracellular space. This net loss of positive charge causes the cell to repolarize. The k⁺ channels close when the membrane potential is restored to about -40 to -45 mV. Phase 3 of the action potential corresponds to the T wave on the ECG.

Abnormal automaticity

The normal activity of the pacemaker cells of the heart is to spontaneously depolarize at a regular rhythm, generating the normal heart rate. Abnormal automaticity involves the abnormal spontaneous depolarization of cells of the heart. This typically causes arrhythmias (irregular rhythms) in the heart.

Ventricular tachycardia

Tachycardia is an abnormally rapid beating of the heart, defined as a resting heart rate of over 100 beats per minute. It can have harmful effects in two ways. First, when the heart beats too rapidly, it performs inefficiently (since there is not enough time for the ventricles to fill completely), causing blood flow and blood pressure to diminish. Second, it increases the work of the heart, causing it to require more oxygen while also reducing the blood flow to the cardiac muscle tissue, increasing the risk of ischemia and resultantly infarction. Tachycardia is a general symptomatic term that does not describe the cause of the rapid rate. Common causes are autonomic nervous system or endocrine system activity, hemodynamic responses, and various forms of cardiac arrhythmia.

Autonomic and endocrine causes

An increase in sympathetic nervous system stimulation causes the heart rate to increase, both by the direct action of sympathetic nerve fibers on the heart, and by causing the endocrine system to release hormones such as epinephrine (adrenaline) which have a similar effect. Increased sympathetic stimulation is usually due to physical or psychological stress (the so-called "fight or flight" response), but can also be induced by stimulants such as caffeine. Endocrine disorders such as pheochromocytoma can cause epinephrine release and tachycardia independent of the nervous system.

Hemodynamic responses

The body contains several feedback mechanisms to maintain adequate blood flow and blood pressure. If blood pressure decreases, the heart beats faster in an attempt to raise it. This can happen in response to a decrease in blood volume (through dehydration or bleeding), or an unexpected change in blood flow. The most common cause of the latter is orthostatic hypotension (also called postural hypotension), a sudden drop of blood pressure that occurs with a change in body position (e.g., going from lying down to standing up). When tachycardia occurs for this reason, it is called postural orthostatic tachycardia syndrome (POTS).

Tachycardic arrhythmias

An electrocardiogram tracing can distinguish several different forms of rapid abnormal heartbeat: If the heart's electrical system is functioning normally, except that the rate is in excess of 100 beats per minute, it is called sinus tachycardia. This is caused by any of the factors mentioned above, rather than a malfunction of the heart itself. Supraventricular tachycardia (SVT) occurs when an abnormal electrical impulse originates above the ventricles, but instead of causing a single beat and a pause, it travels in circles and causes many rapid beats. To distinguish SVT from Sinus Tachycardia one must simply look at the rate: If the rate of contraction is more than 150 bpm, then it is considered SVT. Otherwise it is Sinus Tachycardia. Ventricular tachycardia (VT or "V-tach") is a similar phenomenon occurring within the tissue of the ventricles, causing an extremely rapid rate with poor pumping action. Both of these rhythms normally last for only a few seconds (paroxysmal tachycardia), but if VT persists it is extremely dangerous, often leading to ventricular fibrillation. Arrhythmias can be treated using drugs, intervention or implantable devices. See also: Bradycardia. The vagus reflex may help as a first-aid measure. Category:Cardiology ko:빠른맥

Bioavailability

In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as by mouth), its bioavailability decreases (due to incomplete absorption and first-pass metabolism). Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.

Definition

Bioavailability is a measurement of the rate and extent of therapeutically active drug that reaches the systemic circulation and is available at the site of action. (Shargel & Yu, 1999) It is expressed as the letter F.

Absolute bioavailability

Absolute bioavailability measures the availability of the active drug in systemic circulation after non-intravenous administration (i.e. after oral, rectal, transdermal, subcutaneous, etc administration). In order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous and extravascular administration. The absolute bioavailability is the dose-corrected area under curve (AUC) extravascular divided by AUC intravenous.

F = \frac

Note here that a drug given by the intravenous route will have an absolute bioavailability of 1 (F=1). Drugs given by other routes usually have an absolute bioavailability of less than one.

Relative bioavailability

This measures the bioavailability of the a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability.

\mathit = \frac

Factors influencing bioavailability

As mentioned above the absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one. This means that there are factors at work which reduce the availability of the drug prior to it entering the systemic circulation. Such factors may include, but are not limited to:
- poor absorption from the gastrointestinal tract
- hepatic first-pass effect
- degradation of the drug prior to reaching system circulation

References

- Shargel, L.; Yu, A.B. (1999). Applied biopharmaceutics & pharmacokinetics (4th ed.). New York: McGraw-Hill. ISBN 0-8385-0278-4. Category:Pharmacokinetics th:ชีวปริมาณออกฤทธิ์

Myocardial infarction

and then suddenly ruptures, totally occluding the artery and preventing blood flow downstream. (Please note: the details of artery disease and occlusion, as illustrated in the image above, are misleading; see the links.)]] Acute myocardial infarction (AMI or MI), commonly known as a heart attack, is a serious, sudden heart condition usually characterized by varying degrees of chest pain or discomfort, weakness, sweating, nausea, vomiting, and arrhythmias, sometimes causing loss of consciousness. It occurs when a part of the heart muscle is injured, and this part may die because of sudden total interruption of blood flow to the area. It is often a life-threatening medical emergency which demands both immediate attention and activation of the emergency medical services. Diagnosis is by the combination of medical history, ECG findings and blood tests for cardiac enzymes. The most important treatment in myocardial infarction is restoring the blood flow to the heart, by thrombolysis (enzymatically dissolving the clot in the artery) and/or angioplasty (using a balloon to push the artery open). Close monitoring on a coronary care unit is mandatory to observe for various complications. There is emphasis on secondary prevention, the elimination of risk factors that could lead to further heart attacks. The medical term myocardial infarction derives from myocardium (the heart muscle) and infarction (tissue death), in this case caused by an obstruction of blood flow. The phrase "heart attack" is occasionally used to refer to heart problems other than a myocardial infarction, such as unstable angina pectoris.

Symptoms

Acute myocardial infarction is usually characterized by varying degrees of chest pain or discomfort, weakness, sweating, nausea, vomiting, and arrhythmias, sometimes causing loss of consciousness. Chest pain is the most common symptom of acute myocardial infarction and it is often described as tightness, pressure, or squeezing. Pain may radiate to the jaw, neck, arms, back, and epigastrium, most often to the left arm or neck. Chest pain is more likely caused by myocardial infarction when it lasts for more than 30 minutes. The patient may complain of shortness of breath (dyspnoea) especially if the decrease in myocardial contractility due to the infarct is sufficient to cause left ventricular failure with pulmonary congestion or even pulmonary oedema. Approximately one quarter of all myocardial infarction are silent, without chest pain or other symptoms. This happens more often in elderly patients and patients with diabetes mellitus. They may complain though of atypical symptoms like fatigue, syncope, or weakness. Approximately half of all MI patients have experienced warning symptoms like angina pectoris prior to the infarct.

Diagnosis

Myocardial infarctions vary greatly in severity. Classical cases of myocardial infarction are often identified by ambulance staff, emergency room doctors and cardiac specialist nurse practitioners quickly. Yet many myocardial infarctions, tending to be smaller, are not recognized by victims, never receive medical attention and result in either sudden death or progressive heart weakness. For a more complete diagnosis, the medical history, combined with electrocardiogram results and blood tests for heart muscle cell damage, are vital. Myocardial perfusion tests (see stress tests) and echocardiograms can also be helpful. stress tests

Electrocardiogram

Electrocardiogram (ECG/EKG) findings suggestive of MI are elevations of the ST segment and changes in the T wave. After a myocardial infarction, changes can often be seen on the ECG called Q waves, representing scarred heart tissue. The ST segment elevation distinguishes between:
- STEMI ("ST-Elevation Myocardial Infarction")
- NSTEMI ("Non-ST-Elevation Myocardial Infarction") -- diagnosed when cardiac enzymes are elevated. The leads with abnormalities on the EKG can [http://medstat.med.utah.edu/kw/ecg/ecg_outline/Lesson9/ help] [http://www.madsci.com/manu/ekg_mi.htm identify] the [http://www.usfca.edu/fac-staff/ritter/ekg.htm location]:
- anterior wall (I21.0): V1-V4
- inferior wall (I21.1): II, III, F
- lateral wall (I21.2): I, F, V5, V6
- posterior wall (I21.2): V1, V2

Myocardial markers

Cardiac enzymes are proteins from cardiac tissue found in the blood. Until the 1980s, the enzymes SGOT and LDH were used to assess cardiac injury. Then it was found that disproportional elevation of the MB subtype of the enzyme creatine phosphokinase (CPK) was very specific for myocardial injury. Current guidelines are generally in favor of troponin isoenzymes I or T, which are thought to rise before permanent injury develops. A positive troponin in the setting of chest pain may accurately predict a high likelihood of a myocardial infarction in the near future. The diagnosis of myocardial infarction used to require that all three components (history, ECG, and enzymes) were positive for MI. Currently the cardiac enzymes have become so reliable that enzyme elevations alone are considered reliable measures of cardiac injury, with ECG serving to determine where in the heart the damage has occurred, and history serving to screen patients for further enzyme and ECG testing. In difficult cases or in situations where intervention to restore blood flow is appropriate, an angiogram can be done (see below for an image). Using a catheter inserted into an artery (usually the femoral artery), obstructed or narrowed vessels can be identified, and angioplasty applied as a therapeutic measure (see below). Angiography requires extensive skill, especially in emergency settings, and may not always be available out of hours. It is commonly performed by cardiologists. There is a very small risk of plaque and vessel rupture on ballon inflation; should this occur, then emergency open-chest cardiac surgery may be required. Patients commonly experience bruising at the catheter insertion point in the groin and occasionally a hematoma. Dissection (tearing) of the blood vessel is rare but usually managed with a local thrombotic injection.

Pathophysiology

Ischemia and infarction

thromboticThe underlying mechanism of a heart attack is the destruction of heart muscle cells due to a lack of oxygen. If these cells are not supplied with sufficient oxygen by the coronary arteries to meet their metabolic demands, they die by a process called infarction. The decrease in blood supply has the following consequences: # Heart muscle which has lost blood flow long enough, e.g. 10-15 minutes, ends up dying (necrosis) and does not grow back. Thus the heart ends up permanently weaker as a pump for the remainder of the individual's life; # Injured, but still living, heart muscle conducts the electrical impulses which initiate each heart beat much more slowly. The speed can end up so slow that the spreading impulse is preserved long enough for the uninjured muscle to complete contraction; now the slowed electrical signal, still traveling within the injured area, can re-enter and trigger the healthy muscle (termed re-entry) to beat again too soon for the heart to relax long enough and receive any blood return from the veins. If this re-entry process results in sustained heart rates in the >200 to over 400 beats per minute range called ventricular tachycardia (V-Tach) or ventricular fibrillation (V-Fib), then the rapid heart rate effectively stops heart pumping. Heart output and blood pressure falls to near zero and the individual quickly dies. This is the most common mechanism of the sudden death that can result from a myocardial infarction. The cardiac defibrillator device was specifically designed for stopping these too rapid heart rates. If used properly, it stimulates the entire heart muscle to contract all at once, in synchrony; hopefully stopping continuation of the re-entry process. If used within one minute of onset of V-Tach or V-Fib, the defibrillator has a high success rate in stopping these often fatal arrhythmias allowing a functional heart rhythm to return. Histopathological examination of the heart shows that there is a circumscribed area of ischemic necrosis (coagulative necrosis). In the first 12-48 hours, myocardial fibers are still well delineated, with intense eosinophilic (pink) cytoplasm, but lose their transversal striations and the nucleus. The interstitial space may be infiltrated with red blood cells. When the healing has commenced (e.g. after 5 -10 days) the area of coagulative ischemic necrosis shows myocardial fibers with preservation of their contour, but the cytoplasm is intensely eosinophilic and transversal striations and nuclei are completely lost. The interstitium of the infarcted area is initially infiltrated with neutrophils, then with lymphocytes and macrophages, in order to phagocytose the myocyte debris. The necrotic area is surrounded and progressively invaded by granulation tissue, which will replace the infarct with a fibrous (collagenous) scar.

Atherosclerosis

The most common cause of heart attack by far is atherosclerosis, a gradual buildup of cholesterol and fibrous tissue in plaques in the arterial wall, typically over decades. However plaques can become unstable, rupture, and additionally promote a thrombus (blood clot) that occludes the artery; this can occur in minutes. When a severe enough plaque rupture occurs in the coronary vasculature, it leads to myocardial infarction (necrosis of downstream myocardium). All risk factors for atherosclerosis are also (modifiable) risk factors for ischemic heart disease: older age, smoking, hypercholesterolemia (more accurately hyperlipoproteinemia, especially high low density lipoprotein (LDL) and low high density lipoprotein (HDL), diabetes (with or without insulin resistance) and obesity. obesity The blood flow problem is nearly always a result of exposure of atheroma tissue within the wall of the artery to the blood flow inside the artery, atheroma being the primary lesion of the atherosclerotic process. The many blood stream column irregularities, visible in the single frame angiogram image to the right, reflects artery lumen changes as a result of decades of advancing atherosclerosis. Heart attacks rates are higher in association with intense exertion, be it stress or physical exertion, especially if the exertion is unusually more intense than the individual usually performs. Quantitatively, the period of intense exercise and subsequent recovery is associated with about a 6-fold higher myocardial infarction rate (compared with other more relaxed times frames) for people who are physically very fit. For those in poor physical condition, the rate differential is over 35-fold higher. One observed mechanism for this phenomenon is the increased arterial pulse pressure stretching and relaxation of arteries with each heart beat which, as has been observed with IVUS, increases mechanical "shear stress" on atheromas and the likelihood of plaque rupture. Increased spasm/contraction of coronary arteries in association with cocaine abuse can also precipitate myocardial infarction.

First aid

Immediate care

As myocardial infarction is a common medical emergency, the signs are often part of first aid courses. General management in the acute setting is:
- calling for help as soon as possible
- giving aspirin (162-325 mg), which inhibits formation of further blood clots
- giving the patient nitroglycerin under the tongue if the patient is carrying tablets or liquid spray
- being prepared to administer cardiopulmonary resuscitation (CPR) in case of arrhythmia or cardiac arrest Since the publication of data showing that the availability of automated external defibrillators (AEDs) in public places may significantly increase chances of survival, many of these have been installed in public buildings, public transport facilities and in non-ambulance emergency vehicles (e.g. police cars and fire engines). AEDs analyze the rhythm and determine whether the arrhythmia is amenable to defibrillation ("shockable").

Emergency services

Emergency services may recommend the patient to take nitroglycerin tablets or patches, in case these are available, particularly if they had prior heart attacks or angina. In an ambulance, an intravenous line is established, and the patient is transported immediately if breathing and pulse are present. Oxygen first aid is provided and the patient is calmed. Close cardiac monitoring (with an electrocardiogram) is initiated if available. If the patient has lost breathing or circulation advanced cardiac life support (including defibrillation) may be necessary and (at the paramedic level) injection of medications may be given per protocol. CPR is performed if there is no satisfactory cardiac output. About 20% of patients die before they reach the hospital; the cause of death is often ventricular fibrillation.

Wilderness first aid

In wilderness first aid, a possible heart attack justifies medical evacuation by the fastest available means, including MEDEVAC, even in the earliest or precursor stages. The patient will rapidly be incapable of further exertion and have to be carried out.

Air travel

Doctors traveling by commercial aircraft may be able to assist an MI patient by using the on-board first aid kit, which contains basic cardiac drugs used in advanced cardiac life support, and oxygen. Flight attendants are generally aware of the location of these materials. Pilots are required to divert the flight to the nearest airport.

Treatment

A heart attack, especially because of cardiac arrhythmias, is often a life-threatening medical emergency which demands both immediate attention and activation of the emergency medical services. Immediate termination of arrhythmias and transport by ambulance to a hospital where advanced cardiac life support (ACLS) is available can greatly improve both chances for survivial and recovery. The more time that passes, even 1-2 minutes, before medical attention is available/sought, the more likely the occurrence of both (a) life threatening arrhythmias/death and (b) more severe and permanent the heart damage.

First line

In the hospital, oxygen, aspirin, nitroglycerin and analgesia (usually morphine, hence the popular mnemonic MONA) are administered as soon as possible, if this has not already happened during transport.

Reperfusion

The ultimate goal of the management in the acute phase of the disease is to salvage as much myocardium as possible and restore contractile function of heart chambers. This is achieved primarily with thrombolytic drugs, such as streptokinase, urokinase, alteplase (recombinant tissue plasminogen activator, rtPA) or reteplase. Heparin alone as an anticoagulant is substandard. Although clinical trials suggest better outcomes, angioplasty as a first-line measure is probably still underused. This is largely dependent on the availability of an experienced interventional cardiologist on-site, or the availability of rapid transport to a referral centre. Emergency coronary surgery, in the form of coronary artery bypass surgery is another option, although this option is in decline since the development of primary angioplasty. The same limitations apply here: cardiothoracic surgery services are not available in many hospitals. NSTEMI (non-ST elevation MI) is initially indistinguishable from unstable angina in most cases, and is therefore managed similarly with aspirin, heparin and usually with clopidogrel.

Monitoring and follow-up

Additional objectives are to prevent life-threatening arrhythmias or conduction disturbances. This requires monitoring in a coronary care unit and protocolised administration of antiarrhythmic agents. Long-term beta-blocker medication is routinely commenced. Patients are also initiated on aspirin and/or clopidogrel (Plavix® or Iscover®); other anticoagulant drugs have not shown additional benefit. ACE inhibitors are commenced in the course of follow-up to assist in ventricular remodeling. Recent studies have shown benefit of the initiation of a statin (e.g. simvastatin 40 mg daily), even in patients without known hypercholesterolemia. Patients are discouraged from working and sexual activity for about two months, while they undergo cardiac rehabilitation training. Local authorities may place limitations on driving motorised vehicles. During a follow-up outpatient visit, or increasingly before discharge from hospital, it will be determined if the patient suffers from angina pectoris. If this is the case, treadmill testing, thallium scintigraphy or coronary angiography are often performed to identify treatable causes, as this will decrease the risk of future myocardial infarction.

History

Before the discovery of the electrocardiogram, it was impossible to objectively diagnose myocardial infarction. The term angina pectoris had already been extant for 150 years (William Heberden coined the term in 1772), but little was known about the disease mechanism. As a disease entity, myocardial infarction was described in full by Dr James Herrick in an 1912 article in JAMA. He is credited as the originator of the "thrombogenic theory", i.e. the theory that myocardial infarction is due to thrombosis in the coronary artery. Subsequently, atherosclerosis and plaque rupture were discovered as underlying mechanisms. A major breakthrough in the identification of risk factors was the 1956 British doctors study, which showed an increased risk of myocardial infarction in heavy smokers.

References

- Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA 1912;59:2015-2019.

External links

- [http://www.pathologyatlas.ro/Acute%20Myocardial%20Infarction.html Atlas of Pathology]
- [http://chdrisk.uni-muenster.de/risk.php?iSprache=1&iVersion=1&iSiVersion=0 Risk Score Calculator] Category:Cardiovascular diseases Category:Ischemic heart disease Category:Medical emergencies ko:심근경색 ja:心筋梗塞 ko:심근경색증

Antiarrhythmic agents

Vaughan Williams antiarrhythmic classification

Class I agents

Class Ia agents

Class Ib agents

Class Ic agents

Class II agents

Class II agents are conventional beta blockers. They act by slowing impulse induction in the Sinus node. Class II agents include esmolol, propranolol, and metoprolol.

Class III agents

Class IV agents

Class IV agents are slow calcium channel blockers. They decrease conduction through the AV node. Class IV agents include verapamil and diltiazem.

Class V agents

Class V agents include adenosine and digoxin.

References

Category:Antiarrhythmic agents

Antiarrhythmic agents are drugs which have an effect on the rhythm of the heart. Category:Pharmacologic agents

Shôchû

Shōchū (焼酎; lit. "burned liquor") is a distilled alcoholic beverage which is traditionally produced in Japan. In English, it is often dubbed "Japanese Vodka." Most shochu is around 25% alcohol, although some varieties (particularly Okinawan awamori) can go as high as 43%. right Shochu can be made from rice ("kome-jochu") (米焼酎), although it is more commonly made from barley ("mugi-jochu") （麦焼酎）, sweet potato ("satsuma imo-shochu")（�

Sotalol

References

See also

Drug

Heart

The human heart

Structure

The cardiac cycle

Regulation of the cardiac cycle

Other physiological functions

Diseases and treatments

First aid

The hearts of other animals

Heartbeat

Food use

As an icon

See also

External links

Beta blocker

External links

Antiarrhythmic agents

Vaughan Williams antiarrhythmic classification

Class I agents

Class Ia agents

Class Ib agents

Class Ic agents

Class II agents

Class III agents

Class IV agents

Class V agents

Related topics

References

Adrenergic receptor

Sub-types of adrenergic receptors

Alpha α receptors

Type α1

Type α2

Beta β receptors

Type β1

Type β2

Type β3

External links

Ion channel

Basic features

Biological role

Diversity and activation

Detailed structure

History

References

See also

External links

Repolarization

Related topics

QT interval

See also

References

AV node

Related topics

References

Cardiac action potential

Resting membrane potential

Phases of the cardiac action potential

Phase 4

Phase 0

The fast Na+ channel

Phase 1

Phase 2

Phase 3

Abnormal automaticity

Related topics

Ventricular tachycardia

Autonomic and endocrine causes

Hemodynamic responses

Tachycardic arrhythmias

Bioavailability

Definition

Absolute bioavailability

Relative bioavailability

Factors influencing bioavailability

See also

Type α₁

Type α₂

Type β₁

Type β₂

Type β₃

The fast Na⁺ channel