on 22-Dec-2019 (Sun)

Cells are bathed in an extracellular fl uid (ECF)

ICF is characterized by low Ca2+ , Na+ , and Cl-concentrations compared with ECF

Lipids are ideally suited to a barrier function because they are hydrophobic

Proteins allow cells to interact with and communicate with each other

Membranes contain three predominant types of lipid: phospholipids, cholesterol, and glycolipids

hydrophobic region is usually composed of fatty acid “tails”

Phospholipids comprise a fatty acid tail coupled via glycerol to a head group that contains phosphate and an attached alcohol

Sphingo- myelin is a related phospholipid in which glycerol has been re- placed by sphingosine. The alcohol group in sphingomyelin is choline

adding cholesterol to a membrane reduces its fluidity and makes it stronger and more rigid.

glycolipids, a minor but physiologically significant lipid type comprising a fatty acid tail coupled via sphingosine to a carbohydrate head group

glycolipids create a carbohydrate cell coat that is involved in cell-to-cell interactions and that conveys antigenicity

Peripheral proteins are found on the membrane surface. Their link to the membrane is relatively weak and, thus, they can easily be washed free using simple salt solutions. Peripheral proteins associate with both the intracellular and extracellular plasma membrane surfaces

Intracellular: Proteins that localize to the intracellular surface

Extracellular: Proteins located on the extracellular surface

Integral membrane proteins penetrate the lipid core. They are anchored by covalent bonds to surrounding structures

Fick law: J ⫽ P ⫻ A (C 1 ⫺ C 2 )

Diffusion rates increase when a molecule’s velocity increases

diffusion coeffi cient. The coeffi cient is proportional to temperature and in- versely proportional to molecular radius and the viscosity of the medium through which it diffuses

A molecule’s partition coeffcient is determined by measuring its solubility in oil compared with water.

Net diffusion rate slows when molecules have to traverse thick membranes compared with thin ones

Increasing the surface area available for diffusion also increases the rate of diffusion

The rate at which molecules diffuse across a membrane is directly proportional to the concentration difference between the two sides of the membrane

Pores are integral membrane proteins containing unregulated, water- filled passages that allow ions and other small molecules to cross the membrane. Pores are relatively uncommon in higher organisms because they are always open and can support very high transit rates

Ions (sodium [Na⁺], potassium [K⁺], chloride [Cl^-], and calcium [Ca²⁺]) flow through cardiac membrane channels with pores formed by proteins, with these ion channels encoded by specific genes [3]. The pore-forming protein is called the alpha subunit, which also contains the voltage-dependent sensors and gates. For many ion channels, one or more secondary regulatory subunit proteins are present (usually named beta, gamma, delta, and so on) in association with the alpha subunit, and many ion channel proteins have subunit isoforms adding to their complexity

The dominant channel types in heart cells are Na⁺ channels (I_Na), L-type and T-type Ca²⁺ channels (I_Ca-L, I_Ca-T), and several K⁺ channels (I_K1, I_to1, I_to2, I_Kr, I_Ks). The sodium-potassium pump and the sodium-calcium exchanger are not considered channels because they require energy to drive ions across the membrane against their gradients, however they do generate currents (figure 1).

The resting cardiac cell membrane potential is normally polarized between -80 and -95 mV, with the cell interior negative relative to the extracellular space. The resting membrane potential is determined by the balance of inward (Na⁺ and Ca²⁺) and outward (K⁺) currents and the corresponding equilibrium potentials of these currents

In the heart, the resting membrane potential is generated by the inward rectifier current (I_K1), which is the predominant open channel at rest. Potassium current I_K1 flowing through this channel continues until the interior negative potential is at the same magnitude as the equilibrium potential for potassium. Only small amounts of actual potassium flow are required to maintain this potential. The equilibrium potentials for sodium and calcium are positive (approximately +40 mV and approximately +80 mV, respectively) so that when these channels are open, they tend to depolarize the membrane.

Voltage-sensitive sodium, calcium, and potassium channels play only a small role in the resting state since most of these channels are closed [5,6]. The Na-K-ATPase pump maintains the potassium and sodium gradients by pumping potassium into and sodium out of the cells. The Na-Ca exchanger uses the power of the Na gradient to pump Ca out of the cell

Action potential in fast response tissues —

Tissues that depend upon the opening of voltage-sensitive, kinetically rapid (opening in less than a millisecond) sodium channels to initiate depolarization are called fast response tissues [7].

Fast response tissues include the atria, the specialized infranodal conducting system (bundle of His, fascicles and bundle branches, and terminal Purkinje fibers), and the ventricles (figure 2), while the sinoatrial (SA) and atrioventricular (AV) nodes represent slow response tissues.

It is important to recognize that accessory AV pathways (ie, bypass tracts) associated with Wolff-Parkinson-White syndrome are derived from the atria and are thus also fast response tissues dependent upon sodium current for depolarization.

Phase 0 — Rapid depolarization (phase 0) occurs when the resting cell is brought to threshold, leading sequentially to activation or opening of voltage-dependent sodium channels, rapid sodium entry into the cells down a favorable concentration gradient, and a cell interior positive potential that can approach +45 mV. The marked depolarization initiates voltage-dependent inactivation of the sodium channels. Calcium channels also open during depolarization, but the inward calcium flux is much slower.

Phase 1 — Phase 1 repolarization often inscribes a "notch" and is primarily caused by activation of the transient outward potassium currents (I_to) combined with a corresponding rapid decay of the sodium current. The degree of repolarization in phase 1 is dependent on the density of I_to and varies between cardiac chambers and regions within chambers.

Phase 2 — Following initial repolarization in phase 1, phase 2 represents a plateau that lasts for hundreds of milliseconds and distinguishes the cardiac action potential from nerve and skeletal muscle action potentials, which are significantly shorter. Late inactivating depolarizing calcium and sodium currents are balanced by activating repolarizing potassium currents to maintain the plateau, which is often down-sloping as repolarizing currents begin to dominate.

Phases 3 and 4 — The final rapid repolarizing phase 3 is driven by the decay of the calcium current and progressive activation of repolarizing potassium currents (I_Kr, I_Ks). Terminal repolarization toward the potassium equilibrium potential is dominated in phase 3 by I_K1, which then maintains the resting membrane potential (phase 4).

In the resting state, the channels can be opened positive to the threshold potential. In comparison, the inactivated channel cannot be activated until it cycles or "recovers" to the resting state. These different states are important clinically, since, for example, some antiarrhythmic drugs (such as the class I antiarrhythmic drugs) preferentially bind to open and inactivated sodium channels

Action potential in slow response tissues — The SA and AV nodes represent slow response tissues, which have different properties from the fast response tissues (table 1). Phase 0 depolarization depends on an inward calcium (not sodium) current via L-type calcium channels [10]. These channels are selective for calcium, have a slower conduction velocity than the sodium channels, and take longer to reactivate.

In some cases, as with tissue damage or changes in the extracellular milieu, fast response tissues can be converted to slow response tissues. In this setting, sodium channels become inactivated and depolarization is dependent upon the slow calcium channels.

The gap junctions are actually active, opening and closing in response to changes in pH, calcium, and, at times, voltage.

In addition to ion flow and gap junction resistance, impulse propagation can also be affected by the orientation of fibers and of the collagen matrix in which the fibers reside

In 1812, the British ophthalmologist James Ware relayed a curious finding to the members of the Royal Society in London

L’efficacité des anti-infectieux résulte en général du rapport entre la concentration de la molécule active obtenue au niveau du site d’action et la sensibilité du micro-organisme à cette molécule.

t MB $.* FTU MB QMVT QFUJUF DPODFOUSBUJPO QFS- mettant d’inhiber la multiplication du micro- organisme ; t MB $.& T BQQMJRVF Ë DFSUBJOT BOUJGPOHJRVFT vis-à-vis des champignons filamenteux, et est la plus petite concentration permettant d’obtenir une altération morphologique du champignon ; t M *$ 50 , qui s’applique essentiellement aux anti- viraux, est la plus petite concentration permet- tant d’inhiber 50 % de la réplication virale.

Les molécules dont l’activité est essentiellement bactério-/fongistatique néces- siteront donc l’apport du système immunitaire pour éradiquer le micro-organisme. À l’inverse, les molécules fongicides/bactéricides ne néces- sitent pas l’action du système immunitaire et seront donc privilégiées dans toutes situations d’immunosuppression, qu’elles soient systé- miques (neutropénie, etc.) ou limitées au foyer infectieux (endocardite, méningite, etc.).

L’acti- vité fongicide/bactéricide sera d’autant plus mar- quée que les concentrations minimales fongicides et bactéricides (CMF et CMB : concentrations qui réduisent un inoculum d’au moins 99,9 %) seront peu différentes des CMI.

Les critères PK/PD prédictifs de l’efficacité sont les rapports C max /CMI et AUC/CMI

Degrees of freedom is a critical core concept within the field of statistics

Le paramètre PK/PD prédicitif de l’efficacité est donc le pourcentage de temps entre deux administrations ou sur 24 heures pendant lequel la concentration en antibiotique est supérieure à la CMI ou à un multiple de la CMI (T > CMI ou le fT > CMI si l’on considère la fraction libre)

Parmi les antibiotiques et les antifongiques, cer- tains seront également sensibles à l’effet inocu- lum. Cet effet se traduit par une augmentation de la CMI en présence d’un inoculum bactérien ou fongique important. Les molécules sensibles à cet effet, comme les bêtalactamines et l’amphotéricine B, verront donc leur efficacité diminuer dans les infections sévères à fort inoculum.

Dans le cas des antiviraux, l’efficacité serait cor- rélée au maintien de la concentration au-dessus d’un certain seuil d’efficacité, lequel pourrait correspondre à l’IC 50 , sans que cela ait été for- mellement démontré.

That bothered me increasingly until I bought a Kindle which had 'highlight' functionality and virtual keyboard; and I had discovered it to help a lot with recalling.

L’importance du mode d’administration vis-à-vis de l’efficacité a été démontrée dans de nombreuses études. Par exemple, l’efficacité des aminosides dans les infections à bacilles à Gram négatif, qui est liée au rapport C max /CMI, est meilleure lorsqu’ils sont administrés en dose unique journalière que lorsque la dose journalière est divisée en deux ou trois prises

Leur éradication nécessite donc un niveau de concentration plus élevé. L’objectif est en fait de dépasser un certain seuil de concentration appelé « concentration prévenant l’émergence de mutants » (CPM). Atteindre cette concentration limite l’émergence de mutants résistants. La zone de concentration située entre la CMI des micro-organismes sen- sibles et cette CPM est appelée « fenêtre de sélec- tion de mutants ».

%BOT MF DBT E BENJOJTUSBUJPO FO DPOUJOV TDIÏNB privilégié pour les antibiotiques à activité temps- dépendante, le prélèvement devra être fait au « plateau », lorsqu’on aura atteint l’équilibre phar- macocinétique ou l’état dit « stationnaire », soit après 5 à 7 demi-vies du médicament concerné.

Hypothes.is is a clear winner for me on desktop and I'm using Instapaper for offline reading on Android.

Three distinct mechanisms underlie tachyarrhythmia induction: enhanced automaticity, reentry, and triggered activity

Enhanced automaticity — Enhanced automaticity refers to abnormal phase 4 diastolic depolarization, and occurs when spontaneous depolarization develops during diastole (figure 5). While this is a normal phenomenon in nodal cells, and with subsidiary pacemakers at slower rates in all myocardial cells, enhanced or abnormal automaticity may lead to tachyarrhythmia. A typical example is automatic (ie, focal) atrial tachycardia. Common automaticity stimulants include excess catecholamine or situations causing hypoxia, acidosis, or ischemic related metabolites.

Critical components for reentry include both of the following:

● The presence of fast and slow conduction with varying refractory/recovery periods

● A fixed or functional core about which the circuit moves

Interventions to terminate reentrant arrhythmias differ from other mechanisms and are generally geared to modify the critical components of the reentrant circuit. Blocking Na⁺ or Ca²⁺ channels can slow or block conduction, while blocking K⁺ channels prolongs the action potential and therefore increases refractoriness

Triggered activity — Triggered activity refers to a depolarization that occurs after the initial depolarization wavefront and comes in two forms, either early or late. Secondary depolarizations that occur before the action potential has fully repolarized are early afterdepolarizations (EADs) (figure 5). Those that occur after the action potential has fully repolarized are delayed afterdepolarizations (DADs) (figure 5). Both EADs and DADs depend on the previous action potential to trigger them, hence an afterdepolarization is said to be a triggered arrhythmia. However, it is important to understand that DADs and EADs differ in mechanism.

EADs — EADs are triggered during prolonged action potentials. A prolonged action potential allows a longer window for reopening of L-type Ca²⁺ channels during phase 2 (or occasionally phase 3) of the action potential. L-type Ca²⁺ current depolarizes the membrane before repolarization, triggering an afterdepolarization. Due to L-type Ca²⁺ channel time and voltage dependence, EADs occur at slow stimulation rates or after a ventricular pause when action potential duration (phase 2) is prolonged and they are suppressed with faster heart rates. EADs are thought to initiate the polymorphic ventricular arrhythmias torsades de pointes (TdP) found in inherited and acquired long QT syndrome (LQTS), for example drug-induced LQTS

DADs — DADs, which result from intracellular Ca²⁺ overload, are triggered after the action potential is fully repolarized. Under conditions of Ca²⁺ overload, Ca²⁺ taken back up by the sarcoplasmic reticulum is then transiently re-released into the cytoplasm. This in turn causes a transient rise in cytoplasmic Ca²⁺ activating Ca²⁺-dependent depolarizing membrane current mostly through the Na⁺-Ca²⁺ exchanger. The exchange of three Na⁺ for two Ca²⁺ produces a net inward and transient depolarization or a DAD.

Conditions which enhance cellular Ca ²⁺ loading, such as rapid heart rates, enhance DAD susceptibility

Certain arrhythmogenic substrates are common, such as those induced by ischemia or infarction. In this setting, a certain effect of a drug becomes predominant and predictable, as with class I activity in ischemia, and a drug classification appears accurate. However, the major drug effect may be quite different if a different proarrhythmic substrate exists. Consider, for example, the differences in digitalis action in hypokalemia and hyperkalemia.

Class 0 — Drugs in the newly proposed Class 0 modulate the pacemaker channel HCN4, affecting the pacemaker current I_f [11]. The blocker ivabradine slows heart rate.

Class I — The class I drugs act by modulating or blocking the sodium channels, thereby inhibiting phase 0 depolarization. They are all at least in part positively charged and presumably interact with specific amino acid residues in the internal pore of the sodium channel.

● The class Ic agents have the slowest binding and dissociation from the binding site.

● The class Ib agents have the most rapid binding and dissociation from the binding site.

● The class Ia agents are intermediate in terms of the speed of binding and dissociation from the binding site.

During faster heart rates, less time exists for the drug to dissociate from the receptor, resulting in an increased number of blocked channels and enhanced blockade. These pharmacologic effects may cause a progressive decrease in impulse conduction velocity and a widening of the QRS complex. This property is known as "use-dependence" and is seen most frequently with the class Ic agents, less frequently with the class Ia drugs, and rarely with the class Ib agents

Class Ia drugs (quinidine, procainamide, and disopyramide) depress phase 0 (sodium-dependent) depolarization, thereby slowing conduction. They also have moderate potassium channel blocking activity (which tends to slow the rate of repolarization and prolong action potential duration [APD])

Class Ia agents also have anticholinergic activity and tend to depress myocardial contractility. At slower heart rates, when use-dependent blockade of the sodium current is not significant, potassium channel blockade may become predominant (reverse use-dependence), leading to prolongation of the APD and QT interval and increased automaticity

One difference between the drugs is that quinidine and procainamide generally decrease vascular resistance, whereas disopyramide increases vascular resistance.

The class Ib drugs (lidocaine and mexiletine) have less prominent sodium channel blocking activity at rest, but effectively block the sodium channel in depolarized tissues.

Class Ic drugs (flecainide and propafenone) primarily block open sodium channels and slow conduction. They dissociate slowly from the sodium channels during diastole, resulting in increased effect at a more rapid rate (use-dependence). This characteristic is the basis for their antiarrhythmic efficacy, especially against supraventricular arrhythmias. Use-dependence may also contribute to the proarrhythmic activity of these drugs, especially in the diseased myocardium, resulting in incessant ventricular tachycardia

Flecainide and propafenone also have potassium channel blocking activity and can increase the APD in ventricular myocytes. Propafenone has significant beta blocking activity.

Class II — Class II drugs act by inhibiting sympathetic activity, primarily by causing beta blockade. They may also have a mild inhibitory effect on the sodium channels.

Sympathetic stimulation has the following potential proarrhythmic actions [ 17]:

● An increase in automaticity due to enhancement of phase 4 spontaneous depolarization (see "Enhanced cardiac automaticity").

● An increase in membrane excitability due to shortening in refractoriness (phases 2 and 3 of the action potential).

● An increase in the rate of impulse conduction through the myocardial membrane, resulting from acceleration of phase 0 upstroke velocity or the rate of membrane depolarization.

● An increase in delayed afterpotentials, especially when the cell is calcium loaded, such as in digoxin toxicity.

By blocking catecholamine and sympathetically mediated actions, beta blockers slow the rate of discharge of the sinus and ectopic pacemakers, and increase the effective refractory period of the AV node. They also slow both antegrade and retrograde conduction in anomalous pathways [18].

Carvedilol is a beta-blocker with unique additional properties. In addition to beta- and alpha-adrenergic blockade, carvedilol can also block potassium (KCNH2, formerly HERG), calcium, and sodium currents and modestly prolong APD. However, when administered chronically, carvedilol increases the number of these channels, which is probably a favorable effect in diseased hearts [19].