Lidocaine hydrochloride. 2-(Diethylamino)-2',6'-acetoxylidide monohydro-chloride. This drug was conceived as a derivative of gramine (3-dimethyla-minomethylindole) and introduced as a local anesthetic, is now being used intravenously as a standard parenteral agent for suppression of arrhythmias associated with acute myocardial infarction and cardiac surgery.
Lidocaine is the drug of choice for the parenteral treatment of premature ventricular contractions. Lidocaine hydrochloride administration is limited to the parenteral route and is usually given intravenously, though adequate plasma levels are achieved after intramuscular injections. Lidocaine hydrochloride is not bound to any extent to plasma proteins and is concentrated in the tissues. It is metabolized rapidly by the liver. The first step is deethylation, with the formation of monoethylglycinex-ylidide, followed by hydrolysis of the amide (43). Metabolism is rapid, the half-life of a single injection ranging from 15 to 30 min. Lidocaine hydrochloride is a popular drug because of its rapid action and its relative freedom from toxic effects on the heart, especially in the absence of hepatic disease. Monoethylglycinexylidide, the initial metabolite of lidocaine, is an effective antiarrhythmic agent; however, its rapid hydrolysis by microsomal amidases prevents its use in humans.
2-Amino-2',6'-propionoxylidide hydrochloride. Tocainide hydrochloride (pKa 7.7) is an analogue of lidocaine. It is orally active and has electrophysiological properties similar to lidocaine (44). Total body clearance of tocainide hydrochloride is only 166 mL/min, suggesting that hepatic clearance is not large (Fig. 3).
Because of low hepatic clearance, the hepatic extraction ratio must be small; therefore, tocainide hydrochloride is unlikely to be subject to a substantial first-pass effect. The drug differs from lidocaine in that it lacks two ethyl groups, which provides tocainide hydrochloride some protection from first-pass hepatic elimination after oral ingestion. Tocainide hydro-chloride is hydrolyzed in a manner similar to lidocaine. None of its metabolites are active.
Figure 3 Tocainide hydrochloride.
Figure 3 Tocainide hydrochloride.
Class IC: Antiarrhythmic Agents
Encainide hydrochloride. 4-Methoxy-N-[2-(1-methyl-2-piperidinyl) phenyl] benzamide monohydrochloride. Encainide hydrochloride is a benzanilide derivative that has local anesthetic properties in addition to its class le antiarrhythmic action.
The drug is metabolized extensively, producing products that also have antiarrhythmic properties (45). The metabolite, 3-methoxy-O-demethylencai-nide, is about equipotent to encainide hydrochloride. O-Demethylencainide is considerably more potent than the parent drug.
The half-life of encainide hydrochloride is 2-4 h. The active metabolites have longer half-lives, estimated as being up to 12 h, and may play an important part in the use of this drug in long-term therapy. Encainide hydrochloride also undergoes N-demethylation to form N-demethylencainide.
Flecainide acetate. N-(2-Piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy) benzamide monoacetate. It is a chemical derivative of benzamide. The drug undergoes biotransformation, forming a meta-O-dealkylated compound, the antiarrhythmic properties of which are one-half as potent as those of the parent drug, and meta-O-dealkylated lactam of flecainide (46) with little pharmacological activity. Flecainide acetate has some limitations because of central nervous system side effects (Fig. 4).
Lorcainide hydrochloride. N-(4-Chlorophenyl)-N-[1-(1-methylethyl)-4-pi-peridinyl]benzeneacetamide monohydrochloride. Lorcainide hydrochloride undergoes metabolic N-dealkylation to produce norlorcainide. Metabolism is the product of the first-pass clearance after oral administration. The basis for this observation is that norlorcainide is not produced in significant amounts in the body following intravenous administration. Norlorcainide is an important metabolite of the parent drug, as it is cleared slowly from the body and has a half-life that is approximately three times longer. Accumulation of norlorcainide is of considerable clinical importance because the metabolite is equipotent to the original drug (Figs. 5 and 6).
Figure 4 Flecainide acetate.
Figure 4 Flecainide acetate.
Figure 5 Lorcainide hydrochloride.
Moricizine, ethyl 10-(3-morpholinopropionyl)phenothiazine-2-carbamate, is a phenothiazine derivative used for the treatment of malignant ventricular arrhythmias.
New Chemical Entities
SUN-1165 contains the highly basic pyrolizidinyl moiety of the less basic diethylamine group of lidocaine (47). Electrophysiological studies in vitro revealed that SUN-1165 is a class 1B drug (48,49). Compared to lidocaine and disopyramide, the compound had less central nervous system (CNS) toxicity and anticholinergic activity respectively (Fig. 7) (50).
Recainam (WY-423262) is class IB lidocaine-like drug. Therapeutic intravenous doses failed to produce CNS or negative inotropic (51) side effects in dogs, and the drug safely and effectively reduced premature ventricular contractions (52) in man (Fig. 8).
Droxicainide (ALS-1249) was reported to have antiarrhythmic and local anesthetic properties (53,54) that are qualitatively similar to lidocaine, but
Figure 6 Norlorcainide.
Figure 7 SUN.
with a better therapeutic index over 24 hour period in infarct dogs (55) than lidocaine. The piperidine and azepine analogues of droxicainide (56) which lack the hydroxyethyl moiety are also active (Fig. 9).
Electrophysiological studies showed that ACC-9358 is a class I agent
Disopyramide continues to serve as a prototype for new antiarrhythmics. A series in which the phenyl group of disopyramide was replaced with alkyl moieties (57) was synthesized. One of the compounds in this series, propisomide (CM-7857), was reported to possess a longer duration of action, fewer neurologic and gastrointestinal (58) and less anticholinergic activity than disopyramide. As with disopyramide, the major metabolite (59) in both plasma and urine was the mono-N-dealkylated analogue. A single dose of propisomide was compared to a variety of other antiarrhythmics in 10 patients. The compound (60) was effective in 6; it increased PQ intervals, and had no effects on QRS or QT intervals (Fig. 11).
AHR-10718 is the optimal compound in a series of aminoethylureas that suppressed arrhythmias in the ouabain-intoxicated and Harris dog models. The drug caused a use-dependent decrease in action potential upstroke velocity (Vmax), Purkinje fibre (61) conduction on velocity and APD
Figure 8 Recainam (WY-423262).
Figure 8 Recainam (WY-423262).
Figure 9 Droxicainide (ALS-1249).
Carocainide, a benzofuran antiarrhythmic, decreased Vmax in isolated papillary muscle and Purkinje fibres: it decreased the plateau amplitude and APD. The antagonized digitalis and infarction induced arrhythrnias (62-64) in dogs (Fig. 13).
E-0747 was more potent than quinidine, disopyramide, lidocaine, or phenytoin. Moreover, at therapeutic doses, the compound appeared to have low potential (65) for cardiodepression (Fig. 14).
Indecainide (L Y135837)
Indecainide, is a potent class IC antiarrhythmic agent (66,67) with an exceptionally long half-life time (52 seconds) for recovery (66) from sodium channel block. This compound was more potent than either aprindine or disopyramide against ouabain or Harris arrhythmias in dogs (Fig. 15).
ROLE OF PROTEINS IN CARDIOLOGY AND INTRACELLULAR SIGNALLING
Ischemia injury can result in cell death and irreversible loss of function in a variety of biological systems. The sequential events that produce this cardiac dysfunction include a decreased endothelial release of nitric oxide (NO), up-regulation of adhesion molecules on the endothelial surface leading to enhanced leukocytes-endothelium interaction and release of superoxide radicals. These radicals are largely responsible for producing cardiac dysfunction and enhanced necrosis. The time course of these events starts at 2.5-5 min post-reperfusion.
Cardiovascular Pharmacology C>
Figure 11 Proplsomide (CM-7857).
Cardiovascular Pharmacology C>
Figure 11 Proplsomide (CM-7857).
An understanding of the intracellular signalling mechanisms by which cells protect themselves against ischemia-induced damage bears great clinical significance with respect to the treatment and prevention of tissue injury. Cells start to generate agonists especially those that signal via Ga1, such as adenosine, acetylcholine, opioids and bradykinin, which bind to G protein coupled receptors (GPCR) and initiate a signalling cascade that involves activation of phosphoinositide-3-kinase (PI3K), endothelial NO synthase, tyrosine kinase, protein kinase c, glycogen synthase, mitogen-activated protein kinases, and other signalling pathways.
Activation of these signalling pathways along with generation of reactive species leads to alterations in the activity of key mitochondrial proteins such as mitochondrial ATP-sensitive K+ channels and the mitochondrial permeability transition pore. Alterations on these mitochon-drial proteins results in altered metabolism and inhibition of cell death, thus resulting in cardioprotection (Fig. 4).
Activation of GPCR leads to signalling via Gal and GPy and initiates a signalling cascade. Acetylcholine-induced protection leads to activation of PI3K pathways via GPCR transactivation of the epidermal growth factor, which also signals through GPy and lead to activation of PI3K. At the same time activation of GPCR lead to activation of mitogen-activated protein kinase (MAPK) pathway via Ga-dependant signalling, by transactivation of the epidermal growth factor; MAPK pathway operate through sequential phosphorylation events to phosphorylate transcription factors and regulate gene expression (Fig. 4).
PI3K generates phosphoinositides that localize kinases, such as phosphoinositide-dependant kinase (PDK), with substrates, leading to
Figure 13 Carocainide (MD770207).
activation of downstream kinases such as protein kinase B (PKB, also known as Akt), mammalian target of rapamycin (mTOR) and p70S6-kinase. Both PDK1 and PKB play an important role in the activation of p70S6 kinase. PDK1 phosphorylation of thr 229 is required for activation of p70S6K. Prior phosphorylation of thr 389 by mammalian target of rapamycin (mTor) is necessary before PDK1 can phosphorylate thr 229.
At the same time PKB phosphorylates and activates endothelial NO synthase (eNOS) and phosphorylates and inactivates GSK3P and the proapoptic BAD. PI3K also play a role in the activation of protein kinase C (PKC), but the precise role of PI3K has not been determined; some studies suggested that PI3K activation of PKCg occurs via an eNOS-mediated mechanism.
However, another study (68) suggested that the reactive oxygen species (ROS), is generated by preconditioning is involved in activation of PKC. With regards to PKC there is increasing evidence for functional coupling of PKC to tyrosine kinase in the heart. Both PKC and tyrosine kinase show a cardioprotective effect via activation of transcription regulatory protein nuclear factor (NF-KB) which occur through both tyrosine and serine phosphorylation of IKBa (Fig. 16).
Furthermore PKC activation has been shown to be important in activation of the mitoKATP channel, at the same time NO has been shown to activate mitoKATP channel. PKCg also forms a complex with the components of the mitochondrial permeability transition (MPT) pore. However, the association of PKCg with components of the MPT pore does not demonstrate that this association is important in modulating MPT or cardioprotection. This study also reported that ERK and PKCg are contained in a multimeric mitochondrial signalling complex and that PKCg may lead to activation of ERK in this complex. One study reported that KATP channel
Figure 15 Indecainide (LY135837).
opening can lead to activation of ERK, which is likely to be secondary to ROS generated opening of the mitoKATP channel (Fig. 16).
This disease is usually caused by atherosclerosis which narrows the coronary arteries. Common risk factors include hypertension, genetic disposition, smoking, diabetes, and hyperlipidemia amongst a variety of other conditions (69). The manifestations of ischemic heart disease frequently results in sudden death, myocardial infarction or angina pectoris.
The nitrates in the body dilate blood vessels in three areas: viz. (i) venous circulation, which decreases venous return and preload on the heart, (ii) the arterioles, which reduce peripheral resistance and afterload. Both reduce stress on the myocardial wall and lower oxygen demand, (iii) the coronary arteries, especially in the presence of coronary spasm to improve the oxygen supply.
A large number of patients tend to be tolerant to the anti-anginal effects of the nitrates as a result of depletion of the essential thio (-SH) groups especially if they are taken for prolonged periods (usually for more than 24 h). Whenever it is necessary to prescribe, a nitrate-free period must be built-in into the treatment regimen on an individual basis for each patient.
The nitrates are converted in the body to NO. This in combination with sulphydryl (-SH) groups forms nitrosothiols which thus activate the enzyme guanylyl cyclase to produce the secondary messenger, cyclic GMP. This causes the smooth muscle to relax with vasodilatation.
Typical examples of nitrates: Glyceryl trinitrate is well absorbed sublingually but, if taken orally, it is broken down by the liver by first pass metabolism. Isosorbide dinitrate (can be taken sublingually, orally or intravenously although, the absorption rate is slow, its duration of action is much longer). Isosorbide mononitrate may be taken orally but in general, its use is limited for practical reasons.
These types of drugs block the beta-adrenoceptors, that is, both beta-1 and beta-2, which are present in the heart to reduce the production of cyclic AMP. The beta-blockers may be either non-selective and block both types of beta-receptors, or sufficiently selective to bind to beta-1 receptors. The beta-blockers slow the heart and thereby reduce its force of contraction and decrease oxygen demand. On the other hand, they may also increase oxygen supply in response to a diastole when most of the blood flow in the coronary arteries is extended. Typical examples of beta-blockers: Atenolol: is a hydrophobic beta-1-selective blocker. Propranolol, is lipophilic and a non-selective beta-blocker and Metaprolol, is a lipophilic beta-1-selective blocker.
Clinical uses include:
2. angina pectoris,
3. following myocardial infarction, beta-1-selective blockers cause a reduction in risk of recurrence,
4. useful in anxiety and manifestations of anxiety such as tremor and depression,
The calcium-channel blockers (antagonists) act by antagonising the movement of calcium through channels in the cell membranes. In cardiac muscle or vascular smooth muscle, any change in membrane potential causes calcium to enter the cell through the calcium channels that are voltage-dependent. The calcium channel blockers reduce the force of contraction of the heart and thus slow the heart rate in vitro. They also reduce smooth muscle contraction, and act as vasodilators of coronary and systemic arteries and alter cardiac rhythm.
Activity of calcium antagonists: Calcium antagonists inhibit the slow inward current caused by entry of extra cellular calcium through the cell membrane of excited cells, particularly arteriolar smooth muscles, and cardiac arterial cells.
Calcium ions play an essential role in the regulation of skeletal and smooth muscle contractility in the performance of the normal and diseased heart. The treatment of hypertension with the introduction of calcium channel blockers (CCBs), was a major breakthrough was infact approached when it was discovered that vascular smooth muscle is linked to the movement of calcium ions with the muscle cells from extra-corporeal circulation.
The channels in the cell membrane are normally occupied by calcium ions bound to receptor storage sites and function as voltage-dependant ionic gates. Their opening is controlled by the electronic gradient across the cell membrane. The gates open and allow the calcium ions to enter the vascular muscle cells upon stimulation by noradrenaline, which is released from the nerve endings. This causes the muscle cell system to contract in order to maintain blood pressure. Excessive stimulation, increases the heart rate and myocardial oxygen demand resulting in chronic hypertension and coronary spasm, causing a severe chest pain (angina).
Regulation of calcium channel blockers: There are three major types of calcium channels blockers, viz. (1) voltage-dependent, (2) receptor-operated, and (3) stretch operated.
1. Voltage (potential)-dependent Ca2+-channels (homologous to Na+ and K+ channels, consist of at least three types in the body, L, T, and N). L-type channels:
i. have large sustained conductance, become slowly inactive and are widespread in the cardiovascular system;
ii. are responsible for the plateau phase (slow inward current) of action potential;
iii. may trigger release of internal Ca 2+;
iv. are sensitive to Ca 2+ channel blockers.
Cardiac L-channels are regulated by cAMP-dependent protein kinase.
i. are structurally similar to L-type channels;
ii. become inactive rapidly;
iii. are involved in cardiac pacemaker activity, growth regulation and triggering contraction of vascular smooth muscles.
T-type channels are not very sensitive to most of the L-type Ca2+-channel blockers.
They are found only in neuronal cells and are not very sensitive to Ca2+-channel blockers used for treating cardiovascular disorders.
2. Receptor-operated Ca2+-channels (e.g. alpha-adrenergic receptors): not very sensitive to Ca2+-channel blockers.
3. "Stretch" operated Ca2+ channels are not particularly important in maintaining vascular smooth muscle tone as they do not appear to be sensitive to Ca2+- channel blockers.
Two types of calcium channel blockers are used in clinical situations: those which are selective for L-type (long-lasting, large-currents, or slow) and those that are non-selective. In clinical practice, selective agents are primarily used.
The selective calcium channel blockers share a similar antihypertensive mechanism of action: they inhibit the influx of extracellular calcium through L-type channels, resulting in relaxation of vascular smooth muscle and reduction in vascular resistance.
The reason why calcium antagonists are useful as drugs is probably because they are a heterogeneous group of compounds which have marked differences in chemical structure, binding sites, tissue selectivity, clinical activity, and therapeutic effect.
Calcium antagonists are chemically and pharmacologically a diverse groups of drugs. These include verapamil and its analogues, the benzo-1,5-thiazepine related to diltiazem and the 1,4-dihydropyridines, for example, nifedipine. These were briefly discussed earlier.
Typical examples of calcium-channel blockers: There are generally three types of calcium-channel blockers. They bind to different although related receptor sites on the calcium channel. Their effects vary with different tissues.
1. Verapamil is less effective on peripheral circulation but more active on the heart. It slows the heart and reduces the force of contraction and can be taken orally or intravenously.
2. Diltiazem is more effective on the heart compared with nefedipine and is more active on peripheral circulation than verapamil. It is metabolised by the liver.
3. Dihydropyridines: Examples are nifedipine, nitrendipine, nimodipine, nislodipine and felodipine. They mainly cause arterial vasodilatation and reduce blood pressure and afterload on the heart i.e. the load against which the heart ejects blood. It increases heart rate and the force of contraction. Nefedipine is orally well absorbed and is metabolised by the liver. It can be used in combination with beta-blockers in angina or hypertension. Although rare, combination therapy may precipitate heart failure. Verapamil in combination with beta-blockers has been reported to be dangerous especially when administered intravenously. It can cause severe hypotension and bradycardia.
The pharmacological effects of the newer types of dihydropyridine drugs show that they can improve efficacy and vascular selectivity with a longer duration of action.
Clinical uses include:
2. angina, especially due to coronary artery spasm;
3. Raynaud's phenomenon (nefedipine);
4. supraventricular tachycardia (verapamil).
The binding sites for all three chemical types of calcium channel blockers are present in many tissues, including myocardium, smooth muscle, skeletal muscle, and glandular tissue. Each of the three selective calcium channel blockers interact with a specific receptor domain found on a large membrane-spanning protein that constitute a substantial portion of the L-type, voltage dependent calcium channel.
These receptor sites are all located on the surface on the alpha subunit of the channel. The 1,4-dihydropyridine receptor is most accessible and is located on the surface of the channel. This receptor has been the most widely studied of the three groups, and therefore a relatively greater number of dihydropyridines have been designed to bind and inhibit at that site.
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