Triamterene Action Pathway,Drug Action

Triamterene is a diuretic that belongs to the potassium-sparing class of drugs which are commonly used to manage hypertension and edema. It acts by blocking epithelial sodium channels in the late distal convoluted tubule of the nephron. Specifically, triamterene inhibits amiloride-sensitive sodium channels which are responsible for the reabsorption of sodium in the late distal convoluted tubule in the nephron. This primarily contributes to an increase in sodium excretion and consequentially, fluid excretion which decreases blood volume and blood pressure. Potassium secretion is indirectly affected by the inhibition of sodium reabsorption due to the elimination of the electrochemical gradient that drives potassium loss. This leads to an increase in serum potassium concentration -- a common action for potassium-sparing drugs -- and has the potential to induce hyperkalemia which can potentially lead to severe heart arrhythmias.


Amiloride Action Pathway,Drug Action

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Amiloride is a diuretic that inhibits the sodium channels in the late distal convoluted tubule and collecting tube of the nephron where 1-2% of sodium reabsorption occurs. The inhibition of sodium reabsorption results in increased osmolarity in the lumen and decreased osmolarity in the interstitium of the nephron. This decreased osmotic gradient results in a modest diuresis. The drug is also potassium sparing. Potassium is typically excreted due to the electrochemical gradient produced by sodium reabsorption. Therefore, amiloride's inhibition of sodium reabsorption fails to produce an electrochemical gradient and therefore, inhibits potassium excretion. Amiloride causes an increase in sodium excretion and a decrease in potassium secretion. The drug is typically prescribed to patients with depleted potassium.


Spironolactone Action Pathway,Drug Action

Spironolactone is a potassium-sparing diuretic. It acts by competing with aldosterone for its receptor inside the principal cells of the late distal tubule and collecting tubule. Aldosterone increases sodium reabsorption and potassium excretion by up-regulating the expression of basolateral sodium-potassium ATPases as well as luminal (apical) sodium and potassium channels. Sodium in the nephron lumen enters the principal cells through the luminal sodium channels, where it is then actively pumped out into the interstitium by sodium-potassium ATPases. This causes the interstitium to become hyperosmotic and establishes an osmotic gradient, facilitating water reabsorption through aquaporin channels. On the other hand, potassium is actively pumped from the interstitium into the principle cell. It then diffuses from inside the cell into the nephron lumen via potassium channel, driven by an electrochemical gradient established by sodium leaving the lumen. Potassium entering the nephron lumen is subsequently excreted in the urine. Spironolactone inhibits sodium and water reabsorption as well as potassium excretion by blocking the actions of aldosterone as described above.


Eplerenone Action Pathway,Drug Action

Eplerenone is a potassium-sparing diuretic. It acts by competing with aldosterone for its receptor inside the principal cells of the late distal tubule and collecting tubule. Aldosterone increases sodium reabsorption and potassium excretion by up-regulating the expression of basolateral sodium-potassium ATPases as well as luminal (apical) sodium and potassium channels. Sodium in the nephron lumen enters the principal cells through the luminal sodium channels, where it is then actively pumped out into the interstitium by sodium-potassium ATPases. This causes the interstitium to become hyperosmotic and establishes an osmotic gradient, facilitating water reabsorption through aquaporin channels. On the other hand, potassium is actively pumped from the interstitium into the principle cell. It then diffuses from inside the cell into the nephron lumen via potassium channel, driven by an electrochemical gradient established by sodium leaving the lumen. Potassium entering the nephron lumen is subsequently excreted in the urine. Eplerenone inhibits sodium and water reabsorption as well as potassium excretion by blocking the actions of aldosterone as described above.


Azithromycin Action Pathway,Drug Action

Azithromycin, trade names include Zithromax and Azithrocin, is a semisynthetic azalide derived from erythromycin. Azalides are part of the macrolide antibiotic class. Azithromycin targets protein synthesis of bacteria by binding to the 50S subunit of the bacterial ribosome to inhibit mRNA translation and prevent bacteria growth. Macrolides are broad spectrum antibiotics. It is prescribed to treat bacterial infections including: sexually transmitted infections like chlamydia, pneumonia, strep throat, ear infections, sinusitis and more.


Clarithromycin Action Pathway,Drug Action

Clarithromycin, a semisynthetic macrolide antibiotic derived from erythromycin, is active against a wide range of microorganisms. Clarithromycin inhibits protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. Clarithromycin is effective against Mycobacterium avium complex (MAC) and is used for the treatment of Helicobacter pylori-associated peptic ulcer disease, community-acquired pneumonia, sinusitis, and chronic bronchitis. Clarithromycin is also used to treat respiratory tract, sexually transmitted, otitis media, and AIDS-related infections. Clarithromycin is first metabolized to 14-OH clarithromycin. Like other macrolides, it then binds to the 50S subunit of the 70S ribosome of the bacteria, blocking RNA-mediated bacterial protein synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump.


Clindamycin Action Pathway,Drug Action

Clindamycin is a natural antibiotic that produced by Streptomyces lincolnensis, which can be used for treating various bacterial infections by binding and inhibiting 23S portion of 50S subunit of ribosomes. Blocking the portion of ribosome can prevent transpeptidase reaction that will elongate peptide chain. Clindamycin has a bacteriostatic effect. It is used primarily to treat infections caused by susceptible anaerobic bacteria, including infections of the respiratory tract, skin and soft tissue infections, and peritonitis. In patients with hypersensitivity to penicillins, clindamycin may be used to treat infections caused by susceptible aerobic bacteria as well. Clindamycin may also be used in combination with chloroquine and quinine to treat malaria caused by Pasmodium falciparum. It is commonly used as a topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. Clindamycin may also be used to treat bone and joint infections, particularly those caused by Staphylococcus aureu


Erythromycin Action Pathway,Drug Action

Erythromycin is a bacteriostatic macrolide antibiotic antibiotic that can be used for treating various bacterial infections by inhibiting the bacterial protein synthesis. Erythromycin is produced from Streptomyces erythreus. Erythromycin can bind to 50S ribosomal subunits near the donor site reversibly. Blocking tRNA can prevent the translocation of peptides, which lead to inhibition of bacterial protein synthesis.


Roxithromycin Action Pathway,Drug Action

A member of the semi-synthetic macrolide class of antibiotics, roxithromycin is employed in infections of the respiratory tract, urinary, and soft tissue infections. Its macrocyclic lactone ring and deoxy sugars, defining features of macrolide antibiotics, mediates its mechanism of action as it inhibits peptide translocation by binding to the 50S subunit of the bacterial ribosome. Protein synthesis is thus inhibited by ribosomal binding. It has been demonstrated to have a longer half-life compared to other macrolide antibiotics such as erythromycin and is effective against certain Gram-negative bacteria.


Telithromycin Action Pathway,Drug Action

Telithromycin is a semi-synthetic erythromycin derivative. It belongs to the chemical family called ketolides, a group belonging to the macrolide-lincosamide-streptogramin (MLS) class. Telithromycin prevents bacterial growth by inhibiting bacterial protein synthesis. Similar to macrolides, telithromycin directly blocks translation of the bacterial 23S ribosomal RNA; however, unlike macrolides, telithromycin also blocks bacterial ribosomal assembly (mechanism not shown). Telithromycin binds to two sites on the 50S ribosomal subunit, domains II and V of the 23S rRNA, whereas macrolides bind only to domain V. The C11-12 carbamate side chain is thought to contribute to a higher binding affinity of telithromycin compared to erythromycin A. In erythromycin A-susceptible bacteria, telithromycin exhibits 10 times greater affinity than erythromycin. Its relative binding affinity is further increased to 25 times greater in macrolide-resistant bacteria strains. This is likely due to the additional binding site on domain II since macrolide resistance occurs as a result of alterations in the domain V binding site.


Amikacin Action Pathway,Drug Action

Amikacin is an aminoglycoside antibiotic that inhibits bacterial protein synthesis. Amikacin binds irreversibly to the bacterial 30S ribosomal subunit protein and 16S rRNA and prevents the formation of the initiation complex with messenger RNA. More specifically, amikacin binds four nucleotides of the 16S rRNA and a single amino acid of protein S12. This interferes with the decoding site in the vicinity of nucleotide 1400 in 16S rRNA of the 30S subunit. This region interacts with the wobble base of the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so that incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides, and the breakup of polysomes into nonfunctional monosomes. Aminoglycosides are useful in treating infections from mycobacteria such as, tuberculosis, and aerobic Gram-negative bacteria including, Pseudomonas, Acinetobacter and Enterobacter. Aminoglycosides can also treat Gram-positive bacterial infections but are inferior to other available antibiotics. Aminoglycosides may be used in combination with penicillin type antibiotics. Aminoglycosides are not an effective treatment for anaerobic bacteria, fungi and viruses.


Gentamicin Action Pathway,Drug Action

Gentamicin (also known as Garamycin) is an antibiotic that can be used to treat various bacterial infections by inhibiting bacterial protein synthesis. Gentamicin can bind on bacterial 30S ribosomal subunit protein and 16S rRNA irreversibly to inhibit the formation of mRNA. Since the binding site of gentamicin is the region that interacts with wobble base of anticodon of tRNA, hence, binding will cause misreading of mRNA, which lead to incorrect insertion of amino acids to polypeptide so that the polypeptide is non-functional or toxic. This prevents the bacterial protein synthesis which prevent the growth of the bacteria. Gentamicin is a class of aminoglycosides. Aminoglycosides can effectively against aerobic, Gram-negative bacteria, but it is ineffective against anaerobic bacteria, fungi and viruses.


Kanamycin Action Pathway,Drug Action

Kanamycin is an aminoglycoside antibiotic that can used for inhibiting protein synthesis of bacteria, which can be used for treating bacterial infections and tuberculosis. Kanamycin can bind to bacterial 30S ribosomal subunit protein and four nucleotides of 16S rRNA irreversibly to inhibit the formation of mRNA. Binding of kanamycin can interfere the vicinity of nucleotide 1400 in 16S rRNA that can interact with wobble base of the anticodon of tRNA, which lead to misreading of mRNA and wrong insertion of amino acids. The result is the nonfunctional or toxic peptides that is generated from the ribosome. Aminoglycosides can be used for treating bacterial infections from aerobic, Gram-negative bacteria and also Gram-postive bacteria. However, aminoglycosides may cause more damage to the host than other antibiotics for Gram-positive bacterial infection. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.


Neomycin Action Pathway,Drug Action

Neomycin is a member of the aminoglycoside family of antibiotics. As an aminoglycoside, neomycin can effectively against a wide variety of pathogenic bacteria such as E.coli, Citrobacter sp., etc. Neomycin can also effectively against Hemophilus influenzae, Salmonella sp. and others in vitro. However, netilmicin are ineffective against anaerobic bacteria, fungi and viruses. Neomycin binds irreversibly to the bacterial 30S ribosomal subunit protein and 16S rRNA and prevents the formation of the initiation complex with messenger RNA. More specifically, neomycin binds four nucleotides of the 16S rRNA and a single amino acid of protein S12. This interferes with the decoding site in the vicinity of nucleotide 1400 in 16S rRNA of the 30S subunit. This region interacts with the wobble base of the anticodon of tRNA. Binding of netilmicin can cause misreading of mRNA which result in insertion of incorrect amino acids to polypeptide. This lead to nonfunctional or toxic peptides of protein complex.


Netilmicin Action Pathway,Drug Action

Netilmicin is a member of the aminoglycoside family of antibiotics that is produced by fermentation of Micromonospora inyoensis. Netilmicin can effectively against a wide variety of pathogenic bacteria such as E.coli, Citrobacter sp., etc. Netilmicin can also effectively against Hemophilus influenzae, Salmonella sp. and others in vitro. However, netilmicin are ineffective against anaerobic bacteria, fungi and viruses. Netilmicin binds irreversibly to the bacterial 30S ribosomal subunit protein and 16S rRNA and prevents the formation of the initiation complex with messenger RNA. Binding of netilmicin can cause misreading of mRNA which result in insertion of incorrect amino acids to polypeptide. This lead to nonfunctional or toxic peptides of protein complex.


Spectinomycin Action Pathway,Drug Action

Spectinomycin (also named Togamycin or Trobicin) is an aminocyclitol antibiotic for the treatment of gonorrhea infections such as penicillin-resistant Neisseria gonorrhoeae (experimental studies shows that spectinomycin equips with bacteriostatic effect against most Neisseria gonorrhoeae strains). It is produced from Streptomyces spectabilis, which is a soil microorganism. Spectinomycin reversibly interferes with the interaction between mRNA and the bacterial 30S ribosomal subunit. It is structurally similar to aminoglycosides, but does not cause misreading of mRNA. It is structurally similar to aminoglycosides, but does not cause misreading of mRNA.


Streptomycin Action Pathway,Drug Action

Streptomycin (also named Gerox or Agrimycin) is an aminoglycoside antibiotic for the treatment of bacteria infections by inhibiting the synthesis of bacterial proteins. Streptomycin reversibly binds to 16S rRNA and the bacterial 30S ribosomal subunit so that the initiation complex with mRNA couldn't be formed. Binding of streptomycin on 16S rRNA's four nocleotides will lead to misreading of mRNA which result in insertion of incorrect amino acids into polypeptide. Nonfunctional or toxic peptides will lead to nonfunctional monosomes. Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. Infections caused by Gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past the aminoglycosides have been used in conjunction with penicillin-related antibiotics in streptococcal infections for their synergistic effects, particularly in endocarditis. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.


Demeclocycline Action Pathway,Drug Action

Demeclocycline is a tetracycline antibiotic that inhibits bacterial cell growth by inhibiting translation. It is lipophilic and can easily pass through cell membranes or passively diffuse through porin channels in bacterial membranes. Demeclocycline is bacteriostatic; it impairs bacterial growth but does not kill bacterial directly. Demeclocycline reversibly binds to the bacterial 30S and to a lesser extent the 50S ribosomal subunits. Binding prevents the amino-acyl tRNA from binding to the A site of the ribosome complex, which subsequently impairs protein synthesis. Demeclocycline may be used against susceptible strains of Rickettsiae (e.g. Rocky Mountain spotted fever, typhus fever, Q fever, rickettsial pox and Brill-Zinsser disease), Chlamydiae (psittacosis, lymphogranuloma venereum, uncomplicated sexually transmitted infections), Mycoplasma pneumoniae (PPLO, Eaton agent), Borrelia burgdorferi (Lyme disease), and some uncommon gram-negative infections caused by Brucella sp., Bartonella sp., Calymmatobacterium granulomatis, Vibrio cholera.


Doxycycline Action Pathway,Drug Action

Doxycycline is a long-acting tetracycline derived from oxytetracycline. Like minocycline, it is lipophilic and can diffuse through the lipid bilayer of bacteria. Doxycycline reversibly binds to the bacterial 30S ribosomal subunit and to a lesser extent the 50S subunit, blocking the binding of aminoacyl tRNA to the A site on the ribosome-RNA complex. Binding inhibits bacterial protein synthesis and hence cell growth. Doxycycline may be used to treat treat non-gonococcal urethritis and cervicitis, adult periodontitis, rosacea, inflammatory acne vulgaris and syphilis in patients allergic to penicillin. It may also be used as prophylaxis against chloroquine-resistant and/or mefloquine-resistant  P. falciparum, one of the species of malaria-causing parasites.


Minocycline Action Pathway,Drug Action

Minocycline is the most acitve tetracycline antibiotic that can prevent tRNA binding to 30S ribosomal of bacteria by blocking the 30S ribosomal subunit. Its lipid-solublable property allows it can pass lipid bilayers of membrane directly. Minocycline can also pass the membrane through porin channels in bacterial membrane. Due to blocking of 30S ribosomal subunit, activity of bacterial protein synthesis will be inihibited which lead to inhitation of further growth and colonization of bacteria.


Oxytetracycline Action Pathway,Drug Action

Oxytetracycline, the second of the tetracyclines discovered, is a broad-spectrum antibiotic. Oxytetracycline is lipophilic and easily passes through cell membranes or enters bacterial cells via membrane porin channels. Once inside the cell, it binds to the bacterial 30S ribosomal subunit and prevents aminoacyl tRNA from binding to the A site of the ribosome-RNA complex; binding inhibition likely occurs through steric hindrance. The overall effect is inhibition of bacterial protein synthesis and hence growth.


Tetracycline Action Pathway,Drug Action

Tetracycline is a short-acting antibiotic that is semi-synthetically produced from chlortetracycline, a compound derived from Streptomyces aureofaciens. Tetracycline enters bacterial cells by passively diffusing through membrane porin channels. Once inside the cell, tetracycline reversibly binds to the 30S subunit just above the binding site for aminoacyl tRNA. At its primary binding site, interactions with the sugar phosphate backbone of residues in helices 31 and 34 via hydrogen bonds with oxygen atoms and hydroxyl groups on the hydrophilic side of the tetracycline help anchor the drug in position. Salt bridge interactions between the backbone of 16S rRNA and tetracycline are mediated by a magnesium ion in the binding site. Tetracycline prevents incoming aminoacyl tRNA from binding to the A site on the ribosome-RNA complex via steric hindrance. This causes inhibition of protein synthesis and hence bacterial cell growth.


Lymecycline Action Pathway,Drug Action

Lymecycline is a tetracycline antibiotic that inhibits cell growth by inhibiting translation. Lymecycline is lipophilic and can diffuse across bacterial cell membranes or travel through membrane porin channels. Once inside the bacterial cell, it reversibly binds to the bacterial 30S ribosomal subunit and prevents aminoacyl tRNA from binding to the A site of the ribosome-RNA complex; aminoacyl tRNA binding inhibition likely occurs through steric hindrance. This results in inhibition of bacterial protein synthesis and hence cell growth.


Acebutolol Action Pathway,Drug Action

Acebutolol (also known as Sectral or Prent) is a selective β1 adrenergic receptor antagonist (beta blocker), which can be used for treatment of high blood pressure (hypertension) and irregular heartbeats (arrhythmias). Acebutolol also has the ability to mild intrinsic sympathomimetic activity (ISA) with effective range of dosage. Adrenaline (also known as epinephrine) can activate β1 adrenergic receptor so that the heart rate and output will be increased. Renin is a hormone that generated from kidney, which could lead to constriction of blood vessels. Beta blockers could efficiently prohibit renin release.


Alprenolol Action Pathway,Drug Action

Alprenolol (also known as alfeprol, alpheprol or alprenololum) a beta blocker (non-selective) that block beta-1 adrenergic receptor in heart. Blocking beta-1 adrenergic receptor could prevent the binding of epinephrine and norepinephrine, which could efficiently reduce blood pressure and heart rate. In the juxtaglomerular apparatus, alprenolol can also bind to beta-2 receptors to prevent the production and release of renin (also known as angiotensinogenase). Without renin, angiotensin II and aldosterone could not be produced, which ultimately prevent water retention and vasoconstriction.


Atenolol Action Pathway,Drug Action

Atenolol, trade name Tenormin, is a beta blocker prescribed to treat hypertension. Atenolol is a selective beta-1-adrenoceptor antagonist targeting the heart and vascular smooth muscle to inhibit sympathetic activity. Binding of atenolol inhibits the G protein signalling cascade and reduces heart rate, blood pressure, cardiac output and reflex orthostatic hypotension. Beta blockers were once the first line therapy for hypertension, however, current recommendations favour calcium channel blockers and angiotensin converting enzyme inhibitors.


Betaxolol Action Pathway,Drug Action

Betaxolol (also known as Betoptic or Lokren) is a selective beta blocker that can block beta1-adrenergic receptors and beta2-adrenergic receptors. Blocking of beta1-adrenergic receptors in heart and vascular smooth muscle can lead to reduced heart rate, cardiac output, and decreased blood pressure. Blocking of beta(2)-adrenergic receptors can lead to prevention of bronchospasm.


Bisoprolol Action Pathway,Drug Action

Bisoprolol (also known as Zebeta) is a selective beta blocker that can block beta1-adrenergic receptors and beta2-adrenergic receptors. Blocking of beta1-adrenergic receptors in heart and vascular smooth muscle can lead to reduced heart rate, cardiac output, and decreased blood pressure. Blocking of beta(2)-adrenergic receptors can lead to prevention of bronchospasm.


Esmolol Action Pathway,Drug Action

Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents.


Metoprolol Action Pathway,Drug Action

Metoprolol (also known as Lopressor) is a beta blocker (non-selective) that are used for treat high blood pressure or chest pain. Metoprolol bind to beta1-adrenergic receptors in heart and vascular smooth muscle to block the binding of other adrenergic neurotransmitters such as norepinephrine, which lead to decreased blood pressure, heart rate and cardiac output.


Nadolol Action Pathway,Drug Action

Nadolol (also known as Corgard or Solgol) is a beta blocker (non-selective) that are used for treat high blood pressure or chest pain. Nadolol bind to beta1-adrenergic receptors in heart and vascular smooth muscle to block the binding of other adrenergic neurotransmitters such as norepinephrine, which lead to decreased blood pressure, heart rate and cardiac output. Nadolol can also bind beta-2 adrenergic receptors in juxtaglomerular apparatus and bronchiole smooth muscle. In juxtaglomerular apparatus, nadolol can prevent the production of aldosterone and angiotensin II by inhibiting renin production, which lead to prevention of water retention and vasoconstriction. In bronchiole smooth muscle, binding of nadolol to beta-2 adrenergic receptors can also prevent vasoconstriction.


Oxprenolol Action Pathway,Drug Action

Oxprenolol (also known as Trasacor or Trasicor) is a beta blocker (non-selective) that are used for treat high blood pressure or chest pain. Oxprenolol bind to beta1-adrenergic receptors in heart and vascular smooth muscle to block the binding of other adrenergic neurotransmitters such as norepinephrine, which lead to decreased blood pressure, heart rate and cardiac output. Oxprenolol can also bind beta-2 adrenergic receptors in juxtaglomerular apparatus and bronchiole smooth muscle. In juxtaglomerular apparatus, oxprenolol can prevent the production of aldosterone and angiotensin II by inhibiting renin production, which lead to prevention of water retention and vasoconstriction. In bronchiole smooth muscle, binding of oxprenolol to beta-2 adrenergic receptors can also prevent vasoconstriction.


Penbutolol Action Pathway,Drug Action

Penbutolol (also known as Levatol or Levatolol) is a beta blocker (non-selective) that are used for treat high blood pressure or chest pain. Penbutolol bind to beta1-adrenergic receptors in heart and vascular smooth muscle to block the binding of other adrenergic neurotransmitters such as norepinephrine, which lead to decreased blood pressure, heart rate and cardiac output. Penbutolol can also bind beta-2 adrenergic receptors in juxtaglomerular apparatus and bronchiole smooth muscle. In juxtaglomerular apparatus, penbutolol can prevent the production of aldosterone and angiotensin II by inhibiting renin production, which lead to prevention of water retention and vasoconstriction. In bronchiole smooth muscle, binding of penbutolol to beta-2 adrenergic receptors can also prevent vasoconstriction.


Pindolol Action Pathway,Drug Action

Pindolol (also known as Visken) a beta blocker (non-selective) that block beta-1 adrenergic receptor in heart. Blocking beta-1 adrenergic receptor could prevent the binding of epinephrine and norepinephrine, which could efficiently reduce blood pressure and heart rate. In the juxtaglomerular apparatus, pindolol can also bind to beta-2 receptors to prevent the production and release of renin (also known as angiotensinogenase). Without renin, angiotensin II and aldosterone could not be produced, which ultimately prevent water retention and vasoconstriction.


Propranolol Action Pathway,Drug Action

Propranolol, a non-cardioselective beta blocker, inhibits sympathetic stimulation by competing with neurotransmitters like catecholamines to bind beta(1)-adrenergic receptors of the heart and vascular smooth muscle. Propranolol binding reduces resting heart rate, cardiac output, blood pressure and orthostatic hypotension. Propranolol also reduce sympathetic activity to manage hyperthyroidism, anxiety and tremor. Propranolol also competes for beta(2)-adrenergic receptors on bronchial and vascular smooth muscles.


Quinidine Action Pathway,Drug Action

This pathway illustrates the quinidine targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Quinidine, a diastereomer of quinine, is a Class 1A antiarrhythmic drug that is isolated from the bark of the Cinchona plant or other related species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. At low concentrations, it blocks the voltage-gated sodium (I-Na) and rapid delayed rectifying potassium (I-Kr) channels. I-Na is responsible for the rapid upstroke in cell membrane potential observed on the cardiac myocyte action potential. I-Kr is partially responsible for the final repolarization phase of the action potential. By blocking I-Na, quinidine increases the threshold of excitability and decreases automaticity. I-Kr block results in action potential prolongation. At higher concentrations, quinidine also blocks voltage-gated delayed rectifying potassium channel (I-Ks), inward rectifier potassium channel (I-K1), voltage-gated transient outward delayed rectifying potassium channel (I-Kto), and L-type calcium channels (I-CaL). Quinidine also exerts antimuscarinic effects, which increase AV nodal conduction and antagonize alpha-adrenergic effects. Quinidine may be used to maintain sinus rhythm in atrial fibrillation or flutter and prevent recurrence of ventricular fibrillation or tachycardia. The side effects of quinidine include diarrhea and on rare occasions (2-8%) Torsades de Pointes.


Procainamide (Antiarrhythmic) Action Pathway,Drug Action

This pathway illustrates the procainamide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Procainamide, an analogue of the local anesthetic procaine, is a Class 1A antiarrhythmic drug. It has similar effects to quinidine, but lacks the antimuscarinic and antiadrenergic effects of quinidine. Like other Class 1A drugs, procainamide blocks open sodium channels leading to an increased threshold of excitability. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization seen during cardiac contractile cell action potentials. I-Na block results in delayed excitability of the cells. Procainamide also prolongs action potential duration, likely by slowing the final repolarization phase via potassium channel blocking. This drug may be administered intravenously to treat supraventricular and ventricular arrhythmias. It is better tolerated intravenously than quinidine. Oral administration is poorly tolerated long term.


Disopyramide Action Pathway,Drug Action

This pathway illustrates the disopyramide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Disopyramide is a Class 1A antiarrhythmic drug with similar electrophysiological effects as quinidine. Disopyramide blocks sodium channels in their open state leading to an increased threshold of excitability. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization phase of the cardiac contractile cell action potentials. Inhibition of I-Na results in delayed excitability of the cell. Disopyramide also prolongs action potential duration likely through potassium channel blocking. Disopyramide is administered as a racemic mixture. In vitro studies have demonstrated that the S-(+) isomer has pharmacological action similar to quinidine. The R-(-) isomer blocks sodium channels, but does not prolong action potential duration. Disopyramide may be used to maintain rhythm in atrial fibrillation or flutter or to prevent recurrence of ventricular tachycardia or fibrillation. Disopyramide may depress cardiac contractility, which could precipitate heart failure or Torsades de Pointes.


Fosphenytoin (Antiarrhythmic) Action Pathway,Drug Action

This pathway illustrates the fosphenytoin targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Fosphenytoin, an antiepileptic drug that exhibits Class 1B antiarrhythmic effects, is a soluble pro-drug phosphate ester. It is rapidly absorbed intramuscularly and rapidly metabolized in the blood stream by plasma esterases to the active drug, phenytoin. Fosphenytoin was developed to replace parenteral phenytoin sodium for the treatment of epileptic seizures. Parenteral phenytoin sodium was originally prepared in 40% propylene glycol and 10% ethanol at pH 12. This formulation exhibited a range of toxic effects from severe irritation and pain at the injection site to occasional death from rapid injections. Although fosphenytoin is used to treat epileptic seizures, antiarrhythmic effects have also been observed. The active metabolite, phenytoin, preferentially binds to sodium channels (I-Na) in their inactive state. This causes a slight delay in the rapid depolarization phase of cardiac myocyte action potentials. In contrast to Class 1A antiarrhythmic drugs (e.g. quinidine) which prolong action potential duration, fosphenytoin and other Class 1B antiarrhythmics reduce the refractory period or action potential duration due to their membrane stabilizing effects. Phenytoin has been found to be beneficial in the treatment of atrial and ventricular arrhythmias.


Phenytoin (Antiarrhythmic) Action Pathway,Drug Action

This pathway illustrates the phenytoin targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Phenytoin is an antiepileptic drug that exhibits Class 1B antiarrhythmic activity. Although phenytoin is used to treat epileptic seizures, beneficial antiarrhythmic effects have also been observed. Phenytoin preferentially binds to sodium channels (I-Na) in their inactive state. This causes a slight delay in the rapid depolarization phase of cardiac myocyte action potentials. In contrast to Class 1A antiarrhythmic drugs (e.g. quinidine) which prolong action potential duration, phenytoin and other Class 1B antiarrhythmics reduce the refractory period or action potential duration due to their membrane stabilizing effects. Phenytoin has been found to be beneficial in the treatment of atrial and ventricular arrhythmias.


Lidocaine (Antiarrhythmic) Action Pathway,Drug Action

This pathway illustrates the lidocaine targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Lidocaine is a local anaesthetic that is also used to treat ventricular arrhythmias in emergency situations. It is a Class 1B antiarrhythmic drug that binds to sodium channels in their open and closed inactive state. Voltage-gated sodium channels are responsible for the inward sodium current (I-Na) that causes the rapid depolarization phase of cardiac myocyte action potentials. Inhibition of the sodium current increases the threshold of excitability of cells and decreases automaticity. Like other Class 1B antiarrythmics, lidocaine causes a slight decrease in action potential duration due to its membrane stabilizing effects. Lidocaine is not effective for treating atrial arrhythmias. Lidocaine undergoes rapid hepatic metabolism (t1/2 = 15 – 30 minutes) by cytochrome P450 enzymes, CYP2C6 and CYP3A4. As a result, other related drugs with longer half-lives, such as mexiletine and tocainide, were developed.


Mexiletine Action Pathway,Drug Action

This pathway illustrates the mexiletine targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Mexiletine is a Class 1B antiarrhythmic drug with electrophysiological effects similar to lidocaine and tocainide. Mexiletine preferentially binds to voltage-gated sodium channels in their inactive state inhibiting the sodium current (I-Na) responsible for the rapid depolarization phase of the cardiac myocyte action potential. Inhibition of I-Na increases the cells’ threshold of excitability. The membrane-stabilizing effects of mexiletine causes a slight decrease in the action potential duraction. Mexiletine was developed as an alternative to lidocaine, which is subject to rapid hepatic metabolism and has a short half-life of only 15 – 30 minutes. Mexiletine is subject to less first pass metabolism compared to lidocaine and can be administered as chronic oral therapy. Mexiletine may be used to treat ventricular arrhythmias.


Tocainide Action Pathway,Drug Action

This pathway illustrates the tocainide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cellsÈ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Tocainide, the alpha-methyl analogue of lidocaine, is a Class 1B antiarrhythmic drug. It has similar electrophysiological effects as lidocaine and may be used to treat ventricular arrhythmias. Unlike lidocaine, tocainide may be administered orally and has a long plasma half-life of 12 hours (plasma t1/2 of lidocaine = 15  30 minutes). Like other Class 1B antiarrhythmic agents, tocainide preferentially blocks sodium channels in their inactivated state. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization phase of cardiac myocyte action potentials. Inhibition of I-Na results in an increased threshold of excitability and decreased automaticity. The membrane stabilizing effects of tocainide also cause a slight decrease in action potential duration. Tocainide is administered as a racemic mixture. The R-isomer is four times more potent than the S-isomer and is cleared faster in anephric patients.


Flecainide Action Pathway,Drug Action

This pathway illustrates the flecainide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cellsÈ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Flecainide is a Class 1C antiarrhythmic drug. Like other Class 1 antiarrhythmic agents (e.g. quinidine), flecainide blocks sodium ion currents (I-Na) through voltage-gated sodium channels with preferential binding to channels in their open activated state. The therapeutic effects of flecainide are thought to arise from their slow dissociation from sodium channels, which alters the pattern of action potential propagation. Flecainide also blocks potassium currents via the voltage-gated rapid delayed rectifying potassium channel (I-Kr) and blocks the extrusion of calcium ions from the sarcoplasmic reticulum (SR) to the cytosol via the cardiac ryanodine receptor (RYR2) of the SR membrane. Flecainide shortens the action potential duration in Purkinje cells, but prolongs it in ventricular cells. Due to its proarrhythmic effects, flecainide increased mortality in patients recovering from myocardial infarctions in the CAST study. However, in the absence of heart disease, it is still used to maintain sinus rhythm in patients with supraventricular arrhythmias, such as atrial fibrillation, ventricular tachycardia and supraventricular tachycardia.


Ibutilide Action Pathway,Drug Action

This pathway illustrates the ibutilide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cellsÈ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Ibutilide is a Class III antiarrhythmic drug that blocks potassium current through the voltage-gated rapid delayed rectifying potassium channel (I-Kr). I-Kr is partially responsible for the final repolarization phase of the cardiac myocyte action potential. As such, I-Kr antagonism delays repolarization and increases action potential duration. Ibutilide also activates a slow inward sodium current (not shown) which likely contributes to action potential prolongation. Ibutilide may be used to treat atrial fibrillation or atrial flutter. It may cause Torsades de Pointes in up to 6% of patients.


Diltiazem Action Pathway,Drug Action

Diltiazem is a benzothiazepine calcium channel blocker (CCB) or antagonist, the only drug of this class in clinical use. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Diltiazem is thought to primarily block L-type calcium channels in their open state. It is one of only two clinically used CCBs that are cardioselective. Diltiazem and verapamil, the other cardioselective CCB, shows greater activity against cardiac calcium channels than those of the peripheral vasculature. Other CCBs, such as nifedipine and amlodipine, have little to no effect on cardiac cells (cardiac myocytes and cells of the SA and AV nodes). Due to its cardioselective properties, diltiazem may be used to treat arrhythmias (e.g. atrial fibrillation, atrial flutter and paroxysmal supraventrucular tachycardia) as well as hypertension. The first part of this pathway depicts the pharmacological action of diltiazem on cardiac myocytes and peripheral arterioles and coronary arteries. Diltiazem decreases cardiac myocyte contractility by inhibiting the influx of calcium ions. Calcium ions entering the cell through L-type calcium channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of cardiac myocytes and results in an overall decreased force of contraction by the heart. Diltiazem affects smooth muscle contraction and subsequent vasoconstriction in peripheral arterioles and coronary arteries by the same mechanism. Decreased cardiac contractility and vasodilation lower blood pressure. The second part of this pathway illustrates the effect of calcium channel antagonism on the cardiac action potentials. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside of the cell is negatively charged relative to the cellsÈ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Blocking L-type calcium channels decreases conduction and increases the refractory period. DiltiazemÈs effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation.


Nebivolol Action Pathway,Drug Action

Nebivolol (also known as Bystolic or Nebivololum) is a Î²1-receptor blocker (selective Î²1-receptor antagonist) that can bind and inhibit Beta-1 adrenergic receptor in muscule and heart. Nebivolol competes with epinephrine or other beta-1 adrenergic receptor activator to bind on the receptor, which can reduce the heart rate and blood pressure that could caused by biniding of epinephrine on receptor. Nebivolol can also prevent release of renin (a hormone from kidneys), which can result in reduced level of constriction of blood vessels.


Carvedilol Action Pathway,Drug Action

Carvedilol, trade name Coreg, is a nonselective beta-blocker that blocks both alpha and beta receptors of the heart and blood vessels. It is prescribed to treat hypertension, stable angina pectoris and congestive heart failure. Carvedilol also blocks calcium channels. Its activity decreases heart rate, myocardial contractility and oxygen demand and decreases vascular resistance. It also posses a unique feature for a beta-blocker, it has an anti-free-radical effect. This effect may prevent free radical damage to treat chronic heart failure.


Labetalol Action Pathway,Drug Action

Labetalol (also known as Albetol or Ibidomide) is an inhibitor/antagonist of beta-1 adrenergic receptor that can be used for treating high blood pressure and reducing cardiac output. Labetalol can bind to beta-1 adrenergic receptor on both vascular smooth muscle, which lead to inhibition of vasoconstriction in peripheral blood vessels and adrenergic stimulation of endothelial cell function.


Verapamil Action Pathway,Drug Action

Verapamil is a phenylalkylamine calcium channel blocker (CCB) or antagonist. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Verapamil, an organic cation, is thought to primarily block L-type calcium channels in their open state by interfering with the binding of calcium ions to the extracellular opening of the channel. It is one of only two clinically used CCBs that are cardioselective. Verapamil and diltiazem and, the other cardioselective CCB, shows greater activity against cardiac calcium channels than those of the peripheral vasculature. Other CCBs, such as nifedipine and amlodipine, have little to no effect on cardiac cells (cardiac myocytes and cells of the SA and AV nodes). Due to its cardioselective properties, verapamil may be used to treat arrhythmias (e.g. atrial fibrillation) as well as hypertension. The first part of this pathway depicts the pharmacological action of verapamil on cardiac myocytes and peripheral arterioles and coronary arteries. Verapamil decreases cardiac myocyte contractility by inhibiting the influx of calcium ions. Calcium ions entering the cell through L-type calcium channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of cardiac myocytes and results in an overall decreased force of contraction by the heart. Verapamil affects smooth muscle contraction and subsequent vasoconstriction in peripheral arterioles and coronary arteries by the same mechanism.  Decreased cardiac contractility and vasodilation lower blood pressure. The second part of this pathway illustrates the effect of calcium channel antagonism on the cardiac action potentials. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside of the cell is negatively charged relative to the cellsÈ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Blocking L-type calcium channels decreases conduction and increases the refractory period. VerapamilÈs effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation.


Amlodipine Action Pathway,Drug Action

Amlodipine, trade name Norvasc, is a dihydropyridine calcium channel blocker (CCB) prescribed to treat hypertension and exertion-related angina. The drug acts directly on vascular smooth muscle to cause peripheral vasodilation. Amlodipine inhibits the influx of calcium ions into vascular smooth muscle and cardiac muscle to bind calmodulin. Inhibition of calcium bound calmodulin prevents activation of myosin light chain kinase and phosphorylation of the regulatory light chain subunit of myosin, this inhibits an integral part of muscle contractions. The net effect is decreased contractility of arterial smooth muscle and increased vasodilation resulting in a decrease in blood pressure. Amlodipine has arterial selectivity due to alternative splicing of the channel and has little effect on cardiac muscle.


Felodipine Action Pathway,Drug Action

Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs.  CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction.  Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation.  Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells.  Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity.  At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells.  This pathway depicts the pharmacological action of felodipine on arterial smooth muscle cells.  Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels.  Calcium ions entering the cell through these channels bind to calmodulin.  Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK).  Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction.  Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors.  Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation.  The vasodilatory effects of felodipine result in an overall decrease in blood pressure.  Felodipine may be used to treat mild to moderate essential hypertension.  .


Isradipine Action Pathway,Drug Action

Isradipine (also known as DynaCirc or Prescal) is a calcium channel blocker within dihydropyridine (DHP) class that can be used for treating high blood pressure and essential hypertension. There are at least 5 different types of calcium channels in human which are L-, N-, P/Q-, R- and T-type. Isradipine only targets the L-type that mediate muscle cell contraction by binding for stabilizing their inactive conformation. Inactivated calcium channel are more frequent in smooth muscle cells because of longer depolarizations. This pathway demonstrates the binding of isradipine on arterial smooth muscle cells inhibits the influx of calcium ions, which lead to decreased arterial smooth muscle contractility and subsequent vasoconstriction. Calcium ion enters the cell and bind to calmodulin,  and then calcium-bound calmodulin binds and activates myosin light chain kinase (MLCK). Activated myosin light chain kinase (MLCK) can phosphorylate subunit of myosin, which is an important step for muscle contraction. Therefore, binding and inhibiting of calcium channels can lead to inhibition of influx of calcium that result in decreased contractile activity (vasodilation). Vasodilatory effects can reduced the blood pressure.


Nifedipine Action Pathway,Drug Action

Nifedipine (also known as Adalat or Procardia) is a dihydropyridine calcium channel blocker that may be used for treatment of hypertension and exertion-related angina in the absence of vasospasm. Nifedipine binds the major channel in muscle cells: L-type calcium channels. Binding of Nifedipine on L-type calcium channels can change channels' confirmation to its inactive form, so that the channel couldn't faciltate the influx of calcium ions, which leads to decreased arterial smooth muscle contractility and subsequent vasoconstriction. Activated mysoin light chain kinase (MLCK) is required for muscle contraction since it can catalyze the phosphorylation of the regulatory light chain subunit of myosin. Without calcium ions in muscle cell, calmodulin couldn't form the calcium-bound calmodulin, which is required for binding and activating MLCK. Lack of initial influx of calcium can also reduce the level of contractile activity of muscle cells and results in vasodilation, which ultimately lead to overall decresing in blood pressure.


Nimodipine Action Pathway,Drug Action

Nimodipine (also known as Nimotop or Periplum) is a dihydropyridine calcium channel blocker that may not be used for treatment of hypertension. Compared to other DHP CCBs, nimodipine is more active in the cerebral vasculature than in the periphery. This may be due to its high lipophilicity and ability to penetrate the blood brain barrier. This unique property of nimodipine led to clinical studies for its use to improve neurological outcomes in patients following subarachnoid hemorrhage from ruptured intracranial aneurysms. While it has been approved as adjunct treatment for this indication, the exact mechanism by which it exerts these effects is unclear. Nimodipine has little effect on cardiac myocytes and conduction cells at therapeutic sub-toxic concentrations. Nimodipine binds the major channel in muscle cells: L-type calcium channels. Binding of Nimodipine on L-type calcium channels can change channels' confirmation to its inactive form, so that the channel couldn't faciltate the influx of calcium ions, which leads to decreased arterial smooth muscle contractility and subsequent vasoconstriction. Activated mysoin light chain kinase (MLCK) is required for muscle contraction since it can catalyze the phosphorylation of the regulatory light chain subunit of myosin. Without calcium ions in muscle cell, calmodulin couldn't form the calcium-bound calmodulin, which is required for binding and activating MLCK. Lack of initial influx of calcium can also reduce the level of contractile activity of muscle cells and results in vasodilation, which ultimately lead to overall decresing in blood pressure.


Nisoldipine Action Pathway,Drug Action

Nisoldipine (also known as Sular or Nisocor) is a dihydropyridine calcium channel blocker that may be used for treatment of hypertension, chronic stable angina and Prinzmetal's variant angina. Nisoldipine binds the major channel in muscle cells: L-type calcium channels. Binding of Nisoldipine on L-type calcium channels can change channels' confirmation to its inactive form, so that the channel couldn't faciltate the influx of calcium ions, which leads to decreased arterial smooth muscle contractility and subsequent vasoconstriction. Activated mysoin light chain kinase (MLCK) is required for muscle contraction since it can catalyze the phosphorylation of the regulatory light chain subunit of myosin. Without calcium ions in muscle cell, calmodulin couldn't form the calcium-bound calmodulin, which is required for binding and activating MLCK. Lack of initial influx of calcium can also reduce the level of contractile activity of muscle cells and results in vasodilation, which ultimately lead to overall decresing in blood pressure.


Nitrendipine Action Pathway,Drug Action

Nitrendipine (also known as Bayotensin or Nidrel) is a dihydropyridine calcium channel blocker that may be used for treatment of hypertension. Nitrendipine binds the major channel in muscle cells: L-type calcium channels. Binding of nitrendipine on L-type calcium channels can change channels' confirmation to its inactive form, so that the channel couldn't faciltate the influx of calcium ions, which leads to decreased arterial smooth muscle contractility and subsequent vasoconstriction. Activated mysoin light chain kinase (MLCK) is required for muscle contraction since it can catalyze the phosphorylation of the regulatory light chain subunit of myosin. Without calcium ions in muscle cell, calmodulin couldn't form the calcium-bound calmodulin, which is required for binding and activating MLCK. Lack of initial influx of calcium can also reduce the level of contractile activity of muscle cells and results in vasodilation, which ultimately lead to overall decresing in blood pressure.


Benzocaine Action Pathway,Drug Action

Benzocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Benzocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore benzocaine preferentially inhibits neurons that are actively firing.


Bupivacaine Action Pathway,Drug Action

Bupivacaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Bupivacaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore bupivacaine preferentially inhibits neurons that are actively firing.


Chloroprocaine Action Pathway,Drug Action

Chloroprocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Chloroprocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore chloroprocaine preferentially inhibits neurons that are actively firing.


Cocaine Action Pathway,Drug Action

Cocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Cocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore cocaine preferentially inhibits neurons that are actively firing.


Dibucaine Action Pathway,Drug Action

Dibucaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Dibucaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore dibucaine preferentially inhibits neurons that are actively firing.


Levobupivacaine Action Pathway,Drug Action

Levobupivacaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Levobupivacaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore levobupivacaine preferentially inhibits neurons that are actively firing.


Lidocaine (Local Anaesthetic) Action Pathway,Drug Action

Lidocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Lidocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore lidocaine preferentially inhibits neurons that are actively firing.


Mepivacaine Action Pathway,Drug Action

Mepivacaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Mepivacaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore mepivacaine preferentially inhibits neurons that are actively firing.


Oxybuprocaine Action Pathway,Drug Action

Oxybuprocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Oxybuprocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore oxybuprocaine preferentially inhibits neurons that are actively firing.


Prilocaine Action Pathway,Drug Action

Prilocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Prilocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore prilocaine preferentially inhibits neurons that are actively firing.


Procaine Action Pathway,Drug Action

Procaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Procaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore procaine preferentially inhibits neurons that are actively firing.


Proparacaine Action Pathway,Drug Action

Proparacaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Proparacaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore proparacaine preferentially inhibits neurons that are actively firing.


Ropivacaine Action Pathway,Drug Action

Ropivacaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Ropivacaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore ropivacaine preferentially inhibits neurons that are actively firing.


Codeine Action Pathway,Drug Action

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.


Morphine Action Pathway,Drug Action

Morphine exerts its analgesic by acting on the mu-opioid receptor of sensory neurons. Binding to the mu-opioid receptor activates associated G(i) proteins. These subsequently act to inhibit adenylate cyclase, reducing the level of intracellular cAMP. G(i) also activates potassium channels and inactivates calcium channels causing the neuron to hyperpolarize. The end result is decreased nerve conduction and reduced neurotransmitter release, which blocks the perception of pain signals.


Methadone Action Pathway,Drug Action

Methadone exerts its analgesic by acting on the mu-opioid receptor of sensory neurons. Binding to the mu-opioid receptor activates associated G(i) proteins. These subsequently act to inhibit adenylate cyclase, reducing the level of intracellular cAMP. G(i) also activates potassium channels and inactivates calcium channels causing the neuron to hyperpolarize. The end result is decreased nerve conduction and reduced neurotransmitter release, which blocks the perception of pain signals. Methadone further acts as an antagonist at the NMDA receptor, reducting calcium influx and neuronal excitability.


Oxycodone Action Pathway,Drug Action

Oxycodone (also known as OxyContin or Dihydrohydroxycodeinone) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of oxycodone will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.


Hydromorphone Action Pathway,Drug Action

Hydromorphone (also known as dihydromorphinone or Dilaudid) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of hydromorphone will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.


Hydrocodone Action Pathway,Drug Action

Hydrocodone (also known as Vicodin or Norco) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of hydrocodone will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.


Oxymorphone Action Pathway,Drug Action

Oxymorphone (also known as Numorphan) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of oxymorphone will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.


Alfentanil Action Pathway,Drug Action

Alfentanil (also known as Alfenta or Rapifen) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of alfentanil will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.


Carfentanil Action Pathway,Drug Action

Carfentanil (also known as carfentanyl or Wildnil) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of carfentanil will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.


Fentanyl Action Pathway,Drug Action

Carfentanil (also known as Phentanyl or Fentora) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of carfentanil will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.


Remifentanil Action Pathway,Drug Action

Remifentanil is a pharmacologically-active, synthetic, small molecule derived from fentanyl and belongs to a class of drugs called opioids. Opioids are therapeutically employed to achieve analgesia. Remifentanial’s rapid mechanism of action primarily involves its agonistic effects on mu-type opioid receptors which are inhibitory G-coupled protein receptors and lead to the inhibition of adenylate cyclase and decrease in cAMP production. Analgesia, anesthesia, and respiratory depression are a function of remifentanial’s action on these mu-type opioid receptors.


Sufentanil Action Pathway,Drug Action

Sufentanil is a pharmacologically-active synthetic small molecule derived from fentanyl and belongs to a class of drugs called opioids. Opioids are therapeutically employed to achieve analgesia. Sufentanil’s rapid mechanism of action primarily involves its agonistic effects on mu-type opioid receptors which are inhibitory G-coupled protein receptors and lead to the inhibition of adenylate cyclase and decrease in cAMP production. It also inhibits nociceptive neurotransmitter release and induces membrane hyperpolarization. Analgesia, anesthesia, and respiratory depression are a consequence of remifentanial’s action.