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

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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.


Clopidogrel Action Pathway,Drug Action

Clopidogrel, an antiplatelet agent structurally and pharmacologically similar to ticlopidine, is used to reduce atherosclerotic events such as myocardial infarction, stroke, and vascular death in patients who have had a recent stroke, recent MI, or have established peripheral vascular disease. The active metabolite of clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of clopidogrel.


Ticlopidine Action Pathway,Drug Action

Ticlopidine, marketed as Ticlid, is an antiplatelet drug that targets the P2Y12 receptor of platelets. Ticlopidine is taken orally and is a prodrug that must be metabolically activated before it can be effective. It first enters the liver and enters the endoplasmic reticulum where it is metabolized to form the active metabolite. First, it is catalyzed by cytochromes P450 2C19, 2B6 and 1A2 into 2-oxoclopidogrel. Secondly, it is processed by cytochromes P450 2B6, 2C9, 2C19, 3A4, 3A5, and serum paraoxonase/arylesterase 1 into the active metabolite of clopidogrel. The active metabolite of clopidogrel then enters the blood stream, where it binds irreversibly to the P2Y purinoreceptor 12 on the surface of platelet cells, preventing ADP from binding to and activating it. Clopidogrel prevents the activation of the Gi protein associated with the P2Y12 receptor from inactivating adenylate cyclase in the platelet, leading to a buildup of cAMP. This cAMP then activates calcium efflux pumps, preventing calcium buildup in the platelet, which would cause activation, and later, aggregation.


Clomocycline Action Pathway,Drug Action

Clomocycline is a tetracycline antibiotic that inhibits bacterial cell growth by inhibiting translation. Clomocycline is lipophilic and easily diffuses across cell membranes or enters cells via porin channels in the bacterial membrane. It binds to the 30S ribosomal subunit and prevents the aminoacyl tRNA from binding to the A site of the ribosome-RNA complex. Clomocycline binding is reversible in nature. Clomocycline may be used to treat acne, gum disease, and other bacterial infections such as chalmydia, brucellosis, bartonellosis and cholera. Clomocycline is also effective against certain strains of malaria and may also be prescribed for the treatment of Lyme disease.


Cilostazol Action Pathway,Drug Action

Cilostazol, also sold as Pletal, is a drug used to prevent platelet aggregation, specifically treating symptoms of intermittent claudication caused by peripheral artery disease as well as preventing strokes.Cilostazol is ingested orally, and it enters the liver, where it is metabolized in the endoplasmic reticulum by cytochrome P450 3A4 into 4-hydroxycilostazol, and by cytochrome P450 2C19 and 3A5 into 4-cis-hydroxycilostazol. Each of these metabolites is further metabolized, 4-hydroxycilostazol into 3,4-dehydrocilostazol and 4-cis-hydroxycilostazol into 4'-trans-hydroxycilostazol respectively. These two metabolites are the active metabolites, and they both act to inhibit the action of cAMP-specific 3',5'-cyclic phosphodiesterase 4D in platelets. With this enzyme inhibited, it is unable to metabolize cAMP into AMP, which leads to a buildup of cAMP in the blood. cAMP in turn is known to prevent aggregation of platelets, by inhibiting their adhesion to collagen, as well as decreasing the amount of calcium within the cytosol, preventing granule release, which then prevents activation of other platelets.


Dipyridamole (Antiplatelet) Action Pathway,Drug Action

Dipyridamole (also known as Persantine) can bind and inhibit cAMP-specific 3',5'-cyclic phosphodiesterase 4D at platelet cell, which prevent the release of arachidonic acid form membrane phospholipids that eventually decreasing thromboxane A2 activity. Dipyridamole can also induce adenylate cyclase activity by releasing prostacyclin, which lead to inhibition of platelet aggregation and increased intraplatelet concentration of cAMP.


Abciximab Action Pathway,Drug Action

Abciximab (also known as c7E3 Fab) is integrin (integrin alpha-IIb and integrin beta-3) receptor antagonist. Binding of abciximab to integrin receptor will block any large molecule to attach on the receptor, which will lead to block any associated signal transduction pathways.


Eptifibatide Action Pathway,Drug Action

Eptifibatide (also named Integrilin) is an anti-coagulant drug that is produced from Sistrurus miliarus barbouri, which can block platelet glycoprotein IIb/IIIa receptor to prevent platelet aggregation. Although, inhibition of platelet aggregation occurs in a dose- and concentration-dependent manner.


Tirofiban Action Pathway,Drug Action

Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. Platelet aggregation inhibition is reversible following cessation of the infusion of tirofiban.


Warfarin Action Pathway,Drug Action

Warfarin is a drug part of the anticoagulant drug class, used to dissolve or break down blood clots. Warfarin inhibits vitamin K epoxide reductase complex subunit 1. In the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide would regularly use vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase, but as warfarin inhibits vitamin K epoxide reductase complex subunit 1, this causes a decreased amount of the reduced form of vitamin K, which in turn causes a decreased coagulability of the blood. The enzyme vitamin K-dependent gamma carboxylase catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator (reteplase) through plasminogen,  and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa.  From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Acenocoumarol Action Pathway,Drug Action

Acenocoumarol (also known as Nitrowarfarin or Sinthrome) is an anticoagulant that inhibit the liver enzyme vitamin K reductase, which cause Vitamin K1 2,3-epoxide could not be catalyzed by vitamin K reductase to form vitamin KH2, the reduced form of vitamin K. Vitamin K-dependent coagulation factors (II, VII, IX, and X) requires its cofactor, vitamin K to facilitate the activation and gamma-carboxylation. Inhibition of vitamin K reductase results in reduced concentration of vitamin KH2, which will ultimately lead to decreased coagulability of the blood and reduced cleavage of fibrinogen into fibrin.


Dicumarol Action Pathway,Drug Action

Dicumarol (also known as bishydroxycoumarin) is an anticoagulant that inhibit the liver enzyme vitamin K reductase, which cause Vitamin K1 2,3-epoxide could not be catalyzed by vitamin K reductase to form vitamin KH2, the reduced form of vitamin K. Vitamin K-dependent coagulation factors (II, VII, IX, and X) requires its cofactor, vitamin K to facilitate the activation and gamma-carboxylation. Inhibition of vitamin K reductase results in reduced concentration of vitamin KH2, which will ultimately lead to decreased coagulability of the blood and reduced cleavage of fibrinogen into fibrin.


Phenprocoumon Action Pathway,Drug Action

Phenprocoumon is an anticoagulant that inhibits the liver enzyme vitamin K reductase. This leads to the depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulation factors (II, VII, IX, and X), this ultimately results in reduced cleavage of fibrinogen into fibrin and decreased coagulability of the blood.


Enoxaparin Action Pathway,Drug Action

Enoxaparin is a low molecular weight heparin used to reduce cardiovascular events. Enoxaparin's action is antithrombin-dependent. The drug binds to antithrombin III to reduce thrombin inhibition in the plasma. The drug increases the inactivation of coagulation factors IXa, Xa and XIIa. This increases the antithrombin effects. Compared to unfractionated heparin, low molecular weight heparins have lower affinity for plasma proteins and therefore only few are protein bound. They also are not inactivated by platelet factor 4 and does not bind endothelial cells or macrophages thus are not degraded as fast. Therefore, low molecular weight heparins like Enoxaparin are more stable and predictable heparins.


Fondaparinux Action Pathway,Drug Action

Fondaparinux, also known as Arixtra, is an anticoagulant medication. It is part of a class of antithrombotic drugs, the first of this new class. In the blood capillary bed, Fondaparinux sodium activates antithrombin III. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V and prothrombin. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alphabet, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator through plasminogen and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa. From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Heparin Action Pathway,Drug Action

Heparin (also named unfractionated heparin or Clexane) is an anticoagulant medication. The main mechanism of heparin is acting on increasing the rate of antithrombin-related neutralization of coagulation factors for certain activated type. More specifically, heparin will bind to the antithrombin III (AT) that make antithrombin III changing to its activated form. Activated antithrombin III will inactive prothrombin and factor Xa (also other proteases).


Ardeparin Action Pathway,Drug Action

Ardeparin, trade name Normiflo, is low molecular weight heparin with anticoagulant effects used to prevent thrombosis. Ardeparin binds and increases antithrombin III activity and inactivates thrombin, factor Xa and coagulation factors XIIa, XIa, plasmin and kallikrein to prevent clot formation. In addition, heparin cofactor II is bound by ardeparin to inhibit thrombin. Plasma proteins have a smaller affinity for low molecular weight heparins than unfractionated heparin. Low molecular weight heparins also don't undergo the rapid degradation of unfractionated heparins. These properties increase ardeparin's bioavailability and give a more predictable anticoagulant activity.


Argatroban Action Pathway,Drug Action

Argatroban is a synthetic derivate of L-arginine and a direct thrombin inhibitor anticoagulant prescribed to patients with heparin-induced thrombocytopenia. Direct thrombin inhibitors bind plasma and fibrin bound thrombin independently of co-factor antithrombin.The inhibition of thrombin reduces the stability of the clot and promotes clot break down. Argatroban does not effect serine proteases like, trypsin, factor Xa, plasmin, and kallikrein.  Argatroban is advantageous, particularly for renal failure patients, due to its short-half life and hepatic clearance.


Bivalirudin Action Pathway,Drug Action

Bivalirudin, trade name angiomax, is a direct thrombin inhibitor. It is often prescribed to patients who cannot take unfractionated or low molecular weight heparin. Bivalirudin does not need cofactor antithrobin to act. It binds circulating and clot-bound thrombin at the catalytic site and the anion binding exosite. The inhibition of fibrin prevents the cleavage of fibrinogen into fibrin which activates Factor XIII and Factor XIIIa. This destabilizes the thrombus and inhibits the promotion of thrombin production and platelet activation. As a result, bivalirudin prevents or reduces clot formation.


Lepirudin Action Pathway,Drug Action,Lepirudin (also known as Refludan) is an anticoagulant that can be used for inhibiting thrombin (prothrombin) irreversibly. Binding of thrombin can prevent formation of clot as well as thrombus.  Lepirudin can also reduce thrombocytopenia and break up clot.


Ximelagatran Action Pathway,Drug Action

Ximelagatran is an anticoagulant drug used to prevent and treat blood clots, and was the first drug in the anticoagulant drug class to be able to be ingested orally. It was discontinued from distribution by its parent company AstraZeneca in 2006 as it was found to raise liver enzyme levels in patients and cause liver damage as a result. Ximelagatran inhibits prothrombin. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is inhibited by ximelagatran, and is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V and ximelagatran inhibits prothrombin. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced and inhibited by ximelagatran, which then uses fibrinogen alphabet, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator through plasminogen and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa. Prothrombin is inhibited by ximelagatran here as well. From there, this protein complex is catalyzed into prothrombinase complex, the group of                                                                                proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Alteplase Action Pathway,Drug Action

Alteplase is the generic version of the drugs Activase and Actilyse. It is a thrombolytic drug prescribed to treat acute myocardial infarctions and other blood clotting conditions. Alteplase if often used to treat ischaemic stroke within hours of onset. The drug acts by breaking up blood clots. Alteplase binds fibrin in the blood clot to converts plasminogen to plasmin. Plasmin is a proteolytic enzyme that causing the degradation of fibrin. A side effect of the drug is bleeding, angioedema, allergic reactions and fever.


Anistreplase Action Pathway,Drug Action

Anistreplase, trade name Eminase, is a thrombolytic drug prescribed to treat acute myocardial infarction. The drug is an acylated streptokinase-plasminogen complex. The acylation of the drug renders it temporarily inactive, protecting it from plasmin inhibitors. Anistreplase is deacylated following injection, activating the drug to increase thrombolysis by increasing plasminogen's conversion to plasmin. Plasmin breaks down the fibrin of the thrombus to break up the clot and release arterial blockages. Anistreplase has been shown to be very effective when administered shortly after onset of chest pain. Compared to other thrombolytic drugs, Anistreplase has a longer plasma half-life. It also advantageous as it can be given as a single bolus intravenous injection.


Streptokinase Action Pathway,Drug Action

Streptokinase, or SK, is an enzyme and also a thrombolytic medication. We are focusing on the medication in this pathway, which is used to dissolve clots in patients experiencing heart attacks, or arterial/pulmonary embolisms. Streptokinase works through enabling cleavage of the Arg/Val bond in plasminogen, so that plasmin is formed which breaks down fibrin matrix in the thrombus which in turn creates thrombolytic action. Streptokinase activates plasminogen. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator through plasminogen, which is activated by streptokinase and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa.  From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Tenecteplase Action Pathway,Drug Action

Tenecteplase is an enzyme that is part of the thrombolytics drug class, used to dissolve or break down blood clots. Tenecteplase activates plasminogen. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator (tenecteplase) through plasminogen,  and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa.  From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Urokinase Action Pathway,Drug Action,Urokinase acts on the endogenous fibrinolytic system. It cleaves the Arg-Val bond in plasminogen to produce active plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins.

Urokinase is an enzyme that is part of the thrombolytics drug class, used to dissolve or break down blood clots. Urokinase activates plasminogen. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator (urokinase) through plasminogen,  and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa.  From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Reteplase Action Pathway,Drug Action

Reteplase is an enzyme that is part of the thrombolytics drug class, used to dissolve or break down blood clots. Reteplase activates plasminogen. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator (reteplase) through plasminogen,  and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa.  From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Aminocaproic Acid Action Pathway,Drug Action

Aminocaproic acid, brand name Amicar, is a derivate of lysine and is an antifibrinolytic drug. Antifibrinolytics drugs are commonly used during major surgery to prevent significant blood loss. These drugs reversibly blocks the binding sites on plasminogen. This blockade inhibits plasminogen binding to fibrin and the conversion of plasminogen to plasmin. These prevents fibrin degradation and maintains the stability of fibrin clots.


Tranexamic Acid Action Pathway,Drug Action

Tranexamic acid is a synthetic version of an amino acid found in the body called lysine that plays a role in antifibrinolytic processes. It is used to stop bleeding and hemorrhaging in patients. Tranexamic acid works by inhibiting the activation of plasminogen, which reduces the amount of plasmin that can be produced, thereby slowing the amount of clot degradation that can occur. Tranexamic acid inhibits plasminogen. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator through plasminogen, at which point tranexamic acid inhibits plasminogen which does not allow fibrin degradation products to be created as a result. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa.  From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.


Aprotinin Action Pathway,Drug Action

Aprotinin, trade name Trasylol is a bovine serine protease inhibitor of trypsin, chymotrypsin, kallikrein and plasmin. Aprotinin is administered prophylactically to patients undergoing surgery with a high risk of bleeding to block fibrinolysis and prevent the breakdown of blood clots. The inhibition of kallikrein inhibits factor XIIa production to reduce fibrinolysis and coagulation. Inhibition of plasmin slows down fibrinolysis. Hypersensitivity reactions may occur after repeat exposure to Aprotinin.


Diflunisal Action Pathway,Drug Action

Diflunisal (also known as Dolobid) is a prostaglandin G/H synthase inhibitor that can inhibit prostaglandin G/H synthase 1 and 2 which prevent the production of prostaglandin. Therefore, diflunisal can be used for treating prostaglandin-associated pain, fever, swelling, platelet aggregation and inflammation. Diflunisal can also inhibit the relocation of leukocytes to inflammation site and also the production of the aggregating agent of platelets: thromboxane A2.


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.


Dopamine Activation of Neurological Reward System,Signaling

In the nervous system, dopamine acts as a neurotransmitter with roles in motor control, motivation, arousal, cognition, and reward. The mesolimbic pathway is the main pathway associated with reward, and the dopaminergic neurons of this pathway are found in the substantia nigra (SNc) and  ventral tegmental area (VTA) of the midbrain. Dopamine acts on different G protein-coupled receptor subtyes. The D1-class (D1 and D5) receptors stimulate cAMP production by activating adenylyl cyclase, which activates the reward pathway. The D2-class (D2, D3, and D4) subtypes act oppositely, inhibiting cAMP production by inhibiting adenylyl cyclase. The differing distributions of the receptor subtypes mean that complex outputs often produce a synergistic effect, despite the receptor subtypes having opposite molecular effects (PMID: 20925949, 21303898).


Excitatory Neural Signalling Through 5-HTR 4 and Serotonin,Protein

The 5-HT4 receptor is primarily found in the CNS, GI tract, and PNS. Peripheral receptors have important roles in the function of many organ responses (alimentary tract, urinary bladder, heart, and adrenal gland). Alimentary tract receptors have a role in smooth muscle tone, mucosal electrolyte secretion, and the peristaltic reflex. Urinary bladder receptors control cholinergic/purinergic transmission. Atrial heart receptors produce positive inotropy and tachycardia that can precipitate arrhythmias. This receptor is also thought to have roles in anxiety, appetite, GI motility, learning, memory, mood, and respiration. The 5-HT4 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Corticotropin Activation of Cortisol Production,Protein

Corticotropin (ACTH or adrenocorticotropic hormone) is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is produced from the cleavage of pre-pro-opiomelanocortin by various endopeptidases, along with other physiologically active peptide fragments such as β-lipotropin, γ-lipotropin, melanocyte stimulating hormone (MSH), and β-endorphin. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production of androgens and cortisol from the adrenal cortex. The ACTHR receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to androgen and cortisol production.


Excitatory Neural Signalling Through 5-HTR 7 and Serotonin,Protein

The 5-HT7 receptor is primarily found in the CNS, GI tract, and blood vessels. Serotonin is the primary ligand of the 5-HT7 receptor, which activates G(s) proteins associated with the receptor and leads to the activation of adenylyl cyclase and production of the secondary messenger cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A, phosphorylating downstream effectors that lead to specific cellular responses which mediate physiological functions such as thermoregulation, circadian rhythm, learning and memory, sleep, and potentially mood.


Excitatory Neural Signalling Through 5-HTR 6 and Serotonin,Protein,The 5-HT6 receptor is primarily expressed in the brain and is involved in glutamatergic and cholinergic neuronal activity.  The 5-HT6 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Lactic Acidemia,Disease

Increased lactic acid concentrations in urine or serum can be a result of many metabolic disorders but also of other origin (infections, etc.). Respiratory chain defects account for most of the metabolic causes of lactic acid accumulation. Often alanine is also high. A urine spectrum indicating an increased lactic acid and alanine concentration is shown.


Congenital Bile Acid Synthesis Defect Type II,Disease

Congenital Bile Acid Synthesis Defect Type II is a congenital defect in bile acid synthesis with delta(4)-3-oxosteroid 5-beta-reductase deficiency is caused by mutation in the AKR1D1 gene. 3-oxo-5-beta-steroid 4-dehydrogenase catalyzes the bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one. Chenodeoxycholic acid and cholic acid are decreased in plasma and urine. Symptoms of this disease include cholestatic jaundice, atypical oxo and allo bile acids in urine and serum, liver failure, and steatosis.


Cerebrotendinous Xanthomatosis is caused by mutation in the CYP27A1 gene, which encodes sterol 27-hydroxylase. This enzyme catalyzes the first step in the oxidation of the side chain of sterol intermediates; the 27-hydroxylation of 5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol. Cerebrotendinous Xanthomatosis is a rare, inherited lipid-storage disease with large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Symptoms include progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts.


Zellweger Syndrome,Disease

Zellweger syndrome, also known as cerebrohepatorenal syndrome, is an autosomal recessive peroxisome biogenesis disorder that is part of the family of Zellweger spectrum disorders. It is caused by a defect in one of 12 or more of the PEX genes (PEX1, 2, 3, 5, 6, 10, 12, 13, 14, 16, 19 and 26) that produce proteins called peroxins. Peroxins are used in the formation of peroxisomes, and can be involved in recognition of proteins targeted for the peroxisome, as well as their transport into the peroxisome. Peroxisomes typically break down both very long chain and branched fatty acids, but if they aren't present, these fatty acids build up in the blood and body, harming organs such as the brain and liver. Additionally, due to the fact that some processes, such as plasmalogen biosynthesis, occur in or using peroxisomes, and can lead to deficiencies in plasmalogens. These are important in brain and lung function, leading to other symptoms.Zellweger syndrome is characterized by an increase in levels of very long chain fatty acids in the blood plasma, as well as more visible physical symptoms, such as an abnormally large or small head at birth, characteristic facial features and poor muscle tone, which can lead to an inability of infants to feed. Other symptoms include an enlarged liver, skeletal abnormalities and low CNS function. Infants very rarely live longer than one year, and the only treatment is for symptoms the patient is experiencing, not for the syndrome itself.


Familial Hypercholanemia (FHCA),Disease

Familial Hypercholanemia can be caused by mutations in the TJP2, BAAT or EPHX1 genes which code for bile acid-CoA:amino acid N-acyltransferase, which is involved in bile acid metabolism. In liver hepatocytes, it catalyzes the second step in the conjugation of C24 bile acids (choloneates) to glycine and taurine before excretion into bile canaliculi. The major components of bile are cholic acid and chenodeoxycholic acid. In a first step the bile acids are converted to an acyl-CoA thioester, either in peroxisomes (primary bile acids deriving from the cholesterol pathway), or cytoplasmic at the endoplasmic reticulum (secondary bile acids). May catalyze the conjugation of primary or secondary bile acids, or both. The conjugation increases the detergent properties of bile acids in the intestine, which facilitates lipid and fat-soluble vitamin absorption. In turn, bile acids are deconjugated by bacteria in the intestine and are recycled back to the liver for reconjugation (secondary bile acids). Bile acid-CoA:amino acid N-acyltransferase may also act as an acyl-CoA thioesterase that regulates intracellular levels of free fatty acids. Familial hypercholanemia is characterized by increased bile acids in plasma. Symptoms include rickets and steatorrhea.


Congenital Bile Acid Synthesis Defect Type III,Disease

Congenital Bile Acid Synthesis Defect Type III (CBASIII) is caused by a defect in 25-hydroxycholesterol 7-alpha-hydroxylase, which plays a role in synthesis of bile acids. The synthesis of primary bile acids from cholesterol occurs via two pathways: the classic neutral pathway involving cholesterol 7-alpha-hydroxylase (CYP7A1), and the acidic pathway involving a distinct microsomal oxysterol 7-alpha-hydroxylase (CYP7B1). CBASIII is characterized by accumulation of bile acids in the urine. Symptoms include severe cholestasis, cirrhosis, and liver failure.


Lysosomal Acid Lipase Deficiency (Wolman Disease),Disease

Lysosomal Acid Lipase Deficiency (Wolman disease) is caused by a defect in lysosomal acid lipase (LIPA, or LAL), otherwise known as acid cholesteryl ester hydrolase, which is coded for by a gene (LIPA) on chromosome 10. Two major disorders, the severe infantile-onset Wolman disease and the milder late-onset cholesteryl ester storage disease (CESD), may be caused by mutations in separate parts of the LIPA gene. Wolman disease is characterized by increased transaminases in serum, and increased cholesteryl esters and triglycerides in various tissues. Symptoms include anemia, diarrhea, failure to thrive, enlarged liver, malabsorption, steatorrhea and abdominal pain.


Intracellular Signalling Through Adenosine Receptor A2a and Adenosine,Protein

A member of the G-coupled protein receptor family, the adenosine A2A receptor regulates blood flow to myocardial tissues through the action of vasodilating the coronary arteries, which can potentially lead to hypotension. The adenosine receptor A2a activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response. This occurs through activation of the MAPK/ERK signaling cascade. The A2A receptor has also been demonstrated to play a role in dopamine and glutamate release in the CNS.


Intracellular Signalling Through Adenosine Receptor A2b and Adenosine,Protein,Adenosine is thought to play a role in the pathophysiology of asthma. Stimulation of A2B can induce production of interleukin-8 mast cells. The adenosine receptor A2b activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates down stream effectors that lead to a specific cellular response. This occurs though activation of the MAPK/ERK signaling cascade.


Vasopressin Regulation of Water Homeostasis,Protein

The vasopressin V2 receptor is found in the kidneys. It serves a role in maintaining corporal water homeostasis. Malfunction of this receptor can lead to Nephrogenic Diabetes Insipidus.Vasopressin (aka Antidiuretic hormone) activates both follicle-stimulating hormone receptor as well as the V2 receptor G protein complex. From this complex, Guanine nucleotide binding protein G(s) protein reacts with Adenylate Cyclase Type 2, Adeonsine Triphosphate, as well as GTP and magnesium to produce cAMP and Pyrophosphate. cAMP then activates PKA (protein kinase A) which leads to changes in the concentration of water in urine.


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.