Browsing pathways

The action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as zoledronate appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. It acts solely by inhibiting the actions of thrombin. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran.

Warfarin 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.

Vinorelbine, a semisynthetic vinca alkaloid, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vinorelbine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vinorelbine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vinorelbine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vinorelbine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vinorelbine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vindesine, a semisynthetic vinca alkaloid, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vindesine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vindesine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vindesine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vindesine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vindesine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vincristine, a vinca alkaloid isolated from the leaves of the periwinkle plant _Catharanthus roseus_, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vincristine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vincristine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vincristine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vincristine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vinblastine, a vinca alkaloid isolated from the leaves of the periwinkle plant _Catharanthus roseus_, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vinblastine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vinblastine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vinblastine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vinblastine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vinblastine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Verapamil is a phenylalkylamine calcium channel blocker (CCB) or antagonist. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Verapamil, an organic cation, is thought to primarily block L-type calcium channels in their open state by interfering with the binding of calcium ions to the extracellular opening of the channel. It is one of only two clinically used CCBs that are cardioselective. Verapamil and diltiazem and, the other cardioselective CCB, shows greater activity against cardiac calcium channels than those of the peripheral vasculature. Other CCBs, such as nifedipine and amlodipine, have little to no effect on cardiac cells (cardiac myocytes and cells of the SA and AV nodes). Due to its cardioselective properties, verapamil may be used to treat arrhythmias (e.g. atrial fibrillation) as well as hypertension. The first part of this pathway depicts the pharmacological action of verapamil on cardiac myocytes and peripheral arterioles and coronary arteries. Verapamil decreases cardiac myocyte contractility by inhibiting the influx of calcium ions. Calcium ions entering the cell through L-type calcium channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of cardiac myocytes and results in an overall decreased force of contraction by the heart. Verapamil affects smooth muscle contraction and subsequent vasoconstriction in peripheral arterioles and coronary arteries by the same mechanism. Decreased cardiac contractility and vasodilation lower blood pressure. The second part of this pathway illustrates the effect of calcium channel antagonism on the cardiac action potentials. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside of the cell is negatively charged relative to the 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). Blocking L-type calcium channels decreases conduction and increases the refractory period. Verapamil’s effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation.

Vatalanib is an anti-VEGFR molecule in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration, permeability, invasion, and survival. Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability. In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above. Vatalanib exerts its effect by binding to intracellular tyrosine kinase domain of VEGFR-2 and preventing receptor autophosphorylation and activation of downstream pathways, resulting in suppression of angiogenesis.

Valdecoxib, a selective prostaglandin G/H synthase 2 (better known as cyclooxygenase-2 or COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib was used for its anti-inflammatory, analgesic, and antipyretic effects in the management of osteoarthritis and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2). PGH2 is the precursor of a number of prostaglandins, including prostaglandin E2 (PGE2), prostaglandin I2 (PGI2) and thomboxane A2 (TxA2). Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, a key enzyme in the production of PGE2. PGE2 is a potent mediator of pain, inflammation and fever. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of valdecoxib. The latter portion of this figure depicts valdecoxib’s potential involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, anuclear cells derived from fragmentation from megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Valdexocib preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the rare, but severe, adverse cardiovascular effects observed with rofecoxib, a COX-2 inhibitor which was subsequently been withdrawn from the market. Valdexocib was withdrawn from the Canadian, U.S. and E.U. markets in 2005 due to concerns of possible increased risk of heart attack and stroke.

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.

Trichlormethiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, trichlormethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Triamterene inhibits the epithelial sodium channels on principal cells in the late distal convoluted tubule and collecting tubule, which are responsible for 1-2% of total sodium reabsorption. As sodium reabsorption is inhibited, this increases the osmolarity in the nephron lumen and decreases the osmolarity of the interstitium. Since sodium concentration is the main driving force for water reabsorption, triamterene can achieve a modest amount of diuresis by decreasing the osmotic gradient necessary for water reabsorption from lumen to interstitium. Triamterene also has a potassium-sparing effect. Normally, the process of potassium excretion is driven by the electrochemical gradient produced by sodium reabsorption. As sodium is reabsorbed, it leaves a negative potential in the lumen, while producing a positive potential in the principal cell. This potential promotes potassium excretion through apical potassium channels. By inhibiting sodium reabsorption, triamterene also inhibits potassium excretion.

Trastuzumab is an anti-EGFR drug used in the treatment of HER2-positive breast cancer. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Trastuzumab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.

Tranexamic acid competitively inhibits activation of plasminogen (via binding to the kringle domain), thereby reducing conversion of plasminogen to plasmin (fibrinolysin), an enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins, including the procoagulant factors V and VIII. Tranexamic acid also directly inhibits plasmin activity, but higher doses are required than are needed to reduce plasmin formation.

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Trandolapril is an ACE inhibitor prodrug that is hydrolyzed by liver esterases to its active form, trandolaprilat. Trandolaprilat, which is eight times more active than its parent compound, competes with angiotensin I for binding to ACE and effectively blocks the conversion of angiotensin I to angiotensin II. The resulting decreased concentration of angiotensin II confers blood pressure lowering effects to trandolapril. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of trandolapril. Trandolapril may be used to treat hypertension and congestive heart failure.

Torsemide, also known as torasemide, is a loop diuretic that inhibits water reabsorption in the nephron by blocking the sodium-potassium-chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle. This is achieved through competitive inhibition at the chloride binding site on the cotransporter, thus preventing the transport of sodium from the lumen of the loop of Henle into the basolateral interstitium. Consequently, the lumen becomes more hypertonic while the interstitium becomes less hypertonic, which in turn diminishes the osmotic gradient for water reabsorption throughout the nephron. Because the thick ascending limb is responsible for 25% of sodium reabsorption in the nephron, torsemide is a very potent diuretic.

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 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). 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.

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.

Ticlopidine is a platelet aggregation inhibitor structurally and pharmacologically similar to clopidogrel. The active metabolite of ticlopidine 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 ticlopidine.

Thioguanine is a purine antimetabolite prodrug closely related to mercaptopurine and similarly inhibits purine metabolism. The thioguanine pathway is shown as a part of the mercaptopurine pathway. Thioguanine exerts cytotoxic effects via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Once in a cell, thioguanine is converted to thioguanosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase. Thioguanosine monophosphate is then phosphorylated to thioguanosine diphosphate, which is converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate. Thiodeoxyguanosine triphosphate is incorporated into DNA causing cytotoxicity. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells.

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.

Tenofovir is a nucleotide analogue used in the treatment of HIV and chronic hepatitis B. It is taken up into the cell and is subsequently phosphorylated first by adenylate kinases and then by nucleoside diphosphate kinases into tenofovir diphosphate. Tenofovir diphosphate is an analogue of deoxyadenosine triphosphate (dATP) and competes with dATP for binding to the viral DNA polymerase and subsequent incorporation into the growing DNA strand. Once incorporated into the DNA, tenofovir causes chain termination, thus preventing viral replication.

Teniposide is an podophyllotoxin derative that is used in the treatment of certain cancers. It inhibits mitosis and induces cell death by acting as a topoisomerase II poison. Topoisomerase II is an enzyme in the nucleus of cells that unwinds DNA by making transient double strand breaks, relieving the torsion of supercoiled DNA. In the unwound form, DNA can serve as a template for DNA replication as well as transcription. In the normal state, this effect is transient and the breaks DNA are quickly religated by topoisomerase II itself. Teniposide, however, inhibits religation and stabilizes the DNA-topoisomerase II complex in the cleaved DNA form, ultimately leading to breaks in both DNA chains and cell death. Teniposide is also converted into catechol and o-quinone derivatives in the liver and in lysosomes respectively. These metabolites are highly oxidative and can directly damage DNA, which may also contribute to the drug’s cytotoxic effects.

Tenecteplase cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction.

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

Tamoxifen is a selective estrogen modulator (SERM) used in the treatment of estrogen-sensitive breast cancer. Tamoxifen itself only has weak anti-estrogen effects and must be converted into more active metabolites to have therapeutic activity. Metabolism takes place in the liver and is carried out primarily by cytochrome P450 enzymes. Tamoxifen is hydroxylated by CYP2D6 and demethylated by CYP3A4 and CYP3A5, producing the active metabolites 4-hydroxytamoxifen and endoxifen. These metabolites inhibit estrogen binding to estrogen receptors in breast cancer cells, which in turn inhibit tumour growth.

Suprofen is a non-steroidal anti-inflammatory analgesic and antipyretic. Ophthalmic anti-inflammatory medicines are used in the eye to lessen problems that can occur during or after some types of eye surgery. During surgery, the pupil of the eye may constrict , making it difficult for the surgeon to reach some areas of the eye. Suprofen may be used to help prevent pupil constriction during surgery. Suprofen binds to the prostaglandin G/H synthase 1 and 2 (better known as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)), preventing the production of prostaglandins and reducing the inflammatory response. COX catalyses the formation of prostaglandins and thromboxane from arachidonic acid, which is derived from the cellular phospholipid bilayer by phospholipase A2. Prostaglandins act (among other things) as messenger molecules in the process of inflammation. The overall result is a reduction in pain and inflammation in the eyes and the prevention of pupil constriction during surgery. Normally, trauma to the anterior segment of the eye, especially the iris, increases endogenous prostaglandin synthesis which leads to constriction of the iris sphincter.

Sulindac is a non-steroidal anti-inflammatory drug (NSAID). Like most NSAIDs, sulindac is a non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). COX catalyzes the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor of a number of prostaglandins involved in fever, pain, swelling and inflammation. The analgesic, antipyretic and anti-inflammatory effects of sulindac occurs as a result of decreased prostaglandin synthesis.

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

Streptomycin is an aminoglycoside antibiotic that inhibits bacterial protein synthesis. Streptomycin 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, streptomycin binds four nucleotides of the 16S rRNA and a single amino acid of protein S12. This interferes with the decoding site in the vicinity of nucleotide 1400 in 16S rRNA of the 30S subunit. This region interacts with the wobble base of the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so that incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides, and the breakup of polysomes into nonfunctional monosomes. Aminoglycosides are useful 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.

Streptokinase cleaves the Arg/Val bond in plasminogen to form the proteolytic enzyme plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction.

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

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Spirapril is an ACE inhibitor prodrug that is hydrolyzed by liver esterases to its active form, spiraprilat. Spiraprilat competes with angiotensin I for binding to ACE and effectively blocks the conversion of angiotensin I to angiotensin II. The resulting decreased concentration of angiotensin II confers blood pressure lowering effects to spirapril. Increased bradykinin levels resulting from decreased bradykinin inactivation also contribute to the effects of spirapril. Spirapril may be used to treat hypertension and congestive heart failure.

Spectinomycin is an aminocyclitol antibiotic produced by a soil microorganism called Streptomyces spectabilis. 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. In vitro studies have shown that spectinomycin has a bacteriostatic effect against most strains of Neisseria gonorrhoeae (minimum inhibitory concentration <7.5 to 20 mcg/mL). Footprint studies indicate that spectinomycin exerts regional effects on ribosomal structure. Spectinomycin may be used in the treatment of penicillin-resistant Neisseria gonorrhoeae.

Roxithromycin is a semi-synthetic macrolide antibiotic. It is very similar in composition, chemical structure and mechanism of action to erythromycin, azithromycin, or clarithromycin. Roxithromycin prevents bacteria from growing by interfering with protein synthesis. Roxithromycin binds to the 50S subunit of the bacterial ribosome and inhibits the translocation of peptides. Roxithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Legionella pneumophila. It can be used to treat respiratory tract, urinary and soft tissue infections.

Rosuvastatin inhibits cholesterol synthesis via the mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol synthesis by this pathway. The active form of statins bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Structure-activity relationship studies have demonstrated that statins bind to HMG-CoA reductase at the same site as the reduced intermediate and are held in place by similar chemical interactions. Unlike Lovastatin and simvastatin, which undergo in vivo hydrolysis to their active form rosuvastatin is synthetically produced in active form. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

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

Rofecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a highly selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, rofecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precursor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Rofecoxib antagonizes COX-2 by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors such as celecobix and valdecoxib, rofecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. Studies support the notion that the extra methylene on the isoleucine side chains in COX-1 adds enough bulk to proclude rofecoxib from binding. Rofecoxib is 100 times more selective for COX-2 than COX-1. The analgesic, antipyretic and anti-inflammatory effects of rofecoxib occurs as a result of decreased prostaglandin synthesis. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of rofecoxib. The latter portion of this figure depicts rofecoxib’s involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, anuclear cells derived from fragmentation from megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Rofecoxib preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the rare, but severe, adverse cardiovascular effects observed with rofecoxib, which has since been withdrawn from the market.

The action of risedronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Risedronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

Reteplase cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction.

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Rescinnamine, an alkaloid obtained from Rauwolfia serpentina and other Rauwolfia species, is an ACE inhibitor that competes with angiotensin I for binding to ACE. Rescinnamine effectively inhibits the conversion of angiotensin I to angiotensin II, resulting in decreased concentrations of angiotensin II and blood pressure lowering effects. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of rescinnamine. Rescinnamine may be used to treat hypertension.

Repaglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, repaglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Repaglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with repaglinide therapy compared to sulfonylureas.

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

Ranitidine, a histamine H2-receptor antagonist, competitively inhibits histamine from binding to H2-receptors on parietal cells. It suppresses the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. This is accomplished by two mechanisms: histamine released by ECL cells in the stomach is blocked from binding on parietal cell H2 receptors which stimulate acid secretion, and other substances that promote acid secretion (such as gastrin and acetylcholine) have a reduced effect on parietal cells when the H2 receptors are blocked.

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Like many of the ACE inhibitors, including benazepril, fosinopril, and quinapril, ramipril is a prodrug that is hydrolyzed in vivo by liver esterases to its active form, ramiprilat. Ramiprilat competes with angiotensin I for binding to ACE and effectively blocks the conversion of angiotensin I to angiotensin II. The resulting decreased concentration of angiotensin II gives ramipril its blood pressure lowering effects. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of ramipril. Ramipril may be used to treat hypertension, congestive heart failure and chronic renal failure.

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+/K+ATPase (hydrogen-potassium adenosine triphosphatase) at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds.

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.

Quinethazone inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, quinethazone effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Quinapril, like ramipril, is an ACE inhibitor prodrug that is hydrolyzed in vivo by esterases to its active form, quinaprilat. Quinapril competes with angiotensin I for binding to ACE and effectively blocks the conversion of angiotensin I to angiotensin II. The resulting decreased concentration of angiotensin II confers blood pressure lowering effects to quinapril. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of quinapril. Quinapril may be used to treat hypertension and congestive heart failure.

Propranolol competes with sympathomimetic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart and vascular smooth muscle, inhibiting sympathetic stimulation. This results in a reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension. Higher doses of atenolol also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles.

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

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

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.

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

Prednisone is a synthetic glucocorticoid that is used clinically for its anti-inflammatory properties. Prednisone is converted to the active metabolite prednisolone in the liver. Prednisolone can diffuse passively across the cell membrane, where it binds to glucocorticoid receptors in the cytoplasm. Upon binding, the glucocorticoid receptor (GR) dissociates from heat shock protein 90, and translocate into the nucleus. In the nucleus, GR dimers can bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory genes, which activates their transcription. GRs also inhibit transcription of inflammatory mediators by binding to negative GRE (nGRE). GRs further interact with the transcription factors cAMP-responsive element binding protein and NF-kappa-B, and inihibit their activation of inflammatory gene transcription. GRs also recruit histone deacetylase 2 to inflammatory genes, which leads to DNA condensation at those loci, thus suppressing expression of those genes.

Prednisolone is a synthetic glucocorticoid that is used clinically for its anti-inflammatory properties. Prednisolone diffuses passively across the cell membrane, where it binds to glucocorticoid receptors in the cytoplasm. Upon binding, the glucocorticoid receptor (GR) dissociates from heat shock protein 90, and translocate into the nucleus. In the nucleus, GR dimers can bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory genes, which activates their transcription. GRs also inhibit transcription of inflammatory mediators by binding to negative GRE (nGRE). GRs further interact with the transcription factors cAMP-responsive element binding protein and NF-kappa-B, and inihibit their activation of inflammatory gene transcription. GRs also recruit histone deacetylase 2 to inflammatory gene loci on DNA, which leads to DNA condensation and suppression of gene expression.

Pravastatin inhibits cholesterol synthesis via the mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol synthesis by this pathway. Pravastatin bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Structure-activity relationship studies have demonsotrated that statins bind to HMG-CoA reductase at the same site as the reduced reaction intermediate and are held in place by similar chemical interactions. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels. Pravstatin was derived from the microbial transformation of mevastatin, which is a natural compound produced by Penicillium citinium and the first statin ever studied. Unlike lovastatin and simvastatin, pravastatin is relatively hydrophilic and does not require hydrolysis for activation. Increased hydrophilicity accounts for its decreased penetration of lipophilic peripheral cells, increased selectivity for hepatic tissues and decreased side effects relative to simvastatin and lovastatin.

Polythiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, polythiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Piroxicam is a non-selective prostaglandin G/H synthase (better known as cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). COX catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Piroxicam antagonizes COX by binding to the upper portion of the active site and preventing its substrate, arachidonic acid, from entering the active site. The analgesic, antipyretic and anti-inflammatory effects of piroxicam occurs as a result of decreased prostaglandin synthesis. Piroxicam also inhibits the migration of leukocytes into sites of inflammation and prevents the production of thromboxane A2, an aggregating agent, by platelets.

Pirenzepine is an antimuscarinic drug which inhibits muscarinic acetylcholine M3 receptors on parietal cells in the stomach, inhibiting gastric secretion and reducing muscle spasms. Pirenzipine is used to treat duodenal and stomach ulcers. The drug also is used to prevent nausea, vomiting and motion sickness.

Pindolol non-selectively blocks beta-1 adrenergic receptors mainly in the heart, inhibiting the effects of epinephrine and norepinephrine resulting in a decrease in heart rate and blood pressure. By binding beta-2 receptors in the juxtaglomerular apparatus, Pindolol inhibits the production of renin, thereby inhibiting angiotensin II and aldosterone production and therefore inhibits the vasoconstriction and water retention due to angiotensin II and aldosterone, respectively.

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.

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.

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Perinodpril is an ACE inhibitor that competes with angiotensin I for binding to ACE. Perinodpril effectively inhibits the conversion of angiotensin I to angiotensin II. The resulting reduction in angiotensin II concentration gives perindopril its blood pressure lowering effects. Increased levels of bradykinin resulting from inhibition of its breakdown may also contribute to the effects of perindopril. Perindopril may be used to treat hypertension and congestive heart failure.

Penbutolol competes with adrenergic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart and vascular smooth muscle and beta(2)-receptors in the bronchial and vascular smooth muscle. Beta(1)-receptor blockade results in a decrease in resting and exercise heart rate and cardiac output, a decrease in both systolic and diastolic blood pressure, and, possibly, a reduction in reflex orthostatic hypotension.

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by forming a covalent bond to two sites of the (H+,K+ )- ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus.

Panitumumab is an anti-EGFR drug used in the treatment of some cancers. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Panitumumab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.

The action of ibandronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting farnesyl pyrophosphate (FPP) synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

Paclitaxel is an anticancer agent isolated from the bark of the yew tree. It is classified as a microtubule-stabilizing agent and exerts cell killing effects by disrupting mitosis in dividing cells. Microtubules are made up of α- and β- tubulin heterodimers arranged head to tail and assembled to form a cylinder. Microtubules possess complex polymerization dynamics that are essential for movement of chromosomes and proper segregation of daughter cells during mitosis. Paclitaxel binds directly to the inner surface of β-subunits along the length of microtubules. Binding is thought to induce a conformational change in tubulin that increases its affinity for neighbouring molecules. At sufficiently high concentrations, paclitaxel can bind to β-tubulin in a one to one ratio and stimulate microtubule polymerization. At lower clinically relevant drug concentrations, paclitaxel stabilizes microtubules and prohibits further polymerization and depolymerization. Suppression of microtubule dynamics may prevent chromosomes from moving from the spindle poles to the metaphase plate slowing or preventing progression from metaphase to anaphase. Cells enter a state of mitotic arrest from which they may progress to one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur causing cell death. Paclitaxel is susceptible to cellular drug resistance caused by drug efflux via a number of multidrug resistance-associated proteins.

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.

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

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

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

Oxprenolol competes with adrenergic neurotransmitters such as catecholamines for binding at sympathetic receptor sites. Like propranolol and timolol, oxprenolol binds at beta(1)-adrenergic receptors in the heart and vascular smooth muscle, inhibiting the effects of the catecholamines epinephrine and norepinephrine and decreasing heart rate, cardiac output, and systolic and diastolic blood pressure. It also blocks beta-2 adrenergic receptors located in bronchiole smooth muscle, causing vasoconstriction. By binding beta-2 receptors in the juxtaglomerular apparatus, oxprenolol inhibits the production of renin, thereby inhibiting angiotensin II and aldosterone production. Oxprenolol therefore inhibits the vasoconstriction and water retention due to angiotensin II and aldosterone, respectively.

Oxaprozin is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Oxaprozin is used to treat rheumatoid arthritis, osteoarthritis, dysmenorrhea, and to alleviate moderate pain. Like most NSAIDs, oxaprozin is a non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). COX catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling and inflammation. Oxaprozin antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. The analgesic, antipyretic and anti-inflammatory effects of oxaprozin occurs as a result of decreased prostaglandin synthesis.

Omeprazole is a compound that inhibits gastric acid secretion and is indicated in the treatment of gastroesophageal reflux disease (GERD), the healing of erosive esophagitis, and H. pylori eradication to reduce the risk of duodenal ulcer recurrence. Omeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

Nizatidine competes with histamine for binding at the H2-receptors on the gastric basolateral membrane of parietal cells. Competitive inhibition results in reduction of basal and nocturnal gastric acid secretions. The drug also decreases the gastric acid response to stimuli such as food, caffeine, insulin, betazole, or pentagastrin.

Nitrendipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, nitrendipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives nitrendipine additional arterial selectivity. At therapeutic sub-toxic concentrations, nitrendipine has little effect on cardiac myocytes and conduction cells. This pathway depicts the pharmacological action of nitrendipine on arterial smooth muscle cells. Nitrendipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of nitrendipine result in an overall decrease in blood pressure. Nitrendipine may be used to treat mild to moderate essential hypertension, chronic stable angina and Prinzmetal’s variant angina. It is unique from other CCBs in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive.

Nisoldipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, nisoldipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives nisoldipine additional arterial selectivity. At therapeutic sub-toxic concentrations, nisoldipine has little effect on cardiac myocytes and conduction cells. This pathway depicts the pharmacological action of nisoldipine on arterial smooth muscle cells. Nisoldipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of nisoldipine result in an overall decrease in blood pressure. Nisoldipine may be used to treat mild to moderate essential hypertension, chronic stable angina and Prinzmetal’s variant angina.

Nimodipine is a dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, nimodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives nimodipine additional arterial selectivity. Compared to other DHP CCBs, nimodipine is more active in the cerebral vasculature than in the periphery. This may be due to its high lipophilicity and ability to penetrate the blood brain barrier. This unique property of nimodipine led to clinical studies for its use to improve neurological outcomes in patients following subarachnoid hemorrhage from ruptured intracranial aneurysms. While it has been approved as adjunct treatment for this indication, the exact mechanism by which it exerts these effects is unclear. Nimodipine has little effect on cardiac myocytes and conduction cells at therapeutic sub-toxic concentrations, This pathway depicts the pharmacological action of nimodipine on arterial smooth muscle cells. Nimodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of nimodipine may result in an overall decrease in blood pressure. In clinical studies, the hypotensive effects of nimodipine required a small percentage of patients to discontinue the drug. Nimodipine is not used to treat hypertension and is generally not recommended for use in patients receiving antihypertensive therapy as it may potentiate the hypotensive effects of the therapy.

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

Nicotine is a stimulant drug that acts as an agonist at nicotinic acetylcholine receptors. These are ionotropic receptors composed of five homomeric or heteromeric subunits. In the brain, nicotine binds to nicotinic acetylcholine receptors on dopaminergic neurons in the cortico-limbic pathways. This causes the channel to open and allow conductance of multiple cations including sodium, calcium, and potassium. This leads to depolarization, which activates voltage-gated calcium channels and allows more calcium to enter the axon terminal. Calcium stimulates vesicle trafficking towards the plasma membrane and the release of dopamine into the synapse. Dopamine binding to its receptors is responsible the euphoric and addictive properties of nicotine. Nicotine also binds to nicotinic acetylcholine receptors on the chromaffin cells in the adrenal medulla. Binding opens the ion channel allowing influx of sodium, causing depolarization of the cell, which activates voltage-gated calcium channels. Calcium triggers the release of epinephrine from intracellular vesicles into the bloodstream, which causes vasoconstriction, increased blood pressure, increased heart rate, and increased blood sugar.

Netilmicin is a semisynthetic, water soluble antibiotic of the aminoglycoside group, produced by the fermentation of Micromonospora inyoensis, a species of actinomycete. Netilmicin 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, netilmicin binds four nucleotides of the 16S rRNA and a single amino acid of protein S12. This interferes with the decoding site in the vicinity of nucleotide 1400 in 16S rRNA of the 30S subunit. This region interacts with the wobble base of the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so that incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides, and the breakup of polysomes into nonfunctional monosomes. Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. It is active at low concentrations against a wide variety of pathogenic bacteria including Escherichia coli, bacteria of the Klebsiella-Enterobacter-Serratia group, Citrobacter sp., Proteus sp. (indole-positive and indole-negative), including Proteus mirabilis, P. morganii, P. rettgrei, P. vulgaris, Pseudomonas aeruginosa and Neisseria gonorrhoea. Netilmicin is also active in vitro against isolates of Hemophilus influenzae, Salmonella sp., Shigella sp. and against penicillinase and non-penicillinase-producing Staphylococcus including methicillin-resistant strains. Some strains of Providencia sp., Acinetobacter sp. and Aeromonas sp. are also sensitive to netilmicin. Many strains of the above organisms which are found to be resistant to other aminoglycosides, such as kanamycin, gentamicin, tobramycin and sisomicin, are susceptible to netilmicin in vitro. Occasionally, strains have been identified which are resistant to amikacin but susceptible to netilmicin. The combination of netilmicin and penicillin G has a synergistic bactericidal effect against most strains of Streptococcus faecalis (enterococcus). The combined effect of netilmicin and carbenicillin or ticarcillin is synergistic for many strains of Pseudomonas aeruginosa. In addition, many isolates of Serratia, which are resistant to multiple antibiotics, are inhibited by synergistic combinations of netilmicin with carbenicillin, azlocillin, mezlocillin, cefamandole, cefotaxime or moxalactam. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.

Neomycin is an aminoglycoside antibiotic that inhibits bacterial protein synthesis. 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. This leads to interference with the initiation complex, misreading of mRNA so that incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides, and the breakup of polysomes into nonfunctional monosomes. Aminoglycosides are useful 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.

Nebivolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Nebivolol blocks these receptors which reverses the effects of epinephrine, lowering the heart rate and blood pressure. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels.

Nateglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, nateglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Nateglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with nateglinide therapy compared to sulfonylureas.

Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Naproxen has analgesic and antipyretic properties. Like most NSAIDs, naproxen is a non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (i.e. COX-1 and -2). COX catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling and inflammation. Naproxen antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. The analgesic, antipyretic and anti-inflammatory effects of naproxen occur as a result of decreased prostaglandin synthesis.

Nadolol competes with adrenergic neurotransmitters such as catecholamines for binding at sympathetic receptor sites. Like propranolol and timolol, nadolol binds at beta(1)-adrenergic receptors in the heart and vascular smooth muscle, inhibiting the effects of the catecholamines epinephrine and norepinephrine and decreasing heart rate, cardiac output, and systolic and diastolic blood pressure. It also blocks beta-2 adrenergic receptors located in bronchiole smooth muscle, causing vasoconstriction. By binding beta-2 receptors in the juxtaglomerular apparatus, nadolol inhibits the production of renin, thereby inhibiting angiotensin II and aldosterone production. Nadolol therefore inhibits the vasoconstriction and water retention due to angiotensin II and aldosterone, respectively.

Nabumetone is a naphthylalkanone. Is is a non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. The parent compound is a prodrug that undergoes hepatic biotransformation to the active compound, 6-methoxy-2-naphthylacetic acid (6MNA). The analgesic, antipyretic and anti-inflammatory effects of NSAIDs occur as a result of decreased prostaglandin synthesis.

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

The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown). Moexipril, an ACE inhibitor, is a prodrug that is hydrolyzed in vivo to its active form, moexiprilat. Moexipril competes with angiotensin I for binding to ACE and effectively inhibits the conversion of angiotensin I to angiotensin II. The resulting decrease in angiotensin II gives moexipril its blood pressure lowering effects. Inhibiting the breakdown of bradykinin may also play a role in decreasing blood pressure. Moexipril may be used to treat hypertension, congestive heart failure and nephropathy.

Minocycline, the most lipid soluble and most active tetracycline antibiotic, is a long-acting tetracycline. Minocycline passes directly through membrane lipid bilayers or travels through porin channels in the bacterial membrane. Like other tetracyclines, minocycline binds to the bacterial 30S ribosomal subunit and prevents tRNA from binding to the A site on the ribosome complex; this likely occurs via steric hindrance. Binding inhibits bacterial protein synthesis and inhibits further bacterial growth and colonization.

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.

Metoprolol competes with adrenergic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart and vascular smooth muscle. Beta(1)-receptor blockade results in a decrease in heart rate, cardiac output, and blood pressure.

Metolazone inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, metolazone effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Methyclothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, methyclothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Methotrexate is an antifolate antimetabolite used in the treatment of rheumatoid arthritis and cancer. Methotrexate is taken up into the cell by human reduced folate carriers (SLC19A1). In the cytoplasm, methotrexate is polyglutamated by folylpolyglutamate synthase, which enhances its retention inside the cell. Both methotrexate and methotrexate-polyglutamate inhibit dihydrofolate reductase, an enzyme that catalyzes the conversion of dihydrofolate into tetrahydrofolate, which is the active form of folic acid. Tetrahydrofolate is involved in many single-carbon transfer reactions, including the synthesis of DNA and RNA nucleotides. Inhibition of dihydrofolate reductase causes depletion of intracellular tetrahydrofolate, which has a cytotoxic effect, especially on rapidly dividing cells. Methotrexate-polyglutamate further inhibits de novo purine synthesis and thymidylate synthase, which contribute to methotrexate’s cytotoxic effects.

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

Mercaptopurine is a purine antimetabolite prodrug that exerts cytotoxic effects via three mechanisms: via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA, inhibition of de novo synthesis of purine nucleotides, and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Mercaptopurine travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is then converted to thioguanosince diphosphate through a series of metabolic reactions that produces the metabolic intermediates, thioinosine 5’-monophosphate, thioxanthine monophosphate, and thioguanosine monophosphate. Thioguanosine diphosphate is then converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate, which is incorporated into DNA. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells. Finally, de novo synthesis of purine nucleotides is inhibited by the methyl-thioinosine 5’-monophosphate metabolite, which inhibits amidophosphoribosyl-transferase, the enzyme that catalyzes one of the first steps in this pathway.