Browsing pathways

Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPlIb/IIIa.

Acebutolol is a selective β1-receptor antagonist, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. Activation of β1-receptors by epinephrine increases the heart rate and output. Acebutolol blocks these receptors which lowers 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.

Acenocoumarol 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.

Acetylsalicylic acid, also known as ASA or aspirin, belongs to a class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs). In addition to its anti-inflammatory properties, aspirin also acts as an analgesic, antipyretic and antithrombotic agent. Like most other NSAIDs, aspirin exerts its therapeutic effects by inhibiting prostaglandin G/H synthase 1 and 2, better known as cyclooxygenase-1 and -2 or simply COX-1 and -2. COX-1 and -2 catalyze the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor to a number of other prostaglandins, such as prostaglandin E2, involved in pain, fever and inflammation. The antipyretic properties of aspirin arise from inhibition of prostaglandin E2 synthesis in the preoptic region of the hypothalamus. Interference with adhesion and migration of granulocytes, polymorphonuclear leukocytes and macrophages at sites of inflammation account for its anti-inflammatory effects. The analgesic effects of aspirin likely occur due to peripheral action at the site of injury and possibly within the CNS. Aspirin is unique from other NSAIDs in that it is an irreversible COX inhibitor. Aspirin irreversibly acetylates a serine side chain of COX rendering the enzyme inactive. Enzyme activity can only be regained by production of more cyclooxygenase. This unique property of aspirin and its higher selectivity for COX-1 over COX-2 makes it an effective antiplatelet agent. Platelets contain COX-1, a key enzyme in the production thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation. Since platelets lack the ability to make more enzyme, TXA2 production is inhibited for the lifetime of the platelet (approximately 8 - 12 days). Aspirin is commonly used at low doses to prevent cardiovascular events such as strokes and heart attacks. At higher doses, aspirin may be used as an analgesic, anti-inflammatory and antipyretic. Aspirin may cause gastric irritation and bleeding by inhibiting the synthesis of prostaglandins that enhance and maintain the protective gastric mucous layer.

Adefovir dipivoxil is an ester prodrug of adefovir, a nucleotide analogue used in the treatment of chronic hepatitis B. Adefovir dipivoxil is taken up into the liver cell and is cleaved into adefovir by intracellular esterases. Adefovir is subsequently phosphorylated first by adenylate kinases and then by nucleoside diphosphate kinases into adefovir diphosphate. Adefovir 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, adefovir causes chain termination, thus preventing viral replication.

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.

Alfentanil 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.

Alprenolol 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, alprenolol 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.

Alteplase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. It also produces limited conversion of plasminogen in the absence of fibrin.

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

Amiloride 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, amiloride can achieve a modest amount of diuresis by decreasing the osmotic gradient necessary for water reabsorption from lumen to interstitium. Amiloride 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, amiloride also inhibits potassium excretion.

Aminocaproic acid works as an antifibrinolytic. It is a derivative of the amino acid lysine. The fibrinolysis-inhibitory effects of aminocaproic acid appear to be exerted principally via inhibition of plasminogen activators and to a lesser degree through antiplasmin activity. Aminocaproic acid binds reversibly to the kringle domain of plasminogen and blocks the binding of plasminogen to fibrin and its activation to plasmin.

Amlodipine 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, amlodipine 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 amlodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, amlodipine has little effect on cardiac myocytes and conduction cells. This pathway depicts the pharmacological action of amlodipine on arterial smooth muscle cells. Amlodipine 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 amlodipine result in an overall decrease in blood pressure. Amlodipine is a long-acting CCB that may be used to treat mild to moderate essential hypertension and exertion-related angina (chronic stable angina).

Anistreplase 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.

Aprotinin inhibits several serine proteases, specifically trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/ml, and kallikrein at 300,000 IU/ml. Its action on kallikrein leads to the inhibition of the formation of factor XIIa. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.

Ardeparin binds to antithrombin III, accelerating its activity and inactivating factor Xa and thrombin, thereby inhibiting thrombosis. Ardeparin also binds to heparin cofactor II, inhibiting thrombin. Ardeparin does not effect prothrombin time (PT) assays and may prolong activated partial thromboplastin time (APTT). Ardeparin has double the anti-factor Xa activity of anti-factor IIa activity, compared to unfractionated heparin which has approximately equal anti-factor Xa activity and anti-factor IIa activity.

Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation. Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.

Atenolol 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.

Atorvastatin 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. Atorvastatin bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Structure-activity relationship studies have demonstrated that atorvastatin binds to HMG-CoA reductase at the same site as the reduced 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. Atorvastatin has a unique structure, long half-life, and hepatic selectivity, explaining its greater LDL-lowering potency compared to other HMG-CoA reductase inhibitors.

Azathioprine 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. Azathioprine is first converted _in vivo_ to mercaptopurine in the liver. Mercaptopurine then travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is 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.

Azithromycin, a semisynthetic antibiotic belonging to the macrolide subgroup of azalides, is used to treat STDs due to chlamydia and gonorrhea, community-acquired pneumonia, pelvic inflammatory disease, pediatric otitis media and pharyngitis, and Mycobacterium avium complex (MAC) in patients with advanced HIV disease. Similar in structure to erythromycin, azithromycin reaches higher intracellular concentrations than erythromycin, increasing its efficacy and duration of action. Azithromycin binds to the 50S subunit of the 70S bacterial ribosomes, and therefore inhibits RNA-dependent protein synthesis in bacterial cells.

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). Benazepril is an ACE inhibitor prodrug that is hydrolyzed by liver esterases to its active form, benazeprilat. Benazeprilat 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 benazepril. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of benazepril. Benazepril may be used to treat hypertension, congestive heart failure and chronic renal failure.

Bendroflumethiazide, 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, bendroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

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

Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm.

Bevacizumab is a humanized anti-VEGF monoclonal antibody used 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. Bevacizumab exerts its effect by binding to extracellular VEGF and preventing its binding to receptors on the endothelial cell surfaces. This in turns inhibits the MAP and IP3 and supresses angiogenesis.

Bisoprolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Bisoprolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm.

Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release.

The mechanism of action of Bromfenac is thought to be due to its ability to block prostaglandin synthesis by inhibiting cyclooxygenase 1 and 2 (COX-1 and -2), also called prostaglandin G/H synthase 1 and 2. COX-1 and -2 catalyze the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostglandin H2. Prostaglandin H2 is the precursor to a number of prostaglandins (e.g. PGE2) involved in fever, pain, swelling, inflammation, and platelet aggregation. Bromfenac antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure. The analgesic and anti-inflammatory effects of bromfenac occurs as a result of decreased prostaglandin synthesis.

Bumetanide, a loop diuretic, 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, bumetanide is a very potent diuretic.

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

Capecitabine is a fluoropyrimidine anticancer drug. After absorption, it is metabolized in the liver to the intermediate 5’-deoxy-5-fluorouridine, which is subsequently converted into 5-fluorouracil (5-FU) by intracellular thymidine phosphorylase. 5-FU exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase. Since thymidine phosphorylase is present at 3-10 fold higher concentration in cancer cells compared normal cells, capecitabine’s cytotoxic effect is selective for cancer cells.

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). Captopril is an ACE inhibitor that competes with angiotensin I for binding to ACE. Captopril effectively inhibits the conversion of angiotensin I to angiotensin II. The resulting reduction in angiotensin II concentration confers blood pressure lowering effects to captopril. Increased levels of bradykinin resulting from inhibition of its breakdown may also contribute to the effects of captopril. Captopril may be used to treat hypertension, congestive heart failure and renal nephropathy.

Carfentanil 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.

Carvedilol is a racemic mixture in which nonselective beta-adrenoreceptor blocking activity is present in the S(-) enantiomer and alpha-adrenergic blocking activity is present in both R(+++) and S(-) enantiomers at equal potency. Carvedilol's beta-adrenergic receptor blocking ability decreases the heart rate, myocardial contractility, and myocardial oxygen demand. Carvedilol also decreases systemic vascular resistance via its alpha adrenergic receptor blocking properties. Carvedilol and its metabolite BM-910228 (a less potent beta blocker, but more potent antioxidant) have been shown to restore the inotropic responsiveness to Ca2+ in OH- free radical-treated myocardium. Carvedilol and its metabolites also prevent OH- radical-induced decrease in sarcoplasmic reticulum Ca2+-ATPase activity. Therefore, carvedilol and its metabolites may be beneficial in chronic heart failure by preventing free radical damage.

Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, celecoxib 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 (PGE2) and PGE2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precusor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Celecoxib 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 rofecoxib and valdecoxib, celecoxib 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 celecoxib from binding. Celecoxib is approximately ten times more selective for COX-2 than COX-1. Celecoxib is used mainly to treat rheumatoid arthritis and osteoarthritis which require something more potent than aspirin. The analgesic, antipyretic and anti-inflammatory effects of celecoxib occur as a result of decreased prostaglandin synthesis. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of celecoxib. The latter portion of this figure depicts celecoxib’s potential involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, which are anuclear cells derived from fragmentation of 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 the 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. Celecoxib 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 adverse cardiovascular effects observed with other selective COX-2 inhibitors, such as rofecoxib, which has since been withdrawn from the market.

Cerivastatin 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. Cerivastatin bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Cerivastatin, like fluvastatin, atorvastatin and rosuvastatin, is one of the synthetically derived statins. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

Cetuximab 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. Cetuximab 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.

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

Chlorothiazide is a thiazide diuretic that 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, chlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Chlorthalidone, a thiazide-like 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, chlorthalidone 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). Cilazapril, a pyridazine compound, is an ACE inhibitor prodrug that is hydrolyzed in vivo to its active form, cilazaprilat. Cilazaprilat competes with angiotensin I for binding to ACE and effectively inhibits the conversion of angiotensin I to angiotensin II. The resulting decreased level of angiotensin II confers blood pressure lowering effects to cilazapril. Inhibiting the breakdown of bradykinin may also play a role in decreasing blood pressure. Cilazapril may be used to treat hypertension, congestive heart failure and nephropathy.

The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.

Cimetidine binds to histamine H2-receptors located on the basolateral membrane of the gastric parietal cell, blocking histamine effects. This competitive inhibition results in reduced gastric acid secretion and a reduction in gastric volume and acidity.

Citalopram is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.

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

Clindamycin is a semisynthetic derivative of lincomycin, a natural antibiotic produced by the actinobacterium Streptomyces lincolnensis. Lincosamides (e.g. lincomycin, clindamycin) are a class of drugs that bind to the 23S portion of the 50S subunit of bacterial ribosomes and inhibit early elongation of peptide chain by inhibiting transpeptidase reaction. In this sense, they have a similar action to macrolides. Clindamycin has a bacteriostatic effect. It is used primarily to treat infections caused by susceptible anaerobic bacteria, including infections of the respiratory tract, skin and soft tissue infections, and peritonitis. In patients with hypersensitivity to penicillins, clindamycin may be used to treat infections caused by susceptible aerobic bacteria as well. Clindamycin may also be used in combination with chloroquine and quinine to treat malaria caused by Pasmodium falciparum. It is commonly used as a topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. Clindamycin may also be used to treat bone and joint infections, particularly those caused by Staphylococcus aureus.

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

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

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

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

Cyclophosphamide is an alkylating agent used in the treatment of certain cancers. Following absorption, cyclophosphamide is converted into 4-hydroxyphosphamide by a variety of cytochrome P450 isozymes in the liver. 4-Hydroxyphosphamide is more soluble than cyclophosphamide and is the primary form of the drug that is transported in blood. 4-Hydroxyphosphamide crosses the plasma membrane of the cancer cell and spontaneuosly forms aldophosphamide. This is a reversible reaction. Aldophosphamide can decompose into acrolein and phosphoramide mustard. Phosphoramide mustard is the active alkylating agent and forms alkyl adducts with DNA through a phosphoramide aziridinium intermediate. Alkylation of DNA causes DNA damage and eventually cell death.

Cyclothiazide, 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, cyclothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

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

Desipramine is a tricyclic antidepressant that exerts its therapeutic effects by inhibiting norepinephrine and serotonin reuptake in the brain. It does so by competing for the same binding site as norepinephrine on the sodium-dependent noradraneline transporter (SLC6A2) and by competing with serotonin for binding to the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of both norepinephrine and serotonin in their respective synapses and reverses the state of low concentrations of both neurotransmitters found in depression. Higher concentrations of norepinephrine and serotonin have also been shown to have long-term neuromodulatory effects. Binding of these neurotransmitters to their respective receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.

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

Diclofenac is an acetic acid nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Diclofenac is used to treat pain, dysmenorrhea, ocular inflammation, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and actinic keratosis. The antiinflammatory effects of diclofenac are believed to be due to inhibition of both leukocyte migration and the enzyme cylooxygenase (COX-1 and COX-2 or prostaglandin G/H synthase 1 and 2), leading to the peripheral inhibition of prostaglandin synthesis. As prostaglandins contribute to pain perception, inhibition of their synthesis confers analgesic effects to diclofenac. Antipyretic effects may be due to action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat dissipation.

Dicumarol 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.

Diflunisal 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. Diflunisal 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 diflunisal occur as a result of decreased prostaglandin synthesis. Diflunisal also inhibits the migration of leukocytes into sites of inflammation and prevents the production of thromboxane A2, an aggregating agent, by platelets.

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

Dipyridamole likely inhibits both adenosine deaminase and phosphodiesterase, preventing the degradation of cAMP, an inhibitor of platelet function. This elevation in cAMP blocks the release of arachidonic acid from membrane phospholipids and reduces thromboxane A2 activity. Dipyridamole also directly stimulates the release of prostacyclin, which induces adenylate cyclase activity, thereby raising the intraplatelet concentration of cAMP and further inhibiting platelet aggregation.

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

**Disulfiram is a drug used in the treatment of cocaine addiction and chronic alcoholism. With regards to cocaine addiction, cocaine inhibits dopamine reuptake by blocking dopamine transporter 1 (DAT1). This increases dopamine concentrations in the synapse and dopamine binding to its receptors induces euphoria. Disulfiram inhibits dopamine beta-hydroxylase, which metabolizes dopamine into norepinephrine. This causes more dopamine to accumulate in the axon terminal and more dopamine is released. When used concomitantly with cocaine, this causes an extremely high concentration of dopamine in the synapse that does not increase the euphoric effects of cocaine, but rather induces an unpleasant sensation of anxiety. This serves to discourage the patient from using cocaine while taking disulfiram. With regards to alcoholism, disulfiram inhibits the mitochondrial enzyme acetaldehyde dehydrogenase, an enzyme involved in the second step of alcohol metabolism. This causes an increase in the levels of acetaldehyde, which leads to the development of symptoms of a hangover such as flushing, nausea, vomiting, headache, and confusion, which serves to discourage the patient from consuming alcohol while taking disulfiram.

Docetaxel, a semisynthetic analogue of paclitaxel, is an anticancer agent classified as a microtubule-stabilizing agent. Similar to paclitaxel, it 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. Docetaxel 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, docetaxel can bind to β-tubulin in a one to one ratio and stimulate microtubule polymerization. At lower clinically relevant drug concentrations, docetaxel 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. Docetaxel is susceptible to cellular drug resistance caused by drug efflux via a number of multidrug resistance-associated proteins.

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

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). Enalapril is an ACE inhibitor prodrug that is hydrolyzed in vivo by esterases to its active form, enalaprilat. Enalaprilat 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 enalapril. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of enalapril. Enalapril may be used to treat hypertension, congestive heart failure and chronic renal failure.

The mechanism of action of enoxaparin is antithrombin-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. The antithrombotic effect of enoxaparin is well correlated to the inhibition of factor Xa. Enoxaparin interacts with Antithrombin III, Prothrombin and Factor X.

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

Eptifibatide is an anti-coagulant that selectively blocks the platelet glycoprotein IIb/IIIa receptor. Eptifibatide is a cyclic heptapeptide derived from a protein found in the venom of the southeastern pygmy rattlesnake (Sistrurus miliarus barbouri). It belongs to the class of the so called arginin-glycin-aspartat-mimetics and reversibly binds to platelets. Eptifibatide inhibits platelet aggregation by reversibly binding to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets, thus preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands. Inhibition of platelet aggregation occurs in a dose- and concentration-dependent manner.

Erlotinib 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. Erlotinib acts as an anticancer drug by binding to the intracellular tyrosine kinase domain of the EGFR and blocking its activity. This in turn inhibits downstream signalling and prevents tumour growth.

Erythromycin is a bacteriostatic macrolide antibiotic produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by reversibly binding to 50S ribosomal subunits. After penetrating the bacterial cell membrane, erythromycin binds to the 50S subunit of bacterial ribosomes near the “P” or donor site so that binding of transfer RNA (tRNA) to the donor site is blocked. Translocation of peptides from the “A” or acceptor site to the “P” or donor site is prevented, and subsequent protein synthesis is inhibited. Erythromycin is effective only against actively dividing organisms.

Escitalopram is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.

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

Esomeprazole 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. Esomeprazole 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, Esomeprazole 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.

Ethacrynic acid, a loop diuretic, 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, ethacrynic acid is a very potent diuretic.

Etodolac is a non-steroidal anti-inflammatory drug (NSAID) that can be used to treat rheumatoid arthritis and osteoarthritis. Most NSAIDs are non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitors that act on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. NSAIDs antagonize 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 NSAIDs occur as a result of decreased prostaglandin synthesis. Etodolac was previously thought to be a non-selective COX inhibitor; however, it is now know that it is five to fifty times more selective for COX-2 than COX-1. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of etodolac. The latter portion of this figure depicts etodolac’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. Etodolac 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 adverse cardiovascular effects observed with other selective COX-2 inhibitors, such as rofecoxib, which has since been withdrawn from the market.

Etoposide 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-stranded 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. Etoposide, 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. Etoposide 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.

Famotidine binds competitively to H2-receptors located on the basolateral membrane of the parietal cell, blocking histamine affects. This competitive inhibition results in reduced basal and nocturnal gastric acid secretion and a reduction in gastric volume, acidity, and amount of gastric acid released in response to stimuli including food, caffeine, insulin, betazole, or pentagastrin.

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

Fentanyl 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.

This pathway illustrates the flecainide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the 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). Flecainide is a Class 1C antiarrhythmic drug. Like other Class 1 antiarrhythmic agents (e.g. quinidine), flecainide blocks sodium ion currents (I-Na) through voltage-gated sodium channels with preferential binding to channels in their open activated state. The therapeutic effects of flecainide are thought to arise from their slow dissociation from sodium channels, which alters the pattern of action potential propagation. Flecainide also blocks potassium currents via the voltage-gated rapid delayed rectifying potassium channel (I-Kr) and blocks the extrusion of calcium ions from the sarcoplasmic reticulum (SR) to the cytosol via the cardiac ryanodine receptor (RYR2) of the SR membrane. Flecainide shortens the action potential duration in Purkinje cells, but prolongs it in ventricular cells. Due to its proarrhythmic effects, flecainide increased mortality in patients recovering from myocardial infarctions in the CAST study. However, in the absence of heart disease, it is still used to maintain sinus rhythm in patients with supraventricular arrhythmias, such as atrial fibrillation, ventricular tachycardia and supraventricular tachycardia.

Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug. It exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase.

Fluoxetine is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.

Fluvastatin 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. Fluvastatin bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Fluvastatin was the first synthetically-prepared HMG-CoA reductase inhibitor. Although similar to lovastatin, simvastatin, and pravastatin, it has a shorter half-life, no active metabolites, extensive protein binding, and minimal CSF penetration. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

The antithrombotic activity of Fondaparinux is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, Fondaparinux potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development.

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). Fosinopril, an ACE inhibitor, is a prodrug that is hydrolyzed in vivo by esterases to its active form, fosinoprilat. Fosinoprilat competes with angiotensin I for binding to ACE and effectively inhibits the conversion of angiotensin I to angiotensin II. This results in lower concentrations of angiotensin II and reductions in blood pressure. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of fosinopril. Fosinopril may be used to treat hypertension, congestive heart failure and chronic renal failure.

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

Furosemide, a loop diuretic, 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, furosemide is a very potent diuretic.

Gefitinib 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. Gefitinib acts as an anticancer drug by binding to the intracellular tyrosine kinase domain of the EGFR and blocking its activity. This in turn inhibits downstream signalling and prevents tumour growth.

Gemcitabine is a cytidine analogue used in the treatment of certain cancers. Gemcitabine enters the cell via sodium nucleoside co-transporters (SLC29A1, SLC28A1, and SLC28A3), where it acts through multiple mechanisms to produce a cytotoxic effect. Gemcitabine is phosphorylated into gemcitabine monophosphate by deoxycytidine kinase, which is then subsequently phosphorylated into the diphosphate and triphosphate nucleotides by UMP-CMP kinase and nucleoside diphosphate kinase respectively. Gemcitabine diphosphate inhibits ribonucleoside-diphosphate reductase, a crucial enzyme in the conversion of ribonucleotides into deoxyribonucleotides for DNA synthesis. Gemcitabine triphosphate on the other hand can be incorporated into DNA, causing chain termination. Furthermore, gemcitabine monophosphate can be deaminated into difluoro-deoxyuridine monophosphate, which inhibits thymidylate synthase, an enzyme involved in the production of dTTP for DNA synthesis.

Gentamicin is an aminoglycoside antibiotic that inhibits bacterial protein synthesis. Gentamicin 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, gentamicin 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.

Glibenclamide is a sulfonylurea drug used in the treatment of type 2 diabetes. Glibenclamide 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. Glibenclamide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.

Gliclazide is a sulfonylurea drug used in the treatment of type 2 diabetes. Gliclazide 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. Gliclazide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.

The mechanism of action of heparin is antithrombin-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. The antithrombotic effect of heparin is well correlated to the inhibition of factor Xa. Heparin interacts with antithrombin III, prothrombin and factor X.

Heroin is a mu-opioid agonist. It acts on endogenous mu-opioid receptors that are spread in discrete packets throughout the brain, spinal cord and gut in almost all mammals. Heroin, along with other opioids, are agonists to four endogenous neurotransmitters. They are beta-endorphin, dynorphin, leu-enkephalin, and met-enkephalin. The body responds to heroin in the brain by reducing (and sometimes stopping) production of the endogenous opioids when heroin is present. Endorphins are regularly released in the brain and nerves, attenuating pain.

Hydrochlorothiazide, 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, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.Hydrochlorothiazide, 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, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Hydrocodone 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.

Hydroflumethiazide is a thiazide diuretic that 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, Hydroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Hydromorphone 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 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 of cholesterol biosynthesis. 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 signaling 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.