Browsing pathways

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.