Flecainide Action Pathway,Drug Action

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


Ibutilide Action Pathway,Drug Action

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


Intracellular Signalling Through FSH Receptor and Follicle Stimulating Hormone,Protein

In the ovary, the FSH receptor is necessary for follicular development and is expressed on the granulosa cells. In the male the FSH receptor has been identified on the Sertoli cells that are critical for spermatogenesis.  The FSH receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Pyruvate Decarboxylase E1 Component Deficiency (PDHE1 Deficiency),Disease

Pyruvate Decarboxylase E1 Component Deficiency is caused by a defect in the PDHA1 gene which codes for mitochondrial pyruvate dehydrogenase E1 component subunit alpha, somatic form. This is a homotetrameric enzyme that catalyses the decarboxylation of pyruvic acid to acetaldehyde and carbon dioxide. A defect in this enzyme results in accumulation of lacate and pyruvate. Symptoms and signs include severe lactic acidosis in the newborns that usually leading to death, hypotonic, lethargic, seizures, mental retardation and spasticity.


Intracellular Signalling Through Histamine H2 Receptor and Histamine,Signaling

Histamine is an organic nitrogenous compound that is involved in local immune responses and it is a neurotransmitter for brain. Histamine can mediate various actions by interacting with histamine receptors (H1, H2, H3 and H4). The H2 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Vitamin A Deficiency,Disease

Vitamin A deficiency can be caused by many causes. A defect in the BCMO1 gene which codes for beta,beta-carotene 15,15’-monooxygenase is one of them. Beta,beta-carotene 15,15’-monooxygenase catalyzes the chemical reaction where the two substrates are beta-carotene and O2, whereas its product is retinal. A defect in this enzyme results in decrease of levels of retinal and vitamin A in serum; Signs and symptoms include night blindness, poor adaptation to darkness, dry skin and hair.


Glutathione Synthetase Deficiency (5-Oxoprolinuria; Pyroglutamic Aciduria) is caused by a defect in the GSS gene which codes for glutathione synthetase. Glutathione synthetase is the second enzyme in the glutathione biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. A defect in this enzyme results in accumulation of pyroglutamic acid and gamma-glutamylcysteine in urine and blood; decrease level of glutathione in erythrocytes; increase urinary excretion of 5-oxoproline. Glutathione synthetase deficiency can be classified into three types: mild, moderate and severe. Mild glutathione synthetase deficiency usually results in the destruction of red blood cells (hemolytic anemia). Rarely, affected people also excrete large amounts of a compound called 5-oxoproline in their urine (5-oxoprolinuria). This compound builds up when glutathione is not processed correctly in cells. Individuals with moderate glutathione synthetase deficiency may experience symptoms beginning shortly after birth including hemolytic anemia, 5-oxoprolinuria, and elevated acidity in the blood and tissues (metabolic acidosis). In addition to the features present in moderate glutathione synthetase deficiency, individuals affected by the severe form of this disorder may experience neurological symptoms. These problems may include seizures; a generalized slowing down of physical reactions, movements, and speech (psychomotor retardation); mental retardation; and a loss of coordination (ataxia). Some people with severe glutathione synthetase deficiency also develop recurrent bacterial infections.


Intracellular Signalling Through LHCGR Receptor and Luteinizing Hormone/Choriogonadotropin,Protein

Its activation is necessary for the hormonal functioning during reproduction. LHCGRs are found in the ovary, testis, and many extragonadal tissues.In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as well as luteal function. In the male the LHCGR has been identified on the Leydig cells that are critical for testosterone production, and support spermatogenesis. The LHCGRs receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Hyperinsulinism-hyperammonemia syndrome (HHS; Glutamate dehydrogenase 1; GLUD1), an inherited condition, is caused by a defect in the GLUD1 gene which codes for mitochondrial glutamate dehydrogenase 1. It is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate (Glu) metabolism and the energy homeostasis. An excessive activity of this enzyme results in high insulin and ammonia levels in blood; decrease level of glucose in blood. Symptoms and signs include shakiness, weakness, seizure, rapid pulse and confusion. Maintain normoglycemia is essencial to prevent neurologic damage. Some medications can be used to suppress insulin secretion.


Methylenetetrahydrofolate Reductase Deficiency (MTHFRD),Disease

Methylenetetrahydrofolate reductase deficiency (MTHFRD; Homocystinuria due to defect of n(5,10)-methylene THF deficiency) is caused by a defect in the MTHFR gene which codes for methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A defect in this enzyme results in accumulation of homocysteine and methionine in both plasma and urine. Some of the symptoms and signs include mental retardation, withdrawal, hallucinations, delusions, muscle weakness. Some patients remain asymptomatic until adulthood.


Hypermethioninemia,Disease

Hypermethioninemia is caused by a defect in the AHCY gene which codes for Adenosylhomocysteinase. converts the S-adenosyl homocysteine into the compound homocysteine. Homocysteine may be converted back to methionine or into another amino acid, cysteine. A defect in this enzyme results in accumulation of methionine and cysteine in blood. People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit learning disabilities, mental retardation, and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.


Hereditary Coproporphyria (HCP),Disease

Hereditary coproporphyria (HCP) is caused by a defect in the CPOX gene which codes for mitochondrial coproporphyrinogen-III oxidase. A defect in this enzyme results in accumulation of the porphyrin precursors porphobilinogen and 5-aminolevulinic acid; increase of fecal and urinary excreation of coproporphyrins. Symtpoms include reddish-purple urine, acute neurological problems (typically episodic confusion and sensory changes), and attacks of acute abdominal/nerve pain. Around 30% suffer photosensitive skin eruptions with nail involvement; these can lead to permanent scarring. While there is no cure for this condition, there are preventative measures people can take to regulate symptoms. A diet high in carbohydrates, glucose, as well as avoidance of aggravating factors (such as alcohol and drug use) can prevent attacks.


Intracellular Signalling Through PGD2 receptor and Prostaglandin D2,Signaling,PGD is the major prostanoid released from human mast cells upon immunological challenge. Prostaglandin D2 (PGD2) can trigger asthmatic responses by acting as a cell-derived mediator in mice. The PGD receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Acute Intermittent Porphyria,Disease

Acute intermittent porphyria (AIP), the second most common form of porphyria, is caused by a defect in the HMBS gene which codes for porphobilinogen deaminase. A defect in this enzyme results in accumulation of 5-aminolevulinic acid or porphobilinogen in both urine and serum. Most Patients are completely free of symptoms between attacks. Symtpoms include abdominal pain, constipation, vomitting, hypertension, muscle weakness, seizures, delirium, coma, and depression. A high-carbohydrate diet is typically recommended; in severe attacks, a glucose 10% infusion is recommended, which may aid in recovery.


Congenital Erythropoietic Porphyria (CEP) or Gunther Disease,Disease

Congenital Erythropoietic Porphyria (CEP) or Gunther Disease is a rare inborn error of porphyrin-heme synthesis inherited that is as an autosomal recessive trait. This disorder of bone marrow heme synthesis is caused by a defect in the UROS gene which codes for uroporphyrinogen-III synthase. This enzyme is involved in the fourth step of porphyrin metabolism, involved in the conversion of hydroxymethyl bilane into uroporphyrinogen III. Its defect results in accumulation of uroporphyrin III, coproporphyrin III and porphyrins; Uroporphyrin I in erythrocytes. Symptoms and signs include blistering and fragility of light-exposed skin, discolored urine, concomitant jaundice, reddish color teeth. The severe loss of bone with subsequent contractures and deformities occurs in most adults with erythropoietic porphyria.


Porphyria Variegata (PV),Disease

Porphyria variegata (PV) is caused by a defect in the PPOX gene which codes for protoporphyrinogen oxidase. A defect in this enzyme results in accumulation of the porphyrin precursors porphobilinogen and 5-aminolevulinic acid in plasma; increase of fecal and urinary levels of porphyrin and coproporphyrin. Symtpoms include abdominal pain, vomiting, diarrhea, constipation, muscle weakness, seizures, and mental changes such as anxiety and hallucinations. Some people with variegate porphyria have skin that is overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth.


Metachromatic leukodystrophy (MLD) is caused by a defect in the ARSA gene which does for arylsulfatase A. A defect in this enzyme results in accumulation of 3-O-sulfogalactosylceramide in urine, neural and non neural tisues like kidney and gallbladder. There are several forms of MLD. In the late infantile form, which is the most common form MLD, affected children begin having difficulty walking after the first year of life. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner. Children with the juvenile form of MLD (onset between 3–10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. The adult form commonly begins after age 16 as a psychiatric disorder or progressive dementia. Adult-onset MLD progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.


Globoid Cell Leukodystrophy,Disease

Globoid Cell Leukodistrophy, (GLD; Krabbe disease; Galactosylceramide Lipidosis) is caused by a defect in the GALC gene which codes for Galactocerebrosidase. A defect in this enzyme results in accumulation of galactosylceramide and psychosine in central nervous system. Infants with Krabbe disease are normal at birth. Symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. Other symptoms include muscle weakness, spasticity, deafness, optic atrophy and blindness, paralysis, and difficulty when swallowing. Prolonged weight loss may also occur. There are also juvenile- and adult-onset cases of Krabbe disease, which have similar symptoms but slower progression. In infants, the disease is generally fatal before age 2. Patients with late-onset Krabbe disease tend to have a slower progression of the disease and live significantly longer. Although there is no cure for Krabbe disease, bone marrow transplantation has been shown to benefit cases early in the course of the disease.


Gaucher Disease,Disease

Gaucher disease is caused by a defect in the GBA gene which codes for glucosylceramidase. A defect in this enzyme results in accumulation of glucosylceramide in in brain, bone marrow, liver, spleen, lungs, and other organs. Gaucher’s disease has three common clinical subtypes. Type I (or non-neuropathic type) is the most common form of the disease. Symptoms may begin early in life or in adulthood. They include enlarged liver, grossly enlarged spleen, skeletal weakness and bone disease. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia and leukopenia. Type II (or acute infantile neuropathic Gaucher’s disease) typically begins within 6 months of birth. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2. Type III (the chronic neuropathic form) can begin at any time in childhood or even in adulthood. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood. For type 1 and most type 3 patients, enzyme replacement treatment with intravenous recombinant glucocerebrosidase (imiglucerase) can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. Successful bone marrow transplantation cures the non-neurological manifestations of the disease. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort. Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.


Pyruvate Carboxylase Deficiency,Disease

Pyruvate carboxylase deficiency is caused by mutation in the pyruvate carboxylase gene. Serine—pyruvate aminotransferase catalyzes the reaction of serine and pyruvate to produce 3-hydroxypyruvate and L-alanine, as well as the reaction from L-alanine and glyodxylate to pyruvate and glycine. A defect in this results in accumulation of ammonia, glucose and pyruvate in blood; proline, lysine, citrulline, and alanine in plasma; and 2-oxoglutaric acid, fumaric acid, ketone bodies and succinate in urine. Symptoms include ataxia, lactic acidosis, mental retardation, metabolic acidosis, siezures, and dyspnea.


GABA-Transaminase Deficiency,Disease

GABA-Transaminase Deficiency (Gamma-amino butyric acid transaminase deficiency; GABA-T) is caused by a defect in the gene coding for gamma-aminobutyrate transaminase, which is responsible for catabolism of gamma-aminobutyric acid (GABA), an important, mostly inhibitory neurotransmitter in the central nervous system, into succinic semialdehyde. The active enzyme is a homodimer of 50-kD subunits complexed to pyridoxal-5-phosphate. GABAT is present in several tissues in addition to brain and is most active in liver. GABA-T catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively. This enzyme can also convert delta-aminovalerate and beta-alanine. Defects in GABA-T cause accumulation of beta-alanine and gamma aminobutyric acid in plasma and spinal fluid, as well as accumulation of homocarnosine in spinal fluid. Symptoms include hyperreflexia, hypotonia, lethargia, macrosomia, mental retardation, and seizures.


Primary Hyperoxaluria Type I,Disease

Type I primary hyperoxaluria (Glycolicaciduria) is caused by mutation in the gene encoding alanine-glyoxylate aminotransferase (AGXT). AGXT normally catalyzes the reaction from L-serine and pyruvate to 3-hydroxypyruvate and L-alanine and the reaction from L-alanine and glyoxylate to pyruvate and glycine. A defect in AGXT results in accumulation of glycolic acid, glyoxylic acid, and oxalate in urine. Symptoms include hematuria, myocarditis, nephrocalcinosis, peripheral neuropathy, and renal failure.


Leukotriene C4 Synthesis Deficiency,Disease

Leukotriene C4 synthetase deficiency is caused by a defect in the enzyme leukotriene C4 synthetase (LTC4S). This enzyme catalyzes the synthesis of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH), which is synthesized by glutathione synthetase. Leukotriene C4 and its receptor-binding metabolites LTD4 and LTE4 are cysteinyl leukotrienes that are potent lipid mediators of tissue inflammation. In general, leukotrienes are potent proinflammatory mediators synthesized from membrane-derived arachidonic acid after activation of certain granulocytes. A defect in LTC4 results in decreased concentrations of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in plasma, spinal fluid and urine. Symptoms include early death, failure to thrive, motor retardation, microcephaly, and progressive neurological defect.


Intracellular Signalling Through Prostacyclin Receptor and Prostacyclin,Signaling

Cyclooxygenase is the major producer of prostacyclin. Prostacyclin binding to its receptor increases vasodilation and decreases platelet aggregation. The receptor is a G-protein coupled receptor, upon its binding it activates G proteins causing the activation of adenylyl cyclase and production of cAMP messenger molecules. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.In vasodilation, the PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in dephosphorylation of MLC of myosin. This leads to smooth muscle relaxation resulting in vasodilation.


Mitochondrial Electron Transport Chain,Metabolic

The electron transport chain in mitochondria leads to the transport of hydrogen ions across the inner membrane of the mitochndria, and this proton gradient is eventually used in the production of ATP. Electrons travel down a chain of electron carriers in the inner mitochondrial membrane, ending with oxygen.The outer membrane of the mitochondrion is permeable to ions and other small molecules  and nothing in this pathway requires a specific transporter to enter into the intermembrane space. However, the inner membrane is only permeable to water, oxygen and carbon dioxide, and all other molecules, including protons, require transport proteins. Phosphate is able to enter the mitochondrial matrix via the glucose-6-phosphate translocase, and ADP is able to enter the matrix as ATP leaves it via the ADP/ATP translocase 1 protein.Electrons donated by NADH can enter the electron transport chain as NADH dehydrogenase, known as complex I, facilitates their transfer to ubiquinone, also known as coenzyme Q10. As this occurs, the coenzyme Q10 becomes reduced to form ubiquinol, and protons are pumped from the intermembrane space to the matrix.Lower energy electrons can also be donated to complex II, which includes succinate dehydrogenase and contains FAD. These electrons move from succinic acid to the FAD in the enzyme complex, and then to coenzyme Q10, which is reduced to ubiquinol. Throughout this, succinic acid from the citric acid cycle is converted to fumaric acid, which then returns to the citric acid cycle. This step, unlike the others in the electron transport chain, does not result in any protons being pumped from the matrix to the intermembrane space.Regardless of which complex moved the electrons to coenzyme Q10, the cytochrome b-c1 complex, also known as complex III, catalyzes the movement of electrons from ubiquinol to cytochrome c, oxidizing ubiquinol to ubiquinone and reducing cytochrome c. This process also leads to the pumping of hydrogen ions into the intermembrane space. Finally, the transfer of electrons from the reduced cytochrome c is catalyzed by cytochrome c oxidase, also known as complex IV of the electron transport chain. This reaction oxidizes cytochrome c for further electron transport, and transfers the electrons to oxygen, forming molecules of water. This reaction also allows protons to be pumped across the membrane.The proton gradient that is built up through the electron transport chain allows protons to flow through the ATP synthase proteins in the mitochondrial inner membrane, providing the energy required to synthesize ATP from ADP.


17-beta Hydroxysteroid Dehydrogenase III Deficiency,Disease

Defects in 17-beta hydroxysteroid dehydrogenase III (HSD17B3) are the cause of male pseudohermaphrodism with gynecomastia. These individuals have unambiguous female external genitalia at birth, but fail to menstruate at the time of expected puberty and instead virilize as evidenced by growth of the phallus. A defect in HSD17B3 causes accumulation of dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) as well as androstenedione in plasma.


Argininemia,Disease

Argininemia is caused by a mutation in the gene ARG, encoding liver arginase, which hydrolyses arginine to urea and ornithine in the last step of the urea cycle. A defect in liver arginase causes accumulation of ammonia in blood; arginine, creatine, guanidinoacetate, and homoarginine in plasma; urea nitrogen in serum; arginine and homoarginine in spinal fluid; and arginiosuccinate orotic acid, and uracil in urine. Symptoms include ataxia, cerebral atrophy, chorea, jaundice, and seizures.


Fc Epsilon Receptor I Signaling in Mast Cells,Protein

Fc epsilon receptor 1 (Fc epsilon RI) is a high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotope involved in allergies. The antigens of allergens bind to IgE antibodies, which then interact with Fc epsilon RIs on the surface of mast cells. This activates the mast cells and results in degranulation, a process by which preformed granules containing histamine, proteoglycans, and serine proteases, are released. Activated mast cells also synthesize and secrete lipid-derived mediators (such as prostaglandins, leukotrienes, and platelet-activating factor) and cytokines (notably tumor necrosis factor-alpha, interleukin-4, and interleukin-5). The release of these compounds results in the inflammatory response.


Diltiazem Action Pathway,Drug Action

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


Hyperprolinemia Type II,Disease

Hyperprolinemia (prolinemia Type II, HPII, prolinuria) is caused by mutation in the pyrroline-5-carboxylate dehydrogenase gene (P5CDH), which encodes pyrroline-5-carboxylate dehydrogenase. This enzyme assists in the metabolism of pyrroline-5-carboxylate, converting it to the amino acid glutamine. The conversion between proline and glutamine, and the reverse reaction controlled by different enzymes, are essential factors required to maintain proper metabolism and protein production. A defect in this enyzme causes accumulation of proline in plasma; ornithine in serum; and glycine, hydroxyproline and proline in urine. Symptoms include mental retardation, acute and chronic renal failure and seizures.


Hyperprolinemia Type I,Disease

Hyperprolinemia type I (HPI, proline oxidase deficiency) is caused by mutation in the proline dehydrogenase gene (PRODH), which codes for proline dehydrogenase (proline oxidase). This enzyme converts proline to delta-1-pyrroline-5-carboxylate. A defect in proline dehydrogenase causes accumulation of proline in plasma, and glycine, hydroxyproline, and proline in urine. Symptoms include mental retardation, renal cysts, and seizures.


Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency),Disease

Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency, Creatine Deficiency Syndrome, Creatine Deficiency due to AGAT Deficiency, GATM Deficiency) is caused by mutation in the GATM gene, which codes for L-arginine:glycine amidinotransferase, which catalyzes the reaction between L-arginine and glycine, transferring an amidino group from L-arginine to glycine, producing L-ornithine and guanidinoacetate, a precursor of creatine. A defect in this enzyme causes a decrease in concentration of creatine and guanidinoacetate in plasma and urine. Symptoms include mental and motor retardation, seizures, and delayed or abnormal speech development.


Ornithine Aminotransferase Deficiency (OAT Deficiency),Disease

Ornithine Aminotransferase Deficiency, (OAT Deficiency, Ornithine Keto Acid Aminotransferase Deficiency, OKT Deficiency, Ornithine-Delta-Aminotransferase Deficiency, Hyperornithinemia With Gyrate Atrophy Of Choroid And Retina; Hoga Gyrate Atrophy, Ornithine Aminotransferase) is caused by a defect in the gene that codes for ornithine-delta-aminotransferase, which catalyzes the major catalytic reaction for ornithine. A defect in this enzyme causes accumulation of ornithine. Symptoms include tunnel vision, night blindness, myopia, and progressive vision loss.


Lesch-Nyhan Syndrome (LNS),Disease

Lesch-Nyhan Syndrome (LNS; Hypoxanthin guanine phosphoribosyltransferase deficiency) is caused by a complete defect in the HPRT1 gene which codes for hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase is an enzyme in purine metabolism. Its primarily functions to salvage purines from degraded DNA to renewed purine synthesis. In this role, it acts as a catalyst in the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP. A complete deficiency in this enzyme causes overproduction of uric acid, therefore it results in accumulation of uric acid in serum and increase urinary excretion of uric acid. Symptoms and signs include severe gout and kidney problems, poor muscle control, and moderate mental retardation. These complications usually appear in the first year of life. A striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting, that begin in the second year of life. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease. Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.


Gout or Kelley-Seegmiller Syndrome,Disease

Gout, or Kelley-Seegmiller syndrome, is caused by a partial defect in the HPRT1 gene which codes for hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase is an enzyme in purine metabolism. Its primarily functions to salvage purines from degraded DNA to renewed purine synthesis. In this role, it acts as a catalyst in the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP. A partial deficiency in this enzyme causes overproduction of uric acid, therefore it results in accumulation of uric acid in serum and increase urinary excretion of uric acid. Symptoms and signs include excruciating, sudden, unexpected, burning pain, as well as swelling, redness, warmth, and stiffness in the affected joint, usually in the great toe, tophi in the helix or antihelix of the ear, along the ulnar surface of the forearm, in the olecranon bursa, or in other tissues. Treatment has three objectives: manage symptoms of acute attacks, prevent acute attacks, and reduce serum uric acid.


Nebivolol Action Pathway,Drug Action

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


Carvedilol Action Pathway,Drug Action

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


Labetalol Action Pathway,Drug Action

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


Tyrosinemia Type 2 (or Richner-Hanhart Syndrome),Disease

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.


Tyrosinemia Type 3 (TYRO3),Disease

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).


Congenital Lipoid Adrenal Hyperplasia (CLAH) or Lipoid CAH,Disease

Congenital lipoid adrenal hyperplasia (CLAH; Steroid 20-22 desmolase deficiency; lipoid CAH) is caused by a defect in the CYP11A1 gene which codes for mitochondrial cholesterol side-chain cleavage enzyme. Cholesterol side-chain cleavage enzyme convertes cholesterol to pregnenolone in adrenal cortisol synthesis of all steroid hormones. A defect in this enzyme results in in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of adrenocorticotropic hormone (ACTH). Symptoms include poor feeding, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, hypoglycemia, hyperpigmentation. Sex steroid deficiency can result in ambiguous genitalia. Patients need the mineral replacement and extra glucocorticoid. XX female patients can use estrogen replacement at or after puberty. For XY patients, the testes are uniformly nonfunctional and they are undescended, are removed when the diagnosis is made due to the risk of cancer development in these tissues.


Adrenal Hyperplasia Type 5 or Congenital Adrenal Hyperplasia Due to 17 alpha-Hydroxylase Deficiency,Disease

Adrenal hyperplasia type 5 (AH5; Congenital Adrenal Hyperplasia due to 17 Alpha hydroxylase Deficiency) is a form of congenital adrenal hyperplasia. It is caused by a defect in the CYP17A1 gene which codes for Steroid 17-alpha-hydroxylase/17,20 lyase. These 2 enzymes convert pregnenolone and progesterone to their 17-hydroxy forms in steroidogenesis and mediate three key transformations in cortisol and sex steroid synthesis. A defect in 17-alpha-hydroxylase results in decreased synthesis of both cortisol and sex steroids; increase in mineralocorticoids. Common symptoms include mild hypocortisolism, ambiguous genitalia in genetic males or failure of the ovaries to function at puberty in genetic females, and hypertension. Hypertension and mineralocorticoid excess is treated with glucocorticoid replacement. Genetically female patients need female hormone replacement to induce puberty and regulate menses. Surgery may be needed for males with ambiguous genitalia. Testosterone must be replaced for genetically males (XY) to induce puberty and continued throughout adult life.


Adrenal Hyperplasia Type 3 or Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency,Disease

Adrenal hyperplasia type 3, also called Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, is caused by a defect in the CYP21A2 gene which codes for Steroid 21-hydroxylase (21-hydroxylase). Steroid 21-hydroxylase catalyzes hydroxylation of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway from pregnenolone to cortisol. It also catalyzes hydroxylation of progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway on its way from pregnenolone to aldosterone. A defect in this enzyme results in accumulation of 17-Hydroxyprogesterone, progesterone and 17a-Hydroxypregnenolone, androstenedione, and testosterone; decreased levels of cortexolone, deoxycorticosterone, aldosterone and cortisol. Symptoms include salt-wasting crises in infancy due to the lack of aldosterone, like spitting, poor weight gain, vomiting, severe dehydration, and circulatory collapse. The high level of testosterone results in virilization and genital ambiguity of female infants.


Glycogen Storage Disease Type 1A (GSD1A) or Von Gierke Disease,Disease

Glycogen storage disease type 1A (GSD1A), or von Gierke disease, is caused by a defect in the G6PC gene which codes for Glucose-6-phosphatase. Glucose-6-phosphatase hydrolyzes glucose-6-phosphate to glucose and is responsible for the regulation of blood glucose level. A defect in this enzyme results in accumulation of glycogen in affected tissues, like liver and kidney; decreased glucose level; and accumulation of lactate. Glycogen storage disease type 1A causes clinically significant end-organ disease with significant morbidity. Usually it presents in childhood. Symptoms include seizures, irritability, pallor, hypotonia, tremors, loss of consciousness, apnea and hepatomegaly. There is no cure for glycogen storage disease type 1A. Diet therapy can help to prevent hypoglycemia and reduce the symptoms. Liver transplantation may be indicated in cases of hepatic malignancy.


Verapamil Action Pathway,Drug Action

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


Amlodipine Action Pathway,Drug Action

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


Felodipine Action Pathway,Drug Action

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


Isradipine Action Pathway,Drug Action

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


Nifedipine Action Pathway,Drug Action

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


Nimodipine Action Pathway,Drug Action

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


Nisoldipine Action Pathway,Drug Action

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


Nitrendipine Action Pathway,Drug Action

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


Methylmalonate Semialdehyde Dehydrogenase Deficiency,Disease

Methylmalonate Semialdehyde Dehydrogenase Deficiency (MMSDH Deficiency; Aldehyde Dehydrogenase 6 Family, Member A1; ALDH6A1 Deficiency)is caused by a defect in methylmalonate semialdehyde dehydrogenase, which catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA, respectively. A defect in methylmalonate semialdehyde dehydrogenase causes accumulation of 3-Aminoisobutyric acid, 3-Hydroxyisobutyric acid, 3-hydroxypropionic acid, beta-Alanine, lactate, and methylmalonic acid in urine. Symptoms inclue failure to thrive, large liver, mental and motor retardation and vomiting.


Homocarnosinosis,Disease

Homocarnosinosis is caused by an inherited defect in serum carnosinase, which converts homocarnosine to GABA (gamma aminobutyric acid). A defect in serum carnosinase causes accumulation of the brain specific dipeptide homocarnosine (Hca), in the CSF and brain. Symptoms include hypotonia, mental retardation, retinitis pigmentosa and spastic diplegia/quadriplegia.


Desmosterolosis,Disease

Desmosterolosis is caused by a mutation in the DHCR24 gene, which codes for the enzyme 24-dehydrocholesterol reductase, which catalyzes the reduction of the delta-24 double bond of sterol intermediates. A defect in 24-dehydrocholesterol reductase causes accumulation of desmosterol in plasma. Symptoms include cleft palate, clubfoot, dysmorphism, mental and motor retardation, and speech development.


CHILD Syndrome,Disease

CHILD Syndrome, (Congenital Hemidysplasia with Icthyosiform Erythroderma and Limb Defects; Ichthyosiform Eruthroderma, Unilateral, with Epsilateral Malformations, Especially Absence Deformity of Limbs) is caused by a mutation in the gene encoding NADH steroid dehydrogenase-like protein (NSDHL). A defect in sterol-4 alpha-carboxylate 3-dehydrogenase, which normally catalyzes the reaction 3-beta-hydroxy-4-beta-methyl-5-alpha-cholest-7-ene-4-alpha-carboxylate + NAD+ = 4-alpha-methyl-5-alpha-cholest-7-en-3-one + CO2 + NADH, causes accumulation of 8(9)cholestenol and 8-dehydrocholesterol in plasma. Symptoms of CHILD syndrome include hearing defects, hemidysplasia, unilateral hypomelia, ichthyosiform nevi, limb abnormalities, lung hypoplasia, and punctate calcifications.


The autosomal recessive disorder Smith-Lemli-Opitz Syndrome (SLOS; SLO Syndrome; RSH; Rutledge Lethal Multiple Congenital Anomaly, Syndrome; Polydactyly, Sex Reversal, Renal Hypoplasia, and Unilobar Lung; Lethal Acrodysgenital Syndrome) is characterized by disordered steroid biosynthesis. It results from a mutation in the DHCR7 gene coding for the enzyme sterol delta-7-reducatase. This enzyme catalyzes the production of cholesterol by reducing the C7-C8 double bond of 7-dehydrocholesterol (7-DHC). SLOS causes the accumulation of 7-dehydrocholesterol and 8-dehydrocholesterol, and a decrease of cholesterol in plasma; and 3-methylglutaconic acid in urine. All patients with SLOS have mental retardation, and symptoms include ambiguous genitalia, hypotonia, microcephaly, syndactyly, limb abnormalities and deformities and polydactyly.


Tay-Sachs Disease,Disease

Tay-Sachs Disease (TSD; GM2-Gangliosidosis, type I; B-Variant GM2-Gangliosidosis; Hexosaminidase A Deficiency; HEXA Deficiency; Tay-Sachs Disease Variant B1), is an autosomal recessive lysosomal storage disease. TSD is caused by a mutation in the alpha subunit of the hexosaminidase A gene (HEXA), which codes for the enzyme hexosaminidase A. HEXA degrades GM2 gangliosides and other molecules with terminal N-acetyl hexosamines in the brain and other tissues. A defect in this enzyme causes accumulation of oligosaccharides in urine. The most lethal variant of this disease is the classical infantile Tay-Sachs disease, in which children exhibit developmental retardation, dementia and blindness, finally ending in death by the second or third years. Tay-Sachs disease also has debilitating juvenile and adult forms. The majority of cases of TSD are found among (but not limited to) the Ashkenazi Jews and French Canadians in Eastern Quebec. Symptoms include ataxia, visual impairment and loss, cherry-red spot on retinal macula, dystosis multiplex, mental retardation, myoclonus, encephalopathy and psychosis.


Insulin Signalling,Protein

Insulin is responsible for the regulation of glucose levels in the body. It stimulates the storage of energy and inhibits the breakdown of high energy metabolites. Glycogen and lipid biosynthesis are upregulated, and conversely, glycogen and fatty acid metabolism are down-regulated. Insulin also modulates transcription and translation. Binding of insulin to the insulin receptor (IR) results in the activation of its tyrosine kinase activity leading to IR autophosphorylation. IR then phosphorylates several substrates that lead to the activation of an intracellular signalling cascade. IR activation leads to the activation of H-Ras, MAPK1-3, and PI3-kinase pathways. The activation of these pathways leads to modulation of key proteins in glycogen metabolism/lipid metabolism and transcription/translation.


Benzocaine Action Pathway,Drug Action

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


Bupivacaine Action Pathway,Drug Action

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


Chloroprocaine Action Pathway,Drug Action

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


Cocaine Action Pathway,Drug Action

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


Dibucaine Action Pathway,Drug Action

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


Levobupivacaine Action Pathway,Drug Action

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


Lidocaine (Local Anaesthetic) Action Pathway,Drug Action

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


Mepivacaine Action Pathway,Drug Action

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


Oxybuprocaine Action Pathway,Drug Action

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


Prilocaine Action Pathway,Drug Action

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


Procaine Action Pathway,Drug Action

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


Proparacaine Action Pathway,Drug Action

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


Ropivacaine Action Pathway,Drug Action

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


Codeine Action Pathway,Drug Action

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


Morphine Action Pathway,Drug Action

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


Methadone Action Pathway,Drug Action

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


Oxycodone Action Pathway,Drug Action

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


Hydromorphone Action Pathway,Drug Action

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


Hydrocodone Action Pathway,Drug Action

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


Oxymorphone Action Pathway,Drug Action

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


Alfentanil Action Pathway,Drug Action

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


Carfentanil Action Pathway,Drug Action

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


Fentanyl Action Pathway,Drug Action

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


Remifentanil Action Pathway,Drug Action

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


Sufentanil Action Pathway,Drug Action

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


Adefovir Dipivoxil  Action Pathway,Drug Action

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.


Tenofovir  Action Pathway,Drug Action

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


Bevacizumab Action Pathway,Drug Action

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.


Vatalanib Action Pathway,Drug Action

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


Imipramine Action Pathway,Drug Action

Imipramine 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.  Imipramine is metabolized in the liver mostly through N-demethylation by CYP2C19 into desipramine. Desipramine is an active metabolite and also has similar actions to imipramine on norepinephrine and serotonin reuptake.


Desipramine Action Pathway,Drug Action

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.


Citalopram Action Pathway,Drug Action

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.


Escitalopram Action Pathway,Drug Action

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.


Fluoxetine Action Pathway,Drug Action

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.


Azathioprine Action Pathway,Drug Action

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.


Mercaptopurine Action Pathway,Drug Action

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


Disulfiram Action Pathway,Drug Action

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. Disulfiram can prevent alcohol metabolism by inhibiting acetaldehyde dehydrogenase in mitochondria, which lead to increased level of acetaldehyde, and eventually result in hangover (e.g. flushing, vomiting, headache, etc.) as the main symptoms. Therefore, disulfiram is not suggested to take while patient consuming alcohol.


Thioguanine Action Pathway,Drug Action

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


Nicotine Action Pathway,Drug Action

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


Methotrexate Action Pathway,Drug Action

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