Browsing Pathways

Dasatinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Dasatinib is considered a second generation BCR-ABL inhibitor (Imatinib being the progenitor) that inhibits BCR-ABL activity by binding a highly conserved ATP binding site to effectively lock the tyrosine kinase in an inactive conformation. As a result, phosphate is unable to be transferred from ATP to activate oncogenic signalling cascades. For greater detail, refer to the pathway titled BCR-ABL Action in CML Pathogenesis. Dasatinib is able to bind ABL with greater affinity than Imatinib, partly owing to its ability to recognize multiple states of the enzyme. It is therefore administered to patients with Imatinib resistance. Notably, Dasatinib is ineffective against the T315I mutation in BCR-ABL, and further research is necessary.

Ponatinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Ponatinib is considered a third generation BCR-ABL inhibitor (Imatinib being the progenitor) due to its effectiveness against the T315I mutation in BCR-ABL. For greater detail of some of the signalling pathways inhibited by BCR-ABL inhibition, refer to the pathway titled BCR-ABL Action in CML Pathogenesis.

Clarithromycin, is a macrolide antibiotic. It is used to treat many bacterial infections, from sinusitis to AIDS-related infections, and can be used along with anti-ulcer medications to treat stomach ulcers. The way this antibiotic works is by halting bacteria growth. It stops bacteria growth by binding to 50S ribosomal subunits or the 70S ribosome located on the bacteria, inhibits the movement of aminoacyl transfer-RNA and makes sure that the elongation of peptide chain does not occur. This ensures that RNA-mediated bacterial protein creation is blocked. This drug also blocks the isoenzyme CYP3A4, found in the liver, and P-glycoprotein.

Enalapril (trade name: Vasotec) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Enalapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form enalaprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Alprenolol (also known as alfeprol, alpheprol or alprenololum) a beta blocker (non-selective) that block beta-1 adrenergic receptor in heart. Blocking beta-1 adrenergic receptor could prevent the binding of epinephrine and norepinephrine, which could efficiently reduce blood pressure and heart rate. In the juxtaglomerular apparatus, alprenolol can also bind to beta-2 receptors to prevent the production and release of renin (also known as angiotensinogenase). Without renin, angiotensin II and aldosterone could not be produced, which ultimately prevent water retention and vasoconstriction.

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.

This pathway illustrates the procainamide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Procainamide, an analogue of the local anesthetic procaine, is a Class 1A antiarrhythmic drug. It has similar effects to quinidine, but lacks the antimuscarinic and antiadrenergic effects of quinidine. Like other Class 1A drugs, procainamide blocks open sodium channels leading to an increased threshold of excitability. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization seen during cardiac contractile cell action potentials. I-Na block results in delayed excitability of the cells. Procainamide also prolongs action potential duration, likely by slowing the final repolarization phase via potassium channel blocking. This drug may be administered intravenously to treat supraventricular and ventricular arrhythmias. It is better tolerated intravenously than quinidine. Oral administration is poorly tolerated long term.

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 cellsŠ—È 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.

Oxprenolol (also known as Trasacor or Trasicor) is a beta blocker (non-selective) that are used for treat high blood pressure or chest pain. Oxprenolol bind to beta1-adrenergic receptors in heart and vascular smooth muscle to block the binding of other adrenergic neurotransmitters such as norepinephrine, which lead to decreased blood pressure, heart rate and cardiac output. Oxprenolol can also bind beta-2 adrenergic receptors in juxtaglomerular apparatus and bronchiole smooth muscle. In juxtaglomerular apparatus, oxprenolol can prevent the production of aldosterone and angiotensin II by inhibiting renin production, which lead to prevention of water retention and vasoconstriction. In bronchiole smooth muscle, binding of oxprenolol to beta-2 adrenergic receptors can also prevent vasoconstriction.

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.