Browsing pathways

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

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

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

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

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

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

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

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

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

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