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By U. Olivier. Saint Leo University. 2017.

In humans performing a brisk extension of the little finger order 100 mg allopurinol with visa, a simultaneous rise in tension in the tendon of abductor pollicis longus (APL) often can be palpated; presumably the contraction of APL counter- balances the wrist torque produced by the extrinsic finger muscles used to extend the little finger purchase allopurinol 300 mg, EDC and extensor digiti quinti (EDQ). Comparing the extrinsic finger musculature of macaque monkeys to that of humans suggests that human muscles have evolved to provide a greater degree of independence in finger movements. As noted above, when instructed to move one finger alone, lesser motion of other, noninstructed digits occurs along with that of the instructed digit in both species. Quantitatively, however, humans move their fingers more individually than macaques. The human extensor indicis proprius (EIP), which extends only the index finger, is homologous to the macaque ED23, which extends both the index and middle fingers. The human EDQ, which extends only the little finger, is homologous to the macaque extensor digiti quarti et quinti (ED45), Copyright © 2005 CRC Press LLC which extends both the ring and little fingers. Another factor contributing to decreased coupling among human fingers is the greater mechanical separation of tendons in the extrinsic multitendoned finger muscles, particularly EDC and FDP. As noted above, the juncturae tendinium of EDC are less pronounced in the human than in the macaque. The insertion tendons of the macaque FDP all arise from a continuous aponeurotic sheet which is minimally divided as the common tendon crosses the wrist. In humans, the equivalent tendon to the thumb arises from an independent muscle, flexor pollicis longus (FPL), and the tendons to the other digits are separate before they cross the wrist, though tough fibrous sheets still interconnect adjacent FDP tendons within the palm. The human FDP tendon to the index finger arises from a largely separate portion of the muscle belly. Many mammalian muscles, however, have been shown to consist of multiple neuromuscular compartments. The neuromuscular compartments of a muscle can be activated differentially by the central nervous system, producing different biomechanical effects. Similarly, the multitendoned finger muscles, rather than acting as a single motoneuron pool that pulls simultaneously on all four fingers, may be subdivided to different degrees. The extent to which multitendoned finger muscles are partially subdivided, or even fully com- partmentalized, is an area of active investigation. Of the macaque multitendoned finger muscles, FDP most clearly shows com- partmentalization.

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Enzyme Inhibition hibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme Enzyme inhibition is the most frequently observed re- and prevents any further metabolism by the enzyme buy allopurinol 300 mg otc. The most the enzyme molecule and thus can be overcome only by common type of inhibition is simple competitive inhibi- the proteolytic degradation of that particular enzyme tion order allopurinol 100mg mastercard, wherein two drugs are vying for the same active molecule and subsequent synthesis of new enzyme pro- site and the drug with the highest affinity for the site tein. In this scenario, addition of a second drug with and yet is known to be a mechanism-based inactivator greater affinity for the enzyme inhibits metabolism of of CYP3A4 is the antibiotic erythromycin. In the simplest case, Enzyme Induction each drug has its own unique degree of affinity for the CYP enzyme active site, and the degree of inhibition Induction of drug-metabolizing activity can be due ei- depends on how avidly the secondary (or effector) drug ther to synthesis of new enzyme protein or to a decrease binds to the enzyme active site. Increased zole and triazolam compete for binding to the CYP3A4 enzyme synthesis is the result of an increase in messen- active site and thus exhibit their own unique rate of me- ger RNA (mRNA) production (transcription) or in the tabolism. Regardless of the tabolism of triazolam by the CYP3A4 enzyme (essen- mechanism, the net result of enzyme induction is the in- tially the only enzyme that metabolizes triazolam) is creased turnover (metabolism) of substrate. Whereas decreased to such a degree that the patient is exposed one frequently associates enzyme inhibition with an in- to 17 times as much of parent triazolam as when keto- crease in potential for toxicity, enzyme induction is most conazole is not present. Involved in Human Drug The phase II enzymes typically consist of multiple iso- Metabolism forms, analogous to the CYPs, but to date are less well defined. CYP Isoform Examples of Inducers CYP1A1 Smoking (polycyclic aromatic hydrocarbons), Glucuronosyl Transferases char-grilled meat, omeprazole CYP1A2 Same as CYP1A1 Glucuronosyl transferases (UGTs) conjugate the drug CYP2A6 Phenobarbital, dexamethasone molecule with a glucuronic acid moiety, usually through CYP2B6 Phenobarbital, dexamethasone, rifampin establishment of an ether, ester, or amide bond. CYP2C8 Same as CYP2C9 Examples of each of these types of conjugates are pre- CYP2C9 Rifampin, dexamethasone, phenobarbital CYP2C19 Rifampin sented in Figure 4. The glucuronic acid moiety, being CYP2D6 None known very water soluble, generally renders the new conjugate CYP2E1 Ethanol, isoniazid more water soluble and thus more easily eliminated. CYP3A4 Efavirenz, nevirapine, barbiturates, carba- Typically this conjugate is inactive, but sometimes it is mazepine, glucocorticoids, phenytoin, active. It is now apparent that UGTs are also a superfamily of enzyme isoforms, each with differing substrate speci- The time course of enzyme induction is important, ficities and regulation characteristics. Of the potential since it may play a prominent role in the duration of the products of the UGT1 gene family, only expression of effect and therefore the potential onset and offset of the UGT1A1, 3, 4, 5, 6, 9 and 10 occurs in humans. Both time required for synthesis of Depending on the isoform, these enzymes have varying new enzyme protein (transcription and translation) and reactivity toward a number of pharmacologically active the half-life of the inducing drug affect the time course compounds, such as opioids, androgens, estrogens, of induction. An enzyme with a slower turnover rate progestins, and nonsteroidal antiinflammatory drugs; will require a longer time before induction reaches UGT1A1 is the only physiologically significant enzyme equilibrium (steady state), and conversely, a faster involved in the conjugation of bilirubin. With pears to be inducible by phenobarbital administration, respect to the drug inducer, drugs with a shorter half- and UGT1A7 is induced by the chemopreventive agent life will reach equilibrium concentrations sooner (less oltipraz.

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By U. Olivier. Saint Leo University. 2017.

In humans performing a brisk extension of the little finger order 100 mg allopurinol with visa, a simultaneous rise in tension in the tendon of abductor pollicis longus (APL) often can be palpated; presumably the contraction of APL counter- balances the wrist torque produced by the extrinsic finger muscles used to extend the little finger purchase allopurinol 300 mg, EDC and extensor digiti quinti (EDQ). Comparing the extrinsic finger musculature of macaque monkeys to that of humans suggests that human muscles have evolved to provide a greater degree of independence in finger movements. As noted above, when instructed to move one finger alone, lesser motion of other, noninstructed digits occurs along with that of the instructed digit in both species. Quantitatively, however, humans move their fingers more individually than macaques. The human extensor indicis proprius (EIP), which extends only the index finger, is homologous to the macaque ED23, which extends both the index and middle fingers. The human EDQ, which extends only the little finger, is homologous to the macaque extensor digiti quarti et quinti (ED45), Copyright © 2005 CRC Press LLC which extends both the ring and little fingers. Another factor contributing to decreased coupling among human fingers is the greater mechanical separation of tendons in the extrinsic multitendoned finger muscles, particularly EDC and FDP. As noted above, the juncturae tendinium of EDC are less pronounced in the human than in the macaque. The insertion tendons of the macaque FDP all arise from a continuous aponeurotic sheet which is minimally divided as the common tendon crosses the wrist. In humans, the equivalent tendon to the thumb arises from an independent muscle, flexor pollicis longus (FPL), and the tendons to the other digits are separate before they cross the wrist, though tough fibrous sheets still interconnect adjacent FDP tendons within the palm. The human FDP tendon to the index finger arises from a largely separate portion of the muscle belly. Many mammalian muscles, however, have been shown to consist of multiple neuromuscular compartments. The neuromuscular compartments of a muscle can be activated differentially by the central nervous system, producing different biomechanical effects. Similarly, the multitendoned finger muscles, rather than acting as a single motoneuron pool that pulls simultaneously on all four fingers, may be subdivided to different degrees. The extent to which multitendoned finger muscles are partially subdivided, or even fully com- partmentalized, is an area of active investigation. Of the macaque multitendoned finger muscles, FDP most clearly shows com- partmentalization.

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Enzyme Inhibition hibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme Enzyme inhibition is the most frequently observed re- and prevents any further metabolism by the enzyme buy allopurinol 300 mg otc. The most the enzyme molecule and thus can be overcome only by common type of inhibition is simple competitive inhibi- the proteolytic degradation of that particular enzyme tion order allopurinol 100mg mastercard, wherein two drugs are vying for the same active molecule and subsequent synthesis of new enzyme pro- site and the drug with the highest affinity for the site tein. In this scenario, addition of a second drug with and yet is known to be a mechanism-based inactivator greater affinity for the enzyme inhibits metabolism of of CYP3A4 is the antibiotic erythromycin. In the simplest case, Enzyme Induction each drug has its own unique degree of affinity for the CYP enzyme active site, and the degree of inhibition Induction of drug-metabolizing activity can be due ei- depends on how avidly the secondary (or effector) drug ther to synthesis of new enzyme protein or to a decrease binds to the enzyme active site. Increased zole and triazolam compete for binding to the CYP3A4 enzyme synthesis is the result of an increase in messen- active site and thus exhibit their own unique rate of me- ger RNA (mRNA) production (transcription) or in the tabolism. Regardless of the tabolism of triazolam by the CYP3A4 enzyme (essen- mechanism, the net result of enzyme induction is the in- tially the only enzyme that metabolizes triazolam) is creased turnover (metabolism) of substrate. Whereas decreased to such a degree that the patient is exposed one frequently associates enzyme inhibition with an in- to 17 times as much of parent triazolam as when keto- crease in potential for toxicity, enzyme induction is most conazole is not present. Involved in Human Drug The phase II enzymes typically consist of multiple iso- Metabolism forms, analogous to the CYPs, but to date are less well defined. CYP Isoform Examples of Inducers CYP1A1 Smoking (polycyclic aromatic hydrocarbons), Glucuronosyl Transferases char-grilled meat, omeprazole CYP1A2 Same as CYP1A1 Glucuronosyl transferases (UGTs) conjugate the drug CYP2A6 Phenobarbital, dexamethasone molecule with a glucuronic acid moiety, usually through CYP2B6 Phenobarbital, dexamethasone, rifampin establishment of an ether, ester, or amide bond. CYP2C8 Same as CYP2C9 Examples of each of these types of conjugates are pre- CYP2C9 Rifampin, dexamethasone, phenobarbital CYP2C19 Rifampin sented in Figure 4. The glucuronic acid moiety, being CYP2D6 None known very water soluble, generally renders the new conjugate CYP2E1 Ethanol, isoniazid more water soluble and thus more easily eliminated. CYP3A4 Efavirenz, nevirapine, barbiturates, carba- Typically this conjugate is inactive, but sometimes it is mazepine, glucocorticoids, phenytoin, active. It is now apparent that UGTs are also a superfamily of enzyme isoforms, each with differing substrate speci- The time course of enzyme induction is important, ficities and regulation characteristics. Of the potential since it may play a prominent role in the duration of the products of the UGT1 gene family, only expression of effect and therefore the potential onset and offset of the UGT1A1, 3, 4, 5, 6, 9 and 10 occurs in humans. Both time required for synthesis of Depending on the isoform, these enzymes have varying new enzyme protein (transcription and translation) and reactivity toward a number of pharmacologically active the half-life of the inducing drug affect the time course compounds, such as opioids, androgens, estrogens, of induction. An enzyme with a slower turnover rate progestins, and nonsteroidal antiinflammatory drugs; will require a longer time before induction reaches UGT1A1 is the only physiologically significant enzyme equilibrium (steady state), and conversely, a faster involved in the conjugation of bilirubin. With pears to be inducible by phenobarbital administration, respect to the drug inducer, drugs with a shorter half- and UGT1A7 is induced by the chemopreventive agent life will reach equilibrium concentrations sooner (less oltipraz.

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