USMLE Q BANK: April 2012

Monday, April 9, 2012

USMLE Review

Computation in your Nervous System.
Computation in this Nervous System.
Computation in your Nervous System.
Computation in your Nervous System.
NeuroAnatomy for Medical Students and Doctors

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The connections, or pathways, between groups of neurons in the CNS are in the form of fiber bundles, or tracts (fasciculi). Aggregates of tracts, as seen in the spinal cord, are referred to as columns (funiculi). Tracts may descend (eg, from the cerebrum to the brain stem or spinal cord) or ascend (eg, from the spinal cord to the cerebrum). These pathways are vertical connections that in their course may cross (decussate) from one side of the CNS to the other. Horizontal (lateral) connections are called commissures.

Multiple tracts connect many parts of the nervous system. For example, multiple ascending and descending tracts connect the PNS and lower spinal centers with the brain. This reflects the fact that the nervous system extracts different aspects of its sensory surround (eg, the shape, weight, and temperature of an object touching the body) and encodes them separately and that it controls specific aspects of motor behavior (posture, muscle tone, delicate movements) using different sets of neurons. The multiplicity of tracts also endows the nervous system with a degree of redundancy: After partial destruction of the nervous system, only some functions will be lost; other functions may be retained, increasing the probability that the organism will survive.

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Symmetry of the Nervous System

The nervous system is constructed with bilateral symmetry. This is most apparent in the cerebrum and cerebellum, which are organized into right and left hemispheres. On initial consideration, these hemispheres appear symmetric. Some higher cortical functions such as language are represented more strongly in one hemisphere than in the other, but to gross inspection, the hemispheres have a similar structure. Even in more caudal structures, such as the brain stem and spinal cord, which are not organized into hemispheres, there is bilateral symmetry.

Crossed Representation

Another general theme in the construction of the nervous system is decussation and crossed representation: The right side of the brain receives information about, and controls motor function pertaining to, the left side of the world and vice versa. Visual information about the right side of the world is processed in the visual cortex on the left. Similarly, sensation of touch, sensation of heat or cold, and joint position sense from the body's right side are processed in the somatosensory cortex in the left cerebral hemisphere. In terms of motor control, the motor cortex in the left cerebral hemisphere controls body movements that pertain to the right side of the external world. This includes, of course, control of the muscles of the right arm and leg, such as the biceps, triceps, hand muscles, and gastrocnemius. There are occasional exceptions to this pattern of "crossed innervation": For example, the left sternocleidomastoid muscle is controlled by the left cerebral cortex. However, even this exception makes functional sense: As a result of its unusual biomechanics, contraction of the left sternocleidomastoid rotates the neck to the right. Even for the anomalous muscle, then, control of movements relevant to the right side of the world originates in the contralateral left cerebral hemisphere, as predicted by the principle of crossed representation.

There is one major exception to the rule of crossed motor control: As a result of the organization of cerebellar inputs and outputs, each cerebellar hemisphere controls coordination and muscle tone on the ipsilateral side of the body

Computation in this Nervous System.

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Maps of the World Within the Brain

At each of many levels, the brain maps various aspects of the outside world. For example, consider the dorsal columns (which carry sensory information, particularly with respect to touch and vibration, from sensory endings on the body surface upward within the spinal cord). Axons within the dorsal columns are arranged in an orderly manner, with fibers from the arm, trunk, and leg forming a map that preserves the spatial relationship of these body parts. Within the cerebral cortex, there is also a sensory map (which has the form of a small man and is, therefore, called a homunculus), within the sensory cortex. There are multiple maps of the visual world within the occipital lobes and within the temporal and parietal lobes as well. These maps are called retinotopic because they preserve the geometrical relationships between objects imaged on the retina and thus provide spatial representations of the visual environment within the brain. Each map contains neurons that are devoted to extracting and analyzing information about one particular aspect (eg, form, color, or movement) of the stimulus.

Development

The earliest tracts of nerve fibers appear at about the second month of fetal life; major descending motor tracts appear at about the fifth month. Myelination (sheathing with myelin) of the spinal cord's nerve fibers begins about the middle of fetal life; some tracts are not completely myelinated for 20 years. The oldest tracts (those common to all animals) myelinate first; the corticospinal tracts myelinate largely during the first and second years after birth.

Growing axons are guided to the correct targets during development of the nervous system by extracellular guidance molecules (including the netrins and semaphorins). Some of these act as attractants for growing axons, guiding them toward a particular target.

Computation in your Nervous System.

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Tracts & Commissures

Visual information about the right side of the world is processed in the visual cortex on the left. Similarly, sensation of touch, sensation of heat or cold, and joint position sense from the body's right side are processed in the somatosensory cortex in the left cerebral hemisphere. In terms of motor control, the motor cortex in the left cerebral hemisphere controls body movements that pertain to the right side of the external world. This includes, of course, control of the muscles of the right arm and leg, such as the biceps, triceps, hand muscles, and gastrocnemius. There are occasional exceptions to this pattern of "crossed innervation": For example, the left sternocleidomastoid muscle is controlled by the left cerebral cortex. However, even this exception makes functional sense: As a result of its unusual biomechanics, contraction of the left sternocleidomastoid rotates the neck to the right. Even for the anomalous muscle, then, control of movements relevant to the right side of the world originates in the contralateral left cerebral hemisphere, as predicted by the principle of crossed representation.

Maps of the World Within the Brain

Computation in your Nervous System.

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These pathways are vertical connections that in their course may cross (decussate) from one side of the CNS to the other. Horizontal (lateral) connections are called commissures.

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Symmetry of the Nervous System

Crossed Representation

Maps of the World Within the Brain

NeuroAnatomy for Medical Students and Doctors

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Stroke, for example, is the third most frequent cause of death in industrialized societies; mood disorders such as depression affect more than one person in 10; and dysfunction of the nervous system can be seen in 25% of patients in most general hospitals at some time during their hospital stay. The neuroanatomic basis for many of these disorders is already known, and for other disorders it will soon be discovered.

This book provides a concise but comprehensive and easy-to-remember synopsis of neuroanatomy and of its functional and clinical implications. In this new, 25th edition, each chapter has been extensively revised and carefully focused so that it emphasizes the most important concepts, facts, and structures. As a teacher, researcher, and clinician, I have tried to sculpt this book so that it will provide a resource and learning tool for busy medical students, residents, and students in health-related fields such as physical therapy; for graduate students who need an introduction to neuroanatomy; and for clinicians in practice, for whom minutes are precious. This book is not meant to supplant the longer, more encompassing, and comprehensive handbooks of neuroscience and neuroanatomy. On the contrary, it provides a more manageable and concise overview that presents the essential aspects of neuroanatomy and its functional and clinical correlations.

This book is unique in including a section entitled "Introduction to Clinical Thinking," which appears early in the text to introduce the reader to the logical processes involved in using neuroanatomy as a basis for thinking about the disordered nervous system. Recognizing that some students remember patients better than isolated facts, I have included discussions of clinical correlates and clinical illustrations that synthesize the most important characteristics of patients selected from an extensive clinical experience to help the reader interpret and remember neuroanatomic concepts in terms of function and clinical implications.

Because much of neuroanatomy has a spatial aspect, this book includes numerous figures. The illustrations have been designed to provide clear, explicit, and memorable representations of important pathways, structures, and mechanisms. Many tables are included, and they have been designed to be as clear and easy to remember as possible. These figures and tables incorporate feedback and suggestions from numerous trainees as well as teachers of neuroanatomy.

The advent of modern neuroimaging has revolutionized the clinical neurosciences, and this book takes full advantage of this technological advance by including numerous computed tomography (CT) and magnetic resonance images (MRIs) of the normal brain and spinal cord, together with functional magnetic resonance images (fMRI) which provides a noninvasive window on brain function. Also included are neuroimaging studies that illustrate common pathological entities that affect the nervous system, including stroke, intracerebral hemorrhage, and tumors of the brain and spinal cord.

As with past editions, I owe a debt of gratitude to many colleagues and friends, especially members of the Department of Neurology at Yale Medical School, who have liberally shared their insights and expertise and have helped to create an environment where learning is fun, a motif that I have woven into this book. I hope that readers of this site will join me in finding that neuroanatomy, which provides much of the foundation for both basic neuroscience and clinical medicine, can be enjoyable, memorable, and easily learned.

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Sunday, April 1, 2012

USMLE Review

Importance of Pharmacogenetics to help Variability in Narcotic Response.
Importance of Pharmacogenetics to Variability in Medication Response.
Importance of Pharmacogenetics to Variability in Meds Response.
Importance of Pharmacogenetics to Variability in Narcotic Response.
HOW HUMANS OVERCOME EXPOSURE TO XENOBIOTICS.

Importance of Pharmacogenetics to help Variability in Narcotic Response.

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The exaggerated responses are an inherited trait (Eichelbaum et al., 1975; Mahgoub et al., 1977). At present, a very large number of medications (estimated at 15% to 25% of all medicines in use) have been shown to be substrates for CYP2D6 (Table 4-3). The molecular and phenotypic characterization of multiple racial and ethnic groups has shown that seven variant alleles account for well over 90% of the "poor metabolizer" low-activity alleles for this gene in most racial groups; that the frequency of variant alleles varies with geographic origin; and that a small percentage of individuals carry stable duplications of CYP2D6, with "ultra-rapid" metabolizers having up to 13 copies of the active gene (Ingelman-Sundberg and Evans, 2001). Phenotypic consequences of the deficient CYP2D6 phenotype include increased risk of toxicity of antidepressants or antipsychotics (catabolized by the enzyme), and lack of analgesic effects of codeine (anabolized by the enzyme); conversely, the ultra-rapid phenotype is associated with extremely rapid clearance and thus inefficacy of med school antidepressants (Kirchheiner et al., 2001).

A promoter region variant in the enzyme UGT1A1, UGT1A1*28, which has an additional TA in comparison to the more common form of the gene, has been associated with a reduced medical video transcription rate of UGT1A1 and lower glucuronidation activity of the enzyme. This reduced activity has been associated with higher levels of the active metabolite of the cancer chemotherapeutic agent irinotecan (see Chapters 3 and 51). The metabolite, SN38, which is eliminated by glucuronidation, is associated with the risk of toxicity (Iyer et al., 2002), which will be more severe in individuals with genetically lower UGT1A1 activity. Medicine

CYP2C19 codes for a cytochrome P450, historically termed mephenytoin hydroxylase, that displays penetrant pharmacogenetic variability, with just a few SNPs accounting for the majority of the deficient, poor metabolizer phenotype (Mallal et al., 2002). The deficient phenotype is much more common in Chinese and Japanese populations. Several video odd proton pump inhibitors, including omeprazole and lansoprazole, are inactivated by CYP2C19. Thus, the deficient patients have higher exposure to active parent drug, a greater pharmacodynamic effect (higher gastric pH), and a higher probability of ulcer cure than heterozygotes or homozygous wild-type individuals (Figure 4-10).

The anticoagulant warfarin is catabolized by CYP2C9. Inactivating polymorphisms in CYP2C9 are common (Goldstein, 2001), with 2% to 10% of most populations being homozygous for low-activity variants, and are associated with lower warfarin clearance, a higher risk of bleeding complications, and lower dose requirements (Aithal et al., 1999).

Thiopurine methyltransferase (TPMT) where to get a physical exam methylates thiopurines such as mercaptopurine (an antileukemic drug that is also the product of azathioprine metabolism). One in 300 individuals is homozygous deficient, 10% are heterozygotes, and about 90% are homozygous for the wild-type alleles for TPMT (Weinshilboum and Sladek, 1980). Three SNPs account for over 90% of the inactivating alleles (Yates et al., 1997). Because methylation of mercaptopurine competes with activation of the drug to thioguanine nucleotides, the concentration of the active (but also toxic) thioguanine metabolites is inversely related to TPMT activity and directly related to the probability of pharmacologic effects.

Importance of Pharmacogenetics to Variability in Medication Response.

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If proportions of the observed three genotypes, which must add up to one, differ significantly from those predicted, it may indicate that a genotyping error Medical Books may be present.

Because polymorphisms are so common, haplotype (the allelic structure that indicates whether polymorphisms within a gene are on the same or different alleles) may also be important. Thus far, experimental methods to unambiguously confirm whether polymorphisms are allelic has proven to be feasible but technically challenging (McDonald et al., 2002). Most video odd investigators use statistical probability to assign putative or inferred haplotypes; e.g., because the two most common SNPs in TPMT (at 460 and 719) often are allelic, a genotyping result showing heterozygosity at both SNPs will have a >95% chance of reflecting one allele wild-type and one allele variant at both SNP positions (resulting in a "heterozygote" genotype for TPMT). However, the remote prospect that each of the two alleles carries a single SNP variant, thereby conferring a homozygous variant/deficient phenotype, is a theoretical possibility. Medicine

Candidate Gene versus Genome-Wide Approaches

Because medical mcq pathways involved in drug response are often known or at least partially known, pharmacogenetic studies are highly amenable to candidate gene association studies. After genes in drug response pathways are identified, the next step in the design of a candidate gene association pharmacogenetic study is to identify the genetic polymorphisms that are likely to contribute to the therapeutic and/or adverse responses to the drug. There are several databases that contain information on polymorphisms and mutations in human genes (Table 4-1), which allow the investigator to search by gene for polymorphisms that have been reported. Some of the databases, such as the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), include phenotypic as well as genotypic data.

Because it is currently not practical to what is a physical exam analyze all polymorphisms in a candidate gene association study, it is important to select polymorphisms that are likely to be associated with the drug-response phenotype. For this purpose, there are two categories of polymorphisms. The first are polymorphisms that do not, in and of themselves, cause altered function of the expressed protein (e.g., an enzyme that metabolizes the drug or the drug receptor). Rather, these polymorphisms are linked to the variant allele that produces the altered function. These polymorphisms serve as biomarkers for drug-response phenotype. However, their major shortcoming is that unless they are in 100% linkage with the causative polymorphism, they are not the best markers for the drug-response phenotype.

The second type of polymorphism is the causative polymorphism, which directly precipitates the phenotype. For example, a causative SNP may change an amino acid residue at a site that medical schools is highly conserved throughout evolution. This substitution may result in a protein that is nonfunctional or has reduced function. Whenever possible, it is desirable to select polymorphisms for pharmacogenetic studies that are likely to be causative (Tabor et al., 2002). If biological information indicates that a particular polymorphism alters function, for example, in cellular assays of nonsynonymous variants, this polymorphism is an excellent candidate to use in an association study.

Importance of Pharmacogenetics to Variability in Meds Response.

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New methods in comparative genomics are being refined to identify conserved elements in noncoding regions of genes that may be functionally important (Bejerano et al., 2004; Boffelli et al., 2004; Brudno et al., 2003). Medicine

Pharmacogenetic Phenotypes

Candidate genes for therapeutic and adverse response can be divided into three categories: pharmacokinetic, receptor/target, and disease-modifying.

Pharmacokinetics. what is a physical exam Germline variability in genes that encode determinants of the pharmacokinetics of a drug, in particular enzymes and transporters, affect drug concentrations, and are therefore major determinants of therapeutic and adverse drug response (Table 4-3; Nebert et al., 1996). Multiple enzymes and transporters may be involved in the pharmacokinetics of a single drug. Several polymorphisms in drug metabolizing enzymes were discovered as monogenic phenotypic trait variations, and thus may be referenced using their phenotypic designations (e.g., slow vs. fast acetylation, extensive vs. poor metabolizers of debrisoquine or sparteine) rather than their genotypic designations that reference the gene that is the target of polymorphisms in each case (NAT2 and CYP2D6 polymorphisms, respectively) (Grant et al., 1990). CYP2D6 is now known to catabolize the two initial probe drugs (sparteine and debrisoquine), each of which was associated with exaggerated responses in 5% to 10% of treated individuals. The exaggerated responses are an inherited trait (Eichelbaum et al., 1975; Mahgoub et al., 1977). At present, a very large number of medications (estimated at 15% to 25% of all medicines in use) have been shown to be substrates for CYP2D6 (Table 4-3). The molecular and phenotypic characterization of multiple racial and ethnic groups has shown that seven variant alleles account for well over 90% of the "poor metabolizer" low-activity alleles for this gene in most racial groups; that the frequency of variant alleles varies with geographic origin; and that a small percentage of individuals carry stable duplications of CYP2D6, with "ultra-rapid" metabolizers having up to 13 copies of the active gene (Ingelman-Sundberg and Evans, 2001). Phenotypic consequences of the deficient CYP2D6 phenotype include increased risk of toxicity of antidepressants or antipsychotics (catabolized by the enzyme), and lack of analgesic effects of codeine (anabolized by the enzyme); conversely, the ultra-rapid phenotype is associated with extremely rapid clearance and thus inefficacy of medical mcq antidepressants (Kirchheiner et al., 2001).

A promoter region variant in the enzyme UGT1A1, UGT1A1*28, which has an additional TA in comparison to the more common form of the gene, has been associated with a reduced videos medical transcription rate of UGT1A1 and lower glucuronidation activity of the enzyme. This reduced activity has been associated with higher levels of the active metabolite of the cancer chemotherapeutic agent irinotecan (see Chapters 3 and 51). The metabolite, SN38, which is eliminated by glucuronidation, is associated with the risk of toxicity (Iyer et al., 2002), which will be more severe in individuals with genetically lower UGT1A1 activity.

CYP2C19 codes for a cytochrome P450, historically termed mephenytoin hydroxylase, that displays penetrant pharmacogenetic variability, with just a few SNPs accounting for the majority of the deficient, poor metabolizer phenotype (Mallal et al., 2002). The deficient phenotype is much more common in Chinese and Japanese populations.

Importance of Pharmacogenetics to Variability in Narcotic Response.

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For some multigenic phenotypes, such as response to antihypertensives, the large numbers of candidate genes will necessitate a large patient sample size to produce the statistical power required to solve the "multigene" problem. Medicine

GENOMIC BASIS OF PHARMACOGENETICS

Phenotype-Driven Terminology

Because initial discoveries in osce medical pharmacogenetics were driven by variable phenotypes and defined by family and twin studies, the classic genetic terms for monogenic traits apply to some pharmacogenetic polymorphisms. A trait (e.g., CYP2D6 "poor metabolism") is deemed autosomal recessive if the responsible gene is located on an autosome (i.e., it is not sex-linked) and a distinct phenotype is evident only with nonfunctional alleles on both the maternal and paternal chromosomes. For many of the earliest identified pharmacogenetic polymorphisms, phenotype did not differ enough between heterozygotes and homozygous "wild-type" individuals to distinguish that heterozygotes exhibited an intermediate (or codominant) phenotype (e.g., for CYP2D6-mediated debrisoquine metabolism). Other traits, such as TPMT, exhibit three relatively distinct phenotypes, and thus were deemed codominant even in the premolecular era. With the advances in molecular characterization of polymorphisms and a genotype-to-phenotype approach, additional polymorphic traits (e.g., CYP2C19 metabolism of drugs such as mephenytoin and omeprazole) are now recognized to exhibit some degree of codominance. Some pharmacogenetic traits, such as the long QT syndrome, segregate as dominant traits; the long QT syndrome is associated with heterozygous loss-of-function mutations of ion channels. A prolonged QT interval is seen on the electrocardiogram, either basally or in the presence of certain drugs, and the individual is predisposed to cardiac video odd arrhythmias

In an era of detailed molecular characterization, two major factors complicate the historical designation of recessive, codominant, and dominant traits. First, even within a single gene, a medical mcqs vast array of polymorphisms (promoter, coding, noncoding, completely inactivating, or modestly modifying) are possible, making the assignment of "variant"vs. "wild-type" to an allele a designation that depends upon a complete survey of the gene's polymorphisms and is not necessarily easily assigned. Secondly, most traits (pharmacogenetic and otherwise) are multigenic, not monogenic. Thus, even if the designations of recessive, codominant, and dominant are informative for a given gene, their utility in describing the genetic variability that underlies variability in drug response phenotype is diminished, because most phenotypic variability is likely to be multigenic.

Types of Genetic Variants

A polymorphism is a variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population. Two major types of sequence variation have been associated with variation in human reading ecg phenotype: single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) (Figure 4-3). In comparison to base pair substitutions, indels are much less frequent in the genome and are of particularly low frequency in coding regions of genes (Cargill et al., 1999; Stephens et al., 2001). Single base pair substitutions that are present at frequencies of 1% or greater in a population are termed single nucleotide polymorphisms (SNPs) and are present in the human genome at approximately 1 SNP every few hundred to a thousand base pairs, depending on the gene region (Stephens et al., 2001).

HOW HUMANS OVERCOME EXPOSURE TO XENOBIOTICS.

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Metabolism by the phase 1 cytochrome P450 isoenzymes (CYPs) followed by phase 2 uridine diphosphate-glucuronosyltransferase (UGT) enzymes produces a metabolite that is highly water soluble and readily eliminated from the body (Figure 3-1). Metabolism also terminates the biological activity of the drug. In the case of phenytoin, metabolism also increases the molecular weight of the compound, which allows it to medical lecture be eliminated more efficiently in the bile. Medicine

While xenobiotic-metabolizing ekg ecg enzymes are responsible for facilitating the elimination of chemicals from the body, paradoxically these same enzymes can also convert certain chemicals to highly reactive toxic and carcinogenic metabolites. This occurs when an unstable intermediate is formed that has reactivity toward other compounds found in the cell. Chemicals that can be converted by xenobiotic metabolism to cancer-causing derivatives are called carcinogens. Depending on the structure of the chemical substrate, xenobiotic-metabolizing enzymes produce electrophilic metabolites that can react with nucleophilic cellular macromolecules such as DNA, RNA, and protein. This can cause cell death and organ toxicity. Reaction of these electrophiles with DNA can sometimes result in cancer through the mutation of genes such as oncogenes or tumor suppressor genes. It is generally believed that most human cancers are due to exposure to chemical carcinogens. This potential for carcinogenic activity makes testing the safety of drug candidates of vital importance. Testing for potential cancer-causing activity is particularly critical for drugs that will be used for the treatment of chronic diseases. Since each species has evolved a unique combination of xenobiotic-metabolizing enzymes, nonprimate rodent models cannot be solely used during drug development for testing the safety of new drug candidates targeted for human diseases. Nevertheless, testing in rodent models such as mice and rats can usually identify potential mcq medical carcinogens.

THE PHASES OF DRUG METABOLISM

Xenobiotic metabolizing video odd enzymes have historically been grouped into the phase 1 reactions, in which enzymes carry out oxidation, reduction, or hydrolytic reactions, and the phase 2 reactions, in which enzymes form a conjugate of the substrate (the phase 1 product) (Table 3-1). The phase 1 enzymes lead to the introduction of what are called functional groups, resulting in a modification of the drug, such that it now carries an -OH, -COOH, -SH, -O- or NH2 group. The addition of functional groups does little to increase the water solubility of the drug, but can dramatically alter the biological properties of the drug. Phase 1 metabolism is classified as the functionalization phase of drug metabolism; reactions carried out by phase 1 enzymes usually lead to the inactivation of an active drug. In certain instances, metabolism, usually the hydrolysis of an ester or amide linkage, results in bioactivation of a drug. Inactive drugs that undergo metabolism to an active drug are called prodrugs. An example is the antitumor drug cyclophosphamide, which is bioactivated to a cell-killing electrophilic derivative (see Chapter 51). Phase 2 enzymes facilitate the elimination of drugs and the inactivation of electrophilic and potentially toxic metabolites produced by oxidation. While many phase 1 reactions result in the biological inactivation of the drug, phase 2 reactions produce a metabolite with improved water solubility and increased molecular weight, which serves to facilitate the elimination of the drug from medical surgical the tissue.