O Factors Affecting Drug Metabolism

Factors Affecting Drug Metabolism

Drugs and xenobiotics often are metabolized by several different phase I and phase II pathways to give several metabolites. The relative amount of any particular metabolite is determined by the concentration and activity of the enzyme(s) responsible for the biotransformation. The rate of metabolism of a drug is particularly important for its pharmacological action as well as its toxicity. For example, if the rate of metabolism of a drug is decreased, this generally increases the intensity and...

Cyp Benzylic Oxidation

Tertiary Alcohol Pharmaceutical Drug

The enzyme systems carrying out this biotransformation are referred to as mixed-function oxidases or monooxygen-ases.24,25 There is a large family that carry out the same basic chemical reactions. Their nomenclature is based on amino acid homology and is summarized in Table 3.2. There are four components to the name. CYP refers to the cytochrome system. This is followed by the Arabic number that specifies the cytochrome family (CYP1, CYP2, CYP3, etc.). Next is a capital letter that represents...

Hydralazine Acetylation

The metabolism of the immunosuppressive drug azathio-prine Imuran to and 6-mercaptopurine is an example of hetero-aromatic nucleophilic substitution involving GSH.433-435 Interestingly, 6-mercaptopurine formed in this reaction appears to be responsible for azathioprine's immunosuppressive activity.436 Arene oxides and aliphatic epoxides or oxiranes represent a very important class of substrates that are conjugated and detoxified by GSH.437 The three-membered oxygen-containing ring in these...

Limited access to the CNS

Clonidine Metabolites

A2-receptors located in regions of the brain such as the nucleus tractus solitarius. Stimulation of these a2-receptors brings about a decrease in sympathetic outflow from the CNS, which in turn leads to decreases in peripheral vascular resistance and blood pressure.20,38 Bradycardia is also produced by clonidine as a result of a centrally induced facilitation of the vagus nerve and stimulation of cardiac prejunctional a2-receptors.39 These pharmacological actions have made clonidine quite...

Chemical Structure Of Oxytetracycline

Oxytetracycline Molecule

R., and Ireland, D. S. Adv. Pharmacol. Chemother. 15 161, 1978. Values taken from Colazzi, J. L., and Klink, P. R. J. Pharm. Sci. 58 158, 1969. aValues taken from Brown, J. R., and Ireland, D. S. Adv. Pharmacol. Chemother. 15 161, 1978. Values taken from Colazzi, J. L., and Klink, P. R. J. Pharm. Sci. 58 158, 1969. for example, 7-dimethylamino, 7-chloro, and 6-methyl, have the opposite effect. Accordingly, the partition coefficient of chlortetracycline is...

Oxidation Involving Carbonnitrogen Systems

Tertiary Amine Dealkylation

Metabolism of nitrogen functionalities e.g., amines, amides is important because such functional groups are found in many natural products e.g., morphine, cocaine, nicotine and in numerous important drugs e.g., phenothiazines, antihistamines, tricyclic antidepressants, j-adrenergic agents, sympathomimetic phenylethylamines, benzodiazepines .159 The following discussion divides nitrogen-containing compounds into three basic classes 1. Aliphatic primary, secondary, and tertiary and alicyclic...

Medicinal Chemistry Of Sulfonylurea

Sulfonylurea

See Table 20.1 for structural details of modified insulins. hUltralente (U) and Lente (L) insulins have been discontinued in the United States, supplanted by newer modified insulins and insulin mixtures. iv, intravenous OTC, over-the-counter rDNA, recombinant DNA sc, subcutaneous U, international activity units. See Table 20.1 for structural details of modified insulins. hUltralente (U) and Lente (L) insulins have been discontinued in the United States, supplanted by newer modified insulins and...

O Synthetic Cholinergic Blocking Agents

Immagini Degli Idrocarburi

The solanaceous alkaloids are generally agreed to be potent parasympatholytics, but they have the undesirable property of producing a wide range of effects through their nonspecific blockade of autonomic functions. Efforts to use the antispasmodic effect of the alkaloids most often result in side effects such as dryness of the mouth and fluctuations in pulse rate. Therefore, synthesis of compounds possessing specific cholinolytic actions has been a very desirable field of study. Few...

O General Pathways Of Drug Metabolism

Atorvastatin Metabolites

Drug metabolism reactions have been divided into two categories phase I (functionalization) and phase II (conjugation) reactions.1'7 Phase I, or functionalization reactions, include oxidative, reductive, and hydrolytic biotransformations (Table 3.1).8 The purpose of these reactions is to introduce a functional polar group(s) (e.g., OH, COOH, NH2, SH) into the xenobiotic molecule to produce a more water-soluble compound. This can be achieved by direct introduction of the functional group (e.g.,...

Substituents Of Risperidone

Haloperidol Metabolism

A dibenzoxazepine derivative in use is loxapine succinate, f 1,4 oxazepine succinate (Daxolin). The structural relationship to the phenothiazine antipsychotics is apparent. Examples in this group are clothiapine, metiapine, zotepine, and others. They have electron-withdrawing groups at position 2, relatively close to the side-chain nitrogen atoms. Loxapine, an effective antipsychotic, blocks D2-type receptors and has side effects similar to those reported for the phenothiazines. Its...

Midazolam Log P 367 t12 2 h

Components Pharmaceutical Chemistry

Zolpidem Ambien, an imidazopyridine and eszopiclone Lunesta, a cyclopyrrolone are nonben-zodiazepines and have been introduced as short- and moderate-acting hypnotics, respectively. Zolpidem exhibits a high selectivity for the ai subunit of benzodiazepine-binding site on GABAA receptor complex, whereas es-zopiclone is a superagonist at BzRs with the subunit composition a1p2j2 and a1j2y3. Zolpidem has a rapid onset of action of 1.6 hours and good bioavailability 72 , mainly because it is...

Structure Activity Relationships of the Volatile General Anesthetics

The inhalation anesthetics in use today are nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane. The chemical structures for these compounds and some of historical interest can be seen in Figure 22.1. While it is true that there is no single pharmacophore for the inhaled anesthetics, the chemical structure is related to the activity of the drug molecule. The first SAR studies conducted independently by Meyer and Overton in the 1880s showed a distinct positive correlation between...

O Antibiotics And Natural Products

Chemistry And Antibiotics

A variety of the anticancer agents available today are derived from natural sources with several of these being obtained from microbial sources (antibiotics). Many of the antineo-plastic antibiotics are produced by the soil fungus Streptomyces. Both the antibiotic and natural product classes have multiple inhibitory effects on cell growth however, they primarily act to disrupt DNA function and cell division. There are several mechanisms by which these agents target DNA, including intercalation,...

Structureactivity Relationships

Pharmacophore Thylamine

The structure-activity relationships (SARs) summary is shown in Figure 16.11. Comprehensive reviews of the SARs of a- and -agonists and antagonists33-35 covered their developments in the late 1980s. The parent structure with the features in common for many of the adrenergic drugs is -phenylethylamine. The manner in which -phenylethylamine is substituted on the meta- and para-positions of the aromatic ring, on the amino (R1), and on a-, (R2)-, and -positions of the ethylamine side chain...

Methods Of Vaccine Production

Vaccine production methods have varied greatly over the years and are best discussed according to a parallel chronological and sophistication approach. In this method, the normal pathogen is treated with a strong, denaturing disinfectant like formaldehyde or phenol. The process denatures the proteins and carbohydrates that are essential for the organism to live and infect a host, but if treated properly, the surface antigens are left intact. The process must be done carefully to control the...

O Antibacterial Sulfonamides

The sulfonamide antimicrobial drugs were the first effective chemotherapeutic agents that could be used systemically for the cure of bacterial infections in humans. Their introduction led to a sharp decline in the morbidity and mortality of infectious diseases. The rapid development of widespread resistance to the sulfonamides soon after their introduction and the increasing use of the broader-spectrum penicillins in the treatment of infectious disease diminished the usefulness of sulfonamides....

Sar Of Benzodiazepines

Benzodiazepine Active Metabolites

Although the brain is undoubtedly the most wondrously complex organ, it is possible to distil the way it works into two opposing forces excitation and inhibition (depressing). Central nervous system (CNS) depressants are drugs that can be used to slow down or depress the functions of the CNS. Although many agents have the capacity to depress the function of the CNS, CNS depressants discussed in this chapter include only anxiolytics, sedative-hypnotics, and antipsychotics. There is some overlap...

The Neurogenic Inflammation Theory Of Migraines

This theory suggests that migraine headaches occur as a result of an abnormal firing of meningeal nociceptors at the TGVS. Activation of trigeminal neurons releases vasoac-tive peptides including calcitonin gene-related peptide (CGRP, a vasodilator peptide), substance P, and neurokinin A (both play an important role in pain transmission as well as activation of immune responses and neurogenic inflammation) onto dural tissue where these peptides produce a local response known as neurogenic...