Structure Of Morizicine

Comparative metabolic pathways of lidocaine and tocainide. The N-deethylated metabolite, although still bioactive, is then rapidly cleaved by microsomal amidases to inactive m-xylidine and N-ethylglycine. This readily explains the short half-life of the drug. Tocainide, on the other hand, presents a different picture. Its oral bioavailability is primarily due to slow hepatic metabolism on the first and subsequent passes. The large percentage of the drug excreted without enzymic...

JfY Mo nH

Progabide - NH2 H N N2 r-Nitrophenylisonipecotate j-Nitronipecottte Lamotrigine (Lamigtal) Lamotrigine (Lamigtal) was originally synthesized as a dihydrofolate reductase inhibitor. The compound was much better as an epileptic than it was in its original mission. Its talent is apparently in stabilizing presynaptic neuronal membranes by blocking their sodium channels as well as inhibiting excitory neurotransmitters. These features make it useful in the treatment of partial onset epilepsy....

Agonist Antagonist Analgetics

The disclosure that the antagonist nalorphine was a potent analgetic led to the synthesis of a number of 6,7-benzmorphans that were clinically evaluated as to analgesia, psychotomimetic effects, and the existence of other opioid effects. Phenazocine, which demonstrated high potency but no antagonism, was already mentioned. Cyclazocine, with n-propyl (subsituted) allyl propynyl cyclopropylmethyl cyclobutylmethyl n-propyl (subsituted) allyl propynyl cyclopropylmethyl cyclobutylmethyl 10 This dose...

Topliss Decision Tree In Drug Designing

Square brackets indicate alternates. Asterisk indicates compared with 4-H compound. Figure 1-10. Topliss decision tree. M, more active E, equiactive L, less active. equations can be rapidly calculated.8 This procedure gives useful correlations by both methods in most situations and has been shown to give comparable results. No doubt other refinements and approaches will be made to quantify structure-activity relationships of drugs to help design new agents...

Dpy

The catalytic properties of imidazole. a See text and Bruice and Schmir, 1957. h N-acetylimidazole has been isolated in the B reaction sequence. depolarize the end plate. The enzyme's specific activity is striking the turnover number has been determined at 25,000 sec-1 its turnover time, variously calculated at 30-60 milliseconds, meaning, on average, an ACh molecule is cleaved in that time period. Another way of viewing the activity of the enzyme is to state that it is capable of...

Narcotic Antagonists

Prior to the early 1940s no satisfactory pharmacologic antidote for opiate overdoses and poisoning existed. Treatment was essentially the same as for other CNS and respiratory depressants (i.e., with CNS stimulants and supportive physical methods). Some antagonism to the respiratory depression of morphine had been achieved by replacing the N-CH3 group of codeine with an allylic function (-CH2-CH CH2) during the 1920s. This fact was subsequently utilized as a rationale for the introduction of...

Ureids Drugs That Acts On Sedative And Hypnotics

It has been possible to produce a balanced type of anesthesia wherein low-potency N20 is combined with an opioid analgesic, usually the meperidine analog fentanyl (Fig. 5-10), or the more recent analogs sufentanil and alfentanil. When a butyrophenone-type neuroleptic (see later), particularly droperidol, is added, a state of neuroleptoanesthesia is produced where, without loss of consciousness, analgesia sufficient for surgery is achieved during which the patient still responds to commands.6...

Och3

Available in the United States since 1983 Also known as slow channel inhibitors and calcium channel inhibitors. b Trade names in parentheses. c Phosphodiesterase. events. The Ca2+, in these circumstances, can be said to act as a second messenger for muscle contraction (both smooth and striated) and possibly other processes such as neurotransmitter release. The myocardial slow inward calcium channels are energized by ATP, and can be activated either directly by depolarization, c-AMP-mediated...

S29s

Ribosomes in mitochondria and chloroplasts are also 70S size. b S Svedberg unit, a measure of size. Ribosomes in mitochondria and chloroplasts are also 70S size. b S Svedberg unit, a measure of size. a nonspecific manner. The resulting complex will bind specifically to a particular RNA (see later). Transfer RNA (tRNA). The function of RNA is to transfer activated amino acids to the ribosome for assembly and incorporation into growing polypeptide chains. iRNA is the smallest of the three types...

N R

Antiviral drugs. (Trade names in parentheses.) virus, influenza virus Ax and A2, and parainfluenza pseudorabies virus. The only officially approved antiviral clinical use of amantadine in the United States is for prophylaxis of influenza A2. Amantadine is not active against influenza B. Efficacy has been established. Effectiveness of the drug in preventing Hong Kong flu was reported in 1970. A more recent report also demonstrated the prophylactic effectiveness of amantadine against...

Gr6s630

LSD (Fig. 10-9), as the d-isomer, psilocin, and dimethyltryptamine are all potent hallucinogens containing the indole nucleus. They may therefore be viewed as serotonin analogs. They are 5-HT antagonists. R H, DimethyhrypUmine R OH, Psilocin As might be expected, other semisynthetic ergot derivatives, such as methysergide (Fig. 10-9) and 2-bromo-LSD, act similarly. Other unrelated structures that have antitryptamin-ergic (antiserotoninergic) actions while simultaneously exhibiting other...

Mvc

Prior to the discovery of monobactams and the earlier norcardicin (monocyclic P-lactams with meager antibacterial action that was not improved by structural manipulations), explanations for the reactivity of the P-lactam ring of the various P-lactam antibiotics revolved around its fusion at its 1 and 4 positions to an additional ring. The bicyclic structure, common to all these compounds, was then thought to activate (i.e., destabilize) the P-lactam ring by disallowing it coplanarity with its 1...

Cardiovascular Diseases

Hypertension (High Blood Pressure) Hypertension is termed the silent killer since it is asymptomatic (i.e., without direct characteristic symptoms). Hypertension is a leading cause of death. It is estimated that 20 of 1 In 1900 heart disease killed 27,000 and strokes 21,000 U.S. population was about half of today's. the American population has some elevation of blood pressure. Untreated high blood pressure can result in strokes, congestive heart failure, or kidney failure. All are high...

Gene Therapy

Gene therapy the very name seems so futuristic, almost like science fiction. Not long ago one might have put it in the pipe dream category not any more. It is not likely to explode on the scene with cures, or even with amelioration of hundreds of genetic defects and the pathologies resulting from them, yet between 1990 and mid-1995 a total of 87 gene therapy trials were approved by the Recombinant DNA Advisory Committee to the National Institutes of Health. Of the approximately 600 patients...

Vzk

Ceftizoxime (16) Cefotaxime (15) Moxalactam (19) The numbers in parentheses refer to Table 6-4. b Deacetylated to an active metabolite. the carbamoyl group at C-3 replaces the acetoxy function of the latter. The result is a new antibiotic with high potency against Gm+ bacteria that also retained and improved the Gm-spectrum of cephamycin C. The effect of the thienyl ring, which is already known, is again demonstrated. It is surprising, however, that the thiophene ring also enhanced the already...

Receptor Characterization

The ultimate in understanding receptors would be to know their structures to the degree that we already know small molecules. To date, our most detailed knowledge comes form X-ray crystallographic studies of those enzymes acting as receptors. Enzymes that have been successfully crystallized while complexed with a molecule of an irreversible inhibitor within its tertiary structure have given us a fascinating look at receptor (active-site) topography. It allows identification of the functional...

Dqx

An interesting compound apparently violating the ortho relationship was reported (Gringauz, 1976). This compound, which might be considered a biphenyl aspirin, exhibits both antiinflammatory and analgetic properties in rodents. It was also found to be nonulcerogenic in rats. It is not surprising that the acetaminophen ester (biphenyl benory-late) also exhibited similar pharmacology in rodents. Salicyloylsalicylic acid (salsalate, Table 5-2) is also of interest. This ester of salicylic acid,...

Rve

Biosynthesis of catecholamines. *Denotes enzyme in transformation AADC aromatic -amino acid decarboxylase COMT catechol-o-methyl transferase DBH dopamine-B-hydroxylase MAO monoamine oxidase PNMT phenylethanolamine-N-methyl transferase TH tyrosine hydroxylase. Many drugs in use known to interfere with a particular synthetic or degradative step of a particular neurotransmitter can have their clinical properties ascribed totally to this blockade or stimulation. None of the enzymes...

The Qra Binds To Block

Tardive dyskinesia, once rarely encountered (e.g., Huntington's disease), has become commonplace since the introduction of antipsychotic drugs. Such drug-induced dyskinesia (rhythmic involuntary movements) can be attributed to supersensitive postsynaptic DA receptors. (Such symptoms, of course, can also result from decreased cholinergic activity.) It is doubtful whether any of the antipsychotic drugs considered are significantly lower (better) in producing these symptoms. Table 12-16 lists many...

Fug

Tradename or code number, if experimental, in parentheses. b Ikeo et al., 1986 orally effective in animal studies. c Benassi et al., 1987 in clinical trials, a pro-drug of N-methyldopamine. d Nelson and Leier, 1981 orally effective, since it is not a catecholamine. ' McCaig and Parratt, 1979 a covalent combination of dopamine and theophylline. Five times more potent than dobutamine, but raises blood pressure. Tradename or code number, if experimental, in parentheses. b Ikeo et al., 1986 orally...

Ckjonoj

Table 10-15 lists the several organic nitrites and nitrates available. Nitrites, -0-N 0, are esters of nitrous acid, HN02, whereas nitrates, -0-N02, are esters of nitric acid, HN03. Ethyl nitrite was used as a popular nonprescription diaphoretic for decades (as a 4 alcoholic spirit), but it is no longer sold in the United States. Sodium and other inorganic nitrites, although used in the nineteenth century, have only a fleeting effect. (Today, NaN02 has as its only medical use being a component...

N

The antihypertensive properties of nitroprusside have been known since the late 1920s but they were not clinically used until the 1950s.10 It can be easily synthesized from sodium ferrocyanide and strong nitric acid by heating. Na2 Fe(CN)6 + HNOjacid Sodium ferrocyanide Na2 Fc(CN> 5NO Sodium nitroprusside At first the drug was used orally as an antihypertensive, but it was phased out with the advent of the ganglionic blockers and reserpines. Sodium nitroprusside was subsequently resurrected...

Rgo

Acylations of 6-aminopenicillanic acid. Figure 6-8. Resonance stabilization of oxazole penicillins. Figure 6-8. Resonance stabilization of oxazole penicillins. staphylococcal P-lactamase at a rate less than 1 that of penicillin G. The drug thus became the first penicillinase-resistant penicillin in clinical use. It is still the prototype today. Methicillin is not acid stable, possibly because the very small protonic catalytic species attacking the carbonyl oxygen of azetidinone (the...

Wsf

Digoxigenin, OH Digitoxigenin, H R sugars Digoxin (Lanoxin) Digitoxin (Crystodigin) R tri-digitoxose R tri-digitoxose late eighteenth century that its real medicinal value was recognized in the treatment of CHF (actually, the accompanying edema, or dropsy) by W. Withering in England. After a decade of study and use he wrote a treatise in 1785 on the use of foxglove for dropsy and other diseases. For the next 150 years digitalis was used in the form of decoctions, infusions, tinctures, fluid...

Arsenic In Melarsopol

Cumulative renal, hepatic, and, particularly, cardiac damage were soon recognized. Pentavalent antimonials, being less toxic, are probably safer and more effective. They may be viewed as derivatives of the antimonide ion Sb(OH) . Sodium stibogluconate (Fig. 7-9) can be prepared from Sb205 and gluconic acid in the presence of solubilizing NaOH solution. The exact structure and composition are not known, but are based on tartar emetic by analogy. Polymeric properties of antimonic acid makes...

Iupac Name Of Leucanthone

CH,0 P CH CO, CHj O OH Metrifonate The acetylcholinesterase in schistosomes acts as an inhibitory neurotransmitter so that inhibition of the enzyme results in paralysis. The suckers holding the worm to the wall of the vein let go, and the parasite is swept out (to the lungs) with the blood flow. Shortly after oral administration of the drug, serum cholinesterase levels in the patient are essentially eliminated while erythrocyte levels drop by about three fourths. These take several weeks to be...

Info

Figure 7-7. Metabolic activation of antimalarial pro-drugs. years of World War II as a result of the unavailability of quinine. Like quinine, quinacrine was an exoerythrocytic schizontocide that also controlled symptoms in P. vivax. Its yellow skin discoloration due to collagen binding in the dermis did not endear the drug to German troops. With the discovery of the colorless and otherwise superior chloroquine (see later) later in the war, quinacrine use waned. Its...

Ii

Examples of alkylating primary carcinogens. cinogens than primary carcinogens. Certain endogenous substances such as hormones can help newly formed clones of cancerous cells of organs normally requiring those hormones to grow and develop into tumors. It is well known that testosterone and estrogens, the male and female steroid sex hormones, respectively, are promoters of tumor development in those sex organs whose normal development depends on those hormones. It is now apparent that...

Atp

Filariasis results when tissues become infected with adult filarial worms (Table 7-9). The multitude of larvae produced within the tissues, called microfilaria, then enter the skin and the bloodstream. Filariases are mosquito-borne diseases that present special difficulties of treatment, because available drugs either kill the adult worm (e.g., the very toxic suramin) or the microfilaria. It was shown that the diethylcarbamoyl derivative of piper-azine, diethylcarbamazine (DEC), was selectively...

K118614g6-vintage

Much of the work and theoretical discussions as to the intricacies of the molecular mechanism (and chemical stabilities) of P-lactam antibiotics have previously revolved 10 It can also be named as an azetidine derivative (e.g., 2-azetidinone, or 2-keto-azetidine). Cephalosporins (X-H, Y S) Ccphamycins (X OCHj,Y S) Oxaccphcm (X H, Y 0) Carbacepham (X H, Y CHj ) Cephalosporins (X-H, Y S) Ccphamycins (X OCHj,Y S) Oxaccphcm (X H, Y 0) Carbacepham (X H, Y CHj ) around the penicillins and...

Sickle Cell Disease or Anemia

This is an inherited genetic disease. It was first described by a Chicago physician (Herrick, 1910) who believed it was caused by syphilis. It affects about 60,000 Americans, the majority of whom are black. In India, Iran, and around the Mediterranean, it affects nonblacks as well. Nearly two decades after Herrick's report susceptible erythrocytes were demonstrated to change to sickle cells when deoxygenated. This reversed on oxygenation. It took another two decades before Pauling et al. (1949)...

Bjt

Folic acid and its derived coenzymes. Figure 4-13. Irreversible formation of ternary thymidylate-methylene tetrahydrofolate-deoxyuri-dine phosphate complex. Figure 4-13. Irreversible formation of ternary thymidylate-methylene tetrahydrofolate-deoxyuri-dine phosphate complex. FH4 is carried out by the crucial enzyme thimidylate synthetase (Fig. 4-13). It should be noted that this is a reductive methylation where the tetrahydrofolate coenzyme serves both as a one-carbon donor and...

CNS Depressants

In this section drugs used because of their CNS depressant properties will considered. The volatile general anesthetics (gases and low-boiling liquids), fixed general anesthetics (e.g., certain barbiturates), and sedative hypnotics (as defined earlier) will be included. In subse- Figure 12-8. Schematic relationships between synthesis and metabolic degradation of a biogenic amine. Figure 12-8. Schematic relationships between synthesis and metabolic degradation of a biogenic amine. Table 12-4....

Enzyme Stimulation

Enzymes frequently require coenzymes for optimum activity. The coenzymes are usually vitamins and cofactors, invariably electrolytes such as mono- and divalent metallic ions (e.g., K+, Na+, Ca+2, Mg+2, Zn+2, and Fe+2). These coenzymes activate different enzymes by various means of complexation and stereochemical interactions. A detailed consideration of the mechanisms involved is not within the scope of this discussion. It can be stated, however, that such ions may affect enzymes in one of two...

Ch2occh3

Methylprednisolone acetate Cream, ophthalmic oint-(Medrol Acetate) ment, enema, ointment, Methylprednisolone sodium Injectable solution succinate (Solu-Medrol) 9-Fluoro-11, 16, 17, 21 -tetrahydroxy-( 11,16)-pregna-1,4-diene-3, 20 dione Triamcinolone acetonide (Aristoderm) Cream, ointment, lotion, areosol, injectable acetate Injectable

Oh

Synthesis and metabolism of Esmolol. Figure 10-3. Synthesis and metabolism of Esmolol. of radiolabeled P antagonists has shown it to contain both and P2 receptors. This coexistence helps to explain the increased heart rate in asthmatics even if given highly selective p2 agonists. Much of the effort for highly specific p2-agonists has been based on the convenient belief that the heart had only -receptors. Furthermore, it was suggested that the facilitation of K+ influx from...

O

An offshoot of isosterism is the interchange of groups with similar polar effects, particularly acidities. The first successful use involved the carboxyl and sulfonamido groups, -COOH, -S02NHR. Although serendipitously discovered six decades ago, it resulted in the antibacterial sulfonamides, which several years after their introduction were found to be isosterically antagonistic to the bacterial metabolite p-aminobenzoic acid (the reasons for this antagonism will be discussed in a later...

Xii

Other examples of successful interchanges of O and S and -NH and -CH2 abound in the areas of antihistamines (both H and H2 types), analgesics, anticholinergic drugs, and psy-chopharmacological agents, with surprising results in the case of the latter. These will be pointed out in the sections dealing with those drugs. Equally important isosteric replacements involve trivalent atoms and groups. These include -N and -C , especially in ring compounds, and they will be discussed in the appropriate...

Isosteric Drugs

-NH2), tolbutamide, soon replaced carbutamide in clinical practice. Finally, a third isostere Xc (-C1 for -CH3), chlorpropamide, was introduced whose attributes were both decreased toxicity, and also extended duration of activity (due to nonoxidizability of the CI atom compared to the CH3 group). Bioisosteric interchanges, of course, are not limited to univalent functions. In fact, divalent atoms and groups add the additional factor of steric similarity to the equation since the bond angles...

Ch2cooh

R CH3 Tolmetin I H (Tolectin) R CI Zomepirac* R' CH3 (Zomax) R OH, oxyphenylbutazonefc (Tanderil) Oral potency (100 mg) equivalent to meperidine (75 mg) Analgesic efficacy 30-60 mg IM equivalent to 12 mg morphine or 100 mg merpidine. Also available in 5 and 10 mg oral tablets. ANALGETICS AND NONSTEROIDAL ANTIINFLAMMATORY AGENTS Table 5-2. (Continued)

Histamine Antagonists

By the beginning of the twentieth century the imidazole ring was known to occur in the amino acid histidine, the alkaloid pilocarpine (Chapter 8), and histamine, all of interest to biologically oriented chemists at the time. Its synthesis was accomplished in 1907. The vascular effects of this biogenic amine were not fully recognized for another decade neither was its wide occurrence and distribution in animal tissues. In 1920 it was demonstrated that histamine stimulated secretion of gastric...

Dzv

The lipoidal characteristic of the GC steroids needed to facilitate epidermal entry can be achieved by various derivatizations of OH functions at C-16, C-17, and C-21, specifically esters and ketals (structures B and C). Derivatization of even one hydroxyl can be useful. Table 14-4 gives examples of the type and positions of derivatives that impart increased lipoidal characteristics to steroids to enhance their local antiinflammatory activity. Dioxalones, which are formed from diols that are...

Qow

A simplified chart illustrates the peripheral neural systems. It indicates the voluntary motor neurons to the skeletal muscles of the body and the autonomic system that utilizes chemical transmission at five synapses the two ganglia and the three sites where innervation to muscle or organ occur (Fig. 8-4). It will be noted that ACh is the transmitter at four of these sites, while only one utilizes NE. It must also be appreciated that while ACh is the neurotransmitter at most of the synapses,...

Oh H

The macrolide antibiotics. Sixteen-membered macrolides are represented clinically by spiramycin. It is listed in the French Pharmacopoeia (but not in the United States). It has a similar antibacterial spectrum, but claims higher MIC. Erythromycin-A (EM) obtained from S. erythreus has utility in a wide variety of Gm+ infections, including sexually transmitted diseases such as syphilis, chlamydia, and gonorrhea. The drug can be considered for penicillin-allergic patients. In an...

Hl Cooh

R H, Diphenylacetic R OH, Benzylic Adiphenine (1) Clindinium (3) Oxyphencyclimine (11) b Where a-carbon also carries OH, may be named as a substituted glyoxylic acid, HOCH2COOH. XN-CH2-C-CH2-0-C-CH- C2H5' CH3 Another pharmacological (though not clinical) complication should be pointed out. Many of the tertiary amine compounds do not owe all their antispasmodic properties to antimus-carinic (neurotropic) activity. To varying degrees they also possess a direct spasmolytic (musculotropic) action,...

Cxt

Historical-chemical development of aspirin. able in vivo), variations of the acyl group (to increase stability) or of substitutions into the benzene ring, from a simple alkyl or alkoxy group to fluorinated phenyls such as in diflu-nisal (Table 5-2). The ortho relationship of the acid and phenolic functions, however, seemed inviolate. The acetaminophen ester of aspirin, benorylate (Table 5-2), is a particularly novel example of a pro-drug where both components represent active...

Introduction

Voltaire (1694-1778) stated, Therapeutics is the pouring of a drug of which one knows nothing into a patient of whom one knows less. The medical and pharmaceutical sciences have been working diligently to ameliorate both aspects of the problem. The progress made, especially in the period following World War II, has been impressive, if not astounding. However, there are many important riddles still to be solved and much to be learned. One of the areas of study has concerned itself with the...

Receptor Concept of Drug Action Mechanisms 151 Historical Development

The development of the idea that can be called a drug-receptor theory required over a century to reach its present modest level of sophistication. It expresses the understanding that a drug exerts its biological activity as a consequence of binding, or interacting in some manner, with a specific receptor in a biological system. Not that people did not wonder how the various powders, potions, and infusions worked their imagined, and occasionally real, magical effects they undoubtedly came up...

Mitotic Inhibitors

Compounds known to inhibit the mitotic phase of the cell cycle offer potential usefulness in the treatment of cancer. Few such drugs, however, have reached clinical application either because of unacceptable toxicity or ineffectiveness. Two antimitotic agents are used for other purposes. The antibiotic griseofulvin is utilized for its antifungal properties. The alkaloid colchicine, although having antitumor activity, is used in the treatment of gout. Colchicine, obtained from the seeds of...

Ch2ch2ch2nhch3

Second-generation antidepressants. Trade names in parentheses. *Withdrawn in 1987. monoamine, while cocaine and amphetamine which do are not particularly useful in treating depression. It may be reasoned that if the acute effect of TCAs and MAO inhibitors is to raise the amine levels and yet no symptom relief is discernible for the first 2 weeks of treatment that the amine levels per se are not really significant or that these compounds are achieving their results by a different...

BuspironeIs Anxioselectivity Possible

The question arises whether anxiolytic activity must always be accompanied by concomitant skeletal muscle relaxant and anticonvulsant activity as well as strong sedation. Can an anxioselective drug exist that will not interact significantly and additively with CNS depressant compounds, particularly alcohol More significantly, both from a medical and sociologic viewpoint, will it be possible to treat anxiety and stress without the added complication of potent sedative effects, dependency, and...

A H oc

Another interesting but little utilized drug inhibiting cell wall synthesis during Stage I is cycloserine (oxamycin, Seromycin). It is a broad-spectrum antibiotic produced by Streptomyces orchidaceus (but now made synthetically). Its use over the past three decades has been limited as a second-line antitubercular agent. Chemically, D-cycloserine (D-4-amino-3-isoxazolidone) might be viewed as a cyclic analog of D-alanine.6 The drug competitively inhibits both alanine racemase and...

The Nonsteroidal Antiinflammatory Drug

The ideal NSAID agent has not yet been developed. Efforts have been continuous since the introduction of aspirin in 1899. For example, the patent literature for 1966 alone reveals disclosures of more than 100 groups (not single compounds) of antiinflammatory structures. The pace of research is not likely to have abated. Unfortunately, only a small number of lead compounds emerge with sufficient potency and adequate tolerance for further development. Chronic toxicity determinations in animals...

Rd E

The number of receptors occupied is dependent on the concentration of the drug in a unit area or volume5 and on the total number of receptors, Rt, in it. As more receptors are Figure 1-6. Relationship of drug action to drug concentration. occupied, the pharmacological effect becomes more intense until, when all are filled, a maximal effect, Em, is achieved. Finally, the intensity of the effect will be dependent on the drug-receptor complex concentration, D , Maximal effect is proportional to...

Hypolipidemic Hypocholesterolemic Drugs

The fact that even young men can develop atherosclerosis was reported following autopsies of German soldiers during World War I. However, it was a U.S. Armed Forces Institute of Pathology report toward the end of the Korean War (Enos et al., 1953) showing that young men (average age 22) had evidence of coronary heart disease (CHD) that made the medical profession take note of the epidemic that was CHD. The problem is still extensive in spite of considerable, but slow, progress since the 1950s....

Drugs Affecting Cholinergic Mechanisms

This and the next chapter on adrenergic drugs involve chemical agents that derive their therapeutic use from effects on the peripheral autonomic nervous system, primarily by mimicking or blocking, directly or indirectly, the neurotransmitters of that system acetylcholine, norepinephrine, and dopamine. Drugs affecting these transmitters centrally, rather than peripherally, will also be considered because of chemical or mechanistic similarities. It is therefore necessary to discuss some...

Indirect Sympathomimetics

Indirect sympathomimetics are drugs capable of actively entering the adrenergic neuron and its vesicles to displace NE from its binding sites. Thus the sympathetic effects observed with such compounds are actually elicited as a result of receptor recognition of NE, and not because of any affinity for these drugs. This is particularly true the more unrelated the compounds are to catecholamines or phenylethylamines in structure. Such agents may retain partial direct activity because they have...

O O B

Relationships of Chemistry to Pharmaceutics Tetracyclines are amphoteric compounds that can exist as acid or base salts as well as in the zwitterionic state, depending on the pH of the environment. They may be viewed as tribasic acids, with the 4-dimethylammonium ion (a conjugate acid of the dimethylamino group) being the weakest (pKa3 9.1-9.7). The phenoldiketone system accounts for the pKa2 range of 7.2-7.8 and the tricarbonylmethane moiety generates the strongest acidity (pKai...

H O H

Na+ ft i Chloramphenicol sodium succinate*4 Chloramphenicol -Alicylic pseudo ring Chloramphenicol -Alicylic pseudo ring Figure 6-26. The lincosaminides and chloramphenicol. *Chiral centers **or hemisuccinate. described in 1962 and was originally obtained from S. lincolnensis, although it now can be produced from other species as well. LM is active primarily against Gm+ organisms such as streptococci, staphylococci, and pneumococci. Gm- aerobic bacteria are generally intrinsically resistant....

Antidepressants

Depression, or melancholy, as it was once called, is a sense of lowering mood. It has become a mental health problem of major proportions in modern society. It has been estimated that one-fifth of our population is likely to experience at least one major depres Manic-depressive Pure depressive Pure manic Figure 12-23. Types of manic depressions. Manic-depressive Pure depressive Pure manic Figure 12-23. Types of manic depressions. sive episode in his or her lifetime. For many there will be...

Ch3

Ring systems with relatively few deviations from planarity, by angling of the atoms in the middle ring, begin to show some thymoleptic effects while still maintaining neuroleptic activity. Amitriptyline and doxepin are likely examples. More pronounced twisting of the ring system usually results in exclusive antidepressant action, such as with imipramine. A nonplanar angled thymoleptic receptor concept might be involved. Another supporting example may be the two acridine derivatives as shown...

I

In the narrowest sense isosteres are compounds, groups, or atoms that have the same number and arrangement of electrons in their outermost electron shell. They can be said to be isoelectronic. The concept was originally proposed by Erlenmeyer about a century ago on observations that some simple molecules could be pair based on certain similarities of chemical and physical properties. For example, C 0 and N2, C02 and N20, and CH2N2 and CH2 0 constitute such pairs. The concept soon expanded to...

Carcinolytic Antibiotics

Pyrimldine Charge-Transfer Interactions This is a complex formation process between electron-rich donor molecules and electron-poor acceptor molecules. Energies holding the charge-transfer components rarely exceed 7 kcal mole. These forces are operative over a 3-3.5 A distance. 7t-Electron-rich heterocyclic ring compounds such as thiophene, furan, and pyrrole, or more complex structures containing them, make excellent donor species for CT complex-ation so do aromatic structures having electron...

Oo

This value can vary depending on what the other bondings to the carbon atoms are. h Organic peroxides. This value can vary depending on what the other bondings to the carbon atoms are. h Organic peroxides. bonding that are of primary interest biologically are, of course, O and N. Halogen atoms in drug molecules, particularly F, can also participate. Since hydrogen bonds are relatively weak (1-5 kcal mole) they can be easily dissociated, even by warming. The secondary and tertiary structure of...

Ph

Bioactivity as a function of pH. a high proportion of polar functional groups. The opposite situation, where the ionized form may still have appreciable lipid solubility, where the drug has few polar groups but a relatively large hydrocarbon skeleton, is a possibility. Methyl prednisolone sodium succinate would be an example. Although lipid solubility at physiological pH enhances a drug's penetrability of a membrane, too much may not necessarily result in increased activity. Many...

Opiumand the Strong Analgetics Emanating from It

Medicines Act Images

Opium is the dried exudate of the unripe capsule of Papaver somniferum.4 Varieties of this plant have been cultivated and used for several millennia. Today, it is grown in Turkey, Iran, Afghanistan, Russia, China, Southeast Asia, and Mexico, as well as in other areas of the world, both licitly and illicitly. Crude opium is known to contain over 25 different alkaloids that can be chemically divided into two categories the phenanthrenes and the ben-zylisoquinolines (Fig. 5-7). Only morphine,...

Psychoactive Drugs Chemotherapy of the Mind

It is difficult to exaggerate the complexity of the human brain's chemistry and functions, many of which are only beginning to be understood. Much is still undiscovered. Before embarking on a discussion of mental diseases and mechanistic aspects of the drugs used in their treatment, it is important to define certain terms frequently encountered. Psychosis. A mental disorder of sufficient magnitude to result in personality breakdown and loss of contact with reality. Delusions and hallucinations...

Chemistry Of Sporozotocide

Chemotherapy Malaria Cycle

The number of humans presently afflicted is staggering (e.g., malaria, schistosomiasis, roundworm, hookworm, and whipworm). Overall estimates for the world are as high as 3 billion people. That would easily make parasitic diseases the world's leading health problem. Though many of these diseases were thought of as a third world problem, this is not so anymore. The ease of air travel and large migrations of people into more temperate climates now presents...

Ich2oc2h5

Biosynthesis Diosgenin

9-Chloro-l 1, 20-dione-17,21-diproprionate by the addition of a 9 a-F atom it increased Cortisol's potency tenfold. When further substituted by F (or CI) atoms at positions 6, 9, and 16, and in some cases a CH3 at C-6, the prednisolone molecule produced steroids having potency increases as high as 1000-fold (e.g., 6, 9J3-diF, 16(5-0). While it reduces MC effect modestly ca. 20 when comparing Figure 14-2. Corticosterol biosynthesis major pathways. Abbreviated. Oxygen from 02 with ADP. Figure...

Inhibition of Mediator Release

The discussion so far may have given the impression that allergic, particularly asthmatic, attacks responses are solely mediated by a sudden release of copious quantities of histamine that are stimulated to do so by some pathological event such as an autoimmune reaction, pollen exposure, or an antigen-antibody reaction. While it is true that histamine is released by mast cells and also their circulating counterparts, the basophils , causing swelling of nasal passages by affecting blood vessels...

Meth Gbl And Candida

Gamma-aminobutyric acid metabolic interactions. GA glutaminase GABA y-aminobutyric acid GABA-T GABA a-oxaloglutarate transaminase GAD glutamic acid decarboxylase GS glutamic synthetase NAD nicotinamide adenine dinucleotide PP pyridoxal phosphate vitamin B6 SSA succinic semialdehyde SSADH succinic semialdehyde dehydrogenase GHB y-hydroxybutyric acid GBL y-butyrolactone.

Sq 81402

The evolution of Aztreonam. having a demonstrated low affinity high Km for these enzymes. With respect to P. aeruginosa it was shown that aztreonam inhibited 250 strains of this organism resistant to piperacillin, cefoperazone, and most aminoglycosides, at MICs of less than 6 Xg ml. It is interesting that 3-acyl side chains analogous to those of the cephalosporins show closely similar antibacterial activity against Gm- organisms. It is curious that the analogy even extends to Gm...

Sod

2H2 2 02 -OH' OH O2 7.5 T. cruzi causes South American trypanosomiasis Chagas' disease . One form of the parasite reproduces intracellularly, making its treatment extremely difficult. The experimental drug nifurtimox Bayer 2502 , a 5-nitrofuran derivative Fig. 7-4 , although the current drug of choice, is not satisfactory in spite of high activity against the parasite in vitro. The alternative 2-nitroimidazole benznidazole Fig. 7-4 has similar shortcomings namely, at tolerable levels of...

Drugs That Act On

Compiled from Spratt, 1977 and Spratt, 1983. d A third protein identified in one study. Compiled from Spratt, 1977 and Spratt, 1983. d A third protein identified in one study. potent cell killing of many Gm-organisms. Combining this drug with other broad-spectrum P-lactam compounds e.g., ampicillin, cefamandol produces a synergistic effect. Thienamycins and clavulinic acid also have been shown to bind primarily to PBP2, resulting in the same morphological cellular changes as produced by...

Quantitative Aspects of Drug Action An Overview

The decade of the 1930s was the beginning of attempts to introduce mathematical methods to gain increased understanding of chemical processes such as reaction rates, mechanisms, and certain processes, and to apply these techniques to the art and intuition of prediction. The scientific impetus was the then relatively new discipline of physical organic chemistry pioneered by chemists such as Hammett 1940 . These scientists elucidated the SARs of the electronic and steric effects of various...

Theories of Drug Activity

Although there is no single uniform theory that can explain the activity of drugs, several theories have been advanced over the years in attempts to elucidate drug action. In general we may consider pharmacological action to be of two types. One type is thought to be caused solely by the physicochemical properties of the compound without discernible relationship to chemical structure. These structurally nonspecific drugs are usually administered in relatively large doses. It is presumed that...

Occh3

An acetaminophen-aspirin mutai pro-drug not available in U.S. The names in parentheses represent one of possibly several trade names. h Withdrawn from the U.S. market. Extracts of willow bark containing salicin , used to relieve pain and fever, was known to the Greeks in Hippocrates' time. It became used again in England in the mid-eighteenth century when the bitter principle was also recognized as a useful substitute for quinine as an antipyretic. In 1823 Leroux succeeded in isolating the...

Clonidine Structure In Benzene Ring Type

In the case of the protonated salt form of clonidine, using the analogy with guanidine Fig. 10-6 , in order to retain optimum molecular stability, the proton must be found on the bridge nitrogen. That way, as the following composite resonance structure shows, the electrons of the double bond can be delocalized so that the positive charge is distributed over all three nitrogens. Certain corresponding features between clonidine and NE have also been established, as both are substances that...

Thrombolytics

Thrombolytics are agents capable of lysing thrombi in the cardiovascular system. As was seen earlier, clot formation is governed by the coagulation scheme. Understanding of that scheme has led to agents able, to a degree, to inhibit clot formation prophylactically. Anticoagulants and platelet aggregation inhibitors considered in this chapter are prime examples. Lysis of clots is regulated by another complex series of interrelated biochemical reactions referred to as the fibrinolytic system Fig....

Proton Pump Inhibitors HKATPase

Figure 13-2 implicates in simplistic form the various receptor activations of the parietal cell with H -K -ATPase the proton pump and thereby the release of H into the gastric lumen. Cyclic-AMP, and its production from ATP, which is catalyzed by adenyl cyclase, is the significant mediator system in this process. Omeprazole Fig. 13-4 emerged from a series of benzimidazoles as a compound able effectively and specifically to inhibit the pump's production of gastric acid. Cellular components of the...

Factors Affecting Bioactivity

Factors Affecting Bioactivity

The biochemical systems encountered by a drug molecule are extremely complex. Therefore, it should not be surprising that the factors affecting the drug's interactions and contributing to its final effect are also manyfold. The factors may be divided into three categories 1. Physicochemical properties such as solubility, partition coefficients, and ionization. 2. Chemical structure parameters such as resonance, inductive effect, oxidation potentials, types of bonding, and isosterism. 3. Spatial...

Iv

R1 R2 H, Alkyl or cycloalkyl X Halogen, CN, NO2. Figure 7-14. The evolution of oxamniquine and praziquantel. tion, and elimination rates, as well as body distribution patterns. Differences in metabolism, although frequently minor, are sometimes the major factor, as in this case. It was reported that unlike the methyl group para to the diamine of leucanthone, which was rapidly oxidized to the hydroxymethyl group of hycanthone, the corresponding metabolic reaction of the CH3 group in mirasan,...

Ch3hn

Plasminogen contains lysine-binding sites. These are structural components on the enzyme that interact specifically with lysine and certain other synthetic amino acids whose amino and carboxyl functions are about equally separated. The synthetic lysine analogs aminocaproic and tranexamic acid irans- 4-aminomethyl cyclohexane carboxylic acid are inhibitors of fibrinolysis. By interacting with the lysine binding sites, these acids act as competitive inhibitors of plasminogen activators and, less...

Ch3chchjch3

Meprobamate Exhibits antianxiety muscle Miltown, Equanil relaxant and sedative properties A mild sedative with muscle relaxant properties short-acting intensity and shorter duration. It should be pointed out that the polyol compounds are generally not effective in spasticity due to dyskinesia. There are several chemically unrelated skeletal muscle relaxants. Chlorzoxazone is an example of a drug that evolved from a discovery that certain benzimidazoles had mephen-esinlike activity....

Doxaprost Si Em F

16-Methy 1-18,18-19,19-tetradehydrocarbacyclin Ciloprost 16-Methy 1-18,18-19,19-tetradehydrocarbacyclin Ciloprost Cardiopulmonary bypass surgery hemoperfusion for kidney patients peripheral vascular disease, preinfarction angina, and stroke Extracorporeal circulation, treat coronary or vascular occlusions Marketed or experimental. b Trade names in parentheses. Actual or potential. Among the effects of PGs to be considered are the following 1. Effects on inflammation and pain E- and F-series PGs...

Nh2

Trimazocin shares the polymethoxyquinazoline and piperazinecarbonyl portions of the prazocin molecule, except that the tert-butanol is linked via a carbamate ester. It is not surprising that there are some nuances in its mechanism that still involve inhibition of ar adrenoceptors. In addition, there is a direct action on the vascular musculature leading to dilation. Indoramine is a highly selective a -antagonist. Its pharmacology has since been shown to include MSA as well as antiserotonin and...

Mopa

Methoxyhydroxyi gt henyleihanol MOPE Figure 9-5. Metabolism of dopamine Step not definitely established COMT catechol-O-methyl transferase acronyms derived from underlined letters, except H O, i.e., hydroxy oxy . Methoxyhydroxyi gt henyleihanol MOPE Figure 9-5. Metabolism of dopamine Step not definitely established COMT catechol-O-methyl transferase acronyms derived from underlined letters, except H O, i.e., hydroxy oxy . inhibitors. For example, deprenyl and pargyline, both of which are...

Tha

Compounds capable of blockading nicotinic receptors at ganglia of the autonomic nervous system will be dealt with in the discussions on antihypertensive drugs Chapter 10 . 8.7.1 Anticholinergics Antimuscarinics Drugs in use today because of their ability to elicit mydriasis14 pupillary dilation and cycloplegia ciliary paralysis , reduce spasticity of smooth musculature such as the small intestine, inhibit gastric secretions of HC1, and minimize the symptoms of Parkinson's disease...

Skf 92564

Anonymous, 1984. b Buyniski etal., 1983. laminomethyl serves to supply the basicity the imidazole ring brought to Cimetidine. Ranitidine is actually a stronger base pKa 8.44 . Tiotidine has a thiazole ring replacing the imidazole, while retaining the cyanoguanidine function. Basicity is supplied by the guanido group. Clinical trials stopped following reports of stomach lesions in chronically ct2OH HSCH2CH2NH2, H Furfuryl Alcohol Mannich Reaction CH3' O Cysteamine CH2-0-CH2SCH2 2NH2_ ,NCH2 -G...

Stereochemical Aspects of Psychotropic Drugs

Stereochemical and other geometric factors are significant in determining the type of psychotropic activity obtained. It appears that planar ring systems yield optimal neuroleptic activity. The tricyclic 6-6-6 system i.e., all three rings contain six atoms of the phenoth-iazines seems to prove this. However, compounds with total rigid planarity, as in a 6-5-6 system exemplified by carbazole and fluorene derivatives, are invariably inactive. It might be postulated that neuroleptic receptors are...

Ergosterol Biosynthesis Of Squalene

Ergosterol Synthesis

CH2 CH- CH2 COOH Undecylenic Acid and salts CH3- CH2 -COOH Caprylic Acid and salts CH3 -CH2-COOH Propionic Acid and salts Figure 7-10. Synthetic antifungal drugs. A number of fatty acids possess antifungal properties limited to dermatophytes Fig. 7-10 . Their mechanism of action is not understood. Acetic acid, as glyceryl triacetate Triacetin , is used in cream form against tinea pedis. It apparently acts as a pro-drug, slowly releasing the acetic acid on hydrolysis, and is presumably catalyzed...