By S. Gancka. Bob Jones University.
There are four classes of glucuronide metabolites: O- order zocor 40 mg free shipping, N- generic 20mg zocor amex, S-, and C-glucuronides. It is important that the vulnerability of each of these building blocks to metabolic attack be appreciated during the drug design process. This section lists the major molecular building blocks and briefly outlines their susceptibility to metabolism. Alkyl functional groups tend to be metabolically nonreactive and to be excreted unchanged. Therefore, alkanes can be used to build the framework of a mole- cule or as lipophilic functional groups. Rarely, a linear alkyl group will be oxidized in a process that is catalyzed by a mixed-function oxidase enzyme. When this occurs, it does so either at the end of the hydrocarbon chain or adjacent to the final carbon (the “omega-minus-one carbon”). While cyclopropane may be reactive, due to ring strain, cyclopentane and cyclohexane are metabolically inert. The majority of alkene- containing drugs do not exhibit significant rapid metabolism at the double bond. There are some isolated examples of alkene-containing compounds that undergo epoxidation, catalyzed by mixed-function oxidase, or that add water across the double bond to give an alcohol. Halogenated hydrocarbons are not easily metabolized and show significant stability in vivo. The addition of halogens tends to increase the lipophilicity and to prolong the half-life of the drug. Aromatic rings are very susceptible to oxidation, in par- ticular to aromatic hydroxylation. The oxidation of aromatic rings frequently proceeds via an epoxide intermediate, which may actually be stable enough to be isolated. The hydroxylation of an aromatic ring increases hydrophilicity, thus promoting renal excre- tion and slightly decreasing the half-life of the drug. Aromatic hydrocarbons are oxi- dized in a number of organs, but the liver is a preferred location. If the alcohol is conjugated with glucuronic acid, a glucuronide forms; if it is conjugated with sulfuric acid, a sulfate is formed. Regardless, both of these conjugations increase hydrophilicity and decrease the half-life of the drug molecule. Sometimes, an ether that involves a small alkyl group (occasionally a methyl, rarely an ethyl) will be dealkylated, with the small alkyl group being excreted as an aldehyde; the remainder of the drug molecule is left as an alcohol. Aldehydes are very susceptible to oxidation, which is catalyzed by various enzymes including aldehyde oxidase and aldehyde dehydrogenase; this oxidation yields a carboxylic acid. Ketones, however, frequently undergo reduction to a secondary alcohol; this is particularly true for α,β-unsaturated ketones. Carboxylic acids conjugate with glucuronic acid, glutamine, and glycine; the resulting conjugates are water soluble and more easily excreted. Alternatively, carboxylic acids may be oxidized, especially beta to the carboxyl group. They are readily con- verted to the corresponding free acid and alcohol via hydrolysis, a process that may be either base- or acid-catalyzed. Although similar to esters in terms of being a functional derivative of a car- boxylic acid, amides, unlike esters, are relatively metabolically stable. This stability is related to the overlapping electron clouds within the amide functionality and the corresponding multiple resonance forms. The ester portion of both carbonates and carbamates is hydrolyzed to give the monosubstituted carbonic acid, which is unstable and decomposes with loss of carbon dioxide. Thus, carbonates are hydrolyzed to give alcohol and carbon dioxide; carbamates are hydrolyzed to yield an alcohol, an amine, and carbon dioxide. Compounds that contain urea functionalities are stable and are not com- monly metabolized or hydrolyzed. An important metabolic route for primary and secondary amines is conjuga- tion with either glucuronic acid or sulfuric acid to yield the corresponding water-soluble glucuronides and sulfates. The alkyl groups are sequentially removed and then “lost” as either aldehydes or ketones. The amine is thus converted from a tertiary amine to a secondary amine and then to a primary amine. This form of metabolism occurs most favorably if the alkyl group is small, such as methyl, ethyl, or propyl. Finally, amines may be acetylated, with the resulting amide undergoing typical amide metabolism. The conversion of chlorpromazine to chlorpromazine sulfoxide is a good example of this.
Oligohydrosis and hyperthermia have been reported to occur in 13 pediatric patients during the first 11 yr of marketing of zonisamide in Japan discount 20mg zocor with visa. Although zonisamide is not approved for pediatric use in the United States buy discount zocor 40mg on-line, it is important to recognize that oligo- hydrosis and hyperthermia are potential adverse effects associated with the use of zonisamide (98). Contraindications and Precautions Studies in rats and mice have shown teratogenic effects when zonisamide is admin- istered during organogenesis in pregnancy. Embryo lethality has been demonstrated during the treatment of cynomolgus monkeys. Oligohydrosis and hyperthermia were reported to occur in Japanese children treated with zonisamide but has not occurred in Caucasians. Decreases in clearance will occur in patients with impaired renal function and zonisamide should only be used under close supervision in patients with a glomerular filtration rate of <50 mL/min. In addition, metabolism of zonisamide may be decreased in patients with hepatic dysfunction. The clinical impact of these interac- tions are unknown as no therapeutic level for zonisamide has been determined (94,97). Conclusion Epilepsy is a common neurologic condition that affects patients of all ages, although the incidence is higher among the youngest and oldest segments of the population. Historically, antiepileptic drug use has been fraught with complications, some of which are attributable to the many pharmacokinetic drug interactions encountered with this group of medications. In addition to the pharmacokinetic interactions that occur with antiepileptic drugs, clinicians must remain well informed and aware of the possibility of pharmacodynamic interactions that can occur with other medications known to have similar pharmacologic and toxicologic actions. Though each of these new drugs brings promise to the generations of patients that suffer from epilepsy, none is without risk. Emerging insights into mechanisms of epilepsy: implications for new anti- epileptic drug development. Therapeutic plasma levels of phenytoin, phenobarbital, and carbam- azepine: individual variation in relation to seizure frequency and type. The influence of seizure type on the efficacy of plasma concentrations of phenytoin, phenobarbital, and carbamazepine. Frequency of recurrence after discontinuance of anticonvulsant therapy in patients with epileptic seizures: a new follow-up study after 5 years. Human brain, cere- brospinal fluid, and plasma concentrations of diphenylhydantoin and phenobarbital. A review of its pharmacology and therapeutic poten- tial in epilepsy, trigeminal neuralgia and affective disorders. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glu- tamate and other neurotransmitters. Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action. Reduced bioavailability of moisture-exposed carbam- azepine resulting in status epilepticus. Carbamazepine and its major metabolites in plasma: a summary of eight years of therapeutic drug monitoring. Oxcarbazepine: a new drug in the management of intrac- table trigeminal neuralgia. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique. Pharmacokinetics: time-dependent changes— autoinduction of carbamazepine epoxidation. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Forced normalization induced by etho- suximide therapy in a patient with intractable myoclonic epilepsy. Adverse drug effect-reactive metabolites and idiosyncratic drug reactions: part I. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug. Steady- state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy. Pharmacokinetics of tiagabine, a gamma-aminobuty- ric acid-uptake inhibitor, in healthy subjects after single and multiple doses. Pharmacokinetics of tiagabine, a gamma-aminobutyric acid- uptake inhibitor, in healthy subjects after single and m ultiple doses. Drug concentrations in human brain tissue samples from epileptic patients treated with felbamate.
You can get an Acute Myocardial Infarct with fixed stenosis purchase zocor 40mg, but usually in a restricted subendocardial pattern purchase zocor 20mg without a prescription, when there are other factors that create an imbalance of myocardial oxygen supply and demand. Caused by acute changes in coronary artery atherosclerotic plaques: superficial erosion, ulceration, rupture, or hemorrhage, usually with superimposed thrombosis. Caused by combinations of changed plaque morphology, thrombus, and vasoconstriction leading to severe but transient reductions in blood flow. Usually are conveniently located where interventional cardiologist can reach them by catheter. The preexisting culprit lesion is often not a severely stenotic and hemodynamically significant lesion prior to its acute change (85% had initial stenosis < 70%). Subendocardial zone is defined as the inner half of the ventricular wall; the portion most poorly perfused. In cases of global hypotension, resulting subendocardial infarcts are usually circumferential. The location, severity, and rate of development of coronary atherosclerotic obstructions. Very sensitive but not specific (because it will also be elevated in skeletal muscle damage). TnT may be more sensitive than TnI because there may be a greater percentage of free TnT in cardiac myocytes. Critical abnormalities in cellular biochemistry and function of cardiomyocytes salvaged by reperfusion. Contractile Dysfunction: Common, Early, Proportional to size of infarct; 10% with cardiogenic shock. Many etiologies; Can also be from distortion of supporting structures rather than valve leaflets. They have have less thrombogenicity but have problems of structural valve deterioration D. Surgery is usually repair rather than replacement and often coupled with mitral valve surgery. Dystrophic calcification without significant lipid deposition or cellular proliferation, a process distinct from but with some features of atherosclerosis 3. Calcifications stiffen cusps and fill the sinuses of Valsalva, preventing full opening. Usually cause is unknown, but associated with collagen disorders: Marfan, Ehler-Danlos, and osteogenesis imperfecta. Microscopic: Myxomatous degeneration (weakened collagen with replacement by acid mucopolysaccharide) L. Heart, skin, brain) autoimmune reaction a few weeks after Group A Strep pharyngitis (usually 5-14 yo) 3. Commissures fuse, the chordae tendineae fuse and shorten, the valvular cusps become rigid. Later degenerative changes may be a nonspecific process: Initial deformity -> further chronic injury. Subacute bacterial endocarditis due to less virulent organisms, usually attacking a deformed valve. Cardiac: 1) Previously deformed valves 2) Prosthetic valves 3) Open heart surgery b. Valve vegetations (composed of thrombus, organisms and leukocytes) can be a source for septic emboli to many organs. Non-bacterial thrombotic “marantic” endocarditis: sterile non-destructive thrombi in debilitated patients d. Anorectic drugs, particularly in combination (Fen-Phen) Fenfluramines augment serotonergic activity; phentermine interferes with the pulmonary clearance of serotonin. Valvular sclerosis associated with carcinoid tumors that produce bioactive molecules, such as serotonin and bradykinin. Affects the endocardium downstream from the tumor; then cleared by monoamine oxidase present in microvasculature 3. The kidney may be divided into 2 layers: an outer layer called the cortex and an inner layer called the medulla. These layers are like the rings of a tree since one layer wraps around the other layer. One can consider the kidney as a pie, which is divided into slices, which are called lobes. There are 10 to 18 lobes and each lobe contains a medullary pyramid, which serves as the drainage for the kidneys, to the ureters. In the medulla, the lobes are easily separated but in the cortex distinct lobes are difficulty to see. The circulation of the kidney is critical to its role as a fundamental excretory organ. The kidney is heavily perfused, receiving approximately 20-25% of the cardiac output.
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