By J. Muntasir. University of Texas Health Center at Tyler.
This section describes a number of such tissues and cheap 2mg prandin free shipping, in some cases generic prandin 0.5 mg with visa, how the tissues inter- act with the rest of the body to coordinate their functions generic prandin 0.5mg visa. A The previous chapters of this text have focused primarily on insulin and glucagon as the major mediators for regulating metabolic pathways discount prandin 1 mg otc; however, a large number of other hormones also regulate the storage and utilization of metabolic fuels (see Chapter 43). These hormones primarily counteract the effects of insulin and are called counter-regulatory hormones. They include growth hormone; thyroid hormone; glucocorticoids, such as cortisol; small peptides, such as the somatostatins; and small molecules, such as the catecholamines. Growth hor- mone works, in part, by inducing the synthesis of the insulin-like growth factors. These hormones can exert their effects rapidly (through covalent modification of selected enzymes) or long-term (through alterations in the rate of synthesis of selected enzymes). The interplay of these hormones with insulin and glucagon is discussed, as are the synthesis, secretion, and conditions leading to secretion of each hormone. The proteins and cells in the blood form their own tissue system (see Chapter 44). All blood cells are derived from a common precursor, the stem cell, in the bone marrow. Different cytokine signals trigger differentiation of a particular blood cell lineage. For example, when there is a decreased supply of oxygen to the tissues, the kidney responds by releasing erythropoietin. This hormone specifically stimulates the production of red blood cells. The red blood cell has limited metabolic functions, owing to its lack of internal organelles. Its main function is to deliver oxygen to the tissues through the binding of oxygen to hemoglobin. When the number of red blood cells is reduced, an anemia is said to have developed. This can be attributable to many causes, including nutri- tional deficiencies or mutations (hereditary anemias). The morphology of the red blood cell can sometimes aid in distinguishing between the various types of anemia. Red blood cell metabolism is geared toward preserving the ability of these cells to transport oxygen, as well as to regulate oxygen binding to hemoglobin. Glycol- ysis provides energy and NADH to protect the oxidation state of the heme-bound iron. The hexose monophosphate shunt pathway generates NADPH to protect red blood cell membranes from oxidation. Heme synthesis, which uses succinyl CoA and glycine for all of the carbon and nitrogen atoms in the structure, occurs in the precursors of red blood cells. Inherited defects in heme synthesis lead to a class of diseases known as the porphyrias. Because the red blood cell normally passes through the very narrow capillaries, its membrane must be easily deformable. This deformability is, in part, attributable to the complex cytoskeletal structure that sur- rounds the erythrocyte. Mutations in these structural proteins can lead to less deformable cells. Among other functions, the hematologic system is responsible for hemostasis as well as for maintaining a constant blood volume (see Chapter 45). A tear in the wall 781 of a vessel can lead to blood loss, which, when extensive, can be fatal.
One weekend he became unusually irritable and confused after drinking two fifths of scotch and eating very little prandin 0.5mg online. Physical exam- ination indicated a heart rate of 104 beats/min cheap prandin 1 mg amex. His blood pressure was slightly low generic 2 mg prandin with visa, and he was in early congestive heart failure purchase prandin 1 mg without prescription. THE ENZYME-CATALYZED REACTION S CH3O P SCHCOOC2H5 Enzymes, in general, provide speed, specificity, and regulatory control to reactions CH3O in the body. Enzymes are usually proteins that act as catalysts, compounds that CH2COOC2H5 increase the rate of chemical reactions. Enzyme-catalyzed reactions have three Malathion basic steps: (1) binding of substrate: E S 4 ES O (2) conversion of bound substrate to bound product: ES 4 EP CH3 (3) release of product : EP 4 E P CH3 P CH3 F An enzyme binds the substrates of the reaction it catalyzes and brings them Sarin together at the right orientation to react. The enzyme then participates in the mak- ing and breaking of bonds required for product formation, releases the products, and Fig. Malathion and parathion are organophospho- Enzymes do not invent new reactions; they simply make reactions occur faster. Nausea, coma, convulsions, The catalytic power of an enzyme (the rate of the catalyzed reaction divided by the respiratory failure, and death have resulted 6 14 rate of the uncatalyzed reaction) is usually in the range of 10 to 10. Without the from the use of parathion by farmers who have catalytic power of enzymes, reactions such as those involved in nerve conduction, gotten it on their skin. Malathion is similar in structure to parathion, but not nearly as toxic. The nerve gas Sarin, another organophospho- Each enzyme usually catalyzes a specific biochemical reaction. The ability of an rus compound, was used in a terrorist attack in enzyme to select just one substrate and distinguish this substrate from a group of a Japanese subway. The enzyme converts CHAPTER 8 / ENZYMES AS CATALYSTS 117 this substrate to just one product. The specificity, as well as the speed, of enzyme- CH2OH catalyzed reactions result from the unique sequence of specific amino acids that O H form the three-dimensional structure of the enzyme. The Active Site H OH To catalyze a chemical reaction, the enzyme forms an enzyme–substrate complex in glucokinase ATP its active catalytic site (Fig. The active site is usually a cleft or crevice in the or enzyme formed by one or more regions of the polypeptide chain. Within the active ATP: D–glucose– 6–phosphotransferase ADP site, cofactors and functional groups from the polypeptide chain participate in trans- forming the bound substrate molecules into products. CH2O P Initially, the substrate molecules bind to their substrate binding sites, also called O the substrate recognition sites (see Fig. The three-dimensional arrangement H of binding sites in a crevice of the enzyme allows the reacting portions of the sub- strates to approach each other from the appropriate angles. The proximity of the HO OH H OH bound substrate molecules and their precise orientation toward each other con- H OH tribute to the catalytic power of the enzyme. The active site also contains functional groups that directly participate in the Fig. Reaction catalyzed by glucokinase, reaction (see Fig. The functional groups are donated by the polypeptide an example of enzyme reaction specificity. As the substrate binds, it induces conformational changes in the enzyme phate from ATP to carbon 6 of glucose. It can- not rapidly transfer a phosphate from other that promote further interactions between the substrate molecules and the nucleotides to glucose, or from ATP to closely enzyme functional groups. Additional bonds with the enzyme stabilize the transition state complex and decrease the energy required for its formation.
The soft clot is then subsequently cross-linked by another enzyme order 1 mg prandin with amex. Thrombin itself is a potent activator of platelets purchase 2mg prandin, through binding of aggregated platelets prandin 1 mg otc. The microthrombi to a specific receptor on the platelet surface order prandin 1 mg line. The Blood Coagulation Cascade lium, exposing collagen and releasing high- Thrombus (clot) formation is enhanced by thrombin activation, which is mediated by molecular-weight vWF, promoting more the complex interaction that constitutes the blood coagulation cascade. All of these proteins are present in the plasma as pro- Familial TTP is associated with mutations proteins (zymogens). These precursor proteins are activated by cleavage of the in the vWF-specific metalloprotease, although polypeptide chain at one or more sites. The key to successful and appropriate throm- not all individuals with defective protease bus formation is the regulation of the proteases that activate these zymogens. Sporadic cases of TTP are asso- The proenzymes (Factors VII, XI, IX, X, XII, and prothrombin) are serine pro- ciated with the development of an antibody to teases that, when activated by cleavage, cleave the next proenzyme in the cascade. Because of the sequential activation, a great acceleration and amplification of the response is achieved. That cleavage and activation have occurred is indicated by the addition of an “a” to the name of the proenzyme (e. In response to collagen and throm- The cofactor proteins (tissue factor, Factors V and VIII) serve as binding sites for bin, platelets release vasoconstric- other factors. Tissue factor is not related structurally to the other blood coagulation tors. Serotonin is released from the dense granules of the platelets, and the syn- cofactors and is an integral membrane protein that does not require cleavage for thesis of thromboxane A2 is stimulated. Factors V and VIII serve as procofactors, which, when activated by will reduce blood flow to the damaged area. Platelet-derived growth factor, which stimu- Two additional proteins that are considered part of the blood coagulation cas- lates proliferation of vascular cells, is also cade, protein S and protein C, are regulatory proteins. Only protein C is regulated released into the environment surrounding by proteolytic cleavage, and when activated, is itself a serine protease. The Process of Blood Coagulation Activation of the blood coagulation cascade is triggered by the reaction of plasma The utilization of an active site ser- proteins with the subendothelium at the same time that platelets are adhering to the ine to cleave a peptide bond is subendothelial layer. Historically, two different pathways were discovered, one common to a variety of enzymes dependent on external stimuli (such as blunt trauma, which initiates the extrinsic referred to as serine proteases. Serine pro- pathway) and one using internal stimuli (the intrinsic pathway). As our understand- teases are essential for activating the forma- ing of blood clotting has expanded, it has become obvious that these distinctions are tion of a blood clot from fibrin. Fibrin and no longer correct, because there is overlap between the pathways, but the terms have many of the other proteins involved in blood persisted in the description of the pathways. Thrombin, the serine protease that converts fibrinogen culating Factor VII binds to tissue factor, which autocatalyzes its own activation to to fibrin, has the same aspartate-histidine- Factor VIIa. Factor VIIa then activates Factor X (to Xa) in the extrinsic pathway and serine catalytic triad found in chymotrypsin Factor IX (to IXa) in the intrinsic pathway. Factor IXa, as part of the intrinsic path- and trypsin. Therefore, activation of both the extrinsic and intrin- Thrombin is activated by proteolytic sic pathways result in the conversion of Factor X to Factor Xa. All of these conver- cleavage of its precursor protein, prothrom- sions require access to membranes and calcium; the platelet membrane, which had bin. The sequence of proteolytic cleavages adhered to the damaged site, is used as a scaffold for the activation reactions to leading to thrombin activation requires Fac- occur. The -carboxylated clotting proteins are chelated to membrane surfaces via tor VIII, the blood-clotting protein deficient in electrostatic interactions with calcium and negatively charged phospholipids of the Sloe Klotter. The protein cofactors VIIIa and Va serve as sites for assembling enzyme–cofactor complexes on the platelet surface, thereby accelerating and local- izing the reaction.
Recommended doses vary by practitioner generic 0.5 mg prandin with visa, but one rule is to start with a low dose and increase slowly and conservatively (Table 1) order 2 mg prandin amex. Maximum dosing is limited by the side effect profile of these medications cheap prandin 2mg. T om on A nti ch oli nerg i cs U sed i n Par i nson’ s D i sease M axi m um dose per N am e ech ani sm s Preparati ons I ni ti aldose scalati on sch edule day om ents P rim a ry a n ticho li ergics Tri h exyph eni dyl entral g tabs cheap prandin 2mg without prescription; g / g qd- bi d I ncrease to ti d; ev ery –3 g ti d i rstsynth eti c ( A rtane) ant uscari ni c leli xi r –4 days i ncrease anti ch oli nerg i cs by 1 g each dose B enztropi ne entral g tablets; g bi d I ncrease to ti d; ev ery g ti d lso av ai lable ( C og enti n) ant uscari ni c i nj ecti on 1 g / m –4 days i ncrease parenterally by 1 g each dose B lperi den entral g tablets & g / g bi d I ncrease to ti d; ev ery g ti d lso av ai lable ( A i neton) ant uscari ni c am pules –4 days i ncrease parenterally by 1 g each dose E th opropazi ne entral g tablets g ti d/ qi d I ncrease to ti d; ev ery g ti d- qi d pprov ed by F ( Parsi dol Parsi tan) ant uscari ni c –4 days i ncrease notav ai lable i n by 1 g each. Clinical Uses Since the advent of specific dopaminergic therapy for PD in the 1960s, the usefulness and popularity of anticholinergics waned dramatically. However, they are still used among many clinicians in certain situations. Tremor Predominant Parkinson’s Disease The most recognized use of this class of medication is to treat tremor in early- or young-onset PD representing a levodopa-sparing strategy. In general, it appears that anticholinergics help tremor but do not significantly affect other akinetic or rigid features of PD. Original AAN practice parameters in 1993 stated that there was a common use for anticholinergic agents for initial therapy of tremor predominant PD, but concluded on the basis of class II evidence* that anticholinergics are probably no better than levodopa for tremor. Although anti- cholinergics do not appear to have significant effects on akinesia and rigidity as therapy, deterioration of all parkinsonian symptoms has been described following abrupt withdrawal (59). Anticholinergics are useful in the early treatment of tremor predominant PD in young or mild patients if the primary indication for symptomatic therapy is tremor, and there are relatively minimal associated signs of rigidity or bradykinesia. Anticholinergics can also offer a useful adjunctive option if additional tremor relief beyond the patient’s existing antiparkinsonian regimen is needed. Anticholinergics should be avoided in patients with baseline cognitive deficits, significant orthostatic hypotension, or urinary retention as these patients are at higher risk for exacerbation of these symptoms. For similar reasons, anticholinergics are reserved for rare use in elderly PD patients. Parkinson’s Disease–Associated Dystonia Dystonia can occur in association with PD. Anticholinergics can play an adjunctive role in managing such dystonia. Most PD-associated dystonia occurs in the context of motor complications, but it can occur even in Evidence provided by one or more well-designed clinical studies such as case control, cohort studies, and so forth (57). The AAN 1993 practice parameters summary statement has since been revised (19). Most commonly, an ‘‘off’’ dystonia characteristi- cally causes painful foot and toe posturing when dopaminergic medication wears off in the morning. Levodopa-induced ‘‘on’’ dystonias can follow either biphasic or peak-dose patterns. However, limb dystonia as an early symptom in levodopa- naive patients tended not to respond as well compared to dystonia associated with motor fluctuations. Miscellaneous Considerations Often anticholinergic agents can be used to treat miscellaneous indications. In this setting, agents are often chosen on the basis of secondary anticholinergic side effects. For example, if antidepressants are needed, a tricyclic antidepressant such as amitriptyline might be chosen for its anticholinergic properties to assist with insomnia or PD-related tremor. Diphenydramine (Benadryl) is an antihistamine commonly prescribed for allergies or insomnia and possesses mild anticholinergic side effects that can be used for PD-associated sialorrhea and may help reduce tremor. Another class of medications commonly used in PD is the atypical antipsychotics. Clozapine, in particular, has significant anticholinergic- attributed sedation, but also can reduce tremor (62) and produce paradoxical increased salivation and drooling. Amantadine, discussed earlier in this chapter, shows modest anticholinergic properties, although its antiparkinsonian use is commonly chosen on its own merits (63). A partial list of commonly used medications with either primary or secondary anticholinergic properties and their use is shown in Table 1. Side Effects Side effects of anticholinergic agents are a significant clinical concern, which can limit their usefulness in the treatment of PD symptoms.
Clinical rating scales are extremely useful generic 1mg prandin fast delivery, but ratings may be investigator dependent and are frequently confounded by changes in symptomatic treatment best 2mg prandin. Pathological studies investigating rate of progression have been limited and rely entirely on cross-sectional data (62 order 2mg prandin otc,63) order prandin 2 mg visa. These studies have in general considered patients with severe illness of long duration. In vivo imaging studies provide the opportunity to evaluate patients longitudinally from early to late disease using an objective biomarker for dopaminergic degeneration. In several studies neuroreceptor imaging of the nigrostriatal dopami- nergic system has been used as a research tool to monitor progressive dopaminergic neuron loss in PD. In longitudinal studies of PD progression 18 both F-DOPA and DAT imaging [b-CIT(2b-carboxymethoxy-3b(4- iodophenyl)tropane) and CFT] using both PET and SPECT have 18 18 demonstrated an annualized rate of reduction in striatal F-DOPA, F- 123 CFT, or [ I]b-CIT uptake of about 6–13% in PD patients compared with 0–2. Similar findings have been reported for VMAT2 imaging (K. Evidence from studies of hemi-PD subjects provide further insight into the rate of progression of disease. In early hemi-PD there is a reduction in 18 F-DOPA and DAT uptake of about 50% in the affected putamen and of 25–30% in the unaffected putamen. Since most patients will progress clinically from unilateral to bilateral in 3–6 years, it is therefore likely that the loss of these in vivo imaging markers of dopaminergic degeneration in the previously unaffected putamen will progress at about 5–10% per annum (11,65). Imaging has also been used to monitor progression of PD in patients receiving fetal substantia nigral transplants for PD. Several studies during 18 the past several years show an increase in F-DOPA uptake with follow-up 18 of 6 months to 6 years posttransplant (90,91). The change in F-DOPA Copyright 2003 by Marcel Dekker, Inc. Note the 123 asymmetric reduction in [ I]b-CIT uptake more marked in the putamen than caudate in the patient and the progressive loss of activity. Levels of SPECTactivity are color-encoded from low (black) to high (yellow/white). The most important role of longitudinal imaging studies is to provide a tool to assess objectively potential neuroprotective and restorative therapies for PD. Imaging studies assessing progression of disease have provided data to estimate sample sizes required to detect slowing of disease progression due to study drug treatment. The sample size required depends on the effect of the disease-modifying drug and the duration of exposure to the drug. The effect of the drug is generally expressed as the percent reduction in rate of loss of the imaging marker in the group treated with the study drug versus a control group. More specifically, imaging studies have 18 sought a reduction of between 25 and 50% in the rate of loss of F-DOPA 123 or [ I]b-CIT uptake (i. The sample size needed to detect a 25–50% reduction in the rate of loss of F- DOPA or b-CIT uptake during a 24-month interval ranges from approximately 30 to 120 research subjects in each study arm (85,93). These data support the use of dopamine neuroreceptor imaging to assess the effects of potential neuroprotective drugs in PD, but there are several caveats in the study design and interpretation of these studies. It must be acknowledged that imaging outcomes in studies of PD patients are biomarkers for brain activity, but are not true surrogates for drug effects in PD patients (94). These investiga- tional drugs may have effects on dopamine neurons unrelated to slowed neuronal degeneration and may have effects outside the dopaminergic system. The rate of change in imaging outcomes used to measure disease progression is slow, reflecting the slow clinical progression in PD and requiring the duration of these progression studies to be at least 18–24 months. In a recent study evaluating potential disease modifying effects of Neuroimmunophilin A, the study duration of 6 months resulted in an equivocal outcome necessitating a second, longer study to clarify the drug effects (95). Progressive loss in brain dopaminergic imaging activity also occurs in aging healthy individuals, though at a rate approxi- mately one-tenth that of PD patients (13,29). The reliability of the imaging outcomes must be assessed. Recent test-retest studies using current technology and analyses metho- dology show good test-retest reproducibility of approximately 3– 18 5% for F-DOPA or VMAT2 studies and 5–7% for b-CIT SPECT (95–97).