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When valproic acid dose is increased generic 400mg norfloxacin with mastercard bacteria in the stomach, the unbound fraction increases and causes an increase in hepatic clearance buy norfloxacin 400mg overnight delivery killer virus. Because both dose and hepatic clearance simultaneously increase order 400 mg norfloxacin visa treatment for dogs dermatitis, total valproic acid con- centrations increase 400mg norfloxacin with visa antibiotic resistance news, but by a smaller than expected amount. For example, valproic acid follows concentration-dependent plasma protein binding pharmacokinetics with average unbound fractions of 5% in the lower end of the therapeutic range (50 μg/mL) and 10% in the upper end of the therapeutic range (100 μg/mL). Unfortunately, there is so much interpatient variability in concentration-dependent plasma protein binding parame- ters for valproic acid that predicting changes in unbound fraction and hepatic clearance is extremely difficult. However, since unbound steady-state concentrations are only influ- enced by intrinsic clearance, unbound concentrations increase in a proportional amount to dose: Css, u = [F(D/τ)] / Cl′int. Half-life (t1/2) is related to clearance and volume of distribution using the same equation as for linear pharmacokinetics: t1/2 = (0. However, since clearance and volume of distribution are a function of dose- or concentration-dependent plasma protein binding for valproic acid, half-life also changes with drug dosage or concentration changes. As doses or concentrations increase for a drug that follows concentration-dependent plasma protein binding pharmacokinet- ics, clearance and volume of distribution simultaneously increase, and half-life changes are variable depending on the relative changes in clearance and volume of distribution: ↔t1/2 = (0. The clinical implication of this finding is that the time to steady state (3–5 t1/2) is variable as the dose or concentration is increased for valproic acid. On average, valproic acid half-life is 12–18 hours in adult patients with total concentrations within the therapeutic range. Valproic acid is available as three different entities, and all of them are prescribed as val- proic acid equivalents: valproic acid, sodium valproate (the sodium salt of valproic acid), and divalproex sodium (a stable coordination compound consisting of a 1:1 ratio of valproic acid and sodium valproate). When given intravenously, it should be diluted in at least 50 mL of intravenous solution, and given over 1 hour (injection rates should not exceed 20 mg/min). For oral use, a syrup (50 mg/mL), soft capsule (250 mg), enteric coated capsules (125 mg, 250 mg, and 500 mg), sustained-release tablets (250 mg and 500 mg) and sprinkle capsule (125 mg, used to sprinkle into foods) are available. The enteric coated capsules are not sustained- release products, but only delay the absorption of drug after ingestion. The oral bioavailability of valproic acid is very good for all dosage forms and ranges from 90% for the sustained-release tablets to 100% for the other oral dosage forms. Usually, val- proic acid doses are not fine-tuned to the point of directly accounting for the difference in valproic acid bioavailability. Rather, clinicians are aware that when valproic acid dosage forms are changed, the serum concentration versus time profile may change. Because of this, most individuals recheck valproic acid steady-state serum concentrations after a dosage form change is instituted. The typical maintenance dose for valproic acid is 15 mg/kg/d resulting in 1000 mg or 500 mg twice daily for most adult patients. Similarly, if children receive therapy with other antiepileptic drugs that are enzyme inducers, clearance is 20–30 mL/h/kg and half-life is 4–6 h. The volume of distribution may be larger because of reduced plasma protein binding (free fraction ≈29%). Protein binding may be reduced and unbound fraction may be increased owing to hypoalbuminemia and/or hyper- bilirubinemia (especially albumin ≤3 g/dL and/or total bilirubin ≥2 mg/dL). However, the effects that liver dis- ease has on valproic acid pharmacokinetics are highly variable and difficult to accurately pre- dict. It is possible for a patient with liver disease to have relatively normal or grossly abnormal valproic acid clearance and volume of distribution. For example, a liver disease patient who has relatively normal albumin and bilirubin concentrations can have a normal volume of dis- tribution for valproic acid. An index of liver dysfunction can be gained by applying the Child- Pugh clinical classification system to the patient (Table 12-3). The Child-Pugh score consists of five laboratory tests or clinical symptoms: serum albumin, total bilirubin, pro- thrombin time, ascites, and hepatic encephalopathy. Each of these areas is given a score of 1 (normal) to 3 (severely abnormal; Table 12-3), and the scores for the five areas are summed. The Child-Pugh score for a patient with normal liver function is 5 while the score for a patient with grossly abnormal serum albumin, total bilirubin, and prothrombin time values in addition to severe ascites and hepatic encephalopathy is 15. A Child-Pugh score greater than 8 is grounds for a decrease of 25–50% in the initial daily drug dose for valproic acid. As in any patient with or without liver dysfunction, initial doses are meant as starting points for dosage titration based on patient response and avoidance of adverse effects. Since the drug has been associated with hepatic damage, valproic acid therapy should be avoided in patients with liver disease whenever possible. Valproic acid serum concentrations and the presence of adverse drug effects should be monitored frequently in patients with liver cirrhosis. Elderly patients have lower valproic acid oral clearance rates and higher unbound frac- tions than younger adults so lower initial doses may be used in older individuals. Val- proic acid therapy also decreases the clearance and increases steady-state concentrations of other drugs including zidovudine, amitriptyline, and nortriptyline. As a general rule, when valproic acid is added to a patient’s drug regimen, an adverse effect from one of the other drugs must be considered as a possible drug interaction with valproic acid. Cime- tidine, chlorpromazine, and felbamate are examples of drugs that decrease valproic acid clearance and increase valproic acid steady-state concentrations. Because valproic acid is highly protein bound, plasma protein binding drug interactions can occur with other drugs that are highly bound to albumin. The drug interaction between valproic acid and phenytoin deserves special examination because of its complexity and because these two agents are regularly used together for the treatment of seizures. What makes this interaction so difficult to detect and understand is that these two changes do not occur simultaneously, so the impression left by the drug interaction depends on when in time it is observed in a patient. For example, a patient is stabilized on phenytoin therapy (Figure 12-3), but because adequate control of seizures has not been attained, valproic acid is added to the reg- imen. As valproic acid concentrations accumulate, the first interaction observed is pheny- toin plasma protein binding as the two drugs compete for binding sites on albumin. The result of this portion of the drug interaction is an increase in phenytoin unbound fraction and a decrease in phenytoin total serum concentration, but the unbound phenytoin serum concentration remains the same. As valproic acid serum concentrations achieve steady-state conditions, the higher concentrations of the drug bathe the hepatic microsomal enzyme sys- tem and inhibit the intrinsic clearance of phenytoin. This portion of the interaction decreases intrinsic clearance and hepatic clearance for phenytoin, so both unbound and total phenytoin concentrations increase. Initially, valproic acid decreases phenytoin plasma protein binding via competitive displacement for binding sites on albumin (arrow denotes ↑fB). As valproic acid con- centrations increase, the hepatic enzyme inhibition component of the drug interaction comes into play (arrow denotes ↓Cl′int). The net result is total phenytoin concentrations are largely unchanged from baseline, but unbound phenytoin concentrations and pharmacologic effect increase.
O2 demand is lowered macologically buy norfloxacin 400 mg free shipping bacteria that causes tuberculosis, the less common coronary by β-blockers and calcium-antagonists buy discount norfloxacin 400 mg on line bacteria in florida waters, as spasm can be relieved by appropriate va- well as by nitrates (p generic norfloxacin 400 mg visa antibiotic names starting with a. Arteriolar caliber is determined by myocardial O2 tension and local concen- trations of metabolic products buy 400mg norfloxacin infection questionnaires, and is “au- tomatically” adjusted to the required blood flow (B,healthysubject). Thismet- abolic autoregulation explains why angi- nal attacks in coronary sclerosis occur on- ly during exercise (B, patient). At rest, the pathologically elevated flow resistance is Luellmann, Color Atlas of Pharmacology © 2005 Thieme Angina Pectoris 317 A. O2supply and demand of the myocardium O2-supply O -demand during 2 during diastole systole Flow resistance: Left atrium 1. Pathogenesis of exertion angina in coronary sclerosis Healthy subject Patient with coronary sclerosis Rest Compensa- tory dilatation of arterioles Narrow Wide Rate Contraction velocity Afterload Exercise Additional dilatation not possible Wide Wide Angina pectoris Luellmann, Color Atlas of Pharmacology © 2005 Thieme 318 Therapy of Selected Diseases tion within 1–2 minutes; duration of effect Antianginal Drugs ~30 minutes). Organic nitrates (A) increase blood flow, For sustained daytime angina pro- hence O2 supply, because diastolic wall ten- phylaxis, nitrates are of limited value be- sion(preload)declinesasvenousreturnto cause “nitrate pauses” of about 12 hours the heart is diminished. Thus, the nitrates areappropriateifnitratetoleranceistobe enable myocardial flow resistance to be re- avoided. In angina due to trate,m aybegiveninthem orningandat coronary spasm, arterial dilation overcomes noon (e. Continuous delivery via a that determine systolic wall tension (after- transdermal patch would also not seem ad- load): ventricular filling volume and aortic visablebecauseofthepotentialdevelop- blood pressure. With molsidomine,there Calcium antagonists (B)decreaseO2 de- is less risk of a nitrate tolerance; however, its mand by lowering aortic pressure, one of the clinical use is restricted owing to its poten- components contributing to afterload. Since vasodilating β2-receptors insuf ciency can dangerously jeopardize are blocked, an increased risk of vasospasm heart function. Therefore, monotherapy antagonists can induce spasmolysis and im- with β-blockers is recommended only in an- prove blood flow. For relief of the acute anginal attack, rapidly absorbed drugs devoid of cardiodepressant activityare preferred. Effects of nitrates p Diastole Systole p Vol Vol Resistance vessels Venous capacitance Preload Afterload vessels Nitrate tolerance O2-demand O2-supply Relaxation of Vasorelaxation coronary spasm Nitrates, e. Effects ofβ-blockers p Rest Ca- antagonists Sympathetic system Relaxation of resistance vessels β-Blocker Afterload Rate Contraction velocity Relaxation of O -demand coronary spasm 2 Exercise D. As dilatation of the vascular off from its blood supply dies within a short stenosis by the heart catheter liberates many time owing to the lack of O2and glucose. The thrombogenic mediators, platelet aggrega- loss in functional muscle tissue results in tion must be prevented by administration reduced cardiac performance. The patient experiences severe a cardiac center in time, fibrinolytic treat- pain, a feeling of annihilation, and fear of ment of the coronary thrombus is instituted. At this site, the clot- associated with an increased risk of bleed- ting cascade is activated and the resultant ing; cerebral hemorrhages are of particular thrombus occludes the lumen. When blood pressure teries into smaller branches to produce a and heart rate have stabilized, a β-blocker blockage there. Infu- certained, unstable angina pectoris is sion of lidocaine is required to counter the present, which is initially treated with anti- threat of arrhythmias. When car- control of diabetes mellitus, and physical diomyocytes die, contractile proteins (tropo- exercise (a dog that loves to run is an ideal nin) or myocardial enzymes (creatine kinase, training partner). Myocardial infarction: pharmacotherapeutic approaches Acute symptoms: Acute care measures severe pain – Nitroglycerin (reduction of sense of impending pre- and afterload) doom – Acetylsalicylic acid Patient fear of dying (if needed i. In chronic congestive heart failure, cardiac Since bisoprolol, metoprolol, and carvedilol pump performance falls below a level re- have proved effective in large clinical trials, quired by the body’s organs for maintaining these β-blockers would be the preferred function and metabolism. Ankle edemas, enlarged liver, and compensatory mechanisms improve the ascites signal congestion in front of the right clinical state of patients (less hospitalization) ventricle. Increased release of norepinephrine Drugswithanacutepositiveinotropicac- raises cardiac rate and evokes peripheral tion (e. These compensations increase car- diac afterload and plasma volume is ex- panded because the kidney retains water and sodium. Suc- cessful therapy of chronic congestive failure is therefore contingent on inhibition of compensation mechanisms. Although β-blockers were formerly held to be contraindicated, this drug class has been used successfully since the mid-1990s in the management of heart failure. Every 2–3 weeks, the daily dose Luellmann, Color Atlas of Pharmacology © 2005 Thieme Congestive Heart Failure 323 A. A change from the recumbent to The venous side of the circulation accom- the erect position (orthostasis) will cause modates ~85% of the total blood volume; blood within the low-pressure system to because of the low venous pressure (mean sink toward the feet because the veins in ~15 mmHg), it is referred to as the low-pres- body parts below the heart will be dis- sure system. The arterial vascular beds, rep- tended, despite a reflex venoconstriction, resenting the high-pressure system (mean by the weight of the column of blood in the pressure ~100 mmHg), contain ~15%. The fall in stroke volume is arterial pressure generates the driving force partly compensated by a rise in heart rate. Blood The remaining reduction of cardiac output draining from these collects in the low-pres- can be countered by elevating the peripheral sure systemand is pumped back by the heart resistance, enabling blood pressure and or- into the high-pressure system. In sponding to the product of stroke volume the sympathotonic form,sym patetically- and heart rate (beats/min), stroke volume mediated circulatory reflexes are intensified being determined by, inter alia, venous fill- (more pronounced tachycardia and rise in ing pressure; (2) the counterforce opposing peripheral resistance, i. Primary idiopathic hypoten- cardiovascular fitness training would appear sion generally has no clinical importance. Increas- occur, a program of physical exercise instead ing NaCl intake augments salt and fluid re- ofdrugsisadvisable. In the very rare asympathotonic form, owing to insuf cient blood volume, plasma use of sympathomimetics would certainly be substitutes will be helpful in treating blood reasonable. Treatment of hypotension Low-pressure High-pressure system system Brain Lung β-Sympathomimetics Cardiac Parasym- glycosides patholytics Venous return Stroke vol. Chronic lowering of urate levels below Gout 6 mg/l blood requires (a) an appropriate Gout is an inherited metabolic disease that diet that avoids purine (cell nuclei)-rich results from hyperuricemia, an elevation in foods (e. Apart from infrequent and phagocytose (2) this indigestible mate- allergic reactions, it is well tolerated and is rial. Macrophages attacks may occur at the start of therapy but also phagocytose the crystals, injure them- they can be prevented by concurrent admin- selves, and liberate lysosomal enzymes that istration of colchicine (0. As a result, an acute and very painful bromarone (100 mg/day), promote renal gout attack may develop (4). They saturate the or- The therapy of gout is twofold: (1) treat- ganic acid transport system in the proximal ment of the acute attack; and (2) chronic renal tubules, making it unavailable for urate lowering of hyperuricemia. The acute attack demands prompt action it only the acid secretory system, whichhasa to relieve the patient from his painful smaller transport capacity. The classical remedy (already used is then inhibited and a gout attack is possi- by Hippocrates) is colchicine,analkaloid ble. In patients with urate stones in the uri- from the autumn crocus (Colchicum au- nary tract, uricosurics are contraindicated.
