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The direc- creted into the urine and H CO is reabsorbed cheap 50mg voltaren with amex uric acid arthritis diet, while 3 244 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Urine Blood Na by thick ascending lim bs generic 100mg voltaren with amex arthritis medication that was recalled. Thus, in the absence of principal cell A D H, Na reabsorption contributes to m edullary inter- Na stitial hypertonicity, water abstraction from the collect- Na (filled circle) ing ducts, and the form ation of concentrated urine. K D iuretics blocking Na reabsorption by thick ascending K lim bs will therefore attenuate the form ation of dilute K urine (C ) in hypotonic states when A D H is absent or K H 2O low. Conversely, in hypertonic conditions, when A D H levels are high and diuretics are blocking Na reabsorp- intercalated cell tion by the thick ascending lim bs, the generation of con- K centrated urine is reduced, and Cosm is greater than CH 2O. For example, by in- K CO2 H2O creasing cardiac output in the patient with congestive heart failure, digitalis administration will mobilize edema fluid and diuresis. Na a therapeutic point of view, diuretics are considered to be entry across apical cell membranes is mediated by a Na substances that aid in removing excess extracellular fluid channel. In the main, they accomplish this by de- effected by the Na /K -ATPase, shown by the filled circle in creasing salt and water reabsorption in the tubules. K Carbonic Anhydrase Inhibitors 3 entry and H secretion are mediated by an H /K ATPase, In the late 1930s, it was reported that sulfanilam ide and which is shown by the filled circle in the apical cell membrane of the intercalated cell. It was soon realized that these com pounds inhibited carbonic anhydrase, an little net K transport occurs under K -replete condi- enzym e highly concentrated in renal tissue, and that this tions. This is relevant to the action of anhydrase inhibitors is an unsubstituted sulfonam ide spironolactone, a diuretic that is a com petitive inhibitor m oiety. It is also pertinent be- com pounds capable of inhibiting carbonic anhydrase, cause adm inistration of diuretics can cause secondary the m ost useful of which was acetazolam ide (D iam ox), hyperaldosteronism, which m ay exaggerate the potas- which is considered the prototype of this class of di- sium wasting that is a consequence of the increased de- uretics. A lthough the clinical use of carbonic anhydrase livery of Na and enhanced flow through distal convo- inhibitors has greatly dim inished since the 1960s, when luted tubules and collecting ducts. In the absence of vitally im portant in helping to delineate the physiologi- A D H, the collecting ducts are essentially im perm eable cal role of carbonic anhydrase in electrolyte conserva- to water. In other words, the clear- dichlorphenam ide (D aranide), and m ethazolam ide ance of solute-free water (CH 2O ) is greater than the os- (Neptazane) are the carbonic anhydrase inhibitors m olar clearance (Cosm ). The driving force for water trans- anhydrase decreases bicarbonate reabsorption, and this port is the osm otic gradient between the m edullary in- accounts for their diuretic effect. NaCl and urea are the anhydrase inhibitors affect both distal tubule and col- two m ajor solutes accounting for the hypertonicity. The lecting duct H secretion by inhibiting intracellular car- NaCl in the interstitium results from the reabsorption of bonic anhydrase. The fractional excretion of Na is The thiazidelike com pounds, including chlorthali- generally lim ited to 5%, as a consequence of down- done (H ygroton), quinethazone (H ydrom ox), and stream com pensatory Na reabsorption. A lthough dis- m etolazone (Zaroxolyn) have sim ilar m echanism s of tal nephron sites recapture m uch of the Na, they pos- action, but they differ substantially from one another in sess only a lim ited ability to absorb H CO. Fractional their duration of action, the degree of carbonic anhy- 3 K excretion, however, can be as m uch as 70%. The form ation of alkaline urine and to m etabolic acidosis as Na –Cl cotransport takes place on the lum inal surface a result of both H CO 3 loss and im paired H secretion. Thus, to exert their diuretic The m ain therapeutic use of carbonic anhydrase in- action, the thiazides m ust reach the lum inal fluid. Since hibitors is not for the production of diuresis but in the the thiazide diuretics are largely bound to plasm a pro- treatm ent of glaucom a. This is true especially of the top- teins and therefore are not readily filtered across the ically applied com pound dorzolam ide (Trusopt). The pends on carbonic anhydrase, acetazolam ide has proved drugs then travel along the nephron, presum ably being to be a useful adjunct to the usual therapy for lowering concentrated as fluid is abstracted, until they reach their intraocular pressure. O ral carbonic anhydrase inhibitors are iazide shows any appreciable carbonic anhydrase in- also useful in preventing or treating acute m ountain hibitory activity. A dverse reactions are m inor; they include loss of appetite, drowsiness, confusion, and tingling in the Renal Response extrem ities. A nim al studies have shown som e terato- genic potential, so the use of carbonic anhydrase in- W hen adm inistered at m axim al doses, chlorothiazide hibitors is not recom m ended during the first trim ester m arkedly increases excretion of Na,K,C l, and of pregnancy. M axim al diuresis m ay approach values as high 3 Thiazide Diuretics Thiazide diuretics consist of two distinct groups: those T A B L E 21. The lat- Generic Name Trade Names ter are called thiazidelike diuretics; they include metola- Bendroflum ethiazide Naturetin zone, xipamide, and indapamide. The major thiazide and Benzthiazide A quatag, Exna thiazidelike drugs available in the United States are Chlorothiazide D iuril bendroflumethiazide, benzthiazide, chlorothiazide, hy- H ydrochlorothiazide Esidrix, H ydroD IU RIL H ydroflum ethiazide Saluron, D iucardin drochlorothiazide, hydroflumethiazide, methyclothiazide, M ethyclothiazide Enduron,A quatensen polythiazide, and trichlormethiazide; and chlorthalidone, Polythiazide Renese indapamide, metolazone, and quinethazone, respectively. Trichlorm ethiazide Naqua, M etahydrin D espite the structural distinctions, the drugs share Chlorthalidone H ygroton the functional attribute of increasing sodium and chlo- Indapam ide Lozol M etolazone Zaroxolyn, D iulo ride excretion by inhibiting Na –Cl cotransport in dis- Q uinethazone H ydrom ox tal convoluted tubules.

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Does not reduce the effective- ness of cyclophosphamide plus cisplatin chemotherapy Amikacin (Amikin) COMMON USES: Serious infections caused by gram (−) bacteria and mycobacterial infections ACTIONS: Aminoglycoside antibiotic; inhibits protein synthesis DOSAGE: See also page 620 discount voltaren 50 mg with amex arthritis pain in feet and hands. Toxicity symptoms: Nausea and vomiting order voltaren 100 mg online rheumatoid arthritis fatal, irritability, tachycardia, ventricular arrhythmias, and seizures; follow serum levels carefully (as theophylline, see Table 22–7, pages 631–634); aminophylline is about 85% theophylline; erratic absorption with rectal doses Amiodarone (Cordarone) (Pacerone) COMMON USES: Recurrent VF or hemodynamically unstable VT ACTIONS: Class III antiarrhythmic DOSAGE: Adults. Maintenance: 600–800 mg/d PO for 1 mo, then 200–400 mg/d IV: 15 mg/min for 10 min, followed by 1 mg/min for 6 h, then a maintenance dose of 0. En- cephalopathy possible; obtain aluminum levels, especially in renal insufficiency. Alum soln often precipitates and occludes catheters Amoxapine (Asendin) COMMON USES: Depression and anxiety ACTIONS: Tricyclic antidepressant; reduces reuptake of serotonin and norepinephrine DOSAGE: Initially, 150 mg PO hs or 50 mg PO tid; ↑ to 300 mg/d SUPPLIED: Tabs 25, 50, 100, 150 mg NOTES: ↓ in elderly; taper slowly when discontinuing therapy Amoxicillin (Amoxil, Polymox, others) COMMON USES: Infections resulting from susceptible gram (+) bacteria (streptococci) and gram (−) bacteria (H. Topical: Apply bid–qid for 1–4 wk depending on in- 22 fection 22 Commonly Used Medications 497 SUPPLIED: Powder for inj 50 mg/vial, oral susp 100 mg/mL, cream, lotion, oint 3% NOTES: Monitor renal function; hypokalemia and hypomagnesemia possible from renal wasting; pretreatment with acetaminophen and antihistamines (Benadryl) help minimize adverse effects as- sociated with IV infusion Amphotericin B Cholesteryl (Amphotec) COMMON USES: Refractory invasive fungal infection in persons intolerant to conventional ampho- tericin B ACTIONS: Binds to sterols in the cell membrane, resulting in changes in membrane permeability DOSAGE: Adults & Peds. Infuse at a rate of 1 mg/kg/h SUPPLIED: Powder for inj 50 mg, 100 mg/vial NOTES: Do NOT use in-line filter, final concentration 0. If inf >2 h, manually mix contents of the bag Amphotericin B Liposomal (Ambisome) COMMON USES: Refractory invasive fungal infection in persons intolerant to conventional ampho- tericin B ACTIONS: Binds to sterols in the cell membrane, resulting in changes in membrane permeability DOSAGE: Adults & Peds. Children >1 mo: 100–200 mg/kg/24h ÷ q4–6h IM or IV; 50–100 mg/kg/24h ÷ q6h PO up to 250 mg/dose. Meningi- tis: 200–400 mg/kg/24h ÷ q4–6h IV SUPPLIED: Caps 250, 500 mg; susp 100 mg/mL (reconstituted as drops), 125 mg/5 mL, 250 mg/ 5 mL, 500 mg/5 mL; powder for inj 125 mg, 250 mg, 500 mg, 1 g, 2 g, 10 g/vial NOTES: Cross-hypersensitivity with penicillin; can cause diarrhea and skin rash; many hospital strains of E. Low-dose: 1 million KIU load, 1 million KIU for the pump prime dose, followed by 250,000 KIU/h until surgery ends. Give all patients 1-mL IV test dose to assess for allergic reaction Ardeparin (Normiflo) COMMON USES: Prevention of DVT and PE following knee replacement ACTIONS: Low-molecular-weight heparin DOSAGE: 35–50 U/kg SC q12h. Joseph, others) COMMON USES: Mild pain, headache, fever, inflammation, prevention of emboli, and prevention of MI ACTIONS: Prostaglandin inhibitor DOSAGE: Adults. Tabs Fiorinal, Lanorinal, Marnal: Aspirin 325 mg/butalbital 50 mg/ caffeine 40 mg NOTES: Butalbital habit-forming Aspirin + Butalbital, Caffeine and Codeine (Fiorinal + Codeine) [C] COMMON USES: Mild pain; headache, especially when associated with stress ACTIONS: Sedative analgesic, narcotic analgesic DOSAGE: 1–2 tabs (caps) PO q4–6h PRN SUPPLIED: Each cap or tab contains 325 mg aspirin, 40 mg caffeine, 50 mg of butalbital, codeine: No. AMI: 5 mg IV ×2 over 10 min, then 50 mg PO bid if tolerated SUPPLIED: Tabs 25, 50, 100 mg; inj 5 mg/10 mL Atenolol and Chlorthalidone (Tenoretic) COMMON USES: HTN ACTION: β-Adrenergic blockade with diuretic DOSAGE: 50–100 mg/d PO SUPPLIED: Tenoretic 50: Atenolol 50 mg/chlorthalidone 25 mg; Tenoretic 100: Atenolol 100 mg/chlorthalidone 25 mg Atorvastatin (Lipitor) COMMON USES: Elevated cholesterol and triglycerides ACTIONS: HMG-CoA reductase inhibitor DOSAGE: Initial dose 10 mg/d, may be ↑ to 80 mg/d SUPPLIED: Tabs 10, 20, 40, 80 mg NOTES: May cause myopathy, monitor LFT regularly Atovaquone (Mepron) 22 COMMON USES: Rx and prevention mild to moderate PCP 22 Commonly Used Medications 501 ACTIONS: Inhibits nucleic acid and ATP synthesis DOSAGE: Rx: 750 mg PO bid for 21 d. Prevention: 1500 mg PO once/d SUPPLIED: Suspension 750 mg/5 mL NOTES: Take with meals Atracurium (Tracrium) COMMON USES: Adjunct to anesthesia to facilitate endotracheal intubation ACTIONS: Nondepolarizing neuromuscular blocker DOSAGE: Adults & Peds. Use adequate amounts of sedation and analgesia Atropine Used for emergency care (see Chapter 21) COMMON USES: Preanesthetic; symptomatic bradycardia and asystole ACTIONS: Antimuscarinic agent; blocks acetylcholine at parasympathetic sites DOSAGE: Adults. Interaction with allopurinol Azithromycin (Zithromax) COMMON USES: Acute bacterial exacerbations of COPD, mild community-acquired pneumonia, pharyngitis, otitis media, skin and skin structure infections, nongonococcal urethritis, and PID. Rx and prevention of MAC infections in HIV-infected persons ACTIONS: Macrolide antibiotic; inhibits protein synthesis DOSAGE: Adults. Oral: Respiratory tract infections: 500 mg on the first day, followed by 250 mg/d PO for 4 more d. Pharyngitis: 12 mg/kg/d PO for 5 d SUPPLIED: Tabs 250, 600 mg; susp 1-g single-dose packet; susp 100, 200 mg/5 mL; inj 500 mg NOTES: Take susp on an empty stomach; tabs may be taken with or without food Aztreonam (Azactam) COMMON USES: Infections caused by aerobic gram (−) bacteria, including Pseudomonas aerugi- nosa ACTIONS: Monobactam antibiotic; inhibits cell wall synthesis DOSAGE: Adults. Note: Neosporin ointment different from cream (page 576) Bacitracin, Ophthalmic (AK-Tracin Ophthalmic) Bacitracin and Polymyxin B, Ophthalmic (AK Poly Bac Ophthalmic, Polysporin Ophthalmic) Bacitracin, Neomycin and Polymyxin B, Ophthalmic (AK Spore Ophthalmic, Neosporin Ophthalmic) Bacitracin, Neomycin, Polymyxin B and Hydrocortisone, Ophthalmic (AK Spore HC Ophthalmic, Cortisporin Ophthalmic) COMMON USES: Blepharitis, conjunctivitis, and prophylactic treatment of corneal abrasions ACTIONS: Topical antibiotic with added effects based on components (antiinflammatory) DOSAGE: Apply q3–4h into conjunctival sac SUPPLIED: See Topical equivalents, above Baclofen (Lioresal, others) COMMON USES: Spasticity secondary to severe chronic disorders, eg, MS or spinal cord lesions, trigeminal neuralgia ACTIONS: Centrally acting skeletal muscle relaxant; inhibits transmission of both monosynaptic and polysynaptic reflexes at the spinal cord DOSAGE: Adults. IT: Through implantable pump SUPPLIED: Tabs 10, 20 mg; IT inj 10 mg/20 mL, 10 mg/5 mL NOTES: Use caution in epilepsy and neuropsychiatric disturbances, withdrawal may occur with abrupt discontinuation Basiliximab (Simulect) COMMON USES: Prevention of acute organ transplant rejections ACTIONS: IL-2 receptor antagonists DOSAGE: Adults. Repeat once weekly for 6 wk; repeat 3 weekly doses 3, 6, 12, 18, and 24 mo after the initial therapy SUPPLIED: Inj 27 mg (3. BCG vaccine occasionally used in high risk-children who are negative on the PPD skin test and cannot be given isoniazid prophylaxis. Becaplermin (Regranex Gel) COMMON USES: Adjunct to local wound care in diabetic foot ulcers ACTIONS: Recombinant human PDGF, enhanced formation of granulation tissue DOSAGE: Based on size of lesion; 1¹ ₃-in. May be repeated 3 more × q6h for a max of 4 doses/48h SUPPLIED: Suspension 25 mg of phospholipid/mL NOTES: Administer via 4-quadrant method Betaxolol (Kerlone) COMMON USES: HTN ACTIONS: Competitively blocks β-adrenergic receptors (β1) DOSAGE: 10–20 mg/d SUPPLIED: Tabs 10, 20 mg Betaxolol, Ophthalmic (Betoptic) COMMON USES: Glaucoma ACTIONS: Competitively blocks β-adrenergic receptors (β1) DOSAGE: 1 gtt bid SUPPLIED: Soln 0. Lung toxicity likely when the total dose >400 mg (U) Bretylium COMMON USES: Acute Rx of VF or tachycardia unresponsive to conventional therapy ACTIONS: Class III antiarrhythmic DOSAGE: Adults. Same as adults, except the maintenance dose is 5 mg/kg/dose q6–8h SUPPLIED: Inj 50 mg/mL; premixed inf 1, 2, 4 mg/mL (limited availability) NOTES: Nausea and vomiting associated with rapid IV bolus; gradually ↓ dose and discontinue in 3–5 d; effects seen within the first 10–15 min; transient rise in BP seen initially; hypotension most frequent adverse effect and occurs within the first hours of treatment Brimonidine (Alphagan) COMMON USES: Open-angle glaucoma ACTIONS: α2-Adrenergic agonist DOSAGE: 1 gtt in eye(s) tid SUPPLIED: 0. Dose dependent on procedure, vascularity of tissues, depth of anesthesia, and degree of muscle relaxation required (see Chapter 17) SUPPLIED: Inj 0.

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It is aspartate (NMDA) receptor channels to produce depo- known that the epileptic bursts consist of sodium- larization discount voltaren 100 mg on line arthritis supplements. It is likely that a major part of the anticon- dependent action potentials and a calcium-dependent vulsant activity of felbamate involves blockade of the depolarizing potential voltaren 100mg fast delivery rheumatoid arthritis joints locking up. Modulation of neuronal CLINICALLY USEFUL DRUGS sodium channels decreases cellular excitability and the propagation of nerve impulses. Inhibition of sodium Anticonvulsant drugs may be divided into four classes, channels appears to be a major component of the based on their most likely mechanism of action. Although it may be premature to assign a mechanism of Much interest is also centered on the role of calcium action to some of these compounds, the proposed channels in neuronal activity, since the depolarization classes are a convenient way to group the drugs. For a proposed mechanism of action to be considered relevant for a given drug, the effect must occur at concentrations sim- Extracellular ilar to those that are likely to be achieved therapeuti- cally. Cell membrane Sodium Channel Blocking Agents Drugs sharing this mechanism include phenytoin (Di- lantin), carbamazepine (Tegretol), oxcarbazepine (Tri- A Intracellular leptal), topiramate (Topamax), valproic acid (Depakene), Na zonisamide (Zonegran), and lamotrigine (Lamictal). All of these agents have the capacity to block sustained high-frequency repetitive firing (SRF) of action poten- tials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through an en- hancement of steady-state inactivation. The sodium channel exists in three main conformations: a resting (R) or activatable state, an open (0) or conducting state, and an inactive (I) or nonactivatable state. Because it takes time for the bound drug to dis- sociate from the inactive channel, there is time depen- Na dence to the block. Since the fraction of inactive chan- nels is increased by membrane depolarization as well as by repetitive firing, the binding to the I state by antiepileptic drugs can produce voltage-, use-, and time- dependent block of sodium-dependent action potentials. These agents are discussed together because their pharmacological properties, clinical indications for the C treatment of epilepsy, and presumed mechanisms of ac- tion are similar. An macokinetic properties, their adverse reactions, and activation gate is closed and sodium ions cannot pass their interactions with other drugs. The channel activation gate opens ing sodium channels, some possess other therapeutically rapidly following depolarization and sodium enters freely. Soon after opening, an inactivation gate (C) closes, preventing further entry of sodium ions into the cell. Phenytoin Phenytoin and drugs with a similar mechanism of action stabilize and prolong the existence of the inactivated state, Phenytoin is a valuable agent for the treatment of gen- and therefore, sodium entry is impeded longer than occurs eralized tonic–clonic seizures and for the treatment of in the absence of the drug. The establish- ment of phenytoin (at that time known as diphenylhy- dantoin) in 1938 as an effective treatment for epilepsy ity in the brain and it therefore seemed perfectly rea- was more than simply the introduction of another drug sonable that CNS depressants would be effective in an- for treatment of seizure disorders. Consequently, many patients re- only drugs that had any beneficial effects in epilepsy ceived high doses of barbiturates and spent much of were the bromides and barbiturates, both classes of their time sedated. It was, therefore, revolutionary Peripheral neuropathy and chronic cerebellar degener- when phenytoin was shown to be as effective as pheno- ation have been reported, but they are rare. However, it is search for new anticonvulsant drugs as well as immedi- known that phenytoin can produce a folate deficiency, ately improving the day-to-day functioning of epileptic and folate deficiency is associated with teratogenesis. Only a few well-documented drug combinations An understanding of absorption, binding, metabo- with phenytoin may necessitate dosage adjustment. Following oral administration, elevations of plasma phenytoin levels in most patients: phenytoin absorption is slow but usually complete, and cimetidine, chloramphenicol, disulfiram, sulthiame, and it occurs primarily in the duodenum. Phenytoin often causes a bound (about 90%) to plasma proteins, primarily decline in plasma carbamazepine levels if these two plasma albumin. Phenytoin is one of very few drugs that displays Carbamazepine zero-order (or saturation) kinetics in its metabolism. However, at the higher blood levels usually erated by most patients, and exhibits fewer long-term required to control seizures, the maximum capacity of side effects than other drugs. Its half-life is reported to vary from 12 to of phenytoin may lead to a disproportionate increase in 60 hours in humans. Since the plasma levels says has markedly improved the success of therapy with continue to increase in such a situation, steady-state lev- this drug, since serum concentration is only partially els are not attained, and toxicity may ensue. Carbamazepine is metabolized in the liver, of half-life (t1/2) values for phenytoin often is meaning- and there is evidence that its continued administration less, since the apparent half-life varies with the drug leads to hepatic enzyme induction.

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