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Both losartan and the metabolite are highly Most ACE inhibitors (captopril geriforte 100 mg amex, enalapril buy geriforte 100 mg with visa, fosinopril cheap 100 mg geriforte free shipping, lisino- bound to plasma albumin generic 100 mg geriforte, and losartan has a shorter duration pril, ramipril, and quinapril) also are used in the management of action than its metabolite. When losartan therapy is started, of heart failure because they decrease peripheral vascular re- maximal effects on blood pressure usually occur within 3 to sistance, cardiac workload, and ventricular remodeling. If losartan alone does not control blood pressure, a topril and other ACE inhibitors are recommended as first-line low dose of a diuretic may be added. A combination product agents for treating hypertension in diabetic clients, particu- of losartan and hydrochlorothiazide is available. Antiadrenergics ACE inhibitors are well absorbed with oral administra- tion, produce effects within 1 hour that last approximately Antiadrenergic (sympatholytic) drugs inhibit activity of the 24 hours, have prolonged serum half-lives with impaired SNS. These drugs are well From the ganglia, the impulse travels along postganglionic tolerated, with a low incidence of serious adverse effects fibers to effector organs (eg, heart, blood vessels). Although 802 SECTION 9 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM leads to decreased cardiac output, heart rate, peripheral vas- Angiotensinogen cular resistance, and blood pressure. Chronic use of cloni- dine and related drugs may result in sodium and fluid retention, Renin especially with higher doses. Beta-adrenergic blocking agents (eg, propranolol) de- crease heart rate, force of myocardial contraction, cardiac Angiotensin I output, and renin release from the kidneys. Other anti- adrenergic drugs include guanethidine and related drugs, Converting enzyme which act at postganglionic nerve endings; and two other ACE inhibitors alpha blockers (phentolamine and phenoxybenzamine), block enzyme which occasionally are used in hypertension resulting from action catecholamine excess. Individual antiadrenergic drugs are Angiotensin II ARBs block discussed in Chapter 19. The mechanism of action and secretion water growth use in the management of tachydysrhythmias and angina pec- retention (Remodeling) toris are discussed in Chapters 52 and 53. In hypertension, the drugs mainly dilate peripheral arteries and decrease periph- eral vascular resistance by relaxing vascular smooth muscle. Increased peripheral vascular resistance Increased intravascular fluid volume Most of the available drugs are approved for use in hyper- Increased blood pressure tension. Nifedipine, a short-acting calcium channel blocker, has been used to treat hypertensive emergencies or urgencies, often by puncturing the capsule and squeezing the contents under the Figure 55–1 Angiotensin-converting (ACE) enzyme inhibitors in- tongue or having the client bite and swallow the capsule. Such hibit angiotensin-converting enzyme and thereby prevent formation of angiotensin II; angiotensin II receptor blockers (ARBs) prevent an- use is no longer recommended, because this practice is associ- giotensin II from connecting with its receptors and thereby prevent it ated with an increased risk of adverse cardiovascular events from acting on body tissues containing those receptors (eg, blood precipitated by rapid and severe decrease in blood pressure. As a group, the calcium channel blockers are well absorbed from the gastrointestinal tract following oral administration and are highly bound to protein. SNS stimulation produces widespread effects in the body, the effects relevant to this discussion are the increases in heart rate, force of myocardial contraction, cardiac output, Diuretics and blood pressure that occur. When the nerve impulse is in- hibited or blocked at any location along its pathway, the re- Antihypertensive effects of diuretics are usually attributed to sult is decreased blood pressure (see Chap. In fact, diuretics usually produce Alpha1-adrenergic receptor blocking agents (eg, prazosin) the same effects as severe dietary sodium restriction. In many dilate blood vessels and decrease peripheral vascular resis- cases of hypertension, diuretic therapy alone may lower blood tance. One adverse effect, called the first-dose phenomenon, cardiac output decrease. With long-term administration of a results in orthostatic hypotension with palpitations, dizziness, diuretic, cardiac output returns to normal, but there is a per- and perhaps syncope 1 to 3 hours after the first dose or an in- sistent decrease in peripheral vascular resistance. To prevent this effect, first doses and first in- been attributed to a persistent small reduction in extracellular creased doses are taken at bedtime. Another effect, associated water and plasma volume, decreased receptor sensitivity to with long-term use or higher doses, leads to sodium and fluid vasopressor substances such as angiotensin, direct arteriolar retention and a need for concurrent diuretic therapy. Cen- vasodilation, and arteriolar vasodilation secondary to elec- trally acting sympatholytics (eg, clonidine) stimulate pre- trolyte depletion in the vessel wall. When these drugs are taken, less to a diuretic alone, the diuretic may be continued and another norepinephrine is released and sympathetic outflow from the antihypertensive drug added, or monotherapy with a differ- vasomotor center is reduced. Stimulation of presynaptic ent type of antihypertensive drug may be tried. Reduced sympathetic activity commonly used in the management of hypertension. Loop CHAPTER 55 ANTIHYPERTENSIVE DRUGS 803 diuretics (eg, furosemide) or potassium-sparing diuretics • Oral contraceptives, corticosteroids, appetite sup- (eg, spironolactone) may be useful in some circumstances; pressants, nasal decongestants, non-steroidal anti- see Chapter 56 for discussion of diuretic drugs. Vasodilators (Direct Acting) • Check blood pressure accurately and repeatedly.

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The RIF-PZA regimen is not recommended for persons and adolescents with pyridoxine-deficient diets trusted geriforte 100 mg, and children who have underlying liver disease or who have had INH- who experience paresthesias when taking INH buy 100 mg geriforte with visa. It should be used with caution in pa- Although few studies have been done in infants purchase geriforte 100mg visa, children 100 mg geriforte otc, tients who take other hepatotoxic medications or use alcohol, and adolescents, rifampin alone, rifampin with INH, and ri- even if alcohol use is stopped during treatment. Persons being fampin with pyrazinamide have been used to treat LTBI with considered for treatment with this regimen should be in- effectiveness. Although the optimal length of rifampin therapy formed about potential hepatotoxicity and asked whether in children with LTBI is unknown, the American Academy of they have had liver disease or adverse effects from INH. The RIF-PZA regimen is recommended mainly for clients There have been no reported studies of any regimen for treat- who are unlikely to complete longer courses of treatment ment for LTBI in HIV-infected children. The RIF-PZA regimen does increase risks of hepatotoxicity skin-test reactions (>5 mm) should be treated with one of the in clients with HIV infection. Still, INH daily for 9 months recommended regimens described above, regardless of age. Contacts of patients with INH-resistant, rifampin-susceptible LTBI when completion of treatment can be assured. For patients with intolerance to pyrazinamide, <20 mg/kg/d and a maximum of 2 g/d; giving no more than rifampin alone for 4 months is recommended. If rifampin can- a 2-week supply of rifampin and pyrazinamide at a time; not be used, rifabutin can be substituted. Contacts of patients with multidrug-resistant (MDR)-TB who adherence, tolerance, and adverse effects, and at 8 weeks to are at high risk for developing active TB are generally given document treatment completion. Immunocompetent contacts may be observed with- and seek medical care if abdominal pain, emesis, jaundice, out treatment or treated for 6 months; immunocompromised con- or other symptoms of hepatitis develop. Provider continu- tacts (eg, HIV-infected persons) should be treated for 12 months. Perform liver function tests (eg, serum aspartate and alanine butol are recommended for 9 to 12 months if the isolate is sus- aminotransferases [AST and ALT] and bilirubin) at base- ceptible to both drugs. RIF-PZA treatment should be (continued) 564 SECTION 6 DRUGS USED TO TREAT INFECTIONS BOX 38–2 TREATMENT OF LATENT TUBERCULOSIS INFECTION (LTBI) (Continued) drugs to which the infecting organism is likely susceptible should (eg, the length and complexity, possible adverse effects, and be given. With rifampin, the drug is contraindicated or with intermittent regimens (eg, twice weekly) and when possi- should be used with caution in persons who are taking protease ble with 2-month regimens and in certain settings (eg, institu- inhibitors or nonnucleoside reverse transcriptase inhibitors tional settings, community outreach programs, and for persons (NNRTIs). Rifabutin can be substituted for rifampin in some living in households with patients who are receiving home- circumstances, but it should not be used with hard-gel based DOT for active TB). This is determined by the soft-gel saquinavir and nevirapine because data are limited. For daily INH, the 9-month regimen should include at daily dose (ie, from 300 mg/d to 150 mg/d) with indinavir, least 270 doses in 12 months and the 6-month regimen should in- nelfinavir, or amprenavir and to one fourth the usual dose clude at least 180 doses in 9 months. For twice-weekly INH, the (ie, 150 mg every other day or 3 times a week) with ritonavir. For the 2-month regimen of daily rifampin (or ri- fabutin) and pyrazinamide, at least 60 doses should be given in not recommended as a substitute for rifampin because its 3 months. For the 4-month regimen of daily rifampin alone, at safety, effectiveness, and interactions with anti-HIV medication least 120 doses should be given in 6 months. A history of Bacille Calmette-Guérin though, ideally, patients should receive medication on a regular (BCG) vaccination should not influence the decision to treat schedule until the course of therapy is completed. When Additional Recommendations restarting therapy after interruptions, the original regimen may 1. Before beginning treatment for LTBI, active TB should be be continued as long as needed to complete the recommended ruled out by history, physical examination, chest radiography, duration of the particular regimen or a new regimen may be and bacteriologic studies, if indicated. Allow patients to participate in choosing a treatment regimen, is interrupted for longer than 2 months, the client should be re- when feasible, by discussing options and characteristics of each assessed for active TB before restarting drug therapy. Drugs at a Glance: Primary Antitubercular Drugs Dosage Ranges (Maximum dose) Adults Children Name/Route DAILY TWICE/WEEK DAILY TWICE/WEEK Comments Isoniazid (INH) 5 mg/kg 15 mg/kg 10–20 mg/kg 20–40 mg/kg LTBI: Given at least 6 mo; 9 mo preferred PO or IM (300 mg) (900) (300) (900) Active TB: Given at least 6 mo, with other drugs Rifampin (Rifadin) 10 mg/kg 10 mg/kg 10–20 mg/kg 10–20 mg/kg LTBI: Given 4 mo alone or 2 mo with pyrazinamide PO or IV infusion (600 mg) (600 mg) (600 mg) (600 mg) Active TB: Given for 6 mo, with other drugs Pyrazinamide PO 15–30 mg/kg 50–70 mg/kg 15–30 mg/kg 50–70 mg/kg LTBI: Given 2 mo with rifampin (2 g) (4 g) (2 g) (4 g) Active TB: Given for 2 mo with INH and rifampin Streptomycin IM 15 mg/kg 25–30 mg/kg 20–40 mg/kg 25–30 mg/kg Used for active TB, with other drugs (1 g) (1. It some people are slow acetylators and others are rapid induces hepatic microsomal enzymes and accelerates the acetylators. Slow acetylators have less their serum concentrations, half-lives, and therapeutic effects. In Affected drugs include acetaminophen, anti-AIDS drugs these clients, INH is more likely to accumulate to toxic con- (protease inhibitors and nonnucleoside reverse transcriptase centrations and the development of peripheral neuropathy is inhibitors; see Chap. However, there is no significant difference in the cyclosporine, estrogens, fluconazole, ketoconazole, mexiletine, clinical effectiveness of INH.

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The size of the (Bayoumi & Ashby order geriforte 100 mg on-line, 1989) 100mg geriforte otc, intrinsic foot muscles monosynaptic Ia peak should then decrease as (Marque et al generic 100 mg geriforte amex. Given this preferential distribution of Ia exci- cles in which the different motor unit types have tatory inputs to motoneurones innervating slow- beeninvestigated:seconddorsalinterosseus(Buller geriforte 100mg mastercard, twitch units, it is not surprising that the soleus H Garnett & Stephens, 1980), soleus (Awiszus & Feist- reflex may be obtained in all healthy subjects at ner,1993),ECR(Fig. Hilton-Brown & Stalberg,˚ 1986;Semmler & Turker,¨ 1994) and in abductor digiti minimi (Mazzocchio, Heteronymous monosynaptic Ia Rothwell & Rossi, 1995), the largest responses to Ia excitation in the lower limb input have not been found in low-threshold units. Pattern and strength of distribution Inhibitory mechanisms limiting the efficacy of the monosynaptic Ia input In striking contrast with data for the cat and baboon hindlimb (see pp. The constraints raised above, the conclusions advanced larger the maximal soleus H reflex at rest, the smaller below have generally been confirmed using more the tonic on-going presynaptic inhibition of Ia ter- than one method. Grey cells represent Contamination by oligosynaptic IPSPs muscle–nerve combinations with a statistically sig- nificantconnectioninhumans. This limitation could also based on the average size of the heteronymous peak contribute to the absence of a recordable H reflex relative to that of the homonymous peak, both in at rest in muscles, such as tibialis anterior, abduc- response to stimulation at 1 × MT. As expected, the tor pollicis brevis and ECR, though this would imply stronger the connection, the more frequently was it that the Ia/Ib balance was then shifted in favour of observed: e. In these muscles, the appearance of an trocnemius medialis to biceps femoris, five aster- Hreflex during a tonic voluntary contraction could isks) was observed in 21/21 (100%) units and was, involve depression of non-reciprocal group I inhibi- on average, 54% of the homonymous peak, whereas tion to the active motoneurone pool (see Chapter 6, the weakest connection (from the intrinsic plantar pp. Thresholds for α motor axons and Ia afferents Connections between close synergists operating Alternatively, if the threshold for motor axons was at the same joint closer to that of Ia afferents, the maximal H reflex would probably be smaller and the reflex more diffi- At knee level, strong connections exist between the cult to obtain and, with single motor units, the peak two heads of the quadriceps (vastus lateralis and 82 Monosynaptic Ia excitation Table 2. Monosynaptic heteronymous Ia excitation in the lower limb Columns: nerve stimulated: Sol (inferior soleus), GM (nerve to the gastrocnemius medialis), SP (superficial pero- neal), DP (deep peroneal), FN (femoral nerve), TN (tibial nerve at the ankle). Lines: motoneurone pools (MN) investigated with the PSTH method: Sol (soleus), GM (gastrocnemius medialis), Per Brev (peroneus brevis), TA (tibialis anterior), Q (quadriceps), Bi (biceps femoris), ST (semitendinosus). Grey cells indicate the existence of significantIaexcitationinhumans(crossedcellscorrespondtohomonymouspathways). Thenumberofasterisks indicates the average size of the heteronymous peak relative to the homonymous peak (both recorded using sti- mulationat1×MT):*<10%;**between10and20%;***between20and30%,****between30and40%;*****>40% (from Meunier, Pierrot-Deseilligny & Simonetta, 1993;Marque et al. Connections are compared to those described in the cat (cells with horizontal lines, Eccles, Eccles & Lundberg, 1957)andthebaboon(cellswithverticallines,Hongoetal. Withtheanimalexperiments,onlyconnections with a heteronymous EPSP >5% of the homonymous EPSP are shown. There is no Ia excitation from gastrocnemius medialis to soleus, There are bidirectional connections between soleus a finding confirmed using different techniques: the andperoneusbrevis(Fig. Organisation and pattern of connections 83 Transjoint connections exist between all Phylogenetic adaptations muscle–nerve combinations tested In Table 2. However, it should be emphasised that cat(cellswithhorizontallines,Eccles,Eccles&Lund- conclusions based on stimuli at 1 × MT underesti- berg, 1957) and the baboon (cells with vertical lines, matethestrengthoftheconnectionsbecause,asdis- Hongo et al. These connections are not confined to Connections between close synergists units in the low-threshold range investigated with Theabsenceofconnectionsbetweensomeclosesyn- the PSTH method. Many of the connections have ergists operating at the same joint in humans is pre- alsobeenobservedwithmethodsthatexplorealarge dictable because of their weakness in the baboon. Proximal-to- distal transjoint connections can be explored safely Themoststrikingdifferencesinvolvethepresenceof only from the femoral nerve, because it does not heteronymous connections that do not exist in the contain afferents from distal muscles. Because of cat or the baboon or, when they exist, are <5% of the the difficulty in stimulating the nerves to hamstrings homonymous Ia EPSP (e. Ia connections from tri- without encroaching upon afferents from foot and ceps surae onto quadriceps motoneurones, Edgley, leg muscles in the sciatic nerve (or of stimulating Jankowska&McCrea,1986;Hongoetal. Thus, the posterior tibial nerve without encroaching upon in human subjects, there are transjoint connections afferents from plantar foot muscles), it has not been between all muscle–nerve combinations tested. The possibletodeterminewhethertheconnectionsfrom functionalimplicationsofthesedifferencesinorgan- legmusclestohamstrings(andfromfoottoproximal isation of Ia connections are considered on pp. Projections to antagonists acting at another joint Aremarkable feature of these transjoint connections Heteronymous monosynaptic isthattheyoftenlinkamuscleorgroupofmusclesto Ia excitation in the upper limb a pair of antagonistic muscles operating at another joint, e. There is bidirectional, 84 Monosynaptic Ia excitation though asymmetrical, heteronymous Ia excitation Table 2.

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