Los niveles de Van Hiele en la enseñanza de la Geometría

2.6.1 Overview

Digitalis purpurea, commonly known as “digitalis” or “cardiac glycosides”, has played a prominent role in the treatment of congestive heart failure for over 200 years. During the 1990’s, digoxin was the most commonly prescribed cardiac drug, eliciting positive inotropic effects for the relief of systolic ventricular dysfunction (Hauptman & Kelly, 1999). The following section will examine the specific digoxin inhibitory effects on skeletal muscle NKA and subsequent plasma K+ disturbances during exercise.

2.6.2.1 Inotropic, NKA and plasma K+ responses to digoxin therapy

Congestive heart failure patients (CHF = all patients with left ventricle ejection fraction less than 40%; O'Connor et al, 1998) administered DIG have responded to treatment with positive inotropic, electrophysiological and neurally mediated effects (Mason et al 1964; Edner and Jogestrand 1994; Schmidt et al 1995; McMahon et al 1996; O’Connor et al 1998; Clausen 1998; Hauptman & Kelly, 1999; Demers et al 1999). The molecular target for digoxin is inhibition of the NKA α-subunit (Lichtstein, 1995). Consequently, increased [Na+]i activates the Na+/Ca2+ exchange mechanism (see Fig 2.1, Clausen

1998), leading to increased Ca2+i via Ca2+ entry and/or reduced Ca2+ efflux (Hauptman

& Kelly, 1999; O’Connor et al 1998; Clausen 1998). Elevated sarcoplasmic reticulum Ca2+ stores allow an increase in Ca2+ which mediates activation of contractile filaments and atrial excitation (Levi et al 1995; Clausen 1998). Consequently, positive inotropic and arrhythmogenic actions augment ventricular function, and typically respond by increasing; myocardial excitability; vagal tone; systolic force of ventricular contraction; ventricular emptying, cardiac output, peripheral circulation, oxygen consumption, renal function, and by decreasing; ventricle end diastolic pressure, myocardial enlargement, and venous pressure. While digoxin provides inotropic relief for many congestive heart failure symptoms, the electrogenic effect of cardiac (Smith, 1988) and skeletal muscle (Schmidt 1995) NKA function is significantly reduced, given that 50% of the total amount of digoxin in the body is bound to skeletal muscle, whilst only ~3% of digoxin is bound to cardiac muscle (Steiness, 1978). Digoxin NKA occupancy in skeletal muscle ranges from 9% (Schmidt et al, 1995) to 35% in heart failure patients (Green et al, 2001), and exercise increases digoxin binding to muscle whilst decreasing serum digoxin concentration in healthy humans (Joretag & Jogestrand 1983). Consequently, a therapeutic dose of digoxin will induce K+ loss from the myocardium at rest (Brennan et al, 1972, cited in Clausen 1998) and from skeletal muscle during exercise (Schmidt et at, 1995). Edner and colleagues (1993) found that venous plasma K+ increased by 0.19mM at rest, following 10 days of digoxin therapy at 0.37-0.5mg.d-1. There was no arterial K+ or serum digoxin concentration data reported, therefore the effects of apparent partial NKA inhibition on contracting muscle function was unknown in this study. No changes in serum [K+] were found in healthy humans after digoxin administration (Ericsson et al, 1981), however muscle [K+] content and whole body K+ decreased by 5% and 9% respectively.

2.6.2.2 Neural Effects

The neural resonses to DIG include altered sympathetic nervous activity. Mason and Braunwald (1964) examined acute effects of intravenously infused ouabain (8.5 µg.kg-

1

) on various autonomic nervous system responses in healthy and diseased individuals. Following 10 min ouabain infusion, cardiac patients elicited a decline in resting forearm vascular resistance; decline in resting venous tone; and an increase in resting forearm blood flow from 1.7 to 2.2 ml.100g-1.min-1; with no change in mean arterial pressure. Conversely, healthy individuals elicited an increase in forearm vascular resistance; increase in vascular tone; decrease in forearm blood flow from 3.6 to 2.9 ml.100g-1.min-

1

; and increased mean arterial pressure from 83 to 92 mmHg. Heart rate decreased with DIG infusion in both healthy (69 to 63 beats.min-1) and CHF (108 to 87 beats.min-

1

). The changes observed in cardiac patients might be due to baroreflex mediated sympathetic activity decline (Mason and Braunwald, 1964). In healthy individuals the

Fig 2.2 NKA inhibition hypothesis for digoxin in heart muscle cells. Digoxin binds and inhibits NKA, reduces Na+ extrusion from cell, leading to a rise in intracellular [Na+] (Na+i shown as the activity of Na+I (a

i

Na). This reduces Ca 2+

extrusion from (or increases Ca2+ entry into) the cell via the Na+-Ca2+ exchanger, and causes a rise of Ca2+i and cellular Ca

2+

content. By increasing SR Ca2+ release and generating a larger Ca2+i transient, this results in an increase of the force of contraction of cardiac muscle. From Levi et al, 1995 – cited in Clausen 1998.

authors suggested cardiac output remained stable and systemic arterial pressure increased, whilst ouabain probably acted directly on peripheral vascular tone (Mason and Braunwald, 1964). Interestingly, Grossman et al (1998) suggested chronic digoxin exposure in healthy normotensive subjects elicited similar sympathetic activity changes seen in CHF patients. In healthy normotensive subjects treated with 0.25 mg.day-1 digoxin, heart rate decreased significantly by 8 and 7 beats per minute at day 4 and 10, and diastolic blood pressure decreased by 7 and 5 mmHg respectively. Hauptman & Kelly (1999) also suggested that digoxin-induced decrease in sympathetic and increase in parasympathetic activity may also occur in individuals administered a dose lower than that normally necessary to elicit an inotropic effect.

2.6.2.3 Effects of digoxin on exercise

Several studies have previously demonstrated inhibition of skeletal muscle NKA activity associated with digoxin therapy in heart failure patients (Schmidt et al, 1995) and in healthy humans (Joretag & Jogestrand, 1983). Schmidt et al (1995) found that K+ regulation was impaired during exercise in congestive heart failure patients undergoing chronic digoxin therapy. The [K+]a-v across the exercising leg was increased by 50-

100% during exercise, and ~9% of NKA were blocked, thus ouabain increased muscle K+ release. However there was no exercise or muscle performance data reported in that study. Their findings suggest digoxin therapy and exercise training have opposing effects on plasma K+ during exercise, mediated via either NKA down-or up-regulation, respectively (see Fig 2.2 from McKenna, 1998).

Patients in atrial fibrillation show higher digoxin binding in the right atrium than patients in sinus rhythm, possibly due to a higher activation rate of atrial myocardium, and thus also of NKA in that condition. This has similarly been found in skeletal muscle. Joreteg and Jogestrand (1983) demonstrated that during exercise in healthy volunteers, uptake of digoxin into skeletal muscle was increased and serum digoxin concentration was decreased compared to rest. This effect was also positively related to exercise intensity. During these studies, 10 healthy young adults ingested 0.5 mg digoxin for 2 weeks and performed two exercise tests at 70-90W and at 140-180W, both 24hr after the preceding dose, at 2-7 day interval.

During the lower exercise intensity, skeletal muscle digoxin content increased by 9%, with mean serum digoxin decreasing 26%. Similar, although more pronounced trends, followed during heavier exercise, with increased skeletal muscle digoxin (20%) and decreased serum digoxin (40%). Unfortunately, changes in exercise performance or in plasma or muscle [K+] were not quantified in this study. Schmidt et al (1995) reported digoxin did not change arterial or venous pH following various bouts of exercise in cardiac patients pre and post digoxin therapy. No effect of two weeks digoxin therapy

at 0.5mg.d-1 in healthy humans was found on V•O2peak (Sundqvist et al 1982). However,

NKA content and activity were not measured in this study.

Fig 2.3 Effects of altered NKA concentration in human muscles; K+ loss during exercise. Percent change in muscle K+ loss shown for digoxin therapy (Schmidt et al, 1995) and for endurance training (Kiens and Saltin 1986). From McKenna (1998).

2.6.2.4 Digoxin Dosing and Toxicology

Numerous studies have investigated pharmacokinetics of acute digoxin therapy (dose range: 0.25 to 2.0 mg.day-1) in healthy humans without adverse incident (Lyon et al, 1995; Hornestam et al, 1999; Grossman et al, 1998; Edner and Jogestrand, 1994; Morisco et al, 1996; Cauffield et al, 1997; Mason and Braunwald, 1964). See Appendix 3 for more information on digoxin characteristics, including; composition, description, distribution, elimination, dosing and toxicity.

2.6.2.5 Digoxin-induced compensatory NKA upregulation

The effects of chronic digoxin on adaptive compensatory NKA upregulation in humans are unclear. Digoxin induced compensatory NKA upregulation has been observed in

[Na

_,K

_{-pump] (%change)}

-10 -5 0 5 10 15

Muscle K

_loss

(% change)

human and pig erythrocytes (Ford et al, 1979; Whittaker et al,1983), but not in skeletal muscle in cardiac patient (Schmidt et al,1993; 1995; Green et al, 2001).