Cardiac therapy: Chapter 243 – Angiotensin Converting Enzyme Inhibitors and Vasodilators- Ettinger Flashcards
(32 cards)
The clinical signs of heart failure develop as venous pressures breached the lymphatics capabilities to remove edema or as blood flow to exercising muscles is severely limited.
The clinical signs of heart failure develop as venous pressures breached the lymphatics capabilities to remove edema or as blood flow to exercising muscles is severely limited. The diseased hearts operate on a depressed and flattened Frank-Starling curve so rather than volume retention and vasoconstriction promoting cardiac output and maintenance of blood pressure they merely exacerbated congestive heart failure.
THE RENIN ANGIOTENSIN SYSTEM IN DOGS AND CATS WITH HEART DISEASE
Activation of the neurohormonal cascade often begins with the detection of …………….. underfilling by mechanoreceptors present in the …………………… and …………….(Figure 243-1).
Whether this relative “hypotension” is secondary to low-output heart failure, severe mitral insufficiency, diastolic dysfunction, or profound hypovolemia, the common endpoint is activation of the sympathetic nervous system and RAS. Additional activators of the RAS include ………………. delivery to the …………… and ……………….
THE RENIN ANGIOTENSIN SYSTEM IN DOGS AND CATS WITH HEART DISEASE
Activation of the neurohormonal cascade often begins with the detection of arterial underfilling by mechanoreceptors present in the carotid sinus and kidney (Figure 243-1).
Whether this relative “hypotension” is secondary to low-output heart failure, severe mitral insufficiency, diastolic dysfunction, or profound hypovolemia, the common endpoint is activation of the sympathetic nervous system and RAS. Additional activators of the RAS include reduced sodium delivery to the macula densa and sympathetic stimulation.
- hypotension
- Reduced sodium delivery to the macula dense
- Sympathetic stimulation
Release of the protease renin from the ……………….. promotes conversion of angiotensinogen to angiotensin I. ACE cleaves the C-terminal dipeptide from angiotensin I thereby forming the octapeptide angiotensin II (AT II).
In addition to being a potent vasoconstrictor, AT II:
- In addition to being a potent vasoconstrictor, AT II:
- It is a primary secretagogue for aldosterone;
- It potentiates presynaptic norepinephrine release;
- It stimulates the release of antidiuretic hormone (vasopressin);
- It promotes renal tubular sodium reabsorption;
- It has been linked with cardiomyocyte necrosis, apoptosis and progression of ventricular fibrosis.
In recent years this classical pathway has become far more complex with the identification of a new homolog of ACE, called ACE 2, and additional biologically active AT II metabolites, including the angiotensin-(1-7) peptide. ACE is also capable of cleaving the C-terminal dipeptide from bradykinin so it appears to be a regulator between vasoconstrictive/sodium retaining and vasodilatory/natriuretic mechanisms. Although tissue ACE and additional enzymatic pathways, such as …………, …………..,……………, and ……………………, have been identified that are capable of AT II production, their significance is unknown at this time.
In recent years this classical pathway has become far more complex with the identification of a new homolog of ACE, called ACE 2, and additional biologically active AT II metabolites, including the angiotensin-(1-7) peptide. ACE is also capable of cleaving the C-terminal dipeptide from bradykinin so it appears to be a regulator between vasoconstrictive/sodium retaining and vasodilatory/natriuretic mechanisms. Although tissue ACE and additional enzymatic pathways, such as chymase, cathepsin G, tonin, and tissue plasminogen activator, have been identified that are capable of AT II production, their significance is unknown at this time.
Figure 243-1 Following renin release, angiotensinogen is cleaved to angiotensin I, which is subsequently cleaved by angiotensin converting enzyme (ACE) to angiotensin II (AT II). AT II binds to either AT1 or AT2 receptor subtypes promoting a variety of physiologic actions including vasoconstriction, activation of the sympathetic nervous system, and production of aldosterone. RAS, Renin angiotensin system.
Figure 243-1 Following renin release, angiotensinogen is cleaved to angiotensin I, which is subsequently cleaved by angiotensin converting enzyme (ACE) to angiotensin II (AT II). AT II binds to either AT1 or AT2 receptor subtypes promoting a variety of physiologic actions including vasoconstriction, activation of the sympathetic nervous system, and production of aldosterone. RAS, Renin angiotensin system.
The neurohormonal hypothesis for progression of cardiac disease suggests ACE inhibitors may have benefit in many different forms of heart disease. Their efficacy will largely depend on the degree of RAS activation, which likely varies between species, underlying disease processes, and disease severity.
The neurohormonal hypothesis for progression of cardiac disease suggests ACE inhibitors may have benefit in many different forms of heart disease. Their efficacy will largely depend on the degree of RAS activation, which likely varies between species, underlying disease processes, and disease severity.
In a study by Koch et al, 23 dogs were evaluated; nine dogs with asymptomatic dilated cardiomyopathy (DCM), eight with symptomatic DCM and six with severe congestive heart failure subsequent to DCM.[47] Sixteen giant-breed dogs without evidence of cardiac disease were used to establish the neuroendocrine control values. Asymptomatic dogs with DCM displayed plasma renin activity and aldosterone concentrations that were not significantly different from control dogs (1.48 vs. 0.89 ng/mL/hr and 35 vs. 61 pg/mL, respectively).[47] Dogs with symptomatic DCM and congestive heart failure exhibited significant activation of their neurohormonal axis compared to normal dogs and those with asymptomatic DCM. The plasma renin activity and aldosterone concentrations increased substantially between dogs with functional Class III and Class IV heart failure (3.8 vs. 30.8 ng/mL/hr and 123 vs. 600 pg/mL, respectively).[47] Tidholm et al. further evaluated activation of the neurohormonal systems of 45 dogs; 15 dogs with DCM and radiographic evidence of heart failure, 15 dogs with DCM without evidence of heart failure and 15 age, breed, and sex-matched control dogs.[48] They also found that dogs with asymptomatic DCM displayed plasma renin activity, aldosterone concentrations and NT-proatrial natriuretic peptide levels that were not significantly different from control dogs. Dogs with DCM and congestive heart failure displayed significant differences in all three variables compared to normal and asymptomatic DCM dogs.[48] O’Sullivan and colleagues have reported similar results in Doberman Pinschers wherein normal dogs and those with occult disease have similar circulating concentrations of aldosterone, norepinephrine, and big–endothelin-1.[49] In comparison, Doberman Pinschers with overt DCM had significantly higher concentrations of aldosterone, norepinephrine, and big–endothelin-1 compared to both normal dogs and dogs with occult disease.[49]
In a study by Koch et al, 23 dogs were evaluated; nine dogs with asymptomatic dilated cardiomyopathy (DCM), eight with symptomatic DCM and six with severe congestive heart failure subsequent to DCM.[47] Sixteen giant-breed dogs without evidence of cardiac disease were used to establish the neuroendocrine control values. Asymptomatic dogs with DCM displayed plasma renin activity and aldosterone concentrations that were not significantly different from control dogs (1.48 vs. 0.89 ng/mL/hr and 35 vs. 61 pg/mL, respectively).[47] Dogs with symptomatic DCM and congestive heart failure exhibited significant activation of their neurohormonal axis compared to normal dogs and those with asymptomatic DCM. The plasma renin activity and aldosterone concentrations increased substantially between dogs with functional Class III and Class IV heart failure (3.8 vs. 30.8 ng/mL/hr and 123 vs. 600 pg/mL, respectively).[47] Tidholm et al. further evaluated activation of the neurohormonal systems of 45 dogs; 15 dogs with DCM and radiographic evidence of heart failure, 15 dogs with DCM without evidence of heart failure and 15 age, breed, and sex-matched control dogs.[48] They also found that dogs with asymptomatic DCM displayed plasma renin activity, aldosterone concentrations and NT-proatrial natriuretic peptide levels that were not significantly different from control dogs. Dogs with DCM and congestive heart failure displayed significant differences in all three variables compared to normal and asymptomatic DCM dogs.[48] O’Sullivan and colleagues have reported similar results in Doberman Pinschers wherein normal dogs and those with occult disease have similar circulating concentrations of aldosterone, norepinephrine, and big–endothelin-1.[49] In comparison, Doberman Pinschers with overt DCM had significantly higher concentrations of aldosterone, norepinephrine, and big–endothelin-1 compared to both normal dogs and dogs with occult disease.[49]
Investigation into the effects of mitral valve insufficiency on the circulating neurohormonal system has also proven interesting with some conflicting results. Pedersen et al. evaluated the plasma renin and aldosterone concentrations of 18 Cavalier King Charles Spaniels (CKCS) with asymptomatic or mildly symptomatic mitral insufficiency.[50] Compared with 18 CKCS without signs of heart disease the plasma renin levels (median 3.44 vs. 2.51 ng/mL/hr, p = 0.03) and aldosterone concentrations (median 53 vs. 27 pg/mL, p = 0.03) were significantly higher in dogs with valvular insufficiency.[50] In comparison Haggstrom et al. repeatedly evaluated 11 CKCS with mitral insufficiency at 6 month intervals until signs of decompensation had developed.[51] The dogs did not receive cardiac medications during the study period and their diets remained the same throughout. The time of decompensation was considered the endpoint of the study (situation 2) and the two most recent study periods, at 4.6 ± 2.2 months (situation 1) and 11.7 ± 1.8 months (situation 0) prior to decompensation, completed the three periods analyzed.[51] The investigators identified that N-terminal atrial natriuretic peptide concentrations increased significantly from situation 0 to situation 1 and were further increased from situation 1 until the time of decompensation (situation 2). Plasma aldosterone concentrations were not significantly different from situation 0 to situation 1, but were found to significantly decrease at the time of decompensation (p
Investigation into the effects of mitral valve insufficiency on the circulating neurohormonal system has also proven interesting with some conflicting results. Pedersen et al. evaluated the plasma renin and aldosterone concentrations of 18 Cavalier King Charles Spaniels (CKCS) with asymptomatic or mildly symptomatic mitral insufficiency.[50] Compared with 18 CKCS without signs of heart disease the plasma renin levels (median 3.44 vs. 2.51 ng/mL/hr, p = 0.03) and aldosterone concentrations (median 53 vs. 27 pg/mL, p = 0.03) were significantly higher in dogs with valvular insufficiency.[50] In comparison Haggstrom et al. repeatedly evaluated 11 CKCS with mitral insufficiency at 6 month intervals until signs of decompensation had developed.[51] The dogs did not receive cardiac medications during the study period and their diets remained the same throughout. The time of decompensation was considered the endpoint of the study (situation 2) and the two most recent study periods, at 4.6 ± 2.2 months (situation 1) and 11.7 ± 1.8 months (situation 0) prior to decompensation, completed the three periods analyzed.[51] The investigators identified that N-terminal atrial natriuretic peptide concentrations increased significantly from situation 0 to situation 1 and were further increased from situation 1 until the time of decompensation (situation 2). Plasma aldosterone concentrations were not significantly different from situation 0 to situation 1, but were found to significantly decrease at the time of decompensation (p
Despite the identification that the systemic, circulating RAS is not activated at the onset of heart failure in CKCS or in asymptomatic dogs with DCM, the identification of local, tissue pathways for the RAS may still garner support for the early institution of ACE inhibitors. Canine ventricular myocytes have been recognized to locally contain the constituents of the RAS that may promote ventricular remodeling in an autocrine fashion.[53] Dogs subjected to rapid ventricular pacing to induce heart failure were compared with control dogs that were instrumented but not paced. Utilizing RT-PCR and Western blotting, Barlucchi et al. found significant differences in canine myocyte RAS activity between control and failing hearts.[53] Angiotensinogen expression was increased 2.5 fold (p
Despite the identification that the systemic, circulating RAS is not activated at the onset of heart failure in CKCS or in asymptomatic dogs with DCM, the identification of local, tissue pathways for the RAS may still garner support for the early institution of ACE inhibitors. Canine ventricular myocytes have been recognized to locally contain the constituents of the RAS that may promote ventricular remodeling in an autocrine fashion.[53] Dogs subjected to rapid ventricular pacing to induce heart failure were compared with control dogs that were instrumented but not paced. Utilizing RT-PCR and Western blotting, Barlucchi et al. found significant differences in canine myocyte RAS activity between control and failing hearts.[53] Angiotensinogen expression was increased 2.5 fold (p
To date there is a paucity of literature describing activation of the RAS in cats with naturally occurring myocardial disease. The largest investigation into cats with myocardial disease is an as of yet unpublished study by Sisson and colleagues that suggests cats with symptomatic myocardial disease, compared with controls, have activation of their RAS, and sympathetic nervous system and increased concentrations of circulating natriuretic peptides whereas cats with asymptomatic myocardial disease only display significant increases in natriuretic peptide concentrations.[54]
To date there is a paucity of literature describing activation of the RAS in cats with naturally occurring myocardial disease. The largest investigation into cats with myocardial disease is an as of yet unpublished study by Sisson and colleagues that suggests cats with symptomatic myocardial disease, compared with controls, have activation of their RAS, and sympathetic nervous system and increased concentrations of circulating natriuretic peptides whereas cats with asymptomatic myocardial disease only display significant increases in natriuretic peptide concentrations.[54]
ACTIONS AND COMPLICATIONS OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS
Drugs designed to inhibit ACE …………. the formation of AT II, promote an ……………. in the circulating levels of …………… and may temporarily …………… circulating …………….. levels.
Although ACE inhibitors are frequently categorized as balanced …………….., it appears likely their beneficial effect on mortality is not mediated purely by hemodynamic alterations. They are relatively weak ……………. in comparison with direct-acting arterial …………. like ………………., and their ability to promote ……………… is much overshadowed by the less expensive loop diuretics.
Instead it is believed ACE inhibitors reduce mortality via their ability to blunt the detrimental consequences associated with long-standing activation of the ……. Their early success has helped to spearhead the current pharmacologic trend toward neurohormonal antagonism.
ACTIONS AND COMPLICATIONS OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS
Drugs designed to inhibit ACE block the formation of AT II, promote an increase in the circulating levels of bradykinin, and may temporarily reduce circulating aldosterone levels. Although ACE inhibitors are frequently categorized as balanced vasodilators, it appears likely their beneficial effect on mortality is not mediated purely by hemodynamic alterations.[55] They are relatively weak vasodilators in comparison with direct-acting arterial vasodilators like hydralazine, and their ability to promote diuresis is much overshadowed by the less expensive loop diuretics. Instead it is believed ACE inhibitors reduce mortality via their ability to blunt the detrimental consequences associated with long-standing activation of the RAS. Their early success has helped to spearhead the current pharmacologic trend toward neurohormonal antagonism.
ACE inhibiting compounds are numerous and vary in their chemical structure, potency, bioavailability, and route of elimination. The majority of ACE inhibitors, excluding captopril and lisinopril, are administered in the form of prodrugs with greater lipophilicity to enhance intestinal uptake.
Conversion to their active form occurs via a nonspecific …………..esterase in the ………. Although there are claims that some formulations produce more profound ACE inhibition, prolonged periods of efficacy, or superior tissue ACE inhibition, the importance of these characteristics is uncertain in naturally occurring heart failure. Excretion of the ACE inhibitors is principally via the ………….. although benazepril appears to display significant …………..excretion in companion animals (≈ 50% in dogs, ≈ 85% in cats). When prescribing ACE inhibitors to patients with mild renal insufficiency, recommendations have historically been to reduce both the dosage and frequency interval by approximately ……………….%.
ACE inhibiting compounds are numerous and vary in their chemical structure, potency, bioavailability, and route of elimination. The majority of ACE inhibitors, excluding captopril and lisinopril, are administered in the form of prodrugs with greater lipophilicity to enhance intestinal uptake. Conversion to their active form occurs via a nonspecific carboxyl esterase in the liver.[56] Although there are claims that some formulations produce more profound ACE inhibition, prolonged periods of efficacy, or superior tissue ACE inhibition, the importance of these characteristics is uncertain in naturally occurring heart failure. Excretion of the ACE inhibitors is principally via the kidneys although benazepril appears to display significant biliary excretion in companion animals (≈ 50% in dogs, ≈ 85% in cats).[57] When prescribing ACE inhibitors to patients with mild renal insufficiency, recommendations have historically been to reduce both the dosage and frequency interval by approximately 50%.
Enalapril administration to dogs with experimental mild renal insufficiency is associated with a significant increase in the area under the curve (AUC) for the active metabolite enalaprilat. Following ……………… administration to the same dogs there was no significant increase in the AUC for benazeprilat. Whether concurrent cardiac disease, with its relatively depressed cardiac output, would be associated with impaired benazeprilat excretion is uncertain. Current trends utilizing “standard” doses of enalapril to treat glomerulonephritis and renal insufficiency are difficult to extrapolate to patients with heart failure because of their obvious limited ability to increase renal blood flow via increasing cardiac output.
Enalapril administration to dogs with experimental mild renal insufficiency is associated with a significant increase in the area under the curve (AUC) for the active metabolite enalaprilat. Following benazepril administration to the same dogs there was no significant increase in the AUC for benazeprilat. Whether concurrent cardiac disease, with its relatively depressed cardiac output, would be associated with impaired benazeprilat excretion is uncertain. Current trends utilizing “standard” doses of enalapril to treat glomerulonephritis and renal insufficiency are difficult to extrapolate to patients with heart failure because of their obvious limited ability to increase renal blood flow via increasing cardiac output.[59]
Enalapril
Enalapril, which undergoes …………….hydrolysis to the active metabolite enalaprilat, is one of the few drugs that have been extensively evaluated in dogs with experimental and naturally occurring congestive heart failure. The oral bioavailability of enalapril, in the form of the pro-drug, is reportedly 20% to 40%[60] with peak plasma concentrations occurring approximately 30 to 40 minutes after administration.[56] Hamlin and Nakayama documented that a single 0.5 mg/kg dose of enalapril administered orally to normal dogs achieved 63%, 36%, and 28% ACE inhibition after 1.5, 12, and 24 hours, respectively.[61] Uechi and colleagues identified that 0.25 mg/kg of enalapril administered to normal cats, either once a day or twice a day, achieved 23% and 41% ACE inhibition, respectively, at 24 hours.[62] They found higher doses of enalapril (0.5 and 1.0 mg/kg, once or twice daily) were unable to significantly promote further ACE inhibition beyond that achieved with 0.25 mg/kg twice daily.
Enalapril
Enalapril, which undergoes hepatic hydrolysis to the active metabolite enalaprilat, is one of the few drugs that have been extensively evaluated in dogs with experimental and naturally occurring congestive heart failure. The oral bioavailability of enalapril, in the form of the pro-drug, is reportedly 20% to 40%[60] with peak plasma concentrations occurring approximately 30 to 40 minutes after administration.[56] Hamlin and Nakayama documented that a single 0.5 mg/kg dose of enalapril administered orally to normal dogs achieved 63%, 36%, and 28% ACE inhibition after 1.5, 12, and 24 hours, respectively.[61] Uechi and colleagues identified that 0.25 mg/kg of enalapril administered to normal cats, either once a day or twice a day, achieved 23% and 41% ACE inhibition, respectively, at 24 hours.[62] They found higher doses of enalapril (0.5 and 1.0 mg/kg, once or twice daily) were unable to significantly promote further ACE inhibition beyond that achieved with 0.25 mg/kg twice daily.
Benazepril
Similar to enalapril, benazepril is a prodrug that must undergo …………metabolism to produce the active compound benazeprilat. The bioavailability of orally administered benazepril is reportedly 38%[63] although there have been variable and conflicting degrees of ACE inhibition reported. An initial study found that peak plasma benazeprilat concentrations were achieved 2 hours after oral administration and the percentage of ACE inhibition following a single dose of 0.5 mg/kg of benazepril administered to normal dogs was 99.7%, 95.2%, and 87.3% after 2, 12, and 24 hours, respectively.[64] Similar results were found with dosages of 0.25 mg/kg (97.8%, 89.2%, and 75.7%) and 1.0 mg/kg (99.1%, 94.0%, and 83.1%). Maximal ACE inhibition following 15 doses was attained in dogs receiving 0.25 mg/kg of benazepril once daily, 96.9%, 92.5%, and 83.6% at 2, 12, and 24 hours, respectively.[64] A second study, also evaluating a single dose of 0.5 mg/kg of benazepril administered to normal dogs, found 81.0%, 37.0%, and 10.3% of ACE inhibition after 1.5, 12, and 24 hours.[61] Prolonged administration of benazepril was not evaluated. A final study evaluating 0.5 mg/kg of benazepril administered orally once daily to dogs with mitral valve insufficiency found 33.3%, 28.0%, and 42.7% ACE inhibition at 1, 2 and 4 weeks, respectively.[65] Administration of a single dose of benazepril to normal cats at 0.25, 0.5, and 1.0 mg/kg reportedly produced 92.4%, 95.1%, and 93.9% ACE inhibition, respectively, at 24 hours.[66] Following 8 days of repeated, once daily therapy the 0.25, 0.5, and 1.0 mg/kg dosing produced 93.8%, 100%, and 100% ACE inhibition, respectively, at 24 hours.[66]
Benazepril
Similar to enalapril, benazepril is a prodrug that must undergo hepatic metabolism to produce the active compound benazeprilat. The bioavailability of orally administered benazepril is reportedly 38%[63] although there have been variable and conflicting degrees of ACE inhibition reported. An initial study found that peak plasma benazeprilat concentrations were achieved 2 hours after oral administration and the percentage of ACE inhibition following a single dose of 0.5 mg/kg of benazepril administered to normal dogs was 99.7%, 95.2%, and 87.3% after 2, 12, and 24 hours, respectively.[64] Similar results were found with dosages of 0.25 mg/kg (97.8%, 89.2%, and 75.7%) and 1.0 mg/kg (99.1%, 94.0%, and 83.1%). Maximal ACE inhibition following 15 doses was attained in dogs receiving 0.25 mg/kg of benazepril once daily, 96.9%, 92.5%, and 83.6% at 2, 12, and 24 hours, respectively.[64] A second study, also evaluating a single dose of 0.5 mg/kg of benazepril administered to normal dogs, found 81.0%, 37.0%, and 10.3% of ACE inhibition after 1.5, 12, and 24 hours.[61] Prolonged administration of benazepril was not evaluated. A final study evaluating 0.5 mg/kg of benazepril administered orally once daily to dogs with mitral valve insufficiency found 33.3%, 28.0%, and 42.7% ACE inhibition at 1, 2 and 4 weeks, respectively.[65] Administration of a single dose of benazepril to normal cats at 0.25, 0.5, and 1.0 mg/kg reportedly produced 92.4%, 95.1%, and 93.9% ACE inhibition, respectively, at 24 hours.[66] Following 8 days of repeated, once daily therapy the 0.25, 0.5, and 1.0 mg/kg dosing produced 93.8%, 100%, and 100% ACE inhibition, respectively, at 24 hours.[66]
Adverse Effects
The mechanism through which ACE inhibitors exert their beneficial properties (e.g., inhibition of …………………production) also lends to the potential for adverse consequences.
Although infrequently encountered the complications may include systemic ………….., …………….. and ………………..
Adverse Effects
The mechanism through which ACE inhibitors exert their beneficial properties (e.g., inhibition of AT II production) also lends to the potential for adverse consequences.
Although infrequently encountered the complications may include systemic hypotension, azotemia and hyperkalemia.
ACE inhibitors reduce systemic vascular ……………… by decreasing circulating levels of ………… and increasing circulating levels of ……………….
In patients with severe heart failure wherein an increase in cardiac output is unable to sustain systemic blood pressure, symptomatic ……………..may develop. Although this complication is infrequent, its likelihood increases during concomitant use of high-dose diuretics. Unfortunately the clinical signs associated with severe, low-output heart failure and systemic hypotension are very similar, e.g., weakness, exercise intolerance, and possibly stupor. This should stress that patients appearing refractory to medical management should have their blood pressure evaluated prior to instituting more aggressive measures to combat heart failure.
ACE inhibitors reduce systemic vascular resistance by decreasing circulating levels of AT II and increasing circulating levels of bradykinin.
In patients with severe heart failure wherein an increase in cardiac output is unable to sustain systemic blood pressure, symptomatic hypotension may develop. Although this complication is infrequent, its likelihood increases during concomitant use of high-dose diuretics. Unfortunately the clinical signs associated with severe, low-output heart failure and systemic hypotension are very similar, e.g., weakness, exercise intolerance, and possibly stupor. This should stress that patients appearing refractory to medical management should have their blood pressure evaluated prior to instituting more aggressive measures to combat heart failure.
A second adverse effect attributed to ACE inhibitors unique ability to decrease AT II production is a reduction in ………………. and the development of ……………..
A second adverse effect attributed to ACE inhibitors unique ability to decrease AT II production is a reduction in glomerular filtration rate (GFR) and the development of azotemia.
GFR is determined by the glomerular capillary pressure (GCP). Based on the knowledge that pressure is equal to the product of ……………. and …………… (P = Q * R) we can ascertain that GFR is ultimately determined by renal …………………and the degree of ……………..arteriolar ……………….(Figure 243-2).
GFR is determined by the glomerular capillary pressure (GCP). Based on the knowledge that pressure is equal to the product of flow and resistance (P = Q * R) we can ascertain that GFR is ultimately determined by renal plasma flow and the degree of efferent arteriolar vasoconstriction (Figure 243-2).
In cases of heart failure when renal plasma flow is diminished the GFR is supported by the ability of ……. to constrict the…………… renal arteriole.
ACE inhibitors ability to depress production of ………. will promote efferent renal arteriolar ……………. and hence a reduction in GFR.
The failing heart cannot further increase cardiac output and an acute bout of azotemia may subsequently develop.
In cases of heart failure when renal plasma flow is diminished the GFR is supported by the ability of AT II to constrict the efferent renal arteriole. ACE inhibitors ability to depress production of AT II will promote efferent renal arteriolar vasodilation and hence a reduction in GFR.
The failing heart cannot further increase cardiac output and an acute bout of azotemia may subsequently develop. A recent study evaluating the early institution of enalapril to dogs with compensated mitral valve insufficiency found that dogs allocated to ACE inhibitor were not at a more significant risk of developing azotemia compared to dogs receiving placebo.[67] In our experience mild increases in BUN and creatinine following the institution of an ACE inhibitor and furosemide occur frequently. However the development of severe azotemia, necessitating discontinuation or reduction in the dose of ACE inhibitor, appears infrequent. This complication seems to occur most readily in patients with severe heart failure that require aggressive diuretic administration to control their congestive signs. Prior to the institution of enalapril we evaluate the baseline biochemical parameters and follow with a second measure of BUN, creatinine, and electrolytes 5 to 7 days after starting therapy. If patients become anorectic or develop gastrointestinal signs during this time we instruct the owners to discontinue the administration of all drugs and immediately seek veterinary attention.
Figure 243-2 The glomerular capillary pressure (GCP), and hence glomerular filtration rate (GFR), is determined by the cardiac output and relative resistances imparted by the afferent and efferent renal arterioles. Compared to normal (A) angiotensin converting enzyme inhibitors preferentially dilate the efferent renal arteriole (B) and may therefore decrease GFR and promote the development of azotemia. It appears this consequence is most frequent in animals with low output heart failure that require high doses of diuretics to control their congestive signs.
Figure 243-2 The glomerular capillary pressure (GCP), and hence glomerular filtration rate (GFR), is determined by the cardiac output and relative resistances imparted by the afferent and efferent renal arterioles. Compared to normal (A) angiotensin converting enzyme inhibitors preferentially dilate the efferent renal arteriole (B) and may therefore decrease GFR and promote the development of azotemia. It appears this consequence is most frequent in animals with low output heart failure that require high doses of diuretics to control their congestive signs.
………………… may be encountered during therapy with ACE inhibitors because of a reduction of GFR and a decline in circulating aldosterone levels. In the absence of aldosterone, ………….. loss is favored while ………….levels rise.
Hyperkalemia may be encountered during therapy with ACE inhibitors because of a reduction of GFR and a decline in circulating aldosterone levels. In the absence of aldosterone, sodium loss is favored while potassium levels rise.
It appears this complication is infrequent presumably because most of our potent diuretics display potassium-wasting properties and tend to prevent the development of hyperkalemia. We have rarely encountered an increase in potassium that necessitated dosage reduction or discontinuation of an ACE inhibitor. There is concern that the addition of spironolactone may further potentiate hyperkalemia, therefore periodic electrolyte monitoring is prudent in patients receiving an ACE inhibitor and a potassium-sparing diuretic.
Drug Interactions
Because aspirin inhibits ……………. and decreases …………. formation, there has been concern the administration of aspirin may negate some of the beneficial ……………..properties exerted by ACE inhibitors. There is further concern that the ability of aspirin to reduce renal ………… formation may worsen the ACE-inhibitor induced reduction of GFR.
Drug Interactions
Because aspirin inhibits cyclooxygenase and decreases prostaglandin formation, there has been concern the administration of aspirin may negate some of the beneficial vasodilatory properties exerted by ACE inhibitors.[68] There is further concern that the ability of aspirin to reduce renal prostaglandin formation may worsen the ACE-inhibitor induced reduction of GFR.
A recent retrospective analysis of six long-term randomized trials of ACE inhibitors found that aspirin did not significantly alter the benefits of ACE inhibitors on the development of CHF.[69] Whether other commonly prescribed nonsteroidal antiinflammatory agents blunt the potentially beneficial vasodilatory properties of ACE inhibitors is uncertain
VASODILATORS
Vasodilators are agents that promote ……………………. of the arterioles (arterial vasodilators), veins (venodilators), or arteries and veins (balanced vasodilators). Although these drug classes promote a similar therapeutic endpoint, i.e., vasodilation, they display a variety of mechanisms to achieve their effect.
VASODILATORS
Vasodilators are agents that promote smooth muscle relaxation of the arterioles (arterial vasodilators), veins (venodilators), or arteries and veins (balanced vasodilators). Although these drug classes promote a similar therapeutic endpoint, i.e., vasodilation, they display a variety of mechanisms to achieve their effect.
