nearly all forms of acute glomerulonephritis have a tendency to progress to chronic...

8/6/2019 Nearly All Forms of Acute Glomerulonephritis Have a Tendency to Progress to Chronic Glomerulonephritis

1/85

Nearly all forms of acute glomerulonephritis have a

tendency to progress to chronic glomerulonephritis. The

condition is characterized by irreversible and progressiveglomerular and tubulointerstitial fibrosis, ultimately leading

to a reduction in the glomerular filtration rate (GFR) and

retention of uremic toxins. If disease progression is not

halted with therapy, the net result is chronic kidney disease

(CKD), end-stage renal disease (ESRD), and cardiovasculardisease. The diagnosis of CKD can be made without

knowledge of the specific cause.

The National Kidney Foundation defines CKD as (1)

evidence of kidney damage based on abnormal urinalysis

results (eg, proteinuria, hematuria) or structural

abnormalities observed on ultrasound images or (2) a GFR

of less than 60 mL/min for 3 or more months. Based on this

definition, the National Kidney Foundation developed

guidelines that classify the progression of renal disease into 5

stages, from kidney disease with a preserved GFR to end-

stage kidney failure. This classification includes treatment

strategies for each progressive level, as follows:


2/85

y Stage 1: This stage is characterized by kidney damagewith a normal GFR ( 90 mL/min). The action plan is

diagnosis and treatment, treatment of comorbidconditions, slowing of the progressing of kidney disease,

and reduction of cardiovascular disease risks.

y Stage 2: This stage is characterized by kidney damagewith a mild decrease in the GFR (60-90 mL/min). The

action plan is estimation of the progression of kidneydisease.

y Stage 3: This stage is characterized by a moderatelydecreased GFR (30-59 mL/min). The action plan is

evaluation and treatment of complications.

y Stage 4: This stage is characterized by a severe decreasein the GFR (15-29 mL/min). The action plan is

preparation for renal replacement therapy.

y Stage 5: This stage is characterized by kidney failure.The action plan is kidney replacement if the patient is

uremic.

At the later stages of glomerular injury, biopsy results

cannot help distinguish the primary disease. Histology and


3/85

clues to the etiology are often derived from other systemic

diseases, if present. Considerable cause-specific variability is

observed in the rate at which acute glomerulonephritisprogresses to chronic glomerulonephritis.

Pathophysiology

Reduction in nephron mass from the initial injury reduces

the GFR. This reduction leads to hypertrophy and

hyperfiltration of the remaining nephrons and to the

initiation of intraglomerular hypertension. These changes

occur in order to increase the GFR of the remaining

nephrons, thus minimizing the functional consequences of

nephron loss. The changes, however, are ultimately

detrimental because they lead to glomerulosclerosis and

further nephron loss.

In early renal disease (stages 1-3), a substantial decline in the

GFR may lead to only slight increases in serum creatinine

levels. Azotemia (ie, a rise in BUN and serum creatinine

levels) is apparent when the GFR decreases to less than 60-

70 mL/min. In addition to a rise in BUN and


4/85

creatininelevels, the substantial reduction in the GFR results

in decreased production of (1) erythropoietin, thus resulting

in anemia; (2) decreased production of vitamin D, resultingin hypocalcemia, secondary hyperparathyroidism,

hyperphosphatemia, and renal osteodystrophy; (3) reduction

in acid, potassium, salt, and water excretion, resulting in

acidosis, hyperkalemia, hypertension, and edema; and (4)

platelet dysfunction, leading to increased bleedingtendencies.

Accumulation of toxic waste products (uremic toxins) affects

virtually all organ systems. Azotemia occurring with the

signs and symptoms listed above is known as uremia.

Uremia occurs at a GFR of approximately 10 mL/min. Some

of these toxins (eg, BUN, creatinine, phenols, guanidines)

have been identified, but none has been found to be

responsible for all the symptoms.

Epidemiology

Frequency

United States


5/85

Chronic glomerulonephritis is the third leading cause of

ESRD and accounts for 10% of patients on dialysis in the

United States.

International

Chronic glomerulonephritis accounted for up to 40% of

patients on dialysis in Japan and some Asian countries.

However, more recent data suggest that, in Japan forinstance, the rate of chronic glomerulonephritis in patients

on dialysis is 28%. The cause of this declining rate is not

known. Concurrent with the decline in chronic

glomerulonephritis in these countries is an increase in

diabetic nephropathy in up to 40% of patients on dialysis.

Mortality/Morbidity

ESRD and death are common outcomes unless renal

replacement therapy is instituted.

Physical


6/85

Cause-specific physical examination findings are discussed

in articles on the specific causes. See Causes for links to such

articles.

y Uremia-specific findingso Hypertensiono Jugular venous distension (if severe volume

overload is present)

o Pulmonary rales (if pulmonary edema is present)o Pericardial friction rub in pericarditiso Tenderness in the epigastric region or blood in the

stool (possible indicators for uremic gastritis or

enteropathy)

o Decreased sensation and asterixis (indicators foradvanced uremia)

Causes

The progression from acute glomerulonephritis to chronic

glomerulonephritis is variable. Whereas complete recovery

of renal function is the rule for patients with


7/85

poststreptococcal glomerulonephritis, several other

glomerulonephritides, such as immunoglobulin A (IgA)

nephropathy, often have a relatively benign course andmany do not progress to ESRD.

y Rapidly progressive glomerulonephritis or crescenticglomerulonephritis: Approximately 90% of patients

progress to ESRD within weeks or months.

y Focal segmental glomerulosclerosis: Approximately80% of patients progress to ESRD in 10 years. Patients

with the collapsing variant, which is termed malignant

focal segmental glomerulosclerosis, have a more rapid

progression. This form may be idiopathic or related to

HIV infection.

y Membranous nephropathy: Approximately 20-30% ofpatients with membranous nephropathy progress to

chronic renal failure (CRF) and ESRD in 10 years.

y Membranoproliferative glomerulonephritis:Approximately 40% of patients with

membranoproliferative glomerulonephritis progress to

CRF and ESRD in 10 years.


8/85

y IgA nephropathy: Approximately 10% of patients withIgA nephropathy progress to CRF and ESRD in 10

years.

[1]

y Poststreptococcal glomerulonephritis: Approximately 1-2% of patients with poststreptococcal

glomerulonephritis progress to CRF and ESRD. Older

children who present with crescentic

glomerulonephritis are at greatest risk.y Lupus nephritis: Overall, approximately 20% of

patients with lupus nephritis progress to CRF and

ESRD in 10 years; however, patients with certain

histologic variants (eg, class IV) may have a more rapid

decline.

Differentials

y Azotemiay Chronic Renal Failurey Glomerulonephritis, Acutey Glomerulonephritis, Crescenticy Glomerulonephritis, Diffuse Proliferative


9/85

y Glomerulonephritis, Membranoproliferativey Glomerulonephritis, Membranousy

Glomerulonephritis, Nonstreptococcal Associated WithInfection

y Glomerulonephritis, Poststreptococcaly Glomerulonephritis, Rapidly Progressivey Uremia

Laboratory Studies

y Urinalysiso The presence of dysmorphic RBCs, albumin, or

RBC casts suggests glomerulonephritis as the cause

of renal failure.

o Waxy or broad casts are observed in all forms ofCKD, including chronic glomerulonephritis.

o Low urine-specific gravity indicates loss of tubularconcentrating ability, an early finding in persons

with CDK.

y Urinary protein excretion


10/85

o This can be estimated by calculating the protein-to-creatinine ratio on a spot morning urine sample.

The ratio of urinary protein concentration (inmg/dL) to urinary creatinine (in mg/dL) reflects

24-hour protein excretion in grams. For instance, if

the spot urine protein value is 300 mg/dL and the

creatinine value is 150 mg/dL, then the ratio is 300

divided by 150, which equals 2. Thus, in thisexample, the 24-hour urine protein excretion is 2 g.

o The estimated creatinine clearance rate is used toassess and monitor the GFR. The 2 formulas

available to calculate the value are the Cockroft-

Gault formula, which estimates creatinine

clearance, and the Modification of Diet in Renal

Disease Study (MDRD) formula, which is used to

calculate the GFR. The Cockroft-Gault formula is

simple to use but overestimates the GFR by 10-

15% because creatinine is both filtered and

secreted. The MDRD formula is much more

complex but is available as a PDA through the

National Kidney Foundation or can be calculated


11/85

online through the Hypertension, Dialysis, and

Clinical Nephrology Web site.

oThe estimated creatinine clearance rate is also usedto monitor response to therapy and to initiate an

early transition to renal replacement therapy (eg,

dialysis access placement, transplantation

evaluation). The degree of proteinuria, especially

albuminuria, helps predict renal prognosis inpatients with chronic glomerulonephritis. Patients

with greater than 1 g/d have an increased risk of

progression to ESRD.

o In a study of 38 patients with chronic

glomerulonephritis, Hayakawa et al examined the

relationship between plasma adiponectin, leptin,

and proteinuria levels; glomerular filtration rate;

and metabolic risk factors.[2] They found that

plasma adiponectin levels were much higher in

patients with heavy proteinuria (38.8 +/- 27.8

g/mL) than they were in patients who had mild

(13.3 +/- 5.1 g/mL, P < 0.001) or moderate

proteinuria (18.1 +/- 8.0 g/mL, P < 0.01). Serum


12/85

leptin levels, however, did not differ according to

the degree of proteinuria.

yCBC count

o Anemia is a significant finding in patients withsome decline in the GFR.

o Physicians must be aware that anemia can occureven in patients with serum creatinine levels of less

than 2 mg/dL. Even severe anemia can occur at lowserum creatinine levels. Anemia is the result of

marked impairment of erythropoietin production.

y Serum chemistryo Serum creatinine and urea nitrogen levels are

elevated.

o Impaired excretion of potassium, free water, andacid results in hyperkalemia, hyponatremia, and

low serum bicarbonate levels, respectively.

o Impaired vitamin D-3 production results in

hypocalcemia, hyperphosphatemia, and high levels

of parathyroid hormone.


13/85

o Low serum albumin levels may be present ifuremia interferes with nutrition or if the patient is

nephrotic.

Imaging Studies

y Renal ultrasonogramo Obtain a renal ultrasonogram to determine renal

size, to assess for the presence of both kidneys, and

to exclude structural lesions that may be

responsible for azotemia.

o Small kidneys often indicate an irreversibleprocess.

Procedures

y Kidney biopsyo If the kidney is small, kidney biopsy is usually

unnecessary; no specific pattern of disease can be

discerned at this point.

o A kidney biopsy may be considered in the minorityof patients who exhibit an acute exacerbation of


14/85


15/85

hypocalcemia, hyperparathyroidism) before renal

replacement therapy. Also, aggressively manage comorbid

conditions, such as heart disease and diabetes.

y The target pressure for patients with proteinuriagreater than 1 g/d is less than 125/75 mm Hg; for

patients with proteinuria less than 1 g/d, the target

pressure is less than 130/80 mm Hg.

o Angiotensin-converting enzyme inhibitors (ACEIs)are commonly used and are usually the first choice

for treatment of hypertension in patients with

CRF. ACEIs are renoprotective agents that have

additional benefits beyond lowering pressure.

ACEIs effectively reduce proteinuria, in part by

reducing the efferent arteriolar vascular tone,

thereby decreasing intraglomerular hypertension.

Particularly, ACEIs have been shown to be

superior to conventional therapy in slowing the

decline of the GFR in patients with diabetic and

nondiabeticproteinuric nephropathies. Therefore,

consider ACEIs for treatment of even


16/85

normotensive patients with significant

proteinuria.[3]

oThe role of angiotensin II receptor blockers (ARBs)in renal protection is increasingly being

established, and these medications have been found

to retard the progression of CKD in patients with

diabetic or nondiabetic nephropathy in a manner

similar to that of ACEIs.o Combination therapy with ACEIs and ARBs has

been shown to confer superior pressure control and

preservation of renal function than either therapy

alone. Therefore, in patients without hyperkalemia

or an acute rise in serum creatinine levels following

the use of either therapy, combination therapy

should be attempted.

o Diuretics are often required because of decreasedfree-water clearance, and high doses may be

required to control edema and hypertension when

the GFR falls to less than 25 mL/min. Diuretics are

also useful in counteracting the hyperkalemic

potential of ACEIs and ARBs. However, diuretics


17/85

should be used with caution when given together

with ACEIs or ARBs because the decline in

intraglomerular pressure induced by ACEIs orARBs may be exacerbated by volume depletion

induced by diuretics, potentially precipitating acute

renal failure.

o Beta-blockers, calcium channel blockers, central

alpha-2 agonists (eg, clonidine), alpha-1antagonists, and direct vasodilators (eg, minoxidil,

nitrates) may be used to achieve the target

pressure.

y Because progressive fibrosis is the hallmark of chronic

glomerulonephritis, some investigators have focused

their work on finding inhibitors of fibrosis in an

attempt to slow progression. Of many compounds,

pirfenidone, an inhibitor of transforming growth factor

beta, and hence of collagen synthesis, has emerged as

the candidate compound. Cho et al performed an open

label study on 21 patients with idiopathic and

postadaptive focal segmental glomerulosclerosis.[4] They

found a median 25% improvement in the rate of decline


18/85

of the estimated GFR (P < 0.01). Pirfenidone did not

effect proteinuria or blood pressure. Among the adverse

events attributed to therapy were dyspepsia, sedation,and photosensitive dermatitis. Pirfenidone offers hope

in slowing progressive fibrosis; however, more studies

are needed.

y Renal osteodystrophy can be managed early by

replacing vitamin D and by administering phosphatebinders. Seek and treat nonuremic causes of anemia,

such as iron deficiency, before instituting therapy with

erythropoietin.

y Discuss options for renal replacement therapy (eg,

hemodialysis, peritoneal dialysis, renal transplantation).

Arrange permanent vascular access when the GFR

decreases to less than 20-25 mL/min, when the serum

creatinine level is greater than 4 mg/dL, or if the rate of

rise in the serum creatinine level indicates the need for

dialysis within 1 year. Arteriovenous fistulas are

preferred to arteriovenous grafts because of their long-

term high-patency rates and should be placed whenever


19/85

possible. Place peritoneal dialysis catheters 2-3 weeks

prior to anticipated dialysis therapy.

yTreat hyperlipidemia (if present) to reduce overallcardiovascular comorbidity, even though evidence for

renal protection is lacking.

y Expose patients to educational programs for earlyrehabilitation from dialysis or transplantation.

y Surgical Carey Create access for dialysis when the GFR decreases to

less than 25 mL/min

Consultations

y Nephrologists: Early referral of patients with CRF to anephrologist is important for the management of

complications and the organization of the transition to

renal replacement therapy (eg, hemodialysis, peritoneal

dialysis, renal transplantation). Some evidence indicates

that early referral of a patient with CRF (serum

creatinine, 1.5-2 mg/dL) to a nephrologist improves the

short-term outcome.


20/85


21/85

y Encourage patients to increase their activity level astolerated. Increased activity may aid in blood pressure

control

y Medication Summary

y The goals of pharmacotherapy are to reduce morbidityand to prevent complications.

y Angiotensin-converting enzyme inhibitors

y Class Summaryy For renoprotection. Decrease intraglomerular pressure

and, consequently, glomerular protein filtration, by

decreasing efferent arteriolar constriction.[3]

y View full drug information

y Enalapril (Vasotec)y Competitive inhibitor of ACE. Reduces angiotensin II

levels, thus decreases aldosterone secretion. Decreases

intraglomerular pressure and glomerular protein

filtration by decreasing efferent arteriolar constriction.

y Diuretics


22/85

y Class Summaryy Treat edema and hypertension. Increase urine excretion

by inhibiting sodium and chloride transporters.


y Furosemide (Lasix)y DOC as a diuretic. Increases excretion of water by

interfering with chloride-binding cotransport system,

which, in turn, inhibits sodium and chloride

reabsorption in ascending loop of Henle and distal renal

tubule.


y Metolazo

ne (

Mykrox, Zaroxoly

n)

y Treats edema in congestive heart failure. Increasesexcretion of sodium, water, potassium, and hydrogen

ions by inhibiting reabsorption of sodium in distal

tubules. May be more effective in impaired renal

function.

y Calcium channel blockers


23/85

y Class Summaryy Treat hypertension, angina, and atrial fibrillation.[5]

y View full drug informationy Amlodipine (Norvasc)y Blocks slow calcium channels, causing relaxation of

vascular smooth muscles.


y Nifedipine (Procardia)y Relaxes coronary smooth muscle and produces

coronary vasodilation, which, in turn, improves

myocardial oxygen delivery. SL administration

generally safe, despite theoretical concerns.

y Beta-adrenergic blockers

y Class Summaryy Compete with beta-adrenergic agonists for available

beta-receptor sites. Propranolol, nadolol, timolol,

penbutolol, carteolol, sotalol, and pindolol inhibit both

beta-1 receptors (located mainly in cardiac muscle) and

beta-2 receptors (located mainly in bronchial and


24/85

vascular musculature), thus inhibiting chronotropic,

inotropic, and vasodilatory responses to beta-adrenergic

stimulation.


y Metoprolol (Lopressor)y Selective beta1-adrenergic receptor blocker that

decreases automaticity of contractions. During IV

administration, carefully monitor blood pressure, heart

rate, and ECG.

y Alpha-adrenergic agonists

y Class Summaryy Used in combination with other agents for management

of hypertension.


y Clonidine (Catapres)y

Stimulates presynaptic (central) alpha-2 agonist,thereby reducing norepinephrine release and peripheral

vasoconstriction


25/85

y Further Inpatient Care

y Patients with CKD admitted to the hospital should have

careful monitoring of weight, intake, output, and renal

function so that acute renal failure, if it occurs, can be

diagnosed and treated early. All potentially nephrotoxic

agents must be adjusted for the degree of CKD.

Furthermore, agents, such as nonsteroidal anti-

inflammatory drugs (NSAIDs), aminoglycosides, and

intravenous contrast, must be avoided, unless the

benefits clearly outweigh the risks, because these agents

are highly associated with acute renal failure.

yFurther Outpatient Care

y Patients with any evidence of kidney disease should bereferred to a kidney specialist (nephrologist). Data

suggest that early referral to a nephrologist improves

the overall outcome. The nephrologist will usually

determine the frequency of visits based on the degree of

CKD.

Complications


26/85

y The presence of the following complications generallyindicates a need for urgent dialysis:

oMetabolic acidosis

o Pulmonary edemao Pericarditiso Uremic encephalopathyo Uremic gastrointestinal bleeding

o Uremic neuropathyo Severe anemia and hypocalcemiao Hyperkalemia

y Prognosis

y The prognosis depends on the type of chronicglomerulonephritis (see Causes).

Patient Education

y For further information, see Mayo Clinic - KidneyTransplant Information.

y Dietary education is paramount in managing patientswith CKD. The typical dietary restriction is 2 g of

sodium, 2 g of potassium, and 40-60 g of protein a day.


27/85

Additional restrictions may apply for diabetes,

hyperlipidemia, and fluid overload.

yPatients should be educated regarding the types ofESRD therapy. The specific choices of ESRD therapy

include hemodialysis, peritoneal dialysis, and renal

transplantation.

o Patients opting for hemodialysis should be

educated on home hemodialysis (ie, patients aretrained to do their dialysis at home) and center

hemodialysis (ie, patients must come to a center 3

times a week for 3.5- to 4-hour dialysis sessions).

They should also be educated on the types of

vascular access. Arteriovenous fistulae should be

created when the GFR falls below 25 mL/min or

the serum creatinine level is greater than 4 mg/dL

to allow for maturation of the access prior to the

initiation of dialysis.

o Peritoneal dialysis catheters can be placed ifdialysis is anticipated within 2-3 weeks.

o Preemptive transplantation before the initiation ofdialysis improves survival as compared with


28/85

transplantation after the initiation of dialysis;

therefore, preemptive transplantation should be

explored from live donors. In patients without livedonors, they can be placed on the deceased donor

wait list when the GFR falls below 20 mL/min to

accrue time. Patients who opt for no treatment

when it is indicated should be informed of

imminent renal failure in a shorter time.y In the United States and most developed countries,

patients on dialysis can travel. In fact, there are even

dialysis cruises. However, patients should inform their

social workers to make the necessary arrangements

prior to any travel to ensure that the destination has the

right resources to continue dialysis.

y Sexual dysfunction and loss of libido is common inpatients with kidney disease, especially in men. Patients

should be told to seek medical therapy if they

experience these symptoms

Adult Dosing & Uses


29/85

Dosing Forms & Strengths

injectable solution

y 1.25mg/mL

oral solution

y 1mg/mL

tablet

y 2.5mgy 5mgy 10mgy 20mg

Hypertension

Initial: 2.5-5 mg PO qDay

Maintenance: 10-40 mg/day PO qDay or divided BID

Left Ventricular Dysfunction

Initial 2.5 mg PO BID, may titrate up to 20 mg/day


30/85

Congestive Heart Failure

Initial: 2.5 mg PO qDay/BID

Maintenance: 5-20 mg/day PO

IV: 1.25-5 mg q6hr

Renal Impairment

CrCl


31/85

Good choice in hyperlipidemia pts

Requires weeks for full effect; to start, use low dose & titrate

q1-2wk

Abrupt discontinuance not associated with rapid increase in

BP

See also combo with HCTZ

Other Indications & Uses

Off-label: Diabetic nephropathy

Pediatric Dosing & Uses

Dosing Forms & Strengths

injectable solution

y 1.25mg/mL

oral solution

y 1mg/mL

tablet


32/85


33/85

inhibitors. D/C ACE inhibitor 72h prior to use of

protein A column.

Serious - Use Alternative (2)

y allopurinol

enalapril, allopurinol. Mechanism: unknown. Serious -

Use Alternative.Risk of anaphylaxis, Stevens Johnson

syndrome.

y pregabalin

enalapril, pregabalin. Either increases toxcity of the

other by pharmacodynamic synergism. Serious - Use

Alternative.Additive risk of developing angioedema of

face, mouth, and neck, including respiratory

compromise.

Significant - Monitor Closely (98)

y acetohexamide


34/85

enalapril increases effects of acetohexamide by

pharmacodynamic synergism. Significant - Monitor

Closely.

y aldesleukin

aldesleukin increases effects of enalapril by


Closely. Risk of hypotension.

y alfuzosin

enalapril, alfuzosin. Mechanism: pharmacodynamic

synergism. Significant - Monitor Closely. Exaggerated

first dose hypotensive response.

y aluminum hydroxide

aluminum hydroxide decreases effects of enalapril by

unspecified interaction mechanism. Significant -

Monitor Closely.

y amifostine


35/85

amifostine increases effects of enalapril by


Closely. Risk of hypotension.

y amiloride

enalapril, amiloride. Mechanism: pharmacodynamic

synergism. Significant - Monitor Closely. Risk of

hyperkalemia.

y asenapine

enalapril, asenapine. Mechanism: pharmacodynamic



y aspirin

aspirin decreases effects of enalapril by

pharmacodynamic antagonism. Significant - Monitor

Closely. NSAIDs decrease synthesis of vasodilatingrenal prostaglandins, and thus affect fluid homeostasis

and may diminish antihypertensive effect.


36/85

enalapril, aspirin. Either increases toxcity of the other

by Other (see comment). Significant - Monitor Closely.

Comment: May result in renal function deterioration,particularly in elderly or volume depleted individuals.

y azathioprine

enalapril, azathioprine. Mechanism: pharmacodynamic

synergism. Significant - Monitor Closely. Risk ofneutropenia.

y bumetanide

enalapril, bumetanide. Mechanism: pharmacodynamic

synergism. Significant - Monitor Closely. Risk of acutehypotension, renal insufficiency.

y calcium carbonate

calcium carbonate decreases effects of enalapril by

unspecified interaction mechanism. Significant -Monitor Closely.

y carbamazepine


37/85

enalapril increases levels of carbamazepine by

decreasing metabolism. Significant - Monitor Closely.

y carbidopa

carbidopa increases effects of enalapril by


Closely. Consider decreasing dosage of antihypertensive

agent.

y carbonyl iron

enalapril, carbonyl iron. Mechanism: unknown.

Significant - Monitor Closely. Risk of GI symptoms,

hypotension.

y celecoxib

celecoxib decreases effects of enalapril by





38/85

enalapril, celecoxib. Either increases toxcity of the other


Comment: May result in renal function deterioration,particularly in elderly or volume depleted individuals.

y chlorpropamide

enalapril increases effects of chlorpropamide by

pharmacodynamic synergism. Significant - MonitorClosely.

y choline magnesium trisalicylate

choline magnesium trisalicylate decreases effects of

enalapril by pharmacodynamic antagonism. Significant- Monitor Closely. NSAIDs decrease synthesis of

vasodilating renal prostaglandins, and thus affect fluid

homeostasis and may diminish antihypertensive effect.

enalapril, choline magnesium trisalicylate. Eitherincreases toxcity of the other by Other (see comment).

Significant - Monitor Closely. Comment: May result in


39/85

renal function deterioration, particularly in elderly or

volume depleted individuals.

y cyclosporine

enalapril increases levels of cyclosporine by unknown

mechanism. Significant - Monitor Closely.

enalapril, cyclosporine. Mechanism: unspecifiedinteraction mechanism. Significant - Monitor Closely.

Risk of acute renal failure.

y diclofenac

diclofenac decreases effects of enalapril bypharmacodynamic antagonism. Significant - Monitor

Closely. NSAIDs decrease synthesis of vasodilating

renal prostaglandins, and thus affect fluid homeostasis


enalapril, diclofenac. Either increases toxcity of the

other by Other (see comment). Significant - Monitor

Closely. Comment: May result in renal function


40/85

deterioration, particularly in elderly or volume depleted

individuals.

y diflunisal

diflunisal decreases effects of enalapril by



renal prostaglandins, and thus affect fluid homeostasisand may diminish antihypertensive effect.

enalapril, diflunisal. Either increases toxcity of the


Closely. Comment: May result in renal functiondeterioration, particularly in elderly or volume depleted

individuals.

y digoxin

enalapril increases levels of digoxin by unspecifiedinteraction mechanism. Significant - Monitor Closely.

y doxazosin


41/85

enalapril, doxazosin. Mechanism: pharmacodynamic



y drospirenone

enalapril, drospirenone. Mechanism:


Closely. Risk of hyperkalemia.

y eplerenone

enalapril, eplerenone. Mechanism: pharmacodynamic


hyperkalemia.

y ethacrynic acid

enalapril, ethacrynic acid. Mechanism:


Closely. Risk of acute hypotension, renal insufficiency.

y etodolac


42/85

etodolac decreases effects of enalapril by




enalapril, etodolac. Either increases toxcity of the other

by Other (see comment). Significant - Monitor Closely.Comment: May result in renal function deterioration,

particularly in elderly or volume depleted individuals.

y exenatide

enalapril increases effects of exenatide by Other (seecomment). Significant - Monitor Closely. Comment:

ACE inhibitors may increase hypoglycemic effect.

Monitor glycemic control especially during the first

month of treatment with an ACE inhibitor. .

y fenoprofen

fenoprofen decreases effects of enalapril by



43/85




enalapril, fenoprofen. Either increases toxcity of the



deterioration, particularly in elderly or volume depletedindividuals.

y ferric carboxymaltose

enalapril, ferric carboxymaltose. Mechanism: unknown.

Significant - Monitor Closely. Risk of GI symptoms,hypotension.

y ferric gluconate

enalapril, ferric gluconate. Mechanism: unknown.

Significant - Monitor Closely. Risk of GI symptoms,hypotension.

y ferrous fumarate


44/85

enalapril, ferrous fumarate. Mechanism: unknown.


hypotension.

y ferrous sulfate

enalapril, ferrous sulfate. Mechanism: unknown.


hypotension.

y floctafenine

floctafenine decreases effects of enalapril by




enalapril, floctafenine. Either increases toxcity of the

other by Other (see comment). Significant - MonitorClosely. Comment: May result in renal function


individuals.


45/85

y flurbiprofen

flurbiprofen decreases effects of enalapril by





enalapril, flurbiprofen. Either increases toxcity of the




individuals.

y furosemide

enalapril, furosemide. Mechanism: pharmacodynamic

synergism. Significant - Monitor Closely. Risk of acute

hypotension, renal insufficiency.

y glimepiride


46/85

enalapril increases effects of glimepiride by


Closely.

y glipizide

enalapril increases effects of glipizide by


Closely.

y gliquidone

enalapril increases effects of gliquidone by


Closely.

y glyburide

enalapril increases effects of glyburide by


Closely.

y gold sodium thiomalate


47/85


48/85

indomethacin decreases effects of enalapril by




enalapril, indomethacin. Either increases toxcity of the



individuals.

y insulin aspart

enalapril increases effects of insulin aspart by


Closely.

y insulin detemir

enalapril increases effects of insulin detemir by


Closely.


49/85

y insulin glargine

enalapril increases effects of insulin glargine by


Closely.

y insulin glulisine

enalapril increases effects of insulin glulisine by


Closely.

y insulin lispro

enalapril increases effects of insulin lispro by


Closely.

y insulin nph

enalapril increases effects of insulin nph by


Closely.

y insulin regular human


50/85

enalapril increases effects of insulin regular human by


Closely.

y iron dextran complex

enalapril, iron dextran complex. Mechanism: unknown.


hypotension.

y iron sucrose

enalapril, iron sucrose. Mechanism: unknown.


hypotension.

y itraconazole

itraconazole increases levels of enalapril by decreasing

metabolism. Significant - Monitor Closely.

y ketoconazole

ketoconazole increases levels of enalapril by decreasing

metabolism. Significant - Monitor Closely.


51/85


52/85

enalapril, ketorolac. Either increases toxcity of the



individuals.

y ketorolac intranasal

ketorolac intranasal decreases effects of enalapril bypharmacodynamic antagonism. Significant - Monitor




enalapril, ketorolac intranasal. Either increases toxcity

of the other by Other (see comment). Significant -

Monitor Closely. Comment: May result in renal

function deterioration, particularly in elderly or volume

depleted individuals.

y levodopa


53/85

levodopa increases effects of enalapril by


Closely. Consider decreasing dosage of antihypertensiveagent.

y liraglutide

enalapril increases effects of liraglutide by unknown

mechanism. Significant - Monitor Closely. ACEinhibitors may increase hypoglycemic effect. Monitor

glycemic control especially during the first month of

treatment with an ACE inhibitor. .

y lithium

enalapril increases toxcity of lithium by unknown

mechanism. Significant - Monitor Closely. ACE

inhibitor induced Na+ depletion may increase

reabsorption of lithium from renal tubule.

y lurasidone

lurasidone increases effects of enalapril by Other (see

comment). Significant - Monitor Closely. Comment:


54/85

Potential for increased risk of hypotension with

concurrent use. Monitor blood pressure and adjust dose

of antihypertensive agent as needed.

y meclofenamate

meclofenamate decreases effects of enalapril by




enalapril, meclofenamate. Either increases toxcity of the



individuals.

y mefenamic acid

mefenamic acid decreases effects of enalapril by


Closely. NSAIDs decrease synthesis of vasodilatingrenal


55/85

prostaglandins, and thus affect fluid homeostasis and

may diminish antihypertensive effect.

enalapril, mefenamic acid. Either increases toxcity of

the other by Other (see comment). Significant - Monitor



individuals.

y meloxicam

meloxicam decreases effects of enalapril by




enalapril, meloxicam. Either increases toxcity of the




individuals.


56/85

y moxisylyte

enalapril, moxisylyte. Mechanism: pharmacodynamic



y nabumetone

nabumetone decreases effects of enalapril by





enalapril, nabumetone. Either increases toxcity of the




individuals.

y naproxen


57/85

naproxen decreases effects of enalapril by




enalapril, naproxen. Either increases toxcity of the



individuals.

y oxaprozin

oxaprozin decreases effects of enalapril by





enalapril, oxaprozin. Either increases toxcity of the



58/85



individuals.

y phenoxybenzamine

enalapril, phenoxybenzamine. Mechanism:


Closely. Exaggerated first dose hypotensive response.

y phentolamine

enalapril, phentolamine. Mechanism:


Closely. Exaggerated first dose hypotensive response.

y phenylbutazone

phenylbutazone decreases effects of enalapril by





59/85

enalapril, phenylbutazone. Either increases toxcity of

the other by Other (see comment). Significant - Monitor


individuals.

y piroxicam

piroxicam decreases effects of enalapril bypharmacodynamic antagonism. Significant - Monitor




enalapril, piroxicam. Either increases toxcity of the




individuals.

y polysaccharide iron


60/85


61/85

enalapril, prazosin. Mechanism: pharmacodynamic



y rofecoxib

rofecoxib, enalapril. Mechanism: pharmacodynamic


hyperkalemia.

rofecoxib decreases effects of enalapril by




enalapril, rofecoxib. Either increases toxcity of the




individuals.


62/85

y rose hips

enalapril, rose hips. Mechanism: unknown. Significant -

Monitor Closely. Risk of GI symptoms, hypotension.

y salsalate

salsalate decreases effects of enalapril by





enalapril, salsalate. Either increases toxcity of the other


Comment: May result in renal function deterioration,


y silodosin

enalapril, silodosin. Mechanism: pharmacodynamic




63/85

y sodium bicarbonate

sodium bicarbonate decreases effects of enalapril by

unspecified interaction mechanism. Significant -

Monitor Closely.

y sodium citrate/citric acid

sodium citrate/citric acid decreases effects of enalapril

by unspecified interaction mechanism. Significant -

Monitor Closely.

y spironolactone

enalapril, spironolactone. Mechanism:



y sulfamethoxazole

sulfamethoxazole, enalapril. Mechanism:



y sulfasalazine


64/85

sulfasalazine decreases effects of enalapril by




enalapril, sulfasalazine. Either increases toxcity of the



individuals.

y sulindac

sulindac decreases effects of enalapril by





enalapril, sulindac. Either increases toxcity of the other



65/85

Comment: May result in renal function deterioration,


y tenoxicam

tenoxicam decreases effects of enalapril by




enalapril, tenoxicam. Either increases toxcity of the



individuals.

y terazosin

enalapril, terazosin. Mechanism: pharmacodynamicsynergism. Significant - Monitor Closely. Exaggerated



66/85


67/85

enalapril increases effects of tolbutamide by


Closely.

y tolmetin

tolmetin decreases effects of enalapril by




enalapril, tolmetin. Either increases toxcity of the other

by Other (see comment). Significant - Monitor Closely.Comment: May result in renal function deterioration,


y torsemide

enalapril, torsemide. Mechanism: pharmacodynamicsynergism. Significant - Monitor Closely. Risk of acute

hypotension, renal insufficiency.


68/85

y triamterene

enalapril, triamterene. Mechanism: pharmacodynamic


hyperkalemia.

y trimethoprim

trimethoprim and enalapril both increase serum

potassium. Significant - Monitor Closely. Trimethoprim

decreases urinary potassium excretion. May cause

hyperkalemia, particularly with high doses, renal

insufficiency, or when combined with other drugs that

cause hyperkalemia.

y valdecoxib

valdecoxib decreases effects of enalapril by






69/85

enalapril, valdecoxib. Either increases toxcity of the



individuals.

y xipamide

xipamide increases effects of enalapril bypharmacodynamic synergism. Significant - Monitor

Closely.

y zotepine

enalapril, zotepine. Mechanism: pharmacodynamicsynergism. Significant - Monitor Closely. Exaggerated


Minor (39)

yaceclofenac

aceclofenac decreases effects of enalapril by

pharmacodynamic antagonism. Minor or non-


70/85

significant interaction. NSAIDs decrease prostaglandin

synthesis.

y acemetacin

acemetacin decreases effects of enalapril by



synthesis.

y agrimony

agrimony increases effects of enalapril by

pharmacodynamic synergism. Minor or non-significant

interaction.

y albumin

albumin, enalapril. Mechanism: unspecified interaction

mechanism. Minor or non-significant

interaction.Vasodilation.

y aspirin rectal


71/85

aspirin rectal decreases effects of enalapril by


significant interaction. NSAIDs decrease prostaglandinsynthesis.

y brimonidine

brimonidine increases effects of enalapril by

pharmacodynamic synergism. Minor or non-significantinteraction.

y capsicum

capsicum, enalapril. Mechanism: pharmacodynamic

synergism. Minor or non-significant interaction.Increase ACE inhibitor induced cough.

y chlorpromazine

chlorpromazine increases effects of enalapril by

unspecified interaction mechanism. Minor or non-significant interaction.

y cornsilk


72/85

cornsilk increases effects of enalapril by


interaction.

y creatine

creatine, enalapril. Mechanism: pharmacodynamic

synergism. Minor or non-significant interaction.

(Theoretical interaction) Combination may haveadditive nephrotoxic effects.

y etoricoxib

etoricoxib decreases effects of enalapril by

pharmacodynamic antagonism. Minor or non-significant interaction. NSAIDs decrease prostaglandin

synthesis.

y fenbufen

fenbufen decreases effects of enalapril bypharmacodynamic antagonism. Minor or non-


synthesis.


73/85

y fluphenazine

fluphenazine increases effects of enalapril by

unspecified interaction mechanism. Minor or non-

significant interaction.

y lofexidine

lofexidine increases effects of enalapril by


interaction.

y lornoxicam

lornoxicam decreases effects of enalapril by



synthesis.

y maitake

maitake increases effects of enalapril by


interaction.


74/85

y mercaptopurine

enalapril, mercaptopurine. Mechanism:


interaction.Risk of neutropenia.

y mesoridazine

mesoridazine increases effects of enalapril by



y nesiritide

nesiritide, enalapril. Either increases effects of the other

by pharmacodynamic synergism. Minor or non-

significant interaction.Additive hypotensive effects.

y octacosanol

octacosanol increases effects of enalapril by


interaction.

y parecoxib


75/85

parecoxib decreases effects of enalapril by



y pericyazine

pericyazine increases effects of enalapril by unspecified

interaction mechanism. Minor or non-significantinteraction.

y perphenazine

perphenazine increases effects of enalapril by

unspecified interaction mechanism. Minor or non-significant interaction.

y pipotiazine

pipotiazine increases effects of enalapril by unspecified

interaction mechanism. Minor or non-significantinteraction.

y probenecid


76/85

probenecid increases effects of enalapril by unspecified

interaction mechanism. Minor or non-significant

interaction.

y prochlorperazine

prochlorperazine increases effects of enalapril by



y promazine

promazine increases effects of enalapril by unspecified


interaction.

y promethazine

promethazine increases effects of enalapril by



y reishi


77/85

reishi increases effects of enalapril by


interaction.

y rifampin

rifampin decreases levels of enalapril by increasing

metabolism. Minor or non-significant interaction.

y salicylates (non-asa)

salicylates (non-asa) decreases effects of enalapril by



synthesis.

y shepherd's purse

shepherd's purse, enalapril. Other (see comment).Minor

or non-significant interaction. Comment: Theoretically,

shepherd's purse may interfere with BP control.

y thioproperazine


78/85

thioproperazine increases effects of enalapril by



y thioridazine

thioridazine increases effects of enalapril by unspecified


interaction.

y tizanidine

tizanidine increases effects of enalapril by


interaction.Risk of hypotension.

y tolfenamic acid

tolfenamic acid decreases effects of enalapril by



y treprostinil


79/85

treprostinil increases effects of enalapril by


interaction.

y trifluoperazine

trifluoperazine increases effects of enalapril by



y trimeprazine

trimeprazine increases effects of enalapril by



Adverse Effects

1-10%

Dizziness (4-8%)

Hypotension (0.9-6.7%)

Headache (2-5%)


80/85

Chest pain (2%)

Cough (1-2%)

Rash (1.5%)

Frequency not defined

Asthenia

Nausea

Vomiting

Hyperkalemia

Contraindications & Cautions

Black Box Warnings

Discontinue as soon as possible when pregnancy is detected;

affects renin-angiotensin system causing oligohydramnios,

which may result in fetal injury and/or death

Contraindications

Hypersensitivity to enalapril/other ACE inhibitors


81/85

History of ACEI-induced angioedema, hereditary or

idiopathic angioedema

Pregnancy (2nd & 3rd trimesters): significant risk of fetal &

neonatal morbidity & mortality

Bilateral renal artery stenosis

Cautions

Apheresis (LDL) with dextran sulfate, hypertrophic

cardiomyopathy, collagen vascular disease, hemodialysis

with high flux membrane, renal or arotic stenosis

For HTN pts on diuretics, if possible discontinue diuretics 2-

3 d before starting enalapril

Excessive hypotension if concomitant diuretics,

hypovolemia, hyponatremia

Risk of hyperkalemia, esp in pts w/ renal impairment, DM

or those taking concomitant K+-elevating drugs

Inj contains benzyl alcohol preservative (linked to

potentially fatal 'gasping syndrome' in preemies)


82/85

ACE inhibition also causes increased bradykinin levels

which putatively mediates angioedema

Discontinue STAT if pt becomes pregnant

Less effective in blacks

Renal impairment

Pregnancy & Lactation

Pregnancy Category: C (1st trimester); D (2nd & 3rd

trimesters). During the second and third trimesters of

pregnancy, these drugs have been associated with fetal

injury that includes hypotension, neonatal skull hypoplasia,

anuria, reversible or irreversible renal failure, and death.

Lactation: enters breast milk/not recommended (AAP

Committee states "compatible with nursing")

Pharmacology

Half-Life: parent drug: 1.3 hr, active met (enalaprilat): 11

hr

Onset


83/85

Initial response for HTN: IV: 0.5-4 hr, PO: 1-4 hr

Peak response for HTN: IV: 30 min, PO: 8-18 hr

Excretion

Urine: 61%

Feces: 33% (6% as enalapril, 27% as enalaprilat)

Other Information

Duration: IV: 360 min, PO (multiple dose): 12-24 hr

Peak Plasma Time: IV: 15 min; PO: 1 hr

Bioavailability: 60%

Protein Bound: 50-60%

Metabolism: liver (70%); enalapril undergoes hepatic

biotransformation to enalaprilat within 4 hr following oral

administration

Metabolites: enalaprilat (active)

Renal Clearance: 158 mL/min

Dialyzable: HD: yes


84/85

Mechanism of Action

Enalapril is a prodrug hydrolyzed in vivo to enalaprilat;

enalaprilat prevents conversion of angiotensin I to

angiotensin II (a potent vasoconstrictor) through competitive

inhibition of angiotensin coverting enzyme (ACE) resulting

in decreased plasma angiotensin II concentrations &

consequently, blood pressure may be reduced in part

through decreased vasoconstriction, increased renin activity,

and decreased aldosterone secretion

Also increases renal blood flow

IV & IM Information

IV Incompatibilities

Y-site: ampho B, ampho B chol SO4, cefepime, phenytoin

IV Compatibilities

Solution: D5W, Normosol R

Additive: dobutamine, dopamine, heparin, meropenem,

nitroglycerin, KCl, sodium nitroprusside


85/85

Y-site (partial list): allopurinol, ampicillin, ampicillin-

sulbactam, cefazolin, clindamycin, dobutamine, dopamine,

esmolol, fentanyl, heparin, labetalol, linezolid, MgSO4,metronidazole, morphine SO4, nicardipine, KCl, propofol,

tobramyin, TMP-SMX, vancomycin

IV Administration

Slow IVP over at least 5 min if undiluted, or

Infused in up to 50 mL of compatible IV infusion solution

Storage

Clear colorless solution

Store below 30C

nearly all forms of acute glomerulonephritis have a tendency to progress to chronic...

Documents