Drug Administration in dialysis and renal insufficiency

Exam 1, Dr. Wai

renal insufficiency can interfere with medications

• decreasing clearance due to reduced glomerular filtration

• altering tubular secretion and reabsorption

• changes in renal and on-renal metbaolism

antibiotics, direct oral anticoagulants

common medications that require dose reductions in patients with renal insufficiency.

determining a dosing regimen

• reduce the dose and maintain the dosage interval

• maintain the dose and extend the dosing interval

anticoagulants

• requries special attention in renal insufficiency

• renal adjustments may be required depending on agent and indication

enoxaparin

• anticoagulant that clearance is reduced in patients with renal insufficiency

ACEI/ARB

• require special attnetion in renal insufficiency

• most are cleared renally

• acute but sustained decrease in GFR

• may see a 25-30% decrease in GFR within 307 days after initiation

• not a reason to discontinue therapy *****

alpha blockers

• require special attention in renal insufficiency

• active metabolites that can accumulate in CKF

• Doxazosin, Prazosin, Methyldopa

• Terazosin kinetics unaltered in CKD

beta blockers

• require special attention in renal insufficiency

• some may need adjustment (atenolol, nadolol)

• hepatically metabolized preffered in advanced CKD → metoprolol, labetalol, and propranolol

digoxin

• require special attention in renal insufficiency

• Vd is reduced by 30-50% in ESRD

• not dialyzable, antidote Digifab

• two approached: extend dosing interval, reduce dose

morphine, meperidine

• narcotics that require special attention in renal insufficiency

morphine

• require special attention in renal insufficiency

• metabolized in the liver to 5 metabolites → accumulates in CKD

• dose reductions CrCl < 60ml/min

• adverse effects: CNS depression, respiratory depression

• consider avoiding use in advanced CKD

meperidine

• require special attention in renal insufficiency

• normeperidine → active metabolite

• neurotoxic

• ½ analgesic effect, 2x convulant effect

• accumulates in renal insufficiency

• avoid use in advanced CKD

insulin

• require special attention in renal insufficiency

• dosing reduction may be required

• degradation occurs in liver, muscles, and kidneys

sulfonylureas

• active metabolites may accumualte in renal insufficiency

• glyburide, glipizide

sitagliptin

• requires dosing adjustment for renal insufficiency

• diabetic medication

metformin

• dose recommendations based on eGFR

• potential to cause lactic acidosis

• eGR <30 contraindicated

aminoglycosides

• gentamicin, tobramycin, amikacin

• clearace reduced in renal dysfunction

• increased risk of ADE: Ototoxicity and nephrotoxicity

• Avoid use in CKD if possible

◦Follow serum levels (peaks and troughs) if used

◦PK equations

cephalosporins

◦Most are cleared renally and require dosing adjustments

◦Concern for neurotoxicity

◦Ceftriaxone is exception – no renal adjustment

penicillins

◦Most are cleared renally and require dosing adjustments

◦Concern for neurotoxicity

◦Exceptions: nafcillin, dicloxacillin

fluoroquinolones

◦Most are cleared renally and require dosing adjustments

◦Exception: Moxifloxacin

◦Adverse effects: tendonopathy, aortopathy, neuropathy, arrhythmia, hypoglycemia, hyperglycemia

vancomycin

◦Cleared renally and requires a dosing adjustment

◦Dosed based on serum levels and PK

◦May follow random levels in acute kidney injury and ESRD

◦May extend interval especially in dialysis pts

metoclopramide

◦Clearance reduced by approximately 30% in CKD

◦Dose reduction when CrCl < 50 ml/min

◦Adverse effect: tardive dyskinesia

H2 antagonists

◦Depends on agent

◦Require dosing adjustment at CrCl < 50 mL/min

◦Adverse effect: CNS effects (agitation, confusion, delirium)

metformin, sitagliptin, famotidine, metoclopramide

 TR is a 65 yo M with DM2, HTN, HLD, CKD, anemia, GERD, gastroparesis. His medications include: Lisinopril 20 mg daily, metformin 1000 mg BID, sitagliptin 100 mg daily, atorvastatin 40, erythropoietin 10000 units SQ weekly, famotidine 40 BID, metoclopramide 10 mg TID. His CKD has progressed, his SCr now 2.5 (previously 2.0) and his estimated CrCl (Cockroft-Gault) is 30 ml/min.

which medications should be renally dose adjusted?

SCr increase 0.5, which is <30% of baseline

 TR is a 65 yo M with DM2, HTN, HLD, CKD, anemia, GERD, gastroparesis. His medications include: Lisinopril 20 mg daily, metformin 1000 mg BID, sitagliptin 100 mg daily, atorvastatin 40, erythropoietin 10000 units SQ weekly, famotidine 40 BID, metoclopramide 10 mg TID. His CKD has progressed, his SCr now 2.5 (previously 2.0) and his estimated CrCl (Cockroft-Gault) is 30 ml/min.

why does lisinopril not need dosage adjustment?

dialysis

• lower life expectancy

• increased hospitalizations

• poor quality of life: limited by 3x weekly HD sessions (3-4 hours), fatigue

indications for maintenance dialysis

• Plan for dialysis when progresses to CKD stage 4 (< 30 ml/min/1.73m²)

  • Decision for hemodialysis vs peritoneal dialysis

•  Symptoms usually develop when GFR ~5-10 mL/min/1.73m2

  • Symptomatic uremia (e.g., serositis, acid-base, electrolytes, pruritis)

  • ◦Inability to control volume status or blood pressure

  • Cognitive impairment

  • ◦Deterioration in nutritional status

hemodialysis pros

• intermittent

• defined parameters to detect under-dialysis early

• low techniwue failure rate

• hemostasis parameters better corrected

• close monitoring

hemodialysis cons

• 3x weekly for several hours

• disequilibrium, hypotension, muscle cramps

• infections

• thrombosis

• more rapid residual kidney decline

peritoneal dialysis pros

• hemodynamic stability

• higher clearance of large solutes

• convenient route for antibiotics, insulin

• independence, freedom from machine

• less blood loss and iron deficiency

• no systemic heparinization

• lower physiologic EPO doses

peritoneal dialysis cons

• amino acid loss through peritoneum- malnutrition

• peritonitis

• cather malfunction

• inadequate ultrafiltration and solute clearance

• patient burnout, high rate of technique failure

• risk of obesity with excessive glucose absorption

• hernias, dialysate leaks, hemorrhoids, back pain

• abdominal surgery precludes use

hemodialysis

• Blood is pumped to the dialyzer at 300 to 600 mL/min.

• Heparin prevents clotting.

•  Dialysate is pumped at a rate of 500 to 1000 mL/min countercurrent against semi-permeable membrane.

• Fluid removal is adjusted by pressure in the dialysate compartment.

hemodialysis access

A) Arteriovenous (AV) fistula: Surgical anastomosis of cephalic vein with radial artery. Blood flows from high-pressure artery leading to hypertrophy of vein. 3 months to mature

B) Synthetic AV graft: Connects brachial artery and basilic or cephalic vein. Blood flow may be diminished in radial and ulnar arteries since blood preferentially flows into low-pressure graft.

vascular access

• central venous catheters

• temprary access only

• inserted into jugular, femoral, subclavian vein

• use for emergent dialysis

• or when AV graft or AV fistula are no longer an option

catheter> AV graft > AV fistula

thrombosis rates

thrombosis of vascular access

• most common complications: stenosis, thrombosis, infections

• rates: catheter> AV graft > AV fistula

• early dysfunction (< 5 days after placement)

catheter thrombosis management

• locked with anticoagulant

• installation of a solution into catheter lumen

• low dose unfractionated heparin 5,000 units twice weekly

• sodium citrate 4$

• alteplase 1mg weekly

catheter thrombosis treatment

• nonpharm→ forced saline flush, referral to vascular surgeon

• pharm→ alteplase 2mg/2ml for 30 minutes

• dose is instilled into lumen for 30 min, then attempt to aspirate. repeat if necessary

vascular access infection

• 2^nd leading cause of mortality in dialysis patients

• Accounts for ~20% of access complications

• Infection site rates

  • catheters > AV grafts > AV fistulas

•  Local infection vs extensive infection

  • antibiotic therapy vs antibiotics + surgical revision

• Can lead to endocarditis, osteomyelitis, septic arthritis, septic pulmonary emboli, septic syndrome

catheters > AV graft > AV fistulas

• vascualr access infection site rates

prevention of catheter related infections

◦Minimize the use, access, and duration of catheters

◦Proper handling minimizing use and duration of catheters

◦Proper disinfection and sterile technique

◦Use of exit-site mupirocin or povidone-iodine ointment

AV graft infection treatment

• appropriate antibiotics given IV for 2-4 weeks

• gram + (including enterococcus ) and gram -

• gentamicin + vancomycin then individualized after culture results available

AV fistulae infections

• treat with appropriate antibiotics for at least 6 weeks

• always cover gram positive organisms → vancomycin, cefazolin

• gram negative coverage is indicated for patients with diabetes, HIV, prosthetic valves, or those receiving immunosuppressive agents- > gentamicin

antibiotic locks

• solution that contains a concentrated amount of antibiotic along with heparin

• instilled into the infected catheter or port and left to dwell between dialysis session

sodium citrate, alteplase, heparin

what are some strategies that can prevent HD catheter thrombosus?

intradialytic hypotension

• 10-30% of HD treatments

• increase risk of frequent hypotensive episodes→ autonomic insuffiiency, heart disease, advanced age

• antihypertensive agents should be given with caution prior to dialysis, but should not be routinely held on dialysis days

acute management of intradialytic hypotension

◦Trendelenburg position (lower head)

◦Decrease ultrafiltration rate

◦100–200 mL 0.9% NaCl bolus 

midodrine

• for hypotension

• oral alpha 1 adrenergic agonist

• dosing: 2.5-10mg prior to dialysisto prevent intradialytic hypotension.

• side effects: scalp paresthesia, heartburn, flushing, headache, neck pain, and weakness

peritoneal dialysis catheter complications

• peritonitis (infection)

• exit site tunnel infections

• catheter related infections

peritonitis

• within 1 year of starting CAPD, 40-60% patients develop their first episode

• empiric therapy for both gram positives and gram negatives x 14 days

PD related peritonitis symptoms

• ◦abdominal tenderness, abdominal pain, fever, nausea and vomiting, and chills

PD related peritonitis signs

◦Cloudy dialysate effluent may be observed

◦Temperature may or may not be elevated

PD related peritonitis lab tests

◦Dialysate white blood cell count >100/mm3, of which at least 50% are polymorphonuclear neutrophils

◦Gram stain of a centrifuged dialysate specimen

PD related peritonitis diagnostic tests

◦Culture and sensitivity of dialysate should be obtained

prevention of peritonitis and catheter exit site infections

 Daily application of topical antibiotics

◦Mupirocin cream or ointment

◦Gentamicin ointment

 Eradicating nasal S. aureus

◦Intranasal mupirocin 2% ointment, administered twice daily for 5 days of every month

vancomycin + cefepime

NR has been managing nightly PD for 1 year when she developed a fever 103°F, abdominal pain and noticed that dialysate effluent was cloudy. She sees her nephrologist who suspects peritonitis and cultures the dialysate effluent. Which would be an appropriate empiric antibiotic regimen?

renal clearance, therapeutic index

2 main considerations that determine if a drug requires dose reduction in dialysis

drug dosing in dialysis

 HD is more effective than PD in removing drugs

 Drug dialyzability depends on:

◦Molecular weight (<20 kDa)

◦Protein binding

◦Volume of distribution

 Also depends on filter, dialysate, membrane, flow rate

commonly prescribed drugs that are not renally cleared and do not need adjustment

• PPIs

• statins

• corticosteroids

• calcium channel blockers

• acetaminophen

drug dosing with dialysis

• if no dialysis dose is available, assume GFR <15ml/min/1,73m2

• generally five the dose after dialysis