Download Renal failure & drug management

Renal failure & drug
management
By Dr. Judith Marin
Pharmacist for FHA Renal program
614.0388
Outline
Influence of kidneys on drugs (vice-versa)
Anemia
Bone-mineral disorder
Cardiovascular drugs
Other renal exceptions!!!
Kidney Function
Regulatory
Extra-cellular fluid, acid base balance, osmotic
pressure, electrolyte imbalance, blood pressure
Excretory
Excretion of waste, water
Metabolic
RAAS, Bone mineral disorders (vitamin D
activation), anemia (erythropoietin)
CKD… who is at risk??
Elderly patient
Transplant patient
Diabetics
Hypertensive/ Cardiovascular disease
CKD… who is at risk??
Acute renal failure
↑ in serum creatinine level X 3.0
 in GFR by 75%
Serum creatinine level >350 µmol/L with acute
increase of >44 µmol/L
U/O <0.3 mL/kg/h for 24 hours, or anuria for 12 hours
Chronic renal failure
Kidney damage or decrease eGFR for more than 3
months
CKD Stage
Pharmacotherapeutic goals
Improve signs and symptoms
Improve patient outcomes and slow progression of
disease
Improve surrogate outcomes
Reduce risk of hospitalization
Minimize adverse drug reactions
Improve QOL
Pharmacotherapeutic
management for CKD
Dosage adjustment specific to CrCL
Avoid contraindicated medications/ nephrotoxic
drugs
Normalizing bloodwork
Education
Drug dosage in CKD
Cockcroft-Gault equation
Expressed renal creatinine clearance
More appropriate than eGFR to base drug dosage
adjustment
Drug dosage in CKD
Depends on drug metabolism and excretion
Active vs. inactive metabolites renally excreted
Concerns if ~ 50% or more of drug/active metabolites
eliminated by kidney
Other PK variations: drug absorption, volume of
distribution, protein binding.
Depends on renal function/ AKD or CKD
Drug dosage adjustment starting at eGFR < 60 ml/min
• Depends efficacy/adverse drug reaction profile
• Monitoring available
Drug clearance and
dialysis
Type of dialysis
HD and frequency, PD, CVVH
Drugs properties
Molecular weight, charge, water solubility, volume of distribution,
dialyzer membrane binding, non renal excretion pathway
Dialysis properties
Type of dialyser (pore size, surface area), flow rate/blood flow,
dialysate composition, volume of dialysate (PD), temperature, pH
Patient properties
Residual renal function, blood pressure, Kt/v or PRU
Case with Mr. Kidd Ney
75 y/o man with PMHx of DM type II, CHF
and renal failure (on HD)
Admitted to SMH last night for UTI
E.coli sensitive to Ciprofloxacin
Hospitalist orders
Ciprofloxacin 500 mg PO bid x 5 days for UTI
Starts Metformin, 500 mg PO tid to improve
blood sugar control
Case with Mr. Kidd Ney
Any intervention???
Ciprofloxacin
Dosage adjustment if CrCl < 30 ml/min
30-57% of drug eliminated by kidney
Dialysed out by PD and HD
At high serum concentration, risk of seizure,
myalgia/arthralgia, renal failure, ↑ QTc interval
Dosage should be adjusted by to 500 mg po QD x 5
days (dose to be given post-HD on HD days)
Case with Mr. Kidd Ney
Any intervention???
Metformin
Dosage adjustment if CrCl < 60 ml/min
90% of drug eliminated by kidney
Dialysed out by HD
At high serum concentration, risk of
nausea/vomiting, lactic acidosis, hypotension,
hypothermia, tachycardia, tachypnea
Metformin contraindicated in ESRD patients
References
Bennett’s book. Drug Prescribing in Renal Failure.
http://www.kdp-baptist.louisville.edu/renalbook/
Drug Monography
Micromedex
eCPS
Medscape
Be careful to your references!
Examples
Drugs should never be held before HD run
Except if ordered by physician
Antibiotic should be administered after HD run
Antibiotic
Excretion during HD
Β-Lactams
10-75%
Fluoroquinolones
~ 50%
Aminoglycosides
40-50%
Antibiotic minimally dialysed: azithromycin, chloramphenicol,
clindamycin, doxycyclin/tetracycline, linezolid
Kidney Quiz…
Mr. K.N. is still complaining about UTI symptoms
3 days after starting ciprofloxacin. Another urine
culture is done → still growing E.Coli
Hospitalist is thinking about about changing
antibiotic to tobramycin.
The pharmacist on the ward is concerns since
aminoglycosides (e.g. tobramycin, gentamycin)
are nephrotoxic drugs. What do you think? Would
you think differently if patient was a pre-dialysis
with eGFR of 25 ml/min?
Nephrotoxic drugs
Drugs caused about 20% of community and hospital
acquired acute renal failure
Risk factors:
> 60 years old
eGFR < 60 ml/min
Diabetes
Volume depletion
CHF
Sepsis
Nephrotoxic drugs
Preventive measures
Use of alternative nonnephrotoxic drugs
Identifying and correcting patient-related risk
factors that are amenable to therapy
Determining baseline renal function before starting
potentially nephrotoxic therapy to allow dosage
adjustment, monitoring kidney function and vital
signs during therapy
Avoiding use of nephrotoxic drug combinations
Nephrotoxic drugs
Preventive measures
Use of alternative nonnephrotoxic drugs
Identifying and correcting patient-related risk
factors that are amenable to therapy
Determining baseline renal function before starting
potentially nephrotoxic therapy to allow dosage
adjustment, monitoring kidney function and vital
signs during therapy
Avoiding use of nephrotoxic drug combinations
Nephrotoxic drugs
Antibiotics
Aminoglycosides, amphotericine B
penicillin, cephalosporin, quinolones
acyclovir, sulfa
D/C drug if sCr increases
NSAIDs/COX-2 inhibitors
Contraction of efferent renal
arteriole; D/C drug and switch to
acetaminophen
Diclofenac, naproxen, celecoxib
ACE inhibitors/ARBs
Losartan, irbesartan, ramipril, captopril
Vasodilation of afferent renal
arteriole; D/C drug, hydration
Lithium
Interstitial nephritis at high dosage;
decrease dose; hydration
IV contrast dye
CIN; hydration; holding NSAIDs and
diuretic; N-acetylcystein
Kidney Quiz…
Pt is complaining of being very tired. Nurse
noticed that blood in urine.
Hgb comes back to 100 g/L
Patient has been stable (Hgb 115-120 g/L) while
on Darbepoietin 20 mcg IV Qweek and Ferrlecit
125 mg IV Qmonth x 5 months
What should be done?
Anemia of CKD
Stage of CKD

eGFR
(ml/min/1.73m2)
Anemia
prevalence
Stage 3
30-59
5.2%
Stage 4
15-29
44.1%
Stage 5
< 15 or dialysis
100%
Prevalence higher in african americans and diabetic patients
Anemia of CKD
Causes
EPO deficiency
Blood loss
Shorter RBC life span
Decreased bone marrow responsiveness to EPO
Vitamin deficiencies
Iron deficiency (poor iron absorption)
High uremia level
Intoxication impairing RBC development (Aluminium)
Hemolysis (copper, chloramines)
Chronic inflammation
Anemia of CKD
Target Hgb level → 110-120 g/L
Higher hgb level associated with higher risk of mortality,
higher BP, higher access thrombosis
Minimal benefit on QOL
Studies have limits
Workup before starting ESA
CBC, RC
Iron measurements (serum iron, TIBC, Tsat, ferritin)
Occult blood in stools
Serum vitamin B12 and folate
iPTH level
Talking about EPO
Hormone which principal regulator of erythropoiesis
Stimulates proliferation/maturation and inhibits
apoptosis of erythroid progenitors
Induce release of reticulocytes into bloodstream
Primarily produced by cells of kidney peritubular
capillary endothelium
Talking about EPO
1.
Epoietin agents
Epoetin alpha (Eprex)
1ST recombinant human erythropoietin launched on the
market
Shorter half-life (administration 1-3 times/week)
Darbepoetin alpha (Aranesp)
Longer acting erythropoietin analogues
Administration Q1-2 weeks
Talking about EPO
ADRs
Hypertension
20-40% of patients with partial Hb correction
Mainly due to increase systemic vascular resistance
Mostly during the first 4 months of therapy
Metabolic disturbances
 sCr;  K+;  P04
 Dializer efficiency; and  appetite
Myalgia and Flu-like illness
Only report with IV EPO
Slow drug infusion
Talking about EPO
ADRs
Thrombotic complications
Vascular access thrombosis
Exacerbation of diabetic retinopathy
Seizure
Hypertensive encephalopathy
Injection site pain
Hypertonic citrate in formulation
Red eye syndrom
Correction Hct > 30%
Cosmetic syndrom
Iron deficiency
Definition
Ferritin < 100 ng/ml
Iron transferrin saturation < 20%
Higher ferritin level could be associated with greater ESA
efficacy
Causes
ESA
GI bleeding
Lab tests
Phosphate binders
Adjuvant to ESA
Decreased 33-75% in EPO requirement
Iron deficiency
PO iron supplement
No trial looking at PO iron vs placebo in CKD
Associated with dyspepsia and constipation
Iron salts
Dosage
Elementary iron
Ferrous fumarate
300 mg
66 mg
Ferrous sulfate
300 mg
60 mg
Ferrous gluconate
300 mg
35 mg
Iron polysaccharide
150 mg
150 mg
Iron deficiency
IV iron supplement
5 trials looking at IV vs po iron
Mixed results… but overall IV iron seems more effective
Concern about renal tubular toxicity and damage to blood
vessels
Administration… bolus vs infusion?
Formulation
Usual dosage
Iron dextrose
100 mg
Iron sucrose
100 mg
Sodium ferric gluconate
complex
125 mg
Iron deficiency
IV iron supplement
Adverse drug reactions
Hypotension/hypertension, tachycardia, edema,
itching, phlebitis, rash, anaphylaxis/immune
reaction, legs cramps, arthralgia, back pain,
headache
Hgb variability
Study by Brier and Aronoff.
With 3 months Hb rolling average
66% patients would be in a target range of 110-120 g/L
75% patients would be in a target range of 110-122.4 g/L
90% patients would be in a target range of 110-13- g/L
Do not react to the last Hb value to change
ESA dosage
Patient hydration status
Kidney Quiz…
Pt is complaining that he is “never”
receiving his calcium tablets with his
meals and he insists of having his
calcium tablets before taking the first
bite of his meal.
Should we address his concerns?
Bone and minerals
Bone and minerals
Bone and minerals
Bone lesion of excess PTH (high-turnover disease):
Increased PTH levels enhance osteoclast activity – increased bone
resorption.
As activity increases, marked fibrosis involving the marrow space
develops.
Bone lesion of defective mineralization:
Defective mineralization can lead to osteomalacia.
Osteomalacia is caused by delay in rate of bone mineralization and
accumulation of excess unmineralized osteoid.
Mechanism for osteolmalacia disorder in CKD patients:
Aluminum overload (most important factor).
Due to use of aluminum-based phosphate binders.
Relative or absolute deficiency of vitamin D.
Vitamin D is responsible for collagen synthesis and maturation, stimulating
bone mineralization
Osteoporosis
Hyperphosphatemia
Phosphorous mainly eliminated by kidney and dialysis not
effective at removing phosphorous in blood
Decrease phosphorous GI absorption
Hyperphosphatemia associated with itchiness, bone and joint pain
Oral phosphate binders
Should be initiated when phosphorus or PTH levels are not
within the target range despite dietary phosphorus restriction
Most binders are positive ions that are attracted to a negative
charge of the ion (PO4-)
When taken with food, these compounds bind phosphate in
the gut. Absorption of phosphate into the bloodstream is
avoided, and it is instead excreted in the feces.
Hyperphosphatemia
Type
Examples
Trade Names
Calcium-based
Binders
Calcium Carbonate
Calcium Carbonate
Calcium Acetate
Calcium Acetate
Metal-based Binders Aluminum Hydroxide
Aluminum Hydroxide
Magnesium Hydroxide
Various Brands
Lanthanum Carbonate
Fosrenal™
Noncalcium, NonSevelamer HCl
metal-based Binders
Renagel®
Vitamin D
Active Vitamin D increases the amount of total serum
calcium and phosphorus that is absorbed from the
intestinal tract
As kidney function declines in CKD, the kidneys
become less able to activate vitamin D, resulting in
decreased absorption of calcium and phosphorus from
the intestinal tract
Vitamin D
7 - dehydrocholesterol
Cholecalciferol (Vit D3)
1st hydroxylation
25-OH cholecalciferol
2nd hydroxylation
1,25 (OH)2 Cholecalciferol
One-Alpha (1-OH cholecaciferol)
Hectorol (1-OH ergocaciferol)
Rocaltrol or Calcijex (IV) (1,25 (OH)2 cholecalciferol)
Calcimimetic
Cinacalcet (Sensipar®):
Calcimimetic agent :
Binds on the calcium receptors (CaR), which are the primary
regulators of PTH secretion in parathyroid gland   sensitivity of
CaR to calcium  inhibition of PTH release
Result:
 Calcium
 Phosphorus
 CaXP product
Calcimimetic
Cinacalcet (Sensipar®):
Loading dose - 30 mg PO OD with food
Maintenance doses - titrate Q2-4Wk to max of 180 mg
Side Effects:
Nausea and vomiting
Hypocalcemia
Seizure Cinacalcet (1.4%) vs. placebo (0.4%)  possibly
due to a lowered seizure threshold that can occur with a
reduction in serum calcium levels
Kidney Quiz…
Mr K. N. results during BW week:
This BW
Last BW
Corrected Ca
2.3
2.24
Phosphorus
1.5
62
1.0
30
iPTH
Pt has been on same regimen for last 6 months
Apo-Cal, 1 tab TID cc
One-alpha, 0.25 mcg PO 3 times/week
Kidney Quiz…
Mr K. N. results during next BW week:
This BW
Last BW
Corrected Ca
2.65
2.3
Phosphorus
1.9
55
1.5
62
iPTH
Kidney Quiz…
Mr K. N. results during next BW week:
This BW
Last BW
Corrected Ca
2.65
2.65
Phosphorus
1.9
105
1.9
55
iPTH
Kidney Quiz…
Today, K+ :3.2 for Mr K.N. since had
diarrhea for the last few days (hopefully,
not C.difficiles!). Your colleague suggests
calling the hospitalist to order Potassium
Chloride (Slow K®), 600 mg po BID. What
do you think about this suggestion?
Electrolytes
Potassium mainly eliminated by kidney and dialysis
effective at removing potassium in blood
Hyperkaliemia associated with cardiac arrythmia,
respiratory paralysis, tingling
Hypokaliemia associated with muscle weakness, general
weakness, ECG abnormality
K+ can be adjusted with dialysate K+ bath
No need potassium supplement and rarely need
kayaxelate
Make sure that nephrologist/dialysis unit are aware of
patient K+ level.
Kidney Quiz…
Mr. K.N. unfortunately felt in hospital and
broke his hip. He had hip surgery and he
is complaining about pain after his
surgery. You have an order for morphine
on the MAR, but one of your colleague is
telling you that morphine is
contraindicated in patients with renal
failure. Is it true? What are the options for
pain management?
Pain Management
Multi-modal
Non-Pharmacological
Pharmacological
Heat/Cold
Massage
Distraction
Self Management
Psychology
http://www.brandweeknrx.com/images/2007/05/11/0006.jpg
Analgesics for MSK pain
Acetaminophen
Analgesic without anti-inflammatory propriety
As effective as NSAIDs in relieving mild-moderate
osteoarthritis pain if taken 4 times/day, with less ADRs
Tylenol arthritis pain  8 hours duration
Topical NSAIDs
Localized osteoarthritis pain of superficial joints
For mild to moderate pain (score < 4/10)
Can also be used as co-analgesic / adjuvant
Analgesics for MSK pain
Oral NSAIDs
Analgesic with anti-inflammatory propriety
Avoid in pre-dialysis patients since can
 renal function
Avoid for long-term treatment, since CKD
patient at  risk of bleeding
For mild to moderate pain (score < 4/10)
Can also be used as co-analgesic / adjuvant
Analgesics for
neuropathic pain
Anticonvulsants
Gabapentin, pregabalin
Act on GABA receptors to modulate nerve influx
ADRs: somnolence, dizziness, and ataxia
Capsaicin cream
Stimulates the nerves, to then desensitizes them (depletion
of substance P)
Also use in osteoarthritic pain
Causes erythema and feeling of warmth at application
(lidocaine x 2 weeks)
Wash hands after using it
Can take up to 2-4 weeks before onset of action
Maximum response after 4-6 weeks of regular use
Analgesics for
neuropathic pain
Antidepressants
Good choice if concomitant depression or insomnia
Tricyclic antidepressant (TCAs)
Desipramine and nortriptyline preferred agent
Less anticholinergic effects
ADRs: Cardiac toxicities, orthostatic hypotension,
constipation, dry mouth
Venlafaxine
Less efficacy/safety data available
ADRs: HTN, nausea
Opioids
Efficacy in MSK and neuropathic pain
Usually use in conjunction with other
analgesics  dose of opioid
Opioids have similar efficacy if appropriate
dosage conversion
Routes (PO/IV/SC/IM) have similar efficacy if
appropriate dosage conversion
Pain management
in CKD
Opioids of choice: hydromorphone,
oxycodone, fentanyl
Avoid mepiridine since risk of neurotoxicity (eg.
Seizure, tremors, irritability, etc.) related to
metabolites accumulation.
Avoid morphine since risk of neurotoxicity (eg.
seizure, myoclonia, hallucination, etc.) related to
metabolites accumulation.
Opioids
Administer on a regular schedule with interval
corresponding to duration of action
SR formulation use when daily dosage established
Appropriate breakthrough dose equal to 10% of
daily dosage Q2Hrs PRN
ADRs : Sedation, nausea, constipation, hallucinations,
hyperalgesia, respiratory depression, cognitive
impairment, gait disturbances
Methadone
Opioid analgesic with an antagonist effect on NMDA receptors
(responsible of constant and exaggeration of pain)
Option if pain refractory to usual opioids
Long half-life
High inter-patient variability, multiple drug interaction
Physician needs special privilege to prescribe it
ADRs: Bradycardia, hypotension, general weakness, sedation,
nausea, constipation, respiratory depression, dysphoria, insomnia,
anxiety
Management of ADRs
Nausea/vomiting
Usually tolerance after 5-7 days
GI stasis and impact on chemoreceptive
zone
Domperidone/metoclopramide
Or/and
Prochlorperazine/ Haloperidol
Management of ADRs
Constipation
Proportional to opioid dosage
Unlikely to improve overtime
Stool softener (docusate) and GI stimulant
(sennosides) for all patients on opioids
Lactulose, PEGLyte, glycerin supp., bisacodyl
supp. are other options
To be avoided: fleet phosphate, milk of
magnesia, mineral oil
Management of ADRs
Respiratory Depression
Naloxone 0.1-0.4 mg sc or IV initially
Effective dose can be repeated every 1-2
hours if SR opioid formulation
Management of ADRs
Sedation
Caused by opioid anticholinergic activity
Dose reduction, slow dosage titration
Pruritis
Caused by opioid histaminic activity
Sx also associated with renal failure
Antihistaminic Rx (diphenhydramine,
hydroxyzine), opioid rotation
Management of ADRs
Tremors, myoclonus
Metabolites accumulation can cause CNS
disturbances
Metabolites mostly eliminated by kidney, and
may be not easily dialyzed
Opioid rotation, dosage reduction
Management of ADRs
Tremors, myoclonus
Metabolites accumulation can cause CNS
disturbances
Metabolites mostly eliminated by kidney, and
may be not easily dialyzed
Opioid rotation, dosage reduction
Kidney Quiz…
Mr. K.N. blood pressure is increased post
surgery. The mean BP for the past couple
of days is 175/90, HR 90.
Patient currently taking metoprolol 50 mg
po BID and furosemide 40 mg PO QD.
Should you flag it to the nephrologist?
What other information do you need
before making a decision?
Goals of BP Therapy
Reduce associated morbidity and mortality
Target-organ damage
BP < 140/90 mmHg
Diabetes or chronic kidney disease
BP < 130/80 mmHg
Proteinuric renal disease (Urinary protein excretion
> 1g/24h)
BP < 130/80 mm Hg
Non-Drug Therapy
Weight reduction
DASH diet
Reduce dietary sodium intake
Physical activity
Moderate alcohol consumption
Smoking cessation
Classes of
AntiHypertensives
Diuretics
Angiotensin Converting Enzyme (ACE) Inhibitors
Angiotensin Receptor Blockers (ARB)
β-Blockers
Calcium Channel Blockers (CCB)
Non-dihydropyridine (NDHP)
Dihydropyridine (DHP)
1-Blockers
Central 2-Agonists
Vasodilators
Indications
First Line
Second Line
Uncomplicated HTN
Thiazide diuretic
ACEI; ARB; long acting DHPCCB; β-Blocker
HTN Complicated by Co-Morbid Conditions
Coronary Artery
Disease (CAD)
ACEI
β-Blocker (stable angina)
Long acting CCB
Myocardial
Infarction (MI)
ACEI + β-Blocker
- ARB if ACEI intolerant
- CCB if β-Blocker is CI or
ineffective; avoid NDHP-CCB if
heart failure is present
Left Ventricular
Hypertrophy (LVH)
Thiazide diuretic; ACEI;
long-acting CCB
- ARB if ACEI intolerant
- Avoid direct arterial
vasodilators (hydralazine,
minoxidil)
Cerebrovascular
Disease
ACEI + thiazide diuretic
Long acting DHP-CCB
Indications
First Line
Second Line
HTN Complicated by Co-Morbid Conditions
Heart Failure
-
ACEI + β-Blocker
(systolic dysfunction)
- Aldosterone
antagonists if NYHA
class III or IV
-
ARB if ACEI intolerant
- Hydralazine/isosorbide dinitrate if ACEI &
ARB intolerant
- Diuretics (thiazide), ARB, long acting DHP
CCB as additive tx if BP not controlled
Non-Diabetic
CKD with
Proteinuria
ACEI
- ARB if ACEI intolerant
- Thiazide diuretic as additive therapy or
loop diuretics if volume overloaded
Renovascular Thiazide diuretic; ACEI;
Disease
long-acting CCB
- ARB if ACEI intolerant
- Combination therapy if BP not controlled
DM with
Albuminuria
ACEI
- ARB if ACEI intolerant
- Combination therapy if BP not controlled
DM without
Albuminuria
ACEI; thiazide diuretic;
DHP-CCB
- ARB if ACEI intolerant
- Combination therapy if BP not controlled
Diuretics…Pharmacology
Thiazide
Diuretics…Pharmacology

Inhibition of Na+/Cl- co-transporter in proximal
part of distal convoluted tubule
 tubular reabsorption of Na+ & Cl urinary excretion of Na+, Cl- & H2O
 extracellular volume
 BP

 Ca2+ reabsorption in distal convoluted tubule
Thiazide Diuretics…PK
Onset
(h)
t1/2
(h)
Duration Elimination
(h)
Initial Dose
(max. daily dose)
Chlorthalidone
2-3
40-80
24-72
R
12.5 mg QD (100)
Hydrochloro
-thiazide
(HCTZ)*
2
2.514
6-12
R
12.5 mg QD
(50)
Indapamide
1-2
4-22
36
H
1.25 mg QD (5)
Metolazone
1
4-20
12-24
R
2.5 mg QD (5)
* Dyazide (HCTZ/Triamterene 50/25 mg)  full benefit
* Moduret (HCTZ/Amiloride 50/5 mg)  full benefit (generics)
H = Hepatic; R = Renal
Thiazide
Diuretics…Management

Start at low dose
Baseline SCr/BUN; Na+; K+; Mg2+;
Ca2+; Cl-; BG; lipids; uric acid


↑ dose every 4 weeks
Monitor SCr/BUN; serum electrolytes
at 1-2 weeks; then every 3-6 months
Thiazide Diuretics…CI


Allergy to sulfonylurea, sulfonamides
Chronic renal failure
Minimal efficacy if CrCl < 30 ml/min




Hx of gout (may precipitate an attack)
HypoNa+
HypoK+
DM
May worsen glucose control
Thiazide Diuretics…ADRs








Drowsiness
Orthostatic hypotension
Photosensitivity
Urinary incontinence
HypoK+; HypoNa+; HypoMg2+; HyperCa2+
Hyperuricemia
Hyperglycemia
↑ cholesterol & ↑ LDL
Loop Diuretics…Pharmacology &
PK

Inhibition of Na+/K+/Cl- co-transporter in ascending limb
of the loop of Henle
 reabsorption of Na+ & Cl urinary excretion of Na+, K+, Cl-, Mg2+ Ca2+ & H2O
Furosemide
Onset
(h)
t1/2
(h)
0.5-1
4
Duration Elimination
(h)
6-8
R
Initial Dose
(max. daily dose)
20 mg QD (200)
Loop
Diuretics…Management

Start at low dose
Baseline SCr/BUN; Na+; K+; Mg2+;
Ca2+ ; Cl-; BG; lipids; uric acid


↑ dose every 1-2 weeks
Monitor SCr/BUN; serum electrolytes
at 1-2 weeks; 1-2 months, then every
3-6 months
Loop Diuretics…CI









Allergy to sulfonylurea, sulfonamides
Anuria
Increasing azotemia & oliguria on tx
Hepatic coma
Hypovolemia
HypoNa+
HypoK+
Hx of gout
DM
Loop Diuretics…ADRs








Tinnitus
Orthostatic hypotension
Hypovolemia
HypoK+; HypoNa+; HypoMg2+; HypoCa2+
Hyperuricemia
Hyperglycemia
Metabolic alkalosis
↑ cholesterol & ↑ TG
ACE
Inhibitors…Pharmacology
Angiotensinogen
Renin
Angiotensin I
ACE
ACE inhibitors
Angiotensin II
Aldosterone
Na+ and H2O retention
Vascular smooth
muscles (AT1 receptor)
↑ SVR
ACE Inhibitors…PK
Onset
(h)
t1/2
(h)
Duration Elimination
(h)
Equivalent dose
Benazepril
1-2
10
24
R/Biliary
10 mg QD (40)
Captopril
0.20.3
<2
6-12
R
12.5 mg TID
(450)
Cilazapril
1
9
24
R
2.5 mg QD (10)
Enalapril
1
2
24
R
5 mg QD (40)
Fosinopril
1
12
24
R/H
10 mg QD (40)
Lisinopril
1
12
24
R
10 mg QD (80)
Perindopril
3-7
3-10
24
R
2 mg QD (16)
Quinapril
1
2
24
R/H
10 mg QD (40)
Ramipril
1-2
1317
24
R/H
2.5 mg QD (20)
(max. daily dose)
ACE
Inhibitors…Management



Start at low dose
Baseline SCr/BUN; K+
↑ dose at ≥ 2 week intervals
Monitor SCr/BUN; K+ at 1-2 weeks, 1-3 months,
then q6-12 months
ACE Inhibitors…CI


Angioedema or anaphylactic reaction
Renal insufficiency (pre-dialysis)
>30% increase in SCr



HyperK+
Bilateral renal artery stenosis or unilateral
disease with solitary kidney
Pregnant women (2nd and 3rd trimester)
 risk of major congenital malformations

Volume depletion
Elderly, concomitant diuretic therapy, HF
ACE Inhibitors…ADRs



Tinnitus
Dysgeusia
Cough (3-50%)
Not dose related
Rarely improves from switching to a different ACEI





↑ HR (if volume depleted)
Acute renal failure; proteinuria; oliguria
Angioedema; rash
Neutropenia; anemia
HyperK+
ARBs…Pharmacology
Angiotensinogen
Renin
Angiotensin I
ACE
Angiotensin II
Aldosterone
Na+ & H2O retention
ARBs
Vascular smooth
muscles (AT1 receptor)
↑ SVR
ARBs…Pharmacology

ARBs are AT1 receptor antagonists & they block
Vasoconstriction
Renal Na+ reabsorption
Aldosterone secretion
Sympathetic adrenergic activity
Cardiac & vascular remodeling
Release of vasopressin, luteinizing hormone, oxytocin,
& corticotropin
ARBs…PK
Onset
(h)
t1/2
(h)
Candesartan
2-3
3-4
> 24
R/H
8 mg QD (32)
Eprosartan
1-2
5-9
>24
H
600 mg QD (800)
Irbesartan
1-2
11-15
>24
R/H
150 mg QD (300)
6
1-2
10-15
R/H
50 mg QD (100)
Telmisartan
1-2
24
24
H
40 mg QD (80)
Valsartan
2-4
6
>24
H
80 mg QD (160)
Losartan
Duration Elimination
(h)
Equivalent dose
(max. daily dose)
ARBs…Management

Start at low dose
Baseline SCr/BUN; K+; LFTs


↑ dose at interval 2-4 weeks
Monitor SCr/BUN; K+ at 1-2 weeks, 1-3
months, then q6-12 months
ARBs…CI

Angioedema due to ARB or ACE inhibitors

Anaphylactic reaction




Renal insufficiency (pre-dialysis)
HyperK+
Bilateral renal artery stenosis or unilateral disease with
solitary kidney
Valvular stenosis
–  coronary perfusion

Pregnant women (2nd and 3rd trimester)
ARBs…ADRs







Tinnitus
Cough (3-10%)
↑ LFTs
Acute renal failure; oliguria
Angioedema; rash
Neutropenia; anemia
HyperK+
-Blockers…Pharmacology


Adrenoreceptors  (1/2) and  (1/ 2)
1-receptors
Heart



↑ HR
↑ contractility
↑ AV conduction
Kidney

↑ renin secretion
-Blockers…Pharmacology

2-receptors
Bronchodilation (lung)
Vasodilation (peripheral and coronary)
Glycogenolysis and gluconeogenesis (liver)
↑ Insulin/glucagon (pancreas)
↑ K+ uptake (skeletal muscle)
-Blockers…PK
Onset
(h)
t1/2
(h)
Acebutolol
1-2
6-7
12-24
H/R
200 mg (1200)
Atenolol
2-4
6-9
12-24
R
50 mg (100)
Bisoprolol
1-2
9-12
>24
H
10 mg (20)
Carvedilol
1-2
7-10
>24
H
50 mg (50)
Labetolol
0.3-2
2.5-8
8-24
H
200 mg (2400)
Metoprolol
1.5-4
3-4
10-20
H
100 mg (450)
Nadolol
2-4
1024
17-24
R
80 mg (320)
Pindolol
1-2
2.5-4
12
H/R
7.5 mg (60)
Propranolol
1-2
4-6
6
H
80 mg (640)
0.250.75
2-2.7
4
H
10 mg (60)
Timolol
Duration Elimination Equivalent dose
(h)
(max. daily dose)
-Blockers…Management

Start at low dose

↑ dose at bi-weekly intervals

Monitor BP/HR; weight; mental
status; circulation in extremities
-Blockers…CI

Absolute
Asthma/bronchospasm
HR< 50 bpm
AVB (2° or 3°)
Sick sinus syndrome (SSS)
Severe or decompensated HF
Prinzmetal angina

Relative
PVD
Severe depression
Diabetes
COPD
-Blockers…ADRs






Drowsiness; insomnia; depression
↓ HR; ↓ peripheral circulation; edema; HF
Bronchospasm
Impotence
Rash
Hypoglycemia
CCBs...Pharmacology

Block L-type Ca channels
Non-dihydropyridine  vascular smooth
muscles and myocardium
Coronary vasodilation
 ↓ myocardium contractility
 ↓ AV node conduction
 ↓ Peripheral vascular resistance

Dihydropyridine  vascular smooth muscles
Coronary vasodilation
 Peripheral vasodilation

NDHP CCBs…PK
Diltiazem CD
Verapamil
SR*
Onset
(h)
t1/2
(h)
Duration
(h)
Elimination
Initial Dose
(max. daily dose)
0.5-1
5-8
12-24
H
120 mg QD
(540)
2
6-9
6-8
H
180 mg QD
(360)
* Verapamil  more impact on myocardium contractility
and AV conduction than diltiazem
NDHP CCBs…Management

Start at low dose

↑ dose every 2-3 days

Monitor BP/HR; LFTs
NDHP CCBs…CI




Bradycardia (HR< 50 bpm)
Patients with LVEF< 40%
AV block (2° or 3°)
SSS
NDHP CCBs…ADRs







Dizziness; somnolence (D); insomnia (D)
↓ HR; edema; HF; flushing (D)
Dyspnea
GI bleeding; gingival hyperplasia; constipation (V);
nausea (V)
Polyuria (D)
Muscular weakness (D)
Rash
D = Diltiazem; V = Verapamil
DHP CCBs… Management

Start at low dose

↑ dose at interval of 7 to 14 days

Monitor BP/HR; weight; peripheral
edema
DHP CCBs…PK
Onset
(h)
t1/2
(h)
Duration Elimination
(h)
Initial Dose
(max. daily dose)
Amlodipine
0.5-1
35-50
24
H
2.5 mg QD (10)
Felodipine
2-5
1116
24
H
2.5-5 mg QD
(20)
Nifedipine (XL)
0.3
10
12-24
H
30 mg QD (180)
* NEVER use short acting nifedipine (especially not in hypertensive
emergency)
* Nifedipine has more impact on peripheral vascular resistance
DHP CCBs…CI





Severe HF
Cerebral tumor
Severe aortic stenosis
Hypertensive crisis
Acute MI
Short acting
formulation
DHP CCBs…ADRs






Drowsiness; H/A; nervousness; shakiness;
sleep disturbances
Flushing; ↓ HR; peripheral edema; HF
N/D/C; heartburn; gingival hyperplasia
Impotence
Muscular weakness; muscle cramps
Rash; dermatitis
1-blockers…Pharmacology


Arterioles and venules vasodilation
 systemic vascular resistance
Less tachyphylaxis than non-selective
-blockers

Retention of fluid & salts
1-blockers…PK
Onset
(h)
t1/2
(h)
Duration
(h)
Elimination
Initial Dose
(max. daily dose)
2-3
22
> 24
H
1 mg QD (16)
Prazosin
2
2-4
10-24
H
1 mg B-TID
(20)
Terazosin
1-2
912
>24
H/R
1 mg QD (20)
Doxazosin
1-blockers…Management

Start at low dose

↑ dose bi-weekly

Monitor sitting/supine BP
1-blockers…CI

Volume depleted or elderly
Risk of orthostatic hypotension or
syncope

Concurrent use of PDE-5
1-blockers…ADRs





Dizziness
Blurred vision
Orthostatic hypotension; edema;
palpitation; RSCP
Dry mouth
Urinary incontinence
Central 2-Agonist

Mechanism of action
Inhibition of efferent sympathetic activation

Clonidine
Initial dose: 0.1 mg BID (max. 2.4 mg/d)
ADRs: Drowsiness; depression; agitation; xerostomia;
be careful to withdraw (rebound hypertension);
orthostatic hypotension; RSCP; N/V/C; nocturia;
impotence; rash

Methyldopa
Initial dose: 250 mg B-TID (max. 3g/d)
ADRs: edema; depression; anxiety; nightmares; H/A;
dry mouth
Vasodilators

Mechanism of action
Direct vascular smooth muscle vasodilation

Hydralazine
Initial dose: 10 mg QID (max. 300 mg/d)
ADRs: Anxiety; depression; conjunctivitis;
dyspnea; ↑ HR; angina; N/V/D/C; urinary
retention; impotence; muscle cramps; muscle
weakness; tremors

Minoxidil
Initial dose: 5 mg QD (max. 100 mg/d)
ADRs: Peripheral edema; ↑ HR; angina;
pericarditis; pulmonary edema; ↑ weight; ↑ ALP; ↑
SCr/BUN; hypertrichosis; pruritis
References
Canadian Hypertension Education Program – 2007
Guidelines
http://hypertension.ca/chep/
BC Ministry of Health: Guidelines & Protocols
Advisory Committee  Hypertension
http://www.health.gov.bc.ca/gpac/guideline_hyp
ertension.html
Other “heart” problems

Dyslipidemia
Can be associated with decrease in renal function
↑ in Triglyceride and  HDL
1. Diet modifications
2. Statin
Best choice if ↑ LDL
ADRs: muscle cramps; muscle weakness; muscle pain; ↑ CK;
rhabdomyolysis; hepatotoxicity; headache
3. Fibrate
Best choice if ↑ Tg
Less case of ↑ serum creatinine with Gemfibrozil
ADRs: rash; diarrhea; myalgia; rhabdomyolysis;
hepatotoxicity
Other “heart” problems

Digoxin
Inhibits sodium-potassium ATPase in heart → better heart contraction,
decrease sympathetic response
Use in CHF (low dose) and A. Fib
50-70% eliminated by kidney… usually 0.0625 mg po OD to 3 x/week
Adjustment based on digoxin level (0.8-1.2 for CHF; 0.8 to 2 for A.fib)
ADRs: diarrhea, N/V, cardiac dysrythmia, headahce, visual disturbances

Amiodarone
Antiarrhythmic drug blocking potassium and sodium channel
Use for ventricular/Supraventricular arrythmia; A.Fib
Minimally renally eliminated
ADRs: bradycardia, hypotension, thyroid problems, photosensitivity,
nausea/vomiting, neuropathy, visual disturbances, fatigue, hepatotoxicity
Kidney Quiz…
You and your nursing student is reviewing
Mr. K.N.’s MAR. He is questioning the use
of Renavite in patient with renal failure…
why just not giving them a regular
vitamin?!
What is your answer? Should we switch
Mr. K.N. to Centrum, 1 tablet PO daily?
Vitamins in CKD
Water soluble vitamins are dialysable;
especially vitamin C, vitamins B and folic
acid.
Important to replenish dialysable vitamin for
HD patients. → Replavite, 1 tab po OD
DO NOT GIVE liposoluble vitamins because
of toxicity risk
Vitamin A: in excess, cause osteodystrophy, anemia,
hypercalcemia, skin problems
Vitamin D: ineffective
Vitamin E: generally elevated in CKD pt
Vitamin K: sufficient quantity available and
hypercoagulabitlity
Vitamins in CKD
Zinc
Dialysable, reduced absorption as bound to calcium, poor
dietary intake
Zinc deficiency is associated with:
Impaired taste and poor appetite
Hair loss
Poor wound healing
Recommended dose is 15 mg/day (if deficiency is
suspected)
Zinc sulfate 50 mg 3 x/week
Zinc gluconate 10-20 mg po QD
Reassess after 4-8 weeks
APPETITE STIMULANTS
Malnutrition accounts for significant morbidity
and mortality
Moderate-severe malnutrition ~ 30% of
dialysis patients
Improving nutrition in dialysis patients
optimize dialysis duration
improve oral diet with enteral supplements
total parenteral nutrition (intradialytic)
drug therapy (megestrol acetate)
MEGESTEROL ACETATE (Megace)
Progesterone derivative with appetite
stimulating properties
HPB approved for cancer- or AIDS-related
cachexia, anorexia or weight loss
Currently being studied in dialysis patients as
an appetite stimulant
MEGESTEROL ACETATE (Megace)
Dose: 160-800 mg daily (study dose =
800 mg daily)
Amount and Type of Weight Gained:
average 2-5 kg weight gain within 1-3
months
fat versus lean body mass
MEGESTEROL ACETATE (Megace)
Side Effects:
sexual dysfunction (4-26%)
deep vein thrombosis (< 5%)
withdrawal menses or breakthrough bleeding (early)
hyperglycemia (within first 3 months)
gastrointestinal complaints
excess weight gain (>10 kg)
Contraindications: thromboembolic disease
GASTROINTESTINAL
DISORDERS
Reflux
Peptic Ulcer Disease
Motility Disorders
Nausea
CAUSES
Diabetes gastroparesis
Medications: Calcium, Aluminum phosphate
binders, Diavite, and Iron, prednisone and
cyclophosphamide
Uremia of renal failure and infusion of
peritoneal dialysis fluid
Constipation: due to fluid restriction,
restriction of fruits and fruit juices, iron
supplements, phosphate binders
IMPORTANCE OF MANAGEMENT
Maintenance of nutrition
Symptom control
MEDICAL MANAGEMENT
Determine cause or source of problem
Nausea due to medications - taking with some food
(if no interactions)
Antiemetics such as prochlorperazine, haloperidol or
dimenhydrinate
If gastroparesis - prokinetic agents
If suspected reflux - ranitidine
(not cimetidine - impact on serum creatinine and
interstitial nephritis)
If reflux resistant to ranitidine or UGIB– omeprazole,
rabeprazole etc.
PROKINETIC AGENTS
Metoclopramide
Adverse effects - extrapyramidal
symptoms (EPS) at higher doses + in
children
Start dose of 5 mg qid (max: 20 mg
po QID)
Domperidone
10 - 40 mg PO tid-qid
UREMIC PRURITUS
Causes unknown
Mechanism
understood
poorly
CLINICAL ASPECTS
25-33%
predialysis
patients
60-86% dialysis patients
10-14% less in capd vs.
hemodialysis
Non
age
or
gender
dependent
Persistent
POSSIBLE CAUSES
Uremic skin
Cutaneous
mast
cell
proliferation
Atrophy of the sebaceous and
sweat glands
Increased skin pH
Secondary
hyperparathyroidism
POSSIBLE CAUSES
Hypervitaminosis A
Iron deficiency anemia
Peripheral neuropathy
Middle weight molecules
Bile acids
MANAGEMENT
Regular intensive dialysis
Restricted phosphate diet
Phosphate binders
Erythropoietin
and
iron
supplementation
Emollients/topical
corticosteroids (1% HC, 3% SA,
MANAGEMENT
Antihistamines
Cholestyramine
Activated charcoal
Subtotal parathyroidectomy
Oatmeal/baking
soda/salt
water/bath oils
100% Cotton wear