Renal failure

1
Renal failure drug management

• By Dr. Judith Marin
• Pharmacist for FHA Renal program
• 614.0388

2
Outline

• Influence of kidneys on drugs (vice-versa)
• Anemia
• Bone-mineral disorder
• Cardiovascular drugs
• Other renal exceptions!!!

3
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)

4
CKD who is at risk??

• Elderly patient
• Transplant patient
• Diabetics
• Hypertensive/ Cardiovascular disease

5
CKD who is at risk??

• Acute renal failure
• ? in serum creatinine level X 3.0
• ? in GFR by 75
• Serum creatinine level gt350 µmol/L with acute
  increase of gt44 µmol/L
• U/O lt0.3 mL/kg/h for 24 hours, or anuria for 12
  hours
• Chronic renal failure
• Kidney damage or decrease eGFR for more than 3
  months

6
CKD Stage
7
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

8
Pharmacotherapeutic management for CKD

• Dosage adjustment specific to CrCL
• Avoid contraindicated medications/ nephrotoxic
  drugs
• Normalizing bloodwork
• Education

9
Drug dosage in CKD

• Cockcroft-Gault equation
• Expressed renal creatinine clearance
• More appropriate than eGFR to base drug dosage
  adjustment

10
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 lt 60
  ml/min
• Depends efficacy/adverse drug reaction profile
• Monitoring available

11
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
12
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

13
Case with Mr. Kidd Ney

• Any intervention???
• Ciprofloxacin
• Dosage adjustment if CrCl lt 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)

14
Case with Mr. Kidd Ney

• Any intervention???
• Metformin
• Dosage adjustment if CrCl lt 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

15
References

• Bennetts book. Drug Prescribing in Renal
  Failure.
• http//www.kdp-baptist.louisville.edu/renalbook/
• Drug Monography
• Micromedex
• eCPS
• Medscape
• Be careful to your references!

16
Examples

• Drugs should never be held before HD run
• Except if ordered by physician
• Antibiotic should be administered after HD run
• Antibiotic minimally dialysed azithromycin,
  chloramphenicol, clindamycin, doxycyclin/tetracycl
  ine, linezolid

Antibiotic Excretion during HD
?-Lactams 10-75
Fluoroquinolones 50
Aminoglycosides 40-50
17
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?

18
Nephrotoxic drugs

• Drugs caused about 20 of community and hospital
  acquired acute renal failure
• Risk factors
• gt 60 years old
• eGFR lt 60 ml/min
• Diabetes
• Volume depletion
• CHF
• Sepsis

19
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

20
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

21
Nephrotoxic drugs
Antibiotics Aminoglycosides, amphotericine B penicillin, cephalosporin, quinolones acyclovir, sulfa D/C drug if sCr increases
NSAIDs/COX-2 inhibitors Diclofenac, naproxen, celecoxib Contraction of efferent renal arteriole D/C drug and switch to acetaminophen
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
22
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?

23
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 lt 15 or dialysis 100

• Prevalence higher in african americans and
  diabetic patients

24
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

25
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

26
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

27
Talking about EPO

• 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

28
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

29
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 gt 30
• Cosmetic syndrom

30
Iron deficiency

• Definition
• Ferritin lt 100 ng/ml
• Iron transferrin saturation lt 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

31
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
32
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
33
Iron deficiency

• IV iron supplement
• Adverse drug reactions
• Hypotension/hypertension, tachycardia, edema,
  itching, phlebitis, rash, anaphylaxis/immune
  reaction, legs cramps, arthralgia, back pain,
  headache

34
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

35
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?

36
Bone and minerals
37
Bone and minerals
38
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

39
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.

40
Hyperphosphatemia
Type Examples Trade Names
Calcium-based Binders Calcium Carbonate Calcium Carbonate
Calcium-based Binders Calcium Acetate Calcium Acetate
Metal-based Binders Aluminum Hydroxide Aluminum Hydroxide
Metal-based Binders Magnesium Hydroxide Various Brands
Metal-based Binders Lanthanum Carbonate Fosrenal
Noncalcium, Non-metal-based Binders Sevelamer HCl Renagel
41
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

42
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)
43
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

44
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

45
Kidney Quiz

• Mr K. N. results during BW week
• 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

This BW Last BW
Corrected Ca 2.3 2.24
Phosphorus 1.5 1.0
iPTH 62 30
46
Kidney Quiz

• Mr K. N. results during next BW week

This BW Last BW
Corrected Ca 2.65 2.3
Phosphorus 1.9 1.5
iPTH 55 62
47
Kidney Quiz

• Mr K. N. results during next BW week

This BW Last BW
Corrected Ca 2.65 2.65
Phosphorus 1.9 1.9
iPTH 105 55
48
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?

49
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.

50
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?

51
Pain ManagementMulti-modal

• Non-Pharmacological
• Heat/Cold
• Massage
• Distraction
• Self Management
• Psychology

• Pharmacological

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52
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 lt 4/10)
• Can also be used as co-analgesic / adjuvant

53
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 lt 4/10)
• Can also be used as co-analgesic / adjuvant

54
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

55
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

56
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

57
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.

58
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

59
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

60
Management of ADRs

• Nausea/vomiting
• Usually tolerance after 5-7 days
• GI stasis and impact on chemoreceptive zone
• Domperidone/metoclopramide
• Or/and
• Prochlorperazine/ Haloperidol

61
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

62
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

63
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

64
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

65
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

66
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?

67
Goals of BP Therapy

• Reduce associated morbidity and mortality
• Target-organ damage
• BP lt 140/90 mmHg
• Diabetes or chronic kidney disease
• BP lt 130/80 mmHg
• Proteinuric renal disease (Urinary protein
  excretion gt 1g/24h)
• BP lt 130/80 mm Hg

68
Non-Drug Therapy

• Weight reduction
• DASH diet
• Reduce dietary sodium intake
• Physical activity
• Moderate alcohol consumption
• Smoking cessation

69
Classes of AntiHypertensives

• Diuretics
• Angiotensin Converting Enzyme (ACE) Inhibitors
• Angiotensin Receptor Blockers (ARB)
• ß-Blockers
• Calcium Channel Blockers (CCB)
• Non-dihydropyridine (NDHP)
• Dihydropyridine (DHP)
• ?1-Blockers
• Central ?2-Agonists
• Vasodilators

70
Indications
First Line Second Line
Uncomplicated HTN Uncomplicated HTN Uncomplicated HTN
Thiazide diuretic ACEI ARB long acting DHP-CCB ß-Blocker
HTN Complicated by Co-Morbid Conditions HTN Complicated by Co-Morbid Conditions HTN Complicated by Co-Morbid Conditions
Coronary Artery Disease (CAD) ACEI ß-Blocker (stable angina) Long acting CCB
Myocardial Infarction (MI) ACEI ß-Blocker - ARB if ACEI intolerant - CCB if ß-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
71
Indications
First Line Second Line
HTN Complicated by Co-Morbid Conditions HTN Complicated by Co-Morbid Conditions HTN Complicated by Co-Morbid Conditions
Heart Failure ACEI ß-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 Disease Thiazide diuretic ACEI 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
72
DiureticsPharmacology
73
Thiazide DiureticsPharmacology

• 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

74
Thiazide DiureticsPK
Onset (h) t1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose)
Chlorthalidone 2-3 40-80 24-72 R 12.5 mg QD (100)
Hydrochloro-thiazide (HCTZ) 2 2.5-14 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
75
Thiazide DiureticsManagement

• 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

76
Thiazide DiureticsCI

• Allergy to sulfonylurea, sulfonamides
• Chronic renal failure
• Minimal efficacy if CrCl lt 30 ml/min
• Hx of gout (may precipitate an attack)
• HypoNa
• HypoK
• DM
• May worsen glucose control

77
Thiazide DiureticsADRs

• Drowsiness
• Orthostatic hypotension
• Photosensitivity
• Urinary incontinence
• HypoK HypoNa HypoMg2 HyperCa2
• Hyperuricemia
• Hyperglycemia
• ? cholesterol ? LDL

78
Loop DiureticsPharmacology 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

Onset (h) t1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose)
Furosemide 0.5-1 4 6-8 R 20 mg QD (200)
79
Loop DiureticsManagement

• 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

80
Loop DiureticsCI

• Allergy to sulfonylurea, sulfonamides
• Anuria
• Increasing azotemia oliguria on tx
• Hepatic coma
• Hypovolemia
• HypoNa
• HypoK
• Hx of gout
• DM

81
Loop DiureticsADRs

• Tinnitus
• Orthostatic hypotension
• Hypovolemia
• HypoK HypoNa HypoMg2 HypoCa2
• Hyperuricemia
• Hyperglycemia
• Metabolic alkalosis
• ? cholesterol ? TG

82
ACE InhibitorsPharmacology
Angiotensinogen
Renin
Angiotensin I
ACE inhibitors
ACE
Angiotensin II
Aldosterone
Vascular smooth muscles (AT1 receptor)
Na and H2O retention
? SVR
83
ACE InhibitorsPK
Onset (h) t1/2 (h) Duration (h) Elimination Equivalent dose (max. daily dose)
Benazepril 1-2 10 24 R/Biliary 10 mg QD (40)
Captopril 0.2-0.3 lt 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 13-17 24 R/H 2.5 mg QD (20)
Trandolapril 1-2 6 24-72 R/H 1 mg QD (8)
84
ACE InhibitorsManagement

• 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

85
ACE InhibitorsCI

• Angioedema or anaphylactic reaction
• Renal insufficiency (pre-dialysis)
• gt30 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

86
ACE InhibitorsADRs

• 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

87
ARBsPharmacology
Angiotensinogen
Renin
Angiotensin I
ACE
Angiotensin II
ARBs
Aldosterone
Vascular smooth muscles (AT1 receptor)
Na H2O retention
? SVR
88
ARBsPharmacology

• 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

89
ARBsPK
Onset (h) t1/2 (h) Duration (h) Elimination Equivalent dose (max. daily dose)
Candesartan 2-3 3-4 gt 24 R/H 8 mg QD (32)
Eprosartan 1-2 5-9 gt24 H 600 mg QD (800)
Irbesartan 1-2 11-15 gt24 R/H 150 mg QD (300)
Losartan 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 gt24 H 80 mg QD (160)
90
ARBsManagement

• 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

91
ARBsCI

• 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)

92
ARBsADRs

• Tinnitus
• Cough (3-10)
• ? LFTs
• Acute renal failure oliguria
• Angioedema rash
• Neutropenia anemia
• HyperK

93
?-BlockersPharmacology

• Adrenoreceptors ? (?1/?2) and ? (?1/ ?2)
• ?1-receptors
• Heart
• ? HR
• ? contractility
• ? AV conduction
• Kidney
• ? renin secretion

94
?-BlockersPharmacology

• ?2-receptors
• Bronchodilation (lung)
• Vasodilation (peripheral and coronary)
• Glycogenolysis and gluconeogenesis (liver)
• ? Insulin/glucagon (pancreas)
• ? K uptake (skeletal muscle)

95
?-BlockersPK
Onset (h) t1/2 (h) Duration (h) Elimination Equivalent dose (max. daily dose)
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 gt24 H 10 mg (20)
Carvedilol 1-2 7-10 gt24 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 10-24 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)
Timolol 0.25-0.75 2-2.7 4 H 10 mg (60)
96
?-BlockersManagement

• Start at low dose
• ? dose at bi-weekly intervals
• Monitor BP/HR weight mental status circulation
  in extremities

97
?-BlockersCI

• Absolute
• Asthma/bronchospasm
• HRlt 50 bpm
• AVB (2 or 3)
• Sick sinus syndrome (SSS)
• Severe or decompensated HF
• Prinzmetal angina
• Relative
• PVD
• Severe depression
• Diabetes
• COPD

98
?-BlockersADRs

• Drowsiness insomnia depression
• ? HR ? peripheral circulation edema HF
• Bronchospasm
• Impotence
• Rash
• Hypoglycemia

99
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

100
NDHP CCBsPK
Onset (h) t1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose)
Diltiazem CD 0.5-1 5-8 12-24 H 120 mg QD (540)
Verapamil SR 2 6-9 6-8 H 180 mg QD (360)
Verapamil ? more impact on myocardium
contractility and AV
conduction than diltiazem
101
NDHP CCBsManagement

• Start at low dose
• ? dose every 2-3 days
• Monitor BP/HR LFTs

102
NDHP CCBsCI

• Bradycardia (HRlt 50 bpm)
• Patients with LVEFlt 40
• AV block (2 or 3)
• SSS

103
NDHP CCBsADRs

• 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
104
DHP CCBs Management

• Start at low dose
• ? dose at interval of 7 to 14 days
• Monitor BP/HR weight peripheral edema

105
DHP CCBsPK
Onset (h) t1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose)
Amlodipine 0.5-1 35-50 24 H 2.5 mg QD (10)
Felodipine 2-5 11-16 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
106
DHP CCBsCI

• Severe HF
• Cerebral tumor
• Severe aortic stenosis
• Hypertensive crisis
• Acute MI

Short acting formulation
107
DHP CCBsADRs

• 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

108
?1-blockersPharmacology

• Arterioles and venules vasodilation
• ? systemic vascular resistance
• Less tachyphylaxis than non-selective
  ?-blockers
• Retention of fluid salts

109
?1-blockersPK
Onset (h) t1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose)
Doxazosin 2-3 22 gt 24 H 1 mg QD (16)
Prazosin 2 2-4 10-24 H 1 mg B-TID (20)
Terazosin 1-2 9-12 gt24 H/R 1 mg QD (20)
110
?1-blockersManagement

• Start at low dose
• ? dose bi-weekly
• Monitor sitting/supine BP

111
?1-blockersCI

• Volume depleted or elderly
• Risk of orthostatic hypotension or syncope
• Concurrent use of PDE-5

112
?1-blockersADRs

• Dizziness
• Blurred vision
• Orthostatic hypotension edema palpitation RSCP
• Dry mouth
• Urinary incontinence

113
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

114
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

115
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_hyperte
  nsion.html

116
Other heart problems

• Dyslipidemia
• Can be associated with decrease in renal function
• ? in Triglyceride and ? HDL
• Diet modifications
• Statin
• Best choice if ? LDL
• ADRs muscle cramps muscle weakness muscle
  pain ? CK rhabdomyolysis hepatotoxicity
  headache
• Fibrate
• Best choice if ? Tg
• Less case of ? serum creatinine with Gemfibrozil
• ADRs rash diarrhea myalgia rhabdomyolysis
  hepatotoxicity

117
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

118
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?

119
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

120
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

121
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)

122
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

123
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

124
MEGESTEROL ACETATE (Megace)

• Side Effects
• sexual dysfunction (4-26)
• deep vein thrombosis (lt 5)
• withdrawal menses or breakthrough bleeding
  (early)
• hyperglycemia (within first 3 months)
• gastrointestinal complaints
• excess weight gain (gt10 kg)
• Contraindications thromboembolic disease

125
GASTROINTESTINAL DISORDERS

• Reflux
• Peptic Ulcer Disease
• Motility Disorders
• Nausea

126
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

127
IMPORTANCE OF MANAGEMENT

• Maintenance of nutrition
• Symptom control

128
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.

129
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

130
UREMIC PRURITUS

• Causes unknown
• Mechanism poorly understood

131
CLINICAL ASPECTS

• 25-33 predialysis patients
• 60-86 dialysis patients
• 10-14 less in capd vs. hemodialysis
• Non age or gender dependent
• Persistent

132
POSSIBLE CAUSES

• Uremic skin
• Cutaneous mast cell proliferation
• Atrophy of the sebaceous and sweat glands
• Increased skin pH
• Secondary hyperparathyroidism
• Divalent-ion abnormalities

133
POSSIBLE CAUSES

• Hypervitaminosis A
• Iron deficiency anemia
• Peripheral neuropathy
• Middle weight molecules
• Bile acids

134
MANAGEMENT

• Regular intensive dialysis
• Restricted phosphate diet
• Phosphate binders
• Erythropoietin and iron supplementation
• Emollients/topical corticosteroids (1 HC, 3 SA,
  5 PG, 10 urea in glaxal base)
• UVB/UVA

135
MANAGEMENT

• Antihistamines
• Cholestyramine
• Activated charcoal
• Subtotal parathyroidectomy
• Oatmeal/baking soda/salt water/bath oils
• 100 Cotton wear

136
QUESTIONS???