Documents
Resources
Learning Center
Upload
Plans & pricing Sign in
Sign Out

Drugs and the Kidney - Download as PowerPoint

VIEWS: 43 PAGES: 43

									Drugs and the Kidney
      Drugs and the Kidney
1 Renal Physiology and Pharmacokinetics
2 Drugs and the normal kidney
3 Drugs toxic to the kidney
4 Prescribing in kidney disease
        Normal Kidney Function
•   1 Extra Cellular Fluid Volume control
•   2 Electrolyte balance
•   3 Waste product excretion
•   4 Drug and hormone elimination/metabolism
•   5 Blood pressure regulation
•   6 Regulation of haematocrit
•   7 regulation of calcium/phosphate balance
    (vitamin D3 metabolism)
Clinical Estimation of renal function
• Clinical examination
  pallor, volume status, blood pressure
  measurement, urinalysis
• Blood tests
• Routine Tests
•     haemoglobin level
•     electrolyte measurement (Na ,K , Ca, PO4)
•     urea
•     creatinine normal range 70 to 140 μmol/l
    Serum Creatinine and GFR
• Muscle metabolite - concentration
  proportional to muscle mass
   – High: muscular young men
   – Low: conditions with muscle wasting
      • elderly
      • muscular dystrophy
      • Anorexia
      • malignancy

• “Normal” range   70 to 140 μmol/litre
     Serum Creatinine and GFR
Serum creatinine




                   Glomerular filtration rate
                   (GFR)
           GFR Estimation
• Cockroft-Gault Formula
  CrCl=Fx(140-age)xweight/CreaP
  F♀=1.04
  F♂=1.23
  Example
  85♀, 55kg, Creatinine=95
  CrCl=33ml/min
• MDRD Formula
    Tests of renal function cont.
•    24h Urine sample-Creatinine
     clearance
•    chromium EDTA Clearance
•    gold standard Inulin clearance
The nephron and electrolyte
        handling  +   -
               Na -Cl
               Gitelman's syndrome
               Thiazide sensitive
                         7%

    +
  Na    60%
    +
  K
                                      2%
                                        +   +   +
                                      Na -K , H
                          30%         Liddle’s syndrome
                                      Pseudohypoaldosteronism
              Na-K-2Cl                type-I
              ROMK                    Amiloride sensitive
              Bartter's syndrome 1%
              Bumetanide
              sensitive
          Pharmacokinetics

•   Absorption
•   Distribution
•   Metabolism
•   Elimination
      – filtration
      – secretion
               Diuretics
•   Loop
•   Thiazide
•   Aldosterone antagonist
•   Osmotic
                 Diuretics
• Indications for use
   – heart failure ( acute or chronic )
   – pulmonary oedema
   – hypertension
   – nephrotic syndrome
   – hypercalcaemia
   – hypercalciuria
             Loop diuretics
Frusemide, Bumetanide
Indication
  – Fluid overload
  – Hypertension
  – Hypercalcaemia

Mechanism of action
 Blockade of NaK2Cl (NKCC2) transporter in the
 thick ascending loop of Henle
              Loop diuretics
• Frusemide
  – oral bioavailability between 10 and 90%
  – Acts at luminal side of thick ascending
    limb(NaK2Cl transporter)
  – Highly protein bound
  – Rebound after single dose
  – Half-life 4 hours
     Loop diuretics continued
• Caution
  – Electrolyte imbalance - hypokalaemia
  – Volume depletion (prerenal uremia)
  – Tinitus (acts within cochlea – can synergise
    with aminoglycoside antibiotics)
           Thiazide diuretics
Bendrofluazide, Metolazone
 Site of action distal convoluted tubule
 blocks electroneutral Na/Cl exchanger (NCCT)

Reaches site of action in glomerular filtrate
       – Higher doses required in low GFR
        (ineffective when serum creatinine
        >200μM)
       – T ½ 3-5 hours
             Thiazides
• Indications
  – Antihypertensive: especially in combination
    with ACE inhibitor/ARB (A+D)
  – In combination with loop diuretic for profound
    oedema
  – Cautions
     • Metabolic side effects – hyperuricaemia, impaired
       glucose tolerance & electrolyte disturbance
       (hypokalaemia and hyponatraemia)
     • Volume depletion
   ALLHAT
      Major Outcomes in High Risk
 Hypertensive Patients Randomized to
    Angiotensin-Converting Enzyme
Inhibitor or Calcium Channel Blocker vs
                 Diuretic
          The Antihypertensive and Lipid-Lowering
           Treatment to Prevent Heart Attack Trial
                         (ALLHAT)
             The ALLHAT Collaborative Research Group
             Sponsored by the National Heart, Lung, and Blood
JAMA. 2002;288:2981-2997
                            Institute (NHLBI)
                                                    Cumulative Event Rates for the Primary
ALLHAT                                              Outcome (Fatal CHD or Nonfatal MI) by
                                                    ALLHAT Treatment Group
                                     .2
                                                               RR (95% CI)         p value

                                    .16
                                                   A/C        0.98 (0.90-1.07)      0.65
        Cumulative CHD Event Rate




                                                   L/C        0.99 (0.91-1.08)      0.81

                                    .12                       Chlorthalidone
                                                              Amlodipine
                                                              Lisinopril
                                    .08



                                    .04



                                     0
                                           0              1          2           3         4        5       6       7
                                                                             Years to CHD Event
Number at Risk:
Chlorthalidone                            15,255         14,477     13,820     13,102      11,362   6,340   2,956   209
Amlodipine                                 9,048          8,576      8,218      7,843       6,824   3,870   1,878   215
Lisinopril                                 9,054          8,535      8,123      7,711       6,662   3,832   1,770   195
                     Overall
ALLHAT
                   Conclusions

Because of the superiority of thiazide-type
diuretics in preventing one or more major
forms of CVD and their lower cost, they
should be the drugs of choice for first-step
antihypertensive drug therapy.
  Amiloride and Spironolactone
• Amiloride
   – Blocks ENaC (channel for Na secretion in
     collecting duct under aldosterone control)
• Spironolactone
   – Aldosterone receptor antagonist
   – Reaches DCT via blood stream (not
     dependent on GFR)
• Often Combined with loop or thiazides to
  capitalise on K-sparing action
         Nephrotoxic Drugs
• Dose dependant toxicity
  – NSAIDs including COX 2
  – Aminoglycosides
  – Radio opaque contrast materials
• Idiosyncratic Renal Damage
  – NSAIDs
  – Penicillins
  – Gold, penicillamine
     NSAIDs (Non-steroidal anti
       inflammatory drugs)
• Commonly used
  – Interfere with prostaglandin production,
    disrupt regulation of renal medullary blood
    flow and salt water balance
• Chronic renal impairment
  – Habitual use
  – Exacerbated by other drugs ( anti-
    hypertensives, ACE inhibitors)
  – Typical radiological features when advanced
            Aminoglycosides
• Highly effective antimicrobials
  – Particularly useful in gram -ve sepsis
  – bactericidal
• BUT
  – Nephrotoxic
  – Ototoxic
  – Narrow therapeutic range
  Prescribing Aminoglycosides
• Once daily regimen now recommended in
  patients with normal kidneys
        – High peak concentration enhances
         efficacy
        – long post dose effect
        – Single daily dose less nephrotoxic
• Dose depends on size and renal function
        – Measure levels!
        Intravenous contrast
• Used commonly
       – CT scanning, IV urography, Angiography
       – Unsafe in patients with pre-existing renal impairment

       – Risk increased in diabetic nephropathy, heart failure
         & dehydration
       – Can precipitate end-stage renal failure
       – Cumulative effect on repeated administration


• Risk reduced by using Acetylcysteine ?
       – see N Engl J Med 2000; 343:180-184
 Prescribing in Kidney Disease
• Patients with renal impairment
• Patients on Dialysis
• Patients with renal transplants
                   Principles
• Establish type of kidney disease
     • Most patients with kidney failure will already be
       taking a number of drugs
     • Interactions are common
     • Care needed to avoid drug toxicity
• Patients with renal impairment and renal
  failure
     • Antihypertensives
     • Phosphate binders
    Dosing in renal impairment
• Loading dose does not change (usually)
• Maintenance dose or dosing interval does

  T ½ often prolonged
  – Reduce dose OR
  – Increase dosing interval

  – Some drugs have active metabolites that are
    themselves excreted renally
        – Warfarin, diazepam
            Past Papers
• Write short notes on the following
  – Spironolactone   (Dec2000)
  – Amphotericin     (June99)
  – Cyclosporin      (June99)
              Past Papers
• Discuss the treatment of patients with
  – Digoxin toxicity
  – Lithium toxicity
  Following both deliberate and Iatrogenic
    overdose.
  Which treatments have been shown to improve
    survival?
                Spironolactone
• Class
     • Potassium sparing diuretic
• Mode of action
     • Antagonises the effect of aldosterone at levels MR
     • Mineralocorticoid receptor (MR)–aldosterone complex
       translocates to nucleus to affect gene transcription
• Indication
     • Prevent hypokalaemia in patients taking diuretics or digoxin
     • Improves survival in advanced heart failure (RALES 1999
       Randomised Aldactone Evaluation Study)
     • Antihypertensive (adjunctive third line therapy for
       hypertension or first line for conns patients)
     • Ascites in patients with cirrhosis
             Spironolactone
• Side effects
       – Antiandrogenic effects through the antagonism of DHT
         (testosterone) at its binding site.
       – Gynaecomastia, impotence, reduced libido

• Interactions
       – Other potassium sparing drugs e.g. ACE inhibitors/ARBs
         & potassium supplements (remember „LoSalt‟ used as
         NaCl substitute in cooking)
               Amphotericin
• Class
    • Anti fungal agent for topical and systemic use
• Mode of action
    • Lipid soluble drug. Binds steroid alcohols
      (ergosterol) in the fungal cell membrane causing
      leakage of cellular content and death. Effective
      against candida species
    • Fungistatic or fungicidal depending on the
      concentration
    • Broad spectrum (candida, cryptosporidium)
                   Amphotericin
• Indications
          – iv administration for systemic invasive fungal infections
          – Oral for GI mycosis

• Side effects
          – Local/systemic effects with infusion (fever)
          – Chronic kidney dysfunction
              » Decline in GFR with prolonged use
              » Tubular dysfunction (membrane permeability)
              » Hypokalaemia, renal tubular acidosis (bicarb wasting
                type 1/distal), diabetes insipidus, hypomagnesaemia
              » Pre hydration/saline loading may avoid problems

Toxicity can be reduced substantially by liposomal packing
  of Amphotericin
                 Lithium toxicity
• Lithium carbonate - Rx for bipolar affective disorder
• Toxicity closely related to serum levels
• Symptoms
          – CVS arrhythmias (especially junctional dysrrythmias)
          – CNS tremor – confusion - coma
• Treatment
      • Supportive - Haemodialysis and colonic irrigation for severe
        levels
      • Inadvertent intoxication from interaction with ACEI &
        loop/thiazide diuretic
      • Carbamezepine and other anti epileptics increase
        neurotoxicity
              Digoxin toxicity
• Incidence
       – High levels demonstrated in 10% and toxicity
         reported in 4% of a series of 4000 digoxin
         samples

• Kinetics
       – large volume of distribution (reservoir is skeletal
         muscle)
       – about 30% of stores excreted in urine/day
   Treatment of digoxin toxicity
• Supportive
        – Correction of electrolyte imbalances
        – Atropine for bradycardia avoid cardio stimulants because
          arrythmogenic
• Limitation of absorption
        – Charcoal effective within 8 hours (or cholestyramine)
• Specific measures
        – DIGIBIND Fab digoxin specific antibodies. Binds plasma
          digoxin and complex eliminated by kidneys (used when OD is
          high/near arrest)
• Enhanced elimination
        – Dialysis is ineffective. Charcoal/cholestyramine interrupt
          enterohepatic cycling.

								
To top