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PHARMACOKINETICS AND RENAL DISEASE

 

1. Introduction:

Epidemiological studies indicate that impaired renal function is a major risk factor in predisposing patients to drug toxicity.

Careful dosage adjustments can prevent much of this toxicity.

2. Assessment of Renal Function:

The most widely used test of renal function is the glomerular filtration rate (GFR), which is commonly approximated as the creatinine clearance (Cl).

Creatinine:

Good approximation of GFR:

• Eliminated only by the kidney
• Freely filtered Good approximation
• Neither secreted nor reabsorbed of GFR
• Easily and accurately measured

 

Measurement of Cl (Normal ~ 120ml/min):

Requires timed urine collection and blood sample at midpoint of collection.

	Urine concentration X volume
Cl =	__________________________________
	Plasma concentration X collection time

Since measurements of Cl require a timed urine collection, the estimation of renal function from the serum creatinine level alone is more convenient and widely used.

 

Limitations of serum creatinine measurement (Normal : 0.06 - 0.13 mmol/L):

(a) The relationship between the serum creatinine level and ClCr (GFR) also depends on the endogenous production of creatinine by muscle metabolism, which in turn depends largely on muscle bulk. Eg. the elderly have less skeletal muscle than do younger persons, as so an elderly person with the same serum creatinine level as a young person can still have a low Clcr (GFR). Ie. an elderly person can have renal impairment, despite a normal serum creatinine level.

To correct for age, sex, and weight-related differences in endogenous creatinine production, either measure Clcr directly or use a nomogram or the following equation to convert serum creatinine levels to Clcr values:-

	(140 - age) X weight (kg)	X 0.85 for women
Cl (ml/sec)=	__________________________________
	48,869 X serum creatinine (mmol/L)

 

(b) Changes in serum creatinine occur slowly following changes in renal function, ie. serum creatinine levels provide an inaccurate reflection if renal function (GFR) is changing rapidly, eg. acute renal failure.

 

3. Pharmacokinetic Alterations in Renal Disease:

(a) Distribution:

(i) Highly protein bound drugs:

Eg. Phenytoin, Sodium valproate, Diazepam.

fu due to:

• serum albumin.
• retention of endogenous displacing peptides

Vd may

(ii) Other drugs:

Eg. Digoxin

Vd due to reduced tissue uptake.

Clinical implications:

Loading dose = Vd X Cp

Overall, it appears most practical to administer the usual loading dose to patients with renal failure. However, it has been suggested that the loading dose of Digoxin should be reduced by about one third in these patients.

 

(b) Renal excretion:

In spite of the complexity of the renal drug elimination mechanisms, it has been found that in renal disease the renal clearance of the drug correlates well with Cl, and hence an estimate of the individual patient’s renal drug eliminating capacity can be made readily.

Whether a patient requires a reduction in drug dosage due to renal disease depends on several factors:-

(i) The therapeutic index of the drug.

(ii) The proportion of renal clearance to total clearance of the drug.

Drugs for which the kidney eliminates 75% of more of the administered dose as unchanged drug in urine.
Aminoglycoside agents	Amkiacin, Gentamicin, Kanamycin, Streptomycin, Tobramycin, Netilmicin
Beta-lactam antibiotic agents	Benzylpenicillin, Phenoxymethylpenicillin, Amoxycillin, Ampicillin, Flucloxacillin, Methicillin, Ticarcillin, Carbenicillin, Cephalexin, Cefazolin, Cefoxitin, Cephamandole, Latamoxef
Other anti-infective agents	Colisin, Vancomycin, Sulphamethizole, Flucytosine, Ethambutol, Acyclovir, Amantadine
Others	Digoxin (75%), Metformin, Pyridostigmine, Atenolol, Bethanidine, Baclofen, Methotrexate, Lithium, Aminocaproic acid, Tranexamic acid, Gallamine, Alcuronium

 

Drugs for which the kidney eliminates 25 - 75% of the administered dose as unchanged drug in urine.
Beta-lactam antibiotic agents	Cephalothin (60%), Cefotaxime (30%), Cefaclor (50%), Mezlocillin (70%)
Other anti-infective agents	Lincomycin (25%), Sulphamethoxazole (30%), Sulfisoxazole (50%), Sulphadiazine (50%), Trimethoprim (50%), Chloroquine (50%)
Cardiovascular drugs	Procainamide (60%), Disopyramide (50%), Methyldopa (60%), Pindolol (40%), Clonidine (60%), Captopril (50%)
H2-antagonist drugs	Cimetidine (70%), Ranitidine (70%)
Others	Chlorpropamide (20-80%)*, Phenobarbital (25-5-%)*, Gold sodium thiomalate (60%), Bleomycin (50%), Hydroxyurea (50%), Neostigmine (50%), Bethanechol (60%), Atropine (40%), Hyoscine hydrobromide (70%) D-tubocurarine (40%), Pancuronium (45%), Metocurine (50%)
*Urinary pH dependent

 

(iii) The severity of renal impairment.

Calculation of dosage adjustment:

Clearance approach:

C		F x D
	=	_________
		Cl x
	..
Cl	=	Clm + Cl
	..
	=	Clm + fe.Cl
	..
	=	fm.Cl + fe.Cl
	..
		(1 - fe).Cl + fe.Cl

NB Cl ClCR as fe approaches 1.0

fe	= fraction of systemical available dose that is excreted unchanged.
Cl	= total clearance in normal patient.
Assumption:	Non-renal clearance (Clm) is largely unaffected by renal disease.

Example:

It is necessary to commence oral Digoxin therapy in a patient with renal disease (Clcr = 25ml/min). What is an estimated maintenance dosage?

Given 

F 0.70
fe 0.80
Cl 130ml/min

Cl		(0.2 x 130) + (0.8 x 25) ml/min
	..
	=	46 mL/min
	..
	=	2.76 L/hr

 Aim for level of 1.5 ng/ml (g/L and use t = 24hrs)

C	=	F x D
		_________
		Cl x
	..
D	=	C x Cl x
		____________
		F
	..
	=	(1.5 x 2.76 x 24) / 0.7 g daily
	..
		150g daily

 

Alternative approach:

Fraction of normal MD	=	fm + fe x (Cl/120)
	..
	=	(1 - fe) + fe x (Cl/120)

Eg. Using above data

Fraction of normal MD	=	0.2 + 0.8 x (25/120
	..
	=	0.37
	..
Normal MD		250g daily
	..
predicted MD	=	250 x 0.37g daily
	..
	=	92g daily

 

Determination of doses of drugs eliminated primarily by the kidneys in renal disease:

Our patient has Cl of 25 ml/min

Example 1 : Gentamicin:

Aim for C of mg/ml.

Gentamicin clearance is > 95% by renal route ( Cl = Cl)

C	=	dosage rate
		___________
		Cl

dosage	=	C x Cl
	..
	=	2 x 25 x (24 x 60/100)
	..
	=	72mg/day

 

Example 2:

Aim for C of 1.5 ng/ml.

Digoxin clearance is approx 75% by renal route ( Cl = Cl/0.75)

C	=	dosage rate
		___________
		Cl

dosage	=	C x Cl
	..
	=	1.5 x 25/0.75 x (24 x 60/100)
	..
	=	72g/day

 

Estimating drug dose in renal impairment:

1. Estimate/measure CrCl.

2. Know % excreted unchanged and % metabolised.

3. Estimate altered clearance:-

Cl = Cl + Cl

Eg. Acyclovir:

60% excreted unchanged and 40% metabolised
normal intravenous dosage for 70kg adult: 350mg every 8 hours.

Consider a patient with a creatinine clearance of 32 ml/min:

Cl	=	Cl + Cl
	..
Cl	=	0.60 Cl + 0.40 Cl (Where Cl is total normal clearance)
	..
new ClT	=	0.60 x (32/120)Cl + 0.40Cl
	..
	=	0.16Cl + 0.40Cl
	..
	=	0.56Cl

4. Then, estimate dosage needs:-

= fraction of normal clearance X “normal” dosage

= 0.56 X “normal” dosage

= 350mg every 8/0.56 hours

250mg every 14 hours or 300mg every 12 hours

Basically, the dosage modification process involves:-

(a) Lengthening the dosage interval and/or

(b) reducing the dose size.

 

4. Renal Disease and Protein Binding Changes:

Every acidic drug studied that binds to albumin shows decreased binding in serum from uranemic patients.

Reasons:-

(a) Hypoalbuminaemia.

(b) Competitive displacers : endogenous peptides retained in renal disease.

Binding of acidic drugs to plasma proteins from patients with poor renal function
Drug	Binding	Reference(s)
Axlocillin	St. decreased	Fiegel and Becker (1978)
Bilirubin	Decreased	Oie et al. (1980)
Cefazolin	Decreased	Craig et al. (1973)
Cefoxitin	Decreased	Garcia et al. (1979)
Clofibrate	Decreased	Bridgman et al. (1972); Pierides et al. (1975); Gugler et al. (1979)
Congo red	Decreased	Ehrstrom (1973)
Diazoxide	Decreased	O’Malley et al. (1975); Pearson and Breckenridge (1976)
Dicloxacillin	Decreased	Craig and Wagnild (1974)
Diflunisal	Decreased	Verbeeck and De Schepper (1980)
Fluorescein	Decreased	Reidenberg and Affrime (1973)
Furosemide (frusemide)	Decreased	Andreasen and Jakobsen (1974); Rane et al. (1978)
Indomethacin	Normal	Sjoholm et al. (1976)
Methyl orange	Decreased	Dromgoole (1973)
Methyl red	Decreased	Breyer and Radcliff (1954); Campion (1973)
Naproxen	Decreased	Attila et al. (1980)
Penicillin G (benzylpenicillin)	Decreased	Craig et al. (1976); Farrell et al. (1972)
Pentobarbital	Decreased	Ehrnebo and Odar-Cederlof (1975); Reidenberg et al. (1976)
Phenobarbital	Decreased	Farrell et al. (1972)
Phenol red	Decreased	Baker (1951)
Phenylbutazone	Decreased	Andreasen (1973); Belpaire et al. (1977)
Phenytoin	Decreased	Odar-Cederlof et al. (1970); Reidenberg et al. (1971); Shoeman and Azarnoff (1972); Blum and Riegeiman (1972); Andreasen (1973); Hooper et al. (1974); Olsen et al. (1975); Ehrnebo and Odar-Cederlof (1975); Craig et al. (1976)
Salicylate	Decreased	Farrell et al. (1972); Borga et al. (1976); Andreasen (1973); Craig et al. (1976); Lowenthal et al. (1974)
Sulfadiazine	Decreased	Seppan et al. (1980)
Sulfamethoxazole	Decreased	Craig et al. (1976)
Sulfonamides	Decreased	Scholtan (1961); Buttner et al. (1969); Anton and Corey (1971); Andreasen (1973); Craig and Wagnild (1974)
Theophylline	St decreased	Reidenberg and Restivo (1979)
Thiopental	Decreased	Andreasen (1973); Ghoneim and Pandya (1975)
Thyroxine	Decreased	Arango et al. (1968)
Tryptophan	Decreased	Torrente et al. (1974)
Valporic acid	Decreased	Gugler and Mueller (1978); Brewster and Muir (1980)
Warfarin	Decreased	Belpaire et al. (1977); Sjoholm et al. (1976); Bachmann et al. (1976)

 

Clinical implications:

Decreased protein binding (ie. fu) - total clearance ( fu . Cl) of low hepatic extraction drugs is increased.

total plasma levels free (active) levels

no need to alter dosage.

NB Beware when monitoring total plasma levels - therapeutic responses will be achieved at lower than normal therapeutic plasma levels.

It is obviously preferable to measure free drug levels in these patients.

 

5. Active Metabolites in Renal Disease:

Since most drug metabolites are eliminated by the kidney, if a metabolite is active, it will accumulate in renal disease and a dosage change may be necessary.

TABLE: Drugs which have metabolites that are clinically significant in renal failure
Drug	Metabolite	Action of Metabolite	Management
Pethidine	Norpethidine	CNS stimulation, seizures	Avoid prolonged treatment or use alternative drug
Propoxyphene Allopurinol	Norpropoxyphene Oxypurinol	CNS depression, seizures Hypouricaemia	Avoid Reduce dose in proportion to renal function
Nitroprusside Procainamide	Thiocyanate N-acetyl procainamide	Metabolic acidosis, encephalopathy Same as parent	Shorten duration of treatment Reduce dose in proportion to renal function
Quinidine	3-hydroxyquinidine	Same as parent	Reduce dose 25% - 50% in severe renal failure
Cofibrate	Clofibric acid	Muscle damage	Avoid
CNS = Central Nervous System

 

6. Altered Drug Responses (Pharmacodynamics) in Renal Disease:

Examples:

(a) Urinary tract antibacterial agents:

• Nalidixic acid
• Nitrofurantoin 

do not achieve high enough urine levels in renal disease to be useful

(b) Diuretics:

Only loop diuretics are potent enough to achieve duiresis in patients with renal disease.

(c) Angiotensin - converting enzyme inhibitors:

Captopril/enalapril - in renal disease, risk of 

• reduced renal function
• neutropaenia
• rash

(d) NSAID’s:

Antiprostaglandin effect may produce

• GFR
• fluid retention
• sodium retention
• oedema

Drugs which should not be used in renal failure or used with caution
Drug	Reason
Potassium supplements	Hyperkalaemia
Potassium-sparing diuretic agents	Hyperkalaemia
Anticoagulant agents	Bleeding tendency
Aminoglycoside drugs	Nephrotoxicity
NSAID’s	May affect renal function
Tetracycline drugs	May cause hyperkalaemia, hyperphosphataemia and acidosis
Uricosuric agents	Ineffective
Methenamine Mandelate Nalidixic acid Nitrofurantoin	Ineffective

 

7. Conclusions/Clinical Recommendations:

(a) Whenever possible, use drugs, the pharmacokinetics of which are not influenced by renal disease, and which have a large therapeutic index.

(b) With other drugs, reduced elimination of the drug and/or active metabolite may require a reduction in dose, which can be calculated from the estimated creatinine clearance.

(c) Use TDM if possible. NB preferably free levels of highly bound acidic drugs.

(d) Maintain careful clinical observation of the patient.

 

8. Clinical Example:

A 55 year old male (70kg) is admitted to hospital with extensive burns. The patient has a past history of chronic glomerulonephritis (serum creatinine 0.22mmol/L).

After several days in hospital, microbiological testing reveals that MRSA is present in the patient’s wounds. Because the wounds are extensive, it is decided to commence intravenous Vancomycin therapy.

You are asked to estimate a dose regimen to produce average steady-state levels of 15mg/ml.

(Data: fe = 1.0; average IV dosage: 500mg qid.

 

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RENAL IMPAIRMENT

AND PHARMACOKINETICS QUESTIONS

 

1. What three factors must be considered when deciding whether to alter the dosage regimen of a drug in a patient with renal impairment? Cite at least five examples of drugs (from different groups) whose dosage regimens should be altered even in mild renal impairment.

 

2. Captopril is 60% excreted unchanged in urine and has a normal half-life of 1.9 hours. Estimate its half-life in a 74 year old male patient (73kg) in whom the serum creatinine level has risen to 0.18mmol/L.

 

3. Famotidine is 70% excreted unchanged in urine and has a normal elimination half-life of 3 hours. Estimate its half-life and an appropriate dosage in a 58 year old female patient (71kg) in whom the serum creatinine level has risen to 0.29mmol/L.

(F = 40-45%; Vd = 1.2L/kg and is unchanged in renal impairment; dosage in patients with normal renal function is 40mg daily).

 

4. Estimate the revised Minocycline dose to be given to a patient whose dose during normal renal f unction was 300mg per day, when 10% of the dose was excreted unchanged in urine. The revised dose was required when renal function fell by 80%:-

(a) 150mg
(b) 294mg
(c) 270mg
(d) 276mg
(e) 264mg

 

5. A patient on Digoxin has both renal and hepatic impairment. In place of the normal creatinine clearance of 125ml/min, his creatinine clearance was 50ml/min. His ability to metabolise Digoxin was 50% of normal. Digoxin is excreted 63% unchanged. By what proportion was his Digoxin half-life different from that of “normals”?

(a) 0.437 higher
(b) 0.563 higher
(c) 0.586 higher
(d) 0.404 lower
(e) 0.586 lower

 

6. Cimetidine is 75% excreted unchanged in urine and has a normal elimination half-life of 2 hours. Estimate its half-life in a 60 year old male patient (73kg) in whom the serum creatinine level has risen to 0.19mmol/L.