Pharmacokinetics in Patients with Impaired Renal Functions

Introduction

The two kidneys comprise about 0.5% of the body weight yet together they receive about 25% of cardiac output. This high lights the significance of the kidneys to the well being of the body. It also bring to the fore the risk of drugs causing damage to the kidneys and in-turn the damaged kidneys affecting responses to administered drugs.

Drug Induced Renal Disease

Drugs and other chemicals may cause damage to the kidney by;

1. Direct Biochemical Effect:

This may result from substances that cause direct toxicity including:

1. Heavy metals e.g. Mercury, Lead, Gold, Iron,
2. Antimicrobials e.g. Aminoglycosides (Gentamicin, Kanamycin, Neomycin), Sulphonamides and Cephalosporins
3. X-ray contrast media e.g. Agents for visualizing the biliary tract
4. Analgesics e.g. NSAIDS combinations
5. Organic solvents e.g. Carbon tetrachloride, Ethylene glycol.

 

2. Indirect Biochemical Effect 

This is caused by drugs being used for treatment of other conditions. These drugs include

1. Cytotoxic drugs and uricosurics may cause urate to be precipitated in the kidney tubule.
2. Calciferol (Vit D) may lead renal calcification by causing hypercalcaemia.
3. Diuretic and laxative abuse can cause tubule damage 2o to Potassium and Sodium depletion.

 

3. Immunological Effect 

A wide range of drugs produces a wide range of injuries. For instance,

• Drugs such as Phenytoin, gold, penicillins, sulphonamides (especially the long acting and extensively plasma-protein bound), hydralazine, isoniazid, rifampicin, procainamide, penicillamine, probenicid. 
• Injuries include; arteritis (inflammatory disease of arteries), glomerulitis, interstitial nephritis, systemic lupus erythematosus (LE = chronic inflammatory disease of the connective tissue affecting the skin and various internal organs).

Prescribing for Patients with Renal Disease 

Prescribed drugs may either; 

1. Exacerbate renal disease,
2. Have their effects potentiated due to accumulation as a result of failure of renal excretion,
3. Be ineffective, e.g. Thiazide diuretics in moderate or severe renal failure, uricosurics.
4. Have many side-effects. Many side effects of drugs are poorly tolerated by patients with renal impairment.

Problem of safety arise especially in patients with impaired renal function who must be treated with drugs that are potentially toxic and that are wholly or largely eliminated by the kidney. A knowledge of, or at least access to, sources of pharmacokinetic data is essential for safe therapy of such patients. The table below shows the drastic influence of impaired renal function on some drugs.

Drug	Normal t1/2 (hr)	t1/2 in severe renal impairment (hr)
Captopril	2	25    (1,250%)
Amoxycillin	2	14        (700%)
Gentamicin	2.5	5     (100%)
Atenolol	6	100      (167%)
Digoxin	36	90     (250%)

 
Glomerular filtration rate <5ml/min. (normal GFR is 120ml/min)
These drugs are excreted almost unchanged, thus the prolongation of t1/2 means that special care must be taken if any of them are to be used in patients with impaired renal function. 

DOSE ADJUSTMENT FOR PATIENTS WITH RENAL IMPAIRMENT

1. Adjustment of initial dose is generally unnecessary because the apparent volume of distribution is the same for the healthy subject as the renal impaired patient.
2. Adjustment of maintenance dose involves either reducing each dose given or lengthening the dosage interval.
3. Special caution is needed when the patient is hypoproteinaemic and the drug in question is one that is usually extensively plasma protein bound, or in advanced renal disease when accumulated metabolic products may compete for plasma protein binding sites; particular care is required in the early stages of dosing until response to the drug can be gauged.

GENERAL RULES FOR DOSE ADJUSTMENT

1. For drugs that are wholly or largely excreted by the kidney or drugs that produce active renally eliminated metabolites; give a normal or in special caution (above), a slight reduction in initial dose followed by lower maintenance dose or lengthen the dose interval in proportion to the reduction in creatinine clearance value.
2. For drugs that are wholly or largely metabolized to inactive products; give normal doses. When special caution demand, a modest reduction of initial dose and maintenance dose rate are justified while drug effect are assessed.
3. For drugs that are partly eliminated by the kidney and partly metabolized: give a normal initial dose and modify the maintenance dose or dose interval in light of what is known about the patient’s renal function and the drug, i.e. its dependence on renal elimination and its inherent toxicity.

Remember that the time to reach steady-state blood concentration is a function of t1/2 and that a drug reaches 97% of steady-state concentration in 5 x t1/2. Hence if t1/2 is prolonged by renal impairment, so also will be the time to reach steady-state. 
It should be noted that despite all attempt to adjust doses for patients with renal impairment does not totally eliminate the risk of adverse effects and such patients should be closely monitored throughout drug therapy. This monitoring should be ideally by measurements of drug plasma concentrations if the services are available.