The working capacity of liver in geriatrics should also be considered for estima-

tion of safe and effective drug doses. It is well known that liver dysfunction, as

briefly mentioned before, not only reduces the first-phase metabolic clearance of

certain drugs, but also the biodegradation and/or biliary excretion of unchanged

drugs and their metabolites. Also, low production of plasma proteins by the liver,

especially albumin, can have strong influence on drug transport and distribution in

the body (Verbeeck 2008). No consistent relationship has been observed between

age and microsomal cytochrome P450 coenzymes that are mainly responsible for

hepatic phase I metabolism. However, under certain in vivo conditions, metabolic

clearance of some drugs like amiodarone, amitriptyline, triazolam, fentanyl, nifedi-

pine, warfarin, and verapamil are decreased by 20–40%, whereas the clearance

remains

unchanged

for

alfentanil,

diazepam,

paracetamol,

diclofenac,

and

citalopram, irrespective of which CYP450 coenzyme system is involved. These

changes could be attributed to high or low drug extraction by the liver. As the

blood flow through the liver declines in elderly, drugs extensively cleared by the

liver display an age-related decrease in metabolic clearance. Generally, inter-

individual variations in metabolic drug degradation by CYP450 coenzymes exceed

the decline caused by aging. The nutritional status of a patient also has a marked

influence on the rate of drug metabolism. In frail elderly, drug metabolism is

diminished to a greater extent than in elderly with normal body weight (Walter-

Sack and Klotz 1996).

15.10 Formulas for Drug Dose Adjustments in Frail Elderly With

Special Reference to Age-Dependent GFR Functions

As alluded to earlier, one of the most significant changes that occur in old age is

decline in GFR. The age-dependent GFR functions are illustrated in Fig. 15.1.

Reduction in kidney blood flow is accompanied by decreased drug elimination and

impaired transmembrane transporter functions in the kidneys as well as PK & PD

alterations among elderly. Disregarding the renal drug elimination will result in

increased drug serum levels, because age-related decline in renal functions are

closely related to high incidences of ADRs (Morley 2007). For drugs following

linear pharmacokinetics, a reduction in renal clearance can be compensated by

correcting the maintenance dose by a dose adjustment factor (Q) and by correlating

endogenous creatinine clearance (CLCR) as shown in Eq. (15.1).

D⁰

m ^{¼ Dmk0}

e^{=ke ¼ DmQ,}

ð15:1Þ

where ke is the elimination rate constant. The prime (⁰) designates value in old age.

Creatinine clearance (CLCR)-based drug elimination is calculated as follows:

Q ¼ Q0 þ 1  Q0

ð

Þ CL⁰

CR^=CLCR

ð15:2Þ

where Q0 is the non-renal elimination fraction and Q is dose adjustment factor.

15

The Importance of Drug Dose Adjustment in Elderly Patients with Special. . .

245