6 Dose adjustment

Question 1

How does age affect absorption in children and elderly

Answer 1

• Children < 3 years
– Gastric emptying slower
– Peristalsis less regular (affects transit time)
Peristalsis = muscle contractions that moves food to different processing stations in the digestive tract.

• Elderly
– Delayed gastric emptying
– Elevated gastric pH
– Reduced peristalsis
– Active transport may be decreased

Question 2

How does age affect distribution in children and elderly

Answer 2

• Children
– Vd generally increases with age ( reflects increased weight)
– Binding to plasma protein may be decreased in very young

• Elderly
– Altered body composition may change distribution (change in adipose tissue, muscle mass)
– Drug distribution may be affected by reduced cardiac output and increased peripheral resistance
– BBB permeability may increase
– Hence Vd may change

Question 3

How does age affect metabolism in children and elderly

Answer 3

• Children < 6 months
– Drug metabolic ability increases from birth – 6 months

• Elderly
– P450 Metabolism decreases with age
– Decreased hepatic blood flow

Question 4

How does age affect excretion in children and elderly

Answer 4

• Children < 6 months
– GFR increases from birth – 6 months

• Elderly
– GFR decreases with age but can be very variable

Question 5

How does hepatic disease affect metabolism

Answer 5

• Reduced metabolism (eg CYP450) possible but not inevitable
– Depends on nature of liver disease (eg cirrhosis vs viral hepatitis)
– Route of elimination of drug concerned (some drug don’t undergo extensive hepatic metabolism)
• Half-life may not decrease due to decreased albumin, increasing Vd (k=Cl/Vd) (see below)
• Reduced first-pass effect may increase bioavailability

Question 6

How does hepatic disease affect protein binding

Answer 6

• Drugs which are extensively bound to albumin more likely to be affected!
• Albumin synthesized in liver
• ↓[albumin] →↑ [drug]unbound may cause:
– Increase therapeutic effect
– Increased toxicity
– Change in distribution (Vd) (may cause unexpected toxicity!)

Question 7

What are some possible outcomes of hepatic disease?

Answer 7

• Hepatic encephalopathy
– Impaired (decline in) brain function
– Particular concern with drugs know to have effect on CNS
– Eg sedatives, opioids, diuretics that cause hypokalaemia

• Increased fluid retention
– particular concern with drugs that cause fluid retention
– Eg NSAIDS (inhibit cyclo-oxygenase)

• Hepatotoxicity
– Liver toxicity
– Particular concern with drugs that are intrinsically hepatatoxic » “self-perpetuating”

Question 8

Consequences of reduced renal function

Answer 8

– Decreased glomerular filtration rate(GFR)
– Reduced clearance – higher plasma levels possible
– Longer half-life – time to reach Css is increased

Question 9

Estimation of renal function

Creatine Clearance

Answer 9

• Measurement of creatine clearance as surrogate to estimate GFR
– Creatinine derived from creatine in muscle
– Creatinine produced at constant rate by muscle
– Eliminated largely by glomerular filtration so creatinine clearance ~GFR
– [Creatinine] in serum reflects glomerular filtration rate (GFR) » Eg decrease in GFR leads to increase [creatinine]serum
– Hence [creatinine]serum can be used to estimate GFR

Question 10

Cockroft - Gault equation

Creatinine clearance =

Answer 10

A x (140 - age) x weight/ [creatinine] serum

A= 1.23 if male
A= 1.04 if female

do not need to memorise this equation – just understand its purpose

Question 11

Creatine versus creatinine

Answer 11

Draw creatine and creatinine

Question 12

Estimation of renal function

MDRD method

Answer 12

(modification of diet in renal disease) to estimate GFR

GFR = 175 x A/ [serum creatinine]1.154 x age0.203

A = 1.18 if male
A= 0.762 if female

do not need to memorise this equation – just understand its purpose

Question 13

Limitations of estimation of renal function

Answer 13

– Average muscle mass (source of creatinine) appropriate to patient’s
age, height, age.
– May be inaccurate if » Poor nutrional state » Highly muscular
» Obese
» “Extremes” !
– GFR <20 ml min-1
– [creatinine]serum > 450 μM – Children or elderly
» “Extremes” of age (children or very elderly) » Limb amputation (decreases muscle mass)
– ALSO – some creatinine excreted by tubular secretion so Creatinine clearance may be slightly greater than GFR
» This is inhibited by some drugs, causing increased [creatinine]serum so GFR appears reduced, even though its unchanged

Question 14

Estimation of renal function

• Measurement of creatinine excreted in urine over ~ 24hours

Answer 14

more accurate measure of creatinine clearance

More accurate but inconvenient !
• Need to collect urine over ~24 h and measure volume
• Incomplete collection is a problem
• Need measure creatinine in serum and urine

Question 15

Renal impairment - classification

Answer 15

Grade (BNF definition)
Creatinine clearance (ml min-1)

Mild 20-50
Moderate 10-20
Severe < 10

“Typical” creatinine clearance (ml min-1)
Age 20 (Men-120,
Women-100)
Age 60 (Men-80,
Women-70)
Age 90 (Men-50,
Women-40)

Question 16

Dealing with renal Impairment

Answer 16

Dosed = Doset x Cld/ Clt

The key point here is that Cl may be used to estimate how to modify the dosing regimen.