Variability in drug response

[RD5:p712-p723]

• Types of variability
  * Pharmacokinetics
  * Pharmadynamic
  * Idiosyncratic
• Main causes of variability
  * Ethnicity
  * Age
  * Pregnancy
  * Genetic factors
  * Idiosyncratic reactions
  * Disease
  * Drug interaction

Ethnicity

[RD5:p712]

Examples in ethnic differences:

Ethanol

• Chinese metabolise ethanol differently
  --> Higher plasma concentration of acetaldehyde
  --> Flushing and palpitation

Propranolol

• Chinese are more sensitive to CVS effects of propranolol than Caucasians
  * But metabolise propranolol faster than Caucasians
  --> Pharmacodynamic reasons for the sensitivity
• Afro-Caribbean individuals are less sensitive

Age

[RD5:p713-p714]

• Main reason: Drug elimination is less efficient in neonates and in elderly
• Other factors:
  * Pharmacodynamic sensitivity
  * Physiological factors (e.g. CVS reflexes)
  * Pathological factors (e.g. CVS diseases)
  * Body composition
  * Concurrent drug administration

Effect of age on renal excretion

Paediatrics

• GFR in the newborn is about 20% of adult value
• Tubular function in the newborn is also reduced
• In term babies, renal function increases to adult values in less than a week
  --> Continues to increase up to double the adult values at 6 months of age
  * [RD5:p713]
• Increase in renal function occurs slowly in premature babies

 

Example:

• Gentamicin
  * Halflife > 18 hours in premature babies
  * Halflife = 10 hours in term babies
  * Halflife = 1-4 hours in adults

Elderly

• GFR declines slowly from 20 years of age
  * Falling by 25% at 50 years old
  * Falling by 50% at 75 years old
• Plasma creatinine level may remain normal
  * Creatinine synthesise is reduced in elderly due to reduced muscle mass

Example:

• Chronic administration of digoxin may lead to progressive increase in plasma concentration
  --> A common cause of glycoside toxicity in the elderly

 

 

 

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Placental transfer of drugs increases in late pregnancy

[MCQ, Wood and Wood apparently is the source]

 

Lipid soluble drugs cross placenta with increasing difficulty up to 1000 Da [BGK9:p1025]