Patient Factors Altering Drug Response

Question 1

Pregnancy

Answer 1

Absorption
* decreased gastric emptying
* nausea and vomiting
* increased CO –> increases IM and SC absorption
* volatiles –> increased onset due to increased MV and reduced FRC, decreased onset due to increased CO

Distribution
* increased Vd
– increased total body water
– increased plasma volume
– increased fat mass
* decreased albumin and alpha-1 glycoprotein

Metabolism
* no change to hepatic blood flow
* progesterone induces enzymes
* oestrogen competes for enzymes
* decreased plasma cholinesterase activity

Elimination
* increased renal blood flow
* increased GFR

Pharmacodynamic
* decreased MA
* increased LA sensitivity due to decreased alpha-1 glycoprotein

Question 2

Foetus

Answer 2

Drugs that cross the placenta can be teratogenic to the foetus, besides exerting their usual pharmacological effects.

Pharmacokinetic factors predominantly affect placental transfer, and include:
* lipid solubility - lipid soluble drugs diffuse more rapidly
* molecular size - drugs with a molecular weight >1000 dalton crosses the placenta slowly
* protein binding
* placental transporters - some medications are actively removed from the foetal circulation
* placental metabolism - the placenta can metabolise some medications, although in some cases results in toxic metabolites

Maternal pharmacodynamic factors predominantly affect the uterus and breast, but major organ systems are not significantly affected.
Drugs that cross the placenta can have dramatic effects in the fetus. Thes include teratogenesis, where a drug which adversely affects foetal development, causing a permanent abnormality.

Question 3

Neonates

<1yr of age

Answer 3

Absorption
* delayed gastric emptying, increasing absorption of drugs metabolised in the stomach
* decreased secretion of pancreatic enzymes and bile salts impairs absorption of lipid soluble medications
* smaller muscle mass and higher relative muscle blood flow increases IM onset
* increased Va:FRC ration increases onset of volatiles

Distribution
* total body water is 70-75% (greater proportion than 50-60% of adult), and extracellular water is 40% (compared to 20%), which typically increases Vd
* preterm infants have reduced body fat
* greater proportion of CO goes to head, increasing onset of centrally acting drugs
* decreased albumin and alpha-1 glycoprotein
* immature BBB increases uptake of partially ionised drugs

Metabolism
* enzymatic capacity of all pathways is reduced –> prolongs elimination half lives and reduces clearance
* glucuronide pathway may not mature until age 4

Excretion
* GFR is proportionally lower and does not reach adult equivalence until 6-12 months (further reduced in pre-term infants, increased in 1-3yr olds)

Pharmacodynamic
* smaller ACh reserves increase sensitivity to NMBAs
* increased MAC but more rapid onset
* NSAIDs cause closure of ductus arteriosus

Question 4

Geriatric

Answer 4

Though there is a linear decrease in functional capacity of major systems beginning at 45, alterations are predominantly a consequence of polypharmacy and drug interactions.

Absorption
* laxatives and prokinetic increase gastric emptying and reduce absorption of oral agents

Distribution
* there is a proportional increase in fat
* there is a proportional decrease in lean body mass, total body water, albumin

Metabolism
* decreased hepatic blood flow
* decreased enzymatic activity (Phase I > Phase II)

Elimination
* loss of nephron number with age reduces renal clearance

Pharmacodynamic
* increased sensitivity to sedatives, opioids and hypnotics
* decreased sensitivity to beta agonists and antagonists
* decreased MAC
* polypharmacy increases potential for drug interactions

Question 5

Cardiac Disease

Answer 5

Absorption
* decreased CO decreases PO absorption due to decreased gradient

Distribution
* decreased CO prolongs arm-brain circulation time
* increased alpha1-glycoprotein increasing binding of basic drugs
* decreased volume of distribution

Metabolism
* low CO states reduce hepatic flow and will reduce metabolism of drugs with a high extraction ratio
* high CO states will increase hepatic flow and increase metabolism of drugs with a high extraction ratio

Elimination
* reduced renal blood flow

Question 6

Hepatic Disease

Answer 6

Absorption
* porto-caval shunting - decreased first pass metabolism

Distribution
* impaired synthetic function reduces plasma proteins and increases unbound fraction
* increased volume of distribution due to fluid retention
* metabolic acidosis changes ionised fraction

Metabolism
* impaired phase I and II reactions
* reduced plasma esterase levels

Elimination
* reduced biliary excretion

Pharmacodynamics
* hepatic encephalopathy increases sensitivity to sedatives and hypnotics

Question 7

Renal Disease

Answer 7

Absorption
* uraemia prolongs gastric emptying

Distribution
* increased volume of distribution due to fluid retention
* metabolic acidosis adjusts ionised fraction

Metabolism
* buildup of toxic metabolites may inhibit drug transporters
* uraemic toxins inhibit enzymes and drug transporters

Elimination
* reduced clearance of active metabolites/active drug cleared renally

Question 8

Obesity

Answer 8

Absorption
* delayed gastric emptying
* decreased subcutaneous blood flow
* practical difficulty with IM administration

Distribution
* increased volume of distribution of lipid soluble drugs (dose lipid soluble drugs by actual body weight, dose water soluble drugs by lean body weight)
* increased CO
* increased alpha1-glycoprotein
* increased blood volume
* greater lipid binding to plasma proteins, increasing free drug fractions

Metabolism
* increased plasma and tissue esterase levels
* normal or increased hepatic enzymes

Elimination
* increased renal clearance due to increased CO