Textbook:

MCQ Matrix: General Pharmacology 15%

Principles of prescribing 1.3.1 Drugs and the elderly 1.3.2 Drugs and children 1.3.3 Drugs and pregnancy 

Drugs in the Elderly

Absorption; not significantly altered

Distribution;

  • Reduced total body water (less volume of distribution), means increased concentration of water-soluble drugs e.g. gentamicin
  • Increased body fat, meaning increased volume of distribution of lipid-soluble drugs e.g. diazepam. Lipid-soluble drugs tend to have a longer half-life in the elderly because of this.
  • Decreased Albumin leads to increased free-fraction of highly protein-bound drugs
  • Decreased lean body mass

Metabolism

  • Phase I metabolism is more affected by aging than phase 2
  • Reduced hepatic blood flow, leads to reduced first-pass metabolism

Excretion

  • Reduced renal mass/renal blood flow/egfr leads to reduced renal clearance and increased half life e.g. digoxin (renally cleared)
    • Note that due to reduced muscle mass in the elderly there is lower creatinine production and so a normal serum creatinine does not necessarily equal a normal renal function

Pharmacodynamics

  • Increased CNS sensitivity e.g. to benzodiazepines
  • Polypharmacy

Drugs in Children

Absorption

  • In Neonates there is increased gastric pH, decreased intestinal motility, delayed and variable gastric emptying , affecting oral absorption
  • IM and SC absorption can be unpredictable due to variable muscle mass and peripheral perfusion

Distribution

  • Increased total body water, leads to increased volume of distribution for water soluble drugs
  • Reduced body fat leads to small volume of distribution for lipid-soluble drugs
  • Neonates have less albumin and thus increased free-fraction of highly protein-bound drugs
  • There is greater CNS exposure/sensitivity in neonates, as their blood-brain-barrier is different to older adults

Metabolism

  • Due to immature metabolism neonates have decreased hepatic metabolism in neonates, leading to increased half life
  • Neonates have reduced capacity for Glucuronidation (phase 2 metabolism), which is relevant for morphine metabolism and chloramphenicol ('grey baby syndrome')
  • Infants and young children have a rapidly increasing metabolic capacity so may have higher weight-normalised hepatic clearance than adults

Elimination

  • Neonates have reduced egfr/renal blood flow/immature tubular secretion and thus decreased renal clearance and increased half-life. This increases rapidly during infancy.

Pharmacodynamics

  • Immature CNS and BB leads to different and exaggerated response to CNS-active drugs. Infants are particularly susceptible to respiratory depression from opiods and sedatives
  • Always weight-based dosing. However weight-based calculation can be mathematically correct but clinically inappropriate if it exceeds the recommended maximum dose.

Drugs in Pregnancy

Absorption: minimal effect

Distribution;

  • Increased plasma volume, increased total body water, increased ECF, increased body fat. Leads to increased volume of distribution for both hydrophilic and lipophilic drugs.
  • Haemodulation leads to reduced albumin and creased free fraction of highly protein-bound drugs (e.g. phenytoin, warfarin, valproate)

Metabolism

  • Different CYP enzymes increase or decrease their activity (nuanced)

Elimination:

  • Increased renal blood flow and increased eGFR leads to increased renal clearance and reduced half life of renally-elimiated drugs (e.g. lithium, digoxin). Creatinine falls because EGFR increases.

Pharmacodynamics

  • Small, lipid-soluble, non-ionised drugs cross the placenta more readily. Warfarin crosses the placenta
  • Early pregnancy is when organogenesis happens, so this is when congenital malformations can occur due to drugs
  • Timing of exposure is important: ACE/ARBs cause fetal renal toxicity/oligohydramnios in the later stages of pregnancy. NSAIDS risk is also increased later in pregnancy, and can cause closure of ductus arteriosus.
  • Anti-epileptics preferred in pregnancy: lamotrigine and levetiracetam. Valproate leads to neural tube defects, cardiac and limb malformations.
  • Digoxin is safe to use, but does cross the placenta. Clexane and heparin are safe and do note cross the placenta.

Drugs in Breastfeeding

  • Only free/unbound drug crosses into breast milk and small lipid-soluble drugs cross more readily
  • Weak bases can undergo ion trapping in breast milk (because breast milk is slightly more acidic and the base becomes protonated/ionised in it) e.g. codeine, morphine, citalopram, fluoxetine
  • Relative infant dose (RID) estimates infant exposure; <10% is often reassuring but isn't an absolute safety threshold.
  • Neonates/premature infants are more vulnerable because hepatic and renal clearance are immature
  • Long half-life drugs are more likely to accumulate and are less amenable to dose-timing strategies
  • Codeine and tramadol are classic drugs to avoid during breastfeeding because of opioid toxicity risk