Age-Related Changes in the Hepatic Pharmacology and Toxicology of Paracetamol

Table 1

Physiological changes associated with ageing and frailty that can impact on the pharmacokinetics and pharmacodynamics of drugs.

Physiological change	Pharmacokinetic consequences
↑ Gastric pH	Delay in absorption no change in the overall
↓ Secretory capacity	extent
Gastrointestinal blood flow
Absorption surface
Gastrointestinal motility
Body fat	Vd and t1/2
Lean body mass	Plasma concentration and ↓ Vd of hydrophilic
	drugs
↓ Total body water	↑ Free fraction of highly protein-bound acidic
↓ Serum albumin	drugs
↑α1-acid glycoprotein	↓ Free fraction of basic drugs
↓ Hepatic blood flow	↓ First-pass metabolism
↓ Hepatic mass	Phase I metabolism of some drugs may be slightly
↓ CYP content	impaired
	↓/↔ Phase II in fit older adults, ↓in frail
	?/↓Phase III
Pseudocapillarisation of the liver	Impaired transfer of chylomicrons and possibly
sinusoidal endothelium	medications from sinusoid to space of Disse
↓ Renal blood flow and glomerular	Renal elimination of drugs can be impaired
filtration rate	altering drug half-life
↓ Tubular secretion
Physiological change	Pharmacodynamic consequences
↓ Blood supply to brain	Sensitivity to centrally acting drugs such as
Baroreceptor activity	benzodiazepines
Resting heart rate, stroke volume, and	Response to beta blockers such as metoprolol
cardiac output
Plasma renin; Urine aldosterone
Hepatic GSH	Detoxification ability of the liver
Dysregulation of Kupffer cells	Dysregulation of immune response to drugs and
Dysregulation of the immune system	other toxins
Mitochondrial dysregulation	Susceptibility to DILI

, decreased; , increased; , no change; , unknown; CYP, Cytochrome P450; Vd, volume of distribution; t_1/2, half-life; DILI, drug-induced liver injury; GSH, glutathione; adapted from [13] and references [2, 11–23].