Geriatric Pharmacology
Absorption
Decreases in:
- the gastric parietal cell function leading to an
Ý in gastric pH
motility of the GI tract, gastric emptying, absorptive SA and splanchnic blood flow
uptake of nutrients via active transport in the GI tract; or absorption of digoxin and chlordiazepoxide
No changes in: drug absorption for most drugs (rate nor extent). Why?
- Most drugs absorbed by passive non-ionic diffusion which is unaltered by the above changes
Distribution
Decreases in:
- total body water accompanied by decreases in plasma and extracellular volume; lean body mass; cardiac output
- cerebral, hepatic (40-45%) and renal blood flow
- serum albumin and protein binding (only problematic if concurrent with chronic disease and/or poor nutrition)
- phenytoin, salicylate, warfarin and tolbutamide usually decrease in protein binding with age
Increases in: adipose tissue (body fat)
For water soluble drugs:
distributed in body water or lean body mass so expect smaller volumes of distribution
acetominophen or digoxin Þ water soluble Þ have decreased volumes of distribution
For lipid soluble drugs:
distributed in body fat so predict larger volumes of distribution
diazepam (benzodiazepine) Þ lipid soluble Þ have increased volume of distribution
For women:
have greater % of body fat and less body mass Þ expect greater changes in distribution for these variables
observe more distribution of diazepam (highly lipid soluble) and less distribution of acetominophen (water soluble)
Elimination
Hepatic metabolism
Decreases in:
liver weight and blood flow (alters kinetics of drugs whose clearance is dependent on liver blood flow, e.g. lidocaine)
enzyme activity and inducibility of enzymes; dopadecarboxylase in the GI epithelium
drug metabolism (ie intrinsic clearance) thus leading to higher plasma concentration of drug at steady state
very drug specific Þ theophyline, phenytoin, propranolol and indocyanine green are examples
first pass effect so increase in oral bioavailability (effect seen with propanolol, lidocaine)
Increases in: Fo about 3 fold thru the GI epithelium (very drug specific)
No changes in: conjugation and acetylation reactions; Cl of lidocaine although the VD is larger and half-life is longer
If nutritional status impaired: higher risk of decreased drug metabolism and increased adverse effects of drugs
Anti-pyrine: used to measure oxidative metabolism
- its metabolic clearance is decreased in elderly and to a greater extent in smokers (oxidation, demethylation)
The decrease in clearance of some drugs (antipyrine, diazepam) is greater in aged men than women
Renal metabolism
Decreases in:
renal blood flow; tubular secretion, # of nephrons
GFR (35%) Þ creatinine clearance is used to estimate renal function
Clearance (in drugs such as digoxin, cimetidine, chlorpropamide and antimicrobials)
Procainamide and its active metabolite (acetylprocainamide) show expected decrease in clearance with aging
For renal eliminated drugs: decrease in renal clearance; increase in plasma drug conc; increase in adverse drug effects
For loop diuretics: ß in natriuretic and diuretic effects, due to ß renal function and ß delivery of diuretic to site of action
Pharmacodynamics
CNS is more sensitive
- development of toxicity at usual therapeutic does
Þ due to impaired renal and hepatic function
increase in sensitivity to barbituates Þ due to impaired metabolism and renal excretion
elderly are more sensitive to benzodiazepines (diazepam and nitrazepam) when plasma concentration are equivalent Þ CNS is more sensitive to these
- free plasma diazepam concentration decreases with age
Þ receptors become more sensitive so need less free drug
T ½ is also extended so drug sits around longer
b adrenergic receptor agents Þ resistance in the elderly
- elders are more resistant to the cardiac effects of either
b -agonists (isoproterenol) or b -antagonists (propranolol)
isoproterenol increases HR
propranolol: bioavailability increases, intrinsic clearance in liver decreases, systemic plasma clearance decreases in males (not affected in females)
Þ altered 2nd messenger function due to a change in the effect of a G protein with age
Ca++ antagonists are the most prescribed drugs in the elderly
For an oral dose: Cmax, AUC and T½ increase; Cl decreases; VD is unchanged