AUTHOR: Sandra A. Jacobson, M.D.
- Normal aging does not affect glucuronidation reactions but it does affect oxidation reactions. Let me say that again. Normal aging does not affect glucuronidation reactions but it does affect oxidation reactions. So medications metabolized through glucuronidation are preferred in the elderly.
- The rationale behind the start low and go slow rule is that by reducing the dosing rate, you can counteract reduced drug clearance.
- Greater psychotropic effects in elders may be due to greater drug sensitivity, higher CNS concentrations or to baseline differences.
In terms of pharmacokinetic changes, aging slows hepatic metabolism. However, liver function tests are poorly correlated with drug metabolizing activity.
Normal aging does not affect glucuronidation reactions, but it does affect oxidation reactions. Psychotropics metabolized by glucuronidation are preferred in the elderly.
Pharmacodynamic changes include reduction of M1 signal transduction, among other alterations. This makes elderly patients more sensitive to anticholinergic effects.
The rate of absorption can be slower with aging and with the use of antacids or bowel medications common in very elderly patients that contain calcium or aluminum.
Because the extent of absorption is relatively unaffected by aging (at least in the absence of disease) you don’t hear much about this phase in geriatric psychopharmacology. And in fact, I’m not going to talk more about it now.
IM dosing can be painful in those with small muscle mass and then absorption of drug erratic in that population.
IV dosing can cause peak effects like low blood pressure to occur so rapidly that the frail patient is at risk of events like stroke.
Distribution is a process that can be significantly affected by aging because as lean body mass decreases, there is a relative increase in fat stores. This is true even for thin elderly individuals. I know this idea is counter-intuitive for many.
This is important for several reasons. In the elderly, fat-soluble drugs have a short life in the circulation because they are taken up quickly by these fat sinks. But then with repeated dosing, the drugs can accumulate in fat and subsequent release can be erratic.
Furthermore, as the half-life of a drug is directly proportional to its volume of distribution, any lipophilic drug will remain in the body longer, that is have a longer half-life, in geriatric compared to younger patients.
In general, oxidation reactions are significantly affected by normal aging, whereas glucuronidation actions are not, so that medications metabolized through glucuronidation are preferred in geriatrics.
In fact, however, only two of the CYP450 enzymes important to psychotropic metabolism have activities that are meaningfully reduced with aging, and that would be CYP1A2 and CYP3A. And of those two, CYP3A is the most clinically relevant because of the large number of psychotropics that are substrates and non-psychotropics that are inhibitors of 3A.
It generally slows the metabolism and clearance of drugs although to varying degrees among elderly individuals. There is no good way to test for this clinically. The so-called liver function tests are poorly correlated with drug metabolizing ability.
Clearance is the major determinant of the steady-state plasma concentration of a drug.
P-glycoprotein promotes drug clearance from the liver and the kidneys through its action as an efflux pump, a "pump out" pump.
Reduced drug clearance is associated with an increased steady-state drug concentration with greater therapeutic and toxic effects. Reduced drug clearance can be offset by a reduction in dosing rate.
And this is the reason for the start low and go slow rule in geriatric prescribing.
Usually, the GFR is reported by the lab when the creatinine is ordered. But if it is not, there is an equation online, the MDRD equation which stands for the Modification of Diet in Renal Disease Study can be accessed. That equation requires you to put in the patient’s age, gender, ethnicity and serum creatinine and returns instantly the estimated GFR.
Steady state is reached in four to five times the half-life for a given drug.
Personally, I use 4.5 as the multiplier.
During drug titration, time to steady state determines how soon to increase or decrease the dose. When a drug is stopped, the time to washout also is 4.5 times the half-life. And this is going to help you decide when to start a new drug or to expect withdrawal effects.
I’m going to say a little bit about pharmacodynamics. Pharmacodynamic effects relate to the effects of drugs at the target tissue. These processes can occur at pre-synaptic sites, at post-synaptic sites or they can involve enzyme inhibition.
It’s often observed that elderly patients have greater psychotropic drug effects than younger patients given the same dose of medication.
This may be due to greater sensitivity to drugs or it may be due to higher drug concentrations at CNS receptors or it could be due to baseline differences. As one example, elders are often noted to have some degree of postural sway at baseline. If a drug adds to that, a fall might occur. So this doesn’t actually represent greater sensitivity but it’s just an additive effect.
As one example, muscarinic M1 receptor signal transduction is reduced and acetylcholinesterase enzyme activity is reduced.
And these changes make elders sensitive to the adverse effects of anticholinergic drugs, such that even small doses can be problematic. You may note that I have a case against diphenhydramine and related drugs.
- Greenblatt DJ: Basic pharmacokinetic principles and their application to psychotropic drugs. J Clin Psychiatry 54 Suppl:8-13; discussion 55-6, 1993
- Liston HL, Markowitz JS, DeVane CL: Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 21:500-515, 2001
- Trifirò G, Spina E: Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 12:611-20, 2011