SOURCE: Psychopharmacology Institute
AUTHOR: Sandra A. Jacobson, M.D.
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.
Geriatric Psychopharmacology: How Pharmacokinetic and Pharmacodynamic Changes Affect Prescribing
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.
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.
First, pharmacokinetics. Think for a minute about how an oral drug works. It has to get into the bloodstream by absorption. It has to get to the brain by distribution. It has to have some effect at the level of the receptor. And then it has to be cleared from the body either by direct elimination or more commonly by metabolism and then elimination.
Absorption from the gut is an active process that involves the drug-metabolizing enzyme CYP3A4 as well as P-glycoprotein both expressed in cells lining the gut.
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.
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.
In general, parenteral dosing is avoided in the geriatric population.
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.
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.
Let’s think about the drug in the general circulation which is distributed not only to the brain but also to storage sites in fat, to storage sites in muscle, to the kidneys and to the liver.
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.
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.
Think of the fat storage site in the elderly patient as a large room like a warehouse and the water storage site as a small closet. In older individuals, fat-soluble drugs which include by the way most psychotropic drugs have a large space to be. This is called the volume of distribution. And water-soluble drugs have only a small space to be.
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.
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.
Drug metabolism occurs by Phase I oxidation processes involving cytochrome P450 enzymes and/or Phase II conjugation processes involving UGT enzymes, the most common being glucuronidation. The major actions of these enzymes are in the liver and small intestine.
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.
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.
Another aside here, aging does affect the liver.
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.
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.
Drug elimination or clearance -this is the last pharmacokinetic process. Drug clearance is the rate usually expressed in cm3/min at which a drug is removed from the circulation by hepatic metabolism plus renal excretion.
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.
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.
With aging, not only is pump function reduced but hepatic blood flow and renal clearance also are reduced.
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.
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.
Drugs and metabolites are excreted through the kidneys at a rate determined by the glomerular filtration rate. For a variety of reasons, the serum creatinine alone is not an accurate indicator of renal excreting ability.
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.
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.
The half-life of a drug is inversely related to clearance and directly related to volume of distribution. With aging, both slower clearance and larger volume of distribution result in longer drug half-life.
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Half-life is important to know because it determines the time to steady state and the time to washout for a drug.
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.
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.
Certain receptor changes with aging have been identified.
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.
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.
References
- 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
