Drug clearance. Clearance of a drug from the circulation is a function not only of renal excretion but also of hepatic metabolism. Although oxidative metabolism may be reduced in old age, a more significant factor is decreased hepatic blood flow, which may be as much as 50% decreased.3 This is the primary reason why drug dosing is reduced for hepatically metabolized drugs in elderly patients. The correlation of blood flow reduction with hepatic clearance is a poor one, however, and existing liver function tests are not a good indicator of drug metabolizing capacity.3
Clearance is the principal determinant of the plasma concentration of a drug at steady state. The two quantities are related by the following equation:
drug concentration at steady state = dosing rate/clearance
Reduced GFR and reduced hepatic blood flow result in reduced clearance in elderly patients compared with younger patients. This results in increased steady-state drug concentrations, with enhanced main effects and toxic effects. Reduced clearance can be managed with a smaller dose or a longer dosing interval, giving rise to the “start low and go slow” principle of prescribing for a geriatric patient.
Another reason to “go slow” with dosing in elderly patients is because of the time it takes a drug to reach steady state with repeated dosing. Steady state is the point at which the average drug concentration plateaus. Time to steady state is determined by the drug’s half-life:
steady state = 4.5 x half-life
In general, a drug’s half-life is increased in geriatric patients compared with younger patients, so that it takes longer to reach steady state. Changes in drug dosage are best made when steady state has been achieved, so that main and toxic effects can be observed before the dosage is escalated. The half-life of a drug can also be used to determine the time to washout:
washout = 4.5 x half-life
The time to washout can be helpful in determining when a drug is out of the system so that a new medication can be started or withdrawal effects can be expected.
Basic pharmacodynamic processes
Pharmacodynamic processes are set in motion when the drug reaches the target tissue. Effects can be presynaptic or postsynaptic, or involve enzyme inhibition. Reuptake inhibitors, such as SSRI antidepressants, are examples of drugs that act at presynaptic sites. Acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are examples of enzyme inhibitors.
Most psychotropic drugs act at postsynaptic sites; some also interact with autoreceptors on the presynaptic neuron. In general, the mechanism for these drugs includes drug-receptor binding, signal transduction, and cellular response. Effects are mediated by variables such as receptor density, concentration of the drug at the receptor site, affinity of the drug for the receptor, allosteric modulation of drug binding, intrinsic activity of the drug (the degree to which it influences the receptor to generate a cellular response), the function of second messenger systems, and homeostatic processes that tend to counter drug effects. Different drugs have different effects at the receptor.
Another variable in drug binding that is particularly relevant to drugs such as antidepressants is that of time: acute effects may be different from chronic effects. This occurs because initial pharmacological effects at the receptor induce small changes that over time result in receptor adaptation.
In general, receptors for dopamine, norepinephrine, and serotonin are coupled to G-proteins as second messengers. The mechanisms by which drug-receptor binding ultimately triggers brain effects are complex. Signaling molecules other than G-proteins—Akt, glycogen synthase kinase-3, and β-arrestin 2—have been shown in recent years to be involved in the mechanism of action of antidepressants, lithium, and antipsychotics.6
Although elderly patients experience greater drug effects than younger patients, the reason is not always clear. The differences in drug responses can be attributed either to different baselines or to different sensitivities.7 Baseline differences in postural sway (the elderly have more sway than younger patients), for example, might account for the increased risk of falling with benzodiazepine use in the elderly. It may be that for those with a “normal” amount of postural sway (old or young) at baseline, these drugs are safe.
Another factor in differing drug responses among the elderly for certain psychotropic drugs is the reduced function of the Pgp pump with aging. The EC50 of a drug is the (effective) concentration of that drug that yields a half-maximal response. The value of EC50 for any drug is determined systemically, not in the CNS. When the elderly are found to have a lower EC50 than younger patients for a particular psychotropic drug, is that because of increased brain “sensitivity” to the drug or because of a relatively higher concentration of the drug in the CNS?
When increased sensitivity is actually demonstrated, it may be attributed to the fact that the elderly use an ever-greater proportion of reserves (eg, cognitive, motor) as they age, so that fewer reserves are available to offset a perturbation. For example, the elderly are at increased risk for orthostasis as an adverse drug effect.
Drug interactions are more frequent in elderly patients because more medications are taken. In addition, drug interactions may be more serious because of insufficient physiological reserves. When new medications are started or stopped in elderly patients, it is very important to take note of potential interactions with other drugs or foods.
Drug interactions may be pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions may involve any of the phases of drug processing, although the most important and numerous relate to drug metabolism. An example of a drug interaction influencing drug absorption is the effect of an oral antacid on absorption of an antipsychotic or a benzodiazepine. The combination results in a slowing of the rate of absorption, and adverse effects are not seen as quickly. Interactions relating to drug metabolism are mediated largely by CYP450 and UGT enzyme systems. The various actions of the Pgp pump can interact with drug distribution. Introducing a low-sodium diet to a patient receiving lithium results in competition for excretion and may cause lithium levels to rise.
Pharmacodynamic interactions are numerous and involve both receptor binding effects (eg, antipsychotics given with dopamine agonists), complex remote effects (eg, SSRIs inhibiting platelet function when given with warfarin, causing significant bleeding), and additive effects (eg, MAOIs and SSRIs causing serotonin syndrome).
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