Pharmacokinetics and pharmacodynamics in the elderly

drug–drug interactions and adverse drug effects compared with younger patients makes use of pharmacologic agents in the elderly much more ­difficult.­ Usually,­ elderly­ is­ defined­ by­ a­ chronological age of 65 years or older.­ One­ should­ be­ aware­ of­ the­ great­ variability­ in­ pharmacokinetics and pharmacodynamics in the­ elderly.­ The­ variability­ seen­ in­ younger persons is much increased in­the­elderly.­Hence,­drug­treatment­ in­ elderly­ patients­ should­ be­ monitored­carefully. Drugs­have­been­ tested­primarily­ in­healthy­younger­persons­because­ they are likeliest to yield results uncomplicated­by­concomitant­other­ drugs­ or­ diseases.­ Clinicians,­ therefore, have to make decisions in the absence­ of­ evidence-based­ knowledge.­Studies­on­drug­safety­are­also­ often done on younger patients with a single medical condition receiving few­or­no­other­drugs.­This­is­despite­ the fact that adverse drug reactions (ADRs) are more frequent and more serious in the elderly1.­ Limited­data­ are­ available­ especially­ in­ the­ very­ old. Older­persons­should­be­our­focus­ when studying and reducing drugrelated­ problems­ (DRPs).­ A­ DRP­ is­ defined­as­‘an­event­or­circumstance­ involving drug treatment that actually or potentially interferes with a patient’s experiencing an optimum outcome of medical care’2.­ According­ to­ this­ definition,­ DRPs­ include­ (ADRs),­ but­ also­ overdosage,­ subtherapeutic dosage, noncompliance and­drug–drug­interactions. Older­ people­ are­ vulnerable­ to­ DRPs for several reasons, including physiological alterations that affect pharmacodynamics and pharmacokinetics, resulting in enhanced and prolonged drug effects; increased prevalence of chronic diseases and concomitant use of other medications.­ Another­ complicating­ fact­ is­ that the physician is not always aware of what medications the patient is taking.­ The­ focus­ of­ this­ review­ is,­ however, on pharmacokinetics and pharmacodynamics­in­the­elderly.


Pharmacokinetics and pharmacodynamics in the elderly
P Midlöv* drug-drug interactions and adverse drug effects compared with younger patients makes use of pharmacologic agents in the elderly much more difficult.
Usually, elderly is defined by a chronological age of 65 years or older. One should be aware of the great variability in pharmacokinetics and pharmacodynamics in the elderly. The variability seen in younger persons is much increased intheelderly.Hence,drugtreatment in elderly patients should be monitoredcarefully.
Drugs have been tested primarily in healthy younger persons because they are likeliest to yield results uncomplicatedbyconcomitantother drugs or diseases. Clinicians, therefore, have to make decisions in the absence of evidence-based knowledge.Studiesondrugsafetyarealso often done on younger patients with a single medical condition receiving fewornootherdrugs.Thisisdespite the fact that adverse drug reactions (ADRs) are more frequent and more serious in the elderly 1 . Limited data are available especially in the very old.
Olderpersonsshouldbeourfocus when studying and reducing drugrelated problems (DRPs). A DRP is definedas'aneventorcircumstance involving drug treatment that actually or potentially interferes with a patient's experiencing an optimum outcome of medical care' 2 . According to this definition, DRPs include (ADRs), but also overdosage, subtherapeutic dosage, noncompliance anddrug-druginteractions.
Older people are vulnerable to DRPs for several reasons, including physiological alterations that affect pharmacodynamics and pharmacokinetics, resulting in enhanced and prolonged drug effects; increased prevalence of chronic diseases and concomitant use of other medications. Another complicating fact is that the physician is not always aware of what medications the patient is taking. The focus of this review is, however, on pharmacokinetics and pharmacodynamicsintheelderly.

Age-related physiological alterations
Elderly patients have lower physiological reserves in most organs compared to younger adults, with aging negatively affecting homeostatic mechanisms. Together with the alterations in pharmacodynamics and pharmacokinetics, this increases theriskofADRs.

Pharmacodynamics
Pharmacodynamics affects not only therapeuticeffectsbutalsotoxicand adverse effects. Pharmacodynamics depends on the concentration of the drug at the receptor, the response at the receptor, postreceptor events within cells and homeostatic mechanisms. All these parts of pharmacodynamicsmaybeaffectedwithaging. Thestudyofthesechangesiscomplicated since the effect of many drugs is also affected by reduced drug clearance in the elderly. Therefore, there is relatively little information abouttheeffectofagingonpharmacodynamics.
Usually, there is an increased sensitivitytotheeffectsofdrugsbutfor some drugs there is a decrease in responsiveness. The same plasma concentrationofadrugmaybeassociated with a higher risk of adverse effects in older patients compared to younger patients. All organ systems areaffectedbythesechanges.

Introduction
Pharmacotherapy in the elderly is one of the most challenging aspects of patientcare.Itisimportanttounderstand the pharmacological properties ofdrugsinelderlypatients.Different parts of pharmacokinetics such as distribution, metabolism and renal eliminationareaffectedbyage.Renal eliminationmaybemeasuredorestimated (glomerular filtration rate), whereasotherchangesaredifficultto measure.Pharmacodynamicchanges withagingaffectbothbeneficialand adverseeffectsinmostorgans.
These age-related changes make elderly patients at greater risk of adverse drug effects. Adjustment in choice of drugs and dosage is advisable.Startingatalowdoseandtitrating slowlyfollowedbycareful evaluation of effects may minimise the risk of adverse effects. It is important to choose the lowest dose required for clinicaleffect.Theaimofthisreview was to discuss pharmacokinetics and pharmacodynamicsintheelderly.

Conclusion
Elderly patients are at greatest risk of adverse drug effects. Optimizing a dosage regimen for an individual patient is important for all patients. Drug dosage should, if possible, be adjusted to the individual organ function.

Introduction
Pharmacotherapy in the elderly is one of the most challenging aspects ofpatientcare.Theincreasedriskof

Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure. For citation purposes: Midlöv P. Pharmacokinetics and pharmacodynamics in the elderly. OA Elderly Medicine 2013 Aug 01;1(1):1.

Cardiovascular effects
Theeffectofβ-adrenergic agonists is decreased in the elderly 3 . This may result in a decreased effect of betablockers on heart rate and stroke volume.
For most other cardiovascular drugs, the elderly have higher risk of adverse events. A common adverse effect in the elderly is orthostatic hypotension due to decreased arterial compliance and baroreceptor reflexresponse 4 .Notonlycardiovascular drugs may cause orthostatic hypotension but also, for example, antipsychotic drugs and drugs for Parkinson'sdisease.
Aging is also associated with other cardiovascular effects, for example, enhanced susceptibility to digoxin toxicity 5 .

Effects on central nervous system
Aging is associated with structural and neurochemical changes in the centralnervoussystem(CNS).Dueto lesseffectiveblood-brainbarrier,the brainmaybeexposedtohigherdrug levels in the elderly 6 . Severaldrugsmaycauseconfusion intheelderly.Antipsychotics,anticholinergics and benzodiazepines are commonexamples.Elderlyaremore susceptible to adverse effects of benzodiazepines at a given plasma level 7 . This increased susceptibility aswellasalterationsindistribution (described below) make benzodiazepinesinappropriateinoldpatients.
The acetylcholine neurotransmission may be affected at several levels 8 . Drugs with anticholinergic effects, for example, drugs for urinaryincontinence,causeCNSeffects moreoftenintheelderly.Anticholinergic drugs may induce delirium or increase delirium symptom severity in elderly patients 9,10 .Anotherexample is that elderly patients with epilepsy have a therapeutic response to antiepileptic medications at lower plasma levels and a higher incidence of adverse effects 11 .

Electrolytes
There is a decline in electrolyte homeostatic mechanisms with aging 12 . The ability to cope with sudden changes in electrolyte levels is reduced. Old patients have a grea ter susceptibility to adverse drug effects, for example, hyperkalaemia or hyponatremia. Such adverse effects are quite common.
Many different drugs may cause disturbances in electrolyte levels and the clinician has to be aware ofthis.

Pharmacokinetics
Pharmacokinetic alterations are easier to measure since they affect the plasma concentration of the drug.However,formostdrugspharmacokinetic alterations are seldom measured in clinical practice. The bioavailability of a drug depends on many factors including absorption, distribution, metabolism and elimination (Table 1). For many drugs, thefactsaboutpharmacokineticsare based on studies on younger adults although mainly elderly patients will use these drugs 13 .
The elimination half-life t 1/2 of a medication is determined by the volume of distribution (V d ) in a given individual divided by its clearance(Cl).
This can be expressed as: Clearanceismainlyhepaticmetabolismandrenalelimination.Thehalflife of a medication will increase if clearance decreases or if the volume ofdistributionisincreased.

Drug absorption
Uptake of drugs administered orally depends on the function of ventricle, intestines and blood-flow to the intestines.Mostmedicationsarepassivelyabsorbed.Inmostcases,thisis not significantly affected by aging 14 .
Diseases that affect gastrointestinal organs or their vasculature may of course affect the absorption of oral drugs.
The absorption rate of drugs administered via transdermal or transmucosalroutesmaybeaffected intheelderlybecauseofreducedtissuebloodperfusion.

Distribution of drugs
When a drug enters the systemic circulation it will be distributed throughout the body. There is a decline in fat-free mass and body water, whereas there is an increase inbodyfatintheelderly 15 .
With a decrease in body water, hydrophilic drugs have higher peak plasma concentrations and shorter half-life in the elderly. The eliminationhalf-lifeoflipid-solubledrugson the other hand is increased leading to anaccumulationofthesedrugs.Since many drugs that can affect the brain are lipid-soluble, physicians must be awareoftheincreasedriskofcerebral adverseeffectsinelderlypatients.

Drug metabolism
The liver is the most important site of drug metabolism. Aging is associated with a reduction in liver mass and in hepatic blood flow. Agerelated changes in the liver have a major impact on hepatic clearance that in turn influences variability in response to medicines in the elderly 16 . Liver metabolism depends on the function and capacity of drugmetabolizing enzymes in the liver andhepaticbloodflow.Thedelivery of drugs to the drug metabolising enzymeswithinhepatocytesdepends on hepatic blood flow and this is known to decrease with age 17 .There is great inter-individual variability and chronological age is a relatively poorpredictorofhepaticclearance.

Renal elimination
Many drugs, including metabolites, are excreted by the kidney. Therefore, dosage adjustment must be madebasedonrenalfunction.
Renal function is most often assessed by measuring the glomerular filtration rate (GFR). In a healthy youngadult,GFRis100-130mL/min/ 1.73m 2 .Startingfrom40to50years of age, GFR appears to decrease approximately 10 mL/min/1.73 m 2 per decade 18 .ThedeclineinGFRisdue to a reduced number of functioning glomeruli 19 .Thereare,however,great inter-individual differences in this decline and it is, therefore, necessary toestimateGFRbeforeinitiatingdrug treatmentintheelderly.
Unfortunately, direct measurement of GFR using exogenous markersthe gold standard method-is both cumbersome and costly. Therefore, other techniques are often used to estimate GFR. Plasma creatinine is the most commonly used marker of renal function. However, it does not reflect GFR precisely since it is influenced by muscle mass, physical activity, protein intake and active secretion of creatinine by the proximaltubule,amongotherthings.
Plasma cystatin C has been suggested as an alternative endogenous biomarker of GFR. However, it too seems to have some limitations.Itis,forexample,affectedby thyroid dysfunction and treatment with glucocorticoids 20 . According to a recent systematic review of the literature,thebestwaytoestimate GFRistousethemeanvalueofestimated GFR based on both creatinine and cystatin C 18 . For patients over 80 years of age, the evidence is,however,notsufficientonhowto estimateGFR.

Drug-drug interactions
Numerous drug-drug interactions have been identified. These interactions can affect pharmacokinetics or pharmacodynamics. For pharmacokinetic interactions one drug changestheabsorption,distribution, metabolismoreliminationofanother drug.Pharmacodynamicinteractions occur when one drug changes the responsetoanotherdrug.
Drug-drug interactions play an important role in patient safety 21 . The risk of drug-drug interactions increaseswithageandthenumberof drugs used 22 . Most often drug-drug interactionsarepreventable 23,24 .

Drug-disease interactions
The inter-individual variability in susceptibility to drugs is at least partly explained by differences in multi-morbidity. Diseases that affect the kidneys make the elderly patient more susceptible to ADR due to reductioninrenalelimination.Liver diseases as well as cardiac diseases that affect hepatic blood flow may affect drug metabolism. In the same way, diseases that affect other organ systems may make elderly patients even more susceptible to drugs. A few, of the numerous, examples arepresentedinTable3.

Drug-food interactions
Drug-foodinteractionaddsvariability to effects and adverse effects of drugs.
For example, warfarin is known for its drug-food interactions 25 .Warfarin has a narrow therapeutic interval and food with a high K-vitamin content counteract the effects of warfarin. Other examples are grapefruit juice that inhibits the metabolism of cyclosporine and non-selective monoamine oxidase (MAO) inhibitorwithfoodrichintyramine.Some fermented and stored products (e.g. some cheese, sausages, red wine) containtyraminethatismetabolised to noradrenaline, which in conjunction with MAO inhibitors may block MAO and cause a hypertensive crisis. Seligiline and moclobemide are examplesofMAOinhibitors.

Adverse drug effects
Adverse drug effects can mimic clinical syndromes in geriatrics. Instead of adding a medication, the clinician should consider the possibility of adverse effects and maybe withdrawamedication.TheriskofADRs is increased for several reasons in the elderly. The changes in pharmacokinetics and pharmacodynamics, thehighnumberofmedicationsand multi-morbidity contribute to this increasedriskofADR.Thesymptoms ofADRmaybehardertodetectand misinterpreted as symptoms from a disease or even as 'normal aging' in theelderly.
It is important to recognise that adverse effects can occur with drugs and drug dosages unlikely to cause adverse effects in younger adults. ADRsaremostlypreventableincluding the more severe ADRs 26 . Closer monitoring and thorough evaluation of pharmacotherapy is important to beabletopreventADR.

Adverse drug withdrawal events
Adverse drug withdrawal events (ADWE)maybecausedbyaphysiological withdrawal reaction but it is also possible that an underlying disease is worsened. Known ADWEs occur after abrupt discontinuation of benzodiazepines or alcohol. It has been shown that ADWEs are common in nursing home residents 27 . Knowledge of ADWE is often sparse and drug discontinuation guidelines may be useful.

Conclusion
Elderly patients are at greatest risk of adverse drug effects. Optimizing a dosage regimen for an individual patientisimportantforallpatients. Drug dosage should, if possible, be adjusted to the individual organ function. Sometimes organ functionmaybequantified,forexample, GFRbutthatisnotalwaysthecase. Changesinpharmacodynamicsmost often result in an increased sensitivity. Adjustment in choice of drugs and dosage is advisable especially for drugs with CNS effects. Starting at a low dose and titrating slowly followedbycarefulevaluationofeffects may minimise the risk of adverse effects. It is important to choose the lowest dose required for clinical effect.
The typical frail elderly patient has multiple diagnoses, is taking several different medications, and has reduced renal function, increased bodyfatlevelsandreducedhomeostasis. It is important to be aware of the increased risk of ADRs in frail elderly patients. More studies should focus on this neglected patientgroup.