Changes in drug response in the elderly

This chapter answers parts from Section D(iii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe alterations to drug response due to physiological change, with particular reference to ... the elderly". It also refers to the very similar Section B(vi), where the trainees' objective is to understand "the fate of drugs in the body, including ...  how it is affected by extremes of age, obesity, pregnancy (including foetal) and disease (particularly critical illness)".  Though the other "extremes of age"  have never appeared in the exam, old age certainly comes up now and then. Like the pharmacokinetics of obesity,  this topic has appeared in exam papers from both Part One (Question 20 from the second paper of 2010) and Part Two (Question 28 from the first paper of 2016). Because of a completely arbitrary decision to concentrate all pharmacokinetics notes in the Primary exam resources, the bulk of the notes for extreme genatriac pharmacology is found here. Question 28 from the first paper of 2016 has more of a practical toxicological theme to it, which has influenced the Fellowship revision chapter on pharmacology and toxicology in old age. 

There is little of use in the official textbook, or in the college answer to Question 20. The examiners used 40% of their model answer to congratulate themselves on how relevant the topic was, and to complain that "candidate performance generally lacked sufficient depth". Fortunately for the revising exam candidate, the published literature on this topic is abundant and of a generally high quality.  Jansen et al (2012) is a good representative reference; the reading of a time-poor candidate could be safely limited to this one paper. The next most detailed (free) resource is Klaus Turnheim's 2003 article.  These resources have been pre-chewed and summarised in a manner which should hopefully facilitate self-directed revision. The summary follows the format of mechanism = effect (example), so that specific drugs could be quoted in some future SAQ or viva scenario which calls for examples.

In summary: 

Absorption

• Decreased gastric emptying rate = decreased oral absorption (digoxin, levodopa)
• Increased gastric pH = decreased absorption of drugs which are dependent for pH for their dispersion (enteric-coated drugs); = increased absorption of weak based (methyldopa), decreased absorption of strong acids (amoxycillin)
• Decreased intestinal absorptive surface = age-dependent decrease in drug absorption (indomethacin, prazosin and digoxin)
• Decreased active transport = decreased transport of electrolytes and vitamins (zinc, calcium, folate and B12. )
• Structural changes to stratum corneum = decreased transcutaneous absorption of hydrophilic substances (caffeine, aspirin)
• Poor cutaneous circulation = decreased transcutaneous absorption (clonidine)
• Unpredictable muscle circulation = erratic IM absorption (penicillin)

Distribution

• 10-15% decrease in total body water = decreased Vd for hydrophilic drugs (ethanol, lithium)
• 10-15% increase in total body fat = increased Vd for lipophilic drugs (amiodarone, verapamil)
• Decreased serum albumin = increased free fraction of albumin-bound drugs (phenytoin)
• Increased serum α₁-glycoprotein levels = decreased free fraction of alkaline drugs (metaclopromide, erythromycin)
• P-glycoprotein efflux pump dysfunction = increased permeability of the BBB and this increased  effect-site concentration of CNS drugs (rifampicin, cyclosporin)

Metabolism

• Decreased hepatic tissue mass = decreased clearance by Phase I reactions (ibuprofen, propanolol, fentanyl) but not by Phase II reactions (aspirin, valproate, phenytoin)
• Decreased hepatic blood flow = decreased clearance of high extraction ratio drugs (morphine, verapamil, lignocaine)
• Decreased portal blood flow = increased oral bioavailability of high extraction ratio drugs (propanolol, labetalol)

Elimination

• Decreased glomerular filtration and decreased tubular function = decreased renal clearance of water-soluble drugs and metabolites (β-lactams, aminoglycosides)

Decreased dose response

• Decreased receptor sensitivity = increased dose requirements (β-blockers, adenosine)

Increased dose response

• Increased sensitivity to toxic effects = toxicity at normally safe doses (antimuscarinic drugs, sedatives/hyponotics)
• Decreased homeostatic compensation for drug effects = increased risk of adverse effects, narrowed therapeutic index (eg. antihypertensives and postural hypotension)

Changes in drug absorption associated with old age

Decreased gastric emptying rate

In healthy elderly patients, gastric emptying rate is significantly decreased in comparison to healthy young subjects (Evans et al, 1981). In fact the gastric emptying half-time was more than doubled (the mean age of the elderly subjects was 77). As a major determinant of absorption, this significantly influences all oral bioavailability and oral drug efficacy. Specific examples mentioned in the Evans paper also included drug-drug interactions among substances mingling in the stomach content (penicillin, levodopa and digoxin were quoted).   Turnheim (2011) reports that this effect of old age is still less potent than the effect of classic gut-slowing drugs like antimuscarinic agents and opioids. 

Altered gastric pH

Usually, the elderly person will be on some sort of proton pump inhibitor - and even if they are not, their gastric acid secretion is usually diminished. Drugs which rely on pH changes to liberate from excipients or break down capsule walls may have their absorption altered by this mechanism. Russell et al (1993) suggested that this effect would be most pronounced for drugs with enteric coating and those which have strongly pH-dependent absorption properties. For some, absorption would actually be enhanced - eg. α-methyldopa which is basic (pKa = 10.6) and which has optimal absorption at an intestinal pH of around 6.0 (Merfeld et al, 1986)

Decreased active transport mechanisms

As the gut ages and loses absorptive surface area, so the absorption of drugs and substances which rely on active transport channels will decrease (there are fewer cells to express those channels).  Holt (2007) mentions zinc, calcium, folate and B12. An older study (Bender et al, 1968) adds thiamine to the list.  All sorts of atrophic and endocrine changes are blamed on this, and the author heckles his literature search results for the "abundant discordance" in study methodologies and findings, including elderly volunteers convinced into experimental jejunal biopsies and comparisons of villous height between adolescent and elderly rodents.

Decreased absorptive surface and splanchnic blood flow

According to Turnheim (2011), an age-dependent reduction in absorption (attributed to an overall diminished absorptive capacity or blood flow) has been found in indomethacin, prazosin and digoxin. Beyond this comment, no additional information or references are offered.

Variable transdermal and subcutaneous absorption

Poor circulation results in diminished cutaneous blood flow, which in turn results in poor absorption from skin patches and subcutaneous injections. Particularly, age-related changes in the stratum corneum render it more drug-impermeable (more waxy and less hydrated), particularly for hydrophilic drugs. Roskos et al (1989) tested a series of substances in healthy over-65s and found transdermal absorption of caffeine and aspirin to be significantly impaired, in contrast to the more lipophilic testosterone and oestradiol. This information has little practical benefit because there are so few transdermal preparations of strongly hydrophilic agents; as it defies logic to administer them in that way. When was the last time you saw an aspirin patch, or caffeine cream?

Still, Kaestli et al (2008) explored this topic in even greater detail and found that practically these functional and structural changes play little role in the age-related changes with transdermal administration. Rather, circulatory changes are the main reason the elderly have poorer transdermal absorption. This may be the reason Klein et al (1985) found diminished absorption of clonidine when administered by the transcutaneous route to elderly hypertensive patients. It cannot help that clonidine is an an α-agonist, which - acting locally on the dermis immediately below the patch- would have caused regional vasoconstriction to decrease its own absorption. 

Having said these negative age-ist things about skin absorption, it is worth pointing out that no pharmacokinetic differences in transcutaneous absoprtion have been found which might be so profound as to influence the dosing recommendations for frequently administered drugs. If anything, the elderly skin occasionally absorbs too well. For instance, Holdsworth et al (1994) found their elderly subjects had increased fentanyl concentrations from patches, which could not be explained by altered clearance mechanisms alone. 

Intramuscular absorption is erratic

It would make sense for the IM absorption to be impaired in the extremely emaciated elderly who haver minimal muscle mass and therefore poor muscle blood flow, but otherwise there does not appear to be anything pharmacokinetically unique about the muscles of the elderly (as compared to the muscles of the young). It seems to be a purely vascular thing, as well as the stupidly mechanical fact that the muscle is smaller, thinner and more difficult to access confidently with the needle tip. 

All the literature (eg. Turnheim, 2011) seem convinced that IM administration in the elderly is unreliable and should be avoided. However, there are no studies quoted to support this assertion. Wherever people actually investigate this, either no difference is found (as in the case of diazepam by Divoll et al, 1983) or an increase in the rate of absorption is discovered, as in Kentala et al (1989) who found that the absorption of IM atropine was unexpectedly quick in a group of elderly gynaecological surgical patients.

So, where does this perception come from? Apparently, from the use of intramuscular antibiotics. Collart et al (1980) and Dube (1961) found that the elderly patients receiving IM penicillin had significantly slower absorption, with the peak dose arriving some hours after injection which might "reflect the poor vascularity of the injected tissue" . The authors concluded that oral penicillin is probably better in patients who have "poor buttock tissue".  

Changes in drug distribution associated with old age

Increased ratio of body fat to body water

Old age is associated with a certain unattractive expansion of fatty spaces, and the contraction of watery ones. These are mainly attributable to the decrease in skeletal muscle mass, itself a depressing change. Theoutcome is a decrease in total body water content by 10-15% which is maximal at around the age of 80 (Turnheim, 2003). Fat content increases from 18-33% to 36-45% (more in women and men). Thus, the volume of distribution for hydrophilic drugs decreases, and proportionally the Vd of lipophilic drugs increases. The author lists classics like lithium and ethanol as examples of the former, and amiodarone and verapamil for the latter. The clinically relevant conseqence is a prolonged half-life and therefore mre toxicity and probably a longer period of waiting before a steady state concentration is achieved.

Altered protein binding due to changes in plasma protein levels

The free fraction of highly albumin-bound drugs is going to increase in any condition where albumin levels are low, and there is nothing uniquely geriatric about this process. Albumin levels do decrease with old age, but by a value which is clinically insignificant (eg. Greenblatt et al found in 1979 that the average levels change from 40g/L to 35 g/L for the last four decades of life). The increased free fraction of albumin bound drugs increases their clearance, which in turn renders the increase in free drug concentration clinically irrelevant. If one had to mention an example, one could always fall back on phenytoin as a classical highly albumin-bound drug

In contrast, serum α₁-glycoprotein levels are either maintained or increased in old age. This glycoprotein mainly binds alkaline drugs. No examples are given by Turnheim (2003) who quoted himself in support (Turnheim, 1998) but generally classic examples of these would be metaclopromide and erythromycin (Routledge, 1986).

Increased penetration of drugs into the blood-brain barrier

Due to the age-related decrease in the function of the P-glycoprotein efflux pump, the penetration of some substances into the brain increases with age. Toornvliet et al (2006) was able to demonstrate this with some radiolabelled verapamil, which is a P-glycoprotein substrate and should not be seen inside the brain (but was). It follows that other substrates for this efflux pump should also be affected. Sun et al (2003) list numerous such substrates; among them were rifampicin and cyclosporin.

Changes in drug metabolism associated with old age

Diminished liver mass and metabolic capacity

Old age is associated with the loss of liver tissue, which could shrinkby 25-35%. There is a loss of endoplasmic reticulum.  Number of CYP enzymes is decreased: even though they may still be active, the total amount of CYP molecules is diminished with age (by about 30% - Sotonieri et al, 1997) leading to an overall decreased hepatic intrinsic clearance capacity. In general, it is said that Phase I (CYP-associated) reactions are slower, whereas the rate of conjugation (Phase II) reactions is essentially unchanged in old age. Le Couteur et al (1998) advanced the hypothesis that this might be because the Phase I reactions are somehow more oxygen-expensive, and the expansion of extracellular spaces in the aging liver leads to a sort of "diffusion barrier" which suppresses oxygen dependent metabolic activities. This was based on the observation that CYP-dependent drugs (eg. ibuprofen, propanolol, fentanyl) have reduced clearance in old age, whereas the clearance of conjugation-dependent drugs (eg. aspirin, valproate, phenytoin) remains unchanged. Weidly, this is only ever demonstrated in vivo - pureed liver cells tend to exhibit relatively normal rates of CYP enzyme activity.  

Decreased hepatic blood flow

Hepatic blood flow can decrease by as much as 40% in old age, which seems to be mainly due to a decrease in portal venous blood flow (hepatic arterial blood flow remaining a relatively fixed proportion of cardiac output). For drugs with a low hepatic extraction ratio, this decline has virtually no effect (as their clearance is more dependent on the total amount of metabolically active liver tissue). For the high extraction ration drugs, this change in blood flow could be clinically significant. Le Couteur et al (1998) reports decreased clearance by 35%, 32%, 35% for morphine, verapamil, lignocaine (respectively). This reduction in portal flow also has the effect of decreasing the first pass metabolism of high extraction ratio drugs, increasing their oral bioavailability (propanolol and labetalol, according to Mangoni et al, 2004).

Increased susceptibility to metabolic substrate depletion

Glutathione transferase might still be working for you in your late eighties, but glutathione itself may be depleted. This is a common problem in the nutritionally deficient elderly. It is of course not essential to be elderly in order to become nutritionally depleted, and so this factor is not geri-specific. 

Changes in drug and metabolite clearance associated with old age

Decreased renal function

Renal clearance may be decreased due to age-related changes in renal function, and this seems to be an important topic for the college, as it formed a part of Question 28 from the first Fellowship paper of 2016. The exact change is probably a loss of around 50% of the GFR from age 20 to age 90. Tubular function tends to decline in parallel to glomerular filtration rate. As these functions deteriorate, so the clearance of water-soluble drugs and their metabolites is decreased. Both drugs dependent on active tubular secretion (eg. β-lactams) and drugs which rely on glomerular filtration (aminoglycosides) are affected.

Pharmacodynamics in the elderly

Increased sensitivity to toxic effects

Because of  physiological reserves diminished by old age, the elderly are likely to have impaired defences against side-effects. For instance, anticholinergic side-effects of tricyclic antidepressants may be well tolerated by the young, but may cause constipation and delirium in the elderly.

Decreased homeostatic mechanisms

A part of the aforementioned failure to tolerate side-effects is the failure of homeostatic mechanisms to compensate for physiological challenges offered by drug therapy. A classic example offered in the literature is the increased susceptibility to postural hypotension in response to vasodilators  (Turnheim, 1998).

Altered receptor sensitivity

Turnheim (2003) reports a diminished sensitivity of β-receptors, which is not associated in much of change in response to agonists or antagonists (which makes it fairly irrelevant). Weirdly, α-receptor sensitivity is preserved with age. The cause is supposedly some sort of downregulation as a result of diminished presynaptic α₂-activity. Responsiveness of adenosine (A₁) receptors is also apperently decreased. 

Specific drugs and drug classes:

• Increased adverse effects with anticoagulants: frequency of bleeding events increases with age
• Increased toxicity from negative inotropes: combination of diminished baroreceptor reflexes and already-impaired cardiac conduction makes the elderly more susceptible to bradyarrhythmias and hypotension in response to drugs like verapimil and diliazem
• Increased sensitivity to opiates (by about 50%)
• Increased sensitivity to CNS depressants (eg. propofol)