Age related changes in pharmacodynamics and pharmacokinetics- ta2meen.ppsx

The lecture describes age related changes in pharmacodynamics, pharmacokinetics and how these changes affect drug prescription. Also polypharmacy and precription cascade were discussed.

1. Age related changes in
pharmacokinetics &
pharmacodynamics
& implications on drug
prescription
Presented by
Heba Mohamed Tawfik
Associate Professor of Geriatrics and
Gerontology
Faculty of Medicine , Ain-Shams University
Nasr City Health Insurance hospital
course
August 2023

2. Age related changes in
pharmacokinetics

3. 1)AbsorptionDespite an age-related decrease in small-bowel surface area, slowed
gastric emptying, and an increase in gastric pH, changes in drug
absorption tend to be clinically inconsequential for most drugs.
One clinically relevant exception is calcium carbonate, which requires an
acidic environment for optimal absorption. Thus, increases in gastric
pH—which may be age-related (such as with atrophic gastritis) or drug-
related (such as with proton pump inhibitors)—can decrease calcium
absorption and increase the risk of constipation. Older adults should
use a calcium salt (eg, calcium citrate) that dissolves more easily in a
less acidic environment.

4. Another example of altered
absorption with increased gastric
pH is early release of enteric-
coated dosage forms (eg, enteric-
coated aspirin, enteric-coated
erythromycin), increasing the risk
of gastrointestinal adverse effects.

5. 2)Distribution
Withage,bodyfatgenerallyincreasesandtotalbodywaterdecreases.Increased
fatincreasesthevolumeofdistributionforhighlylipophilicdrugs(eg,diazepam)
andmaymeaningfullyincreasetheireliminationhalf-lives.
Serumalbumindecreaseswithage,buttheclinicaleffectofthesechangeson
serumdrugbindingvarieswithdifferentdrugs.Phenytoinandwarfarinare
examplesofhighlyprotein-bounddrugswithahigherriskoftoxiceffectswhen
theserumalbuminleveldecreasesinacutedisorferormalnutrition.

6. •Distributiontoperipheralstoragesitesissignificantlyaffectedbyaging,
becauseasleanbodymassdecreases,thereisarelativeincreaseinfatstores
(evenforthinelderlypatients).
•Thesechangescreatealargervolumeofdistributionforfat-solubledrugs
(includingmostpsychotropics)andasmallervolumeofdistributionforwater-
solubledrugs,suchaslithium.
•Becausetheeliminationhalf-lifeofadrugisdirectlyproportionaltoitsvolume
ofdistribution,thepracticalsignificanceofthesechangesisthatmost
psychotropicsremaininthebodylongeringeriatricpatients.

7. Another result of the relative increase in body fat with aging is that highly
lipophilic drugs, such as diazepam are rapidly taken up by fat storage sites, so
that drug concentration in the blood falls quickly below a minimum effective
threshold.
With one-time dosing, the duration of effect is short for diazepam. The
drug is removed slowly from fat stores, and significant accumulation of the
drug can occur with repeated dosing.
Moreover, the drug may be released erratically, which can result in changing
serum levels over time. For these and other reasons, diazepam is not
recommended for the elderly.

8. 3)Hepatic metabolism
Overall hepatic metabolism of many drugs through the
cytochrome P-450 enzyme system decreases with age. For
drugs with decreased hepatic metabolism, clearance
typically decreases 30 to 40%. Theoretically, maintenance
drug doses should be decreased by this percentage;
however, rate of drug metabolism varies greatly from person
to person, and dose adjustments should be individualized.
Hepatic clearance of drugs metabolized by phase I
reactions (oxidation, reduction, hydrolysis) is more
likely to be prolonged in older adults. Usually, age
does not greatly affect clearance of drugs that are
metabolized by conjugation and glucuronidation
(phase II reactions).

9. Age related changes in the liver
↓Hepatic mass
↓Hepatic blood flow
↓Activity of CYP 450 enzyme system

10. First-pass metabolism
•Metabolism,typicallyhepatic,thatoccursbeforeadrug
reachessystemiccirculationisalsoaffectedbyaging,
decreasingbyabout1%/yearafterage40.Thus,fora
givenoraldose,olderadultsmayhavehighercirculating
drugconcentrations.
•Importantexamplesofdrugswithahigherriskoftoxic
effectsbecauseofage-relatedreductionsinfirst-pass
metabolismincludenitrates,propranolol,phenobarbital,
andnifedipine.

11. 4)Renalelimination
Oneofthemostimportantpharmacokineticchanges
associatedwithagingisdecreasedrenaleliminationof
drugs.Afterage40,glomerularfiltrationrate(GFR)
decreasesanaverageof8mL/min/1.73m2/decade(0.1
mL/sec/m2/decade);however,theage-relateddecrease
variessubstantiallyfrompersontoperson.
Serumcreatininelevelsoftenremainwithinnormallimits
despiteadecreaseinglomerularfiltrationrate(GFR)
becauseolderadultsgenerallyhavelessmusclemass.
Maintenanceofnormalserumcreatininelevelscan
misleadclinicianstoassumethoselevelsreflectnormal
kidneyfunction.Decreasesintubularfunctionwithage
parallelthoseinglomerularfunction.

12. Age related changes in the kidney
↓Renal blood flow
↓Renal mass
↓Glomerular filtration
↓Renal tubular secretion and reabsorption

15. •Pharmacodynamics is defined as what the drug does to the body or the
response of the body to the drug; it is affected by receptor binding, post-
receptor effects, and chemical interactions.
•In older adults, the effects of similar drug concentrations at the site of
action (sensitivity) may be greater or smaller than those in younger
people.
•Differences may be due to changes in drug-receptor interaction, post-
receptor events, or adaptive homeostatic responses and, among frail
patients, are often due to pathologic changes in organs.

16. Receptornumberandresponsivenessalso
declineswithage;however,thisdoesnot
necessarilychangedrugsensitivityor
effectiveness.Instead,itcantakelonger
foradrugtoreachmaximumeffect,and
theeffectcanbestrongerintheelderly.
Resultantly,theelderlyaremorelikelyto
sufferdrugsideeffectswhendosedto
thesametargetconcentrationasyounger
adults.
Older adults are particularly sensitive to
anticholinergic drug effects (eg, TCAs, sedating
antihistamines, urinary antimuscarinic agents, some
antipsychotic drugs, antiparkinsonian drugs, many over-the-
counter hypnotics and cold preparations) .
Older adults, most notably those with cognitive impairment, are
prone to central nervous system adverse effects of such drugs
and may become confused. Anticholinergic drugs also commonly
cause constipation, urinary retention (especially in older men
with BPH), blurred vision, orthostatic hypotension, and dry
mouth. Even in low doses, these drugs can increase risk of
heatstroke by inhibiting diaphoresis. Older adults should avoid
drugs with anticholinergic effects when possible.

17. Themostimportantpharmacodynamic
differenceswithageforcardiovascular
agentsarethedecreaseineffectforbeta-
adrenergicagents.

18. Important drug-drug
interactions

19. Drug-Disease Interactions of Concern in Older Adults (Based on the
American Geriatrics Society 2019 Beers Criteria® Update)

20. DrugstoBeUsedWith
CautioninOlder
Adults(Basedonthe
AmericanGeriatrics
Society2019Beers
Criteria®Update)

21. Potentially Inappropriate Drugs in Older Adults (Based on the American Geriatrics
Society 2019 Beers Criteria® Update)

22. SSRIs drug-drug
interactions
Adopted from Bleakley, 2016

23. POLYPHARMACY
•Polypharmacyisdefinedastheuseofmultiplemedicationsbyapatient.The
preciseminimumnumberofmedicationsusedtodefine"polypharmacy"is
variable,butgenerallyrangesfrom5to10.Itisimportanttoalsoconsiderthe
numberofover-the-counterandherbal/supplementsused.Problematic
polypharmacyisdefinedastheuseofmultiplemedicationsinawaythatisnot
consideredtobeappropriate.
•Theissueofpolypharmacyisofparticularconcerninolderpeoplewhotendto
havemorediseaseconditionsforwhichtherapiesareprescribed.Among
ambulatoryolderadultswithcancer,84percentwerereceivingfiveormore
and43percentwerereceiving10ormoremedications.

24. When people take multiple medications, they are at
greater risk of:
•Falls and associated harms, such as fractures
•Dehydration
•Functional decline
•Cognitive impairment
•Delirium
•Malnutrition
•Adverse drug events(ADE)
•Hospitalisation
•Mortality

25. Whyolderadultsareespeciallyimpactedby
polypharmacy?
TheyareatgreaterriskforADEsduetometabolicchangesand
decreaseddrugclearanceassociatedwithaging;thisriskis
compoundedbyincreasingnumbersofdrugsused.
Polypharmacyincreasesthepotentialfordrug-druginteractionsand
forprescriptionofpotentiallyinappropriatemedications.
Polypharmacymaybeanindependentriskfactorforhipfracturesin
olderadults,althoughthehighernumberofdrugsmayhavebeen
anindicatoroffalloccurrence(eg,[CNS]-activedrugs).
Polypharmacyincreasesthepossibilityof"prescribingcascades".A
prescribingcascadedevelopswhenanADEismisinterpretedasanew
medicalconditionandadditionaldrugtherapyisthenprescribedto
treatthismedicalcondition.Prescribingcascadesarepartofthe
definitionofproblematicpolypharmacy.
Useofmultiplemedicationscanleadtoproblemswithadherence,
especiallyifcompoundedbyvisualorcognitiveimpairment.

26. Rules in prescribing medications
•Startlowandgoslowtoreachthetargetdose.
•Prescribeonedrugformorethanoneproblem.
•Givedrugcombinationsifneededtodecreasethe
numberofmedicationsused.
•Askaboutvitamins,herbsandoverthecounter
medications.
•Checkthepatientmedicationsinaregularway,always
askaboutchangingdoseoraddingnewonesandask
thepatienttobringallhismedicationsinhisvisit.
•Stopunnecessarymedicationsandde-escalatedoses
ifnecessary.
•Checkfordruginteractions.
•Donotforgetdrugsneedingadjustment.

27. References
https://www.psychiatrictimes.com/view/effects-pharmacokinetic-and-pharmacodynamic-changes-elderly
https://www.msdmanuals.com/professional/geriatrics/drug-therapy-in-older-adults/pharmacokinetics-in-older-adults
https://www.msdmanuals.com/professional/geriatrics/drug-therapy-in-older-adults/pharmacodynamics-in-older-adults
https://step1.medbullets.com/pharmacology/107006/phase-i-vs-phase-ii-metabolism
The American Geriatrics Society 2019 Beers Criteria Update Expert Panel:American Geriatrics Society updated Beers Criteria®forpotentially inappropriate
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Nightingale G, Hajjar E, Swartz K, et al. Evaluation of a pharmacist-led medication assessment used to identify prevalence of and associations with polypharmacy
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BleakleyS. Antidepressant drug interactions: evidence and clinical significance: Antidepressant drug interactions.Progressin Neurology and Psychiatry. May
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28. Thank you