PHARMACOKINETICS AND

PHARMACODYNAMICS IN THE ELDERLY AND

THEIR IMPACT ON ANESTHETIC AGENTS

Samantha P. Jellinek, PharmD, BCPS, CGP

Clinical Pharmacy Manager

THE AMERICAN GERIATRICS SOCIETY

Geriatrics Health Professionals.

Leading change. Improving care for older adults.

AGS

THE PROBLEM

• Elderly patients require dose reductions for most agents

Become more sensitive to the therapeutic and adverse effects

Increased sensitivity results from a combination of pharmacokinetic/pharmacodynamic (PK/PD) alterations

• Pathophysiology may also affect the PK/PD of anesthetic agents

Slide 2

PHYSIOLOGIC VS. CALENDAR AGE

• Wide variability in dose-response relationships occur with increasing age

• Physiologic age and comorbidity are the primary influences on postoperative outcome

Slide 3

OBJECTIVES

• To review the physiological changes that occur with age

• To review how these changes affect the PK/PD of the agents used in anesthetic practice in the elderly

Slide 4

CHANGES IN BODY COMPOSITION: MEN

• Total body weight declines

• Contraction of total body water and loss of lean tissue mass

• Body fat fraction returns toward young adult values

Slide 5

CHANGES IN BODY COMPOSITION: WOMEN

• Little change in total body weight

• More persistent trend of increasing body fatOffsets resorption of skeletal elements and loss of

total body waterResult: increment in the fat fraction of the total body

weight

Slide 6

ALTERED VOLUME DISTRIBUTIONOF DRUGS (1 of 2)

• A decrease in total body water causes a decrease in the central compartment (V1)

Results in higher peak drug concentrations following boluses or rapid infusions

• A decrease in lean body mass causes a decrease in the rapid equilibrating compartment (V2)

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ALTERED VOLUME DISTRIBUTIONOF DRUGS (2 of 2)

• An increase in body fat causes an increase in the slow equilibrating compartment (V3)

Results in an increase in total volume of distribution and alterations in the duration of drug effect

• Computer simulations are used to interpret how these changes affect dose and time course of drug effect

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HOW CAN WE APPLY THIS TO CLINICAL PRACTICE?

• Neuromuscular blocking agents given on a weight-related basis may have a more prolonged effect in the elderly

• Steady-state Vd (Vdss) of thiopentone increases to 125% of the adult value, yet the initial Vd is reduced

Same is seen with soluble anesthetic vapors such as halothane

• Water-soluble drugs such as cimetidine have a reduced Vdss

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CHANGES IN THE CENTRAL NERVOUS SYSTEM (1 of 2)

• Between the ages of 20 and 80 years there is approximately a:

30% reduction in cerebral blood flow36% reduction in cerebral oxygen consumption30% reduction in cortical neuronal density

• Neuronal activity, autoregulation, and cerebrovascular response to CO2 remain intact

Neuronal composition, cell number, and regeneration capacities in the CNS diminish

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CHANGES IN THE CENTRAL NERVOUS SYSTEM (2 of 2)

• Depletion of brain neurotransmitters

• Number of receptor sites and composition of receptors decrease and change

May explain why most anesthetic agents exert their effects in the elderly at lower blood and effect-site concentrations

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CHANGES IN THE CARDIOVASCULAR SYSTEM (1 of 5)

• Decreased number of myocytes

• Stiffening of myocardial cells

• Reduced response to β-adrenergic stimulation

• Large arteries dilate

• Increased wall thickness and smooth muscle tone

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CHANGES IN THECARDIOVASCULAR SYSTEM (2 of 5)

• Results in an increase in systolic BP, elevated left ventricular (LV) afterload, and LV wall thickening

• Reduces LV compliance, causing impairment of diastolic function

• More sensitive to the arrhythmogenic effects of anesthetics

• Increased tendency to develop pulmonary edema

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CHANGES IN THECARDIOVASCULAR SYSTEM (3 of 5)

• No age-associated decline in cardiac output in healthy older adults

Sedentary lifestyle or degenerative changes would produce a decline in cardiac output

• Decreases in cardiac output with a lower tissue perfusion may lengthen the time required to transport drugs to tissues and delay the time to peak effect

Slide 14

CHANGES IN THECARDIOVASCULAR SYSTEM (4 of 5)

• Reduction in perfusion is unevenResults in increased duration of action of

anesthetic agents

• Virtually all anesthetics decrease cardiac output to some degree

Dose needed for induction is reduced Slower onset of block seen with neuromuscular

blocking agents

Slide 15

CHANGES IN THECARDIOVASCULAR SYSTEM (5 of 5)

• Increased risk of hypotensionDecreased baroreceptor sensitivityDecreased response to β-stimulationDecreased response of

renin/aldosterone/angiotensin system

Slide 16

CHANGES IN THERESPIRATORY SYSTEM (1 of 2)

• Vital capacity, maximum voluntary ventilation, and total lung capacity decrease with increasing age

• Functional residual capacity and closing volume increase

Results in collapse of small airways and air trapping

Slide 17

CHANGES IN THERESPIRATORY SYSTEM (2 of 2)

• Marked suppression of hyperventilation in response to imposed hypoxia or hypercapnia

• Anesthesia, supine position, and use of narcotics worsen hypoxia

• Increased risk of aspiration and postoperative pneumonia

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CHANGES IN THEHEPATIC SYSTEM (1 of 2)

• Decrease in liver volume

• 40% reduction in liver blood flowAnesthesia and abdominal surgery also reduce

blood flowReduced maintenance requirements for drugs that

are rapidly cleared by the liverModest reduction in the rate of hepatic metabolism

for drugs slowly cleared by the liverFall in metabolism for other anesthetics

Slide 19

CHANGES IN THEHEPATIC SYSTEM (2 of 2)

• Intrinsic hepatic capacity unchangedNo significant age-dependent difference in the

activity of hepatic phase 1 and 2 drug metabolism

• Hepatic cytochrome P450 activity unchanged

• Production of albumin decreased Increased free fraction of drugs that bind primarily

to it, with reduced dose requirements

• Alpha-1 acid glycoprotein increasedDecreased free fraction of drugs and reduced

elimination

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CHANGES IN THE RENAL SYSTEM

• Delay in the offset of renally excreted drugs

• Glomerular filtration rate decreases by about 1% per year over 40 years of age

Result of decreased cardiac output and glomerular sclerosis

• Elimination of drugs undergoing renal excretion is prolonged

Tubocurarine

Slide 21

NEUROMUSCULARBLOCKING AGENTS

• Onset of action is prolonged Cisatracurium

• Duration of action is prolonged Succinylcholine, rocuronium, mivacurium, vecuronium Atracurium and cis-atracurium not prolonged Long-acting agents are associated with longer PACU stays

and postoperative pulmonary complications

• Maintenance infusion rate for adequate neuromuscular blockade is reduced

Vecuronium

• Recovery from muscle relaxation is delayed

Slide 22

VOLATILE ANESTHETICAGENTS (1 of 2)

• 66%75% anesthetic concentration is required by an 80-year-old compared to a young adult

• Rate of induction may be slowed Dose should not be hastened to induce induction

• Larger decrease in BP seen in elderly Impairment of reflex heart rate responses to BPReduced myocardial contractility by inhalation

anestheticsVolume contraction

Slide 23

VOLATILE ANESTHETICAGENTS (2 of 2)

• Isoflurane and desflurane are metabolized less

• Advantages of sevoflurane and desflurane:More rapid control of anesthetic depthFaster emergence from anesthesiaMore rapid recovery of mental function to pre-

anesthesia levels

Slide 24

INTRAVENOUS AGENTS

• Must cross the blood-brain barrierNon-ionized and protein-boundSmall changes in pH greatly alter the availability

of the drug

• Slow infusion rates are saferToo slow a rate may increase the dosage

requirement

Slide 25

HYPNOTICS: PROPOFOL

• Anesthetic depth synergistically increased when administered with other induction agents

• Decreased maintenance requirement with increasing age

• Slowly administer a reduced dose to avoid hypotensive effects

11.5 mg/kg without opioids; 0.51 mg/kg with opioids Mask induction with sevoflurane causes less hypotension

than IV propofol induction Hypotensive response of propofol is offset by intubation

response

Slide 26

HYPNOTICS: THIOPENTAL

• Higher concentrations are seen for any given dose

• Recovery can be significantly prolonged after continuous infusions or repeated bolus doses

• Elderly require a 20% reduction in infusion rate

Concentration will decline nearly as rapidly when infusion is turned off

Slide 27

HYPNOTICS: METHOHEXITAL

• Clearance is greater and elimination half-life is shorter than that of thiopental

• Clearance largely dependent on hepatic blood flow

Elimination will be prolonged

Slide 28

HYPNOTICS: ETOMIDATE

Initial volume of distribution is decreased• Requires less than half the dose to reach the same

stage EEG endpoint as younger patients

Slide 29

BENZODIAZEPINES: MIDAZOLAM

• Increased potency

• 30% reduction in clearance in the elderly

• Takes twice as long for concentration to fall

• 50%75% dose reduction required when administered as a bolus

Slide 30

BENZODIAZEPINES: DIAZEPAM

Desmethyldiazepam has more CNS activity than diazepam• Accumulation with long-term use can prolong its

clinical effects in the elderly

Slide 31

BENZODIAZEPINES: KETAMINE

• Can exert a negative inotropic effect on ischemic myocardium

Lower induction dose for elderly critically ill patients

• Decreased clearance and prolonged duration of action expected

Slide 32

OPIOIDS: SUFENTANIL

• Small decrease in Vd of the central compartment

• Undergoes hepatic metabolismRequires reduction in both loading and

maintenance doses with increasing age

Slide 33

OPIOIDS: REMIFENTANIL

• Has twice the intrinsic potency in elderly

• Central compartment volume decreases 20%

• Clearance decreases 30%Decrease bolus and maintenance dose by 50% Peak effect expected about 23 minutes after

bolus

Slide 34

OPIOIDS: FENTANYL AND ALFENTANIL

• PK does not appear to be changed

• Fentanyl: Increased potency of about 50%Reduce dose by half to achieve the same effect

Slide 35

OPIOIDS: MORPHINE

Clearance decreased by 50%• Prolonged duration of action• Reductions in maintenance dosing

Slide 36

LOCAL ANESTHETICS

PK/PD changes result from:

•Decline in the neuron population and slowing of conduction velocity in the peripheral nerves

•Deterioration in myelin sheaths and connective tissue barriers

•Changes in anatomical configuration of the lumbar and thoracic spine

•Progressive sclerotic closure of the intervertebral foramina

Slide 37

BUPIVACAINE

• Rapid initial absorption followed by a much slower phase

• Epidural space Fast: High initial concentration gradient and large vascularity Slow: Slow uptake of local anesthetic sequestered in epidural

fat

• Peak plasma concentrations and peak times do not change

• Terminal half-life increases Protein binding or metabolizing hepatic enzyme activity

Slide 38

REGIONAL VS. GENERAL ANESTHESIA

• There are no large prospective studies preferentially supporting the use of regional anesthesia in elderly

Outcome studies suggest no difference in mortality and major morbidity

• Regional anesthesia has the advantages of: Reduced postoperative negative nitrogen balance Amelioration of stress response to surgery Decreased incidence of postoperative thromboembolic

complications Decreased blood loss Decreased postoperative mental confusion

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SPECIAL CONCERNS: PRE-OXYGENATION

• Elderly patients desaturate faster

• Time to peak relaxation from succinylcholine is also increased

• Arteriolar, alveolar, venous, and tissue compartments are filled with oxygen

• Maximum oxygen in a short period of time 8 deep breaths of 100% oxygen in 60 seconds with an

oxygen flow of 10 L/min

• More likely to suffer a cardiac event from desaturation

Slide 40

SPECIAL CONCERNS:HYPOTHERMIA (1 of 3)

• Elderly are susceptible to effects of hypothermia:BleedingDecreased immune functionDecreased wound strength

• Hypothermia is more pronounced and lasts longer because of:

Low basal metabolic rateHypothyroidismHigh ratio of surface area to body mass

Slide 41

SPECIAL CONCERNS:HYPOTHERMIA (2 of 3)

• Core temperature must fall to 35.2 °C before:ShiveringCold-induced vasoconstrictionAutonomic mechanisms for thermoregulation

• Oxygen consumption increases 38% over nonshivering levels

• Reduction in skeletal muscle mass decreases post-op shivering

Slide 42

SPECIAL CONCERNS:HYPOTHERMIA (3 of 3)

• Inhibition of thermoregulatory responses by anesthetics is exaggerated

Prolonging clearanceFurther renders the elderly susceptible to post-op

hypothermia

• Rewarming may precipitate sudden hypotension

VasodilationHypovolemia

Slide 43

PRACTICE POINTS (1 of 4)

• Induction dose in the elderly should be reduced

• Administer only 50% of the induction dose of a hypnotic/opioid or neuromuscular blocking agent in an 80-year old compared to a 20-year old to ensure the same hypnotic/analgesic or neuromuscular relaxant effect

Slide 44

PRACTICE POINTS (2 of 4)

• Onset of most agents is delayed

• Wait an appropriate period of time for the maximal effect to occur in the elderly, to avoid undesired side effects

Slide 45

PRACTICE POINTS (3 of 4)

• Maintenance dose requirements should be reduced dramatically in the elderly

For example, remifentanil by 70%; propofol by 40%

Slide 46

PRACTICE POINTS (4 of 4)

• PK/PD variability appears to increase with age because of the increasing gap between the healthy and the very ill elderly

• Titration to effect thus becomes increasingly important with age

Slide 47

RECOMMENDATIONS FORDOSE ADJUSTMENT

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