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AGS
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.
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 fat
 Offsets resorption of skeletal elements and loss
of total body water
 Result: increment in the fat fraction of the total
body weight
Slide 6
ALTERED VOLUME DISTRIBUTION
OF 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)
Slide 7
ALTERED VOLUME DISTRIBUTION
OF 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
Slide 8
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
Slide 9
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 flow
 36% reduction in cerebral oxygen consumption
 30% 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
Slide 10
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
Slide 11
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
Slide 12
CHANGES IN THE
CARDIOVASCULAR 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
Slide 13
CHANGES IN THE
CARDIOVASCULAR 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 THE
CARDIOVASCULAR SYSTEM (4 of 5)
• Reduction in perfusion is uneven
 Results 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 THE
CARDIOVASCULAR SYSTEM (5 of 5)
• Increased risk of hypotension
 Decreased baroreceptor sensitivity
 Decreased response to β-stimulation
 Decreased response of
renin/aldosterone/angiotensin system
Slide 16
CHANGES IN THE
RESPIRATORY 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 THE
RESPIRATORY 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
Slide 18
CHANGES IN THE
HEPATIC SYSTEM (1 of 2)
• Decrease in liver volume
• 40% reduction in liver blood flow
 Anesthesia and abdominal surgery also reduce
blood flow
 Reduced maintenance requirements for drugs that
are rapidly cleared by the liver
 Modest reduction in the rate of hepatic metabolism
for drugs slowly cleared by the liver
 Fall in metabolism for other anesthetics
Slide 19
CHANGES IN THE
HEPATIC SYSTEM (2 of 2)
• Intrinsic hepatic capacity unchanged
 No 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 increased
 Decreased free fraction of drugs and reduced
elimination
Slide 20
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
NEUROMUSCULAR
BLOCKING 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 ANESTHETIC
AGENTS (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 BP
 Reduced myocardial contractility by inhalation
anesthetics
 Volume contraction
Slide 23
VOLATILE ANESTHETIC
AGENTS (2 of 2)
• Isoflurane and desflurane are metabolized less
• Advantages of sevoflurane and desflurane:
 More rapid control of anesthetic depth
 Faster emergence from anesthesia
 More rapid recovery of mental function to preanesthesia levels
Slide 24
INTRAVENOUS AGENTS
• Must cross the blood-brain barrier
 Non-ionized and protein-bound
 Small changes in pH greatly alter the availability
of the drug
• Slow infusion rates are safer
 Too 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
 11.5 mg/kg without opioids; 0.51 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 metabolism
 Requires 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 23 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
Slide 39
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:
 Bleeding
 Decreased immune function
 Decreased wound strength
• Hypothermia is more pronounced and lasts
longer because of:
 Low basal metabolic rate
 Hypothyroidism
 High ratio of surface area to body mass
Slide 41
SPECIAL CONCERNS:
HYPOTHERMIA (2 of 3)
• Core temperature must fall to 35.2 °C before:
 Shivering
 Cold-induced vasoconstriction
 Autonomic 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 clearance
 Further renders the elderly susceptible to post-op
hypothermia
• Rewarming may precipitate sudden
hypotension
 Vasodilation
 Hypovolemia
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 FOR
DOSE ADJUSTMENT
Drug/Class
Dose Adjustment
Barbiturates
Modest reduction in bolus dose and infusion rates
Etomidate
Reduction of up to 50% in bolus dose
Propofol
Reduction of up to 30%50% in bolus dose and infusion rates
Benzodiazepines
Reduction of up to 75% in bolus dose and infusion rates
Opioids
Reduction of up to 50% in bolus dose and infusion rates
Non-depolarizing
neuromuscular
blocking agents
No reduction in bolus dose but generally reduced infusion
rates depending on drug
Volatile agents
Reduction in inspired concentrations of 6% per decade
Local anesthetics Small to moderate reduction in segmental dose
Slide 48
THANK YOU FOR YOUR TIME!
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