THE AMERICAN GERIATRICS SOCIETY Geriatrics Health Professionals.

1. PHARMACOKINETICS AND PHARMACODYNAMICS IN THE ELDERLY AND THEIR IMPACT ON ANESTHETIC AGENTSSamantha P. Jellinek, PharmD, BCPS, CGPClinical Pharmacy Manager AGS THE AMERICAN GERIATRICS SOCIETY Geriatrics Health Professionals. Leading change. Improving care for older adults.

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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)

8. 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

9. 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

10. 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

11. 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

12. Changes in theCardiovascular 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

13. 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

14. 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

15. Changes in theCardiovascular 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

16. Changes in theCardiovascular System (5 of 5) • Increased risk of hypotension • Decreased baroreceptor sensitivity • Decreased response to β-stimulation • Decreased response of renin/aldosterone/angiotensin system

17. 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

18. 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

19. Changes in theHepatic 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

20. Changes in theHepatic 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

21. 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

22. 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

23. 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 BP • Reduced myocardial contractility by inhalation anesthetics • Volume contraction

24. Volatile AnestheticAgents (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 pre-anesthesia levels

25. 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

26. 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

27. 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

28. 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

29. HYPNOTICS: Etomidate Initial volume of distribution is decreased • Requires less than half the dose to reach the same stage EEG endpoint as younger patients

30. 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

31. Benzodiazepines: Diazepam Desmethyldiazepam has more CNS activity than diazepam • Accumulation with long-term use can prolong its clinical effects in the elderly

32. 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

33. OPIOIDS: Sufentanil • Small decrease in Vd of the central compartment • Undergoes hepatic metabolism • Requires reduction in both loading and maintenance doses with increasing age

34. 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

35. 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

36. OPIOIDS: Morphine Clearance decreased by 50% • Prolonged duration of action • Reductions in maintenance dosing

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. Practice Points (3 of 4) • Maintenance dose requirements should be reduced dramatically in the elderly • For example, remifentanil by 70%; propofol by 40%

47. 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

48. RECOMMENDATIONS FORDOSE ADJUSTMENT

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