Population Variability in Pharmacology Case Study Review PDF

**Population Variability in Pharmacology** **Case Study Review** **Older Adult/Geriatric** Cameron 1-3 81-year-old Mr. X is scheduled for posterior lumbar 4-5 discectomy under general anesthesia. Past medical history includes chronic renal insufficiency (no dialysis), coronary artery disease (ba...

**Population Variability in Pharmacology** **Case Study Review** **Older Adult/Geriatric** Cameron 1-3 81-year-old Mr. X is scheduled for posterior lumbar 4-5 discectomy under general anesthesia. Past medical history includes chronic renal insufficiency (no dialysis), coronary artery disease (bare metal stent x1), and mild emphysema. ECG -- sinus bradycardia (58) with occasional PVCs Meds -- metoprolol, atorvastatin, albuterol, aspirin, fish oil 1. The surgeon plans to inject 50 ml of the highly protein-bound local anesthetic, ropivacaine. What pharmacokinetic alterations might you expect in this patient? Why? - Larger volume of distribution greater unbound drug fraction - Longer half-life greater distribution - More active drug - Lower albumin levels 2. You plan to give the water-soluble neuromuscular blocker, rocuronium, throughout the case. Will its volume of distribution change? How so and why? - Decrease- decreased total body water 3. Propofol is highly lipophilic. Let's say you plan to use a propofol infusion during the anesthetic. How might this affect the volume of distribution, drug clearance, and duration? - Large volume of distribution -- increased adipose (fat stores) & decreased lean body mass - Decreased, slower clearance- accumulation in far - Prolonged duration -- prolonged half-life David 4-6 4. Mr. X takes a longer than expected time to wake up and recover neurologically from the effects of the propofol anesthesia. What are some pharmacodynamic reasons for this? - Blood-brain barrier changes 'Neurotransmitter receptor changes - Possible neuro inflammation - Increased sensitivity r/t pharmacokinetic changes and prolonged half-life - Also high risk for delirium and postop cognitive decline Possible reasons include reduced hepatic metabolism, impaired renal clearance, increased sensitivity to central nervous system effects, and decreased cardiac output limiting drug distribution and clearance. 5. During the surgery, Mr. X becomes hypotensive (BP 78/45) with sustained bradycardia (HR 54). You desire to increase heart rate in an effort to improve cardiac output and blood pressure and decide to give the drug, ephedrine to increase circulating catecholamines. Mr. X's heart rate only increases to 58 and BP to 84/51 after your ephedrine administration. Why the minimal response to the drug ephedrine? - Cate3cholamine receptor down-regulation decreased responsiveness - Competition with metoprolol - Reduced cardiac function with age (and with some anesthetics) - Maximal heart rate with stress is decreased in older adult Mr. X's limited response to ephedrine may be due to reduced catecholamine receptor sensitivity, often seen in older adults, and the baseline use of beta-blockers (metoprolol), which can blunt ephedrine's effects. 6. You ran out of rocuronium and decide to give Mr. X the neuromuscular blocker, cisatracurium. Cisatracurium is primarily metabolized by Hofmann elimination which depends on temperature and pH (*not* elimination organs). Your cisatracurium doses are fairly predictable in Mr. X whereas your rocuronium (metabolized by the liver and excreted in urine & bile) was found to be prolonged. What physiologic changes might contribute to this? - Reduced glomerular filtration, renal function - Reduced hepatic function, hepatic blood flow - Rocuronium metabolism relies on liver function and renal excretion, both of which may be impaired in Mr. X due to chronic renal insufficiency. Cisatracurium is metabolized via Hofmann elimination, which is unaffected by organ dysfunction, leading to more predictable effects. Kate 1-4 **Neonatal/Pediatric** 11-month-old little M is scheduled for tympanostomy with ear tube placement. Past medical history includes chronic otitis media. VS -- sinus tachycardia (120), blood pressure (85/60), respiratory rate (30) 1. What are the expected differences in little M's total body water and plasma protein levels compared to their parents? Little M has higher total body water (70--80% of body weight) and lower or higer plasma protein levels compared to adults. This can increase the volume of distribution for water-soluble drugs and reduce binding of protein-bound drugs. - Increased TBW relative to body mass - About the same plasma protein levels (greater than 6 months) 2. You desire to give little M the highly lipophilic drug fentanyl for pain. How would you expect volume of distribution of fentanyl to differ in little M compared to their older 7-year-old sister, miss Y? How would you expect volume of distribution to differ in little M compared to their grandfather, Mr. O? Little M would have a larger volume of distribution for fentanyl compared to her sister Miss Y (due to lower fat stores) and her grandfather Mr. O (due to reduced fat stores and protein levels with aging). - Little M'volume of distribution is larger than miss Y because of greater body fat than in older children - Little M's volume of distribution is smaller than Grandpa O because of lower body fat percentages compared to the adults. 3. Little M is placed on a whole body bair hugger to provide warm air for surgery. The room temperature has also been elevated to 29 C or about 84 F. Why is this necessary? - Lare surface area for accelerated heat loss - Limited thermogenesis, unstable thermoregulation - Also: general anesthesia with inhaled anesthetics affects hypothalamus' ability to regulate body temp Infants have a high surface area-to-mass ratio, making them more susceptible to hypothermia. Warming measures are necessary to maintain normothermia and prevent complications like metabolic acidosis. 4. You expect little M to better tolerate the effects of neuromuscular blockers, opioids, and anesthetics than if they were a neonate. Why? Little M's liver and kidney function are more developed than a neonate's, allowing better metabolism and excretion of drugs. Additionally, neuromuscular junctions are more mature, improving drug tolerance. - Maturing CNS, blood-brain barrier, neuromuscular junction - Eli long -- 5-8 5. Will little M have higher or lower inhaled anesthetic requirements than older sister miss Y? Little M has higher minimum alveolar concentration (MAC) requirements for inhaled anesthetics than older children due to increased metabolic rates and oxygen consumption. - Higer anesthetic requirements are higher at 6 months and decreased with age 6. Little M's had an intraoperative laryngospasm and was given succinylcholine twice for urgent airway intubation. Repeated doses of succinylcholine can decrease little M's heart rate drastically so atropine was given preventatively. Why? - Cardiac output dependent on heart rate -- avoid bradycardia Succinylcholine can stimulate parasympathetic pathways, causing bradycardia. Atropine blocks these effects, preventing severe bradycardia. 7. Little M is more resistant to the effects of water-soluble, succinylcholine than older sister Miss Y. What are some pharmacokinetic reasons for this? - Immature liver leads to lower levels of plasma cholinesterase enzymes - Larger volume of distribution -- increased ECF, body water (also dilutional effect) Little M has a higher extracellular fluid volume and immature acetylcholine receptors, leading to increased resistance to water-soluble succinylcholine. Immature liver leads to lower levels of plasma cholinesterase enzymes Larger volume distribution -- increased ECF body water also dilutional effect 8. Little M is given PO Tylenol after surgery. What gastrointestinal factors might affect the pharmacokinetics of this drug? Little M's immature gastrointestinal enzymes and altered gastric emptying could affect Tylenol absorption. Additionally, hepatic enzyme immaturity could prolong its metabolism. - Prolonged gastric emptying - Slower absorption - Gut bacteria may metabolize some drugs **Obstetric** Sam 1-4 30-year-old Mrs. Z is 32 weeks pregnant and is scheduled for open reduction internal fixation of a finger fracture under deep sedation with local anesthesia. VS -- sinus tachycardia (105), blood pressure (135/80), respiratory rate (25) 1. What would be the expected pharmacokinetic effects of water-soluble, highly protein-bound drugs in Mrs. Z? Pregnancy increases plasma volume, reducing plasma drug concentrations. Hypoalbuminemia in pregnancy decreases protein binding, increasing the free fraction of highly protein-bound drugs. - Increased volume distribution -- increased toral body water - Lower plasma concentration -- increased TBW (and drug movement) as well as dilutional effect - Increased fraction of free drugs available to have an effect -- decreased plasma albumin levels 2. You plan to put Mrs. Z on a propofol infusion for the surgery. Propofol is a highly lipophilic drug. How might this affect pharmacokinetics in Mrs. Z? - Large volume of distribution -- increased adipose in pregnancy - Longer duration of action, slower clearance Propofol's lipophilicity leads to increased distribution into fat tissues, which are higher in pregnancy. Clearance may be enhanced due to increased hepatic blood flow in pregnancy. 3. How might you need to adjust your propofol dosing in Mrs. Z? Why? - Lower doses expected -- increased progesterone levels & increased sensitivity to anesthetics A slight reduction in initial doses may be needed to prevent over-sedation, but maintenance doses may need to be increased due to enhanced metabolism and clearance. 4. Mrs. Z denies anxiety or pain prior to surgery and is very calm in her preoperative room. What cardiovascular and respiratory changes in pregnancy might explain why Mrs. Z's blood pressure and respiratory rate are slightly elevated. Increased blood volume, cardiac output, and respiratory rate are increased pregnancy and can explain Mrs. Z's elevated vital signs. - Increased blood volume and cardiac output likely - Increased O2 consumption and minute ventilation (close to term) Cody 5-7 5. The surgeon desires to inject tetracaine for the procedure. How might the duration of action of tetracaine -- which is metabolized by plasma cholinesterase -- affect the pregnant patient? Plasma cholinesterase activity decreases in pregnancy, potentially prolonging the action of tetracaine. Prolong action - Prolonged -- due to decreased serum cholinesterase levels 6. You desire to give Mrs. Z a small dose of fentanyl for pain during surgery. How might the duration of action of fentanyl change in Mrs. Z? - Increased fat stores in pregnancy can prolong the redistribution phase of fentanyl, extending its duration of action. - Shortened increased level of 3A4 enzyme - Increased adipose tissue -- prolonged duration of action 7. You are trying to determine which drugs have the lowest risk of transferring across the placenta. What four factors would **decrease** the rate of diffusion to Mrs. Z's fetus? - Large molecular weight - Water soluble (low lipid solubility) - Ionized - Protein-bound \- Drugs with high molecular weight -- b/c of passive diffusion / large and charge \- high protein binding -- decreased Albumin \- low lipophilicity -- water soluble \- ionization at physiological pH crosses the placenta less readily