Geriatric Geriatric PharmacotherapyPharmacotherapy

Linda Farho, Pharm.D.Linda Farho, Pharm.D.University of Nebraska Medical CenterUniversity of Nebraska Medical Center

College of PharmacyCollege of Pharmacy

ObjectivesObjectives

1.1. Understand key issues in geriatric Understand key issues in geriatric pharmacotherapypharmacotherapy

2.2. Understand the effect age on Understand the effect age on pharmacokinetics and pharmacokinetics and pharmacodynamicspharmacodynamics

3.3. Discuss risk factors for adverse drug Discuss risk factors for adverse drug events and ways to mitigate themevents and ways to mitigate them

4.4. Understand the principles of drug Understand the principles of drug prescribing for older patientsprescribing for older patients

The Aging ImperativeThe Aging Imperative

Persons aged 65y and Persons aged 65y and older constitute 13% older constitute 13% of the population and of the population and purchase 33% of all purchase 33% of all prescription prescription medicationsmedications

By 2040, 25% of the By 2040, 25% of the population will population will purchase 50% of all purchase 50% of all prescription drugsprescription drugs

Challenges of Geriatric Challenges of Geriatric PharmacotherapyPharmacotherapy

New drugs available each yearNew drugs available each year FDA approved and off-label indications are FDA approved and off-label indications are

expandingexpanding Changing managed-care formulariesChanging managed-care formularies Advanced understanding of drug-drug interactionsAdvanced understanding of drug-drug interactions Increasing popularity of “nutriceuticals”Increasing popularity of “nutriceuticals” Multiple co-morbid statesMultiple co-morbid states PolypharmacyPolypharmacy Medication complianceMedication compliance Effects of aging physiology on drug therapyEffects of aging physiology on drug therapy Medication costMedication cost

Pharmacokinetics (PK)Pharmacokinetics (PK) AbsorptionAbsorption

– bioavailabilitybioavailability: the fraction of a drug dose reaching the : the fraction of a drug dose reaching the systemic circulationsystemic circulation

DistributionDistribution– locations in the body a drug penetrates expressed as locations in the body a drug penetrates expressed as

volume per weight (e.g. L/kg)volume per weight (e.g. L/kg)

MetabolismMetabolism– drug conversion to alternate compounds which may be drug conversion to alternate compounds which may be

pharmacologically active or inactivepharmacologically active or inactive

EliminationElimination– a drug’s final route(s) of exit from the body expressed in a drug’s final route(s) of exit from the body expressed in

terms of half-life or clearanceterms of half-life or clearance

Effects of Aging on Effects of Aging on AbsorptionAbsorption

Rate of absorption may Rate of absorption may be delayedbe delayed– Lower peak concentrationLower peak concentration– Delayed time to peak Delayed time to peak

concentrationconcentration Overall amount Overall amount

absorbed absorbed (bioavailability) is (bioavailability) is unchangedunchanged

Hepatic First-Pass Hepatic First-Pass MetabolismMetabolism

For drugs with extensive first-pass For drugs with extensive first-pass metabolism, bioavailability may metabolism, bioavailability may increase because less drug is increase because less drug is extracted by the liverextracted by the liver– Decreased liver massDecreased liver mass– Decreased liver blood flowDecreased liver blood flow

Factors Affecting AbsorptionFactors Affecting Absorption

Route of administrationRoute of administration What it taken with the drugWhat it taken with the drug

– Divalent cations (Ca, Mg, Fe)Divalent cations (Ca, Mg, Fe)– Food, enteral feedingsFood, enteral feedings– Drugs that influence gastric pHDrugs that influence gastric pH– Drugs that promote or delay GI motilityDrugs that promote or delay GI motility

Comorbid conditionsComorbid conditions Increased GI pHIncreased GI pH Decreased gastric emptyingDecreased gastric emptying DysphagiaDysphagia

Effects of Aging on Volume of Effects of Aging on Volume of Distribution (Vd)Distribution (Vd)

Aging EffectAging Effect Vd EffectVd Effect ExamplesExamples body waterbody water Vd for Vd for

hydrophilic drugshydrophilic drugsethanol, lithiumethanol, lithium

lean body masslean body mass Vd for for drugs Vd for for drugs that bind to that bind to musclemuscle

digoxindigoxin

fat storesfat stores Vd for lipophilic Vd for lipophilic drugsdrugs

diazepam, trazodonediazepam, trazodone

plasma protein plasma protein (albumin)(albumin)

% of unbound % of unbound or free drug or free drug (active)(active)

diazepam, valproic diazepam, valproic acid, phenytoin, acid, phenytoin, warfarinwarfarin

plasma protein plasma protein

((11-acid -acid glycoprotein)glycoprotein)

% of unbound % of unbound or free drug or free drug (active)(active)

quinidine, propranolol, quinidine, propranolol, erythromycin, erythromycin, amitriptylineamitriptyline

Aging Effects on Hepatic Aging Effects on Hepatic MetabolismMetabolism

Metabolic clearance of drugs by the Metabolic clearance of drugs by the liver may be reduced due to:liver may be reduced due to:– decreased hepatic blood flowdecreased hepatic blood flow– decreased liver size and massdecreased liver size and mass

ExamplesExamples: morphine, meperidine, : morphine, meperidine, metoprolol, propranolol, verapamil, metoprolol, propranolol, verapamil, amitryptyline, nortriptylineamitryptyline, nortriptyline

Metabolic PathwaysMetabolic Pathways

PathwayPathway EffectEffect ExamplesExamples

Phase IPhase I: oxidation, : oxidation, hydroxylation, hydroxylation, dealkylation, dealkylation, reductionreduction

Conversion to Conversion to metabolites of metabolites of lesser, equal, or lesser, equal, or greatergreater

diazepam, diazepam, quinidine, quinidine, piroxicam, piroxicam, theophyllinetheophylline

Phase IIPhase II: : glucuronidation, glucuronidation, conjugation, or conjugation, or acetylationacetylation

Conversion to Conversion to inactive inactive metabolitesmetabolites

lorazepam, lorazepam, oxazepam, oxazepam, temazepamtemazepam

** NOTE: Medications undergoing Phase II hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation)

Other Factors Affecting Drug Other Factors Affecting Drug MetabolismMetabolism

GenderGender Comorbid conditionsComorbid conditions SmokingSmoking DietDiet Drug interactionsDrug interactions RaceRace FrailtyFrailty

Concepts in Drug Concepts in Drug EliminationElimination

Half-lifeHalf-life– time for serum concentration of drug to time for serum concentration of drug to

decline by 50% (expressed in hours)decline by 50% (expressed in hours) ClearanceClearance

– volume of serum from which the drug is volume of serum from which the drug is removed per unit of time (mL/min or removed per unit of time (mL/min or L/hr)L/hr)

Reduced elimination Reduced elimination drug drug accumulation and toxicityaccumulation and toxicity

Effects of Aging on the Effects of Aging on the KidneyKidney

Decreased kidney sizeDecreased kidney size Decreased renal blood flowDecreased renal blood flow Decreased number of functional Decreased number of functional

nephronsnephrons Decreased tubular secretionDecreased tubular secretion Result: Result: glomerular filtration rate (GFR) glomerular filtration rate (GFR) Decreased drug clearanceDecreased drug clearance: atenolol, : atenolol,

gabapentin, H2 blockers, digoxin, gabapentin, H2 blockers, digoxin, allopurinol, quinolonesallopurinol, quinolones

Estimating GFR in the Estimating GFR in the ElderlyElderly

Creatinine clearance (CrCl) is used to Creatinine clearance (CrCl) is used to estimate glomerular rateestimate glomerular rate

Serum creatinine alone not accurate in the Serum creatinine alone not accurate in the elderlyelderly lean body mass lean body mass lower creatinine lower creatinine

productionproduction glomerular filtration rateglomerular filtration rate

Serum creatinine stays in normal range, Serum creatinine stays in normal range, masking change in creatinine clearancemasking change in creatinine clearance

Determining Creatinine Determining Creatinine ClearanceClearance

MeasureMeasure– Time consumingTime consuming– Requires 24 hr urine collectionRequires 24 hr urine collection

EstimateEstimate– Cockroft Gault equationCockroft Gault equation

(IBW in kg) x (140-age)(IBW in kg) x (140-age)------------------------------ x (0.85 for females)------------------------------ x (0.85 for females) 72 x (Scr in mg/dL)72 x (Scr in mg/dL)

Example: Creatinine Example: Creatinine Clearance vs. Age in a 5’5”, Clearance vs. Age in a 5’5”,

55 kg Woman55 kg Woman

30301.11.19090

41411.11.17070

53531.11.15050

65651.11.13030

CrClCrClScrScrAgeAge

Limitations in Estimating Limitations in Estimating CrClCrCl

Not all persons experience significant Not all persons experience significant age-related decline in renal functionage-related decline in renal function

Some patient’s muscle mass is Some patient’s muscle mass is reduced beyond that of normal agingreduced beyond that of normal aging– Suggest using 1 mg/dL if serum creatinine Suggest using 1 mg/dL if serum creatinine

is less than normal (<0.7 mg/dL)is less than normal (<0.7 mg/dL)– Not precise, may underestimate actual Not precise, may underestimate actual

CrClCrCl

Pharmacodynamics (PD)Pharmacodynamics (PD)

Definition: the time course and intensity of Definition: the time course and intensity of pharmacologic effect of a drugpharmacologic effect of a drug

Age-related changes:Age-related changes: sensitivity to sedation and psychomotor sensitivity to sedation and psychomotor

impairment with impairment with benzodiazepinesbenzodiazepines level and duration of pain relief with level and duration of pain relief with narcotic narcotic

agentsagents drowsiness and lateral sway with drowsiness and lateral sway with alcoholalcohol HR response to HR response to beta-blockersbeta-blockers sensitivity to sensitivity to anti-cholinergic agentsanti-cholinergic agents cardiac sensitivity to cardiac sensitivity to digoxindigoxin

PK and PD SummaryPK and PD Summary

PK and PD changes generally result in PK and PD changes generally result in decreased clearance and increased decreased clearance and increased sensitivity to medications in older adultssensitivity to medications in older adults

Use of lower doses, longer intervals, Use of lower doses, longer intervals, slower titration are helpful in decreasing slower titration are helpful in decreasing the risk of drug intolerance and toxicitythe risk of drug intolerance and toxicity

Careful monitoring is necessary to Careful monitoring is necessary to ensure successful outcomesensure successful outcomes

Optimal PharmacotherapyOptimal Pharmacotherapy

Balance between overprescribing and Balance between overprescribing and underprescribingunderprescribing– Correct drugCorrect drug– Correct doseCorrect dose– Targets appropriate conditionTargets appropriate condition– Is appropriate for the patientIs appropriate for the patient

Avoid “a pill for every ill”Avoid “a pill for every ill”Always consider non-pharmacologic Always consider non-pharmacologic

therapytherapy

Consequences of Consequences of OverprescribingOverprescribing

Adverse drug events (ADEs)Adverse drug events (ADEs) Drug interactionsDrug interactions Duplication of drug therapyDuplication of drug therapy Decreased quality of lifeDecreased quality of life Unnecessary costUnnecessary cost Medication non-adherenceMedication non-adherence

Adverse Drug Events (ADEs)Adverse Drug Events (ADEs) Responsible for 5-28% of Responsible for 5-28% of

acute geriatric hospital acute geriatric hospital admissionsadmissions

Greater than 95% of ADEs Greater than 95% of ADEs in the elderly are in the elderly are considered predictable considered predictable and approximately 50% and approximately 50% are considered are considered preventablepreventable

Most errors occur at the Most errors occur at the ordering and monitoring ordering and monitoring stagesstages

Most Common Medications Most Common Medications Associated with ADEs in the Associated with ADEs in the

ElderlyElderly

Opioid analgesicsOpioid analgesics NSAIDsNSAIDs AnticholinergicsAnticholinergics BenzodiazepinesBenzodiazepines AlsoAlso: cardiovascular agents, CNS : cardiovascular agents, CNS

agents, and musculoskeletal agentsagents, and musculoskeletal agents

Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89.Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89.

The Beers CriteriaThe Beers Criteria

High Potential for High Potential for

Severe ADESevere ADEHigh Potential for High Potential for

Less Severe ADELess Severe ADE

amitriptylineamitriptyline

chlorpropamidechlorpropamide

digoxin >0.125mg/ddigoxin >0.125mg/d

disopyramidedisopyramide

GI antispasmodicsGI antispasmodics

meperidinemeperidine

methyldopamethyldopa

pentazocinepentazocine

ticlopidineticlopidine

antihistamines antihistamines

diphenhydraminediphenhydramine

dipyridamoledipyridamole

ergot mesyloidsergot mesyloids

indomethacinindomethacin

muscle relaxantsmuscle relaxants

Patient Risk Factors for Patient Risk Factors for ADEsADEs

PolypharmacyPolypharmacy Multiple co-morbid conditionsMultiple co-morbid conditions Prior adverse drug eventPrior adverse drug event Low body weight or body mass indexLow body weight or body mass index Age > 85 yearsAge > 85 years Estimated CrCl <50 mL/minEstimated CrCl <50 mL/min

Prescribing CascadePrescribing Cascade

Drug 1

ADE interpreted as new medical condition

Drug 2

ADE interpreted as new medical condition

Drug 3

Rochon PA, Gurwitz JH. Optimizing drug treatment in elderly people: the prescribing cascase. BMJ 1997;315:1097.

Drug-Drug Interactions Drug-Drug Interactions (DDIs)(DDIs)

May lead to adverse drug eventsMay lead to adverse drug events Likelihood Likelihood as number of medications as number of medications Most common DDIs:Most common DDIs:

– cardiovascular drugscardiovascular drugs– psychotropic drugspsychotropic drugs

Most common drug interaction effects:Most common drug interaction effects:– confusion confusion – cognitive impairmentcognitive impairment– hypotensionhypotension– acute renal failureacute renal failure

Concepts in Drug-Drug Concepts in Drug-Drug InteractionsInteractions

Absorption may be Absorption may be or or Drugs with similar effects can result Drugs with similar effects can result

additive effectsadditive effects Drugs with opposite effects can Drugs with opposite effects can

antagonize each otherantagonize each other Drug metabolism may be inhibited or Drug metabolism may be inhibited or

inducedinduced

Common Drug-Drug Common Drug-Drug InteractionsInteractions

CombinationCombination RiskRiskACE inhibitor + potassiumACE inhibitor + potassium HyperkalemiaHyperkalemia

ACE inhibitor + K sparing diureticACE inhibitor + K sparing diuretic Hyperkalemia, hypotensionHyperkalemia, hypotension

Digoxin + antiarrhythmicDigoxin + antiarrhythmic Bradycardia, arrhythmiaBradycardia, arrhythmia

Digoxin + diureticDigoxin + diuretic

Antiarrhythmic + diureticAntiarrhythmic + diureticElectrolyte imbalance; arrhythmiaElectrolyte imbalance; arrhythmia

Diuretic + diureticDiuretic + diuretic Electrolyte imbalance; Electrolyte imbalance; dehydrationdehydration

Benzodiazepine + antidepressantBenzodiazepine + antidepressant

Benzodiazepine + antipsychoticBenzodiazepine + antipsychoticSedation; confusion; fallsSedation; confusion; falls

CCB/nitrate/vasodilator/diureticCCB/nitrate/vasodilator/diuretic Hypotension Hypotension

Doucet J, Chassagne P, Trivalle C, et al. Drug-drug interactions related to hospital admissions in older adults: a prospective study of 1000 patients. J Am Geriatr Soc 1996;44(9):944-948.

Drug-Disease InteractionsDrug-Disease Interactions

Obesity alters Vd of lipophilic drugsObesity alters Vd of lipophilic drugs Ascites alters Vd of hydrophilic drugsAscites alters Vd of hydrophilic drugs Dementia may Dementia may sensitivity, induce sensitivity, induce

paradoxical reactions to drugs with CNS paradoxical reactions to drugs with CNS or anticholinergic activityor anticholinergic activity

Renal or hepatic impairment may impair Renal or hepatic impairment may impair metabolism and excretions of drugsmetabolism and excretions of drugs

Drugs may exacerbate a medical Drugs may exacerbate a medical conditioncondition

Common Drug-Disease Common Drug-Disease InteractionsInteractions

CombinationCombination RiskRisk

NSAIDs + CHFNSAIDs + CHF

Thiazolidinediones + CHFThiazolidinediones + CHFFluid retention; CHF exacerbationFluid retention; CHF exacerbation

BPH + anticholinergicsBPH + anticholinergics Urinary retentionUrinary retention

CCB + constipationCCB + constipation

Narcotics + constipationNarcotics + constipation

Anticholinergics + constipationAnticholinergics + constipation

Exacerbation of constipationExacerbation of constipation

Metformin + CHFMetformin + CHF Hypoxia; increased risk of lactic Hypoxia; increased risk of lactic acidosisacidosis

NSAIDs + gastropathyNSAIDs + gastropathy Increased ulcer and bleeding riskIncreased ulcer and bleeding risk

NSAIDs + HTNNSAIDs + HTN Fluid retention; decreased Fluid retention; decreased effectiveness of diureticseffectiveness of diuretics

Principles of Prescribing in the Principles of Prescribing in the ElderlyElderly

Avoid prescribing prior to diagnosisAvoid prescribing prior to diagnosis Start with a low dose and titrate Start with a low dose and titrate

slowlyslowly Avoid starting 2 agents at the same Avoid starting 2 agents at the same

timetime Reach therapeutic dose before Reach therapeutic dose before

switching or adding agentsswitching or adding agents Consider non-pharmacologic agentsConsider non-pharmacologic agents

Prescribing AppropriatelyPrescribing Appropriately Determine therapeutic endpoints and plan for Determine therapeutic endpoints and plan for

assessmentassessment Consider risk vs. benefitConsider risk vs. benefit Avoid prescribing to treat side effect of another Avoid prescribing to treat side effect of another

drugdrug Use 1 medication to treat 2 conditionsUse 1 medication to treat 2 conditions Consider drug-drug and drug-disease interactionsConsider drug-drug and drug-disease interactions Use simplest regimen possibleUse simplest regimen possible Adjust doses for renal and hepatic impairmentAdjust doses for renal and hepatic impairment Avoid therapeutic duplicationAvoid therapeutic duplication Use least expensive alternativeUse least expensive alternative

Preventing PolypharmacyPreventing Polypharmacy

Review medications regularly and Review medications regularly and each time a new medication started each time a new medication started or dose is changedor dose is changed

Maintain accurate medication Maintain accurate medication records (include vitamins, OTCs, and records (include vitamins, OTCs, and herbals)herbals)

““Brown-bag”Brown-bag”

Non-AdherenceNon-Adherence

Rate may be as high as 50% in the Rate may be as high as 50% in the elderlyelderly

Factors in non-adherenceFactors in non-adherence– Financial, cognitive, or functional statusFinancial, cognitive, or functional status– Beliefs and understanding about disease Beliefs and understanding about disease

and medicationsand medications

Enhancing Medication Enhancing Medication AdherenceAdherence

Avoid newer, more expensive Avoid newer, more expensive medications that are not shown to be medications that are not shown to be superior to less expensive generic superior to less expensive generic alternativesalternatives

Simplify the regimenSimplify the regimen Utilize pill organizers or drug calendarsUtilize pill organizers or drug calendars Educate patient on medication purpose, Educate patient on medication purpose,

benefits, safety, and potential ADEsbenefits, safety, and potential ADEs

SummarySummary

Successful pharmacotherapy means Successful pharmacotherapy means using the correct drug at the correct using the correct drug at the correct dose for the correct indication in an dose for the correct indication in an individual patientindividual patient

Age alters PK and PDAge alters PK and PD ADEs are common among the elderlyADEs are common among the elderly Risk of ADEs can be minimized by Risk of ADEs can be minimized by

appropriate prescribingappropriate prescribing

QuestionsQuestions

Case 1Case 1

A 73 y/o woman is seen for a routine visit:A 73 y/o woman is seen for a routine visit:

• Blood pressure is 134/84 mmHg and HgbA1c is 8.1%Blood pressure is 134/84 mmHg and HgbA1c is 8.1%

• Metformin is increased to 500mg bid and other daily Metformin is increased to 500mg bid and other daily medications are continued: amlodipine 5mg qd, medications are continued: amlodipine 5mg qd, timolol ophthalmic 1 drop ou bid, aspirin 81mg qd, timolol ophthalmic 1 drop ou bid, aspirin 81mg qd, and calcium citrate 500mg qdand calcium citrate 500mg qd

• At 6 month follow-up, blood pressure is 130/82 At 6 month follow-up, blood pressure is 130/82 mmHg, finger stick BS is 93 mg/dL, and HgbA1c is mmHg, finger stick BS is 93 mg/dL, and HgbA1c is 9.2%9.2%

Case 1Case 1

Which of the following is the most Which of the following is the most likely explanation for the increase in likely explanation for the increase in HgA1c?HgA1c?

• Incorrect choice of antidiabetic medicationIncorrect choice of antidiabetic medication• Inadequate dose of antidiabetic medicationInadequate dose of antidiabetic medication• Long-term non-adherence with medicationLong-term non-adherence with medication• Altered pharmacokineticsAltered pharmacokinetics• Altered drug absorptionAltered drug absorption

Case 1Case 1

Which of the following is the most Which of the following is the most likely explanation for the increase in likely explanation for the increase in HgA1c?HgA1c?

• Incorrect choice of antidiabetic medicationIncorrect choice of antidiabetic medication• Inadequate dose of antidiabetic medicationInadequate dose of antidiabetic medication• Long-term non-adherence with medicationLong-term non-adherence with medication• Altered pharmacokineticsAltered pharmacokinetics• Altered drug absorptionAltered drug absorption

Case 2Case 2

A 68 y/o woman has a hx of Parkinson’s A 68 y/o woman has a hx of Parkinson’s disease, hypertension, and disease, hypertension, and osteoarthritisosteoarthritis

• Daily medications are carbidopa 25mg/levodopa Daily medications are carbidopa 25mg/levodopa 100mg tid, selegiline 5mg bid, losartan 50mg, 100mg tid, selegiline 5mg bid, losartan 50mg, celecoxib 200mg qd, and MVI qdcelecoxib 200mg qd, and MVI qd

• In the past 3 weeks, she has taken diphenhydramine In the past 3 weeks, she has taken diphenhydramine at bedtime for insomniaat bedtime for insomnia

• The patient now reports the onset of urinary The patient now reports the onset of urinary incontinenceincontinence

Case 2Case 2

Which of the following is the most Which of the following is the most appropriate intervention?appropriate intervention?

• Discontinue celecoxibDiscontinue celecoxib• Discontinue diphenhydramineDiscontinue diphenhydramine• Discontinue losartanDiscontinue losartan• Substitute fosinopril for losartanSubstitute fosinopril for losartan• Begin tolterodineBegin tolterodine

Case 2Case 2

Which of the following is the most Which of the following is the most appropriate intervention?appropriate intervention?

• Discontinue celecoxibDiscontinue celecoxib• Discontinue diphenhydramineDiscontinue diphenhydramine• Discontinue losartanDiscontinue losartan• Substitute fosinopril for losartanSubstitute fosinopril for losartan• Begin tolterodineBegin tolterodine

Case 3Case 3

An 83 y/o woman is brought to the ER An 83 y/o woman is brought to the ER because of dizziness on standing, because of dizziness on standing, followed by brief LOC; the patient now followed by brief LOC; the patient now feels wellfeels well

• She has hypertension but is otherwise healthyShe has hypertension but is otherwise healthy

• Daily medications: metoprolol 50mg/d, captopril 25 Daily medications: metoprolol 50mg/d, captopril 25 mg/d, and nitroglycerin 0.4mg SL prnmg/d, and nitroglycerin 0.4mg SL prn

• BP is 130/70 mmHg sitting and 100/60 standing; PE is BP is 130/70 mmHg sitting and 100/60 standing; PE is otherwise normal; CBC, BUN, ECG, CMP are all normalotherwise normal; CBC, BUN, ECG, CMP are all normal

Case 3Case 3

Which of the following is the most Which of the following is the most likely cause of this syncopal episode?likely cause of this syncopal episode?

• SepsisSepsis• Drug-related eventDrug-related event• Hypovolemic hypotensive episodeHypovolemic hypotensive episode• Cardiogenic shockCardiogenic shock• Unidentifiable causeUnidentifiable cause

Case 3Case 3

Which of the following is the most Which of the following is the most likely cause of this syncopal episode?likely cause of this syncopal episode?

• SepsisSepsis• Drug-related eventDrug-related event• Hypovolemic hypotensive episodeHypovolemic hypotensive episode• Cardiogenic shockCardiogenic shock• Unidentifiable causeUnidentifiable cause