2016 Winter Anesthesia Conferencecsa.societyhq.com/meetings/2016winter/guide/syllabus/...thiopental...

Evan Kharasch, MD, PhDRussell D. and Mary B. Shelden Professor of Anesthesiology

Professor of Biochemistry and Molecular BiophysicsWashington University in St. Louis

Adjunct Professor of Pharmaceutical SciencesSt. Louis College of Pharmacy

Director, The Center for Clinical Pharmacology

Drug Interactions2016 Winter Anesthesia Conference

Disclosures:Company ActivityTEN Healthcare ConsultantAstra-Zeneca Grand Rounds lectureMedicines Co Attended a consultants meeting

gabapentin bethanechol acyclovir cream pseudoephedrinecyclobenzaprine clindamycin albuterol inhaler cetirazineoxycodone zolpidem timolol gtt Vit Bmethadone tamsulosin olopatadine gtt multivitaminslevodopa/carbidopa metformin latanoprost gtt calciumfurosemide lansoprazole erythromycin ocular

creamzinc

paroxetine sucralfatecelecoxib trazodonenitrofurantoin fludrocortisonemontelukast hydrocortisonelevothyroxine valacyclovirdiclofenac KClpolyethylene glycol

Oral Prescriptionn=25

Parenteral Prescription

n=6

OTCn=6

A 66 yo female presents for surgery. Medication history:

Anesthesia:The skillful manipulation of drug interactions

to therapeutic advantage

•Avoidance or attenuation of undesirable or dangerous drug interactions

•Conversion of undesirable drug interactions to desirable drug interactions

•Use of desirable drug interactions to therapeutic advantage

Drug interactions in anesthesiology

Drug interactions

Context and importance Terminology Pharmacokinetic drug interactions Pharmacodynamic drug interactions Concept/prototypic examples Clinical examples

http://www.bu.edu/slone/SloneSurvey/AnnualRpt/SloneSurveyWebReport2006.pdf

Patterns of medication use in the United States (2006)

•82% of adults take ≥1 medication per week (non-prescription or prescription drug, vitamin/mineral, herbal/natural supplement)

•29% of US adults take 5 or more per week•Elderly (≥65 yr) are greatest drug consumers:

58% take ≥5 per week, 18% take ≥10 per week, 28% take ≥5 prescription drugs per week

•Polypharmacy (≥5 drugs) has increased since 2000:23% to 29% for medications, 6.3% to 12% for prescription drugs

0

5

10

15

20

25

30

2000 2001 2002 2003 2004 2005 2006Year

% o

f Pop

ulat

ion 5+ medications

5+ Rx drugs10+ medications

Relationship between number of drugs and potential drug-drug interactions in the elderly

Johnell: Drug Safety 2007;30:911-18

631,000 pts ≥75 yr; mean 82 ± 5 yr Swedish Prescribed Drug Register

(Oct-Dec, 2005) 6 ± 4 drugs per person Most common:

antithrombotics, ß-blockers, diuretics, sedative/hypnotics, non-opioid analgesics/antipyretics

DDI focus:Type C (potentially clinically relevant)Type D (potentially serious)

012345678

75-79 80-84 85-89 >89

Age (yr)

# D

ispe

nsed

Dru

gs0

10

20

30

40

2-4 5-7 8-10 11-13 14-16 17-19 >19

# Dispensed Drugs

Per

cen

t

Relationship between number of drugs and potential drug-drug interactions in the elderly

Johnell: Drug Safety 2007;30:911-18

0102030405060708090

2 4 6 8 10 12 14 16 18 20+

# of Dispensed Drugs

DD

Is (

% o

f pa

tient

s)

Type C (potentially clinically relevant)Type D (potentially serious)

Odds Ratio for DDI

# Drugs Type C Type D

2-4 Ref Ref

5-7 4 4

8-10 8 8

11-13 14 13

14-16 20 21

17-19 30 32

≥20 46 56

6 ± 4 drugs per person

Types of Drug Interactions

1. Pharmaceutic (physicochemical incompatability)

2. Pharmacokinetic• absorption• distribution• metabolism• excretion

3. Pharmacodynamic

Consequences of Drug Metabolism

Inactive Prodrug Active Drug Active Metabolite Inactive metabolite Toxic Metabolite

(al, su)fentanyl nor-(al, su)fentanylmethadone EDDPwarfarin 6, 7, 10-OH-warfarinlorazepam lorazepam glucuronideestradiol estradiol sulfatemidazolam 1-OH-midazolam

1-OH-midazolam glucuronidediazepam nordiazepam oxazepam

temazepamoxazepam glucuronide

fospropofol propofol propofol propofol glucuronide

codeinemorphine

morphine morphine-6-glucuronidemorphine normorphine

morphine sulfateL-dopa

dopamine(multiple)

irinotecan SN-38 SN-38 glucuronideAPC, NPC

cyclophosphamide 4-OH-cyclophosphoramide phosphoramide mustard

acrolein

meperidine normeperidineacetaminophen NAPQI

0%

20%

40%

60%

80%

100%

Routes of elimination for the top 200 prescription drugs in the US according to the RxList data April 2008 (www.rxlist.com)

Zanger: Anal Bioanal Chem 2008; 392:1093-108

3A4/5 (37%)

2E1 (1%)2D6 (15%)

2C19 (10%)

2C9 (17%)

1A2 (9%)2A6 (1%)

2B6 (4%)2C8 (6%)

Hepatic

Renal

Primary elimination

routeHepatic enzyme

CYP isoform

Not known

CYP

Other Phase 1:esterasesflavin monooxygnaseN-acetyl transferasemonoamine oxidase

Phase I MetabolismPathways: chemical modification (e.g. hydrolysis, hydroxylation,

demethylation)increases water solubility

Enzymes: cytochrome P450s (CYPs)non-P450 enzymes (Ester and amide hydrolysis)plasma, liver, tissue carboxylesterase, cholinesterase,

pseudocholinesterase, nonspecific esterasesincreasingly important for prodrug formulation

(fospropofol) & ultra-short duration (remifentanil)Location: hepatic & extrahepatic (gut, kidney, lung, blood, others)

Phase II MetabolismPathways: adds endogenous molecule

increases solubility & elimination glucuronidation, sulfation, acetylation, GSH conjugate

Pathways and Enzymes of Drug Metabolism

% of total hepatic P450 % of total intestinal P450

Human Hepatic and Intestinal Cytochrome P450

3A4

2C9

2J2

Rowland-Yeo: Br J Clin Pharmacol 2004;57:687-8Paine: JPET 2006;34:880-6

3A4/52E1

2D62C19

2C91A2

2A6

2B62C8

2D62C19

Oral Administration

IV Administration

intestinal metabolism & transport

Drug metabolism & interactions

portal vein

hepatic metabolism &

transport

Interactions are multiplicative, not additive

Enzyme & transporter induction and inhibition

Induction: Increase in enzyme/transporter activity• Increased content: ⇑ translation or ⇓ degradation• Heteroinduction vs autoinduction• Usually takes several days to become apparent• Active drugs: ⇑ clearance, ⇓ concentration, ⇓ clinical effect• Prodrugs: ⇑ active metabolite formation, ⇑ clinical effect

Inhibition: Decrease in enzyme/transporter activity• Typically occurs by enzyme inhibition (competitive,

noncompetitive, mechanism-based)• May be immediate• Active drugs: ⇓ clearance, ⇑ concentration, ⇑ clinical effect,

potential toxicity• Prodrugs: ⇓ active metabolite formation, ⇓ clinical effect

Induction and inhibition: Oral drugs typically affected more than IV drugs (due to first-pass metabolism)

Anesthetics Undergoing Clinically Significant Metabolism

Sedative-hypnotics Opioids Benzodiazepines

Local Anesthetics NMJ Blockers

propofol fentanyl midazolam lidocaine SUXfos-propofol sufentanil diazepam bupivacaine rocuronium

thiopental alfentanil triazolam ropivacaine vecuroniumetomidate remifentanil alprazolam cocaine (cis)atracurium

ketamine morphine lorazepam mivacuriumcodeine pancuroniumoxycodonehydrocodonehydromorphonemeperidinemethadone

Anesthetic Metabolism by Cytochrome P450

CYP1A2: ropivacaineCYP2A6: halothaneCYP2B6: propofol, methadone, meperidine, ketamineCYP2C19: hexobarbital, diazepamCYP2D6: codeine, dextromethorphan, dihydrocodeine,

hydrocodone, oxycodone, tramadolCYP2E1: halothane, enflurane, isoflurane, sevofluraneCYP3A: lidocaine, bupivacaine, ropivacaine, cocaine

fentanyl, sufentanil, alfentanil, methadone, LAAM, buprenorphine, dextromethorphan,midazolam, triazolam, diazepam, alprazolamcodeine

codeine morphine

norcodeine normorphine

O-demethylation(10%)

CYP2D6

N-demethylation

CYP2D6

CYP3A4 CYP3A4

cytochrome P450 and codeine metabolism/bioactivation

Diminished CYP2D6 activity decreases codeine metabolism to morphine, and decreases analgesia

M-6-G

CYP2D6 drug interactions and codeine metabolism/analgesia

CYP2D6 drug interactions and codeine metabolism/analgesia

0.1

1

10

100

1000Control Quinidine

PlasmaCodeine

CSFCodeine

PlasmaMorphine

CSFMorphine

CYP2D6 inhibition by quinidine

EurJClinPharmacol49:503-9, 1996

codeine (prodrug) morphine (active metabolite)CYP2D6

The CYP2D6 inhibitor paroxetine diminishes tramadol O-demethylation to desmethyltramadol, and reduces the analgesic effect of tramadol

CYP2D6tramadol O-desmethyltramadol (active)

Laugesen: Clin Pharmacol Ther 2005;77:312-23

0

0.05

0.1

0.15

0.2

2 4 6 8

Plas

ma

(+)-O

-de

smet

hyltr

amad

ol (µ

M)

Time (hr)

ControlParoxetine

Tramadol (150 mg) ± paroxetine (20 mg/d) for 3d

0

0.2

0.4

0.6

0.8

1

2 4 6 8

Cold

pre

ssor

pain

Time (hr)

CYP2D6 drug interactions and tramadol metabolism/analgesia

0

0.2

0.4

0.6

0.8

1

2 4 6 8

Plas

ma

(+)-t

ram

adol

(µM

)

Time (hr)

ControlParoxetine

tramadol O-desmethyltramadol analgesia

0

2

4

6

8

10

12

14

16

0 2 4 6 8 10 12

Pla

sma

S-k

etam

ine

(ng/

ml)

Time (hr)

Oral ketamine

Itraconazole(CYP3A inhibitor)

Ticlopidine (CYP2B6 inhibitor)

Rifampin(CYP2B6 inducer)

CYP2B6 drug interactions: Ketamine

Control

Peltoniemi: Clin Pharmacol Ther 2011;90:296-302 Peltoniemi: Basic Clin Pharmacol Toxicol 2012;111:325-32

0

5

10

15

20

25

30

35

40

45

0 2 4 6 8 10 12

Pla

sma

S-k

etam

ine

(ng/

ml)

Time (hr)

Rifampin(CYP2B6 inducer)

Control

IV ketamine

CYP2B6ketamine norketamine

CYP2B6 activity affects ketamine metabolism and ketamine plasma concentrationsOral ketamine is affected more than IV ketamine

Human Cytochrome P450 3A (CYP3A)SubstratesOpioids: fentanyl, sufentanil, alfentanil, methadone,

buprenorphine, codeine, dextromethorphanBenzodiazepines: midazolam, triazolam, diazepam, alprazolamLocal anesthetics: lidocaine, bupivacaine, ropivacaine, cocaineCa channel blockers: verapamil, diltiazem, nifedipine, felodipineImmunosuppressants: cyclosporine, tacrolimusProtease inhibitors: ritonavir, saquinavir, indinavir, nelfinavirMisc: tamoxifen, paclitaxel, ondansetron, statins

Inhibitors (strong, moderate)Macrolides: erythromycin, troleandomycin, clarithromycinAntifungals: ketoconazole, miconazole, itraconazole, fluconazoleCa channel blockers: diltiazem, verapamilProtease inhibitors: ritonavir, saquinavir, indinavir, nelfinavirMisc: grapefruit juice (GI only), many 3A4 substrates

InducersAntiepileptics: phenobarbital, phenytoin, carbamazepineRifamycins: rifampin (prototype), rifabutin, rifapenteneOther: dexamethasone, efavirenz, nevirapine, St. John’s Wort

Time (hr)

0 2 4 6 8 10 12

Mid

azol

am (n

g/m

l)

0

5

10

15

20

25

30

Rifampin

Troleandomycin

Grapefruit JuiceControl

Time (hr)

0 2 4 6 8 10 12

Mid

azol

am (n

g/m

l)

0.1

1

10

100

Troleandomycin

Grapefruit Juice

Control

Rifampin

CYP3A drug interactions: Midazolam

Rifampin: liver and intestine CYP3A induction Troleandomycin: liver and intestine CYP3A inhibitionGrapefruit juice: intestine only CYP3A inhibition

IV midazolam oral midazolam

Kharasch: Clin Pharmacol Ther 2004;76:452-66

15 mg po midazolam

control

itraconazole

rifampin

control

itraconazole

rifampin

Eur J Clin Pharmacol 54:53-8, 1998

CYP3A drug interactions: Midazolam

control

High extractionER = 0.9

Low extractionER = 0.1

Clh = HBF Clh = Clint

fentanyl, sufentanil alfentanil

Not all drugs are created equal: Drug clearance concepts

Clh = Q • ER

Hepatic extraction of drugs used in anesthesia

thiopental methohexital etomidatediazepam midazolam propofollorazepam vecuronium ketaminetriazolam rocuronium bupivacainetheophylline ropivacaine lidocainephenytoin hydromorphone metoprololalfentanil propranololmethadone labetolol

fentanylsufentanilremifentanilmeperidinemorphinenaloxone

Low extraction Intermediate High Extraction(ER < 0.3) (ER 0.3-0.7) (ER > 0.7)

Drug Clearance Concepts

Changes in intrinsic clearance (metabolism) primarily affect low extraction drugs generally do not affect high extraction drugs (except

at profound levels of inhibition)

Changes in hepatic blood flow primarily affect high extraction drugs but only at profoundly decreased hepatic blood flow generally do not affect low extraction drugs

Whether due to disease or drug interactions

Effect of extraction ratio: alfentanil vs fentanyl

Time (hr)

0 4 8 12 16 20 24

Pla

sma

Alfe

ntan

il (n

g/m

l)

0.01

0.1

1

10

100

Time (hr)

0 4 8 12 16 20 24

Pla

sma

Fen

tany

l (ng

/ml)

0.01

0.1

1

10

Control

TAO

Control

TAO

Strong CYP3A inhibition with troleandomycin (TAO)

Renalepithelium

Intestinalepithelium

Hepatocyte

Brain capillary endothelium

Brain

Urine

Blood

Bile

Glomerularfiltrate

Gut Lumen

OAT1-3

OCT1-3

MRP1,3,6

OAT4

PEPT1/2

MRP2,4

P-gpexcretion

reabsorption

PEPT1OATP2B1

BCRPP-gpMRP2

absorption

P-gpBCRP

MRP2

BSEP

MRP3,4,5,6

OCT1

OAT2

OATP1B1/3,2B1

P-gp BCRPMRP1,2,4,5OATP1A2 OATP2B1

OAT3

Blood-brain barrier

MRP1,3

?

MATE1,2BCRP

Active carrier-mediated influx/efflux

Transporter-mediated pharmacokinetic drug interactions:

Tweedie: Clin Pharmacol Ther 2013; 94:113-25Yoshida: Ann Rev Pharm Tox 2013;53: 581-612

Changes in plasma AUC of statins, sartans & antidiabetic drugs after coadministration with cyclosporine A, rifampin, or gemfibrozil

Giacomini: Nature Drug Disc 2010; 9:215-36Konig: Pharm Rev 2013;65:944-66

Transporter Interacting drug Affected drug Clinical PK impact on affected drug

Organic anion transporting polypeptides (intestinal) Grapefruit juice fexofenadine AUC ↓

Organic anion transporting polypeptides (hepatic)

Cyclosporine Pravastatin AUC ↑890%; Cmax ↑678%Cyclosporine Rosuvastatin AUC ↑610%Rifampicin (single dose) Glyburide AUC↑125%Rifampicin (single dose) Bosentan Ctrough ↑500%

Lopinavir/ritonavir Bosentan day 4: Ctrough ↑4700%day 10: Ctrough ↑400%

Lopinavir/ritonavir Rosuvastatin AUC ↑107%; Cmax↑365%Organic anion transporters (renal)

Probenecid Furosemide CLr ↓66%Probenecid Acyclovir CLr ↓32%; AUC ↑40%

Organic cation transporters (renal)

Cimetidine Metformin AUC ↑50%; CLr ↓ 27%Cimetidine Pindolol CLr ↓34%Cimetidine Varenicline AUC ↑29%Cetirizine Pilsicainide CLr ↓41%

P-glycoprotein (gut, liver)Quinidine Digoxin CLr ↓40%Ritonavir Digoxin AUC ↑86%Rifampin Digoxin AUC ↓

Breast cancer resistance protein Elacridar Topotecan AUC ↑143%


Uptake transporterEfflux transporter

Fruit juice can reduce oral bioavailability of drugs relying on GI uptake by organic anion transporting polypeptides (OATPs)

Grapefruit juice Orange juice Apple juice


Dolton: Clin Pharmacol Ther. 2012;92:622-30

Types of Drug Interactions

1. Pharmaceutic (physicochemical incompatability)

2. Pharmacokinetic• absorption• distribution• metabolism• excretion

3. Pharmacodynamic

Terminology

Addition

Combined effect of two drugs given together equals the sum of the effects when each is given alone

Half the dose of drug A plus half an equieffective dose of drug B evokes the same effect as entire dose of A or B alone

2 + 2 = 4

Common mechanism of action

Example: MAC

Terminology

Synergy

Combined effect of two drugs given together is greater than the sum of the effects when each is given alone

2 + 2 = 5

Different mechanism of action

Example: opioid + benzodiazepine - - sedation, respirationmilrinone + epinephrine

Terminology

Potentiation

Enhancement of the effect of one drug by a second drug that has no efficacy of its own

0 + 2 = 4

Different mechanism of action

Example: NMJ blockers & aminoglycosidesepinephrine + local anesthetics

Terminology

Antagonism

Combined effect of two drugs given together is less than sum of the individual effects

0 + 2 < 21 + 2 < 3

Common mechanism of action

Example: opioid agonist + antagonistopioid agonist + partial agonist

Pharmacodynamic drug-drug interactions

synergy

antagonism

dose drug A

dose

dru

g B additivity

All or none response (quantal response)

Egan & Minto

Additive drug interaction Synergistic drug interaction


Graded response

0

20

40

60

80

100

02

46

810

1214

010

2030

4050

% o

f max

imum

stim

ulus

to

lera

ted

Propofol

( ug-mL-1 )

Remifentanil(ng-mL -1)

PressurePain

0

20

40

60

80

100

02

46

810

1214

010

2030

4050

% o

f Max

imum

Stim

ulus

tole

rate

d

Propofol

( ug-mL-1 )

Remifentanil (ng-mL -1)

ElectricalPain

0

20

40

60

80

100

02

46

810

1214

010

2030

4050

Prob

abili

ty o

f bei

ng s

edat

ed (%

)

Propofol

( ug-mL-1 )


Shake & Shout

0

20

40

60

80

100

02

46

810

1214

010

2030

4050

Prob

abili

ty o

f No

Res

pons

eto

Stim

ulus

(%)

Propofol

( ug-mL-1 )


Laryngoscopy

Kern: Anesthesiology 2004;100:1373-81


Multiple graded responses

Pharmacodynamic DDIs: Clinical application

Synergism in anesthetic induction

Propofol dose (mg/kg)

0.2 0.3 0.5 0.7 20.1 1

Pro

port

ion

Unr

espo

nsiv

e

0.0

0.2

0.4

0.6

0.8

1.0 Prop + Alf + Mdz

PropofolProp + AlfProp + Mdz

BJAnaesth 69:162-7, 1992

Opioid (ng/ml)

0 2 4 6 8 10 12

Isof

lura

ne M

AC

(%

)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Conc. for 50% ↓ SchemeOpioid in ISF MAC bolus (µg/kg) Infusion (µg/kg/hr)

fentanyl 1.7 ng/ml 5 2sufentanil 0.14 0.15 0.2alfentanil 29 15 10remifentanil 1.4 0.35 2

Pharmacodynamic interaction betweenopioids and volatile anesthetics:MAC reduction by opioids JClinAnesth 9:18S-22S, 1997

fentanyl

remifentanil

Time (hr)

0 2 4 6 8 10 25

Mio

sis

(mm

)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5ControlCyclosporine

Meissner: Anesthesiology 119:941-53, 2013

Clinical inhibition of brain P-gp by cyclosporine:Effect on morphine pharmacodynamics

CsA 2.5 mg/kg/hr x 2 hrMorphine infusion (1 hr)

CsA-inhibitable efflux transport influences morphine brain access

Postop (Postdischarge) nausea & vomiting (PONV/PDNV)

Risk Factors PointsFemale sex 1History of PONV 1Postop opioids 1Non-smoker 1

Sum 0- - 4

0

20

40

60

80

100

0 1 2 3 4

Ris

k of

PO

NV

(%)

# of Risk Factors

Anesth Analg 2014;118:85–113

Risk score:PONV in adults

Risk Factors PointsFemale sex 1History of PONV 1Postop/PACU opioids 1PACU nausea 1age <50 yr 1

Sum 0- - 5

0

20

40

60

80

100

0 1 2 3 4 5

Ris

k of

PO

NV

(%)

# of Risk Factors

Risk score:PDNV in adults

Risk Factors Pointsage ≥3 yr 1surgery ≥30 min 1strabismus surgery 1Hx of PONV in relatives 1

Sum 0- - 4

Risk score:for PONV in children

0

20

40

60

80

100

0 1 2 3 4R

isk

of P

ON

V (%

)# of Risk Factors

Baseline patient risk factors

Patient considerations:• Fear of PONV• Freq. of PONV causing headache

Anesthetic considerations:Avoid/minimize N2O, volatile anesthetics, post-op opioids

Patient risk

Modified from: Algorithm for management of PONV

Low riskWait & see

High risk>2 interventions; multimodal

Moderate risk1 or 2 interventions

Cost-effectiveness

Consensus guidelines for the management of postoperative nausea and vomiting Anesth Analg 2014;118:85–113

Postop (Postdischarge) nausea & vomiting (PONV/PDNV)

propofol anesthesia

perphenazine

regional anesthesia

scopolamine

Nonpharmacologic: acupuncture

dexamethasone

NK-1 antagonist

droperidol haloperidol

5HT3 antagonist

dimenhydrinate

propofol (subhypnotic

infusion

Portfolio of prophylaxis and

treatment strategies


Postop (postdischarge) nausea & vomiting (PONV/PDNV)

Combination Antiemetic Therapy Combination therapy for PONV prophylaxis and treatment is

preferable to a single drug alone Effects of antiemetics acting on different receptors are additive Efficacy is optimized when a combination of drugs with different

mechanisms of action are administeredMultiple studies confirm effectiveness of combination therapy

with ondansetron, and combination therapy with dexamethasone

Combination therapy with ondansetron and either droperidol or dexamethasone is most widely studied, and more effective than ondansetron alone

Dexamethasone in combination with ondansetron, granisetron, or haloperidol is more effective than these alone


Postop (postdischarge) nausea & vomiting (PONV/PDNV)

Combination Antiemetic Therapy

Adults5-HT3 receptor antagonist + dexamethasone5-HT3 receptor antagonist + droperidol5-HT3 receptor antagonist + dexamethasone + droperidolondansetron + casopitantdroperidol + dexamethasone

Childrenondansetron, 0.05 mg/kg + dexamethasone, 0.15 mg/kgondansetron, 0.1 mg/kg + droperidol, 0.015 mg/kgtropisetron, 0.1 mg/kg + dexamethasone, 0.5 mg/kg

450 studies80,410 patients

Comparative efficacy of serotonin (5-HT3) receptor antagonists in patients undergoing surgery: a systematic review and network meta-analysis

Tricco: BMC Medicine (2015) 13:136

Comparative efficacy of serotonin (5-HT3) receptor antagonists in patients undergoing surgery


Network meta-analysis results for vomiting (all ages)


Network meta-analysis for children only

Treatment comparison - Emesis NMA estimate: OR (95 % CI)

tropisetron vs. placebo 0.18 (0.08–0.41)granisetron vs. placebo 0.23 (0.12–0.48)ondansetron vs. placebo 0.30 (0.24–0.38)dolasetron vs. placebo 0.39 (0.19–0.78)

ondansetron + DEX vs. placebo 0.07 (0.03–0.15)granisetron + DEX vs. placebo 0.09 (0.02–0.31)ondansetron + DROP vs. placebo 0.11 (0.04–0.33)gndansetron + METO vs. placebo 0.18 (0.06–0.53)

ondansetron + DEX vs. ondansetron 0.23 (0.11–0.49)granisetron + DEX vs. granisetron 0.36 (0.09–1.50)ondansetron + DROP vs. ondansetron 0.37 (0.13–1.09)

Comparative efficacy of serotonin (5-HT3) receptor antagonists in patients undergoing surgery

Prevalence of alternative medicine use in surgical patients

JAMA 2000;286:208-16 AnesthAnalg 2001;93:1062-8 JPeranesthesiaNursing 2002;17:170-7

1990: 2% of general population 1997: 12% of general population 2000: 22-32% of surgical patients 2000: 2560 pts, 5 Ca hospitals

67% used ≥ 1 prescription drug 2002: 500 outpts43% used CAM products 39% used CAM product26% Herbals 20% decrease coagulation

echinacea (13%) 14% affect BP ginko biloba ( 9%) 7% have cardiac effects garlic ( 8%) 8% have sedative effectsginseng ( 7%)St John’s wort ( 5%)

15% vitamins7% minerals

11% other (melatonin, antioxidants, etc)

70% of patients do not reveal their herbal use

CYP1A2 Inhibition Chamomile, ginkgo, grapefruit, ipriflavone, kava, red clover, Siberian Ginseng

Induction Evodia, indole-3-carbinol, St. John's wortCYP2C9 Inhibition Devil's claw, feverfew, ginkgo, grapefruit, ipriflavone, kava,

quercetin, red clover, Siberian GinsengInduction St. John's wort, Shisandra

CYP2C19 Inhibition Devil's claw, feverfew, grapefruit, kava, red cloverInduction Ginkgo, St. John's wort

CYP2D6 Inhibition Ginkgo, goldenseal, kava, quercetin, Siberian GinsengInduction

CYP2E1 Inhibition Garlic, kavaInduction

CYP3A4 Inhibition Cat's claw, chamomile, danshen, Devil's claw, evodia, feverfew, ginkgo, goldenseal, grapefruit, Hu Zhang, kava, quercetin, red clover, Shisandra, Siberian Ginseng, valerian

Induction Garlic, ginkgo, St. John's wort, Shisandrab

Selected dietary supplements that interact with CYP450

Abe: Best Pract Res Clin Anaesthesiol 2014;28:183-9

Drug interactions with complementary and alternative medicine

Pharmacokinetic drug interactions with St John’s wort

Zhou: J Psychopharmacol 2004;18:262–76Dresser: Clin Pharmacol Ther 2003;73:41-50

Plasma concentrations after oral midazolam

02468

1012141618

0 2 4 6 8

Plas

ma

mid

azol

am (n

g/m

l)

Time (hr)

Control

St Johns Wort (2 weeks)

Drug Effect of St John’s wort

IV midazolam 1.4-fold increase in clearance

oral midazolam 2.7-fold increase in clearance

oral methadone 2-fold increase in clearance

Tan: Can J Anaesth 2015:62:203-18

Joshi: Best Pract Res Clin Anaesthesiol 2014;28:191-201

Kehlet: The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg 1993;77:1048-56

Multimodal analgesia

Concept: Combining analgesics with different mechanisms or sites of action should lead to improved analgesia, reduced opioid requirements and/or reduced adverse effects

Based on assumed synergistic effects of combinations of systemically and locally administered analgesic drugs Additive analgesia, with sub-additive or diminished toxicity

or Synergistic analgesia, with only additive toxicity

Based almost exclusively on drug interactions which are pharmacodynamic (receptor or post-receptor) not pharmacokinetic (changes in drug concentration)

Kharasch: Anesthesiology 2016;124:10-2

Multimodal analgesia

Lee: Anesthesiology 2015;122:659-65

Central neuraxial, regional, local analgesia

• epidural analgesia• spinal analgesia• regional analgesia

• surgical site infiltration

Systemic Analgesia• opioids (iv, oral, transdermal iontophoretic, sublingual)

• acetaminophen• lidocaine infusion

• NSAIDs• COX-2 inhibitors• NMDA receptor antagonists

• gabapentin • pregabalin• α2 agonists

• capsaicin• glucocortocoids

Non-pharmacologic techniques• acupuncture• music therapy• TENS

Tan: Can J Anaesth 2015:62:203-18Dahl: Acta Anaesthesiol Scand 2014;58:1165-81, 1182-98

Paracetamol, NSAIDs, COX-2 inhibitors, gabapentin seem to have well-documented, clinically relevant analgesic & opioid-sparing properties; pregabalin awaits clarification Benefits may be procedure-specific Studies focus on analgesia & opioid sparing, adverse effects data are insufficientGabapentinoids cause increased sedation, dizziness and visual disturbancesConcurrent administration of opioids with nonopioid sedating medications may

contribute to serious postoperative opioid-induced respiratory depression

No between-group differences in overall pain or morphine consumption Dizziness more pronounced, more severe adverse reactions with high dose gabapentin

Analgesic and sedative effects of perioperative gabapentin in total knee arthroplasty Lunn: Pain 2015;156:2438-48

Outcome Mean [95% CI] Placebo Gabapentin “low dose”

Gabapentin “high dose”

Pain on ambulation at 24hr, VAS (0-100) 42 [37-47] 41 [36-45] 41 [37-46]

Sedation at 6 hr postop, NRS (0-10), 6 h 2.3 [0-9] 2.6 [0-9] 3.2 [0-10]*

300 opioid-naive pts for total knee arthroplasty; randomized to placebo or gabapentin daily from 2 hrpreop to POD 6 in addition to a standardized multimodal analgesia• placebo• gabapentin “low dose” (900 mg/d): 600 mg preop & 300 mg at 2200 on day of surgery, then 300 mg at

0800 & 600 mg at 2200• gabapentin “high dose” (1300 mg/d): 900 mg preop & 400 mg at 2200 on day of surgery, then 400 mg

at 0800 & 900 mg at 2200

*p=0.015

In conclusion, gabapentin may have a limited if any role in acute postoperative pain management of opioid-naive patients undergoing total knee arthroplasty and should not be recommended as a standard of care

placebo

pregabalin

remifentanil

pregabalin+

remifentanilplacebo

pregabalinremifentanil

pregabalin+

remifentanil

Analgesia (cold-pressor)

remifentanil: dose-dependent analgesiapregabalin: analgesiacombination: additive analgesia

remifentanil: dose-dependent depressionpregabalin: no effectcombination: potentiation

Ventilatory depression

Analgesic, ventilatory and cognitive effects of remifentanil and pregabalin combination

The combination of pregabalin & remifentanil had additive analgesia, pregabalin potentiated remifentanil ventilatory depression, and the combination adversely affected cognition. These results question the clinical benefit of the combination compared with higher doses of opioids

Myhre: Anesthesiology 2016;124:141–149

The skillful manipulation of drug interactionsto therapeutic advantage

• use of desirable drug interactions to therapeutic advantage• conversion of undesirable drug interactions to desirable

drug interactions • avoidance or attenuation of undesirable or dangerous drug

interactions• KEY: high index of suspicion, remember OTCs, in-hospital

medications, herbals, and nonconventional routes of administration. A careful history is important

Anesthesia

2016 Winter Anesthesia Conferencecsa.societyhq.com/meetings/2016winter/guide/syllabus/...thiopental...

Documents

Transcript of 2016 Winter Anesthesia Conferencecsa.societyhq.com/meetings/2016winter/guide/syllabus/...thiopental...