2016 winter anesthesia conferencecsa.societyhq.com/meetings/2016winter/guide/syllabus/...thiopental...
TRANSCRIPT
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
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%
Transporter-mediated pharmacokinetic drug interactions:
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
Transporter-mediated pharmacokinetic drug interactions:
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
Pharmacodynamic drug-drug interactions
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 )
Remifentanil (ng-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 )
Remifentanil (ng-mL -1)
Laryngoscopy
Kern: Anesthesiology 2004;100:1373-81
Pharmacodynamic drug-drug interactions
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
Consensus guidelines for the management of postoperative nausea and vomiting Anesth Analg 2014;118:85–113
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
Consensus guidelines for the management of postoperative nausea and vomiting Anesth Analg 2014;118:85–113
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
Tricco: BMC Medicine (2015) 13:136
Network meta-analysis results for vomiting (all ages)
Tricco: BMC Medicine (2015) 13:136
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