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7/30/2019 20110606-Fkg-Pharmacokinetics and Pharmacodynamics of Drugs Used in Oral Surgery AKHIR
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Pharmacokinetics (PK) &
pharmacodynamics (PD)
PK - What the body does to the drug?
Absorption; distribution, metabolism,excretion (ADME)
PD - What the drug does to the body? Drug concentration at the site of action or
in the plasma is related to a magnitude of
effect
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Pharmacokinetics Pharmacodynamics
DosageRegimen
Effects
Plasma
Concen
tration
Site ofAction
Pharmacokinetics (PK) andpharmacodynamics (PD)
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GI Absorption
Blood
Renal
excretion
Pharmacokinetics
Extracellular
compartment
of tissues
Oral ingestion
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V
Volume 100 L (Vi)
Clearance10 L/hr
V2
Cardiac and
Skeletal Muscle
Volume of Distribution =
Dose_______
Plasma Concentration
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Volume of Distribution
An abstract concept
Gives information on HOW the drug is
distributed in the body
Used to calculate a loading dose
Loading Dose
Dose = Cp(Target) x VD
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Clearance Ability of organs of elimination (e.g. kidney,
liver) to clear drug from the bloodstream
Volume of fluid which is completely
cleared of drug per unit time Units are in L/hr or L/hr/kg
Pharmacokinetic term used in
determination of maintenance doses
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Maintenance Dose
Calculation
Maintenance Dose = CL x CpSSav CpSSav is the target average steady state
drug concentration
The units of CL are in L/hr or L/hr/kg
Maintenance dose will be in mg/hr so fortotal daily dose will need multiplying by 24
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Half-Life and k
Half-life is the time taken for the drug
concentration to fall to half its original
value
The elimination rate constant (k) is the
fraction of drug in the body which is
removed per unit time.
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Evaluating antibacterial efficacy using
pharmacokinetics and pharmacodynamics
Pharmacokinetics (PK)
serum concentration profile
penetration to site of infection Pharmacodynamics (PD)
susceptibility MIC (potency)
concentration- vs. time-dependent killing persistent (post-antibiotic) effects (PAE)
Jacobs. Clin Microbiol Infect 2001;7:58996
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Drug Pharmacokinetics in blood
SerumA
ntibiotic
Concentration
0
2
4
6
8
10
0 1 2 3 4 5 6 7 8
Time (hours)
(mcg/mL)
9 10 11 12
Dose Dose
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Pharmacokinetic Parameters
SerumA
ntibiotic
Concentration
0
2
4
6
8
10
0 1 2 3 4 5 6 7 8
Time (hours)
(mcg/mL)
9 10 11 12
Dose Dose
Concentration present for
50% of dosing interval (6 h if
given q12h)
Area undercurvePeak
serum
conc.
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Bacteria by Site of InfectionMouth
PeptococcusPeptostreptococcus
Actinomyces
Skin/Soft Tissue
S. aureusS. pyogenes
S. epidermidis
Pasteurella
Bone and Joint
S. aureusS. epidermidis
Streptococci
N. gonorrhoeae
Gram-negative rods
AbdomenE. coli, Proteus
Klebsiella
Enterococcus
Bacteroides sp.
Urinary TractE. coli, Proteus
Klebsiella
Enterococcus
Staph saprophyticus
Upper RespiratoryS. pneumoniae
H. influenzae
M. catarrhalis
S. pyogenes
Lower RespiratoryCommunityS. pneumoniae
H. influenzae
K. pneumoniae
Legionella pneumophila
Mycoplasma, Chlamydia
Lower RespiratoryHospital
K. pneumoniae
P. aeruginosa
Enterobacter sp.
Serratia sp.
S. aureus
MeningitisS. pneumoniae
N. meningitidis
H. influenza
Group B Strep
E. coli
Listeria
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Important PK/PD Parameters
concentration dependent
Antibiotic
concentrat
ion
Time
Cmax
MIC
Area under the curve
over MIC
AUC/MIC is the
ratio of the AUC
to MIC Cmax/MIC is the
ratio of the peak
concentration
to MIC
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Important PK/PD Parameters
time dependent
Time above MICTime
Ant
ibioticconcentration
(ug/ml)
2
Drug A
B
4
6
8
0
Drug B
A
MIC
Time above MIC
Proportion of the
dosing interval
when the drug
concentration
exceeds
the MIC
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Patterns of antibacterial activity
Pattern of Activity AntibioticsGoal of
Therapy
PK/PD
Parameter
Type I
Concentration-dependent
killing and
Prolonged persistenteffects
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
Maximize
concentrations
24h-AUC/MIC
Peak/MIC
Type II
Time-dependent killing
and
Minimal persistent effects
Carbapenems
Cephalosporins
Erythromycin
Linezolid
Penicillins
Maximize
duration of
exposure
T>MIC
Type III
Time-dependent killing
and
Moderate to prolonged
persistent effects.
Azithromycin
Clindamycin
Oxazolidinones
Tetracyclines
Vancomycin
Maximize
amount of drug24h-AUC/MIC
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PD parameters predictive of outcome
Parameter
correlating
with efficacy
T>MIC AUC:MIC Cmax:MIC
RepresentativeAntimicrobial
Agents
PenicillinsCephalosporins
Carbapenems
Macrolides
AzithromycinFluoroquinolones
Ketolides
FluoroquinolonesAminoglycosides
Metronidazole
Organism kill Time-dependent Concentration-
dependent
Concentration-
dependentTherapeutic
goal
Optimise
duration of
exposure
Maximize
concentration
exposure
Maximize
concentration
exposureDrusano & Craig. J Chemother ;9:3844,1997
Drusano et al. Clin Microbiol Infect 4(Suppl. 2):S27
41,1998Vesga et al. 37th ICAAC 1997
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Pharmacodynamics of BacterialKillingConcentration-dependent (greater bacterial kill at higher concentrations) vs.
Concentration-independent (time dependent)
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Surgical Inflammatory Pain
functio
laesiarubor
calortumor
inflammation
acute chronic
pain
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PGD2inhibits platelet
aggregation,
vasodilator
PGE2vasodilator,
hyperalgesia
PGF2alfabronchodilatation
myometrial contr.
hyperalgesia
PGI2inhibits platelet
aggregation,
vasodilator,hyperalgesia
TXA2stimulates platelet
aggregation,
vasoconstriction
5-HPETE
LTA4
LTB4chemotaxis
LTC4
LTD4
LTE4
brochoconstriction
increase
vascular
permeability
cyclicendoperoxides
phospholipids
arachidonic acid
COX LOXCOX-1COX-2
Nociceptive inflammatory pain
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Inflammatory mediatorand its actions
Mediator Pain Vascularpermeability
Vaso-
dilatation
Chemo
taxis
Histamine - ++ -Serotonin - +/- -Bradykinin +++ +++ -
Prosta-
glandin +
+++ +++
Leuko-
triene- - +++
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Classification of some majorfeatures of pain
Type Dura-tion
Charac-teristics
Cells Adaptiveresponse
Examples
Acute Seconds Proportional
to the cause
Nociceptive Withdrawal,
escape
Contact with
hot surfaceSub-chronic
Hours todays
Hyperalgesia,Allodynia,Spontaneouspain
NociceptiveNeurogenic
Quiescence,Avoidance ofcontact withinjuredtissues
Inflammatorywound
Chronic Months toyears
Hyperalgesia,Allodynia,SpontaneouspainAffectivecomponent
NociceptiveNeurogenic
Psychologicaland cognitive
Arthritis, CNSinjury,metastaticdisease
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Nociceptive Pain
Examples:
Post-surgical
metastatic bone pain musculoskeletal pain
arthritic pain
What to know Responds to NSAIDs and Opioids
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Factors that modify post-
operative pain :1. Site, nature and duration of surgery.
2. Type and extent of incision.
3. Physiologic and psychologic makeup ofthe patient.
4. Pre operative preparation of the patient.
5. Presence of complications of surgery.
6. Anesthetic management.
7. Quality of perioperative care.
8. Preoperative treatment of painful stimuli .
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Pharmacodynamics of NSAID
Analgesic, anti-inflammatory, antipyretic,platelet inhibitory properties.
When prescribed at equipotent doses
NSAIDs show similar clinical efficacy Rapidly absorbed PO & highly protein-
bound.
NSAIDs (unlike narcotics) have a ceiling
effect. Sigmoidal curve
Wang RY, Girard DD, Aleguas A. EMR reports Over-the-Counter (OTC) Medications: A Quick Consult Guide to the Evaluation and
Management of Toxic Effects and Adverse Reactions Part II: Systemic, Oral, and Miscellaneous Preparations Feb 2001
Emerman CL, Spenetta J. EMR reports: Pain Management in the Emergency Department Feb 2002
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Summary of analgesic, anti-inflammatory and
antipyretic activity of NSAIDs (ED50 in mg/kg)
0
10
20
30
40
50
60
anti-inflammatory
ketorolac indomethacin diclofenac
naproxen ibuprofen piroxicam
01
2
3
4
5
6
7
8
antipyretic
ketorolac indomethacin diclofenac
naproxen ibuprofen piroxicam
0
20
40
60
80
100
120
analgesic
ketorolac indomethacin diclofenac
naproxen ibuprofen piroxicam
NSAID Analgesic Anti-inflammatory Antipyretic
ketorolac 0.7 2 0.9
indomethacin 3 4 2.1
diclofenac 8 7 0.4
naproxen 13 56 0.5
ibuprofen 45 10 7
piroxicam 100 3 1.7
tenoxicam 100 5 1.7
aspirin 228 162 18
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NNT of NSAIDs at different doses
NSAID Dose NNT
Ibuprofen 50 mg 4.7
100 mg 3.7
200 mg 2.7400 mg 2.5
600/800 mg 1.7
Diclofenac 25 mg 2.6
50 mg 2.7
100 mg 1.8
200 mg 4.5
400 mg 3.7
600/800 mg 3.0
0
10
20
30
40
50
Placebo C 2x100 C 2x200 C 2x400
PlaceboCelecoxib
2 x 100
Celecoxib
2 x 200
Celecoxib
2 x 400
PercentResponders
Incidence of Hypertension
as adverse effect of Rofecoxib
0
2
4
6
8
10
Rofecoxib 12.5 mg
(n=1215)
Rofecoxib 25.0 mg
(n=1614)
Rofecoxib 50.0 mg (n=476)
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Etoricoxib:efficacy-dose response at 6 weeks
Shibuya RB, 2009
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T-max and Onset of action of
NSAIDs
Onset NSAID T-max (hr)
Rapid Diclofenac 0.8
Nimesulide 1.2 2.7
Slow Celecoxib 2 4Meloxicam 6
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T-1/2 and Duration of action of
NSAIDs
Duration NSAID T-1/2 (hr)
short Diclofenac 1.1Nimesulide 1.8 4.7
moderate Celecoxib 11
Naproxen 14
long Meloxicam 20
Etoricoxib 22
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NSAID use
Acute inflammatory pain or
Breakthrough pain
Short half-life NSAID Ibuprofen, diclofenac, etc
Chronic inflammatory pain
Long half-life NSAID Oxicam, COXIB
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COX-1/COX-2 selectivity of NSAIDs
non
selective
Pref.
COX-2
COX-2
selective
COX-1
selective
Pref.COX-1
anti-inflammation
analgesicNNT
Zh X C kli DR Ei h JC
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Zhu X, Conklin DR, Eisenach JC.
Preoperative Inhibition of Cyclooxygenase-1
in the Spinal Cord Reduces Postoperative Pain
Anesth Analg 00:1390-3,2005 5 minutes before surgery, rats received
intrathecally: the COX-1 preferring inhibitor, ketorolac,
the specific COX-1 inhibitor, SC-560, the specific COX-2 inhibitor, NS-398, or vehicle.
Ketorolac and SC-560 increased withdrawalthreshold to mechanical stimulation, but NS-398
had no significant effect. These results suggest that COX-1 plays an
important role in spinal cord pain processing andsensitization after surgery and that preoperativeintrathecal administration of specific COX-1
inhibitors may be useful to treat postoperative pain.
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Ng A, Temple A, Smith G, Emembolu J
Early analgesic effects of parecoxib versusketorolac following laparoscopic sterilization:
a randomized controlled trialBritish Journal of Anaesthesia, 92(6):846-9,2004
double blind RCT, early postoperative pain. 36 ASA I/II patients who received a standardized general
anaesthetic for laparoscopic sterilization allocatedrandomly: parecoxib 40 mg i.v. or ketorolac 30 mg i.v., at induction.
After surgery, patients were assessed on awakening and
then at 1, 2, and 3 h. Abdominal pain at rest and oninspiration, in addition to nausea and sedation wereassessed on a 100 mm visual analogue scale.
parecoxib 40 mg i.v. given at induction of anaesthesiawas less effective thanketorolac 30 mg i.v., in the first
hour after laparoscopic sterilization.
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Ketorolac tromethamine
a member of the pyrrolo-pyrrole group of
NSAIDs.
()-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-
carboxylic acid, 2-amino-2-(hydroxymethyl)-1,3-propanediol.
a racemic mixture of [-]S- and [+]R-
enantiomeric forms, with the S-form having
analgesic activity. Protein binding > 99%, half-life 4 6 hours
Hepatic metabolism and renal excretion
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Parecoxib iv 40 mg
Diclofenac 50 mg
Ibuprofen 400 mg
Lumiracoxib 400 mg
Ketorolac 10 mg
Morphine im 10 mg
Celecoxib 200 mg
Paracetamol 1000 mg
Tramadol 100 mg
1.7
95% Cl of the NNT
10
5.0
3.8
2.9
2.9
2.6
2.4
2.3
2.2
987654321
Number-needed-to-treat (vsplacebo)Oxford acute pain league table www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html
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Boni J, et al.
Pharmacokinetic and pharmacodynamic
action of etodolac in patients after oralsurgery.
J Clin Pharmacol. 1999;39(7):729-37.
Parameter immediate
release (IR)
extended
release (ER)
Clearance (L/hr) 3.01 (5.3%) 3.68 (11%)
Volume ofdistribution (L)
13.6 24.3
Ka (per-hour) 2.31 0.172
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Tissue concentrations of total radiolabeled componentsat 1, 4, 8 and 24 h after oral administration of
[14C] diclofenac sodium at a dose of 2 mg/kg to male
rats injected with carrageenan (T) or saline (C) into theleft front footpad and the left hind paw
Concentration of total radiolabeled
components (nmol/g)
1 hour 4 hours 8 hours 24 hours
Tissue T C T C T C T C
Injection site
nape neck
0.79
0.120.18
1.20
0.30tc
1.30
0.10tc
0.20
0.04nd
Untreatedfootpads
0.16 0.04
0.20 0.15
0.100.20 tc nd nd nd
Injection site
footpads
1.00
0.230.12
1.30
0.5nd
0.84
0.10nd tc nd
Schweitzer A, N Hasler-Nguyen N, Zijlstra J. BMC, 2009
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Fawcett JP, et al. Comparative efficacy and
pharmacokinetics of racemic bupivacaine and
S-bupivacaine in third molar surgery.
J Pharm Pharmaceut Sci. 2002;5(2):199-204
Rac-bupivacaine
AUC t-max (min) C-max Clearance
R S R S R S R SMean 545 692 21.0 23.3 194 231 564 463
sd 193 286 3.0 13.7 68 75 210 201
R vs S P
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Slowly
Chronic
Correlation between absorption, T-
max and onset of action
Time
Concentratio
n
Effective concentration
Acute
NSAID short half life
rapid onsetbut short duration
NSAID long half life
long durationbut slow onset
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Slowly
Chronic
How to change the onset of
action of the long half-life NSAID
Time
C
oncentrat
ion
Effective concentration
Acute
NSAID long half life
long durationbut slow onset
increasedthe dose !By increasing the dose ???:onset becomes earlier
but adverse effects enhanced
Principles of Analgesic Prescribing
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NSAIDadjuvant analgesic
weak opioid(codeine)
paracetamol
orNSAIDadjuvant analgesic
Strong opioidNSAID
adjuvant analgesic
Principles of Analgesic PrescribingWHO Analgesic Ladder
0 1 2 3 4 5 6 7 8 9 10
Pain tolerancePain threshold
mild moderate severe
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Opioid Pharmacokinetics
Morphine
First-pass metabolism results in poor and
unpredictable bioavailability from oral dosing
30% plasma protein-bound
Detoxification by glucoronidation in liver
Prolonged clearance and lower clearance
rates in infants Half-life decreases with increasing age
High inter-individual variability
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Reversal Agents
Naloxone and flumazenil
available whenever opioids orbenzodiazepines administered
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Dosing issues in children
Children are not little adults
Dosing should not be guided by fears of
addiction
Use of established guidelines as a starting
point
Escalate doses with goal of comfort with
tolerable side effects
Pharmacokinetics
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The pattern of NSAID plasma concentration
based on the dose and half-life of drug given
0
200
400
600
800
1000
1200
1400
1600
0 2 4 6 8 10 12 14 16 18 20 22 24
Plasmaconcen
tration(mg/L) 500 mg tid, 2 hrs
1500 mg od, 2 hrs500 mg tid, 12 hrs
1500 mg od, 12 hrs
Drug accumulation
3 x 1 1 x 3Efek terapeutik Efek samping obat
Choose the sho rtest half-l i fe
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Suggested dosages of some NSAIDs for
postoperative pain management
NSAID Dose Route
Diclofenac 0.7 - 2 mg/kg Oral, Rectal, IM
Ibuprofen 5 - 10 mg/kg oral
Flurbiprofen 1 mg/kg oral
Ketorolac 0.3 0.5 mg/kg IM, IV
Ketoprofen 1 2 mg/kg IV
Naproxen 4 - 6 mg/kg oral
Nimesulide 1.5 mg/kg oral
Tenoxicam 0.75 mg/kg IM
Kokki H. Pediatr Drugs 5(2):103-23,2003
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Cytochrome P450 Phase I Isoenzymes, % Total
and Substrate Examples
Isoenzymes % Substrate
CYP1A2 17 Olanzapine, Theophylline
CYP2C9/19 26 Phenytoin, Warfarin
CYP2D6 2-4 Codeine, Desipramine, Tramadol
CYP2E1 9-10 Chlorzoxazone, Ethanol
CYP3A4 35-45 Diazepam, Triazolam, Quinidine,
Methadone, Carbamazepine
www.drug-interactions.com
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Inhibitors of Hepatic Cytochrome P450
1A2 2C9/19 2D6 3A4
Fluvoxamine Amiodarone Fluoxetine Erythromycin
Cimetidine Fluconazole Paroxetine Azole antifungal
Ciprofloxacin Fluvastatin Quinidine NefazodoneFluoxetine Ritonavir Clarithromycin
Isoniazid Bupropion Ritonavir
Sertraline Cimetidine Cimetidine
Omeprazole
Cimetidine
www.drug-interactions.com
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Inducers of Hepatic Cytochrome P450
1A2 2C9/19 2D6 3A4
Smoking Rifampin None Carbamazepine
Omeprazole Phenobarbital Phenytoin
Phenytoin Phenytoin Phenobarbital
Rifampin
St. Johns wort
www.drug-interactions.com
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Selected Drugs Secreted
by Renal Tubules
Basic (cationic) Agents
Amiodarone
Cimetidine
Digoxin
Procainamide
Quinidine
Ranitidine
Trimethoprim Verapamil
Acidic (Anionic) Agents
Cephalosporins
Indomethacin
Methotrexate
Penicillins
Probenecid
Salicylates
Thiazides
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Drug-NSAID PD Interactions
Object Drug Interacting Drug Outcome
Antihypertensives NSAIDs BP
Corticosteroids NSAIDs risk of PUD
Diuretics NSAIDs diuretic effect
Triamterene Indomethacin K+
Warfarin NSAIDs anticoagulant
effect
En me characteristics
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Enzyme characteristics
Genetic Polymorphism
CY2D6PM- 5-10% Caucasians,
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Pharmacokinetic interactions
Absorption
Protein binding
P450 interactions
2D6
2C9
2C19
3A4
Renal elimination
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CYP2C9
NSAID substrates:
celecoxib, diclofenac, etodolac, ibuprofen,
indomethacin, meloxicam, naproxen,
piroxicam
NSAID inhibitors:
diclofenac, etodolac*, ketoprofen,
*incredibly weak
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CYP2D6
Inhibited by celecoxib
Substrates
Beta blockers
Antidepressants/antipsychotics
Antihistamines
Opiates
Clinical significance?
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CYP2C19
Inhibited by indomethacin
Metabolizes carisoprodol, citalopram,
clozapine, diazepam, doxepin, fluoxetine,
phenytoin, propranolol
Clinical trials are lacking for these
interactions!!
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CYP3A4
Metabolizes meloxicam, diclofenac
Amiodarone, chloramphenicol, clarithromycin,cyclosporine, ethinyl estradiol, azole antifungals,grapefruit inhibit
Barbiturates, carbamazepine, phenytoin, rifampin, StJohns Wort induce
Lacking studies!!
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Renal elimination
Probenecid is a competitive inhibitor of organic
acid transport in the kidney
Get increased levels of NSAIDs by several fold
May lead to decreased effect of probenecid Methotrexate and Lithium may have decreased renal
clearance in the presence of NSAIDs though this may
be attributable to the pharmacodynamic effects of
the NSAIDs
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Inhibition of renal prostaglandins
Loss of BP control with beta blockers, ACE
inhibitors, diuretics
Toxic levels of methotrexate due to decreased
excretion
Toxic levels of lithium due to decreased
excretion
Recommended