20110606-fkg-pharmacokinetics and pharmacodynamics of drugs used in oral surgery akhir

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



0

20

40

60

80

100

120

analgesic



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



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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



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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

20110606-fkg-pharmacokinetics and pharmacodynamics of drugs used in oral surgery akhir

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