Pharmacokinetics and pharmacodynamics of drugs used in oral surgery

Aznan Lelo
Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran Universitas Sumatera Utara

6 Juni 2011, KBK FKG USU

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

Pharmacokinetics (PK) and pharmacodynamics (PD)

Plasma Concen tration

Dosage Regimen

Site of Action

Effects

Pharmacokinetics

Pharmacodynamics

Pharmacokinetics
Oral ingestion Extracellular compartment of tissues

Blood

Renal excretion

GI Absorption

V2 Cardiac and Skeletal Muscle

V

Volume 100 L (Vi)

Clearance 10 L/hr

Volume of Distribution = Dose_______ Plasma Concentration

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

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

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 for total daily dose will need multiplying by 24

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.

Therapeutic Index
Therapeutic index = toxic dose/effective dose
This is a measure of a drugs safety
A large number = a wide margin of safety A small number = a small margin of safety

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

Drug Pharmacokinetics in blood

10 Serum Antibiotic Concentration (mcg/mL) 8 6 4 2 0

10

11

12

Time (hours)

Dose

Dose

Pharmacokinetic Parameters
10 Serum Antibiotic Concentration (mcg/mL) 8 6 4 2 0

Concentration present for 50% of dosing interval (6 h if given q12h)

Area under Peakcurve

serum conc.
0 1 2 3 4 5 6 7 8
9 10 11

12

Time (hours)

Dose

Dose

Bacteria by Site of Infection

Mouth
Peptococcus Peptostreptococcus Actinomyces

Skin/Soft Tissue
S. aureus S. pyogenes S. epidermidis Pasteurella

Bone and Joint

S. aureus S. epidermidis Streptococci N. gonorrhoeae Gram-negative rods

Abdomen
E. coli, Proteus Klebsiella Enterococcus Bacteroides sp.

Urinary Tract
E. coli, Proteus Klebsiella Enterococcus Staph saprophyticus

Upper Respiratory
S. pneumoniae H. influenzae M. catarrhalis S. pyogenes

Lower Respiratory Community

S. pneumoniae H. influenzae K. pneumoniae Legionella pneumophila Mycoplasma, Chlamydia

Lower Respiratory Hospital

K. pneumoniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus

Meningitis
S. pneumoniae N. meningitidis H. influenza Group B Strep E. coli Listeria

Important PK/PD Parameters concentration dependent

Area under the curve over MIC

Cmax
MIC

AUC/MIC is the ratio of the AUC to MIC Cmax/MIC is the ratio of the peak concentration to MIC

Antibiotic concentration

Time

Important PK/PD Parameters time dependent

Antibiotic concentration (ug/ml) 8 6 4 2 0
B Drug A

Drug B

Time above MIC Proportion of the dosing interval when the drug concentration exceeds MIC the MIC
A

Time above MIC

Time

Patterns of antibacterial activity

Pattern of Activity Type I Concentration-dependent killing and Prolonged persistent effects Antibiotics Aminoglycosides Daptomycin Fluoroquinolones Ketolides Goal of Therapy Maximize concentrations PK/PD Parameter 24h-AUC/MIC Peak/MIC

Carbapenems Type II Cephalosporins Time-dependent killing Erythromycin and Linezolid Minimal persistent effects Penicillins Type III Time-dependent killing and Moderate to prolonged persistent effects. Azithromycin Clindamycin Oxazolidinones Tetracyclines Vancomycin

Maximize duration of exposure

T>MIC

Maximize 24h-AUC/MIC amount of drug

PD parameters predictive of outcome

Parameter correlating with efficacy
Representative

T>MIC

AUC:MIC

Cmax:MIC

Penicillins Antimicrobial Cephalosporins Carbapenems Agents Macrolides

Azithromycin Fluoroquinolones Fluoroquinolones Aminoglycosides Ketolides Metronidazole Concentrationdependent

Organism kill Time-dependent Concentrationdependent

Therapeutic goal

Optimise duration of exposure

Maximize concentration exposure

Maximize concentration exposure

Drusano & Craig. J Chemother ;9:3844,1997 Drusano et al. Clin Microbiol Infect 4(Suppl. 2):S2741,1998 Vesga et al. 37th ICAAC 1997

Pharmacodynamics of Bacterial Killing

Concentration-dependent (greater bacterial kill at higher concentrations) vs. Concentration-independent (time dependent)

Surgical Inflammatory Pain

functio laesia
tumor

inflammation

rubor calor

pain

acute

chronic

Nociceptive inflammatory pain

phospholipids arachidonic acid
COX-2

COX

COX-1

LOX
5-HPETE

cyclic endoperoxides
PGI2
inhibits platelet aggregation, vasodilator,

TXA2
stimulates platelet aggregation, vasoconstriction

LTA4

hyperalgesia PGD2
inhibits platelet aggregation, vasodilator

LTB4
chemotaxis

PGE2
vasodilator,

PGF2alfa
bronchodilatation myometrial contr.

LTC4 LTD4 LTE4

brochoconstriction increase vascular permeability

hyperalgesia

hyperalgesia

Inflammatory mediator and its actions

Mediator
Pain
Vascular VasoChemo permeability dilatation taxis

Histamine Serotonin Bradykinin +++ Prosta+ glandin Leukotriene

++ +/+++ +++ -

+++ +++

Classification of some major features of pain

Type Acute Subchronic DuraCharaction teristics Seconds Proportional
to the cause
Hours to days Hyperalgesia, Allodynia, Spontaneous pain Hyperalgesia, Allodynia, Spontaneous pain Affective component Nociceptive Neurogenic

Cells
Nociceptive

Adaptive response
Withdrawal, escape Quiescence, Avoidance of contact with injured tissues

Examples
Contact with hot surface Inflammatory wound

Chronic

Months to years

Nociceptive Neurogenic

Psychological Arthritis, CNS and cognitive injury, metastatic disease

Nociceptive Pain
Examples:
Post-surgical metastatic bone pain musculoskeletal pain arthritic pain

What to know
Responds to NSAIDs and Opioids

Factors that modify postoperative pain :

1. Site, nature and duration of surgery. 2. Type and extent of incision. 3. Physiologic and psychologic makeup of the 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 .

Pharmacodynamics of NSAID
Analgesic, anti-inflammatory, antipyretic, platelet inhibitory properties. When prescribed at equipotent doses NSAIDs show similar clinical efficacy Rapidly absorbed PO & highly proteinbound. NSAIDs (unlike narcotics) have a ceiling effect.
Sigmoidal curve
Emerman CL, Spenetta J. EMR reports: Pain Management in the Emergency Department Feb 2002
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

Summary of analgesic, anti-inflammatory and antipyretic activity of NSAIDs (ED50 in mg/kg)

ketorolac naproxen indomethacin ibuprofen diclofenac piroxicam ketorolac naproxen indomethacin ibuprofen diclofenac piroxicam ketorolac naproxen indomethacin ibuprofen diclofenac piroxicam

120 100 80 60 40 20 0 analgesic

60 50

8 7 6

40
30 20 10 0 anti-inflammatory

5 4 3 2 1 0 antipyretic

NSAID ketorolac
indomethacin
diclofenac naproxen ibuprofen piroxicam

Analgesic
0.7

Anti-inflammatory
2

Antipyretic
0.9

3
8 13 45 100

4
7 56 10 3

2.1
0.4 0.5 7 1.7

tenoxicam
aspirin

100
228

5
162

1.7
18

NNT of NSAIDs at different doses

NSAID
Ibuprofen

Dose
50 mg 100 mg 200 mg

NNT
4.7 3.7 2.7

Percent Responders

50 40 30 20 10 0
Placebo

400 mg 600/800 mg
Diclofenac 25 mg 50 mg 100 mg 200 mg

2.5 1.7
2.6 2.7 1.8 4.5
10 8 6 4 2 0

Placebo

C 2x100 C 2x200 C 2x400 Celecoxib Celecoxib Celecoxib 2 x 100 2 x 200 2 x 400

400 mg
600/800 mg

3.7
3.0

Rofecoxib 12.5 mg (n=1215)

Rofecoxib 25.0 mg (n=1614)

Rofecoxib 50.0 mg (n=476)

Incidence of Hypertension as adverse effect of Rofecoxib

Etoricoxib:
efficacy-dose response at 6 weeks

Shibuya RB, 2009

T-max and Onset of action of NSAIDs

Onset NSAID T-max (hr) Rapid Diclofenac 0.8 Nimesulide 1.2 2.7 Slow Celecoxib 24 Meloxicam 6

T-1/2 and Duration of action of NSAIDs

Duration short NSAID Diclofenac Nimesulide Celecoxib Naproxen Meloxicam Etoricoxib T-1/2 (hr) 1.1 1.8 4.7 11 14 20 22

moderate long

NSAID use
Acute inflammatory pain or Breakthrough pain
Short half-life NSAID Ibuprofen, diclofenac, etc

Chronic inflammatory pain

Long half-life NSAID Oxicam, COXIB

COX-1/COX-2 selectivity of NSAIDs

COX-2 selective Pref. COX-2 non selective Pref. COX-1 COX-1 selective

analgesic NNT anti-inflammation

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 withdrawal threshold 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 and sensitization after surgery and that preoperative intrathecal administration of specific COX-1 inhibitors may be useful to treat postoperative pain.

Ng A, Temple A, Smith G, Emembolu J

Early analgesic effects of parecoxib versus ketorolac following laparoscopic sterilization: a randomized controlled trial
British 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 allocated randomly:
After surgery, patients were assessed on awakening and then at 1, 2, and 3 h. Abdominal pain at rest and on inspiration, in addition to nausea and sedation were assessed on a 100 mm visual analogue scale. parecoxib 40 mg i.v. given at induction of anaesthesia was less effective than ketorolac 30 mg i.v., in the first hour after laparoscopic sterilization.
parecoxib 40 mg i.v. or ketorolac 30 mg i.v., at induction.

Ketorolac tromethamine
a member of the pyrrolo-pyrrole group of NSAIDs.
()-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1carboxylic acid, 2-amino-2-(hydroxymethyl)-1,3propanediol.

a racemic mixture of [-]S- and [+]Renantiomeric forms, with the S-form having analgesic activity. Protein binding > 99%, half-life 4 6 hours Hepatic metabolism and renal excretion

Number-needed-to-treat (vs placebo)

Oxford acute pain league table www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html

Lumiracoxib 400 mg Parecoxib iv 40 mg Diclofenac 50 mg Ibuprofen 400 mg Ketorolac 10 mg Morphine im 10 mg Celecoxib 200 mg Paracetamol 1000 mg Tramadol 100 mg

1.7 2.2 2.3 2.4 2.6 2.9 2.9 3.8 5.0

10

95% Cl of the NNT

Boni J, et al. Pharmacokinetic and pharmacodynamic action of etodolac in patients after oral surgery. J Clin Pharmacol. 1999;39(7):729-37. immediate extended release (IR) release (ER) Clearance (L/hr) 3.01 (5.3%) 3.68 (11%) Volume of 13.6 24.3 distribution (L) Ka (per-hour) 2.31 0.172 Parameter

Tissue concentrations of total radiolabeled components at 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 the left front footpad and the left hind paw
Concentration of total radiolabeled components (nmol/g) 1 hour 4 hours 8 hours 24 hours T C T C T C T C
0.79 1.20 1.30 0.18 tc 0.12 0.30 0.10 0.16 0.15 0.20 0.20 tc 0.04 0.10 1.00 1.30 0.84 0.12 nd 0.23 0.5 0.10 tc 0.20 0.04 nd

Tissue
Injection site nape neck Untreated footpads Injection site footpads

nd
nd

nd
tc

nd
nd

Schweitzer A, N Hasler-Nguyen N, Zijlstra J. BMC, 2009

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 Mean sd R vs S R S 545 692 193 286 P <0.05 t-max (min) R S 21.0 23.3 3.0 13.7 NS C-max R S 194 231 68 75 P<0.01 Clearance R S 564 463 210 201 P<0.01

S-bupivacaine
AUC

R
Mean sd

S 1347 442

t-max (min) R S 14.5 6.8

C-max R S 578 101

Clearance R S 465 178

Correlation between absorption, Tmax and onset of action

NSAID short half life NSAID long half life

rapid onset
but short duration

long duration
but slow onset

Concentration

Effective concentration

Time
Acute Slowly Chronic

How to change the onset of action of the long half-life NSAID

NSAID long half life

long duration

Concentration

but slow onset

increased By increasing the dose ???: onset!becomes earlier the dose

but adverse effects enhanced
Effective concentration

Acute

Time Slowly Chronic

Principles of Analgesic Prescribing

WHO Analgesic Ladder

NSAID adjuvant analgesic weak opioid (codeine) Strong opioid NSAID adjuvant analgesic

paracetamol or NSAID adjuvant analgesic

Pain threshold Pain tolerance

10

mild

moderate

severe

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

Reversal Agents
Naloxone and flumazenil available whenever opioids or benzodiazepines administered

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

The pattern of NSAID plasma concentration based on the dose and half-life of drug given
Plasma concentration (mg/L)
1600 1400 1200 1000 800 600 400 200 0 0 2 4 6 8 10 12 14 16 18 20 22 24 500 mg tid, 1500 mg od, 500 mg tid, 1500 mg od, 2 hrs 2 hrs 12 hrs 12 hrs

Drug accumulation 3x11x3 Efek terapeutik Efek samping obat Choose the shortest half-life

Suggested dosages of some NSAIDs for postoperative pain management NSAID

Diclofenac Ibuprofen Flurbiprofen Ketorolac Ketoprofen Naproxen Nimesulide Tenoxicam

Dose

Route

0.7 - 2 mg/kg Oral, Rectal, IM 5 - 10 mg/kg oral 1 mg/kg oral 0.3 0.5 mg/kg IM, IV 1 2 mg/kg IV 4 - 6 mg/kg oral 1.5 mg/kg oral 0.75 mg/kg IM
Kokki H. Pediatr Drugs 5(2):103-23,2003

Cytochrome P450 Phase I Isoenzymes, % Total and Substrate Examples

Isoenzymes CYP1A2 CYP2C9/19 CYP2D6 CYP2E1 CYP3A4 % 17 26 2-4 9-10 35-45 Substrate Olanzapine, Theophylline Phenytoin, Warfarin Codeine, Desipramine, Tramadol Chlorzoxazone, Ethanol Diazepam, Triazolam, Quinidine, Methadone, Carbamazepine

www.drug-interactions.com

Inhibitors of Hepatic Cytochrome P450

1A2 Fluvoxamine Cimetidine Ciprofloxacin 2C9/19 Amiodarone Fluconazole Fluvastatin Fluoxetine Isoniazid Sertraline Omeprazole Cimetidine 2D6 Fluoxetine Paroxetine Quinidine Ritonavir Bupropion Cimetidine 3A4 Erythromycin Azole antifungal Nefazodone Clarithromycin Ritonavir Cimetidine

www.drug-interactions.com

Inducers of Hepatic Cytochrome P450

1A2 Smoking Omeprazole Phenytoin 2C9/19 2D6 Rifampin None Phenobarbital Phenytoin 3A4 Carbamazepine Phenytoin Phenobarbital Rifampin St. Johns wort

www.drug-interactions.com

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

Drug-NSAID PD Interactions
Object Drug Antihypertensives Corticosteroids Diuretics Triamterene Warfarin Interacting Drug Outcome NSAIDs BP NSAIDs risk of PUD NSAIDs diuretic effect Indomethacin K+ NSAIDs anticoagulant effect

Enzyme characteristics Genetic Polymorphism

CY2D6 PM- 5-10% Caucasians, <1% Asians (Also super-fast metabolisers) CYP2C9 PM 1-3% Caucasians CY2C19 PM- 3-5% Caucasians, 15-20% Asians

Pharmacokinetic interactions
Absorption Protein binding P450 interactions
2D6 2C9 2C19 3A4

Renal elimination

CYP2C9
NSAID substrates: celecoxib, diclofenac, etodolac, ibuprofen, indomethacin, meloxicam, naproxen, piroxicam NSAID inhibitors: diclofenac, etodolac*, ketoprofen,
*incredibly weak

CYP2D6
Inhibited by celecoxib Substrates
Beta blockers Antidepressants/antipsychotics Antihistamines Opiates

Clinical significance?

CYP2C19
Inhibited by indomethacin Metabolizes carisoprodol, citalopram, clozapine, diazepam, doxepin, fluoxetine, phenytoin, propranolol Clinical trials are lacking for these interactions!!

CYP3A4
Metabolizes meloxicam, diclofenac Amiodarone, chloramphenicol, clarithromycin, cyclosporine, ethinyl estradiol, azole antifungals, grapefruit inhibit Barbiturates, carbamazepine, phenytoin, rifampin, St Johns Wort induce Lacking studies!!

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

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