Medical Pharmacology by DR Jim Rutkowski

Analgesic Protocol Get the Information
Antibiotics Diabetes Glucocorticosteroids
Anti-coagulant,
Epinephrine Drug
Anti-platelet, Drug Effects on Bone
Interactions
Anti-thrombotic
Top Ten Things to

Bisphosphonates Drugs to Know
Know
James L. Rutkowski DMD, PhD

NON-OPIOID ANALGESICS
James L. Rutkowski, D.M.D., Ph.D.

• COX-1 CONSTITUTIVELY EXPRESSED
• GOOD THINGS – KIDNEY PERFUSION, ANTI-
COAGULATION, VASODILATION, GI PROTECTION
• COX-2 INDUCED BY:

• CYTOKINES, GROWTH FACTORS, ENDOTOXIN
• LEADS TO INFLAMMATION CASCADE

• ANALGESIC
• ANTI-INFLAMMATORY
• ANTIPYRETIC
• INHIBIT CYCLOOXYGENASES
• Prostaglandins
• Thromboxanes

• LACK UNWANTED SIDE EFFECTS OF THE OPIOIDS ON
THE CNS
• RESP. ↓ & PHYSICAL DEPENDENCE
• DO NOT CHANGE THE PERCEPTION OF SENSORY

MODALITIES OTHER THAN PAIN
• CHRONIC POST-OP PAIN OR PAIN FROM

INFLAMMATION IS WELL CONTROLLED BY NSAIDS

• PIROXICAM (FELDENE)
• SULINDAC (CLINORIL)
• KETOROLAC (TORADOL)
• FLURBIPROFEN (ANSAID)
• DICLOFENAC (CATAFLAM)
• IBUPROFEN (MOTRIN)

•NABUMETONE (RELAFEN)
•CELECOXIB (CELEBREX)
•MELOXICAM (MOBIC)
•GONE
• ROFECOXIB (VIOXX)
• VALDECOXIB (BEXTRA)
•COMING SOON
• LUMIRACOXIB (PREXIGE)
• ETORICOXIB (ARCOXIA)

• CROSS HYPERSENSITIVITY
• USUALLY NOT IgE MECHANISM
• SHUNTING TOWARDS LEUKOTRIENE SYNTHESIS

• BRONCHOSPASM & ANAPHYLAXIS
• DO NOT USE ANOTHER NSAID

• USE ACETAMINOPHEN
James L. Rutkowski, D.M.D., Ph.D. 10

•ASPIRIN 650 mg. MORE EFFECTIVE THEN CODEINE 30mg.
• Clinical Pharmacology Therapy 1976
• MORE ANALGESIC EFFICACY
• LESS SIDE EFFECTS

• SUPERIOR TO:
• ASPIRIN 650 MG
• ACETAMINOPHEN 1000MG.
• COMBINATIONS OF ASA/ACETAMINOPHEN AND

CODEINE 60 MG.

• SUPERIOR TO 30 MG.
DIHYDROCODEINE
• COMPARABLE TO ALL OTHER NSAIDS
• FEWER SIDE EFFECTS

• PRE-EMPTIVE ANALGESIA
• INHIBITS THE “FORMATION” OF PROSTAGLANDINS
• HAVE ON BOARD BEFORE START

• DIONNE J. CLIN. PHARMACOL. 1983
• JACKSON, MOORE, JADA 1989

• CURRENT HX
• NEPHROPATHY
• EROSIVE ULCERATION OF GI
• ANTICOAGULANT TX
• HEMORRHAGIC DISORDER
• PRIOR HX OF NSAID/ASA ALLERGY OR INTOLERANCE
• CONCURRENT ANTIHYPERTENSIVE THERAPY (RELATIVE)

• LITTLE EFFECT ON RENAL FUNCTION IN NORMAL PATIENT – FOR SHORT TERM USE
• ↓ RENAL FLOW IN:

• CHF, CIRRHOSIS, CHRONIC RENAL DISEASE,HYPOVOLEMIA
• PROMOTES SALT AND H2O RETENTION

• REDUCES PGE2 -INDUCED INHIBITION OF BOTH THE
REABSORPTION OF CHLORIDE AND ACTION OF ADH
• CAUSES EDEMA
• REDUCES EFFECTIVENESS OF ANTI-HYPERTENSIVES AGENTS

• BINDING OF PGI2, PGE1, AND PGD2 TO PLATELET
RECEPTORS ACTIVATES GS (↑ cAMP – ACTIVATES
KINASES – THE KINASES PHOSPHORYLATE INTERNAL
CALCIUM PUMP PROTEINS - ↓ FREE INTRACELLULAR
CA2+ CONCENTRATION = VASODILATION
• BINDING OF TXA2 TO ITS RECEPTORS (GQ) ACTIVATES

PHOSPHATIDYLINOSITOL METABOLISM – LEADING TO
FORMATION OF IP3, - IP3 BINDS TO CALMODULIN
AND ↑ INTRACELLULAR Ca2+ = VASOCONSTRICTION

•PGE1 & ESPECIALLY PGI2 – INHIBIT PLATELET
AGGREGATION
•TXA2 IS A POTENT PLATELET AGGREGATOR
•PLATELETS RELEASE TXA2 DURING ACTIVATION

AND AGGREGATION

O
RENAL MEDULLA (1 ) AND CORTEX SYNTHESIZE
PROSTAGLANDINS
PROSTAGLANDINS = REGULATION
RENAL CORTEX – PGE2 AND PGI2 - ↑ RENIN RELEASE
PGE1, PGE2, & PGI2 ↑ GLOMERULAR FILTRATION VIA

VASODILATING EFFECTS

•⇑ BP (FLUID RETENTION)
•DIZZINESS
•RASH
•GI IRRITATION (ULCER)
•RENAL PAPILLARY NECROSIS + OTHER RENAL MEDULLARY CHANGES
•LICHEN PLANUS

• T1/2β 2 HR.
• 400 mg. PEAK PLASMA LEVEL 29 ug/ml IN 90 MIN.
• 3ug/ml IN 8 HR.
• NON DETECTED IN 12 HR.
• 17 CHILDREN 2.4 g. ASYMPTOMATIC
• 13 ADULTS UP TO 24 g. NO ILL AFFECTS

Bone Formation

Spinal Fusion/NSAIDS
• In a retrospective study of 83 patients undergoing
spinal fusion, those patients who postoperatively
used NSAIDs for longer than 3 months showed
only 37% fusion rate compared to a 93% fusion
rate in patients not taking NSAIDs
• Deguchi M, Rapoff AJ, Zdeblick TA.
Posterolateral fusion for isthmic
spondylolisthesis in adults: analysis of fusion
rate andclinical results. J Spinal Disord
1998;11:459–64.
COX-2 Effects on Fracture Healing
• The healing of stabilized tibia fractures was delayed in COX-2 knockouts

compared to wild-type animals and to COX-1 knockouts
• In radiographic analysis at 21 days post-fracture normal healing found in:
• 8 out of 10 wild-type mice

• five out of six COX-1 knockouts
• three out of eight COX-2 knockouts
•Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN,O’Keefe RJ.
Cyclooxygenase-2 regulates mesenchymal cell differentiation into the
osteoblast lineage and is critically involved in bone repair. J Clin Invest
2002;109:1405–15.
Indomethacin vs. Coxibs on
fracture healing
• Celecoxib or Rofecoxib evaluated in femur fracture in rats
• All three drugs inhibited fracture healing
• 8 week results healed:

• Control 7/7
• Indomethacin 6/8
• Celecoxib 0/6
• Rofecoxib 0/5
Acetaminophen vs. Celecoxib
Femur fracture repair in rats
• Acetaminophen - no delayed healing

• Celecoxib - impaired healing when observed at
8 weeks
• Bergenstock M, et al. A comparison between the effects of acetaminophen
and celecoxib on bone fracture healing in rats. J Orthop Trauma
2005;19:717-23
Bone formation process
• Ostoclasts ➙ resorption ➙ free up BMPs
• BMPs ➙ osteoblasts ➙ bone formation

Prostaglandins & bone
formation
• PGs ↑ # and activity of osteoclasts = bone resorption
• PGs ↑ replication and differentiation of osteoblasts = bone

formation
• PGs ↑ blood supply through vasodilation & ↑ angiogenesis

• Raisz LG. Prostaglandins and bone: physiology and pathophysiology. Osteoarthritis Cartilage 1999;7:419-21
• Krischak GD etal. The non-steroidal anti-inflammatory drug diclofenac reduces appearance of osteoblasts in bone
defect healing in rats. Arch Orthop Trauma Surg 2007;127:453-8
Cylooxygenases
• COX-1: expressed in normal bone and at bone fracture

sites
• COX-2: up-regulated during initial stages of bone

repair
• Osteoclasts and osteoblasts produce PGs (PGE2)

• Radi ZA et al. Effects of cyclooxygenase inhibition on bone tendon, and ligament
healing. Inflamm Res 2005;54:358-66
Pharmacology Principles
• Dose
• Route of administration
• Duration
Glucocorticosteroids
• Long-term chronic use ↓ COX-2 expession and

therefore PG production
• Result: Bone loss

• Devogelear JP. Glucocorticoid-induced osteoporosis:
mechanisms and therapeutic approach. Rheum Dis Clin
North Am 2006;32:733-57
NSAIDs
• Therapeutic effect achieved by inhibition of

COX-2
• Selective COX-2 inhibitors reduce risk of GI

adverse events
• ? - Will these drugs impact bone healing

COX-2 effect on bone
healing
• Abundant experimental data suggest that non-

selective NSAIDs delay fracture healing.
(Vuolteenaho K, et al. Non-steroidal Anti-
Inflammatory Drugs, Cycloxxygenase-2 and the
Bone Healing Process)
A-HA study
• Non-selective naproxen and Cox-2 selective rofecoxib - harvest

chamber implanted in rat tibia
• ↓ bone formation observed at 4 weeks

• Effect was dependent upon duration of treatment
• 2 week course at the beginning or at the end of a 6 week harvest
period did not inhibit bone ingrowth to the same degree as did
continuous treatment (Pharmacology principle)
• Goodman Sb, et al. Temporal effects of a COX-2-selective NSAID on bone ingrowth. J Biomed Mater Res A
2005;72:279-87
• Goodman SB, et al. Cox-2 selective NSAID decreases bone in growth in vivo. J Orthop Res 2002;20:1162-9
Semi-selective COX-2
• Etodolac at 3 time frames

• Group 1: treatment for the entire 3-week duration
• Group 2: treatment for the first week
• Group 3: treatment for the final third week
• Results: Impaired healing for groups 1 and 2 only

• Endo K, et al. Cyclooxygenase-2 inhibor delays fracgtue healing in rats. Acta Orthop
2005;76:470-4
Celecoxib - Treatment time
• Impaired femoral fracture healing in rats when

administered during the first 2 weeks after fractue
• No significant effect when administered starting

14 days later
• Simon AM, et al. Dose and time-dependent effects of cyclooxygenase-inhibition on
fracture-healing. J Bone Joint Surg Am 2007;89:500-11
Selective and nonselective cyclooxygenase-2 inhibitors and
experimental fracture-healing. Reversibility of effects after short-
term treatment
• ED50 doses used of ketorolac (non-selective) and valdecoxib (COX-2 selective) for
either 7 or 21 days after fracture in rats
Text
• 7-day treatment produced a trend for nonunion fracture healing for both ketorolac
and valdecoxib
• 21-day treatment produced significantly nore non unions in the valdecoxib group vs
ketorolac or controls
• PGE2 levels decreased but if drugs d/c after 6 days the levels of PGE2 rebounded
2-fold by day 14
• Gerstenfel LC, Eet al. Selective and nonselecxtive cyclooxygenase-2 inhibitors and experimental fractue-healing. Reversibility of
effects after short-term treatmen. J Bone Joint Surg A, 2007 Jan;89:(21): 114-25
Flurbiprofen - a friend
• The Effect of Systemic Flurbiprofen on Bone Supporting Dental
Implants. Jeffcoat MK et al. JADA Vol 126 March 1995: 305-11
• Observed alveolar bone changes surrounding mandibular dental implants in 29

patients at 6, 9, and 12 months after implant placement to determine the effect of
the flurbiprofen treatment on the implant’s success or failure
• Digital subtraction radiography as measurement tool
• Group 1: placebo BID
• Group 2: 50 mg flurbiprofen BID
• Group 3: 100 mg flurbiprofen BID
• Dosing began on day of implant surgical placement

Results
• Significant changes in bone height occurred

following exposure and loading of the implant,
between the 3rd and 6th months of the study
Results
Results
• PUT FIGURE 3 PAGE 308 JADA ARTICLE HERE

Results
Conclusion
• The basic pathophysiology and pharmacokinetics underlying
the effect(s) of NSAIDs on bone could be used to support either
positive or negative effects on bone.
• THINK ABOUT THIS:

• Excessive PGE2 formation can result in bone loss
• Controlling PGE2 formation may be good
• However, PGE2 in the right concentration promotes bone

formation
• What should we do?

Conclusion
• This study provides preliminary data that

suggest that systemic administration of
flurbiprofen may reduce bone loss around dental
implants in the first year of service
Case: 62 yr. Old Caucasian
Osteoarthritis
• Meloxicam (Mobic™) 15 mg/day for past 3 years
• Mechanism of Action: Reversibly inhibits

cyclooxygenase-1 and 2 (COX-1 and 2) enzymes,
which results in decreased formation of prostaglandin
precursors; 10:1 preference for COX-2 over COX-1
July 12, 2010
July 12, 2010
July 12, 2010
July 19, 2010
August 2, 2010
December 9, 2010
December 9, 2010
December 9, 2010
December 9, 2010
December 9, 2010
December 9, 2010
December 9, 2010
December 16, 2010
No Mobic: March-April 2012
Agents with Periodontal Regenerative Potential Regulate
Cell-mediated Collagen Lattice Contraction in vitro
Ref. MacNeil RL et al. Agents with Periodontal Regenerative Potential Regulate Cell-mediated Collagen
Lattice Contraction in vitroy J Dent Res 75(3):903-11 March 1996
• In vitro study that examined effects of TGF-β1, PDGF, and IGF-1;

indomethacin ibuprofen, naproxen, and flurbiprofen; and
alcohol on cell-mediated gel contraction
• Represents in vivo wound contraction and remodeling

• Results:
• TGF-β1, PDGF, and IGF-1 promoted cell-gel contraction -
similar to wound healing
• NSAIDs inhibited cell-gel contraction
• Alcohol inhibited cell-gel contraction

Arachidonic
Acid
PRP
IL-1α
NSAIDs
TGF-β1
Chronic PDGF-BB
PGE2 VEGF
OPG
Bone Formation
• Limit routine NSAID use to 5 days thereafter PRN
and/or switch to Acetaminophen with/without
narcotic
• Use a non-specific COX inhibitor
• Use PRP

• Use Flurbiprofen 50 – 100 mg twice a day
• Bone. 1989;10(1):35-44
• J Oral Implantol. 1990;16(4):272-6
• Monitor patients blood pressure
• Take “Drug-Free” holidays

• MOST DENTAL PAIN IS DUE TO INFLAMMATION
• NSAIDS HELP PREVENT THIS CASCADE
• 1ST LINE OF ANALGESIA
• OFTEN SUPERIOR TO OPIOIDS
• IF CONTRA. THEN ACETAMINOPHEN

• 81 MG. INHIBITS THROMBOXANES, BUT NOT
PROSTACYCLIN (PGI2)
• SO PREVENTS CLOTTING AND STILL

ALLOWS VASODILATION AND PREVENTION
OF PLATELET CLUMPING

• 325 MG. PREVENTS CLOTTING BY
THROMBOXANES
• BUT THERE IS MUCH MORE TBX2 DUE TO

RELEASE FROM MONCYTES AND
EOSINOPHILS

•PROSTAGLANDIN PATHWAYS IN CNS - COX-3 INHIBITOR
•LITTLE PERIPHERAL INFLUENCE
•LITTLE ANTI-INFLAMMATORY
•NONE OF NSAID PERIPHERAL SIDE EFFECTS

• ONLY INHIBITS CYLCOOXYGENASE IN AREAS
OF LOW PEROXIDE FORMATION
• HYPOTHALAMUS
• SITES OF INFLAMMATION USUALLY HAVE

HIGH PEROXIDES GENERATED BY
LEUKOCYTES
•REF. MARSHALL 1987

• EQUAL IN POTENCY AND EFFICACY TO
ASPIRIN
• ∴ INFERIOR TO IBUPROFEN AND OTHER

NSAIDs

• HEPATOTOXICITY
• TOXIC DOSE 10-15 Grams
• LOWER TOXICITY IF:
• DEPLETED GLYCOGEN
• CHRONIC ALCOHOLISM MAX. DAILY DOSE IS 2 Grams

VS NORMAL 4 Grams

NAPQI=Toxic!
NAPQI + Glutathione = Non-
toxic
Chronic alcohol consumption =
↑ CYP2E1, ↓ Glutathione
Alcohol + Acetaminophen= NAPQI
Acetaminophen = ↑↑ NAPQI
↑↑ NAPQI ! Hepatotoxicity
The enzyme that metabolizes acetaminophen to its toxic metabolite is CYP2E1. This same
enzyme metabolizes ethanol. Ethanol can increase CYP2E1 and decrease
Glutathione concentrations , potentially leading to more NAPQI formed.
Hass D. Adverse Drug Interactions in Dental Practice. JADA 1999;130:397-407

Test ?
1. Which Cyclooxygenase enzymes provide
prostoglandens that result in good things when they land
on their receptors?
A. Cox-1
B. Cox-2
C. Cox-3
D. Cox-4
Test ?
2. You are planning to do an all-on-4 procedure for a 72 year old female
patient who takes Celebrex BID. How should this drug be managed
during the surgical phase?
A. Discontinue the Celebrex one week prior to the surgery and for at
least 2 weeks post-operatively
B. Discontinue the Celebrex on the day of surgery, but restart after 3

days.
C. Make no changes in the patients Celebrex use
D. D/C the Celebrex and put the patient on oxycodone for the arthritic
pain and Colace for the constipation
Test ?
3. Your 58-yo patient presents with an abscessed mandibular left 1st
molar and he rates the pain as a 10 on the scale of 1-10. He has a
history of drinking 4 to 6 Bud Lights each evening. He also takes
Paxil (SSRI) and Tagamet. The best pain medication for this
patient is:
A. An NSAID plus acetaminophen 1 gram every 6 hours and have him stop drinking the alcohol
B. Oxycodone with acetaminophen and have him stop drinking the alcohol
C. Hydrocodone with acetaminophen 1 gram every 6 hours and have him continue drinking the
alcohol
D. An NSAID plus acetaminophen 500 mg every 6 hours and have him continue drinking the Bud
Light
ANALGESIC PROTOCOL
•NON-OPIOIDS AND OPIOIDS

ANALGESIC REGIMENS
•STEP 1
– START WITH IBUPROFEN 600 MG. ONE HOUR PRE-OP
•STEP 2
– CONTINUE IBUPROFEN 600 MG. Q 6 HRS FOR 3-5 DAYS OR
FLURBIPROFEN 100 MG BID FOR 3 TO 5 DAYS
•STEP 3
– IF IBUPROFEN IS NOT CONTROLLING PAIN THEN ADD
ACETAMINOPHEN 500-1000 MG. Q 6 HRS.
ANALGESIC REGIMENS
•STEP 4
•ADD A NARCOTIC + ACETAMINOPHEN
COMBINATION DRUG (i.e. Lortab 10/500) one
or two tablets q 4 to 6 hrs as needed.
•Discontinue the previously prescribed

individual acetaminophen
ANALGESIC ADJUVANTS
•TRI-CYLIC AND ATYPICAL ANTIDEPRESSANTS

HAVE BENEFIT
•TRAMADOL (ULTRAM)
•OPIOID AND ANTIDEPRESSANT
•PARENT DRUG LIKE TRI-CYLIC ANTIDEPRESSENT
•METABOLITE –m1- WEAK AGONIST ON MU
RECEPTORS
•GOOD FOR CHRONIC PAIN
ANALGESIC ADJUVANTS
•CAFFEINE
•INCREASES POTENCY OF ASA & TYLENOL,
BUT NOT THE EFFICACY
ANALGESIC ADJUVANTS
•SEDATIVE/ANXIOLYTICS
• NO BENEFIT TO ANALGESIC EFFICACY
• ANTIEMETICS
• USE TO TX N & V OF OPIOIDS
• CANNOT PREVENT N & V OF OPIOIDS

ANTIBIOTICS
• MANAGE ORO-FACIAL INFECTIONS
• PROPHYLAXIS

Antibiotic Usage
Reference: Pharmacology and Therapeutics for Dentistry
• Most widely abused prescribed drugs on

the basis of
• Inappropriate indications
• Inappropriate dosages
• Duration of use

Questions - we need answers
1. What are the empiric antibiotics of choice

1.1.contemporary double blinded trial comparing all of the relevant antibiotics in a
large, multicenter, North American population of patients with well-defined OI,
combined with appropriate surgical treatments, would be ideal
2. How long should the treatment choice last?

2.1.study of the duration of the antibiotic treatment course, with its
long-term effects on selection for antibiotic-resistant bacteria,
would provide the answer
Ref . Flynn Oral Maxillofacial Surg Clin N Am 23 (2011) 519–536

Antibiotic Usage
• 1/2 all antibiotics given in hospitals are to
patients without signs of infection
• Mainly to prevent infections
• To cover errors of omission or commission
• Prevent a claim of negligence
• Reference: Pharmacology and Therapeutics for
Dentistry

Antibiotic Usage
• “80:80” rule: 80% of the antibiotics are used in
the community and of that 80% are used for
respiratory infections
• Of the 50% of the patients with acute

respiratory illness - 80% receive an antibiotic -
however, pneumonia is the only respiratory
disorder that requires and antibiotic accounts
for only 2% of the cases

Antibiotic Usage - Dentistry
• Dentists prescribe 7 to 11% of all common

antibiotics: β-lactams, macrolides, tetracycline,
metronidazole, clindamycin
• England: 33 to 87% antibiotic usage by
Dentists deemed unnecessary

Inappropriate Antibiotic
use in Dentistry
1. Initiated after surgery to prevent an
infection unlikely to occur
2. Failure use antibiotics according to the
principles established
3. Used as analgesics in endodontics

use in Dentistry
4. Overuse in situations in which patients are not at
risk for metastatic infections
5. Treatment of chronic periodontitis that is almost
totally amenable to mechanical therapy
6. Administration of antibiotics instead of mechanical
theapy for periodontitis
7. Long-term administration in the management of
periodontal disease

use in Dentistry
8. Antibiotic therapy insead of incision and
drainage
9. Administration to avoid claims of
negligence
10.Administration in improper situations,
dosage, and duration of therapy

Antibiotics Mechanism of Action
• Most often derived from

yeasts and fungi
• Only 3 synthetics:
sulfonamides,
fluoroquinolones,
oxazolidinones

Antibiotics
• ANTIBIOTIC EFFECTIVENESS
• MIC-90
• SERUM CONCENTRATION
NEEDED TO INHIBIT 90% OF THE
SPECIES OF A MICRO-ORGANISM
• PEAK SERUM LEVEL

• SERUM HALF LIVE (T1/2) 2

3

Bacteria – the problem
• > 400 known morphologic and biochemically
distinct bacterial groups that colonize in the
oral ecological niche
• Mixed gram (+) aerobic and gram (+) and (-)

anaerobic polymicrobial bacteria
• Anaerobes normally out # aerobes by 10:1 or

100:1
• Infectious microorganisms are usually native

to the host’s normal flora
4

Oro-facial Infections
• Streptococci viridans
• Prevotell, Porphyromonas, Fusobacerium,
Peptostreptococcus, Eubacterium,Veillonella,
actinomyces
• Polymicrobial (2-8 species/infection)
• Precise etiologic microbe identity almost
impossible

Otitis Media and
Sinusitis
• Otitis media and sinusitis are almost
always associated with Streptococcus
pneumoniae, Moraxella catarrhalis, or
Haemophilus influenzae,
• Infections usually one of the three

pathogens
• Yagiela, John A.; Dowd, Frank J.; Johnson, Bart; Mariotti, Angelo;
Neidle, Enid A. (2010-03-19). Pharmacology and Therapeutics for
Dentistry (Kindle Locations 37827-37828). Elsevier Health. Kindle
Edition.

Oro-facial
infections
• Associated with viridans group streptococci (VGS),
Prevotella, Porphyromonas, Fusobacterium,
Peptostreptococcus, Eubacterium,Veillonella, and
Actinomyces.
• Infection usually associated with 2 to 8 or more

pathogens
• Yagiela, John A.; Dowd, Frank J.; Johnson, Bart; Mariotti, Angelo; Neidle, Enid A.
(2010-03-19). Pharmacology and Therapeutics for Dentistry (Kindle Locations
37828-37829). Elsevier Health. Kindle Edition.

Probiotics
• Live microorganisms that confer
a health benefit to the host
• Lactobacillus rhamnosus GG +
Bifidobacterium strains +
Saccharomycs boulardii

Beta-lactams
• Penicillin •Amoxicillin
• Only indicated for minor • Better bioavailability
infections – this includes dental • Downside
abscesses •Beta-lactamases inactivate
•Add Clavulanic acid
• Ampicillin •Multiple resistant
• Greater activity against gram (-) bacterial strains
because it penetrates the gram
(-) cell membrane
• Downside
• Beta-lactamases inactivate
• Multiple resistant bacterial strains

Resistance to Penicillin
1. Inactivation by β-lactamase
2. Gram (-) permeability barrier that
prevents penicillins from entering the
cell
3. Confirmation changes in the PBP
structure (MRSA)

Penicillin Allergy
• Allergic reactions to penicillins common
• allergic fatalities are far less common.
• Penicillins allergies ranges from 0.7% to 8%
(average of 2%)
• Most allergic manifestations are

maculopapular or urticarial skin reactions.
• Yagiela, John A.; Dowd, Frank J.; Johnson, Bart; Mariotti, Angelo; Neidle, Enid A. (2010-03-19).
Pharmacology and Therapeutics for Dentistry (Kindle Locations 38595-38599). Elsevier Health.
Kindle Edition.

• Penicillin most common cause of
anaphylactic death in the United States,
accounting for 75% of all cases and 400 to
800 annual deaths.
• Penicillin-induced anaphylaxis is most
common in adults 20 to 49 years old.
• Yagiela, John A.; Dowd, Frank J.; Johnson, Bart; Mariotti, Angelo; Neidle,
Enid A. (2010-03-19). Pharmacology and Therapeutics for Dentistry
(Kindle Locations 38600-38608). Elsevier Health. Kindle Edition.

• Estimates of severe penicillin anaphylaxis range
from 0.004% to 0.015% of individuals exposures
• Based upon number of exposures, 1 in 1200 to 1 in

2500 penicillin exposures.
• Fatality rate from penicillin anaphylaxis by all routes

of administration: 1 in 60,000 patient courses (16
per 1 million),
Kindle Edition.

MULTIPLE ANTIBIOTIC ALLERGY SYNDROME
• Constitute 1% to 4% of all patients who

have taken multiple antibiotics
• Serious adverse drug reactions such as
anaphylaxis with antibiotics are rare except
for the β-lactams.
Edition.

• Some difficulties with the health history

• patients may confuse any adverse drug reaction with
“allergy,”
• rarely are any of these “allergies” confirmed by skin

testing
• often the patient’s history is nebulous

Pharmacology and Therapeutics for Dentistry (Kindle Locations 38678-38688). Elsevier
Health. Kindle Edition.

• Management of such patients requires a detailed

medical history, including
• when during the treatment the reaction

occurred
• what infectious disease was being treated
• what doses of antibiotics were taken and for

how long, and, most important
• what were the signs and symptoms
Kindle Edition.

MULTIPLE ANTIBIOTIC ALLERGY
SYNDROME
• Determine the signs and symptoms of an acute IgE-mediated allergic reaction—rash,
angioedema, bronchospasm, and syncope
• Time between drug ingestion or administration and onset of symptoms
• If the onset of signs and symptoms occurred within 1 hour of ingestion or

administration, it was likely an immediate allergic reaction
• Possible skin test (reliable only for β-lactams) is indicated and a specific
management plan.
• Comorbid conditions that may increase the incidence of allergy in general are
atopic disease (asthma, eczema), chronic urticaria, nonsteroidal anti-
inflammatory drug (NSAID) intolerance, immunosuppression, human
immunodeficiency virus (HIV) positivity, and a history of multiple antibiotic use.
66
• Yagiela, John A.; Dowd, Frank J.; Johnson, Bart; Mariotti, Angelo; Neidle, Enid A. (2010-03-19). Pharmacology and
Therapeutics for Dentistry (Kindle Locations 38678-38688). Elsevier Health. Kindle Edition.

Cephalosporins
• Broader spectrum than β-lactams
• More stable to β-lactamases
• 1st generation (cephalexin): gram (+) activity and
anaerobes sensitive
• Later generations (Cefaclor, Cefotaximer,

Cefepine): improved gram(-) activity
• Less expensive than Augmentin®

• Less bacterial resistance
Cephalosporins
• Most effective treatment for sinusitis

• Cellulitis + other soft tissue infections

Tetracyclines
• Broad spectrum
• Bacteriostatic for many gram (+) and (-)
aerobes and anaerobes
• Bound to developing teeth and bones

• Inhibits bone growth
• Used to treat Helicobacter pylori (HP) in
7

TETRACYCLINES
• OPPORTUNISTIC CANDIDA INFECTIONS

• SUN SENSITIVITY

Tetracyclines
• Doxycycline (Vibramycin)
• MOA: inhibit protein synthesis by preventing

aminoacyl transfer RNA from entering the
acceptor sites on the ribosome
• Dose: 100 mg 1 or 2 a day for 14 days
• Contraindications:
• Food
• Pregnancy - Category D
• Adverse events: GI
• Drug interactions: anti-epileptics

Macrolides
• Erythromycin
• Gram (+) and Gram (-) activity
• Low doses bacteriostatic
• High doses bactericidal
• Suitable alternative for penicillin allergic pt.
9

What’s Good
• Property of macrolides and highly fat-

soluble tetracyclines and clindamycin is
selective uptake by phagocytic cells and
fibroblasts, which function as repository
drug depots and as a drug delivery system
to areas of inflammation and infection
Neidle, Enid A. (2010-03-19). Pharmacology and Therapeutics
for Dentistry (Kindle Locations 39167-39172). Elsevier
Health. Kindle Edition.

• Phagocytic and fibroblasts cells concentrate the
macrolides and then transport them to areas of tissue
pathology where they are released for their anti-infective
and anti-inflammatory properties
• Tissue concentrations of azithromycin may reach 100 to

1000 times that of blood and persist long after blood
levels have declined because of their significant
postantibiotic effects
• The tissue concentration of azithromycin may exceed the

microorganism’s MIC for 2 to 10 days, and the elimination
1/2 life in abscesses is 4 days
Edition.

Macrolides
• Drug interactions (inhibits P450 enzymes in liver)
• Increases serum concentrations
• Theophylline, warfarin, cyclosporine,
methylprednisolone, digoxin
• Decreases activity
• Plavix
9

Macrolides
• Clarithromycin (Biaxin®)
• Greater acid stability and oral absorption
• Twice day dosing
• Major metabolite (14-hydroxyclarithomycin) has antibacterial

activity also
• Decreased GI intolerance
• Downside
• Expensive
• CLARICOR study 500 mg daily for 14 days ↑ mortality in pts.

with stable coronary artery disease

Macrolides
• Azithromycin
• Less activity against staphylococci and

streptococci
• Greater activity against HP
• Penetrates tissues better (exceeding serum

concentration by 10 – 100 fold)
• Slowly released from tissues with a tissue half-life

of 2 to 4 days and an elimination half-life of 3
days.

• Most attractive aspect of azithromycin is a 15-
member lactone ring as opposed to the
shoddy 14-member lactone ring of
erythromycin and clarithromycin!
• Why?
• The 15 member ring does not inhibit P450
enzyme activity and therefore azithromycin
is free of the multiple drug interactions!!!
12

Macrolide Adverse Effects
• Serious adverse reaction associated with macrolides, particularly
erythromycin, is potentially severe epigastric pain resulting from
stimulation of the gastric smooth muscle motilin receptor
• Motilin is a regulatory peptide of the gastrointestinal tract that

stimulates enzyme secretions by the stomach and pancreas and
induces strong phasic contractions of the stomach
• Most significant agonists of the motilin receptor are the 14-

membered macrolides (erythromycin); azithromycin and
clarithromycin are lesser stimulants.
• Yagiela, John A.; Dowd, Frank J.; Johnson, Bart; Mariotti, Angelo; Neidle, Enid A. (2010-03-19). Pharmacology and
Therapeutics for Dentistry (Kindle Locations 39204-39208). Elsevier Health. Kindle Edition.

Azithromycin
• FDA warning Heart Risks March 2013
• May cause prolonged cardiac repolarization and
QT interval
• High risk patients: history of existing QT-interval

prolongation torsade de pointes, congential long
QT syndrome, uncompensated heart failure,
hypokalemia, hypomagnesemia or significant
bradycardia

Clindamycin
• Activity against streptococci staphylococci,
pneumococci
• Enterococci and gram(-) aerobes resistant (does not

penetrate gram(-) outer membrane) (Clostridium
difficile is resistant)
• Well absorbed orally – food does not reduce

absorption significantly

Pseudomembranous Colitis
280,000 patients
Rate per 100,000 population
Antibiotic Rate per 100,000 population
Ampicillin 1.6
Dicloxacillin 2.9
Tetracycline 2.6
Clindamycin 0

Fluoroquinolones
• Excellent Gram (-) aerobes and little gram(+) activity
• Newer agents more gram (+) activity
• Well absorbed
• Wide volume of distribution
• Since most dental infections have high concentrations

of anaerobes – and most fluoroquinolones demonstrate
little or no activity against anaerobes – rarely a good
choice
15

FLUOROQUINOLONES
• CIPROFLOXACIN (CIPRO)
• INTERFER WITH DNA REPLICATION BY
INHIBITING DNA GYRASE
• GOOD STAPH AND GRAM -

• POOR STREP AND ANAEROBES
• NO INDICATIONS IN DENTISTRY
• EXPENSIVE
25

Dr. Rutkowski,
My name is Marcus Palermo. I am an endodontist practicing in Scottsdale, AZ and currently enrolled in the Loma Linda
Maxi Course. I am writing to ask about the use of Ciprofloxacin and it's side effects. I have a patient who has an abscess
that hasn't cleared up with endodontic retreatment and prior to attempting apical surgery I elected to attempt an
antibiotic protocol that I have never used.
I had a friend tell me that they have used it with some success in the past, so I gave it a try. Basically, I placed the patient
on 250mg Cipro bid for 3 days and combined it with Metronidazole 250mg bid as well for 3 days. The patient is a 33 year
old healthy male. He is not taking any medications and has only an allergy to sulfa medications. He took the medication
without consequence for the 3 days. On day 5 he began to notice some joint pain, especially in his knees. He is a bright
fellow (bachelor's in astrophysics) and did some research over the weekend and read about ligament damage as a side
effect from Cipro. He has started taking magnesium supplements and glucosamine as a prophylactic measure.
He contacted me and informed me of his condition and noted that he has some discomfort on waking in the joints and it
progressively gets worse as the day goes on. I advised him to take 400mg ibuprofen q6h prn pain and told him that the
supplements may help and they certainly won't hurt. He has researched several forums and read many posts about
similar side effects and that they are nearly impossible to resolve and that they can get worse or recur up to 6 months
post-treatment. He has asked me what to do and I advised him that I would have to do some of my own research and
consult with colleagues (hence this message) and I would get back to him. He has had the pain for about 5 days and it is
not getting any worse, but it also is not any better.
I am embarrassed that I used this regimen without consulting further for possible side-effects and management of the
sequellae from taking Cipro. Now, I am just trying to understand what has happened and what I might tell my patient that
could help him recover quickly. Please share any advice you might have regarding the joint tenderness associated with
Cipro.
Thank you for your time!
Sincerely,

Hello Marcus, Thanks for your patience on this. Attached is an article that
explains the collagen breakdown that seems to be the cause of the tendonitis. A
second article attached described treatment with the anti-inflammatory
medication (100 mg flurbiprofen daily) and a rehabilitation program. In 15 days
after stopping ciprofloxacin treatment, his symptoms
gradually improved. On the 35th day, his symptoms disappeared totally. I think
any NSAID would have done the job.
Hopefully this will help you and the patient. It was great communicating with you
on this interesting case. I would like to know how it resolves as I will most likely
include this little know side effect in my pharmacology lecture on antibiotics now.
Please email back that you received this and were able to open the attachments.
Best,
Jim

Metronidazole
• Great anaerobic activity
• Well absorbed
• Widely distributed
• Anaerobic bacteria reduce the nitro group to give the

antimicrobial activity
• May give a metallic taste
• Do not consume alcohol – re. disulfiram-like reaction
16

Metronidazole
• Chance observation that the symptoms of
acute necrotizing ulcerative gingivitis were
relieved in a woman receiving metronidazole
for the treatment of vaginal trichomoniasis
stimulated research on the drug’s
antibacterial effects, culminating in its
approval in 1981 for the treatment of
anaerobic bacterial infections

Metronidazole
• Effective against gram-negative anaerobic
pathogens responsible for acute orofacial
infections and chronic periodontitis
• Combination of metronidazole with a β-lactam

antibiotic for oral infections may be indicated for
serious acute orofacial infections and in the
management of aggressive periodontitis.
• Yagiela, John A.; Dowd, Frank J.; Johnson, Bart; Mariotti, Angelo; Neidle, Enid A. (2010-03-19). Pharmacology and Therapeutics for Dentistry (Kindle Locations 39463-39466).
Elsevier Health. Kindle Edition.

Questions
• What are the empiric antibiotics
of choice for odontogenic
infections (OI)
• How Long should the treatment
course last?

What are the Antibiotics of Choice for Odontogenic Infections, and
How Long Should the Treatment Course Last?, Flynn TR Oral
Maxillofacial Surg Clin N AM 23(2011)519-536Analysis - relevant
articles
• 40 review articles - 3 review articles

found to meet criteria
• Potentially relevant articles
• 1003 potential articles
• 772 articles for antibiotic treatment in OI
• 228 articles for antibiotic sensitivity in OI
• 3 trials of antibiotic treatment course
duration
Articles used
• 23 clinical trials of antibiotic

treatments in OI
• 18 laboratory studies of
antibiotic sensitivity from OI
• 3 trials of antibiotic treatment
course duration

Clinical Trials of Antibiotics
8 trials 488 patients
• Antibiotics examined
• Penicillin VK, Penicillin G-IM,
• Amoxicillin/Clavulanate, Ampicillin,
Amoxicillin, Clindamycin, Lincoycin,
Cephalexin, Metronidazole,
Ornidazole, Moxifloxacin

Which Antibiotic?
• No statistically significant difference in clinical
cure rates at day 7
• Randomized, non-blinded trial compared
amoxicillin, cephalexin, and surgery alone
• Amoxicillin - 4.5 days, cephalexin 4.7 days,
surgery alone 6.2 days

Laboratory Studies
4 publications - 280 patients
• Bacterial strains 3.0 ± 1.3 (2.4 - 5.5)

• Penicillin, ampicillin, beta-lactam/beta-lactamaze
inhibitor combination, clindamycin,
fluoroquinolone, doxycycline, minocycline,
erythromycin, cephalosporins, imipenem,
metronidazole, gentamicin

Which Antibiotic
• No one antibiotic is likely to be effective in vitro
against all strains of all species
• The combination of penicillin and metronidazole
would have been effective against all strains of all
species, consistent with the clinical strategy of
using 1 antibiotic highly effective against the oral
Streptococci and another for the oral anaerobes

How Long?
2 studies 101 patients
• Compared short (1-3 days) with long (5-7 days)

courses of therapy
• Antibiotics: penicillin and amoxicillin
• Surgery in both groups

How Long
• No clinically signifiant cure at 7 days
when either a 1-3 day or a 5-7 day
therapy when used in combination with
surgery
• More rapid decrease of welling with
amoxicillin vs penicillin

Dental Infection
Acute - rapid Chronic > 3days
growth <3 days Choose one
Pen VK 1000 mg initially, then 500 mg q 6 h Think Anaerobes: Add

or Metronidazole 500 mg 1st
Amoxicillin 1000 mg initially, then 500 mg q 8 h
or time then 250 q 8 hr
Cephalexin 1000 mg initially, then 500 mg q 6 h for 14 days
(all of the above for 7 to 10 days or longer)
Penicillin allergy: Clindamycin 300 mg

Clindamycin 300 mg initially, then initially, then 150 mg q
150 mg q 6 h or 6 h for 7 to 10 days
Cephalexin (for 7 to 10 days)or
Azithromycin (5 days)

Therapeutic
rationale
• Empirical therapy
• Early intervention will improve the outcome
• Accepted by placebo-controlled, double-blind

prospective clinical trials
• Base on scientific knowledge & clinical

experience

Therapeutic
regimen
• Step 1. Penicillin-like antibiotic meets criteria for
activity against anaerobic gram (-) and aerobic
gram(+) bacteria
• Amoxicillin logical 1st choice, with exception of

anaerobes possessing beta-lactamase activity –
then consider Augmentin® - BUT very
expensive -- so cephalexin (demonstrates
greater stability than penicillins and less
expensive than Augmentin ®

Therapeutic
• Step 1. summary:
• Cephalexin 1000 mg initially, followed by

500 mg every 6 hours for a total of 7 to
10 days.

Therapeutic regimen
• Step 2. If the beta-lactam antibiotic (cephalexin)
fails to bring resolution after 48 to 72 hrs. then
consider improving anaerobe coverage
A. Add metronidazole 500 mg initially followed by
250 mg every 8 hours for 7 to 10 days.
OR
B. D/C cephalexin and begin clindamycin 300 mg
initially follow by 150 mg every 6 hours for 7 to 10
day.

Vojnosanit Pregl. 2009 Jul;66(7):544-50.
Empirical antimicrobial therapy of acute dentoalveolar abscess.
Matijević S, Lazić Z, Kuljić-Kapulica N, Nonković Z.
Military Medical Academy, Clinic for Maxillofacial, Oral Surgery and Implantology,
Belgrade, Serbia. drmatijevic@sezampro.yu
• BACKGROUND/AIM: The most common cause of

acute dental infections are oral streptococci and
anaerobe bacteria. Acute dentoalveolar infections
are usually treated surgically in combination with
antibiotics. Empirical therapy in such infections
usually requires the use of penicillin-based
antibiotics. The aim of this study was to investigate
the clinical efficiency of amoxicillin and cefalexin in
the empirical treatment of acute odontogenic
abscess and to assess the antimicrobial
susceptibility of the isolated bacteria in early
phases of its development.

RESULTS: The infection signs and symptoms
lasted on the average 4.47 days, 4.67 days,
and 6.17 days in the amoxicillin, cephalexin,
and surgically only treated group,
respectively. A total of 111 bacterial strains
were isolated from 90 patients. Mostly, the
bacteria were Gram-positive facultative
anaerobs (81.1%). The most
common bacteria isolated were Viridans
streptococci (68/111). Antibiotic susceptibility
of isolated bacteria to amoxicillin was 76.6%
and cefalexin 89.2%.

•CONCLUSION: Empirical, peroral use of
amoxicillin or cefalexin after surgical
treatment in early phase of development of
dentoalveolar abscess significantly reduced
the time of clinical symptoms duration in the
acute odontogenic infections in comparison
to surgical treatment only. Bacterial strains
isolated in early stages of dentoalveolar
abscess showed high sensitivity to
amoxicillin and cefalexin.

THERAPEUTIC REGIMEN
• Penicillin 500-1000 mg QID

• Cephalexin 500-1000 mg QID
• Erythromycin 250-500 mg QID
• Amoxicillin 500-1000 mg TID
• For 2-3 days if better continue
• If not better then:

THERAPEUTIC REGIMEN
• Add metronidazole
• 500 mg stat then 250 mg TID
• Switch to clindamycin
• 150-300 mg QID
• If not successful then:
• Culture & sensitivity
• Always consider incise & drain and moist
heat

SURGICAL
PROPHYLAXIS
• Adequate serum level within 2 hrs. of incision
• Serum level should not Best continued for
more than 24 hours
• Prolonged
• Growth of resistant organisms

SURGICAL
PROPHYLAXIS
• Use bacterial endocarditisd prophylaxis
regimen
• Plus 1 or 2 additional doses

• Oral amoxicillin, cephalexin, penicillin VK,
clindamycin
• IV cefazolin then oral cephalexin

MEDICAL
PROPHYLAXIS
• Compromised immune function
• Poorly controlled insulin dependent diabetic
• Renal failure with dialysis
• Evidence of significant malnutrition or
alcoholism
• Symptomatic HIV
• Immunosuppressant drugs
• Radiation of head an neck
MEDICAL
PROPHYLAXIS
• Inflammatory arthropathies including
rheumatoid arthritis and systemic lupus
erythematous
• First 2 years following joint placement

• Previous prosthetic joint infection

Infective
Endocarditis (IE)
Substantial Morbidity & Mortality

IE

Cardiac conditions related with the greatest risk of
adverse outcome from IE for which prophylaxis with
dental procedures is recommended
Prosthetic cardiac valve

Previous infective endocarditis
Congenital heart disease (CHD)*
Unrepaired cyanotic CHD, including palliative shunts
and conduits
Completely repaired congenital heart defect with
prosthetic material or device, whether placed y
surgery or by catheter intervention, during the first
six months after the procedure**
Repaired CHD with residual defects at the site or
adjacent to the site of a prosthetic patch or prosthetic
device (which inhibit endothelialization)
Cardiac transplantation recipients who develop
cardiac valvuopathy
*Except for the conditions listed above, antibiotic

prophylaxis is no longer recommended for any other
form of CHD
**Prophylaxis is recommended because
endothelialization of prosthetic material occurs within
six months after the procedure

IE regimen: Single dose 30 to 60
minutes before procedure:
Condition Agent Adults Children
Oral Amoxicillin 2 gms 50 mg per kg
Ampicillin 50 mg/kg IM
Unable to take OR 2 gms IM or IV or IV
oral meds Cefazolin or 1 gm IM or IV 50 mg/kg IM
Ceftriaxone or IV
Cephalexin 2 gms. 50 mg/kg
Allergic to OR
Pencillins or Clindamycin 600 mg 20 mg/kg
Ampicillin OR
Oral Azithromycin 500 mg 15 mg/kg
or
Allergic to
Cefazolin or 1 gm IM or IV 50 mg/kg
Penicillins or
Ceftriaxone
Ampicillin and
OR 600 mg IM or
Unable to take
Clindamycin IV 20 mg/kg
oral meds

Metronidazole with Lithium 
l Lithium is a monavalent cation

l Lithium is indicated for bipolar
l Met. interferes with renal excretion of
lithium
l Close supervision with lithium
lTherapeutic Index
James L. Rutkowski, D.M.D. 160

Blood Levels
l 0.8 to 1.5 mEq/L during acute manic

attack
l 0.6 to 1.2 mEq/L for maintenance
therapy
l Toxicity occurs at 1.5 to 2.0 mEq/L
l Above 2.5 mEq/L - life threatening

Metronidazole with Lithium
l Three cases of metronidazole for one
week 500-1000 mg. per day leading to
toxicity (JAMA 1987 and Int. Drug The
News 1982)
l Avoid metronidazole with lithium
patients
l Significance rating is 1

ANTIBIOTICS + ORAL
CONTRACEPTIVES
• Rifampin (TB) only confirmed

• Anecdotal reports
• OC failure 0.5 -1.0% (Teens 8%)
• Enterohepatic recycling
• Studies do not substantiate this
• MILLER et al HANDOUT

Oral Contraceptives
l Semisynthetic estrogens
l Semisynthetic progesterones
l Estrogens block release of FSH and
LH
l Progesterones enhance viscosity of
cervical fluid

Oral Contraceptives
l Typical failure rate 3% - Teens 8%

l Most likely due to failure to take pill

Rifampin Interaction
l Tx: TB
l 76% of interactions
l Decrease in blood levels of BC Pills
l Inducer of liver Cytochrome P-450

Ref.
Hersh, E., JADA Feb. 1999

Antibiotics and Oral
Contraceptives
l 1975 - 3 cases Ampicillin

l 1980 - 1 report Tetracycline
l 1982 - 13 cases Ampicillin, Penicillin,
Tetracycline
l 1986 - I.M. Penicillin

ADA Health Foundation Research
Institute
l “Unfortunately, many antibiotics commonly
used in dentistry interfere with the action of
oral contraceptives, resulting in unexpected
pregnancies. Failure to inform a patient
using oral contraceptives during antibiotic
therapy resulting in a birth could leave the
dentist responsible for damages--including
child support payments”
JADA, 1991

Ref. Hersh, E., JADA Feb. 1999

Ref. Hersh, E., JADA Feb. 1999
JADA Statement
l “The failure of oral contraceptives in
women simultaneously ingesting
antibiotics may indicate background
noise--that is, the normal failure rate of
these drugs or a relatively rare
interaction that cannot be detected by
clinical trials”
JADA, February 1999

“Wrongful Life”
l GYN and OS - Plaintiff lost
lher experts cited review articles with no data
lher experts failed to show a scientifically validated
interaction existed
lCA law - physicians do not have to discuss risks
of a very low incidence
lher experts failed to prove that she became
pregnant when she was taking penicillin

Antibiotics and Oral
Contraceptives
l Significance rating 4
(except Rifampin)

Erythromycin, Clarithromycin or
Tetracyclines with Digoxin
l Digoxin has low therapeutic index

l 10% of population harbors enteric
bacteria that inactivates digoxin
l> average dose - antibiotic kills off bacteria
⇒ very high levels of digoxin
Ref: CHF 1998, NEJM 1981

Tetracyclines with Digoxin
l Erythromycin ⇒ problems in less than

three days
l Tetracycline ⇒ 30% rise in digoxin
levels

Metronidazole with Alcohol
l Metronidazole (like Antabuse) inhibits
activity of acetaldehyde
dehydogenase
l ⇒ get accumulation of acetaldehyde
when taken with alcohol
l unpleasant reaction

Metronidazole with Alcohol
l No alcohol for at least 3 days after

Metronidazole therapy

Tetracyclines/Broad Spectrum
Antibiotics with Oral
Anticoagulants
l Coumadin has a low therapeutic index
l Antagonist of Vitamin K dependent clotting
factors
l Tetracycline, Amoxicillin and Ampicillin
lreduce endogenous Vit. K levels
lenhance the effects of oral anticoagulants by
decimating normal gut flora that produce Vit. K
James L. Rutkowski, D.M.D.

Tetracyclines/Broad Spectrum
Antibiotics with Oral
Anticoagulants
l Reaction if unpredictable
l Concern in patients with low Vitamin K
diet
l Normal Vitamin K intake ⇒ no problem

Metronidazole with Oral
Anticoagulants
l Can get marked increase in Warfarin

levels

Metronidazole with Oral
Anticoagulants
l Erythromycin etc. - 30% reduction in
clearance of Warfarin
l Marked increase in anticoagulant activity
l Block the cytochrome P-450 ⇒ interferes
with Warfarin metabolism

ANTICOAGULANT CLASSES
• INHIBITORS OF CLOTTING FACTOR SYNTHESIS
• WARFARIN (COUMADIN®)
• Rivaroxaban (Xarelto®)
• INHIBITORS OF THROMBIN

• HEPARIN, LEPIRUDIN (REFLUDAN™)
• Dabigatran Etexilate Mesylate (Pradaxa™)
• PREVENTION OF PLATELET AGGREGATION

• ASA
• TICLOPIDINE (TICLID™)
• CLOPIDOGREL (PLAVIX™)
• TIROFIBAN (AGGRASTAT™)
• EPTIFIBATIDE (INTEGRILIN™)
• Prasugrel (Effient™)
• Ticagrelo (Brilinta®)
ANTICOAGULANTS
• WARFARIN (COUMADIN)
– ACTS IN LIVER BY INHIBITING REDUCTION OF VIT. K TO A
FORM NEEDED FOR SYNTHESIS OF FACTORS VII, IX, X,
AND PROTHROMBIN
• HEPARIN
– POTENTIATES THE ANTICOAGULANT ACTIVITY OF
ENDOGENOUS ANTITHROMBIN III
COUMADIN®
• EFFECT IN 24 HRS.
• PEAK 3 – 4 DAYS
• MAY CAUSE SERIOUS HEMORRHAGE
– ANTIDOTE – VIT. K
• REQUIRES 12 –24 HRS.
– MAY REQUIRE TRANSFUSION

Warfarin
• OutpaYent Rx’s 2004 -‐ 31 million
st
• Ranked 1 in 2003 and 2004 for drug related deaths due to
“adverse effects” in therapeuYc use
• 10 to 16 % of paYents will have a major bleed at some point
• No longer acceptable to D/C warfarin rou5nely!!!

COUMADIN®
• Monitor with INR (InternaYonal normalized raYo)
– Standardizes the various laboratories

thromboplasYns (human or rabbit)
Recommended range for oral
anYcoagulant therapy:
INR target range 2.0 to 3.0
• Prophylaxis/treatment of venous thrombosis
• Treatment of pulmonary embolism
• Prevention of systemic embolism
• recurrent systemic embolism
• Acute myocardial infection
• Valvular heart disease
• Valvular replacement with tissue
• Atrial fibrillation
INR target range 2.5 to 3.5

• Mechanical replacement heart valves (High
risk)
INTERNATIONAL NORMALIZED
RATIO (INR)
• INR > 4.0 out of

• INR < 2.0 out of • INR 2.0 → 4.0 therapeutic range
therapeutic range ok to do surgery – (warfarin
(poorly managed with local dosage needs
– needs measures adjustment )
adjustment)
Warfarin (Coumadin )
®
ConYnue warfarin therapy

Good
• Hemorrhagic disorders
• Correct INR
D/C warfarin therapy

• Malpractice
Bad • Cerebrovascular
complications
• Thrombosis formation
John Kern PhD - email
Also, I have finished reviewing the OOOOE
article on warfarin. Bottom line, there is no
communication
statistical weight whatsoever behind the
article's recommendation to withhold
warfarin. The EUV estimates are
separated by only 0.02, and all of the
probabilities used to estimate the two EUV
values are themselves estimates (from
other literature, no less).
This article is in no way a breakthrough or

landmark. Would it be okay for me to call
you and discuss in more detail my critique
of the article? I can call most any time/day
this week or next; just let me know.
I hope your new year has gotten off to a

Ref. Herman W., et. al.,
Current PerspecYves
On Dental PaYents
Receiving Coumarin
AnYcoagulant Therapy,
JADA March 1997
TAKE-HOME MESSAGE
• MUST HAVE A RECENT INR (WITHIN 30 DAYS IF NO CHANGES IN
MEDS)
• IF ANY MED OR DOSAGE CHANGES – THEN MUST REPEAT INR
• BEST IF SAME-‐DAY FOR MAJOR PROCEDCURES!!!

dabigatran (Pradaxa®)
Boehringer Ingelheim
• For prevention of stroke and systemic embolism

(blood clots) in patients with atrial fibrillation
• first replacement for warfarin (Coumadin®) since

Coumadin was approved in 1954.
“Serine protease”
anticoagulant
• acts by inhibiting thrombin, an enzyme in the blood that is

involved in blood clotting
• thrombin (serine protease) enables the conversion of

fibrinogen to fibrin during the coagulation cascade, its
prevention prevents the development of a thrombus.
• recommended dose is a 150 mg capsule taken orally

• Warfarin therapy requires patients to undergo periodic
monitoring with blood tests
• INR monitoring not necessary for dabigatran.

• Measure of Effect
• At therapeutic doses prolongs the activated partial
thromboplastin time (aPTT)
• oral dose of 150 mg twice daily, the median peak aPTT is

approximately twice that of control values
• Twelve hours after the last dose, the median aPTT is 1.5x
control
• INR test is relatively insensitive to the activity of dabigatran

and may not be elevated in patients on dabigatran.
Dabigatran (Pradaxa®)
• Absorption and Metabolism

• After swallowing a dabigatran (Pradaxa) capsule, peak blood
level occurs in 1 hour. The half-life is 12 to 17 hours.
• not metabolized by CYP enzymes
• After oral administration, dabigatran etexilate is converted to

dabigatran through esterase-catalyzed hydrolysis of the
molecule in plasma
• Dabigatran is not a substrate, nor inhibitor, nor inducer of

CYP 450 enzymes
Dabigatran and Risk of Bleeding
• ↑ risk of bleeding and can cause significant, and sometimes fatal, bleeding
• Drugs that can increase the risk of bleeding include antiplatelet agents and
chronic use of NSAIDs
• RE-LY trial, life-threatening bleeding occurred at an annualized rate of 1.5% for

Pradaxa 150 mg and 1.8% for warfarin.
• Discontinuing Pradaxa for surgery places the patient at an↑ risk of stroke
• If anticoagulation must be temporarily discontinued for any reason, therapy should
be restarted as soon as possible.
• Dental patients who may have a high risk of bleeding if taking Pradaxa include those
over 75 years of age, or are taking aspirin, or long term NSAIDs, or clopidogrel
(Plavix®) or prasugrel (Effient®).
• RE-LY study Connolly SJ, Ezekowitz MD, Yusuf S, et al, "Dabigatran Versus Warfarin in
Patients With Atrial Fibrillation," N Engl J Med, 2009, 361(12):1139-51.
Rivaroxaban (Xarelto®)
• Mechanism: Factor Xa inhibitor
– In coagulaYon factor X → Xa (produces fibrin)

• Prophylaxis of deep vein thrombosis (DVT) which may

lead to pulmonary embolism (PE) in pts undergoing
knee or hip replacement surgery
• 10 mg once daily
• 5 -‐6% pts have “a bleeding event”

• Measurement of Effect
– Prolongs prothrombin Yme (PT) and acYvated parYal

thromboplasYn Yme (aPTT)
• PredicYve treatment values not established
– No data on INR use
– Hip replacement -‐ 35 days
– Knee replacement -‐ 12 days

• Dental consideraYons
– ↑ bleeding occurs with 10mg/day
– Consult
– No reports of interacYons with amoxicill,

cephalexin, cefazolin, ampicillin, & clindamycin
• Drug interacYons
– Inhibitors of CYP3A4
• Ketocanazole (anYfungal)
• Clarithromycin (Biaxin®)
• Erythromycin
– NSAIDS
THROMBOGENESIS
• PLATELET AGGREGATION
• COAGULATION
ARTERIAL COAGULATION
– CASCADE TO FIBRIN STRANDS
• ARTERIES
– PLATELETS ADHERE TO DAMAGED VESSSEL WALLS
– AGGREGATE
– CORE FOR FIBRIN STRANDS
– OCCLUDE ARTERIAL FLOW
– ISCHEMIA OF LOCAL TISSUES

VENOUS THROMBI
• FIBRIN STRANDS
– EMBOLIZE GREAT DISTANCES
• LODGE IN PULMONARY ARTERIES

THROMBOGENESIS
• LOCALIZED RESPONSE
– INITIATED BY SUBSTANCES RELEASED FROM

PLATELETS AND ENDOTHELIUM
– LIMITED BY LOCALIZED ANTICOAGULANT

MECHANISMS
• ANTITHROMBIN II
ANTIPLATELET DRUG
• ASPIRIN
– TX: PREVENTION OF MI & THROMBOTIC STROKE
– 81 mg/day
– LITTLE RISK FOR DENTAL SURGERY

ANTIPLATELET DRUG
• DIPYRIDAMOLE (PERSANTINE)
– PREVENTS PLATELET ADHESION TO ENDOTHELIAL

SURFACES
– MIXED WITH ASA
• ENHANCES ANTITHROMBOTIC ON ARTIFICIAL SURFACES
– VALVULAR & CARDIAC PROSTHESES
– DIALATES CORONARY ARTERIES

PLAVIX -‐ CLOPIDOGREL
®
• BLOCKS THE ADP RECEPTOR WHICH PREVENTS THE

BINDING OF FIBRINOGEN TO THAT SITE
• DOES NOT ALTER THE RECEPTOR
• REDUCES # OF FUNCTIONAL ADP RECEPTORS

PLAVIX -‐ CLOPIDOGREL
®
• MONITOR WITH PLATELET AGGREGATION

• INITIAL 2 TO 4 WEEKS MAY CAUSE
THROMBOCYTOPENIA – CHECK PLATELETS
• RARELY NECESSARY TO D/C
• SURGERY IF MULTIPLE SITES OR EXTENSIVE ? – get
consultaYon
– DISCONTINUE 7 DAYS PRIOR TO PROCEDURE (RARELY
NECESSARY!)
PLAVIX -‐ CLOPIDOGREL -‐ WOW!!!!
®
• 30% of populaYon has a geneYc variant in liver metabolizing enzymes that
affect efficacy of clopidogrel -‐ no effect at all
– CYP2C19 converts clopidogrel to an acYve metabolite.
– Genes which encode and express liver enzymes responsible for metabolism exist in several
polymorphic states (CYP2C19 has 4 variants with reduced funcYon)
– RelaYve reducYon of 32% in acYve metabolite
– 53% higher risk for primary efficacy outcome of death from cardiovascular causes, MI, stroke
– Stent thrombosis in carriers 3 X that of non-‐carriers
– Ref. Mega JL et al., “Cytochrome P-‐450 Polymorhisms and Response to Clopidogrel” NEJM,
2009, 360(4):354-‐62
Prasugrel (Effient™)
• AnYplatelet agent and aggregaYon inhibitor
– For ➡ thromboYc cardiovascular events (stent

thrombosis
Prasugrel
Clopidogrel
Non-‐fatal
Non-‐fatal subsequent
subsequent heart
heart aEacks
aEacks
9.1% 7%
Deaths and strokes equal
Risk of significant fatal bleeding
+ ++
• Pro-‐drug
• Irreversibly blocks P2Y12 component of adenosine

diphosphate (ADP) receptors on platelets for their lifespan
– ➡ platelet acYvaYon and platelet aggregaYon
– Normal platelet acYvity does not return (new platelets in 5 to 9 days
azer D/C
– Loading dose 60 mg followed by maintenance dose of 10 mg daily.
– Should take with ASA 75 to 325 mg daily

• GeneYc variants in liver metabolizing enzymes do not

affect efficacy
– Undergoes rapid intesYnal and serum metabolism

via esterase-‐mediated hydrolysis to a thiolactone
(inacYve metabolite), which is then converted, via
CYP3A4 & CYP2B6 enzyme oxidaYon, to the acYve
metabolite designated as R-‐138727.
Ticagrelor (Brilinta®)
• Reduce rate of thromboYc cardiovascular events in

pts with acute coronary syndrome (ACS): unstable
angina, non-‐ST elevaYon MI, ST elevaYon MI
• More effecYve than clopridogrel

– Inhibitors of CYP3A4
– Ketocanazole
– Itaconazole
– Voriconazole
– Clarithromycin (Biaxin®)
– Erythromycin
• NSAIDs
• Mechanism: An acYve, reversible platelet inhibitor
• CYP3A4 converts Ycagrelor to another acYve reversible

platelet inhibitor -‐ which is the major acYve metabolite
• Act at the ADP-‐receptor
• Loading dose 180 mg then 90 mg BID
– Give with loading dose ASA 325 mg then 75 -‐ 100 mg. Daily
– ASA doses above 100 mg/day reduce effecYveness of Ycagrelor and
should be avoided
• Do NOT D/C without consultaYon
• Expect bleeding and echymosis
• Pts ozen have SOB
• No coagulaYon parameters suggested

Bisphosphonates
• 1st generation (no nitrogen)

– Etidronate (Didronel™)
• 2nd generation - 10 to 100 X more potent than
1st gen. (nitrogen)
– Alendronate (Fosamax™)
– Pamidronate (Aredia™)
– Ibandronate (Boniva™)
• 3rd generation 10,000 X more potent then 1st

gen. (nitrogen with
– Zoledronic acid (Zometa™)
a heterocyclic ring)
– Risedronate (Actonel™)
Bisphosphonates
• Analogs of pyrophosphate (P-O-P)
• Oxygen is replaced by a carbon
• Concentrate in bone
– Long ½ life
• Most effective inhibitors of bone resorption
Bisphosphonate: Mechanism of
Action
• Capable of chelating Ca2+ - thus strong affinity for remodeling
bone
• Prevent hydroxyapatite dissolution (all)
• Anti-resorptive activity also includes
– Osteoclast apoptosis (1st generation)
– Inhibition of components of the cholesterol biosynthetic pathway (2nd & 3rd
generation)
Bisphosphonate: Mechanism of
AcYon
• Nitrogen containing BPs are incorporated into the osteoclasts
– Inhibit farnesyl diphosphate synthase (enzyme involved in

cholesterol synthesis)
• Leads to ↓ geranylgeranyl diphosphate
– Protein that is involved in attachment of other proteins and

molecules to the cell membrane
Am Fam Physician. 2008 Sep 1;78(5):579-81.
Alendronate for fracture prevention in postmenopause.
Holder KK, Kerley SS.
• vertebral fractures, a 45 percent relative risk reduction

was found (relative risk [RR] = 0.55; 95% confidence
interval [CI], 0.45 to 0.67).
• nonvertebral fractures, 16 percent relative risk reduction
was found (RR = 0.84; 95% CI, 0.74 to 0.94).
• 40 percent relative risk reduction in hip fractures (RR =
0.60; 95% CI, 0.40 to 0.92)
CONCLUSIONS: alendronate clinically and statistically had

significant reductions in vertebral, nonvertebral, hip, and
wrist fractures were observed for secondary prevention.
New development in bisphosphonate treatment. When and how
long should patients take bisphosphonates for osteoporosis?
• Long-term alendronate administration may

inhibit normal repair of microdamage arising
from severe suppression of bone turnover
(SSBT), which, in turn,
• results in accumulation of microdamage.

This process would lead to brittle bone and
the occurrence of unexpected stress
fractures, characteristically at the
subtrochanter of femur.
New development in bisphosphonate treatment. When and
how long should patients take bisphosphonates for
osteoporosis?
• A large-scale study suggests that for more

women, discontinuation of alendronate after 5
years for up to 5 more years does not
significantly increase fracture risk.
• Thus, alendronate treatment might be stopped for a

while a6er 5 years to prevent SSBT and subsequent
stress fractures.
Bisphosphonate Side Effects
BISPHOSPHONATES AND ALVEOLAR BONE
NECROSIS
• Seen with IV bisphosphonate therapy for

treatment of osteolytic bone diseases
– Bisphosphonates are inhibitors of bone

resorption via
• Dissolution of hydroxyapaptie
• Inhibit osteoclast function

Fosamax® (alendronate)
• Reports of bone necrosis with dental surgery ?
– Most likely with bisphosphonates used to treat

osteolytic bone lesions such as cancer
– Not likely with low short term doses of

Fosamax® used to prevent osteoporosis
BONJ Mandible 6/8/09
BONJ -‐ Mandible 8/12/09
BONJ-‐ October 19, 2009
• IMG_4445.JPG
Post-‐Surgery November 4, 2009
Post-‐op
Post-‐Surgery November 9, 2009
November 2, 2010
April 27, 2011
Have You or Your Loved Ones Taken Fosamax®?
NECROSIS
• Literature:
– Editorial Martin Greenberg, DDS
• Oral Surgery, Oral Medicine, Oral Pahology, Oral Radiology,
and Endodontology Vol 98 #3 Sept. 2004
– Letter to Editor Cesar Migliorati DDS, MS, PhD
• OOOE Feb. 2005
– Aust Dent J. 2003 Dec;48(4);268
– Ann Acad Med Singapore 2004 Jul;33(4 suppl):48-9
NECROSIS
• Literature:
– J. Clin Oncol. 2003 Nov 15;21(22):4253-4
– J. Oral Maxillofac Surg. 2004 Jun;62(6):763-4

Comment
– J. Oral Maxillofac Surg 2004 Dec;62(12):1563-5
– J Oral Maxillofac Surg 2004 May;62(5):527-534

Ruggiero SL
NECROSIS
• Marx RE, J Oral Maxillofac Surg 63:1567-1575,

2005
• Hellsgrin JW J Oral Maxillofac Sug May

63:1248-9, 2005
• Altundal H Oral Surg Oral Med Oral Pathol Oral

Radiol Endod 99(#):285-291, 2005
NECROSIS
• Tx of bone lesions of multiple myeloma and

metastatic bone lesions in pts. with breast and
prostate cancer
– Zoledronate IV (Potent)
– Pamidronate IV (relatively potent)
– Alendronate – oral (less potent)

Bisphosphonates & Other ComplicaYons
• Severely Suppressed Bone Turnover (SSBT) Journal

of Clinical Endocrinology & Metabolism. 90(3):1294-1301
– Decreased bone turnoverà microfractures
• Alendronate & Atrial Fibrillation. C.I. 0.97 to 2.40;

p=0.07 N. Engl. J Med. May 2007 356;18
– Possibly due to release of inflammatory

cytokines
This is it!
The Healing Socket And Socket Regeneration
Steiner GG, Francis W, Burrell R, Kallet MP, Steiner DM, Macias R.
Compend Contin Educ Dent. 2008 Mar;29(2):114-6, 118, 120-4The Healing Socket And Socket Regeneration
• If the first stage of extraction-socket healing is

resorption and disposal of necrotic bone, then this
would explain why tooth extraction in patients on
bisphosphonates occasionally leads to osteonecrosis
• Bisphosphonates prevent osteoclastic undermining

and disposal of necrotic bone lining the socket wall
• The inability of the alveolus to dispose of the necrotic

bone lining the socket wall could then lead to
progressive osteonecrosis
ALENDRONATE EFFECT OF CELLS
• [10-5M] to [10-11] ↑ cell proliferation
• [10-4] inhibited cell proliferation (inhibition ↑ with

time)
– Ref. Gun-II Im, Biomaterials 25;4105-4115, 2004
– Bone concentration (vol. 3.63L)
• 70 mg/week = 2.48 yrs.
• 35 mg/week = 4.97 yrs.

Bisphosphonates, ONJ and
Toxicity
• What is toxic level?
– Literature states most oral B-ONJ occurs

around 2 to 3 years (70 mg/week) or 5 years
(35 mg/week)
• Bisphosphonates vary in potency (see next

slide!)
BISPHOSPHONATES AND INHIBITION OF
BONE RESORPTION
FPP – Farnesyl
diphosphonate
Synthase: Important
in: organization of
cytoskeleton,
membrane trafficking
and formation of the
ruffled boarder
Bisphosphonates, ONJ and
Toxicity
• Based on this information:
• After 5 years (35 mg/week) à 3.36 nmol/ml
• After 3 years (70 mg/week) à 4.032 nmol/ml
• Or, 3.36 times and 4.032 times the toxicity level of oral
epithelium
ONJ Hypothesized Gene
• Matrix metalloproteinase 2 (MMP2)
– MMP2 associated with bone abnormalities
– Bisphosphonates associated with atrial fibrillation
– MMP2 only gene known to be associated with both bone

abnormalities and atrial fibrillation
– Known disorder-gene asssociations indicates that

cardiovascular disease and bone disease are closely related
• Lehrer et al. J Oral Maxillofac Surg 67:159-161, 2009

Components of BONJ
1. Inhibition of angiogenesis/vasculargenesis
2. Inhibition of osteogenesis/resorption
3. Changes in oral flora competition/Actinomyces
4. Inhibition of normal oral epithelial growth and migration/

supression of endothelial cells/fibroblasts
5. Inhibition of typical immune function/inactivation of T-cells
6. Disruptived event in the oral mucosa/oral procedcures surgery

Changes in Oral Flora CompeYYon/
AcCnomyces
Changes in Oral Flora Competition/Actinomyces
Journal of Oral and Maxillofacial Surgery 66(4)
Classical Clinical PresentaYons
BISPHOSPHONATES AND INHIBITION OF BONE
RESORPTION
• How to treat?
– Suggestions:
• No implants or elective surgery on patients
taking Zometa or Aredia
• Delay implants or elective surgery on pts. with
high doses of Fosamax – D/C Fosamax prior
to surgery then restart Fosamax at a later time
• Test bone turnover for global picture of bone
cell vitality
Bone Strength
• Combination of Bone Mineral Density (BMD) and

bone quality
• BMD = grams of mineral per area or volume
• Bone quality = characteristics of the bone matrix

(micro-architecture, bone turnover, micro-
damage accumulation, degree of calcification
and collagen
Bone Turnover Markers
• Change earlier than BMD

• More consistent results than BMD
• Bone Resorption markers
– DPD(urinary), NTX(serum/urinary), CTX(urinary)
• Bone formation markers
– BAP (Bone alkaline phosphatase)(serum)
– PINP (type I procollagen-N-propeptide)(serum)
• Bisphosphonates
• Raloxifene,
• Estrogen
CTX Lab Values
(C-‐teminal cross-‐linked telopepYde)
• >150 pg/mL = Minimal Risk
• 100 - 150 pg/mL = Moderate Risk
• <100 pg/mL = High Risk
• Standard grafting techniques and dental implant

placements cab be used if guided by the published
serum CTX values
– Ref. Marx, RE; Reconstruction of defects caused by

bisphosphonate-induced osteonecrosis of the jaws; J Oral
Maxillofac Surg 2009 My;67(5 Suppl):107-19
Bone Marker Guidelines
J Bone Miner Metab (2005)23:97-‐104

Lab PerscripYon
• Please obtain the following lab tests and fax

results to my office (fax: xxx-xxx-xxxx)
1.sNTX (serum cross-linked N-telopeptides of type I

collagen)
2.sBSAP (serum bone specific alkaline

phosphatase) - NOTE: this is not a total alk phos
with a bone fraction
PRP and ONJ
• PRP has been shown to be successful in treating
ONJ
– J Am Dent Assoc. 2007 Jul;138(7):971-7
– J Oral Maxillofac Surg. 2007 Feb;65(2):349-55
• Success due to growth factors that stimulate soft

tissue healing, promote angiogenesis
ONJ - Other Drugs
• Monoclonal antibodies
•Denosumab
•Incidence of ONJ following similar to bisphosphonate therapy
•Bevacizumab
• Multikinase inhibitor
•Sunitinib
Denosumab (Prolia™)
(den OH sue mab)
• Newer bone antiresorptive agent
• Monoclonal antibody
• FDA approved for:
– Osteoporosis
– Metastatic cancer of bone
• Given as a subcutaneous injection twice a year
• Inhibits the RANK ligand - a key regulator of bone-resorbing

osteoclasts
Denosumab -‐ Why should we
care?
• Approved by the FDA
• Multiple cases relate its use with osteonecrosis of the jaws
• All Dentists (General and Specialists) must understand:
– denosumab’s mechanism of action &

pharmacokinetics
– Similarities and differences with
bisphosphonates
Case Report
• 67-year-old male
• Exposed bone in the maxilla an mandible 6-months

following the removal of teeth #’s 3 ,4, 5, & 30
• Hypertension, obesity, prostate cancer
• No bisphosphonates or radiation
• 40-pack/year history of tobacco use
• Meds: HCTZ, lisinopril, metoprolol, ibuprofen, calcium,

vitamin D supplements
Case Report
• Chlorhexidine gluconate for exposed bone in jaw
• Goserelin aetate - 3 years - (Gonadotropin

releasing hormone agonist) treatment of prostate
cancer
• Denosumab (Xgeva) for 22 months prior to ONJ

- stopped denosumab 4 months post-tooth
extractions (26 total injections)
Case Report
• Presented for treatment of ONJ 6 months

following tooth removal
• No facial edema
Bevacizumab, Sunitinib, &
Denosumab
• All 3 of these drugs have been reported to
• cause ONJ when administered in isolation or found to increase the

severity of ONJ when given in conjunction with bisphosphonates.
• 55 bevacizumab cases of ONJ among
• 800,000 patients
• 30 Sunitinib-related ONJ in 100,000 patients

Denosumab (Prolia®)
• Monoclonal antibody with affinity for

nuclear factor-kappa ligand (RANKL)
Denosumab (Prolia®)
• Prevention of skeletal-related events in bone

metastases from solid tumors
• Treatment of osteoporosis in postmenopausal

females (Prolia™):
• Prevention of androgen-induced bone loss in

nonmetastatic prostate cancer
• Prevention of aromatase inhibitor-induced bone loss

in nonmetastatic breast cancer (unlabeled use)
Labeling on denosumab
• ONJ, which can occur spontaneously, is generally associated with
tooth extraction and/or local infection with delayed healing, and
has been reported in patients receiving Prolia. An oral exam
should be performed by the prescriber prior to initiation of Prolia.
A dental examination with appropriate preventive dentistry should
be considered prior to treatment in patients with risk factors for
ONJ. Good oral hygiene practices should be maintained during
treatment with Prolia.
• For patients requiring invasive dental procedures, clinical

judgment should guide the management plan of each patient.
Patients who are suspected of having or who develop ONJ should
receive a thorough examination should receive care by a dentist
or an oral surgeon.
The Future of Clinical Osteoporosis
Prevention/Treatment
• Conclusion
did not enha
treatments. A
neither agen
in combinati
Journal of Biological Chemistry, Vol. 280, No. 8, February 25, pp.7317-‐7325, 2006
Pancreatic hormones
Diabetes Type I and II
In Dentistry

DIABETES MELLITUS
• > 18.4% Population over age 65 have some form of
diabetes
• Diabetes type 2 IS ↑ 6% per year
• Ref. Rees 2000
• Complications
• Retinopathy, nephropathy, neuropathy,
micro- and macro-vascular disease,
altered wound healing

Natural
Course of
Diabetes
Diagnosing Diabetes
• Fasting (8 hours) blood glucose >126 mg/dl

• Random blood glucose > 200 mg/dl
• 4 hour Post prandial glucose >140 mg/dl
SUCCESS RATES AND
DIABETES MELLITUS
• IMPLANT SUCCESS RATES 85.6% (Fiorellini et al.,

2000) to 94.3% (Balshi & Wollfinger, 1999)
• EARLY IMPLANT FAILURE RATE 3.2% vs. LATE

IMPLANT FAILURE RATE 5.4% (Esposito et al., 1997)
• VARIOUS REPORTS SHOW INCREASED FAILURE

RATE AFTER 1 YEAR (Fiorellini et al., 2000; Morris et al., 2000; Shernoff
et al., 1994)

SUCCESS RATES AND
DIABETES MELLITUS
• IMPLANT SUCCESS RATES 85.6% (Fiorellini et al.,
2000) to 94.3% (Balshi & Wollfinger, 1999)
• EARLY IMPLANT FAILURE RATE 3.2% vs. LATE

IMPLANT FAILURE RATE 5.4% (Esposito et al., 1997)
• VARIOUS REPORTS SHOW INCREASED FAILURE

RATE AFTER 1 YEAR (Fiorellini et al., 2000; Morris et al., 2000; Shernoff
et al., 1994)

DIABETES MELLITUS
• ANIMAL STUDIES
• SIG. REDUCED BONE-TO-IMPLANT CONTACT IN

UNCONTROLLED DIABETICS vs. NON-DIABETICS
• Nivens et al., 1998; Takeshita et al., 1998
• INSULIN-CONTROLLED DM HAD GREATER BONE

DENSITY THAN IN NON-DM CONTROLS
• Fiorellini et al., 1999
• FOR DM OSSEOINTEGRATION WAS REDUCED 1o IN

TRABECULAR BONE, WHEREAS NO DIFFERENCES
WERE SEEN IN CORTICAL BONE
• McCracken et al., 2000

DIABETES MELLITUS
• INSULIN DEFICIENCY
• HYPERGLYCEMIA
• KETOACIDOSIS & ATHEROSCLEROSIS (DUE TO ABSENCE OF
INFLUENCE ON LIPID METABOLISM)
• ABSOLUTE
• TYPE 1 DIABETES
• RELATIVE
• TYPE 2 DIABETES
• BETA CELLS SYNTHESIZE INSULIN BUT AN INADEQUATE AMOUNT
• OR TISSUES ARE RESISTANT TO INSULIN ACTION

INSULIN
• PURPOSE – TRANSPORT GLUCOSE INTO CELLS
WHERE IT CAN BE USED FOR ENERGY
REACTIONS
• IN SKELETAL MUSCLE & LIVER GLUCOSE IS STORED

AS GLYCOGEN FOR LATER USE
• THIS CAN RESULT IN HYPOGLYCEMIA

TYPE 1 DIABETES
• IDDM
• Rx: INSULIN
• RAPID ACTING
• LISPRO
• SHORT ACTING
• REGULAR, SEMILENTE
• INTERMEDIATE ACTING
• NPH, LENTE
• LONG ACTING
• PZI, ULTALENTE

SURGERY REQUIREMENTS
• REVIEW HbA1C (IDEAL <7 mg%)
• STABLE DM, KNOWLEDGABLE PATIENT, NOT

EXTENSIVE PROCEDURE & WITHIN YOUR
COMFORT LEVEL – ? NEED FOR CONSULT
• IF NOT STABLE, POOR KNOWLEDGE BASE FOR

PATIENT, EXTENSIVE PROCEDURE – CONSULT

Insulin Diabetic Patient Surgery
Requirements
• Eat a light breakfast - do surgery in a.m.

• Half (2/3) the dose of A.M. intermediate insulin
• Check blood glucose level in office prior to beginning
surgery
• Plasma glucose level 100-140 preferred
• Use D5W
• Plasma levels may remain elevated for 3-4 days,
especially if steroids are used, but attempt to keep
between 80 and 140
• Ref. Gill, The Care of the Diabetic Patient During Surgery, 1993

Type II Diabetes Drugs
 Sulfonylureas
 Biguanides
 Thiazolidinediones
 α-glucosidase inhibitors
 Meglitinides
 DPP-4 inhibitiors
SURGERY REQUIREMENTS
• REVIEW HbA1C (IDEAL <7 mg%)
• STABLE DM, KNOWLEDGABLE PATIENT, NOT

EXTENSIVE PROCEDURE & WITHIN YOUR
COMFORT LEVEL – ? NEED FOR CONSULT
• IF NOT STABLE, POOR KNOWLEDGE BASE FOR

PATIENT, EXTENSIVE PROCEDURE – CONSULT

Diabetes Controlled with Oral Agents
• Hold medication day of surgery
• Eat a light breakfast - do surgery in a.m.
• Ref. Gill, The Care of the Diabetic Patient During Surgery, 1993

Top 25 Drugs
2013

Top 25 Drugs by Spending
Total US Market $307.4 B

#1 Lipitor (Atorvastatin) $7.2B
• Antilipemic agent (HMG-CoA Reductase
inhibitor)
• Inhibits the rate limiting enzyme in
cholesterol synthesis (reduces
production of mevalonic acid from HMG-
Co-A)
• Results in a compensatory ↑ in LDL
receptors on hepatocyte membranes and
stimulation of LDL catabolism.
• Drug interaction with macrolides
#2 Nexium (Esomeprazole) $6.3B
• Proton pump inhibitor - suppresses gastric

acid secretion by inhibition of the H /K ion
+ +
exchange pump
• Xerostomia - normal salivary flow resumes
upon discontinuation
• High dose long-term interfers with bone
repair

#3 PLAVIX -‐ CLOPIDOGREL $6.1 B
®
• BLOCKS THE ADP RECEPTOR WHICH PREVENTS THE

BINDING OF FIBRINOGEN TO THAT SITE
• DOES NOT ALTER THE RECEPTOR
• REDUCES # OF FUNCTIONAL ADP RECEPTORS
James L. Rutkowski D.M.D., Ph.D.

PLAVIX ® -‐ CLOPIDOGREL
• MONITOR WITH PLATELET AGGREGATION -‐ ? value

• INITIAL 2 TO 4 WEEKS MAY CAUSE THROMBOCYTOPENIA
– CHECK PLATELETS
• RARELY NECESSARY TO D/C
• SURGERY IF MULTIPLE SITES OR EXTENSIVE ? – get
consultaYon
– DISCONTINUE 7 DAYS PRIOR TO PROCEDURE (RARELY
NECESSARY!)

PLAVIX ® -‐ CLOPIDOGREL -‐ WOW!!!!
• 30% of populaYon has a geneYc variant in liver metabolizing
enzymes that affect efficacy of clopidogrel -‐ no effect at all
–CYP2C19 converts clopidogrel to an acYve metabolite.
–Genes which encode and express liver enzymes responsible for
metabolism exist in several polymorphic states (CYP2C19 has 4 variants
with reduced funcYon)
–RelaYve reducYon of 32% in acYve metabolite
–53% higher risk for primary efficacy outcome of death from cardiovascular
causes, MI, stroke
–Stent thrombosis in carriers 3 X that of non-‐carriers
–Ref. Mega JL et al., “Cytochrome P-‐450 Polymorhisms and Response to
Clopidogrel” NEJM, 2009, 360(4):354-‐62
James L. Rutkowski D.M.D., Ph.D. 315

• AnYplatelet agent and aggregaYon inhibitor
–For ➡ thromboYc cardiovascular events (stent
thrombosis
Prasugrel
Clopidogrel
Non-‐fatal
Non-‐fatal subsequent
subsequent heart
heart aEacks
aEacks
9.1% 7%
Deaths and strokes equal
Risk of significant fatal bleeding
+ ++

• Pro-‐drug
• Irreversibly blocks P2Y12 component of adenosine
diphosphate (ADP) receptors on platelets for their
lifespan
–➡ platelet acYvaYon and platelet aggregaYon
–Normal platelet acYvity does not return (new platelets in
5 to 9 days azer D/C
–Loading dose 60 mg followed by maintenance dose of 10
mg daily.
–Should take with ASA 75 to 325 mg daily

• GeneYc variants in liver metabolizing enzymes
do not affect efficacy
–Undergoes rapid intesYnal and serum metabolism via
esterase-‐mediated hydrolysis to a thiolactone (inacYve
metabolite), which is then converted, via CYP3A4 &
CYP2B6 enzyme oxidaYon, to the acYve metabolite
designated as R-‐138727.

• Reduce rate of thromboYc cardiovascular events
in pts with acute coronary syndrome (ACS):
unstable angina, non-‐ST elevaYon MI, ST
elevaYon MI
• More effecYve than clopridogrel

–Inhibitors of CYP3A4
–Ketocanazole
–Itaconazole
–Voriconazole
–Clarithromycin (Biaxin®)
–Erythromycin
• NSAIDs

• Mechanism: An acYve, reversible platelet inhibitor
• CYP3A4 converts Ycagrelor to another acYve
reversible platelet inhibitor -‐ which is the major acYve
metabolite
• Act at the ADP-‐receptor
• Loading dose 180 mg then 90 mg BID
–Give with loading dose ASA 325 mg then 75 -‐ 100 mg. Daily
–ASA doses above 100 mg/day reduce effecYveness of
Ycagrelor and should be avoided

• Do NOT D/C without consultaYon
• Expect bleeding and echymosis
• Pts ozen have SOB
• No coagulaYon parameters suggested

Boehringer Ingelheim
• For prevention of stroke and systemic

embolism (blood clots) in patients with
atrial fibrillation
• first replacement for warfarin
(Coumadin®) since Coumadin was
approved in 1954.

“Serine protease”

anticoagulant
• acts by inhibiting thrombin, an enzyme in the blood
that is involved in blood clotting
• thrombin (serine protease) enables the conversion of
fibrinogen to fibrin during the coagulation cascade, its
prevention prevents the development of a thrombus.
• recommended dose is a 150 mg capsule taken orally
• Warfarin therapy requires patients to undergo
periodic monitoring with blood tests
• INR monitoring not necessary for dabigatran.
• Measure of Effect
• At therapeutic doses prolongs the activated
partial thromboplastin time (aPTT)
• oral dose of 150 mg twice daily, the median
peak aPTT is approximately twice that of
control values
• Twelve hours after the last dose, the median
aPTT is 1.5x control
• INR test is relatively insensitive to the activity of
dabigatran and may not be elevated in patients
on dabigatran.
• Absorption and Metabolism

• After swallowing a dabigatran (Pradaxa) capsule, peak
blood level occurs in 1 hour. The half-life is 12 to 17
hours.
• not metabolized by CYP enzymes

• After oral administration, dabigatran etexilate is
converted to dabigatran through esterase-catalyzed
hydrolysis of the molecule in plasma
• Dabigatran is not a substrate, nor inhibitor, nor

inducer of CYP 450 enzymes

Dabigatran and Risk of Bleeding
• ↑ risk of bleeding and can cause significant, and sometimes fatal, bleeding
• Drugs that can increase the risk of bleeding include antiplatelet agents
and chronic use of NSAIDs
• RE-LY trial, life-threatening bleeding occurred at an annualized rate of
1.5% for Pradaxa 150 mg and 1.8% for warfarin.
• Discontinuing Pradaxa for surgery places the patient at an↑ risk of stroke
• If anticoagulation must be temporarily discontinued for any reason,
therapy should be restarted as soon as possible.
• Dental patients who may have a high risk of bleeding if taking Pradaxa
include those over 75 years of age, or are taking aspirin, or long term
NSAIDs, or clopidogrel (Plavix®) or prasugrel (Effient®).
• RE-LY study Connolly SJ, Ezekowitz MD,Yusuf S, et al, "Dabigatran Versus
Warfarin in Patients With Atrial Fibrillation," N Engl J Med, 2009, 361(12):
1139-51.

#4 Advair Diskus(Salmeterol and FluYcasone)
$4.7B
• Long acYng β2 agonist (bronchodilaYon)
• CorYcosteroid inhalant (anY-‐inflammatory,
immunosuppressive, anY-‐proliferaYve, potent
vasoconstrictor)
• Act locally -‐ li~le effect on heart rate
• Dental: Localized infecYons with Candida
albicans or Aspergillus niger frequently occur in
mouth and pharynx

TreaYng Candida albicans or Aspergillus niger infecYons
• Diflucan (fluconazole)
–Loading dose: 200 mg on day 1; maintenance dose 100 mg daily
for ≥2 weeks. Note: Therapy with 100 mg daily is associated with
resistance development (Rex, 1995).
–AlternaYve dosing: 100-‐200 mg daily for 7-‐14 days for
uncomplicated, moderate-‐to-‐severe disease; chronic therapy of
100 mg 3 Ymes weekly is recommended in immunocompromised
paYents with history of oropharyngeal candidiasis (OPC) (Pappas,
2009)
• Dental UseTreatment of suscepYble fungal infecYons in the oral
cavity including candidiasis, oral thrush, and chronic mucocutaneous
candidiasis treatment of esophageal and oropharyngeal candidiasis
caused by Candida species; treatment of severe, chronic
mucocutaneous candidiasis caused by Candida species
• Numerous drug interacYons
#5 Abilify (Aripiprazole) $4.6B
• AnYpsychoYc agent
• Exhibits high affinity for D2, D3, 5-‐HT1A, and 5-‐
HT2A receptors; moderate affinity for D4, 5-‐HT2c,
5HT7, alpha adrenergic, and H1 receptors plus
serotonin reuptake transporter
• ParYal agonist at the D2 and 5-‐HT1A receptors
• Antagonist at the 5-‐HT2A receptor

#5 Abilify (Aripiprazole)
• Effect on dental treatment
–Extrapyramidal symptoms
–Xerostomia and changes in salvaYon (normal salivary
flow resumes upon disconYnuaYon)
–RecomendaYon: extra fluoride

#6 Seroquel (QueYapine) $4.4B
• AnYpsychoYc agent
• Antagonist at the D2 and 5-‐HT2 receptors
• No affinity for the benzodiazepine receptors
• Local anesthesia/vasoconstrictor precauYons
–Prolongs QT interval → torsade de pointes
–Epinephrine effect is unkown, therefore exercise
cauYon!!!!
• Use epi 1:200,000 -‐ one carpule -‐ observe for 5 minutes
• Xerostomia (normal flow resumes upon disconYnuaYon

#7 Singulair (montelukast) $4.1B
• Leukotriene-‐receptor antagonist
• Dental treatment: may cause tooth pain
• Effects on Bleeding: Increased bleeding and
thrombocytopenia
• Dose: Adult 10 mg once a day

#7 Singulair (montelukast)
• Mechanism of AcYon: SelecYve leukotriene receptor
antagonist that inhibits the cysteinyl leukotriene receptor.
Cysteinyl leukotrienes and leukotriene receptor occupaYon
have been correlated with the pathophysiology of asthma,
including airway edema, smooth muscle contracYon, and
altered cellular acYvity associated with the inflammatory
process, which contribute to the signs and symptoms of
asthma. Cysteinyl leukotrienes are also released from the
nasal mucosa following allergen exposure leading to
symptoms associated with allergic rhiniYs.

#8 Crestor (RosuvastaYn) $3.8B
• Antilipemic agent
• Inhibits the rate limiting enzyme in cholesterol
synthesis (reduces production of mevalonic
acid from HMG-Co-A)
• Results in a compensatory ↑ in LDL receptors
on hepatocyte membranes and stimulation of
LDL catabolism.

#9 Actos (piogliazone) $3.5B
• Thiazolidinedione anYdiabeYc agents
• Improves target cell response to insulin without
increasing pancreaYc insulin secreYon
• Effect on dental treatment
–Tooth pain
–Appointments in AM to minimize stress-‐induced
hypoglycemia
–Major procedures -‐ hold drug day of surgery

#10 Epogen (epoeYn alfa) $3.3B
• Pharmacologic Category: Colony SYmulaYng Factor; Erythropoiesis-‐
SYmulaYng Agent (ESA); Growth Factor; Recombinant Human
ErythropoieYn
• Use: Treatment of anemia due to concurrent myelosuppressive
chemotherapy in pa5ents with cancer (nonmyeloid malignancies)
receiving chemotherapy (palliaYve intent) for a planned minimum of 2
addiYonal months of chemotherapy; treatment of anemia due to
chronic kidney disease (including paYents on dialysis and not on
dialysis) to decrease the need for RBC transfusion; treatment of
anemia associated with HIV (zidovudine) therapy when endogenous
erythropoieYn levels ≤500 mUnits/mL; reducYon of allogeneic RBC
transfusion for elecYve, noncardiac, nonvascular surgery when
perioperaYve hemoglobin is >10 to ≤13 g /dL and there is a high risk for
blood loss

#10 Epogen (epoeYn alfa)
• Mechanism of AcYon
–Induces erythropoiesis by sYmulaYng the
division and differenYaYon of commi~ed
erythroid progenitor cells
–Induces the release of reYculocytes from
the bone marrow into the bloodstream,
where they mature to erythrocytes.

#11 Remicade (Infliximab) $3.3B
• Pharmacologic Category
–AnYrheumaYc, Disease Modifying; GastrointesYnal
Agent, Miscellaneous; Immunosuppressant Agent;
Monoclonal AnYbody; Tumor Necrosis Factor (TNF)
Blocking Agent
• Effects on Bleeding

–associated with thrombocytopenia, anemia, and
hemolyYc anemia

#11 Remicade (Infliximab)
–Mechanism of AcYon
• chimeric monoclonal anYbody that binds to human
tumor necrosis factor alpha (TNFα), thereby interfering
with endogenous TNFα acYvity
• Elevated TNFα levels have been found in involved
Yssues/fluids of paYents with rheumatoid arthriYs,
ankylosing spondyliYs, psoriaYc arthriYs, plaque
psoriasis, Crohn’s disease and ulceraYve coliYs
• Biological acYviYes of TNFα include the inducYon of
proinflammatory cytokines (interleukins),
enhancement of leukocyte migraYon, acYvaYon of
neutrophils and eosinophils, and the inducYon of acute
phase reactants and Yssue degrading enzymes
#11 Remicade (Infliximab)
• InfecYons: [U.S. Boxed Warning]
–increased risk for serious infecYons
–infecYons usually developed in paYents receiving

concomitant immunosuppressive agents (eg,
methotrexate or corYcosteroids) and may present as
disseminated (rather than local) disease
– Monitor closely for signs/symptoms of infecYon.

DisconYnue for serious infecYon or sepsis
–Consider 7-‐ to 10-‐day anYbioYc coverage for dental

surgeries James L. Rutkowski D.M.D., Ph.D. 342
#12 Enbrel (etanersept) $3.3B
–AnYrheumaYc, Disease Modifying; Tumor Necrosis
Factor (TNF) Blocking Agent
• Use
–Treatment of moderately-‐ to severely-‐acYve
rheumatoid arthriYs (RA); moderately-‐ to severely-‐
acYve polyarYcular juvenile idiopathic arthriYs (JIA);
psoriaYc arthriYs; acYve ankylosing spondyliYs (AS);
moderate-‐to-‐severe chronic plaque psoriasis

#12 Enbrel (etanersept)

• a recombinant DNA-‐derived protein composed of tumor
necrosis factor receptor (TNFR) linked to the Fc porYon of
human IgG1
• binds tumor necrosis factor (TNF) and blocks its interacYon
with cell surface receptors.

#12 Enbrel (etanersept)
• infecYons: [U.S. Boxed Warning]
–infecYons usually developed in paYents receiving

concomitant immunosuppressive agents (eg,
methotrexate or corYcosteroids) and may present as
disseminated (rather than local) disease
– Monitor closely for signs/symptoms of infecYon.

DisconYnue for serious infecYon or sepsis

#13 Cymbalta (duloxeYne) $3.2B
• AnYdepressant
• Potent inhibitor of neuronal serotonin and NE
reuptake and weak inhibitor of dopamine
reuptake
• Local AnestheYc/vasoconstrictor precauYons
–With inhibiYon of NE reuptake -‐ use cauYon with epi
• Use 1:200,000 one carpule and monitor
• Xerostomia and changes in salivaYon (normal
flow returns upon disconYnuaYon

#13 Cymbalta (duloxeYne)
• May impair platelet aggregaYon → risk of bleeding
especially if used with NSAIDs
• Bleeding has been reported to range from minor
bruising and epistaxis to life-‐threatening
hemorrhage
• No need to disconYnue for dental treatment -‐ be
aware of a potenYal for a prolonged bleeding Yme
• NSAIDs drug interacYon is a Risk level C : Monitor
therapy

#14 AvasYn (bevuhsizuhmab) #3.1B
–AnYneoplasYc Agent, Monoclonal AnYbody; Vascular
Endothelial Growth Factor (VEGF) Inhibitor
• Use
–Treatment of metastaYc colorectal cancer (first-‐or
second-‐line treatment and second-‐line azer
progression on a first-‐line treatment containing
bevacizumab); treatment of unresectable, locally
advanced, recurrent or metastaYc nonsquamous,
nonsmall cell lung cancer; treatment of progressive
glioblastoma; treatment of metastaYc renal cell cancer
(not an approved use in Canada)
#14 AvasYn (bevuhsizuhmab)
• a recombinant, humanized monoclonal anYbody which
binds to, and neutralizes, vascular endothelial growth
factor (VEGF), prevenYng its associaYon with endothelial
receptors, Flt-‐1 and KDR
• VEGF binding iniYates angiogenesis (endothelial

proliferaYon and the formaYon of new blood vessels)
• inhibiYon of microvascular growth is believed to retard the

growth of all Yssues

–Effects on Dental Treatment
• Xerostomia (normal salivary flow resumes upon
disconYnuaYon), stomaYYs, taste disorder
• Minor gum bleeding has been reported in 2% to 4% of
paYents
• Thrombocytopenia has been reported
• osteonecrosis of the jaw (ONJ)

• Three case reports describe the development of ONJ in
associaYon with bevacizumab therapy
• All cases were cancer paYents treated with bevacizumab
10 mg/kg every 2 weeks and 15 mg/kg every 3 weeks
(EsYlo, 2009; Greuter, 2008)
• Another report showed that a combinaYon of
bisphosphonates and anYangiogenic factors (primarily
bevacizumab) induces ONJ more frequently than
bisphosphonates alone. Of the 25 paYents receiving
concurrent treatment with bisphosphonates and the
anYangiogenic drug bevacizumab, four developed ONJ
(16%). Of the 91 paYents receiving bisphosphonates
without anYangiogenic factors, one developed ONJ (1.1%),
a significant staYsYcal difference (Christodoulou, 2009).
• Hemorrhage: [U.S. Boxed Warning]
–Severe or fatal hemorrhage, including hemoptysis, gastrointesYnal
bleeding, central nervous system hemorrhage, epistaxis, and vaginal
bleeding have been reported (up to 5 Ymes more frequently if
receiving bevacizumab)
• Wound dehiscence: [U.S. Boxed Warning]

–incidence of wound healing and surgical complicaYons is
increased in paYents who have received bevacizumab;
disconYnue with wound dehiscence. Although the appropriate
interval between withholding bevacizumab and elecYve surgery
has not been defined, bevacizumab should be disconYnued at
least 28 days prior to surgery and should not be reiniYated for at
least 28 days azer surgery and unYl wound is fully healed

#15 OxyConYn (dihydrohydroxycodeinone;
oxycodone) $3.1B
• Binds to CNS opiate receptors → inhibiYon of
ascending pain pathways → altering pain
percepYon and response
• Produces CNS ↓
• Xerostomia (normal salivary flow resumes upon
disconYnuaYon)
• SedaYon in denYstry ?

#16 Neulasta (pegfilgrasYm) $3.0B
–Colony SYmulaYng Factor
• Use
–To decrease the incidence of infecYon, by sYmulaYon
of granulocyte producYon, in paYents with
nonmyeloid malignancies receiving myelosuppressive
therapy associated with a significant risk of febrile
neutropenia

#16 Neulasta (pegfilgrasYm)
• SYmulates the producYon, maturaYon, and acYvaYon of
neutrophils
• acYvates neutrophils to increase both their migraYon and
cytotoxicity

#17 Zyprexa (olazapoine) $3.0B
• AnYmanic and anYpsychoYc agent
• Potent antagonist at serotonin and dopamine,
histamine and α adrenergic receptors
• Weak agonist at benzodiazepine receptors

#18 Humira (adalimyoomab) $2.9B
– AnYrheumaYc, Disease Modifying; GastrointesYnal Agent, Miscellaneous;
Monoclonal AnYbody; Tumor Necrosis Factor (TNF) Blocking Agent
• Use
– acYve rheumatoid arthriYs (moderate-‐to-‐severe)
– acYve psoriaYc arthriYs
– ankylosing spondyliYs
– Crohn’s disease
– ulceraYve coliYs in paYents unresponsive to immunosuppressants
– plaque psoriasis
– juvenile idiopathic arthriYs

#18 Humira (adalimyoomab)

–recombinant monoclonal anYbody that binds to human tumor
necrosis factor alpha (TNF-‐alpha), thereby interfering with
binding to TNFα receptor sites and subsequent cytokine-‐driven
inflammatory processes
–Reduces signs and symptoms and maintains clinical remission
in Crohn’s disease and ulceraYve coliYs
–reduces epidermal thickness and inflammatory cell infiltraYon
in plaque psoriasis.

#18 Humira (adalimyoomab)
–infecYons: [U.S. Boxed Warning]
–infecYons usually developed in paYents receiving concomitant

immunosuppressive agents (eg, methotrexate or
corYcosteroids) and may present as disseminated (rather than
local) disease
– Monitor closely for signs/symptoms of infecYon. DisconYnue

for serious infecYon or sepsis

#19 Lexapro (escitalopram) $2.8B
• AnYdepressant
• Inhibits reuptake of serotonin with li~le to no
effect on NE or dopamine
• Xerostomia (normal flow returns upon
disconYnuaYon)

#19 Lexapro (escitalopram)
hemorrhage

#19 Lexapro (escitalopram)
• Opioid analgesics -‐ may enhance the
serotonergic effect → serotonin syndrome Risk
level C: Monitor therapy
• Macrolide anYbioYcs may decrease metabolism
of escitalopram; Risk level C: Monitor therapy
–ExcepYon azithromycin

#20 Rituxan (rituksimab) $2.8B
• AnYneoplasYc Agent, Monoclonal AnYbody; AnYrheumaYc Miscellaneous;
Immunosuppressant Agent; Monoclonal AnYbody
• Use
– non-‐Hodgkin lymphomas (NHL):
– Relapsed or refractory, low-‐grade or follicular B-‐cell NHL (as a single agent)
– Follicular B-‐cell NHLNonprogressing, low-‐grade B-‐cell NHL (as a single agent azer
first-‐line CVP treatment)
– Diffuse large B-‐cell NHLTreatment of CD20-‐posiYve chronic lymphocyYc
leukemia (CLL) (in combinaYon with fludarabine and cyclophosphamide)
– rheumatoid arthriYs (in combinaYon with methotrexate) in adult paYents with
inadequate response to one or more TNF antagonists
– granulomatosis with polyangiiYs (GPA; Wegener’s granulomatosis) (in
combinaYon with glucocorYcoids)
– microscopic polyangiiYs (MPA) (in combinaYon with glucocorYcoids)
#20 Rituxan (rituksimab)
–Effects on Bleeding
• significant myelosuppression, potenYally
including significant reducYon in platelet counts
(thrombocytopenia grades 3/4: 2% to 11%)
• altered hemostasis
• medical consult is suggested

• monoclonal anYbody directed against the CD20
anYgen on B-‐lymphocytes.
#21 Aricept (donepezil) $2.5B
• Tx Alzheimer’s disease
• Acetylcholinesterase inhibitor
• Reversibly and non-‐compeYYvely inhibits
centrally-‐acYve acetylcholinesterase →
increased concentraYons of acetylcholine
available for synapYc transmission in the CNS
• ↑ saliva

#22 Lovenox (eenoksaparin) $2.3B
– Low Molecular Weight Heparin
• Use
–Acute coronary syndromes: Unstable angina (UA), non-‐ST-‐elevaYon
(NSTEMI), and ST-‐elevaYon myocardial infarcYon (STEMI)
–DVT prophylaxis: Following hip or knee replacement surgery, abdominal
surgery, or in medical paYents with severely-‐restricted mobility
–DVT treatment (acute): InpaYent treatment (paYents with and without
pulmonary embolism) and outpaYent treatment (paYents without
pulmonary embolism)

#22 Lovenox (eenoksaparin)
–Effects on Bleeding

• Hemorrhage may occur at virtually any site
• RouYne coagulaYon tests, such as prothrombin Yme
(PT) and aPTT, are relaYvely insensiYve measures of
enoxaparin injecYon acYvity and, therefore, unsuitable
for monitoring
• Moderate thrombocytopenia occurred at a rate of ~1%
• Medical consult is suggested.

#22 Lovenox (eenoksaparin)

–an anYcoagulant by enhancing the inhibiYon rate of
cloˆng proteases by anYthrombin III impairing
normal hemostasis and inhibiYon of factor Xa
–Low molecular weight heparins have a small effect
on the acYvated parYal thromboplasYn Yme and
strongly inhibit factor Xa
• No NSAIDS

#23 Atripla (efaverenz) $2.2B
–AnYretroviral Agent, Reverse Transcriptase Inhibitor
(Non-‐nucleoside); AnYretroviral Agent, Reverse
Transcriptase Inhibitor (Nucleoside); AnYretroviral
Agent, Reverse Transcriptase Inhibitor (NucleoYde)
• Use
–HIV infecYon

#23 Atripla (efaverenz)

–xerostomia (normal salivary flow resumes
upon disconYnuaYon)
–abnormal taste

#24 Copaxone (glaYramerasetate) $2.2B
–Biological, Miscellaneous
• Use
–Management of relapsing-‐remiˆng type mulYple
sclerosis, including paYents with a first clinical episode
with MRI features consistent with mulYple sclerosis

#24 Copaxone (glaYramerasetate)

• UlceraYve stomaYYs, salivary gland enlargement, and
oral moniliasis
• induces and acYvate T-‐lymphocyte suppressor cells
specific for a myelin anYgen
• interferes with the anYgen-‐presenYng funcYon of
certain immune cells opposing pathogenic T-‐cell
funcYon

#25 Spiriva $2.0B
• CompeYYvely and reversibly inhibits the acYon
of acetylcholine at muscrinic receptors (M3) in
bronchial smooth muscle → broncholdilaYon
• Xerostomia (normal saliva flow resumes upon
disconYnuaYon)

Other Drugs to Know

Lantus (Insulin glargine)
• Long-‐acYng insulin analog
• PaYents with type I diabetes should be
appointed in the morning to minimize chance of
stress-‐induced hypoglycemia
–Make certain they eat something unless deep/general
anesthesia

Lyrics (pregabalin)
• Analgesic, anYconvulsant
• Binds to α2Δ subunits of voltage-‐gated calcium

channels in CNS, inhibiYng excitatory
neurotransmi~er release
• Structurally related to GABA -‐ does not bind to

GABA or benzodiazepine receptors
Lyrics (pregabalin)
• AnYnocicepYve and anYconvulsant acYvity
• ↓ symptoms of peripheral neuropathies
• ↓ frequency of seizures
• Xerostomia and changes in salivaYon (normal
flow returns upon disconYnuaYon)
• Bleeding -‐ may rarely be associated with
thrombocytopenia

Diovan (valsartan)
• Tx hypertension
• Angiotensin II receptor blocker
• Antagonist at angiotensin II (AT2) receptors
–Displaces angiotensin II from the AT1 receptor and
produces ↓BP by antagonizing AT1-‐induced
vasoconstricYon, aldosterone release, catecholamine
release, arginine vasopressin release, water intake, and
hypertrophic responses.
–Results in more efficient blockade of the cardiovascular
effects of angiotensin II and fewer side effects than the ACE
inhibitors.

Diovan (valsartan)
• NSAID -‐ valsartan drug interacYon
–NSAIDs may diminish receptor blockade, glomerular
filtraYon and renal funcYon
• Risk level C: Monitor therapy

NSAIDs - Antihypertensive
Drug Interaction
• An analysis of >12 randomized trials of
antihypertensive therapy found that a 20% to 40%
reduction in cardiovascular disease required only a 5-
to 6-mm-Hg decrease in diastolic BP.
• This magnitude of BP reduction is typically seen with
any single antihypertensive drug treatment.
• It is also represents the usual increase in BP seen
when nonsteroidal anti-inflammatory drugs (NSAIDs)
interact with antihypertensive drugs.
• Horne, Hansten; Pharmacy Times April 2006
Effexor XR (venlafaxine)
• AnYdepressant
• Potent inhibitor of neuronal serotonin and NE
reuptake and weak inhibitor of dopamine
reuptake
• AcYve metabolite o-‐desmethylvenlafaxine (ODV)

• Local anestheYc/vasoconstrictor precauYon:
–Blockade of NE reuptake in CNS synapses may lead to
an ↑ BP
– Venlafaxine has been known to produce a sustained
increase in diastolic BP and HR as a side effect
– ∴ administer epinephrine with cauYon
• Use 1:200,000 monitor BP and HR

hemorrhage

Concerta (methilfenidate)
• CNS sYmulant
• Up to 10% of paYents taking amphetamine-‐like
drugs may present with hypertension.
• ∴ monitor BP prior to using vasoconstrictor
(monitor intra-‐procedure also)

Levaquin (levofloxacin)
• Fluoroquinolone anYbioYc
• Inhibits DNA-‐gyrase in suscepYvle organsms
thereby inhibits relaxaYon of supercoiled DNA
and promotes breakage of DNA strands.
• DNA gyrase (topoisomerase II) is an essenYal
bacterial enzyme that maintains the superhelical
structure of DNA and is required for DNA
replicaYon and transcripYon, DNA repair,
recombinaYon and transposiYon

Levaquin (levofloxacin)
• Levofloxacin prolongs QT interval and can cause
torsade de pointes
• Is is not known what effect vasoconstrictors in
local anestheYc (Epi) will have on paYents with a
known history of congenYtal prolonged QT
interval or in paYents taking medicaYons that
prolong QT interval
• ∴ use epi 1:200,000 and monitor

Celebrex - celecoxib
• COX-2 selective NSAID
• Inhibits prostaglandin synthesis by ↓ the
activity of COX-2 resulting in decreased
formation of prostaglandin precursors
• Analgesic, anti-inflammatory, and antipyretic
properties
• Does not inhibit COX-1 at normal doses,
but may at high doses

• Stomatitis, abnormal taste, xerostomia

(normal flow resumes upon discontinuation
• Tooth pain
• May enhance the adverse/toxic effect of
other NSAIDs given simultaneously
• Risk level C: Monitor therapy
• Since COX-2 and not COX-1 is inhibited there
may not be a bleeding issue
• COX-1 is involved in platelet aggregation

• Doses up to 800 mg and multiple doses of 600
mg twice a day had no effect on platelet
aggregation or bleeding time.
• Naproxen 500 mg BID, ibuprofen 800 mg TID,

or diclofenac 75 mg BID significantly reduced
platelet aggregation and prolonged the bleeding
time
Diovan HCT
(valsartan/ hydrochloriathiazide)
• Same as #18 Diovan except with

hydrochloriathiazide (HCT)
• HCT may cause hypokalemia -‐ resulYng in cardia
arrhythmia
– Use vasoconstrictors (epi) with cauYon
– RecommendaYon: use epi 1:200,000 and monitor

Januvia (sitaglipYn)
• AnYdiabeYc agent [dipepidyl pepYdase IV (DPP-‐
IV) inhibitor
• Inhibits DPP-‐IV enzyme resulYng in prolonged
acYve increYn levels [increYn regulates glucose
homeostasis by ↑ insulin synthesis and release
from pancreaYc beta cells and decreasing
glucagon secreYon from pancreaYc alpha cells]
• IncreYn is normally inacYvated by DPP-‐IV
enzyme

• SitaglipYn-‐dependent paYents should be
appointed for dental treatment in morning to
minimize chance of stress-‐induced hypoglycemia
• May want to hold day of surgery
• Make sure paYent eats unless deep/general
anesthesia

• CorYcosteroids may diminish the hypoglycemic
effect which can lead to ↑ blood glucose levels
• OR -‐ if prolonged corYcosteroid use and get HPA
axis suppression,then may have episodes of
acute adrenal crisis, which may manifest as
enhanced hypoglycemia, parYcularly in the
seˆng of insulin or other anYdiabeYc agent use
–Risk level C: Monitor therapy

Suboxone
(buprenorphine and naloxone)
• Sublingual administraYon for opioid dependence
• SedaYve effects may be potenYated with
conscious sedaYon techniques

REALITY
• “Expected changes in the nation’s demographics, patient
populations and drug consumption make a
comprehensive review and evaluation of drug
interactions in dental practice particularly timely”
– JADA January 1999
• Keeping up with the volume of new medications, the
aging population, and the increased number of
mediations taken by patients results in a nearly
impossible task. Non-the-less, as clinicians we are
expected to know enough to protect the patient during
treatment appointments.

Drugs used in the Management of
Hypertension
Diuretics
Beta-Blockers
Combined Alpha and Beta Blockers
Angiotensin-Converting Enzyme Inhibitors
(ACEIs)Angiotensin Receptor Blockers (ARBs)
Calcium Channel Blockers (CCBs)
Alpha Blockers
Central Alpha2 Agonists and Other Centrally Acting
Drugs
Direct Vasodilators

NSAIDs - Antihypertensive
Drug Interaction
• An analysis of >12 randomized trials of
antihypertensive therapy found that a 20% to 40%
reduction in cardiovascular disease required only a 5-
to 6-mm-Hg decrease in diastolic BP.
• This magnitude of BP reduction is typically seen with
any single antihypertensive drug treatment.
• It is also represents the usual increase in BP seen
when nonsteroidal anti-inflammatory drugs (NSAIDs)
interact with antihypertensive drugs.
• Horne, Hansten; Pharmacy Times April 2006
NSAIDs + Antihypertensives
• NSAIDs can interfere with renal perfusion

and PGI2 (prostacyclin)
• Interfere with action of antihypertensive
agent
• Result is an increase in BP
• Occurs usually in 4 to 9 days
Beta Blockers (BBs)
• Nonselective
• Propranolol (Inderal ) ®
• Timolol (Blocadren ) ®
• Nadolol (Corgard ) ®
• Pindolol (Visken )®

Non-selective β blockers & Epinephrine
• Oral manifestations
• Taste changes, lichenoid reactions
• Other considerations
• Avoid prolonged use of NSAIDs -
Hypertensive effects

Non-selective β blockers- Epinephrine
Interaction
• Propranolol provides blockade of β - and 1
β2-receptors
• Does not alter α-action

• Addition of epinephrine (α-, β - β - action)
1 , 2
leads to unopposed α action
• Resulting in MASSIVE VASOCONSTRICTION =
possible HYPERTENSIVE CRISIS

Non-selective β blockers & Epinephrine

Selective β1 Blockers
(Cardioselective)
• Meoprolol (Lopressor®)
• Acebutolol (Sectral )®
• Atenolol (Tenormin ) ®
• Betaxolol (Kerlone ) ®
• Bisoprolol (Zebeta )®

Selective β1 Blockers
(Cardioselective)
• Vasoconstrictor interactions
• Cardioselective - normal use
• Oral Manifestations
• Taste changes, lichenoid reactions
• Other considerations
• Avoid prolonged use of NSAIDs
• May reduce antihypertensive effects
Logical Combinations
β- ACE α-
Diuretic CCB
blocker inhibitor blocker
Diuretic -   -    
β-blocker   -  * -  
CCB -  * -    
ACE inhibitor   -   -  
α-blocker         -
* Verapamil + beta-blocker = absolute contra-indication
Kieran McGlade Nov 2001 Department of General Practice QUB

Aspirin for Cardioprotection: Latest
Recommendations from the U.S. Preventive
Services Task Force
Annals of Internal Medicine 2009; 150:396-404.
• Known:
• Heart attack and stroke are the leading causes of death in the
United States.
• ASA is effective in ↓ the risk of CVD

• Task Force found good evidence that ASA ↑ the incidence of
GI bleeding and fair evidence that ASA ↑ the incidence of
hemorrhagic stroke
• Benefits vs risk of ASA use for cardioprotection in adult men

and women without a history of coronary heart disease or
stroke recommendations are:
• Women 55 to 79 years of age to use ASA
when the potential benefit of a reduction in
ischemic strokes outweighs the potential
harm of an increase in GI hemorrhage
• Men 45 to 79 years of age to use ASA when

the potential benefit of a reduction in MI
outweighs the potential harm of an increase
in GI hemorrhage
• Task Force could not recommend the use of

ASA in men and women 80+ years because
current evidence is insufficient to assess the
balance of benefits and risks of ASA
• Annals of Internal Medicine 2009; 150:396-404.

Men 45-59 Years of Age Taking ASA daily for
10 years
• CHD risk of 1 % = 3.2 MIs prevented for

every 1000 men and 8 GI bleeding cases
• CHD risk of 5% = 16 MIs prevented for
every 1000 men and 8 GI bleeding cases.

Women 50-59 Years of Age Taking ASA daily
for 10 years
• Stroke risk of 1% =1.7 strokes prevented for
every 1000 women and 4 GI bleeding cases
• Stroke risk of 5% = 8.5 strokes prevented for
every 1000 women and 4 GI bleeding cases
• Stroke risk of 10% = 17 strokes prevented
for every 1000 women and 4 GI bleeding
cases
• Stroke risk of 15% = 25.5 strokes prevented
for every 1000 women and 4 GI bleeding
cases

• The Task Force recommends against the
use of ASA in
• women < 55 years of age for stroke

prevention
• Men < 45 years of age for MI prevention

• Reasoning is moderate to high certainty
that ASA in these groups have no net
benefit or that the harms outweigh the
benefits.

Aspirin Daily Dose
• Studies show that doses between 75 and 100 mg daily or 100 mg
and 325 mg every other day are beneficial for cardioprotection
• A dosage of approximately 75 mg daily is as effective as higher

doses
• Risk of GI bleeding may increase with dose, the daily dose of 75

mg would seem to be appropriate
• ASA is commercially available as the 81 mg "baby" strength

product and an 81 mg daily dose is consistent with the task force
recommendations.
• "U.S. Preventive Services Task Force, Aspirin for the Prevention

of Cardiovascular Disease: U.S. Preventive Services Task Force
Recommendation Statement," Ann Intern Med, 2009, 150(6):
396-404.

Ketorolac Nasal Spray (Sprix®)
• 3 studies evaluating the efficacy of

ketorolac (nasal spray) for pain relief in
postsurgical patients
• Study #1 describes its use in dental oral
surgery patients
• Studies #2 & 3 describe its use in medical
surgery patients

"Intranasal Ketorolac for Pain Secondary to Third Molar
Impaction Surgery: A Randomized, Double-Blind, Placebo-
Controlled Trial" - Results
Grant GM and Mehlisch DR, J Oral Maxillofac Surg, 2010, 68(5):1025-31.
• 54% women; 79% of the subjects were white. The mean age was 24 years.
• At each time point up to 8 hours, the mean pain intensity difference scores were greater for nasal
ketorolac than placebo.
• Mean pain relief scores over time (where 0 was no relief and 4 was complete relief) - significantly
greater in the ketorolac group compared to the placebo group at all time points, from 20 minutes
(1.3± 0.2 vs 0.4 ± 0.1) through 8 hours (1.1± 0.2 vs 0.4 ± 0.1). 
• Global assessment of pain was significantly better in the ketorolac vs placebo, group - 60% of the
patients who received ketorolac considered pain control as "good" (20%), "very good" (30%) or
"excellent" (10%) vs 13% of patients who received placebo reporting "good" (7.5%) or "very
good" (5%) pain control.
• Median time to rescue medication use in the ketorolac group was 360 minutes, compared to 96
minutes in the placebo group. 
• Finally, the placebo group reported more adverse events (8 subjects with 10 events), compared with
the ketorolac group (3 patients with 3 events). Headache was the only adverse event in the
ketorolac group.

In summary, a single dose of IN ketorolac 31.5 mg was well tolerated and effectively managed
postoperative pain in oral surgery patients for up to 8 hours.

"Intranasal Ketorolac for Postoperative Pain: A Phase
3, Double-Blind, Randomized Study"
Brown et al, Pain Med, 2009, 10(6):1106-14.
• Following major surgery, primarily hysterectomies and hip

replacements
• Patients receiving ketorolac IN had superior quality of

analgesia ratings and significant reduction in morphine use
compared to those receiving placebo IN
• Nasal irritation occurred more frequently with ketorolac

than with placebo (24% vs 2%).
• Conclusion: ketorolac IN well tolerated and effective in

treating moderate-to-severe postoperative pain.

"Intranasal Ketorolac for Acute Postoperative Pain"
Singla N, et al, Curr Med Res Opin, 2010, 26(8): 1915-1923.
• Mean of summed pain intensity difference scores at 6 hours were significantly

greater in the ketorolac group, indicating better analgesic efficacy compared to
placebo (117.4 vs 89.9)
• Pain intensity difference indicated significantly better pain relief in the ketorolac
group at 20 minutes after the first dose
• Morphine use over 48 hours decreased 26% in the ketorolac group compared to
placebo
• global pain control scores on day 1 were significantly higher in the ketorolac
group compared to placebo
• Adverse events and serious adverse event incidences were similar in both groups
(Rhinalgia and nasal irritation occurred more frequently with ketorolac)
• The conclusion of the study was ketorolac nasal spray was well tolerated and
provided effective pain relief within 20 minutes with reduced opioid analgesic use.

"Pharmacokinetics and Safety of Ketorolac Following Single
Intranasal and Intramuscular Administration in Healthy Volunteers",
McAleer SD, et al, J Clin Pharmacol, 2007, 47(1):13-8.
• Pharmacokinetics of IN ketorolac were similar to those

following IM administration
• Ketorolac was administered to 15 healthy volunteers using
single doses of the drug and a cross-over design. Subjects
received open-label randomized 15- and 30- mg intramuscular
(I.M.) ketorolac and blinded randomized 15- and 30- mg
intranasal (I.N.) ketorolac after appropriate washout periods
• Ketorolac IN was rapidly and well absorbed with a half-life of
5-6 hours which was similar to the values after I.M.
administration. The bioavailability of ketorolac nasal spray dose
was 75% compared to the bioavailabity after the I.M. dosing.
The only nasal symptoms were some instances of mild
irritation.

• Pharmacologic CategoryNonsteroidal Anti-

inflammatory Drug (NSAID), Nasal
• UseShort-term (≤5 days) management of

moderate-to-moderately-severe acute pain
requiring analgesia at the opioid level
• Effects on Dental Treatment: Nasal
discomfort, rhinalgia, throat irritation

• NSAIDs are known to reversibly decrease

platelet aggregation via mechanisms
different than observed with aspirin
• Platelet function is restored as the drug is
eliminated from the body
• No evidence to warrant discontinuance of
NSAIDs prior to dental surgery.
• If therapy is continued without interruption,
the clinician should anticipate the potential
for slower clotting times.
• One issue that often presents is the recovering
narcotic addict undergoing dental surgery and
requiring effective post-surgical pain relief
• Narcotic pain relievers would be contra-indicated

• Ketorolac nasal spray would seem to be a good
choice in managing pain in these patients.
• Sprix®: 15.75 mg/spray (1.7 g)

• <65 years and ≥50 kg: One spray (15.75 mg) in each
nostril (total dose: 31.5 mg) every 6-8 hours;
maximum dose: 4 doses (126 mg)/day

"Comparison of the Analgesic Efficacy of Concurrent Ibuprofen and
Paracetamol With Ibuprofen or Paracetamol Alone in the Management
of Moderate to Severe Acute Postoperative Dental Pain in Adolescents
and Adults: A Randomized, Double-blind, Placebo-controlled, Parallel-
group, Single-dose, Two-center, Modified Factorial Study,
" Mehlisch DR, Aspley S, Daniels SE, et al, Clin Ther, 2010, 32:882-95.
• A total of 234 patients were randomly assigned to treatment and included in the
intent-to-treat population.
• Sum of pain relief and pain intensity differences, the group receiving the combination
of ibuprofen 400 mg/acetaminophen 1000 mg had significantly better mean scores
compared with ibuprofen 400 mg alone, acetaminophen 1000 mg alone and the
combination of ibuprofen 200 mg/acetaminophen 500 mg.
• Sum of pain relief and pain intensity differences, the group receiving the combination
of ibuprofen 200 mg/acetaminophen 500 mg had significantly better mean scores
compared with acetaminophen 1000 mg alone, but not compared to ibuprofen 400
mg alone.
• Results for secondary endpoints
• Ibuprofen 400 mg/acetaminophen 1000 mg was associated with significantly better
scores than was single agent therapy for total pain relief, sum of pain intensity
differences, and sum of pain intensity differences on the visual analog scale at all time
intervals, and for sum of pain relief and pain intensity differences from 4 to 6 hours.

FDA Limits Acetaminophen in
Prescription Combination Pain
Relievers to 325 mg
• FDA is asking manufacturers of prescription
combination products that contain
acetaminophen to limit the amount of
acetaminophen to no more than 325 mg/
tablet or capsule
• FDA is also requiring manufacturers to
update labels of all prescription combination
acetaminophen products to warn of the
potential risk for severe liver injury.

Drug effects on Bone

The Effects of Medications on Bone
Stuart B. Goodman, William Jiranek, Edward Petrow, and Alan W. Yasko
J Am Acad Orthop Surg August 2007 ; 15:450-460
• NSAIDs
• Anticoagulants
• Antacids
• Bisphosphonates
• Antiepileptic
• Corticosteroids
• Disease-Modifying
Antirheumatic Drugs
• Anti-neoplastic (DMARDS)
Disease-Modifying Anti-
rheumatoid Drugs (DMARDS)
• Methotrexate (MTX) (Trexall™)
• Cyclosporine (Gengraft™)
• Leflunomide (Arava™)
• Anti-tumor necrosis factor-α (TNF-α) (Intron® A)
• Anti-interleukin-1 (IL-1) (Kineret®)
• Used singly or in combination with other drugs

Methotrexate (MTX) (Trexall™)
• Folic acid antagonist
• Causes a dose-dependent ↓ osteoblast

proliferation (although may not be significant at
lower doses used to Tx rheumatoid arthritis)
• Effects on Dental Treatment:

• Ulcerative stomatitis, gingivitis, glossitis, and
mucositis (dose dependent; appears 3-7 days
post-therapy and resolves within 2 weeks)
• NSAIDS concurrent administration may cause
severe bone marrow suppression, aplastic anemia,
and GI toxicity
•Risk is lower at the methotrexate dosages used for
rheumatoid conditions/psoriasis, the addition of an
NSAID or salicylate may still lead to unexpected
toxicities;
• Bleeding effects
•Chemotherapy may result in significant

myelosuppression, potentially including significant ↓ in
platelet counts and altered hemostasis
•Risk of thrombocytopenia is low with dosages used in

rheumatoid management
Cyclosporine (Gengraft™)
• Cyclic fungal peptide that inhibits the activation of

T-lyphocytes
•inhibits the transcription of the IL-2 gene
•used in rheumatoid arthritis and prevention of organ

rejection
•↑ osteoclast-mediated bone resorption exceeds bone

formation
•Low dose not much of a problem

Cyclosporine (Gengraft™)
• Effects on Dental Treatment
•Mouth sores, swallowing difficulty, gingivitis, gum

hyperplasia, xerostomia (normal salivary flow resumes
upon discontinuation), abnormal taste, tongue disorder,
tooth disorder, and gingival bleeding.
Leflunomide (Arava™)
• Inhibits pyrimidine biosynthesis → inhibits T cell

proliferation and activation
• Inhibits osteoclastogenesis and osteoclast function

•Xerostomia (normal salivary flow resumes upon
discontinuation), stomatitis, oral candidiasis, abnormal
taste, tooth disorder, enlarged salivary gland,
esophagitis, and gingivitis.
• Bleeding effects:
•associated with rare thrombocytopenia
Anti-tumor necrosis factor-α
(TNF-α) (Intron® A)

•Xerostomia (normal salivary flow resumes upon
discontinuation), metallic taste, taste alteration, and
gingivitis.
• Bleeding effects
•Chemotherapy may result in significant
myelosuppression, potentially including significant
reduction in platelet counts and altered hemostasis. In
patients who are under active treatment with these
agents, medical consult is suggested.
Psychotropic Drugs
• Neuroleptic medication (schizophrenia) →
hyperprolactinemia → decreased bone density
•1st generation
•Phenothiazines (Thorazine, Trilafon, Stelazine, Melleril,
Phenergan)
•2nd generation
•Clozapine, Seroquel
•3rd generation
•Abilify
Psychotropic Drugs
• antidepressants
•Imipramine = ↑ density
•SSRIs = no change
• Lithium = ↑ secretion of parathyroid hormone ∴ ↓

BMD (?)
• Recommendation:
•Therapy (> 1 year) perform BMD studies yearly
•Calcium 1,500 mg/day
•Vitamin D 400-800 IU/day
Anti-epileptic Drugs (AEDs)
• Induce cytochrome P-450 enzymes = affect bone
metabolism
•↑ catabolism of vitamin D =↓ bioavailability of vitamin D
•impaired calcium absorption
•alterations in bone formation and degradation
•↑ PTH release
•abnormalities in calcitonin or Vitamin K
•Hypocalcemia, hypophosphatemia
•Phenytoins (Dilantin)
•Phenobarbital
•Carbamazepine (Tegretol ®)
•Valproate disodium (Depakote®)
Vitamin K
• ↓ vitamin K = ↑ bone fractures
• warfarin (Coumadin®) induces ↓ vitamin K
• OsteoK ® (Vitamin D3, Vitamin K2, Calcium)

Statins
• Atrovastatin (Lipitor®), Fluvastatin (Lescol®),
Lovastatin (Mevacor®), Mevastatin (Compactin®),
Pravastatin (Pravachol®), Dosuvastatin (Crestor®),
Simvastatin (Zocor®)
• Prevent cardiovascular events

•↓ production of cholesterol and low-density lipoproteins,
↑ coronary vasodilation, ↓ inflammation
•↑ BMP-2 release by osteoblasts
•↓ osteoclast differentiation
•∴ increase BMD
Antacids
• Phosphorus essential for bone formation
• Aluminum-containing antacids bind phosphate ∴

cannot be absorbed from the gut
• lead to hypophosphatemia = metabolic bone

disease
• Dexamethasone (Decadron®)
• Prednisone
• Methylprednisolone (Medrol®)
• Bone effects
•Suppression of intestinal calcium absorption
•↓ renal tubular calcium reabsorption
•↑ urinary calcium excretion
• Suppressed osteoblast function = ↓ bone formation
• ↑ parathyroid secretion
• ↓ estrogen and testosterone = bone resorption
• promote apoptosis of osteoblasts and osteocytes
• ↑ production of RANKL = ↑ osteoclasts
• Long-term chronic use ↓ COX-2

expression and therefore PG production
• Result: Bone loss
• Devogelear JP. Glucocorticoid-induced osteoporosis:
mechanisms and therapeutic approach. Rheum Dis
Clin North Am 2006;32:733-57
Medications for Arthritis
NSAIDs Inhibits Cox 1 & 2 Inhibits fracture healing
enzymes and bone growth -
reversible with D/C of
drug
Score = -1
Methotrexate High Doses: Interferes Anti-rheumatoid dose of

with osteoblast 10 mg/wk does not
proliferation interfere with bone
Low Doses: May be Score = 0
anti-inflammatory
Cyclosporin Inhibits activation of T- Anti-rheumatoid dose of

Lymphocytes 5mg/kg/day does not
interfere with bone
Score = 0
Medications for Arthritis
Leflunomide 1.Inhibits pyrimidine Overall effects on bone
biosynthesis clinically unknown
2.Inhibits T cell
proliferation and Score = Undecided
activation
3.Inhibits
osteoclastogenesis and
osteoclast function
Anti-TNF-α and anti- Inhibit inflammatory Clinical studies on the
IL-1 drugs cytokines that normally effect of these
upregulate medications on bone
osteoclastogenesis and inconclusive
suppress osteoblast Score = undecided
function
Net score = -1
0x2
undecided x2
Commonly Prescribed Medications
Bisphosphonates 1.Interfere with 1.Inhibit bone resorption
osteoclast recruitment 2.Improve BMD and
and function fracture risk
2. osteoclast 3.Long term = negative
apoptosis effects
Antiepileptics Affect the cytochrome 1.May lead to rickets

P-450 enzyme pathway, and osteomalacia
which adversely affects 2.Requires monitoring
VitaminD-PTH - of vitamin D, Calcium,
calcitonin axis Phosphorus
Commonly Prescribed Medications
Statins 1.Inhibit production of 1.Improve BMD
mevalonate 2.➡fracture risk of hip
2. BMP-2 release by
osteoblasts
3.➡ osteoclast
differentiation
Aluminum-containing Bind phosphate in the In excess, may lead to
antacids gut hypophosphatemia,
rickets, and
osteomalacia
Net Score = 1 +
2-
1+/-
Cancer Treatment - Induced Bone Loss
Direct: ➡bone formation 2° to effects on
•Antineoplastic agents: osteoblast and osteoclast activity
•Methotrexate
•Doxorubicin
•Cyclophosphamide
•Ifosamide
•Glucocorticosteroids
•Prednisone Suppress osteolast/bone formation
Indirect: Act as an estrogen antagonist at β
•Selective estrogen receptor receptors
modulators
•Tamoxifen
•Torenmifene
•Raloxifene
Indirect: Inhibit enzymatic conversion of adrenal
•Aromatase inhibitors androgens to estrogen
•Anastrozole
•Letrozole
•Exemestane
Indirect: Inhibit release of folicle-stimulating
•Gonadotropin-releasing hormone hormone and leuteinizing hormone
analogs (agonists) resulting in chemical castration
•Leuprolide
•Goserelin
•Triptorelin
Indirect: Androgen receptor antagonist;
•Antiandrogens (steroidal) lowers circulation testosterone and
estradiol
•Cyproterone
Indirect: Competitive inhibitors of androgen
•Antiandrogens (nonsteroidal) receptors
•Flutamide
•Bicalutamide
Indirect: Cause ovarian insufficiency

•Antineoplastic agents
•Mechlorethamine
•Vincristine
•Procarbazine
•Cyclophosphamide
Indirect: Suppress osteoblasts/bone formation
•Glucocorticosteroids
•Prednisone
Net Score = 21 -
Epinephrine Key Drug
Interactions

Selected Adrenergic
Agonists
Drug Receptor Affinity
Alpha β1 β2
Epinephrine + + + + + + + + + + + +
Norepinephrine + + + + + + + 0,+
Levonordefrin + + + + + + + O,+
Ephedrine + + + + + + +
Isoproterenol O + + + + + + + +
Methoxamine + + + + O O
Albuterol O O,+ + + + +
Metaproterenol O + + + + + +
Non-Specific Beta Blockers
• Treatment
Angina Dysrhythmia
Tremors Glaucoma
Hypertension Migraine
M.I. Pheochromocytoma
Non-Specific Beta Blockers
• Competitively block stimulation of beta receptors

by Epi and Norepi
Types of Beta Blockers
• Non-selective
• Propranolol - Rx Inderal
• Nadolol - Rx Corgard
• Selective
• Selective B-1
• Atenolol - Rx Tenormin
• Metoprolol - Rx Lopressor
Non-Selective Beta Blockers
with Epi
• Massive unopposed alpha vasoconstriction

• Hypertensive crisis
• Significance rating 1
COMT Inhibitors
• A New Drug Interaction?

COMT Inhibitors
CATECHOL-O-METHYL
TRANSFERASE
• COMT Inhibitors
• Tolcapone (Rx Tasmar)
• Entacapone (Comtan)
• Tx Parkinson’s Disease
Catechol-O-Methyl-
Transferase
• Enzyme responsible for inactivating catechols
• levodopa
• vasoconstrictors
• epinephrine
• levonordefrin
COMT Inhibitors with Epi
!400 mg of Entacapone + Epinephrine

⇓
Tachycardia
COMT Inhibitors with Epi 
Reasonable Precaution
One carpule of 1:100,000 epinephrine
and monitor patient’s B.P. and pulse
for 5 minutes
COMT Inhibitors with Epi 
Patients at Risk
• Low COMT activity
• Selegiline - Rx Eldepryl
• specific (MAO)-B inhibitor
• high doses block (MAO)-A also
• both pathways for epinephrine metabolism are

blocked
COMT Inhibitors with Epi
• Also unique to Tolcapone is acute liver failure -
watch Tylenol
Monoamine Oxidase
Inhibitors
• Antidepressants
• Marplan and Parnate
• Antimicrobial
• Furazolidone - Rx Furoxone
• Antiparkinson
• Selegiline - Rx Eldepryl
MAO Inhibitors
• Prevent metabolism of drugs metabolized by

MAO
• Block intraneuronal breakdown of norepi -

increases the pool of neurotransmitter capable of
being released by amphetamine,
pseudoephedrine and tyramine
MAO Inhibitors with Epi
• No evidence of problem with epi or levonordefrin

- reason COMT
• Bureaucracy?
MAO Inhibitors
• Remember Sudafed and MAO - sinus elevations

• Remember MAOI’s and Meperidine - Rx Demerol
• Muscle rigidity, stupor, agitation, increased
temperature, hallucinations, death (?) Talwin,
Nubain
TCA with Epi
• Block active reuptake of amine neurotransmitters

• Get potentiation of affected neurotransmitter
• Epi subject to same affects
Tricyclic Antidepressants
• Imipramine - Rx Tofranil
• Amitriptyline - Rx Elavil
• Doxepin - Rx Sinequan
• Tx: depression, anxiety, neuropathic pain,

nocturnal enuresis
TCA with Epi 
Boakes Found
• Increase in systolic B.P.

• Dysrhythmia
TCA with Epi
• Tofranil potentiates epi 3 X

• Potentiates Levonordefrin 6-8 X
TCA with Epi 
Persson and Siwers 1975
• 2 1/2 Carpules of Lido 2% with Epi 1:100,000

• causes headache
• increased systolic pressure 45 mm Hg over

baseline
TCA with Epi 
Brown and Lewis in 3-0 1988
• Prolonged use of TCA’s

• desensitization to adrenergic vasoconstrictors
• decrease chance of interaction significance

TCA with Epi 
Treatment Plan
• No levonordefrin
• no epi cord
• no greater 1:100,000 epi
• 1/3 maximum dose
• wait 30 minutes before re-injecting
TCA with Vasoconstrictor
• Significant rating is a 1
Thyroid Hormones and
Vasocontrictors
• Thyroxine - Rx Synthroid
• May cause dysrhythmias, ⇑ cardiac output,
ischemia
Cocaine
• Has L.A. action

• Blocks the re-uptake of norepi and dopamine
• Enhances adrenergic neurotransmitter release
Cocaine with Epi 
Treatment Plan
• Discontinue Cocaine use at least 24 hours prior

to dental appointment
Efficacy of Articaine: Amide
Local Anesthetic
Articaine 4% with Epi 1:100,000 vs. Xylo 2% with
Epi 1:100,000
882 received Articaine
443 received Xylocaine
No difference between two groups
Ref. JADA, May 2000

Articaine vs. Citanest Forte
Articaine 4% with Epi 1:200,000 found to be no

different than Citanest Forte (Epi 1:200,000)
Ref. Scand. J. Dent. Res. 1972

Articaine
Same recommended maximum dose as

Xylocaine 7 mg per Kg.
Formulation is twice as strong - WHY?

Articaine
Has epi 1:100,000 - ? Mandibular blocks
Prilocaine (Citanest Epi 1:200,000)
lower recommended dose
WHY?
TOP 10 THINGS TO KNOW
ABOUT
DRUGS IN DENTISRY

488
# 10
l STEROIDS AND NSAIDS ARE A
DENTIST’S BEST FRIEND
– BECAUSE IT CAN MAKE YOU LOOK GOOD,
EVEN IF YOUR NOT
489
#9
l NSAIDS AND ANTIHYPERTENSIVES
CAN LEAD TO INCREASED BLOOD
PRESSURE (FOR BOTH YOU AND THE
PATIENT)
– BECAUSE OF A DRUG INTERACTION
490
#8
l EPINEPHRINE IS OK IN A
PATIENT WITH CONTROLLED
CARDIOVASCULAR DISEASE
– BUT YOU MUST KNOW WHAT YOU ARE
DOING
• ALWAYS HAVE A BASELINE PULSE AND BP
491
#7
l NSAIDs can destroy your bone grafts
l Especially Cox-2 specific
l STOP the Cox-2 before it stops you!!
l Flurbioprofen - New Best Friend
492
#6
l EPINEPHRINE WITH INDERAL OR
CORGARD (or high dose selective β-1
bockers) CAN LEAD TO A BAD DAY
– HYPERTENSIVE CRISIS
493
#5
l ACETAMINOPHEN IN THE ALCOHOLIC
– KEEP HIM DRINKING, THIS ISN’T THE TIME
TO QUIT!
494
#4
l COUMADIN – IF YOU KNOW HOW TO
WORK WITH IT, ITS OK TO SEE RED
– KNOW THE PATIENT’S
• TARGET INR
• CURRENT INR
• RISK OF YOUR PROCEDURE
– KNOW YOUR STUFF AND YOUR COMFORT
LEVEL
495
#3
l DIABETICS NEED DENTAL
TREATMENT TOO
– KNOW HOW TO DEAL WITH THEIR INSULIN
AND HYPOGLYCEMIC AGENTS – LET’S
EAT
496
#2
l ANTIBIOTICS
– HAVE A SOUND PROTOCOL FOR THEIR
USE
• DO NOT OVERUSE
• KNOW WHEN TO USE
• KNOW HOW TO USE
– WORK BEST WITH MOIST HEAT!
497
#1
l KNOW YOUR PATIENT
– VALID MEDICAL HISTORY
• REVIEWED EVERY APPT. (This is how they will
get to know you too)
– BASELINE VALUES
• BLOOD PRESSURE
• PULSE
– THIS IS #1
498
TAKE-HOME MESSAGE
l “Through diligence, moral clarity,
ingenuity and a simple willingness to
try, better is possible!”
– Better by Atul Gawande - 2007
499
PHARMACOLOGY

500
Glucocorticosteroid
•USE IN DENTISTRY
During therapy:
• Prescribe drug with food
• Diet low in calories and sodium and rich in potassium
• Check periodically for weight gain, hypertension,
hyperglycemia
Rule of 2’s
• Adrenocortical suppression should be suspected if a patient has
received Glucocoticoid therapy
• In a dose of 20 mg or more of cortisone or its equivalent
daily
• Via oral or parenteral route or a continuous period of 2
weeks or longer within 2 years of the dental
appointment
• Ref. Medical emergencies in dental office, Stanley F.
Malamed Complications in Anesthesia - John L. Atlee;
Page-132
Protocol for Supplementation of Patients on Glucocorticoid
Therapy Who Are Undergoing Dental Care (Burket’s 10th ed)
Dental Previous Current Daily Current

Procedure Systemic Steroid Systemic Steroid alternating topical
Use Use Systemic Systemic
Steroid Use Steroid Use
Routine If prior usage No Treat on steroid No
procedures lasted for > 2 supplementation dosage day; no supplementatio
weeks and ceased needed further n needed
< 14–30 days ago, supplementatio
give previous n needed
maintenance
dose
If prior usage
ceased > 14–30
days
ago, no
supplementation
needed
Procedure Systemic Steroid Systemic Steroid alternating topical
Use Use Systemic Systemic
Routine If prior usage No Treat on steroid No
procedures lasted for > 2 supplementation dosage day; no supplementatio
weeks and ceased needed further n needed
< 14–30 days ago, supplementatio
give previous n needed
maintenance
dose
If prior usage
ceased > 14–30
days
ago, no
supplementation
needed
Procedure Systemic Steroid Systemic alternating topical
Use Steroid Use Systemic Systemic
Extractions, If prior usage Double daily Treat on
surgery, or lasted > 2 weeks dose on day of steroid dosage
extensive and ceased < 14– procedure day, and give
procedures 30 days ago, give double daily
previous dose on day of
maintenance procedure No
dose supplementation
needed
If prior usage Double daily Give normal
ceased > 14–30 dose on first daily dose on
days ago, no postoperative first
supplementation day when pain postoperative
needed is anticipated day when pain
is anticipated
Scenario One
Patient requiring extractions
took a 7 day course of 20 mg. of
prednisone for exacerbation of
asthma one week ago
No supplementation required.
E ve n t h o u g h t h e d o s e w a s
supraphysiologic, the course of
time it was taken was less than 2
weeks
507
Scenario Two
Patient requiring extractions
is taking 10 mg of
prednisone for the past year
to treat rheumatoid arthritis
This patient’s HPA axis is probably

suppressed due to supraphysiologic
dose of corticosteroids for longer
than 2 weeks. Supplement with at
least 100 mg of cortisol equivalent
(25 mg prednisone) in the morning
on the day of the surgery
508
INFLAMMATION
• VASCULAR & CELLULAR IS A PROTECTIVE
MECHANISM
• ANTI-INFLAMMATORY MEDS.
• INTERRUPT SYNTHESIS AND/
OR RELEASE OF MEDIATORS
OF THE VASCULAR RESPONSE
PHYSIOLOGICAL ASPECTS
• CORTISOL (STEROIDAL HORMONE)
• RELEASED BY ADRENAL
CORTEX
• REGULATES GLUCOSE
METABOLISM
• HENCE GLUCOCORTICOSTEROIDS
ADRENAL CORTEX
• UNDER CONTROL OF HYPOTHALMUS
• HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
• “HPA AXIS”
STEROID EFFECTS
PHYSIOLOGICAL EFFECTS ADVERSE EFFECTS
ASSOCIATED WITH
GLUCORTICOID ACTIONS: SUPRAPHYSIOLOGIC DOSES
GLUCONEOGENESIS HYPERGLYCEMIA
POTENTIATE CATECHOLAMINES HYPERTENSION
INHIBIT POLYCYTHEMIA
ERYTHOPHAGOCYTOSIS
INHIBIT PRODUCTION OF IMMUNOSUPPRESSION
LYMPHOCYTES & MONOCYTES
MINERALCORTICOID ACTIONS: EDEMA, HYPERTENSION
POORLY UNDERSTOOD FUNCTIONS: OSTEOPOROSIS, MYOPATHY, PEPTIC ULCER,

FAT REDISTRIBUTION, PSYCHOLOGICAL
CHANGES
ANTI-INFLAMMATORY
ACTION
• SUPRAPHYSIOLOGICAL DOSES
• MECH. OF ACTION
• DECREASE IN INFLAMMATORY MEDIATORS
• SYNTHESIZE AN ENZYME THAT DEGRADES

BRADYKININ
IMMUNOSUPPRESSANT
EFFECTS
• ANTIBODY PRODUCTION ↓ BY LARGE
STEROID DOSE, NOT MODERATE DOSE
• RETARD LYMPHOCYTE ACTIVITY

• STEROIDS ↑ MIGRATION OF ANTI-
INFLAMMATORY MONOCYTES TO SITES OF
INFECTION
STEROIDS - THE BAD SIDE
• CHRONIC STEROID THERAPY

• SUPPRESSION OF HPA AXIS
• COMPROMISED IMMUNE STATUS
• OSTEOPOROSIS
• INCREASED BLOOD SUGAR LEVELS

How does stress induce
↑ Corticosteroid production?
• At the hypothalamus, fear-signaling impulses activate both the
sympathetic nervous system and the modulating systems of the
HPA axis.
• E/NE will positively feedback to the pituitary and increase the

breakdown of POMCs (Pro-opiomelanocortin) into ACTH
• Increase dose in case of stress
• Instruct patient not to stop
abruptly
• When stopping therapy:

• Taper dose
ADDITIONAL STEROIDS
• IF PATIENT TAKES DAILY STEROIDS:
• DOUBLE OR TRIPLE THERE DAILY DOSE
FOR THE DAY OF SURGERY
• TAPER OFF OVER THE NEXT 2 DAYS TO

NORMAL DOSE
• OR GIVE IV SHORT ACTING STEROIDS AND

LONGER ACTING IM SUSPENSION
STEROIDS
Precautions before administering
glucocorticosteroids
• Ask and check for hypertension, diabetes mellitus,
peptic ulcer, infection, psychosis
Relative Contraindications 
• Peptic ulcer
• Diabetes mellitus • Osteoporosis
• Hypertension • Psychosis
• Pregnancy • Epilepsy
• Herpes simplex • Renal failure

keratitis
• Tuberculosis
CYP3A4
• Dexamethasone is a strong inducer of
CYP3A4
• Dexamethasone is a substrate of
CYP3A4
• Benzodiazepines are substrates of

CYP3A4
• “A SINGLE DOSE OF GLUCOCORTICOID,
EVEN A LARGE ONE, IS VIRTUALLY WITHOUT
HARMFUL EFFECTS, AND A SHORT COURSE
OF THERAPY (UP TO 1 WEEK), IN THE
ABSENCE OF SPECIFIC
CONTRAINDICATIONS, IS UNLIKLY TO BE
HARMFUL”
• GOODMAN & GILLMANS – 10TH EDITION

STEROIDS
• ALL EQUIPOTENT
• VARY IN
• POTENCY
• HALF-LIFE
• MINERALCORTICOID ACTIVITY
• SALT RETENTION – FLUID RETENTION

DENTAL APPLICATIONS
• SURGERY
• PRE-OPERATIVE
• PREVENT INFLAMMATION (SWELLING)
• TRAUMATIC OR APHTHOUS ULCERS

• NEURITIS OF INFERIOR ALVEOLAR OR MENTAL
NERVES
• PHELBITIS FROM IV SEDATION

STEROID EFFECT ON INFERIOR ALVEOLAR
NERVE HYPERSENSITIVITY
• 14 PATIENTS
• 3RD MOLAR REMOVAL
• DEXAMETHASONE/DIPYRONE VS DIPYRONE ALONE
• DIPYRONE ONLY PTS. HAD SIGNIFICANTLY REDUCED

LINGUAL AND INFERIOR ALVEOLAR NERVE ELECTRILAL
DETECTION THRESHOLDS 2 DAYS AFTER SX
• PTS RECEIVING DEXAMETHASONE HAD NO

SIGNGICANT REDUCTION IN ELECTRICAL DETECTION
THRESHOLD
• J. ORALFAC PAIN 2004 Barron RP et al

STEROID REGIMEN
• ORAL – USE THE DOSE PAKS AVAILABLE
(MEDROL DOSE PAK)
• PT. TAKES ALL OF THE FIRST ROW IN THE

AM PRIOR TO SURGERY (OR SPLITS DOSE –
½ IN AM AND ½ EARLY AFTERNOON
• THEN FOLLOW DIRECTIONS FOR

FOLLOWING DAYS
STEROID REGIMENS
• IV OR IM
• USE DEXAMETHASONE SODIUM PHOSPHATE

4mg/ml (SOLUTION – CLEAR)
• GIVE 4 – 8 mg IV OR IM PRIOR TO SURGERY

• LASTS 24 - 48 HRS.
• OR USE SOLU-CORTEF 100 mg IM OR IV

• LASTS 24 – 36 HRS.
STEROID REGIMENS
• IM FOR LONGER DURATION
• DEXAMETHASONE LA 8 mg/ml
• SUSPENSION (WHITE) GIVE 1 ML
• OR DEPO-MEDROL 40 mg/ml
• SUSPENSION (WHITE) GIVE 1 –2 ml
• THESE WILL LAST 5 TO 7 DAYS
• NEVER GIVE SUSPENSIONS IV

Betamethasone sodium phosphate and
Bethamethasone acetate Suspension
Contains both short acting and

long acting betamethasone
FOR IM USE ONLY
Give 1 -2 mL IM
CONTRAINDICATIONS 
(even short term use)
• UNCONTROLLED DIABETES
• IMMUNOCOMPROMISED
• ACTIVE PEPTIC ULCER
• OSTEOPOROSIS
• ACTIVE HERPETIC OR FUNGAL INFECTIONS
• AVOID HIGH DOSE IN PTS. WITH PSYCHOSES
Conclusion
• Corticosteroids play an important role in control of
pain & inflammation associated with numerous
disease states of oral cavity.
• Currently corticosteroids are drugs with one of the

broadest spectrum of clinical utility.
• But it should never be used as a substitute to other

treatments.
• Lets keep it mind that these drugs do not cure the

disease but rather control or relieve the symptoms.
• It should be used cautiously as it is two edged sword
536
Steroid doses (InjecYon) -‐ Guidelines
DOSES MUST BE INDIVIDUALIZED FOR EACH PATIENT AND A

CONSULTATION WITH THE PATIENT’S HEALTH CARE PROVIDER MAY BE
INDICATED
Dexamethasone Sodium
Depo-‐Medrol (IM only)
Procedure Phosphate (IV or IM)
white suspension
Clear SoluYon
Single implant small
2-‐4 mg 10-‐20 mg or none
flap
Single implant med flap 4 to 6 mg 20-‐40 mg
MulYple implants large

6 to 8 mg 40-‐60 mg
flap
Full arch flap with

8 mg 60 to 80 mg
mulYple implants
537
Steroid doses (Oral) Guidelines
DOSES MUST BE INDIVIDUALIZED FOR EACH PATIENT AND A CONSULTATION
WITH THE PATIENT’S HEALTH CARE PROVIDER MAY BE INDICATED
Procedure Number of Dexamethasone 0.75 mg tablets Number of Prednisone 5 mg tablets
Day Day Day Day Day Day Day Day Day Day Day Day Day Day
1 2 3 4 5 6 7 1 2 3 4 5 6 7
Single
implant 4 3 2 1 none none none 4 3 2 1 none none none
small flap
Single
implant 5 4 3 2 1 none none 5 4 3 2 1 none none
med flap
MulYple
implants 6 5 4 3 2 1 none 6 5 4 3 2 1 none
large flap
Full arch
flap
7 6 5 4 3 2 1 7 6 5 4 3 2 1
mulYple
implants 538
CONTRAINDICATIONS 
(even short term use)
• DIABETES
• Pregnancy
• IMMUNOCOMPROMISED
• ACTIVE PEPTIC ULCER
• OSTEOPOROSIS
• ACTIVE HERPETIC OR FUNGAL INFECTIONS
• AVOID HIGH DOSE IN PTS. WITH PSYCHOSES
Get the slides (PDFs)
• Check email Monday afternoon (August 31, 2015)
• Login and password will be provided
• If no email: Call Dustin 1-814-226-6390
• Content information contact
• Jim Rutkowski
• email: jim@rutkowskidmdphd.com
• phone: (office) 1-814-226-8690
(Mobile) 1-814-229-7692

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Analgesic Protocol Get the Information

Antibiotics Diabetes Glucocorticosteroids

Top Ten Things to

James L. Rutkowski DMD, PhD

James L. Rutkowski, D.M.D., Ph.D.

• COX-2 INDUCED BY:

• LEADS TO INFLAMMATION CASCADE

James L. Rutkowski, D.M.D., Ph.D.

James L. Rutkowski, D.M.D., Ph.D.

• RESP. ↓ & PHYSICAL DEPENDENCE

• DO NOT CHANGE THE PERCEPTION OF SENSORY

• CHRONIC POST-OP PAIN OR PAIN FROM

James L. Rutkowski, D.M.D., Ph.D.

James L. Rutkowski, D.M.D., Ph.D.

James L. Rutkowski, D.M.D., Ph.D.

• SHUNTING TOWARDS LEUKOTRIENE SYNTHESIS

• DO NOT USE ANOTHER NSAID

James L. Rutkowski, D.M.D., Ph.D. 10

• Clinical Pharmacology Therapy 1976

• MORE ANALGESIC EFFICACY

• LESS SIDE EFFECTS

James L. Rutkowski, D.M.D., Ph.D.

• COMBINATIONS OF ASA/ACETAMINOPHEN AND

James L. Rutkowski, D.M.D., Ph.D.

• COMPARABLE TO ALL OTHER NSAIDS

• FEWER SIDE EFFECTS

• INHIBITS THE “FORMATION” OF PROSTAGLANDINS

• HAVE ON BOARD BEFORE START

• JACKSON, MOORE, JADA 1989

James L. Rutkowski, D.M.D., Ph.D.

• PRIOR HX OF NSAID/ASA ALLERGY OR INTOLERANCE

• CONCURRENT ANTIHYPERTENSIVE THERAPY (RELATIVE)

James L. Rutkowski, D.M.D., Ph.D.

• ↓ RENAL FLOW IN:

• PROMOTES SALT AND H2O RETENTION

• REDUCES EFFECTIVENESS OF ANTI-HYPERTENSIVES AGENTS

James L. Rutkowski, D.M.D., Ph.D.

• BINDING OF TXA2 TO ITS RECEPTORS (GQ) ACTIVATES

James L. Rutkowski, D.M.D., Ph.D.

•TXA2 IS A POTENT PLATELET AGGREGATOR

•PLATELETS RELEASE TXA2 DURING ACTIVATION

James L. Rutkowski, D.M.D., Ph.D.

RENAL CORTEX – PGE2 AND PGI2 - ↑ RENIN RELEASE

PGE1, PGE2, & PGI2 ↑ GLOMERULAR FILTRATION VIA

James L. Rutkowski, D.M.D., Ph.D.

•GI IRRITATION (ULCER)

•RENAL PAPILLARY NECROSIS + OTHER RENAL MEDULLARY CHANGES

James L. Rutkowski, D.M.D., Ph.D.

• 400 mg. PEAK PLASMA LEVEL 29 ug/ml IN 90 MIN.

• NON DETECTED IN 12 HR.

• 17 CHILDREN 2.4 g. ASYMPTOMATIC

• 13 ADULTS UP TO 24 g. NO ILL AFFECTS

James L. Rutkowski, D.M.D., Ph.D.

James L. Rutkowski, D.M.D., Ph.D.

• The healing of stabilized tibia fractures was delayed in COX-2 knockouts

• In radiographic analysis at 21 days post-fracture normal healing found in:

• 8 out of 10 wild-type mice

• 8 week results healed:

• Acetaminophen - no delayed healing