Dr. James Rutkowski Friday, June 10 9:30

Bisphosphonates

Diabetes

Anti-coagulant, Anti-platelet,

Anti-thrombotic

Analgesic Protocol

Glucocorticosteroids

Non-Opioids

James L. Rutkowski DMD, PhD

Considerations for Recombinant and Autogenous Growth Factors

Bone Grafting Principles

Bone Grafting and the use of Bioactivators

Buffy Coat PRP PRF Drug Effects on Bone

Epinephrine Drug Interactions

Steroid dose sheet

Contact Information

• Email: [email protected]

• Phone: Office: 814-226-8690

• Phone: Mobile: 803-415-4838

• Text is good

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)

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

• CROSS HYPERSENSITIVITY

• USUALLY NOT IgE MECHANISM

• SHUNTING TOWARDS LEUKOTRIENE SYNTHESIS

• BRONCHOSPASM & ANAPHYLAXIS

• DO NOT USE ANOTHER NSAID

• USE ACETAMINOPHEN


•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)


•⇑ 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 FormationBone 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

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

• 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

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

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

NSAIDs

PRP

PGE2

TGF-β1 PDGF-BB

VEGF OPG

IL-1α

Bone Formation

Chronic

24


• 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


•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

Enzyme CYP2E1 metabolizes Acetaminophen to the toxic metabolite NAPQI

NAPQI=Toxic! NAPQI + Glutathione = Non-toxic

34James L. Rutkowski, D.M.D., Ph.D.

The enzyme that metabolizes alcohol to its non-toxic metabolite is CYP2E1. Chronic alcohol consumption ↑ CYP2E1 and ↓ Glutathione

Hass D. Adverse Drug Interactions in Dental Practice. JADA 1999;130:397-407


NO Alcohol + Acetaminophen = ↑↑ NAPQI

↑↑ NAPQI leads to Hepatotoxicity


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


Generic Trade Name Dose (mg) Frequency Daily Maximum Dose (mg)

Ibuprofen Advil, Nuprin, Motrin 400-600 q 4-6 h 2400

Naproxen Anaprox, Naprosyn,

Naproxin sodium 275 Naproxin base 250 q 8-12 h Naproxin sodium 1375

Naproxin base 1250

Flurbiprofen Ansaid 50 - 100 q 12 h 300 (maximum

Diflunisal Dolobid 500 q 12 h 1500

Ketorolac Toradol 10 q 4-6 h 40 (5 days maximum)

Ketoprofen Orudis 25-50 q 6-8 h 300

Acetylsalicylic Acid Aspirin 325 -1000 q 4-6 h 4000

Acetaminophen Tylenol 500 - 1000 q 4-6 h 4000

NSAIDs and Acetaminophen Dosing Regimens (Adults)

Ref. Haas, D J Can Dent Assoc 2002; 68(8):476-82


Generic Trade Name Dose (mg) Frequency Daily Maximum Dose (mg)

Ibuprofen Children’s Advil

Age 2-12: 10mg/kg q 6-8 h

Age > 12: 200-400 q 4 h 1200

Acetaminophen Tylenol, Tempra 10 - 15mg/kg q 4-6 h

65mg/kg DO NOT EXCEED

ADULT DOSE

NSAIDs and Acetaminophen Dosing Regimens (Pediatric)



Trade Name Opioid Dose (mg) Frequency Daily Maximum Dose

(mg)

AdultCodeine, with acetaminophen or an NSAID

30 - 60 q 4-6 h

Oxycodone (Percodan, Percoet) 5 - 10 q 4-6 h

Hydrocodone (Lortab, Vicodin) 2.5 - 10 q 4-6 h

Pediatric

Codeine, with acetaminophen or an NSAD

0.5 - 1 mg/kg q 4-6 h 3mg/kg

Opioid with Acetaminophen Dosing Regimens



FDA Pregnancy Categories Five categories to indicate the potential of a drug to cause birth defects if used during

Category A

Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

Category B

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

64


FDA Pregnancy Categories Five categories to indicate the potential of a drug to cause birth defects if used during

Category D

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category X

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

65


Analgesic Concerns for Pregnancy or Lactation

66

FDA Category for Use during Pregnancy

? Use During Pregnancy

? Use While Breast Feeding

Acetaminophen B Yes Yes

Aspirin C- 1st and 2nd trimesters D- 3rd trimester

DO NOT USE IN 3RD TRIMESTER USE WITH CAUTION

Difunisal C- 1st and 2nd trimesters D- 3rd trimester

DO NOT USE IN 3RD TRIMESTER USE WITH CAUTION

Flurbiprofen B- 1st and 2nd trimesters D- 3rd trimester

DO NOT USE IN 3RD TRIMESTER yes

Ketorolac B- 1st and 2nd trimesters D- 3rd trimester


Ketoprofen B- 1st and 2nd trimesters D- 3rd trimester


Naproxen B- 1st and 2nd trimesters D- 3rd trimester


Codeine C low dose, short duration is acceptable yes

Ocycodone B low dose, short duration is acceptable yes

Hydrocodone C low dose, short duration is acceptable yes


Selected Adrenergic Agonsists

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

Tricyclic Antidepressants

• Imipramine - Rx Tofranil

• Amitriptyline - Rx Elavil

• Doxepin - Rx Sinequan

• Tx: depression, anxiety, neuropathic pain, nocturnal enuresis

TCA with Epi

• Block active re-uptake of amine neurotransmitters

• Get potentiation of affected neurotransmitter

• Epi subject to same affects

TCA with EpiBoakes Found

• Increase in systolic B.P.

• Dysrhythmia

TCA with Epi

• Tofranil potentiates epi 3 X

• Potentiates Levonordefrin 6-8 X

TCA with EpiPersson 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 EpiBrown and Lewis in 3-0 1988

• Prolonged use of TCA’s

• desensitization to adrenergic vasoconstrictors

• decrease chance of interaction significance

TCA with EpiTreatment 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

COMT Inhibitors

• A New Drug Interaction?

COMT Inhibitors

• 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 intra-neuronal breakdown of nor-epi 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

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 EpiTreatment Plan

• Discontinue Cocaine use at least 24 hours prior to dental appointment

Efficacy of Articaine: A New 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?

Glucocorticosteroid•USE IN DENTISTRY

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”

PHYSIOLOGICAL EFFECTS ADVERSE EFFECTS ASSOCIATED WITH

SUPRAPHYSIOLOGIC DOSESGLUCORTICOID ACTIONS:

GLUCONEOGENESIS HYPERGLYCEMIA

POTENTIATE CATECHOLAMINES HYPERTENSION

INHIBIT ERYTHOPHAGOCYTOSIS

POLYCYTHEMIA

INHIBIT PRODUCTION OF LYMPHOCYTES & MONOCYTES

IMMUNOSUPPRESSION

MINERALCORTICOID ACTIONS: EDEMA, HYPERTENSION

POORLY UNDERSTOOD FUNCTIONS: OSTEOPOROSIS, MYOPATHY, PEPTIC ULCER, FAT REDISTRIBUTION, PSYCHOLOGICAL

CHANGES

STEROID EFFECTS

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

• 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

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

Precautions before administering glucocorticosteroids

• Ask and check for hypertension, diabetes mellitus, peptic ulcer, infection, psychosis

Relative Contraindications• Peptic ulcer

• Diabetes mellitus

• Hypertension

• Pregnancy

• Herpes simplex keratitis

• Tuberculosis

• Osteoporosis

• Psychosis

• Epilepsy

• Renal failure

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

CONTRAINDICATIONS (even short term use)

• UNCONTROLLED DIABETES

• IMMUNOCOMPROMISED

• ACTIVE PEPTIC ULCER

• OSTEOPOROSIS

• ACTIVE HERPETIC OR FUNGAL INFECTIONS

• AVOID HIGH DOSE IN PTS. WITH PSYCHOSES

• 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

Conclusion

Steroiddoses(Injec/on)-Guidelines

DOSESMUSTBEINDIVIDUALIZEDFOREACHPATIENTANDACONSULTATIONWITHTHEPATIENT’SHEALTHCAREPROVIDERMAYBE

INDICATED

ProcedureDexamethasoneSodiumPhosphate(IVorIM)

ClearSolu/on

Depo-Medrol(IMonly)whitesuspension

Singleimplantsmallflap 2-4mg 10-20mgornone

Singleimplantmedflap 4to6mg 20-40mg

Mul/pleimplantslargeflap 6to8mg 40-60mg

Fullarchflapwithmul/pleimplants 8mg 60to80mg

Steroiddoses(Oral)Guidelines

DOSESMUSTBEINDIVIDUALIZEDFOREACHPATIENTANDACONSULTATIONWITHTHEPATIENT’SHEALTHCAREPROVIDERMAYBEINDICATED

Procedure NumberofDexamethasone0.75mgtablets NumberofPrednisone5mgtablets

Day1

Day2

Day3

Day4

Day5

Day6

Day7

Day1

Day2

Day3

Day4

Day5

Day6

Day7

Singleimplantsmallflap

4 3 2 1 none none none 4 3 2 1 none none none

Singleimplantmedflap

5 4 3 2 1 none none 5 4 3 2 1 none none

Mul/pleimplantslargeflap

6 5 4 3 2 1 none 6 5 4 3 2 1 none

Fullarchflap

mul/pleimplants

7 6 5 4 3 2 1 7 6 5 4 3 2 1

CONTRAINDICATIONS (even short term use)

• DIABETES

• Pregnancy

• IMMUNOCOMPROMISED

• ACTIVE PEPTIC ULCER

• OSTEOPOROSIS

• ACTIVE HERPETIC OR FUNGAL INFECTIONS

• AVOID HIGH DOSE IN PTS. WITH PSYCHOSES

Anti-CoagulantAnti-Thrombotic

Anti- PlateletDrugs

ANTICOAGULANTCLASSES• INHIBITORSOFCLOTTINGFACTORSYNTHESIS

• WARFARIN(COUMADIN®)• Rivaroxaban(Xarelto®)

• INHIBITORSOFTHROMBIN• HEPARIN,LEPIRUDIN(REFLUDAN™)• DabigatranEtexilateMesylate(Pradaxa™)

• PREVENTIONOFPLATELETAGGREGATION• ASA• TICLOPIDINE(TICLID™)• CLOPIDOGREL(PLAVIX™)• TIROFIBAN(AGGRASTAT™)• EPTIFIBATIDE(INTEGRILIN™)• Prasugrel(Effient™)• Ticagrelo(Brilinta®)

ANTICOAGULANTS

• WARFARIN(COUMADIN)– ACTSINLIVERBYINHIBITINGREDUCTIONOFVIT.KTOAFORMNEEDEDFORSYNTHESISOFFACTORSVII,IX,X,ANDPROTHROMBIN

• HEPARIN– POTENTIATESTHEANTICOAGULANTACTIVITYOFENDOGENOUSANTITHROMBINIII

COUMADIN®

• EFFECTIN24HRS.

• PEAK3–4DAYS

• MAYCAUSESERIOUSHEMORRHAGE

– ANTIDOTE–VIT.K

• REQUIRES12–24HRS.

– MAYREQUIRETRANSFUSION

Warfarin

• Outpa/entRx’s2004-31million

• Ranked1stin2003and2004fordrugrelateddeathsdueto“adverseeffects”intherapeu/cuse

• 10to16%ofpa/entswillhaveamajorbleedatsomepoint

• NolongeracceptabletoD/Cwarfarinrou/nely!!!

COUMADIN®

• MONITORWITHINR(INTERNATIONALNORMALIZEDRATIO)

– STANDARIZESTHEVARIOUSLABORATORIESTHROMBOPLASTINS(humanorrabbit)

Recommendedrangefororalan/coagulanttherapy:

• 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 < 2.0 out of therapeutic range (poorly managed – needs adjustment)

INR 2.0 → 4.0 ok to do surgery with local measures

INR > 4.0 out of therapeutic range – (warfarin dosage needs adjustment )

Con/nuewarfarintherapy• Hemorrhagicdisorders• CorrectINR

D/C warfarin therapy • Malpractice • Cerebrovascular

complications • Thrombosis formation

Good

Bad

Warfarin (Coumadin®)

I have finished reviewing the OOOOE article on warfarin. Bottom line, there is no 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.

John Kern PhD - email communication

Ref.HermanW.,et.al.,CurrentPerspec/vesOnDentalPa/entsReceivingCoumarin

An/coagulantTherapy,JADAMarch1997

TAKE-HOME MESSAGE

• MUSTHAVEARECENTINR(WITHIN30DAYSIFNOCHANGESINMEDS)

• IFANYMEDORDOSAGECHANGES–THENMUSTREPEATINR

• BESTIFSAME-DAYFORMAJORPROCEDCURES!!!

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”

dabigatran (Pradaxa®) 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.

dabigatran (Pradaxa®)• 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:FactorXainhibitor

– Incoagula/onfactorX→Xa(producesfibrin)

Rivaroxaban(Xarelto®)

• Prophylaxisofdeepveinthrombosis(DVT)whichmayleadtopulmonaryembolism(PE)inptsundergoingkneeorhipreplacementsurgery

• 10mgoncedaily

• 5-6%ptshave“ableedingevent”


• MeasurementofEffect

– Prolongsprothrombin/me(PT)andac/vatedpar/althromboplas/n/me(aPTT)

• Predic/vetreatmentvaluesnotestablished

– NodataonINRuse

– Hipreplacement-35days

– Kneereplacement-12days


• Dentalconsidera/ons

– ↑bleedingoccurswith10mg/day

– Consult

– Noreportsofinterac/onswithamoxicill,cephalexin,cefazolin,ampicillin,&clindamycin


• Druginterac/ons

– InhibitorsofCYP3A4

• Ketocanazole(an/fungal)

• Clarithromycin(Biaxin®)

• Erythromycin

– NSAIDS

THROMBOGENESIS

• PLATELETAGGREGATION

• COAGULATION

ARTERIALCOAGULATION

– CASCADETOFIBRINSTRANDS

• ARTERIES

– PLATELETSADHERETODAMAGEDVESSELWALLS

– AGGREGATE

– COREFORFIBRINSTRANDS

– OCCLUDEARTERIALFLOW

– ISCHEMIAOFLOCALTISSUES

VENOUSTHROMBI

• FIBRINSTRANDS

– EMBOLIZEGREATDISTANCES

• LODGEINPULMONARYARTERIES

THROMBOGENESIS

• LOCALIZEDRESPONSE

– INITIATEDBYSUBSTANCESRELEASEDFROMPLATELETSANDENDOTHELIUM

– LIMITEDBYLOCALIZEDANTICOAGULANTMECHANISMS

• ANTITHROMBINII

ANTIPLATELETDRUG

• ASPIRIN

– TX:PREVENTIONOFMI&THROMBOTICSTROKE

– 81mg/day

– LITTLERISKFORDENTALSURGERY

ANTIPLATELETDRUG

• DIPYRIDAMOLE(PERSANTINE)

– PREVENTSPLATELETADHESIONTOENDOTHELIALSURFACES

– MIXEDWITHASA

• ENHANCESANTITHROMBOTICONARTIFICIALSURFACES

– VALVULAR&CARDIACPROSTHESES

– DIALATESCORONARYARTERIES

PLAVIX®-CLOPIDOGREL

• BLOCKSTHEADPRECEPTORWHICHPREVENTSTHEBINDINGOFFIBRINOGENTOTHATSITE

• DOESNOTALTERTHERECEPTOR

• REDUCES#OFFUNCTIONALADPRECEPTORS

PLAVIX®-CLOPIDOGREL

• MONITORWITHPLATELETAGGREGATION• INITIAL2TO4WEEKSMAYCAUSETHROMBOCYTOPENIA–CHECKPLATELETS

• RARELYNECESSARYTOD/C• SURGERYIFMULTIPLESITESOREXTENSIVE?–getconsulta/on– DISCONTINUE7DAYSPRIORTOPROCEDURE(RARELYNECESSARY!)

PLAVIX®-CLOPIDOGREL-WOW!!!!

• 30%ofpopula/onhasagene/cvariantinlivermetabolizingenzymesthataffectefficacyofclopidogrel-noeffectatall

– CYP2C19convertsclopidogreltoanac/vemetabolite.

– Geneswhichencodeandexpressliverenzymesresponsibleformetabolismexistinseveralpolymorphicstates(CYP2C19has4variantswithreducedfunc/on)

– Rela/vereduc/onof32%inac/vemetabolite

– 53%higherriskforprimaryefficacyoutcomeofdeathfromcardiovascularcauses,MI,stroke

– Stentthrombosisincarriers3Xthatofnon-carriers

– Ref.MegaJLetal.,“CytochromeP-450PolymorhismsandResponsetoClopidogrel”NEJM,2009,360(4):354-62

Prasugrel(Effient™)

ClopidogrelNon-fatalsubsequent

hearta?acks

PrasugrelNon-fatal

subsequenthearta?acks

9.1% 7%

Deathsandstrokesequal

Riskofsignificantfatalbleeding

+ ++

• An/plateletagentandaggrega/oninhibitor

– For⬇thrombo/ccardiovascularevents(stent

thrombosis


• Pro-drug

• IrreversiblyblocksP2Y12componentofadenosinediphosphate(ADP)receptorsonplateletsfortheirlifespan

–⬇plateletac/va/onandplateletaggrega/on

– Normalplateletac/vitydoesnotreturn(newplateletsin5to9daysa{erD/C

– Loadingdose60mgfollowedbymaintenancedoseof10mgdaily.

– ShouldtakewithASA75to325mgdaily


• Gene/cvariantsinlivermetabolizingenzymesdonotaffectefficacy

– Undergoesrapidintes/nalandserummetabolismviaesterase-mediatedhydrolysistoathiolactone(inac/vemetabolite),whichisthenconverted,viaCYP3A4&CYP2B6enzymeoxida/on,totheac/vemetabolitedesignatedasR-138727.

Ticagrelor(Brilinta®)

• Reducerateofthrombo/ccardiovasculareventsinptswithacutecoronarysyndrome(ACS):unstableangina,non-STeleva/onMI,STeleva/onMI

• Moreeffec/vethanclopridogrel


• Druginterac/ons

– InhibitorsofCYP3A4

– Ketocanazole

– Itaconazole

– Voriconazole

– Clarithromycin(Biaxin®)

– Erythromycin

• NSAIDs


• Mechanism:Anac/ve,reversibleplateletinhibitor

• CYP3A4converts/cagrelortoanotherac/vereversibleplateletinhibitor-whichisthemajorac/vemetabolite

• ActattheADP-receptor

• Loadingdose180mgthen90mgBID

– GivewithloadingdoseASA325mgthen75-100mg.Daily

– ASAdosesabove100mg/dayreduceeffec/venessof/cagrelorandshouldbeavoided


• Dentalconsidera/ons

• DoNOTD/Cwithoutconsulta/on

• Expectbleedingandechymosis

• Ptso{enhaveSOB

• Nocoagula/onparameterssuggested

Ways to stop bleeding 1.Presssure

2.Local Anesthesia with epinephrine on gauze

3.Suture

4.Bone wax

5.Collagen

6.PRP

7.PPP

8.PRF

9.I-PRF

10.Stop Bleed

Ways to stop bleeding 16.Hemostat (clamp)

17.Injecting local anesthesia with epinephrine

18.Ice packs

19.Burnish bone

20.Ligate vessel

21.Periacryl (gel)

11.Surgicel (oxidized celluler polymer)

12.Avitene (microfilbular collagen)

13.Laser

14.Bovie (high-temperature cautery)

15.Bovine Thrombin

Pancreateic Hormones

Diabetes Type I and II

In Dentistry1James L. Rutkowski, D.M.D., Ph.D.

Diabetes•> 18.4% Population over age 65 have some form of

diabetes

•Diabetes type 2 IS ↑ 6% per year • Ref. Rees 2000

•Complication

•Retinopathy, nephropathy, neuropathy,micro- and microvascular 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

Infection and Wound Healing

• Difficulty managing infections

• Hyperglycemia reduces phagocytic action of granulocytes

• Hyperglycemia promotes growth of microorganisms

• Impaired wound healing

• Ketoacidosis inhibits migration of granulocytes

• Vascular wall changes, vascular insufficiency, decreased blood blow and reduced Oxygen tension

Oral Complications of Diabetes

• Uncontrolled Diabetes Mellitus

• Xerostomia

• Infection

• Poor healing

• Increased incidence and severity of periodontal disease

• Burning mouth syndrome

• Oral fungal infections (Candida, Mucomycosis)

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 non-controlled DM • 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 at an inadequate amount • Tissue receptors are resistant to insulin action


Gluconeogenesis

•Complex biochemical pathway

•Results in the synthesis of glucoses from AA’s derived from protein catabolism

•Insulin inhibits this process •By promoting protein synthesis •Inhibiting enzymes vital for gluconeogenesis


Insulin

•Protein •2 polypeptide chains

•Human, bovine, & porcine •Similar (only differ by 1-2 AA’s)


Insulin

•⇑ blood glucose is sensed by beta cells (islets of langerhans - pancreas)

•Provides stimulus for insulin secretion


INSULIN

•Purpose - transport glucose into cells where it can best 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, semi-lente

•Intermediate acting • NPH, Lente

•Long acting • PZI, Ultralente


Surgery Requiements

• Review HbA1C (IDEAL <7 mg%)

• Stable DM, knowledgable patient, not extensive procedure & within your comfort level - ? need for consultation

• If not stable, poor knowledge base for patient, extensive procedure - consultation


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 Type II

• Review HbA1C (ideal <7 mg%)

• Stable DM, knowledgable patient, not extensive procedure & within your comfort level - ? need for consultation

• If not stable, poor knowledge base for patinet, extensive procedure - consultation


Diabetes Controlled with Oral Agents

•Hold all oral diabetic medication day of surgery

•Eat a light breakfast - do surgery in a.m.

• Ref. Gill, The Care of the Diabetic Patient During Surgery, 1993


Treatment

Hold dose day of surgery (renal impairment - hold additional 24 hrs.)

Pranden Amaryl Glipizide Glucotrol Orinase Tolinase Dymelor Glucophage Actos Avandia ? Janumet


REMEMBER

•Epinephrine causes increased gluconeogenisis and creased glycolysis (∴ ↑ blood glucose)

•Glucocorticosteroids increased gluconeogenisis (∴ ↑ blood gluscose)


Glucagon

•Released by alpha cells of pancreatic islets •Sympathetic stimulation as a response to low serum

glucose

•Glucagon •⇑ glycogenolysis in liver •Accelerates lipolysis in adipose tissue


Glucagon

•TX: Hypoglycemia

•Get response 10 – 15 minutes •⇑ contractility of myocardium (+ ionotropic) • Cardiogenic shock •Spasms of GI & biliary tracts


Pre- & intra-operative Considerations for Diabetes Mellitus Type II

• Metabolic control should Best analyzed & optimizes prior to implant surgery

• Gylcosylated hemoglobin (G-Hb or Hb A1C) level < 7 mg% is best

• Antibiotic prophylaxis is recommended

• Peri-postoperative rinse with 0.12% chlorhexidine digluconate -?


Considerations for Recombinant and

Autogenous Growth Factors

Bone-Growth Modifying Methods

• Recombinant Growth Factors • rhBMP-2 (Infuse) • rhPDGF-BB (Gem-21S)

• Blood Concentrates • PRP • PRF • PRF

What are recombinant Growth Factors?

• Recombinant: an organism or cell in which genetic recombination has taken place (material produced by genetic engineering)

• Growth factors: chemical messengers that induce cell growth by tissue type (e.g., osteoinductive, epidermal, vascular endothelial,TGF-β1).

How is rhBMP-2 made?

• Recombinant Human Bone Morphogenetic protein-2

• Produced in E.Coli as a homodimeric, non-glycosylated, polypeptide chain containing 115 amino acids

• Molecular mass of 26018 Daltons

• BMP-2 is purified and reproduced using recombinant DNA technology.

Recombinant BMPs• rhBMP-2 (recombinant human BMP-2)

• rhBMP-7 [recombinant human osteogenic protein-1 (rhOP-1)]

• rhGDF-5 [recombinant human growth ⁄ differentiation factor-5 (rhGDF-5); also known as recombinant human cartilage derived morphogenetic protein-1(rhCDMP-1)]

• All of the above have been combined with a variety of candidate biomaterials used as delivery systems

BMPs• Soluble

• Delivered in a buffer solution

• clearance rapid

• < 5% of the BMP dose remains at the site, whereas combinations with gelatin foam or collagen showed increased retention ranging from 15 to 55% (Hollinger et al. 1998)

• Biomaterials that retain and sequester BMPs at the site enhance efficacy and reduce protein dose by localizing the morphogenetic stimulus (Chen and Mooney 2002)

Infuse® Bone Graft Oral Maxillofacial Indications

• Alternative to autogenous bone graft for:

• Sinus augmentation

• Augmentations of defects associated with extraction sockets

Delivery of recombinant bone morphogenetic proteins (rhBMPs) for bone regeneration and

repair. Part A: Current challenges in BMP delivery • Biotechnol Lett (2009) 31:1817-1824Haidar ZS,

Hamdy RC, Tabrizian M.

• Exact cellular and molecular mechanisms not fully characterized

• Small amounts induce cellular responses in vitro

• In vivo, rapid degradation and insufficient and improper tissue regeneration occurred (Engstrand et al. 2008)

• Clinical efficacy of recombinant human forms of BMPs depends on the carrier system used to ensure an effective delivery of adequate protein concentrations (Mont et al. 2004)

A comprehensive clinical review of recombinant human bone morphogenetic

protein-2 (INFUSE® Bone Graft)• Combination of recombinant human bone morphogenetic protein-2

(rhBMP-2) on an absorbable collagen sponge (ACS) carrier has been shown to induce bone formation in a number of preclinical and clinical investigations

• 2002, FDA-approved Infuse as an autograft replacement for certain interbody spinal fusion procedures

• 2004, INFUSE® Bone Graft was approved for open tibial fractures with an intermedullary (IM) nail fixation

• March 2007, INFUSE® Bone Graft was approved as an alternative to autogenous bone grafts for sinus augmentations, and localized alveolar ridge augmentations for defects associated with extraction sockets.

Critical-size Supra-alveolar Peri-Implant Defect Model -Litmus Test

Sigurdsson TJ, Fu E, Tatakis DN, Rohrer MD, Wikesjo¨ UME. Bone morphogenetic protein-2 enhances peri-implant bone regeneration and osseointegration. Clin Oral Implants Res 1997;8:367–74.

rhBMPs - Side Effects• Tissue effects are occasionally overwhelming

• Soft tissue edema, erythema, local inflammation, heterotopic ossification and immune response are the most remarkable

• Osteoclastic activation noted in some cases

• Large doses = bone resorption occurred (Gautschi et al. 2003)

Adverse Events Reported After the Use of Recombinant Human Bone Morphogenetic Protein 2

Emily Jane Woo; J Oral Maxillofac Surg 2011.

• Results: As of April 30, 2011

• 83 reports of adverse events after oral and maxillofacial operations involving rhBMP-2

• 55 (66.3%) described off-label uses, such as reconstruction of the mandible after fracture or cancer or alveolar cleft repair

• Most commonly reported adverse events included local reactions, graft failure, infections, and other wound complications

• 30.1% stated that the patient required additional surgery to address the reported adverse event.

Adverse Events Reported After the Use of Recombinant Human Bone Morphogenetic Protein 2

• Conclusions: Serious adverse events, some of which may require a second operation, can occur after the use of rhBMP-2 in oral and maxillofacial procedures. In this analysis graft, failure and pseudarthrosis were more commonly reported after off-label uses of rhBMP-2 than approved uses.

Conclusion

• The gene expression levels of BMP-2 and the components of the BMP-signaling pathway are highly conserved among most OCCA cell lines

• Continued caution should be used for considering the therapeutic use of rhBMP-2 for reconstruction of bone defects in oral cancer patient

• Background: rhBMP-2 is used as a bone graft substitute in spinal fusion

• Accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms

of rhBMP-2 has been called into question

• Purpose: To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications

rhBMP-2 total cancer cases 38 (total pts. = 1116)

Dose range 4.2 - 40 mg.

ICBG or AD total cancer cases 17 (total pts. =

1517)

Typical dental dose of rhBMP-2 = 1 to 12

mg.

It’s all Pharmacology

1. Is it the dose? 1mg or 40 mg? 2. Is it the route of administration? Collagen sponge or

no Collagen sponge? 3. Is it the duration? retained at the site or free to move

about the body ? 4. Is it the site of administration? Spine or jaw?

Secret to staying out of trouble with Infuse

USE THE SPONGE!!!!! Keep it at the site of

administration Use as little as possible

Why Use PRF• Autologous source for chemoattractant and

mitogenic growth factors

• Enhances

• Bone healing cascade: Stem cell recruitment, angiogenesis, extracellular matrix production, and remodeling

• Biological activity of demineralized bone matrix

Platelet

Latent

Latent

Why Platelets Repair Bone

Platelet ∝-Granule

Platelet Platelet

∝-

Granule

Platelet Activation

Blood Clot

Latent

Latent

Thrombospondin-1

Thrombospondin-1


Throm

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OsteoblastNucleus

Transcription


Platelet

What went wrong with PRP?

Platelet

Platelet Platelet

Latent

FREE

Platelet Activation TGB-β1 metabolized

in 6 minutes

Objective: Determine if PRP can ↑ the osteoinductivity of

demineralized bone matrix (DBM) when used with or

without thrombin activation

Bone Formation (3 samples) 56 days post intramuscular implantation

Conclusion: Platelet-rich plasma significantly increased in vivo demineralized bone matrix osteoinductivity only when used without thrombin activation.

Inflammation

Bovine Thrombin Controversy

• Study: when properly administered PRP can enhance the osteoinductivity of demineralized bone matrix (DBM) preparations

• Bovine-derived thrombin-activated PRP (1000U/mL) inhibits osteoinducivity

• Bovine thrombin-activated PRP is not recommended to be used in combination with demineralized bone matrix

• PRP is an attractive adjuvant to DBM only without the prior activation by bovine thrombin

A-PRF & I-PRF rhPDGF-BB with TCP

rhBMP-2 with Sponge (Infuse)

Procedure

Use

Benefit 1-10

Risk 1-10

$ Use

Benefit 1-10

Risk 1-10 $ Use

Benefit 1-10

Risk 1-10 $

Socket Graft X 10 1 20 X 3 1 250 X 10 10 840

Sinus augmentation

X 10 1 30 X 3 1 250 X 10 10 1250+

Lateral augmentation

X 10 1 40 X 3 1 250 NO 10 10 1250+

Vertical augmentation

X 10 1 40 X 3 1 500 NO 10 10 3000+

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

Platelet Rich Plasma - What is it?

• Varieties:

1. Pure-Platelet-Rich Plasma (P-PRP)

2. Leukocyte- and Platelet-Rich Plasma (L-PRP)

3. Pure Platelet-Rich Fibrin (P-PRF)

4. Leukocyte- and Platelet-Rich Fibrin (L-PRF)

5. Buffy Coat Platelet-Rich Plasma (BC-PRP)


Classification of PRP

• classification dependent upon

• leukocyte content

• fibrin content


Platelet Concentrates

• used to treat hemorrhage due to severe thrombopenia

• standard platelet concentrate for transfusion has been named platelet-rich plasm (PRP)

• contains 0.5 x 1011 platelets per unit

• unit = 40 mL

• 1.25 x 106 platelets/μL

• Baseline is 150,000 to 400,000/μL

• need 3 - 8 fold increase in platelets to be PRP


Platelets• produced in blood cell formation (thrombopoiesis in

bone marrow

• bud from megakayocytes

• one megakaryoctyes = 5,000 to 10,000 platelets

• life span 7 to 10 days

• contain granules

• dense - ADP, ATP, serotonin

• α - TGF-β, PDGFs, VEGF, etc

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

TGF‐β1

PDGF‐AA

PDGF‐BB

NGF

ILGF

VEGF

OPG

BMP‐2

BMP‐6

FGF‐2

SCF

Lactoferrin

Platelets

http://en.wikipedia.org/wiki/Image:Platelet_blood_bag.jpg

http://livepage.apple.com/


Granulocytes Neutrophils 65% Basophils <1% Eosinophils 4%

AgranulocytesLymphocytes 25%Monocytes 6%Macrophages

White Blood Cells


•FGF-2 •G-CSF •HGF •IGF-1 •LIF

•NGF •Osteopontin •PDGF •TGF-β1 •VEGF

Monocytes


• 70% growth factors released in initial 10 minutes

• remaining 30% released within one hour

Remember


• Commercial interests might obscure a lack of true-clinical benefits

• There has been commercial exploitation with the development of a wide range of preparation protocols, kits and centrifuges

• They are not all the same -- they all work to some degree because of the platelet contents


• Common points

• blood collected with anticoagulant

• immediately processed by centrifugation

• platelet concentration completed within one hour

• separates blood into 3 layers

• Platelet-Poor Plasma (PPP)

• Platelet-Rich Plasma (PRP)

• Red Bood Cells (RBCs)

PRP Techniques


• relates to

• preparation kits and centrifuges used

• content of the concentrate

• fibrin network that supports the platelet and leukocyte concentration

Parameters


Buffy Coat-PRP Process

• centrifuge type: light

• duration: quick (10 minutes)

• cost: very inexpensive


Buffy Coat-PRP Content

• Volume: small

• platelet collection: excellent (possibly the best)

• leukocyte collection: excellent (possibly the best)

• preservation: healthy, unactivated


Buffy Coat-PRP: Fibrin content

• density: very low

• polymerization: none


PPP

BUFFY COAT (PRP)

RBCs


• whole blood collected without anticoagulant and immediately centrifuged

• natural process occurs for the easy collection of a leukocyte- and platelet-rich bring (L-PRF) clot

• no anticoagulant, thrombin, or calcium chloride

PRF (Platelet-Rich Fibrin)










Text


2-24-04 8-27-04

30 Weeks


8-2-06 1-16-07

22 Weeks


3-26-07 6-20-07

11 Weeks


7-11-07 9-12-07

8 Weeks







Relative Fold Increase in

Gene Expression

In Treatment Media

vs Growth Medium (control)


% Radiographic Density Change PRP vs Control


Platlelet-Rich Fibrin (PRF)


December 22, 2010Day of

Tooth Removal


12/29/20091-week post-op


January 4, 2010 2-week post-op


January 18, 20101-month post-op









• Supplies can be purchased through Salvin • Vacutainer Needle (20 Ga)/100 $42.50 • Vacutainer Needle Holder/100 $75.00 • Vacutainer (Yellow 8.5mL)/ 100 $74.90 • Vacutainer (Blue 4.5 mL)/100 $62.50 • Collection Tube Rack $20.90 • 3cc Syringe/100 $36.50 • Centrifuge $1050

• Total for 100 patients = 1362.30 (Yellow + Blue)

• $13.63 per patient

Supplies


• $13.63 per patient for the first 100 patients

• Greater predictability for implants

• Virtually no complications

• Better bone faster

• Decrease dry-socket incidence

• Even with an implant failure rate of 1%, using PRP could save you thousands

• No other prevention for dry socket as effective – could save hundreds

• New insurance code for PRP use: D4265 “Biological Material to Aid in Soft and Osseous Tissue Regeneration”

PRP saves the bottom line


BC-PRP and PRF

• use BC-PRP to mix with bone graft material, coat acellular dermal matrix, collagen, etc.

• use PRF as a membrane

• ? how long does the membrane last

• is it really a membrane


BC-PRP — PRF

• A. There are platelet accumulations (the Buffy Coat)

• B. There are no platlet or any other cellular bodies in the upper part of the PRF fibrin clot

Platlet-rich fibrin (PRF): A seond-generation platelet concentrate. Part II: Platelet-related

biologic features; Dohan Oral Med Oral Pathol Oral Radiol Endod 2006;101:E45-50


A comparative study of platelet-rich fibrin (RPF) and platlet-rich plasma (PRP) on the effect of proliferation and differentiation of rat osteoblasts in vitro Ling, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:707-713

• Objective. The purpose of this study was to evaluate the effect of biologic characteristics of platelet-rich plasma (PRP)and platelet-rich fibrin (PRF) on proliferation and differentiation of rat osteoblasts.

Study design. Blood samples were collected from 14 healthy volunteers (7 male) with a mean age of 23.2 2.24years. PRP and PRF were prepared with standard protocols. The exudates of PRP and PRF were collected at the timepoints of 1, 7, 14, 21, and 28 days. The levels of platelet-derived growth factor AB (PDGF-AB) and transforminggrowth factor 1 (TGF-1) were quantified in PRP and PRF. Then the exudates of PRP and PRF were used to culturerat calvaria osteoblasts. The biologic characteristics of osteoblasts were analyzed in vitro for 14 days.Results. PRP released the highest amounts of TGF-1 and PDGF-AB at the first day, followed by significantlydecreased release at later time points. PRF released the highest amount of TGF-1 at day 14 and the highest amountof PDGF-AB at day 7. Exudates of PRP collected at day 1 and exudates of PRF collected at day 14 expressedmaximum alkaline phosphatase (ALP) activity, though no significance was shown. Cells treated with exudates of PRFcollected at day 14 reached peak mineralization significantly more than both negative control and positive controlgroups. PRF is superior to PRP, from the aspects of expression of ALP and induction of mineralization.

Conclusions. PRF released autologous growth factors gradually and expressed stronger and more durable effect on proliferation and differentiation of rat osteoblasts than PRP in vitro.


TGF-β1 Concentrations

• BC-PRP: 485 pg/105 platelets = 1.0185 x106 ng/mL

• c PRP = 4.6713 x 102 ng/mL

• activated with bovine thrombin

• BC-PRP 2.2 x 103 times more TGF-β1/mL

• PRF = 6.634 x 10-6 ng/mL

• BC-PR 1.5 x 109 times more TGF-β1/mL than PRF


6,634 ? = really or is it 6.634 (1000 fold difference



Steroid Dose Sheets

Steroiddoses(Injec/on)-Guidelines

DOSESMUSTBEINDIVIDUALIZEDFOREACHPATIENTANDACONSULTATIONWITHTHEPATIENT’SHEALTHCAREPROVIDERMAYBE

INDICATED

ProcedureDexamethasoneSodiumPhosphate(IVorIM)

ClearSolu/on

Depo-Medrol(IMonly)whitesuspension

Singleimplantsmallflap 2-4mg 10-20mgornone

Singleimplantmedflap 4to6mg 20-40mg

Mul/pleimplantslargeflap 6to8mg 40-60mg

Fullarchflapwithmul/pleimplants 8mg 60to80mg

Steroiddoses(Oral)Guidelines

DOSESMUSTBEINDIVIDUALIZEDFOREACHPATIENTANDACONSULTATIONWITHTHEPATIENT’SHEALTHCAREPROVIDERMAYBEINDICATED

Procedure NumberofDexamethasone0.75mgtablets NumberofPrednisone5mgtablets

Day1

Day2

Day3

Day4

Day5

Day6

Day7

Day1

Day2

Day3

Day4

Day5

Day6

Day7

Singleimplantsmallflap

4 3 2 1 none none none 4 3 2 1 none none none

Singleimplantmedflap

5 4 3 2 1 none none 5 4 3 2 1 none none

Mul/pleimplantslargeflap

6 5 4 3 2 1 none 6 5 4 3 2 1 none

Fullarchflap

mul/pleimplants

7 6 5 4 3 2 1 7 6 5 4 3 2 1

The Top 25 Drugs that Affect Dental Implant Outcomes


The Facts • > 15,000 FDA approved prescription and OTC drugs, diagnostics, & IV supplements on the market

• + 100’s of herbal and dietary supplements • • = growing # of drug interactions

• + foods (i.e. grapefruit juice) = issues for the clinician

297


Older Population vulnerable to Drug Actions

• ⬆ age → ⬆disease → ⬆drugs = poly-pharmacy

• ⬇cardiac output → ⬇blood flow → ⬇ drug to liver and kidney → ⬇ pre-hepatic and hepatic metabolism → ⬇renal activity

•⬆receptor sensitivity in CNS

•⬇ in hemostatic mechanisms

• = COMPLEXITY= CHAOS

298


It’s Not Simple

• Drugs do not work in a vacuum • Receptors are not just expressed on

just one cell type • It is not one neuron and one

receptor • It’s much more complex than we

think

299


Drugs

• Pharmacodynamics vary with • Dose • Duration • Route of administration

300


Drugs

• New drug classes • 30 years ago no SSRIs (Prozac 12/29/87), monoclonal antibodies

• Today: 5 SSRIs in the top 100 prescribed drugs

–adults and children –depression, anxiety, panic attacks, obsessive compulsive disorder (OCD)

• Knowledge of drug effects and interactions still evolving

301


SSRIs

• Serotonin receptors found in: • Nervous tissue • Digestive tract • Platelets (Dense granules) • Bone

• (Tsapakis et al., 2012)

302


SSRIs• Celexa: Citalopram

• Paxil: Paroxetine

• Lexapro: Escitalopram

• Prozac: Fluoxetine

• Zoloft: Sertraline

303


SSRIs

Selective Serotonin Re-uptake Inhibitors and the Risk of Osseointegrated Implant Failure: A Cohort Study

X. Wu1, K. Al-Abedalla, E. Rastikerdar1, S. Abi Nader1, N.G. Danie, B. Nicolau, and F. Tamimi J Dent Res 93(11):1054-1061, 2014

304


Serotonin

• Regulates bone cells by acting on serotonin receptors and transporters • Resulting in complex signal

transmissions in osteoblasts and osteoclasts • (Tsapakis et al., 2012)

305

James L. Rutkowski, D.M.D., Ph.D.306

SSRI Use Effect on Dental Implant Failure Rate

SSRI Use # Implants Failure rate

p value (multilevel)

(Significance <0.05)

Hazard Ratio

(95%CI)

NO 784 38 4.6%

YES 84 10 10.6% 0.03* 6.28 (1.25-31.61)


SSRIs What Happened

• Initially Implants were successful • Good mechanical primary

stability • Acceptable bone quality and

quantity • Appropriate implant dimensions • Good initial and early healing

• Failures • Occurred when loaded

307


Loading Issues - Why

• Serotonin plays important role in anabolic response of bone to mechanical loading (Sibilia et al. 2013)

• Hypothesis: Excess serotonin might cause bone mass loss by inhibiting the anabolic bone-remodeling processes triggered by mechanical loading

308


SSRI Failure - Possible Solutions

• Longer healing times • Longer progressive loading time

periods • Splinting of implants

309


GERD Drugs: Proton Pump Inhibitors (PPIs)

• Esomeprazole: Nexium

• Lansoprazole: Prevacid

• Omeprazole: Prilosec

310


PPIs

• Suppress gastric acid secretions by the parietal cells of the stomach

• Inhibit the enzyme H+K+ATPase • May last up to 48 hours

311


PPIs mechanism

• Elevates gastric pH • Interferes with calcium absorption • Prolonged use results in decreased

BMD • Effects of long-term administration of omeprazole on

bone mineral density and the mechanical properties of the bone Yanagihar tR, et al., Rev Bras Ortop 2015 Mar 14;50(2)232-8

312


H2-Receptor Anatgonists (H2 Blockers)

• Cimetidine: Tagamet • Famotidine: Pepcid • Ranitidine: Zantac

313


• Chronic use of H2 Receptor Antagonists had little effect on BMD

314

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

• Bisphosphonates

• Corticosteroids

• Anti-neoplastic

• Antiepileptic

• Disease-Modifying Antirheumatic Drugs (DMARDS)

Anticoagulants

• Warfarin inhibits two reactions of the vitamin K cycle at the quinone reductase and epoxide reductase levels, causing a functional shortage of vitamin K - which is important for bone formation and skeletal integrity

• Dabigatran is a direct inhibitor of thrombin (serine protease), blocking the conversion of fibrinogen into fibrin and thereby preventing thrombosis

• Conclusions

• Treatment with warfarin was associated with decreased bone volume, increased trabecular separation and higher turnover compared to that observed in dabigatran-treated or control rats

• These findings suggest that dabigatran has a better bone safety profile than warfarin. Since warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization, these differences could translate into a lower incidence of fractures in dabigatran treated patients.


Arthritis Drugs

• Non-steroidal Anti-Inflammatory Drugs (NSAIDs)

• Disease-Modifying Antirheumatic Drugs (DMARDs)

The Mechanisms of the Inhibitory Effects of Non-

Steroidal Anti-Inflammatory Drugs on Bone Healing: A

Concise Review

Adam T. Harder and Yuehuei H. AnJ Clin Pharmacol 2003 43:807


Bone Formation

23

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)

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.

324

COX-2 Effects on Fracture Healing

The healing of stabilized tibia fractures was delayedin 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.

325

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

AH-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 fracture •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 •7-day treatment produced a trend for nonunion fracture

healing for both ketorolac and valdecoxib •21-day treatment produced significantly more 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

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

•Preliminary data suggest that systemic administration of flurbiprofen may reduce bone loss around dental implants in the first year of service


Summary • Continual usage of NSAIDs and COX-2 inhibitors

in patients with chronic arthritis, chronic pain syndromes, and other chronic diseases undoubtedly interferes with fracture healing, bone ingrowth, and other related processes. When the patient has sustained a fracture, it may be prudent to discontinue these medications, at least temporarily, to promote fracture healing.

• Goodman, SB, et al., J Am Acad Orthop Surg 2007;15:450-460

Disease-Modifying Anti-Rheumatic Drugs (DMARDS)

•Methotrexate (MTX) (Trexall™)

•Cyclosporine (Gengraft™)

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)

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

• At 12 weeks, there was a negative impact of CsA on the quality of bone around dental implants

•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.

Clin. Oral Impl. Res. 18, 2007 / 34–39

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

•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 •Vitamin K2

Anti-epileptic Drugs (AEDs)

• Induce cytochrome P-450 enzymes = affect bone metabolism •↑ catabolism of vitamin D → decreased bioavailability

of vitamin D; impaired calcium absorption; alterations in bone formation and degradation; abnormal PTH release; abnormalities in calcitonin or Vitamin K •Hypocalcemia, hypophosphatemia, ↓ activity of vitamin

D metabolites, ↑ PTH release •Phenytoins (Dilantin) •Phenobarbital •Carbamazepine (Tegretol ®) •Valproate disodium (Depakote®)

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

negative

negative

< 5mg/kg/day no affect > 5mg /kg/day negative

unknown

unknown or maybe be positive

Initially positive > 2.5 yrs. negative

Negative

Positive

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative


Osteoporosis Therapy

• Inhibitors of bone resorption

• Reduce osteoclast generation • Estrogens - ↑ release of OPG and ↓ RANKL signaling

• Calcium regulation: Vitamin K

353



• Inhibitors of bone resorption • Reduce osteoclast activity

• Bisphosphonates: alendronic acid, zolindronic acid, pamidonic acid, ibandronic acid

• Initially depress osteoclast activity and stimulate osteoblast activity •>2.5 years induces osteonecrosis in skeletal areas of high

concentration •Necrosis of osteoclasts, osteoblasts, and osteocytes •Dead bone

354



• Monoclonal Antibodies to RANKL: denosumab (like OPG) Promote bone formation

• Teriparatide (Forteo®) Stimulates osteoblast activity

355

Bone Grafting Techniques and Utilization of Bio-Activators

Bone - Why we are lucky

• Regenerate and repair itself

• Heals without scar formation (usually)

Bone - Why we are unlucky• Insufficient blood supply

• Infection

• Systemic disease

• Osteoporosis, Diabetes Mellitus, Renal Disease, Hypocalcemia

• Effect of medications

• DMARDs, Monoclonal antibodies, Bisphosphonates, Steroids,

Today = Tissue Engineering• Relevant scaffolds

• Growth factors and cells

• Stem cells

• Design scaffolds and tissue grafts to decrease the disadvantages of traditional grafts

• Improve graft incorporation, osteogenicity, osteoconductivity, and osteoinductivity

Tissue Engineering Limitations

• Host graft interaction

• Immune response to these implants, scaffolds, and viable grafts are still not clear

Five stages of graft incorporation

• Inflammation

• Re-vascularization (capillary buds invade the graft)

• Osteoinduction (differentiation of multipotent cells into osteoblasts)

• Osteoconduction (ingrowth into the graft by means of the host)

• Remodeling

Inflammation

GranulationInflammation

Pro-inflammatoryAnti-inflammatoryPro-angiogenic signalling

Bone formation time

Osteogenic signalling

Bone

Pharmacologically managed Inflammation

GranulationInflammation

Pro-inflammatoryAnti-inflammatoryPro-angiogenic signalling

Bone formation time

Osteogenic signalling

Bone

Inflammation• Th-1 lymphocytes produce pro-inflammatory cytokines (IL-2,

interferon-ɣ, TNF-∝)

• Poor tissue remodeling and rejection of both allo- and xenografts

• Th-2 lymphocytes produce anti-inflammatory cytokines (IL-4, IL-5, IL-6, Il-10) and do not activate macrophage

• Graft integration

Activation of lymphocytes

• Cellular grafts elicit M1 macrophage response

• Activates Th-1 lymphocytes leading to connective tissue formation and graft rejection

• Acellular grafts elicit M2 macrophage response

• Activates Th-2 lymphocytes leading to tissue remodeling and graft acceptance

Re-vascularization• Cortical grafts

• Vascularization is slower and occurs along Haversian canals

• Osteoclastic resorption is a prerequisite before osteoblasts can produce new bone

• Cancellous grafts converted by creeping substitution

• Vascularization is faster

• Newly formed osteoblasts line the trabeculae to form new bone simultaneous to resorption of bone by osteoclasts

Clin Oral Implants Res. 2015 May 20. doi: 10.1111/clr.12614. [Epub ahead of print]

Bone grafting materials in critical defects in rabbit calvariae. A systematic review and quality evaluation using ARRIVE guidelines

• Four parameters were analyzed by histomorphometry:

• New bone formation (NB)

• Defect closure (DC)

• Residual graft (RG)

• Connective tissue (CT)

• Animal Research Reporting in In Vivo Experiments (ARRIVE) guidelines

• List of 20 aspects for scoring to ensure comparison between different experimental studies in animals were used to evaluate the quality of the selected works.

Bone grafting materials in critical defects in rabbit calvariae




Particulate size

• Conclusion 100-μm to 500-μm is ideal

• For larger volume then use above mixed with 750-μm to 1000-μm

Scaffold Pore Size and Interparticulate space• pores must facilitate diffusion of oxygen and nutrients

• Optimal pore size, definitely greater than 100 μm

• Must optimize the surface area that is available for cell attachment

• Pores too small inhibit cellular migration and produce necrosis

• Pores too large, don’t provide sufficient surface area for cell attachment and compromise structural integrity

• recent study of interconnected porous scaffolds found that 350-μm and 800-μm pores play a limited role in bone regeneration, thus pore features other than size may play important roles

• Another study showed that although initial cell adhesion (48 h postseeding) reaches a maximum value for a mean pore size of 120 μm, overall cell migration is greatest for pore sizes larger than 300 μm

Scaffold pore size and Inter-particulate space

• Conclusion: most likely scaffold pore size and inter-particulate spaces of 300-μm is ideal

When Should Biologics be Used?

• Severe atrophic jaws

• Medically compromised

• Systemic disease

• Medications

• Sites with low vascularity

• Previous failures

Which Biologic

• Blood concentrates - Every case

• Recombinant growth factors - medically compromised, no history of cancer, previous failure, esthetically demanding

• Stem cells - medically compromised, previous disaster, esthetically demanding, hopeless case

Confidential © 2013

Loss of teeth #s 7-9 with thin lingual plate of bone remaining

Minimally inflamed graft site tissues 3-weeks post-op

Bone with intermediate drill implant osteotomies 5.5 months post onlay grafting

Graft site sutured day of surgery

Confidential © 2013

CT scan sections for various tooth position acquired 5.5 months post onlay grafting

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Bone with implant

osteotomy

Radiograph of implant day of

placement

Resulting bone 12 weeks

post tooth removal

Fragmented Adipose Tissue Graft for Bone Healing: Histological and

Histometric Study in Rabbit’s Calvaria

• Study design

• 42 rabbits

• CSD that were 15 mm in diameter

• defects were randomly divided into two groups

• Group C (control), the defect was filled only by a blood clot

• Group FAT (i.e., fragmented adipose tissue), the defect was filled with fragmented autogenous adipose tissue grafts.

Fragmented Adipose Tissue Graft for Bone Healing


Control group: 15 days - 40 days - 12X magnification

FAT group: 15 days 12X - 40X magnification

Control group: 40 days 12X - 40X magnification

FAT group: 40 days 12X - 40X magnification



Vertical Bone Regeneration

• 4 mm vertical augmentation IS feasible when using titanium reinforced ePTFE membranes and NO grafting material under the membrane • Simion, Int J Periodontics Restorative Dent 1994; Jovanovic, Int J Oral MaxillofacImplants 1998

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Documents

Dr. James Rutkowski Friday, June 10 9:30