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Better Medicine, Better Dentistry

Clinically Useful Pharmacology – Part 2

Dr. Mark Donaldson, BSP, RPH, ACPR, PHARMD, FASHP, FACHE

Friday, June 17th, 2016, 1:00 – 4:30pm

Dr. Mark Donaldson, BSP, RPH, ACPR, PHARMD, FASHP, FACHE received his baccalaureate degree from the University of British Columbia and his Doctorate in Clinical Pharmacy from the University of Washington. He has further completed a residency at Canada’s largest tertiary care facility, Vancouver General Hospital, and is the current Director of Clinical Pharmacy Performance Services for Vizient, in Whitefish, Montana. Dr. Donaldson is a faculty member and Full Professor in the Department of Pharmacy at the University of Montana in Missoula, and Clinical Assistant Professor in the School of Dentistry at the Oregon Health & Sciences University in Portland, Oregon. He is also a continuing education speaker for the University of Washington, Washington State University, Oregon Health Sciences University, the University of Pennsylvania, and the University of British Columbia. Dr. Donaldson has a special interest in dental pharmacology and has lectured internationally on a number of related topics for both dental and medical practitioners. He has been a primary author and investigator for the National Institutes of Health

(N.I.H.) Consensus Development Committee to define the guidelines for enteral sedation in the United States, as well as an invited expert to compose a whitepaper on Enteral Conscious Sedation for the Academy of General Dentistry (A.G.D.). Dr. Donaldson is on the Editorial Board for the Journal of the American Dental Association (J.A.D.A.), has a number of published works in the peer-reviewed literature, and has spent three years in Japan focussing on cross-cultural communication and internationalization.

[email protected]

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Other Notes or Questions to Ask:

What’s in Your Emergency Kit and Why What is an Emergency? Any condition which if left untreated may lead to patient morbidity or mortality.

Why Should You Care About Emergencies? • In a survey of 2,704 dentists throughout

North America, a total of 13,836 emergencies occurring within a 10-year period was reported.

• None of these emergencies were truly dental emergencies. They were potentially life-threatening medical problems that patients developed while they were in a dental office.

• Almost all medical emergencies that occur in a dental office are fear-related.

• If fear and apprehension are reduced, the chances of having a medical emergency are also reduced.

Three-quarters of all of these medical

emergencies developed as sequelae of pain (i.e., inadequate local anesthesia), the dentist’s failure to recognize and treat a patient’s fear of dental care, or both.

Malamed SF. Managing medical emergencies. JADA 1993;124(8):40-53.

How Do You Manage Emergencies?

The Best Preparation is Prevention:

Know your patient: get a complete medical and pharmacological history. Review any problem areas. Take training.

o Practice o Practice o Practice

Manual - Simple with flow charts. Emergency Kit. Equipment - Less is better. Phone – Cell. Medication - Only what you will use and are comfortable using . . .

Friday, June 17, 2016 Copyright, Dr. Mark Donaldson Page 1 of 17


Stress-Reduction Protocol Recognize medical risk.

Consult patient’s physician(s).

Pharmacosedation, as indicated.

Short appointments. Rosenberg, M. Preparing for Medical Emergencies: Essential Drugs and Equipment for the Dental Office. J Am Dent Assoc 2010; 141;14S-19S.

#1: Epinephrine 1:1,000 Injection

Uses: to reverse hypotension, bronchospasm, and laryngeal edema that result from an acute

anaphylactoid type reaction. Also used to reduce bronchospasm resulting from an acute asthmatic episode that is refractory to inhaler therapy.

Pharmacology: Causes vasoconstriction that in turn increases blood pressure, heart rate, and force of contraction. Also causes bronchial dilatation. Reduces the release of histamine. Can be ineffective if the patient is taking beta-blocker.

Adverse Effects: a) Cardiovascular: Tachycardia, Tachyarrhythmia’s, and hypertension. b) Central Nervous System: Agitation, headache, and tremors. c) Endocrine System: Increased blood glucose. d) Pregnant Female: Can decrease placental blood flow.

Dose: Supplied in vials, ampules, or pre-loaded syringes in concentration of 1:1000 (1mg/mL). IV give 0.5-2.0mg (0.5ml-2.0ml) depending on severity of hypotension, titrate to effect repeat in 2 minutes if needed. IM give 0.3mg (0.3ml) repeat in 10-20 minutes as needed.

Morning appointments.

Excellent intraoperative pain control.

Minimize waiting room time.

Excellent post-operative pain control.



#1: EpiPen Instead??

Stecher D, Bulloch B, Sales J, et al. Epinephrine Auto-injectors: Is Needle Length Adequate for Delivery of Epinephrine Intramuscularly? Pediatrics 2009;124;65-70 CONCLUSION: The needle on epinephrine auto-injectors is not long enough to reach the muscle in a significant number of children. Increasing the needle length on the auto-injectors would increase the likelihood that more children receive epinephrine by the recommended intramuscular route.

#2: Diphenhydramine (Benedryl) 50mg Injection

Uses: To reduce the affects of histamine release that is associated with allergic reactions, anaphylaxis, and acute asthma attack precipitated by exogenous causes.

Pharmacology: An antihistamine that blocks the release of histamine in the body. It does not prevent the action of the histamine once released and thus must be given quickly. Prevents histamine responses suck as bronchospasm, hypotension, rash, and edema.

Adverse Effects: 1. Cardiovascular: Tachycardia. 2. Central Nervous System: CNS depression (sedative effects including

drowsiness, lethargy, and mental confusion). 3. Gastrointestinal: Xerostomia.

Dose: 50-100mg IM or IV. For mild cases of pruritis, urticaria, or erythema

an oral dose of 50mg every 6 hours can be used. #3: Nitroglycerin If patients have a history of angina and you are considering giving them their nitro or yours (from the EMG kit), what MUST you know? For Viagra and Levitra, at least 24 hours should have elapsed

since the last dose of a PDE5 inhibitor. For Cialis, allow at least 48 hours before using nitrates.

J Am Coll Cardiol 1999; 33:273-82 J Am Coll Cardiol 2003; 42:1855-60

Uses: Used to relieve or eliminate chest pain associated with angina pectoris, to differentiate between angina and a myocardial infarction.

Pharmacology: A coronary and peripheral vasodilator and as such helps increase the flow of oxygenated blood to the heart muscle.



It also causes venous pooling of blood decreasing venous return to the heart thus improving the pumping efficiency of the heart. Because of this improved efficiency myocardial oxygen demand is decreased.

Adverse Effects:

a) Cardiovascular: Rapid heart rate, facial flushing, and orthostatic (Postural) hypotension. b) Central Nervous System: Dizziness and headache.

Dose: a) Tablet: 1 tablet sublingually repeat after 2 minutes if no relief up to 3 doses. b) Metered Dose Spray: 1 spray sublingually repeat after 2 minutes if no relief up to 3 doses.

Called "remote ischemic preconditioning," the procedure developed by Toronto's Hospital for Sick Children was found to significantly limit the amount of damage to the heart muscle caused by a blockage in a cardiac blood vessel. Ischemic preconditioning involves using the device to interrupt blood flow in the arm, off and on over a period of 35 to 40 minutes: the cuff is inflated for five minutes, then deflated for five minutes, with the procedure being repeated consecutively four times. http://www.cbc.ca/health/story/2010/02/26/heart-attack-blood-pressure-cuff.html#ixzz0gfLoHNbP

#4: Oxygen Bag-Valve Concentrations:

Without oxygen - 21% With oxygen, no reservoir - 60% With oxygen and reservoir - 90 to 95% With demand valve attachment - 100%

Angina Angina

Symptoms/Signs: chest pain

Position comfortableAirway N/ABreathing N/ACirculation check pulse, monitor BPDefinitive Treatment

1. Let patient take their nitro2. Administer O2 or O2 with N2O3. Chew one aspirin tablet (81mg or 325mg)4. Call 9115. Terminate appointment

M.I. M.I. ““Heart AttackHeart Attack””

Symptoms/Signs: Crushing sensation in chest, tingling or numbness of left arm or hand, rapid breathing, sweating, ashen color, may be nauseated and vomit. Clenched fist on chest is 80% predictive! Call 911!

Position ComfortableAirway MonitorBreathing Assist if they stop breathingCirculation Check pulse, monitor BP

Definitive Treatment: 1. Call 9112. Administer O23. Chew one aspirin tablet 81 or 325mg4. Monitor and record vital signs5. Be prepared to administer CPR



#5: Aspirin (for Acute Coronary Syndromes) Pharmacology: Irreversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes,

via acetylation, which results in decreased formation of prostaglandin precursors; irreversibly inhibits formation of prostaglandin derivative, thromboxane A2, via acetylation of platelet cyclooxygenase, thus inhibiting platelet aggregation; has antipyretic, analgesic, and anti-inflammatory properties.

Uses: Treatment of mild-to-moderate pain, inflammation, and fever; prevention and

treatment of myocardial infarction (MI), acute ischemic stroke, and transient ischemic episodes; management of rheumatoid arthritis, rheumatic fever, osteoarthritis, and gout (high dose); adjunctive therapy in revascularization procedures (coronary artery bypass graft [CABG], percutaneous transluminal coronary angioplasty [PTCA], carotid endarterectomy), stent implantation.

Precautions: • Bleeding disorders: Use with caution in patients with platelet and bleeding disorders. • Dehydration: Use with caution in patients with dehydration. • Ethanol use: Heavy ethanol use (>3 drinks/day) can increase bleeding risks. • Gastrointestinal disease: Use with caution in patients with erosive gastritis or peptic ulcer disease. • Hepatic impairment: Avoid use in severe hepatic failure. • Renal impairment: Use with caution in patients with mild-to-moderate renal impairment (only

at high dosages); avoid in severe impairment.

#6: Albuterol Inhaler (bronchodilator)

Uses: Used during acute asthma or Anaphylaxis to reduce or control bronchospasm.

Pharmacology: A β2-adrenergic drug that relaxes the bronchial smooth muscle. It has rapid onset and duration of action of up to 6 hours. Also reduces the stimulation of mucous production.

Women are different !Women are different !Most frequent symptoms:

Prodromal During Acute MI71% unusual fatigue 58% short of breath48% sleep disturbance 55% weakness42% shortness of breath 43% unusual fatigue39% indigestion 39% cold sweat35% anxiety 39% dizziness> 30% had chest pain

43% did not have chest pain during Acute MI95% knew their symptoms were new and different a month or more prior to the Acute MI.


1.1. Call 911Call 9112.2. M.O.N.AM.O.N.A

MMorphineorphine for pain controlfor pain controlOO22 AdministrationAdministrationNNitroglycerineitroglycerine 1 dose q5min to max of 3.1 dose q5min to max of 3.

Ask both men and women if they Ask both men and women if they have had Viagra in the last 24 hr. have had Viagra in the last 24 hr. No nitro if yes as it can lead to No nitro if yes as it can lead to dangerously low BP.dangerously low BP.

AASASA Chew one tablet (81mg or 325mg).Chew one tablet (81mg or 325mg).This is as important as nitroglycerin.This is as important as nitroglycerin.

3.3. Be prepared to administer CPR. Be prepared to administer CPR. 4.4. The sooner they get to the hospital the better for The sooner they get to the hospital the better for

dilation of vessels or dilation of vessels or fibrinolysisfibrinolysis..




Albuterol and Beta-Blockers tend to inhibit each other.

Adverse Effects: Should be used with caution in patients with cardiovascular disorders especially coronary artery

disease, arrhythmias, and hypertension.

Dose: 2 puffs every 2 minutes to a maximum of 20 puffs. Hold inhaler about 2 inches from mouth. Have

patient take two deep breaths and then exhale forcefully. Dispense one puff on slow deep inhalation. Hold breath for 10 seconds and repeat.

#7: Glucose (for hypoglycemia) Symptoms: - Appears confused - Cool, moist skin - May be hungry - May seem “drunk” but not alcohol breath odor - Slurred speech

– If patient becomes unconscious or does not respond readily after sugar/carbohydrate administration, activate EMS. They will give IV treatment.

– Never give unconscious patient anything orally!

Should I Have Other Drugs?

Midazolam (Versed®)? Flumazenil (Romazicon®)? Nitrous Oxide? Corticosteroids? Aromatic Ammonia? Naloxone (Narcan®)?

Do Not Get Yourself Locked Into A Serious Drug Collection!



#8: Midazolam (Versed®) for Seizures

Uses: For seizures, since it can be injected IM or subcutaneously or swallowed (orally). Realistically you want to call 911 if the seizure lasts more than a minute or if it is the first seizure for a patient.

Pharmacology: A short-acting hypnotic-sedative drug with anxiolytic and amnesic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients.

Dose: Inject 1-1.5mg (1-1.5mL) into buccal fold and repeat after a minute or two if the

seizure has not stopped. If buccal fold is too difficult due to patient clenching inject IM on upper arm.

Beware: Midazolam is also available as a 5mg/mL vial in which case 5mL would be 25mg: too much!!

#9: Flumazenil (Romazicon®)

for Benzodiazepine Sedation Reversal

Uses: Selectively blocks benzodiazepine receptors, reversing sedation and respiratory depression

Preparation: 0.1 mg/ml, in 5 ml and 10 ml MDV

Dose: IV or sublingual, 0.2 mg every 1 minutes up to 5 doses

“Respiratory depression mediated by benzodiazepines can be reversed using the specific antagonist flumazenil (Romazicon). It can be titrated intravenously or injected sublingually in 0.2 mg increments every 2-3 minutes, up to 1 mg. Flumazenil should not be administered to patients with a history of seizure disorder or dependence on benzodiazepines.”

Dionne R, Phero J, Becker D; Management of Pain and Anxiety in the Dental Office. WB Saudners

2002;18:289

“Intraoral submucosal injection of flumazenil appears to be a viable concept based upon the following findings. The drug is rapidly and complete absorbed into the systemic circulation, as evidenced by comparable serum concentrations to those obtained by IV administration.”

Oliver F, Sweatman W, Unkel J, et al. Comparative pharmacokinetics of submucosal vs. intra-

venous flumazenil (Romazicon) in an animal model. American Academy of Pediatric Dentistry; 2002:26

#9: Corticosteroids for Acute Adrenal Insufficiency

The adrenal cortex produces over 25 different steroids. These steroids are broken into three groups: sex steroids, mineralocorticoids, and glucocorticoids. Of primary concern in dentistry are the glucocorticoids. A physiologic dose of approximately 20mg/day of cortisol is produced. This plays a key role in the body’s



ability to adapt to stress. Cortisol provides a chemical link within the cells of the body allowing regulation of vital functions including blood pressure and glucose utilization. Cortisol production is triggered by real or threatened “stress” such as trauma, illness, fright, and anesthesia. In a patient with suppressed adrenal function a failure of this cortisol production eliminates the chemical link to regulate vital functions resulting in sudden shock and possibly death. Suppressed adrenal function or Adrenal Failure is classified as either Primary (Addison’s disease caused by Disease states such as TB, Bacteremia, Carcinoma, and Amyloidosis.) or Secondary (caused by Pituitary disorders, Hypothalmic disorders, or Steroid Therapy). Steroid therapy suppresses the function of the adrenal cortex reducing the production of natural cortisol. Because of this suppression patient’s who have been on long term steroid therapy lose their ability to respond to stress. If these patients are stressed symptoms of acute adrenal insufficiency may result. Signs and Symptoms of Acute Adrenal Insufficiency: 1. Mental confusion. 2. Muscle weakness. 3. Fatigue. 4. Nausea and vomiting. 5. Hypotension.

6. Intense pains in abdomen, lower back, and/or legs. 7. Mucocutaneous pigmentation. 8. Hypoglycemia. 9. Hyperkalemia. 10. Increase heart rate, decreased blood pressure.

Dental Treatment Considerations For patients with a history of glucocorticoid therapy use stress reduction protocols. The following guidelines can be used to determine if replacement therapy is indicated but it is always a good idea to get a medical consult in such cases. If the patient has undergone supraphysiologic (more than 20mg/day) glucocorticoid therapy that was discontinued more than 30 days prior to the planned dental treatment no supplementation is required. If the patients has undergone supraphysiologic glucocorticoid therapy within 30 days of the planned dental procedure considered the patients suppressed and provide steroid supplementation equivalent to 100mg of cortisol. If the patient has undergone or is undergoing alternate day dosing schedule glucocorticoid therapy no supplementation is required but it is best to provide dental treatment on the off day of the patient’s dose schedule. If the patient is currently receiving daily glucocorticoid therapy at a supraphysiologic level (more than 20mg) supplementation is required. If the daily dose is subphysiologic supplementation is not required.

Equivalent Doses of Corticosteroids

Cortisone 25mg Hydrocortisone 20mg Prednisolone 5mg Prednisone 5mg

Methylprednisolone 4mg Triamcinolone 4mg Dexamethasone 0.75mg Betamethasone 0.6mg

Fundamentals of Emergency Preparation Training (BLS, ILS, ACLS, PALS). Development and implementation of an emergency

plan. Purchase and maintenance of emergency equipment and

drugs. Periodic mock emergency drills. Training new staff members. Monitoring and Patient Assessment.



Naloxone (Narcan®) – Narcotic Antagonist

Indications: • Reversal of narcotic depression including

respiratory depression induced by opioids, (both natural and synthetic narcotics), propoxyphene, and narcotic-antagonist analgesics

• Diagnosis of suspected acute narcotic overdosage • Not effective in counter-acting depression due to

barbiturates, tranquilizers or other non- narcotic anesthetics or sedatives

Routes of Administration: • IM, SC - when IV route not feasible; onset of

action not as prompt as with IV and may be delayed in patients who are hypotensive and have impaired peripheral circulation

• IV direct - slowly over at least 1 minute

Rando J, et al. Intranasal naloxone administration by police first responders is associated with decreased opioid overdose deaths. Am J Emerg Med. 2015 Sep;33(9):1201-4.

Dosage, Adults: • Known or suspected overdose: 0.4-2 mg IV; if no response, repeat 2-4 mg in minutes; in cases of

large narcotic overdoses, or methadone, pentazocine, propoxyphene overdose, higher doses may be required; if no response after 10 mg, reassess diagnosis; effective dose may be repeated every 20-60 minutes

• Post-operative respiratory depression: 0.1-0.2 mg at 2-3 minute intervals until desired response is obtained; repeat doses may be required at 1-2 hour intervals

• Partial reversal of opioid-associated respiratory depression in palliative patient: if respiratory rate < 6/minute, administer 0.1-0.2mg IV q2-3 minutes or 0.1-0.2mg SC q5-10minutes until respiratory rate > 10/minute. Continue to monitor respiratory rate q15minutes until no naloxone given x 1 hour.

Dosage, Children: • Known or suspected overdose: • Birth to 5 yrs or 20 kg: 0.1 mg/kg/dose; repeat at

2-3 minute intervals until desired response obtained

• > 5 yrs or > 20 kg: 2 mg; repeat as above • Post-operative respiratory depression: 0.005-

0.01 mg/kg IV repeated if necessary at 2-3 minutes intervals

• Onset of effect: within 1-2 minutes following IV, within 2-5 minutes following IM or SC

• Duration of effect: 45 minutes to 3-4 hours • Since duration of action of narcotic agent may

exceed that of naloxone, repeated doses or administration of naloxone via IV infusion may be required

Edwards ET, et al. Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for

Naloxone Delivery. Pain Ther. 2015 Jun;4(1):89-105.



Update on Osteonecrosis of the Jaw and Medication Concerns

Understanding the pathophysiology of osteoporosis requires knowledge of the basic process of bone remodelling, a process that occurs in all bones, throughout life. At any given time, most bone units are in a resting stage, metabolically quiescent. When the remodelling process is initiated, osteoclasts are activated, and bone resorption occurs, resulting in loss of bone substance. This phase typically lasts two or three weeks. The process is reversed with the action of osteoblasts, which lay down new bone matrix, which is in turn mineralized. The active phase of bone deposition and mineralization usually takes two or three months.

In osteoporosis, the central pathophysiological defect is increased bone turnover, leading to skeletal fragility and increased risk of fracture through two mechanisms. An uncoupling of the remodelling process occurs, with bone resorption being greater than bone formation, leading to net loss of bone, low bone mass, and thus increased risk of fracture. However, at the same time, there is a more subtle change. Bone resorption specifically weakens trabeculae, with trabecular strut perforation. On a microarchitectural basis, this loss of mechanical support directly leads to skeletal fragility and thus increased fracture risk.

This slide illustrates the negative effects of both increased bone turnover, and of remodelling imbalance, typical in osteoporosis. On the left, high bone turnover (because of increased frequency of activation of the remodelling sequence) means that at any given time, more bone pits can be found, decreasing biomechanical strength. At the same time, the imbalance in remodelling means that less bone is laid down than was removed. Both of these processes – increased bone turnover, and negative bone balance – lead to rapid loss of bone in osteoporosis. Definition of Osteoporosis: A progressive systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to increased bone fragility and risk of fracture. The diagnosis of osteoporosis is clear in a patient with progressive deformity from vertebral fractures. Some of the physical sequelae of severe osteoporosis includes: increasing number and severity of vertebral fractures; loss of overall height; presence of a dorsal kyphosis (dowager’s hump); protruberant abdomen; crowding of the ribs and; reduction in lung volume. These changes are commonly preventable with appropriate treatment.

Bone Remodelling Process

Bone H. Clin Ther 2000;22:15

2 to 3 weeks

2 to 3 months

Resting StageRemodellingCompleted Initiation

ResorptionOsteoclast

Formation

Osteoblasts

Increased Bone Remodelling and Fracture Risk in Osteoporosis

Increased Bone Turnover

Resorption > Formation

Net Bone Loss

Low Bone Mass

Skeletal Fragility and Fracture

Trabecular Strut Perforation Loss of Mechanical Support

Bone Resorption

Pathophysiology of Osteoporosis: Unbalanced Turnover

Normal Turnover Remodelling Balance

High Turnover Remodelling Imbalance

Increasedactivationfrequency

Increasederosiondepth plusreducedwall width



The reason that this particular talk is included in a dental presentation is because of new evidence in the literature that affects both dental and medical professionals. The following prescribing information can be found in print or at the website, http://www.us.zometa.com/hcp/safetyinformation.jsp: "Osteonecrosis of the Jaw (ONJ) has been reported in patients with cancer receiving treatment including bisphosphonates, chemotherapy, and/ or corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors. While on treatment, these patients should avoid invasive dental procedures if possible. No data is available as to whether discontinuation of bisphosphonates therapy reduces the risk of ONJ in patients requiring dental procedures." There is also some preliminary evidence that discontinuation of certain bisphosphonates does not seem to help. So let’s first review this medication class and understand how these agents work. The Bisphosphonates Indications: - Prevention and treatment of osteoporosis - Treating Paget's disease of bone

- Hypercalcemia associated with malignancy - Osteolytic lesions associated with metastatic bone disease

- Multiple myeloma Mechanism of action: bone resorption inhibitors increase bone density by binding to the bone matrix and slow down osteoclastic activity, thereby facilitating osteoblastic effectiveness.

Inorganic pyrophosphates are orally inactive, as they are hydrolyzed in the GI tract. The bisphosphonates were developed to circumvent this limitation, and are effective agents when administered orally (although they are all poorly absorbed, and should be taken while fasting). They are not metabolized significantly. Absorbed drug that is not bound to bone is excreted unchanged by the kidneys. Bisphosphonates also have a high affinity for calcium, and bind strongly to bone mineral, hydroxyapatite, especially at sites of bone resorption where mineral is most exposed. The bisphosphonate is absorbed by osteoclasts, and suppresses osteoclast function – osteoclast apoptosis is also enhanced.

ste l t

Loss of resorptive functionand apoptosis of osteoclasts

Uptake b y osteoclasts

Bone

Bone

PCP

PCP PCPPCP

PCPPCP

PCPPCP

PCPPCPPCP PCP

PCP PCPPCP

PCPPCP

PCPPCP

PCPPCPPCP

Bone

Bisphosphonate (PCP)concentrated at sites

of bone turnover

Bisphosphonates: Mechanism of Action

Rogers M. Bone 1999;24:73S

Osteoclasts

Uptake by Osteoclasts

Loss of resorptivefunction and apoptosis of osteoclasts

The Bisphosphonates

OH

P

OH

R1

C

R2

OH

P

OH

O O

Licata AA. Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 2005;39:668-77.

PCP acts as a “bone hook”and is essential for binding

to hydroxyapatite

The R2 side chain determines potency (N>>Cl)

When R1 is an OH radical, group binding to

hydroxyapatite is enhanced

The PCP group is essential for biological activity



The Bisphosphonates

In the U.S.

alendronate (Fosamax) etidronate (Didronel) ibandronate (Boniva) pamidronate (Aredia) risedronate (Actonel) tiludronate (Skelid) zoledronic acid

(Zometa, Reclast)

In Canada

alendronate (Fosamax) clodronate (Bonefos,

Ostac) etidronate (Didronel) pamidronate (Aredia) risedronate (Actonel) zoledronic acid (Zometa)

In the U.S.

etidronate (IV)

pamidronate (IV)

zoledronic acid (IV)

In Canada

clodronate (IV) etidronate (IV) pamidronate (IV)

zoledronic acid (IV)

The Bisphosphonates

The action of bisphosphonates that should concern dentists is that they destroy osteoclasts, without which there cannot be bone healing. The rationale for their use is that osteoclasts produce an enzyme that stimulates the growth of a certain type of breast cancer cells. Without the growth stimulus, the cancer cells respond more amenably to other chemotherapy.

As stated in the "Dear Doctor" letter from Novartis, bisphosphonates are used to treat several other conditions related to bone metabolism and neoplasms. What is not known yet is whether the osteoclasts ever come back. Unlike osteoradionecrosis, this condition is not helped by hyperbaric O2 therapy. There are two forms of bisphosphonates, one with a chloride ion for oral use that is "relatively" benign. Oral surgery for patients taking these is risky, at least requiring extensive informed consent, not that there is good or sufficient information yet. The other form with a nitrogen ion is used IV and is probably an absolute contraindication to tooth extraction. The suggested alternative is to cut off the tooth crown, do endo and let the tooth extract itself over time.

In 2003 and 2004, there were several reports of osteonecrosis of the jaw (ONJ) in cancer patients receiving chronic intravenous bisphosphonates. The reports associated pamidronate (Aredia) and zoledronic acid (Zometa) with ONJ. Both products are produced by Novartis Pharmaceuticals Corporation. As a result, the products' labeling was updated in the U.S. in August 2004 and in Canada in December 2004 to include precautions about ONJ (see quote above from website).

Antiresorptive Potencies

Watts NB. Treatment of osteoporosis with bisphosphonates. EndocrinolMetab Clin North Am 1998;27:419-39.

OOIV

1,000-10,0001,000-10,000

> 10,000

Nitrogen-containing Side Chain

Risedronate (Actonel)Ibandronate (Boniva)Zoledronic Acid (Zometa, Reclast)

IVO

100100-1,000

Aminoterminal Chain

Pamidronate (Aredia)Alendronate (Fosamax)

O10Cyclic Chloro Side Chain

Tiludronate (Skelide

Oral (O) and Intravenous (IV)1

Short Alkyl or Halide Side Chain

Etidronate (Didronel)

Route of Administration

AntiresorptiveRelative Potency

Compound



Novartis is not the only company marketing these drugs, there are at least five of these drugs in use. With so many patients taking bisphosphonates for prevention and treatment of osteoporosis he thinks we will start to see this complication with increasing frequency.

Osteonecrosis of the Jaw Also known as avascular necrosis of the bone or osteochondritis dissecans (the death of bone resulting in the collapse of the bones' structural architecture). Leads to bone pain, loss of bone function, and bone destruction and is the result of a number of conditions leading to an impairment of the blood supply to the bone. Risk factors include systemic corticosteroid therapy and anti-cancer treatment (both radiation and chemotherapy). The jaw bone is particularly vulnerable to osteonecrosis because of tooth and gum susceptibility to infection. A special added risk factors for ONJ are trauma, as from dental procedures and local anesthetics.

In a 2004 report from the FDA Adverse Event Reports database a total of 139 cases of osteonecrosis were identified from the marketing approval date of Aredia, Zometa, Fosamax, and Actonel until May 24, 2004:

– 34% were associated with Aredia

– 24% per associated with Zometa

– 42% per associated with patients who received both Aredia and Zometa

– 8.6% were associated with Fosamax

– one case was associated with Actonel. The majority of these patients were diagnosed with osteonecrosis of the jaw. Some had a diagnosis of mixed osteonecrosis and osteo-myelitis. Because of these findings, the report stated that osteonecrosis may be a class effect of the bisphosphonates (BONJ). BONJ has since been defined as, “an area of exposed bone in the maxillofacial region that does not heal within 8 weeks after its identification by a health care provider, in a patient who is receiving or has previously been receiving bisphosphonates and who has not had radiation therapy to the craniofacial region.” The oral bisphosphonates are not as potent as the intravenous agents but they all have the same mechanism of action. Labeling for both Fosamax and Actonel is in the process of being updated to include this class osteonecrosis risk. Boniva labeling already has been updated.

Primary Diagnosis of 368 ONJ Cases Subsequent to Bisphosphonate Use

Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: Bisphospho-nates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761.

Concomitant estrogen, corticosteroid or anti-cancer treatment (both radiation and chemotherapy).

Comorbid conditions (e.g., malignancy) Poorly fitting dental appliances Intraoral trauma (e.g., dentistry, LA injections) Presence of tori or other bony exostoses Pre-existing dental or periodontal disease Older age (> 65 years) Alcohol and/or tobacco use

ONJ Risk Factors



The Questions to Ask: The patients level of risk must first be determined (see Risk Factors Slide), recognizing that these risk factors are additive. If a patient has yet to begin bisphosphonate therapy, then preven-tative measures are the key, otherwise what is the recommended dental management if the patient is already receiving oral bisphosphonates? What if they are already receiving IV bisphos-phonates? Can you do restorative and prosthetic dentistry? How can you treat periodontal diseases? Is oral and maxillofacial surgery safe? Endodontics? What if my patient has BONJ? What is the recommended dental management for patients who are receiving oral bisphosphonate therapy? First and most importantly, patients should be informed that the health benefits of oral bisphosphonate therapy far outweigh the minimal risk BONJ. In addition, good oral hygiene, accompanied by regular dental care, is the best way to minimize this risk, if it exists. Patients receiving bisphosphonate therapy should be advised to contact their dentist if any problem develops in the oral cavity. In general, patients who are taking oral bisphosphonates without other risk factors can be treated according to normal protocols and procedures, including surgery. Restorative and Prosthetic Dentistry: All restorative procedures may be performed. At present, there is no evidence that malocclusion or occlusal forces increase the risk of BONJ. Prosthodontic appliances should be adjusted for fit to avoid mucosal irritation. Periodontal Diseases: Treatment protocols are similar to those for the general population (i.e., patients not taking the medication). Oral and Maxillofacial Surgery: Treatment protocols are similar to those for the general population (i.e., patients not taking the medication), unless other risk factors are present as outlined above. In such cases, conservative surgical technique, with primary tissue closure, should be considered when extractions or surgery are necessary (including elective dentoalveolar surgical procedures such as implant placement, reduction of tori or extraction of asymptomatic teeth). Patients may use a chlorhexidine-containing rinse immediately before and after surgical procedures. Systemic antibiotic therapy may be considered for perioperative prophylaxis or if there is evidence of infection. Endodontics: If the tooth is salvageable, endodontic treatment is preferred to extractions or surgical manipulation. If extractions or surgical manipulations are necessary, such procedures should follow the recommendations discussed in the section “Oral and Maxillofacial Surgery” above. What is the recommended dental management for patients who are receiving IV bisphosphonate therapy? The risk of BONJ appears to range between 1% and 10% in patients receiving IV bisphosphonate treatment. Any patient receiving such therapy should be informed of the signs and symptoms of BONJ. In addition, before the IV bisphosphonate therapy is started, the patient should undergo a dental evaluation by a qualified dental professional, and dental recall examinations should be performed throughout the course of bisphosphonate therapy. The frequency of such examinations will be dictated by the patient’s clinical and dental status. If the patient’s situation permits, invasive dental procedures should be performed before the IV bisphosphonate therapy is started, with follow up at 14–21 days to ensure complete healing at the surgical site. The following sections outline treatment recommendations for patients who are already receiving IV bisphosphonate therapy.



Restorative and Prosthetic Dentistry: All restorative procedures may be performed. At present, there is no evidence that malocclusion or occlusal forces increase the risk of BONJ. Prosthodontic appliances should be adjusted for fit to avoid mucosal irritation. Periodontal Diseases: Nonsurgical therapy is preferred (such as scaling and root planing). Periodontal surgery is not recommended. When necessary, surgical treatment should be aimed primarily at obtaining access to root surfaces. Oral and Maxillofacial Surgery: Whenever possible, nonsurgical endodontic or periodontal therapy is preferred to extraction, unless there is a risk of aspiration. Elective dentoalveolar surgical procedures, such as implant placement, reduction of tori and extraction of asymptomatic teeth, should be avoided. When an extraction or surgery is necessary, conservative surgical technique, with primary tissue closure, should be considered. The greater incidence of BONJ in the mandible than the maxilla, especially in the posterior region of the mouth, must be taken into account in the decision to perform surgery. Endodontics: For salvageable teeth, endodontic treatment is preferred to extractions or surgical manipulation. Manipulation beyond the apex should be avoided. Surgical procedures should be guided using the same recommendations mentioned in the Oral and Maxillofacial Surgery section above. Patients should use a chlorhexidine-containing rinse immediately before and after surgical procedures. Systemic antibiotic therapy may be considered for perioperative prophylaxis or if there is evidence of infection for 10-14 days as shown in the slide. What is the recommended dental management for patients who have BONJ? If BONJ is suspected but not yet confirmed (e.g., duration of unhealed exposed bone less than 8 weeks), the patient should be followed carefully. Additional common findings include pain, swelling, paresthesia, suppuration, soft-tissue ulceration, intraoral or extraoral sinus tracks, and loosening of teeth. Radiographic findings can vary from changes in bone density to no obvious alteration to the bone pattern. The differential diagnosis for BONJ includes gingivitis, periodontal diseases (e.g., necrotizing ulcerative periodontitis), osteomyelitis, sinusitis, temporomandibular disorder, trauma, periapical lesions, osteoradionecrosis, bone tumours and metastasic lesions. Standard radiography such as panoramic and periapical radiography may help in the detection of BONJ in the early stages. Computed tomography may also be considered. No imaging is required for patients with established clinical evidence of BONJ. The dental professional should alert the patient’s physician to the diagnosis and should report cases of BONJ to the appropriate agencies, such as the manufacturer of any agent implicated. There is no published evidence to suggest that discontinuation of bisphosphonates will promote resolution of BRONJ. If pain is present, it should be managed appropriately with nonsteroidal anti-inflammatory drugs or narcotic analgesics. The patient should be advised to use chlorhexidine (0.12%) or another similar oral antimicrobial rinse, and systemic antibiotic therapy may be prescribed if there is evidence of secondary infection. Establishing and maintaining good oral hygiene is essential. Any patient with established BRONJ needing surgical procedures should be referred to an oral and maxillofacial surgeon, who may consult other

American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006;137(8):1144–50.

Proposed Antibiotic Therapy for Perioperative Prophylaxis

250mg t.i.d. x10dAzithromycin

300mg t.i.d. x14dClindamycinAllergic to penicillin

250mg t.i.d. x14dMetronidazole

500mg t.i.d. x14dAmoxicillinNot allergic to penicillin

Oral RegimenSuggested Antibiotic

Patient’s Penicillin status



qualified specialists as appropriate. Any dentoalveolar surgical procedure (i.e., extractions, implants or apical surgery) should be avoided since the surgical sites will likely result in additional areas of exposed necrotic bone. However, loose teeth should be removed from the exposed bone if there is a danger of aspiration. Similarly, loose segments of bony sequestra should be removed, but without exposing uninvolved bone. Sharp bone edges should be removed, to prevent trauma to the adjacent soft tissues. Segmental jaw resection may be required for symptomatic patients with large segments of necrotic bone or pathologic fracture. Conclusions The majority of cases with osteonecrotic jaw lesions occurred after a dental extraction yet some occurred spontaneously. Because of this association with dental procedures, potential preventative measures are suggested prior to bisphosphonate initiation. Preventative measures include:

– Avoiding any elective jaw procedure

– Baseline and routine dental exams including panoramic jaw radiography

– Delaying bisphosphonate therapy, if risk factors allow, to complete dental procedures for teeth or dental structures with poor prognosis

– Educating patients about the importance of good oral hygiene, symptom reporting, and regularly scheduled dental assessments Patients already receiving bisphosphonates should:

– Maintain excellent oral hygiene and have routine dental examinations

– Obtain routine dental cleanings where careful attention is given to avoiding soft tissue injury

– Have aggressive nonsurgical management of any dental infection

– Have root canal treatment if needed rather than dental extraction when possible Remember, the majority of cases with osteonecrotic jaw lesions occurred after a dental extraction yet some occurred spontaneously. Patients with osteonecrosis or suspected osteonecrosis should receive immediate attention from an oral surgeon or dental oncologist. Suspected problems associated with bisphosphonates should be reported: In the US, call the FDA MEDWATCH program at 1-800-FDA-1088 or go on-line to www.fda.gov/medwatch. In Canada, call the Canadian Adverse Drug Reaction Monitoring Program at 1-866-234-2345 or go on-line to http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adverse_e.pdf. Devlin H, Allen PD, Graham J, Jacobs R, Karayianni K, Lindh C, van der Stelt PF, Harrison E, Adams JE, Pavitt S, Horner K. Automated osteoporosis risk assessment by dentists: a new pathway to diagnosis. Bone. 2007 Apr;40(4):835-42.

Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW. Identification of

microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonatetherapy. J Oral

Maxillofac Surg. 2008 Apr;66(4):767-75.



Article in press on the use of serum and urine bone markers (collagen break-down products):

“C-terminal telopeptides (CTx)” Only one lab in California currently

running these tests on patients taking ORAL therapy (US-Quest Diagnostics in San Juan Capistrano):

<100pg/mL = little or no risk100-150pg/mL = moderate risk

>151pg/mL = high risk

The VERY Latest

Treating ONJ with PRP (platelet rich plasma) – Buffy Coat technique

Courtesy of James Rutkowski, D.M.D, PhD: [email protected]

1. Reflect soft tissue. Remove obvious necrotic bone. 2. Irrigate site with a minimum of 50 mL of sterile normal saline. Irrigate with clindamycin

injectable (150 mg per mL) – use 2 to 4 mL. 3. Let clindamycin sit at site for 5 minutes – DO NOT suction away clindamycin from the site. 4. Apply PRP – (1 or 2 draws from 4.5 mL blood collection tubes). Apply PRP to a sheet of Collatape

or other collagen membrane. 5. Place Collatape over the site. Take Alloderm GBR and prepare it according to manufacturers

instructions. Apply PRP to Alloderm GBR let it soak in. Suture the Alloderm in place with Vicryl or similar suture material – sutures should remain in place for a minimum of 3 weeks.

6. Take an alginate impression and pour in snap stone. Take the PPP from the PRP collection, apply it to gauze and have the patient bite on that for 30 minutes.

7. Using the model made from step 12 make a suck-down type clear retainer with the surgery site blocked with wax (This will act as a spacer for the triple antibiotic ointment that will be used).

8. Apply triple-antibiotic ointment (Neosporin) to the retainer at the surgical site. Have the patient wear the retainer 24 hours a day for 3 weeks. They should take it out for cleaning 4 to 5 times a day. (If the patient is really good about keeping the tongue off of the surgical site they can go without the retainer for 1 hour at a time several times a day. I would not recommend doing this until you are at least 2 weeks post-op).

9. When the retainer is out of the mouth for cleaning, have the patient rinse with Biotene mouth rinse – holding it in the mouth and swishing gently for 2 minutes.

10. When the patient re-inserts the retainer they should re-apply the triple-antibiotic ointment.

11. After 3 weeks if the Alloderm is granulating over, then they only need to wear it when eating. They will wear it for eating for probably 4 to 8 weeks – or until the site is completely covered with soft tissue.

12. Patient should be given an Rx for Clindamycin 150 mg. #50 – Take two capsules every 6 hours for the first 2 days, then one capsule every 6 hours until gone. (Provided there is not an allergy).

Estilo CL, FornierM, Farooki A,

Carlson D, Bohle G 3rd, Huryn JM.

Osteonecrosis of the jaw related to

bevacizumab. J ClinOncol. 2008 Aug

20;26(24):4037-8.

ONJ Due to Other Drugs

Christodoulou C, Pervena A, Klouvas G, et al. Combination of Bisphosphonates and Antiangiogenic Factors Induces Osteonecrosis of the Jaw More Frequently than Bisphosphonates Alone. Oncology. 2009 Feb 12;76(3):209-211.

The VERY, VERY Latest:

MRONJ-expert recommendations trend toward proceeding with dental treatment

with little to no modification in osteoporotic patients on bisphosphonates.

Napeñas JJ, Kujan O, Arduino PG, Sukumar S, Galvin S, BaricevicM, Costella J, Czerninski R, Peterson DE, Lockhart PB. World

Workshop on Oral Medicine VI: Controversies regarding dental management of medically complex patients: assessment of current

recommendations. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Aug;120(2):207-26.


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