Bupivacaine

By: Martinez

EXECUTIVE SUMMARY Brand name - Marcaine

Molecule - Bupivacaine

Inj – 5 mg/mL in 10 mL ampule

Target Doctors – Dentists, Surgeons, Anaesthetists, General Physicians and other doctors.

Total market for Bupivacaine is Php 1802.25 cr

Market growth – 18%

DRUG USE AND MARKET DEFINITIONLocal Infiltration

Pain Relief during and after relatively minor procedures like:

Filling or wisdom tooth removalMinor skin operation, such as removal of

moles and wartsEye surgery (cataract removal)Biopsy

DRUG USE AND MARKET DEFINITIONEpidural anaesthetic Injected

through a tube into the epidural space

E.g. prostate surgery

DRUG USE AND MARKET DEFINITIONEpidural Test Dose

Determine accidental intravenous or intrathecal catheter placement

Peripheral nerve block Injection administered to nerves at

an appropriate area of one’s body extremity requiring surgeryE.g. arm, leg

DRUG USE AND MARKET DEFINITIONCaudal anaesthesia

Analgesia for urgent procedures involving the lower body below umbilicus

Superficial operations like Skin graftingPerineal proceduresLower limb surgery

DRUG USE AND MARKET DEFINITION Sympathetic nerve

block Diagnostic to

determine presence of damage at sympathetic nerve chain found on spine

Sympathetic nerve - control involuntary functions of the body E.g. opening and

narrowing blood vessels

PAIN - INTRODUCTION Provides the body with a warning of

potential or actual injury

Triggered by activation of nociceptors Distributed throughout the body like skin,

viscera, muscles

Stimuli that activate nociceptors Mechanical Thermal Chemical

PAIN –ACCORDING TO DURATION Acute pain

sudden and limited duration caused by damage to tissue such as bone,

muscle, or organs, Initially accompanied by anxiety or emotional

distress

Chronic pain Longer than acute pain Associated with a long-term illness like

osteoarthritis

PAIN –ACCORDING TO TYPE OF DAMAGE Nociceptive pain

Damage or injury to the body's tissues E.g. bone, soft tissue, or organs Caused by

Disease like cancer or inflammationPhysical injury such as a cut or a broken

bone.

PAIN –ACCORDING TO TYPE OF DAMAGE

E.g. burning sensation present although no heat is applied to the area that burns

Nerves damaged

Transmission of pain signals

affected/hindered

Abnormal pain signals are

transmitted to the brain

Neuropathic pain

MECHANISM OF NEUROTRANSMISSION Action potentials

Produced to transmit information from neurons to other body tissues such as muscles

Voltage or difference in electrostatic potential, always exists between the inside and outside of a cell Ion distribution Permeability of the membrane to these ions

MECHANISM OF NEUROTRANSMISSION

1. Resting Potential2. Depolarization3. Repolarization4. Return to Resting Potential

MECHANISM OF NEUROTRANSMISSION 1. Resting potential of inactive cell

Negative value (inside relative to outside the cell)

Maintained by the active transport of potassium and sodium ions into and out of the cell, respectively Via sodium-potassium pumps scattered

across cell membrane More sodium outside the cell than inside More potassium inside the cell than outside

MECHANISM OF NEUROTRANSMISSION 2. Depolarizationa) Stimulus causes voltage-gated Na+

channels in the neuron cell membrane to open

b) Sodium ions diffuse into the cell through channels along electrochemical gradient

c) As sodium ions enter, the membrane potential becomes less negative

MECHANISM OF NEUROTRANSMISSION 2. Depolarization – Peak As cell reaches membrane potential

of +30 mVa) Voltage-gated Na+ channels closes

preventing further influx of sodium.

b) Simultaneously, voltage-gated K+ channels begin to open – triggering exit of potassium ions from the cell

MECHANISM OF NEUROTRANSMISSION 3. Repolarizationa) As voltage-gated potassium channels

open, there is a large outward movement of potassium ions

b) While potassium ions diffuse out – causes reversal of the membrane potential from positive to negative

MECHANISM OF NEUROTRANSMISSION 4. Return to Resting Potentiala) As potassium exits the cell, cell membrane

potential continues to be negative

b) K+ channels do not close immediately – potassium continues to flow out of the cell even after the membrane has fully repolarized exceeding -70 mV

c) Na+/K+ pumps opens and transport K+ into cell to reach resting potential

MECHANISM OF DRUGDrug administered at site of administration

Non-ionized drug enters nerve cell

Drug inside cell becomes ionized

Ionized drug binds at Calcium-binding sites at the inside of Na+ channel

MECHANISM OF DRUGNa+ channels become closed preventing entry of

Na+ ions

No Na+ influx leads to decreased depolarization

Action Potential Generation and Propagation stopped

Transmission of sensory signal (e.g. pain) does not reach the spinal cord and brain temporarily

MECHANISM OF ACTION

Mechanism of Action

DOSAGE AND ADMINISTRATION Dose administered for desired result–

small

Factors influencing dosage of local anaesthetics Anaesthetic procedure Area to be anesthetized Vascularity of tissues

DOSAGE AND ADMINISTRATION Factors influencing dosage of local

anaesthetics Degree of muscle relaxation required Duration Individual tolerance Physical condition of the patient (weight and state)

Dosages for the following types of patients - reduced: Elderly and/or debilitated patients Patients with cardiac and/or liver disease

DOSAGE AND ADMINISTRATION Marcaine

complete sensory block at recommended doses effect on motor function differs among three

concentrations 0.75% of Marcaine - abdominal operations to

induce complete muscle relaxationCONCENTRATION SENSORY

FUNCTIONMOTOR

FUNCTION0.25% COMPLETE INCOMPLETE0.50% COMPLETE MODERATE0.75% COMPLETE COMPLETE

DOSAGE AND ADMINISTRATIONTYPE OF BLOCK CONC.

EACH DOSE MOTOR BLOCK(ML) (MG)

Local infiltration 0.25% Up to max. Up to max. -

Epidural

0.75% 10-20 75-150 complete

0.5% 10-20 50-100 Moderate to complete

0.25% 10-20 25-50 Partial to moderate

Caudal 0.5% 15-30 75-150 Moderate to complete

0.25% 15-30 37.5-75 complete

Peripheral nerves

0.5% 5 to max. 25 to max. Moderate to complete

0.25% 5 to max. 12.5 to max. Moderate to complete

DOSAGE AND ADMINISTRATION

Duration of anaesthesia for most indications Single dose is sufficient

TYPE OF BLOCK CONC.

EACH DOSE MOTOR BLOCK(ML) (MG)

Sympathetic 0.25% 20-50 50-125 -

Dental 0.5% with Epi

1.8-3.6 per site

9-18 per site -

Epidural Test Dose

0.5% with Epi 2-3

10-15 (10-15 mcg

epinephrine)

-

DOSAGE AND ADMINISTRATION Maximum dosage limit -

individualized Size Physical status Rate of systemic absorption from

particular injection site

Maximum dosage limit for most patients: Single doses of Marcaine up to 225 mg

with epinephrine 1:200,000 175 mg without epinephrine

DOSAGE AND ADMINISTRATIONFrequency and Daily Limit of Dosing of Marcaine

Repeated as needed - once every 3 hours

In clinical studies to date, total daily doses have been up to 400 mg

Maximum SQ dose 2 mg/kg

INDICATION Local or regional anaesthesia or

analgesia to relieve or prevent pain during: Surgery Dental Oral surgery procedures Diagnostic procedures Therapeutic procedures Obstetrical procedures

Does not lead to loss of consciousness

KEY ISSUES – SIDE EFFECTS Hypotension Bradycardia Ventricular arrhythmia Cardiac arrest excitation CNS depression Convulsion Allergic reaction

KEY ISSUES - CONTRAINDICATIONS Hypersensitivity to bupivacaine or

other amide-type anaesthetics or any component of drug

Obstetrical paracervical block anaesthetic

KEY ISSUES - WARNINGS DENTAL

Inform patient receiving dental injection Avoid chewing solid foodAvoid biting or probing area injected

CAUDAL OR EPIDURAL ANAESTHESIA Warn patient of temporary loss of

sensation and motor activity at lower body

KEY ISSUES – ADVERSE DRUG REACTIONS [SERIOUS] Cardiovascular

Cardiac arrest Hypotension Negative inotropic effect on heart Ventricular Arrhythmia

Immunologic Allergic reaction - Rare

Musculoskeletal Chondrolysis of articular cartilage

KEY ISSUES – ADVERSE DRUG REACTIONS [SERIOUS] Neurologic

Bacterial meningitis Central Nervous System Depression Central Nervous System Stimulation Paraplegia (paralysis of lower body) Seizure (0.1%, rare) Total spinal nerve blockade following local

anaesthetic injection Respiratory

Respiratory arrest

KEY ISSUES – ADVERSE DRUG REACTIONS (TREATMENT) CENTRAL NERVOUS SYSTEM TOXICITY First-line treatment of local

anesthetic-induced seizure Benzodiazepines – less potential to cause

cardiac depression

If benzodiazepines not available, other alternatives at lowest effective dose include Propofol Thiopental

KEY ISSUES – ADVERSE DRUG REACTIONS (TREATMENT) ALLERGIC REACTIONS - rare Mild cutaneous reactions

Oral or IV dipenhydramine – 25-50 mg Serious allergic reactions – respiratory

distress & hypotension SubQ Epinephrine – 0.3mL of 1:1000 dilution Corticosteroids

125 mg methylprednisolone IV push60 mg prednisone oral

KEY ISSUES – ADVERSE DRUG REACTIONS (TREATMENT)

CARDIOVASCULAR TOXICITY – Cardiac Arrest

Use standard Advanced Cardiac Life Support (ACLS) with the following modifications:

Epinephrine Small initial doses (10-100 μg boluses in adults)

Vasopressin - not recommended Avoid calcium channel blockers and beta-

blockers Ventricular arrhythmias develop

Amiodarone

KEY ISSUES – ADVERSE DRUG REACTIONS (TREATMENT)

CARDIAC TOXICITY Avoid lidocaine and 1B antiarrhythmic

agents (mexiletine, tocainide)

KEY ISSUES – DRUG INTERACTIONSDRUGS SEVERITY SUMMARY

Bupivacaine – Propanolol Major

Concurrent use of these may result in

increased bupivacaine toxicity

Bupivacaine – Verapamil Major

Concurrent use may result in increased risk of heart block

Bupivacaine – Propofol Major

Concurrent use may result in hypnotic effect of propofol

KEY ISSUES – DRUG INTERACTIONSDRUGS SEVERITY SUMMARY

Bupivacaine – Hyaluronidase Major

Result in increased incidence of

systemic reaction to anaesthetic

St. John’s Wort – Anaesthetic Major

Increased risk of cardiovascular collapse and or

delayed emergence from anaesthesia

Bupivacaine – ACE Inhibitors Moderate

Concurrent use may result in bradycardia

and hypotension with loss of

consciousness

KEY ISSUES – DRUG INTERACTIONSSOLUTION: PREVENTION

Advise patients to make list of all medicines being taken Share this with pharmacist and doctors

Update taking new medicine

Pharmacist or doctors inform patient about benefits and potential risks of medications being taken

KEY ISSUES – DRUG INTERACTIONSSOLUTION: PREVENTION

Patient educationExpected side effects and adverse reactions during medication use

Encourage patient to inform pharmacist or doctors if side effects or adverse reactions are experienced

PRECAUTIONS Obstetrical epidural anaesthesia

Never use 0.75% bupivacaine solution. Use causesCardiac arrest with difficult resuscitationDeath

Epidural or Caudal Anaesthesia Do not use solutions containing

antimicrobial preservatives Repeated Local Administration

Risk of significant increase in plasma concentration

PRECAUTIONS Head and neck administration

Related to events occurring with systemic toxicityConvulsion, confusion, Respiratory depression and or

respiratory arrestCardiovascular stimulation or

depression Recommended monitoring

Intravenous Regional Anaesthesia Cardiac arrest and death reported

PRECAUTIONS Cardiovascular

Serious dose-related arrhythmia – using bupivacaine with vasoconstrictors like epinephrine

Use cautiously in patients with history of cardiac rhythm disturbances, shock, hypotension

Endocrine and Metabolic Familial malignant hyperthermia may

be triggered

PRECAUTIONSDebilitated, elderly and acutely ill patients Lower tolerance to elevated blood

levels Recommended: Dose adjustment

Hepatic Increased risk of developing toxic

plasma concentrations in patients with hepatic disease

SWOT Analysis

Strengths

Multiple indications (pain relief, diagnostic)

Long duration of action

Post-procedural pain management

SWOT Analysis

OpportunitiesAlternative to Narcotics for Pain

relief of knee replacement patient

New Combination with other drugs

COMPETITIVE ANALYSIS

Mepivacaine (1-4%)

Prilocaine (1-2%)

Lidocaine (1-2%)

Bupivacaine (0.25-0.75%)

3

3

4

5

5

4

6

11

ONSET OF ACTIONMaximum (min.) Minimum (min.)

COMPETITIVE ANALYSIS

Bupivacaine Lidocaine Prilocaine Mepivacaine

1.50.75 0.5 1

8

1.5 12

DURATION OF ACTIONMinimum (h) Maximum (h)

COMPETITIVE ANALYSIS

Bupivacaine Lidocaine Prilocaine Mepivacaine

3

4.5

8

4.5

Max Dose (mg/kg)

COMPETITIVE ANALYSIS

Bupivacaine

Lidocaine

Mepivacaine

2.7

1.5

1.9

2.7

2

3.2

Elimination Half-lifeMaximum (h) Minimum (h)

BUPIVACAINE’S 5 C’S INSIGHTSCustomer Consumer Competitio

nCompound Channel

• Doctors need to continuously monitor patient during drug use

• Doctors acknowledge importance of Local Anaesthetic

• Address specific cases because of drug characteristics

• Instruct patients to monitor and report side effects and adverse drug effects during drug use

• Sales measured quarterly, then semi-annually 2016

• Observe and analyze activity of competitor and market

• Safe

• Long-acting Local Anaesthetic

• Possible alternative to narcotics for pain relief of knee replacement patients

• Seminars provided to groups of hospitals to convey message to doctors

• Websites as online sources for physicians

REFERENCE – INFORMATION American Society of Regional Anaesthesia and Pain Medicine.

(2016). Regional anaesthesia for surgery. Retrieved from https://www.asra.com/page/41/regional-anesthesia-for-surgery.

American Pharmaceutical Association. (2013). Frequently Asked Questions About Drug-Drug Interactions Involving OTC Medications. Retrieved from: http://www.bemedwise.org/quiz_facts/facts.htm.

Bernardino, C. R. (15 July 2008). In-Office Surgery: Preventing and Treating Surgical Pain. Review of Ophthalmology. Retrieved from: https://www.reviewofophthalmology.com/article/in-office-surgery-preventing-and-treating-surgical-pain

Blahd, W. (14 August 2015). Pain Types and Classifications. WebMD Medical References. Retrieved from: http://www.webmd.com/pain-management/guide/pain-types-and-classifications.

REFERENCE – INFORMATION Bupivacaine. (2016). Truven Health Analytics-

Micromedex Solutions. Retrieved from: http://www.micromedexsolutions.com/micromedex2/librarian/CS/79FAB7/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/65B8CC/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearch?SearchTerm=bupivacaine&UserSearchTerm=bupivacaine&SearchFilter=filterNone&navitem=searchALL#

Bupivacaine Formula Cuts Narcotic Use. (2014). MedPageToday. Retrieved from http://www.medpagetoday.com/meetingcoverage/aaos/44735

REFERENCE - INFORMATION Dougherty, P., & Tsuchitani, C. (2016). Chapter 2: Somatosensory

Systems. University of Texas-Health. Retrieved from: http://neuroscience.uth.tmc.edu/s2/chapter02.html.

Kapitanyan, R., & Su, M. (2016). Local Anesthetic Toxicity Treatment and Management. Medscape. Retrieved from: http://emedicine.medscape.com/article/1844551-treatment#d10.

Local Anaesthesia. (2015). NHS. Retrieved from: http://www.nhs.uk/conditions/anaesthetic-local/Pages/Introduction.aspx.

Local anesthetics: systemic toxicity. (2016). Open Anesthesia-International Anesthesia Research Society. Retrieved from https://www.openanesthesia.org/local_anesthetics_systemic_toxicity/

Marcaine. (2012). RxList. Retrieved from: http://www.rxlist.com/marcaine-drug/indications-dosage.htm.

REFERENCE – INFORMATION Press, C. D. (18 November 2015). Infiltrative Administration

of Local Anaesthetic Agents. Medscape. Retrieved from http://emedicine.medscape.com/article/149178-overview.

Reddi, D. (2009). An introdution to pain pathways and mechanisms Feb12. [doc]. University College London. Retrieved from: https://www.ucl.ac.uk/anaesthesia/StudentsandTrainees/PainPathwaysIntroduction.

WebMD.(9 September 2014). Dealing with Medicine Side Effects and Interactions-Using Medicines Safely. Healthwise, Incorporated. Retrieved from http://www.webmd.com/a-to-z-guides/dealing-with-medicine-side-effects-and-interactions-using-medicines-safely.

REFERENCE - IMAGES https://psnet.ahrq.gov/media/cases/images/

case90_fig1.jpg http://newbridgespine.com/wp-content/

uploads/2013/07/nerve_block_procedure.jpg https://www.completenaturecure.com/wp-

content/uploads/2015/04/burning-sensation.jpg

http://www.vce.bioninja.com.au/_Media/action_potential_med.jpeg

http://pocketdentistry.com/wp-content/uploads/285/QE06_Meechan_fig002.jpg