Drug Used In Orthopedic

Conditions
Pn. Chew Lan Sim
Pegawai Farmasi U1-2
Hospital Raja Permaisuri Bainun
Outline
• Analgesics
• Antibiotics
• Anti-tuberculosis drugs
• Anti-cancer agents
• Anticoagulants
ANALGESICS
• Pain is the most common symptom of any
illness. The physician’s therapeutic task is two
fold:
▫ to discover and treat the cause of the pain
▫ to treat the pain itself, irrespective of whether the
underlying cause is treatable, in order to provide
relief from it and reduce the suffering caused by it.
WILDA ASSESSMENT
• Words to Describe Pain
Aching Nagging Stabbing
Burning Numb Tender
Dull Penetrating Tiring
Exhausting Radiating Throbbing
Gnawing Sharp Unbearable
Miserable Shooting
• LOCATIONS OF PAIN

• DURATION OF PAIN
▫ Does it hurt all the time
or does it come and go?

• Aggravating and/or
Alleviating factors
▫ What makes the pain
better?
▫ What makes the pain
worse?
Analgesics ladder
• WHO has produced an analgesic ladder
to be used as a guide for prescribing
analgesics.
• Analgesics are staggered according to
pain severity: mild, moderate and severe
pain.
• If a patient does not experience pain
relief on one step of the analgesic ladder,
they should progress to the next step.
WHO Analgesic Ladder
• Mild pain:
▫ Step 1: Simple analgesics (non-opioid)
 Initiate topical and/or simple oral non-opioid analgesics
(e.g. paracetamol, NSAIDs and COX-2 inhibitors )
 + adjuvant e.g. tricyclic antidepressants, anticonvulsants
(pregabalin or gabapentin) for neuropathic pain.

• Moderate pain:
▫ Step 2: Weak opioid
 Weak opioid (e.g. tramadol, dihydrocodeine or
dextropropoxyphene)
 + adjuvant e.g. tricyclic antidepressants, anticonvulsants

• Severe pain:
▫ Step 3: Strong opioid
 Opioids (e.g. morphine, oxycodone, fentanyl)
 + adjuvant e.g. tricyclics, anticonvulsants
(A) Non-opioid analgesics
• non-opioid analgesics = aspirin, paracetamol
and non-steroidal anti-inflammatory drugs
(NSAIDs)
• can be useful alone for mild to moderate pain
(step 1 of the analgesic ladder)
Acetaminophen
• Mechanism of actions (MOA):
Inhibits the synthesis of prostaglandins in the CNS
and peripherally blocks pain impulse; produces
antipyresis from inhibition of hypothalamic heat-
regulating centre
• Dosing
▫ Single agent or adjunct
▫ 500 – 1000mg PO 4 hourly as needed, max 4g/day
▫ (Extra Strenght Tylenol®)1000mg PO 6 hourly as
needed, max 3g/24hrs
▫ 650mg RECTALLY every 4-6 hour, max 6 supp/24hr
Acetaminophen
• Contraindications
▫ hepatic disease, active and severe
▫ hepatic impairment, severe
▫ hypersensitivity to acetaminophen or any other
components of the product
• Serious Adverse Effects
▫ liver failure
▫ Stevens-Johnson syndrome
▫ toxic epidermal necrolysis
Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• MOA
▫ 2 COX enzymes, COX-1 and COX-2.
▫ Both produce prostaglandins that promote
inflammation, pain, and fever.
▫ COX-1 produces prostaglandins that support
platelets and protect the stomach.
▫ NSAIDs block the COX enzymes and reduce
prostaglandins throughout the body - ongoing
inflammation, pain, and fever are reduced.
▫ Since the prostaglandins that protect the stomach
and support platelets and blood clotting also are
reduced, NSAIDs can cause ulcers in the stomach
and promote bleeding.
 NSAIDs
prostaglandin
platelets COX-1 COX-2
protect stomach

prostaglandin

Inflammation, pain, fever

Commonly used NSAIDs
• Aspirin
• Celecoxib (Celebrex) selective COX-2 inhibitor
• Etericoxib (Arcoxia)
• Diclofenac (Voltaren)
• Ibuprofen (Motrin)
• Indomethacin (Indocin)
• Ketoprofen (Orudis)
• Ketorolac (Toradol)
• Mefenemic acid (Ponstan)
• Meloxicam (Mobic)
• Naproxen (Aleve, Naprosyn)
• Piroxicam (Feldene)
NSAIDs
• Vary in their
▫ potency
▫ duration of action
▫ how they are eliminated from the body
▫ how strongly they inhibit COX-1 and their
tendency to cause ulcers and promote bleeding.
(↑blocks COX-1, ↑ulcers and promote bleeding)
▫ selective COX-2 inhibitors cause less bleeding
and fewer ulcers than other NSAIDs.
NSAIDs - Aspirin
• Unique NSAID
▫ the only NSAID that inhibits the clotting of blood for a
prolonged period (4 to 7 days) (others only few hours).
▫ an ideal drug for preventing blood clots that cause
heart attacks and strokes.

• Dosing:
▫ Pain: 325 to 650 mg ORALLY every 4 hours; MAX: 3.9
grams/24 hour
▫ Osteoarthritis & Rheumatoid Arthritis: up to 3g/day in
divided doses
NSAIDs -Aspirin
• Contraindications
▫ hypersensitivity to NSAIDs
▫ children and teenagers with chickenpox or flu
symptoms (risk of Reye's syndrome)
▫ syndrome of asthma, rhinitis, and nasal polyps
• Serious Adverse Effects
▫ Angioedema
▫ Bleeding
▫ Bronchospasm
▫ Gastrointestinal ulcer
▫ Reye's syndrome
▫ Tinnitus
NSAIDs
• Contraindications
▫ pregnancy
▫ treatment of peri-operative pain in setting of
coronary artery bypass graft (CABG) surgery
▫ hypersensitivity
▫ patients who have experienced asthma,
urticaria, or allergic-type reactions after taking
aspirin or other nonsteroidal anti-inflammatory
agents; severe, even fatal, anaphylactic-like
reactions have been reported
NSAIDs
• The frequency of adverse effects varies among NSAIDs.
• Common adverse effects :
▫ nausea & vomiting
▫ abdominal pain
▫ diarrhea
▫ decreased appetite
▫ rash
▫ edema
• Serious adverse effects
▫ kidney failure
▫ liver failure
▫ gastrointestinal ulcers & bleeding
▫ prolonged bleeding after an injury or surgery
▫ myocardial infarction
Question
• How many stages in WHO Analgesic Ladder?

• Please give 5 examples of NSAIDs

• Please give 3 adverse reactions of NSAIDs

• Why is COX- 2 favourable?

(B) Opioid analgesics
• Can be useful for moderate to severe pain (step
2 and 3 of the analgesic ladder)
• Classification is based on their interactions with
the various receptor subtypes:
▫ agonist: most commonly used in clinical pain
management, no ceiling effect
▫ agonist-antagonist (pentazocine, nalbuphine and
butorphanol): ceiling effect for analgesia.
Selecting patients for opioid therapy

• Severe pain - treated with a ‘strong’ opioid from

the start.
• Moderate pain - combination drug containing
paracetamol / aspirin plus codeine/ oxycodone /
propoxyphene.
• The dose of these combination products can be
increased until the max dose of the non-opioid
co-analgesic is attained (e.g. 4000 mg
paracetamol).
Opioid selection
• Factors to consider include the following:
▫ pain intensity
▫ patient age
▫ prior opioid therapy (response to previous trials of
opioid therapy)
▫ co-existing disease
▫ influence of underlying illness and characteristics
of the opioid and concurrent
Classification of Opiods
• Strong Agonist- Morphine, Methadone &
Fentanyl (good analgesics effect)
• Moderate Agonist- Codeine
• Mixed Agonist-Antagonist- Nalbuphine (Nubain),
Buprenorphine
• Antagonist – Naloxone (reverse respiratory
depression and coma due to morphine
overdose)
Tramadol (Weak Opioid)
• Dosing
▫ 50-100mg PO every 4hrs. Max 400mg/day
▫ 50-100mg IV/IM every 4-6hrs. Max 600mg/day
• Adverse Reactions
▫ dizziness, headache, somnolence, vertigo
▫ constipation, nausea, GIT disturbances
▫ pruritus, rash
▫ urinary retention
▫ visual disturbance
Question
• Please give 2 examples of strong opioids

• Please give 1 example of weak opiods

• Please give 3 side effects of opioid.

(C) Adjuvant analgesics
• a drug that has a primary indication other than pain
but is analgesic in some conditions.

• may be combined with primary analgesics in any of

the three steps of the ‘analgesic ladder’ to improve
the outcome for patients who cannot otherwise
attain an acceptable balance between relief and
side-effects.

• Can be divided into 4 groups:

1. Corticosteroids
2. Tricyclic Antidepressants
3. Anticonvulsants
4. Benzodiazepines
1) Corticosteroids
• analgesic effects
• improve quality of life significantly
• mechanism of analgesia produced by these drugs
may involve anti-oedemic effects, anti-inflammatory
effects, and a direct influence on the electrical
activity in damaged nerves.
• Examples:
▫ Prednisolone 5-60mg/day PO
▫ Dexamethesone
 ORAL; 0.75 - 9 mg/day
 IV or IM; 0.5 - 9 mg/day
 INTRA-ARTICULAR 0.2 - 6 mg;
 usual single doses are 2-4 mg in large joints, 0.8-1 mg in
small joints, 2-3 mg in bursae, 0.4-1 mg in tendon sheaths;
frequency ranges from once every 3-5 days to once every 2
to 3 weeks
1) Corticosteroids
• Adverse Effects
Common
▫ Cardiovascular: Hypertension
▫ Dermatologic: impair skin healing
▫ Endocrine metabolic: Cushing's syndrome, decreased
body growth
▫ Gastrointestinal: Disorder of gastrointestinal tract
▫ Immunologic: At risk for infection
▫ Musculoskeletal: Osteoporosis
▫ Ophthalmic: Cataract (5% ), Raised intraocular
pressure (25% )
▫ Psychiatric: Depression, Euphoria
SERIOUS
▫ Endocrine metabolic: Hyperglycemia, primary
adrenocortical insufficiency
▫ Ophthalmic: Conjunctival hemorrhage (22% ),
glaucoma, vitreous detachment
2) Tricyclic Antidepressants

• Neuropathic pain or post-herpetic neuralgia

• Amitriptyline
▫ 10 to 25 mg PO at bedtime; may increase at
weekly intervals to a max dose of 150 to 200
mg/day
▫ Adverse Effects
 Weight gain , constipation, dizziness, headache
3) Anticonvulsants

• Neuropathic pain or post-herpetic neuralgia

• Example:
▫ Gabapentin (Neurontin)
 300 mg PO on D1, 300 mg bd D2, and 300 mg tds
on D3; may increase dosage up to 1800 mg/day
(divided into 3 doses)
▫ Pregabalin (Lyrica)
 75 to 150 mg ORALLY two times a day OR 50 to
100 mg ORALLY three times a day (max:
600mg/day)
4) Benzodiazepines
• Benzodiazepines have an analgesic effect but
this must be balanced by the potential for side-
effects, including sedation and confusion.
• These drugs are generally used only if another
indication exists, such as anxiety or insomnia.
• Examples:
▫ Clonazepam
▫ Diazepam
▫ Lorazepam
What is Neuropathic Pain?
• a complex, chronic pain state that usually is
accompanied by tissue injury.
• the nerve fibers themselves may be damaged,
dysfunctional or injured.
• damaged nerve fibers send incorrect signals to
other pain centers.
• causes: alcoholism, diabetes, amputation,
multiple sclerosis
Treatment of Neuropathic Pain
Principles of Pain Management
1.Use a multi-drug approach by combining opioids with non-
opioid adjuvants.
2.Chronic pain almost always requires scheduled and rescue
dosing. Scheduled dosing maintains serum levels of
medication and provides constant relief. Rescue dosing
should be available as needed for breakthrough pain.
Frequent rescue dosing indicates a need for increased
scheduled medication.
3.Use long-acting agents for scheduled dosing and short-
acting agents for rescue dosing.
4.Use a non-invasive route whenever possible. Acute,
severe, or escalating pain may require IV analgesics every
5-15 minutes. If IV dosing must be used for chronic pain, a
continuous infusion is indicated.
5.Aggressively manage the side effects of opioids. There is
no tolerance to the constipating effects of opioids.
Question
• Please give 3 examples of adjuvant analgesics
ANTIBIOTICS
(National Antibiotic Guideline 2008)
Bone & Joint Infections

Osteomyelitis

Soft Tissue Infection

Bone & Joint Infections

Diabetic Foot Infection

 Infection/ Likely Suggested Treatment Comments
organism Preferred Alternative
BONE AND JOINT INFECTIONS
Septic Arthritis Cloxacillin 1-2 g If Penicillin allergy Drainage, debridement and
Staph. Aureus IV q6h (immediate washout of infected joint is
hypersensitive type) important to limit further
damage
Clindamycin 300-
600mg IV q8h Empirical therapy wherever
followed by oral possible should be directed
therapy (same by the result of the Gram
dose) stain of the joint aspirate

If initial gram stain is gram

positive cocci use:
-Cloxacillin

If initial gram stain is gram

negative bacilli use:
-3rd gen. Cephalosporins,
e.g. Ceftriaxone 2g IV
daily
 Infection/ Likely Suggested Treatment Comments
organism Preferred Alternative
OSTEOMYELITIS
Acute Cloxacillin 1-2 g If Penicillin allergy Duration:
Osteomyelitis IV q6h (immediate Initial IV therapy for 2-4
•Staph. Aureus hypersensitive type) weeks followed by oral
(80%), PLUS Clindamycin 300- therapy.
•Group A Strep 3rd gen. 600mg IV q8h Minimum 6 weeks. Modify
Pyogenes, Cephalosporins, followed by oral according to clinical
•rarely gram –ve e.g. therapy (same response
Bacilli Ceftriaxone 1- dose)
2g IV q24h if
gram negative
bacilli on gram
stain
Chronic Empirical Surgical debridement if
Osteomyelitis treatment is not necessary
(after 3 mths of indicated
appropriate Ab
therapy or presence Choice of Ab
of dead bone on X-
depends on C&S
ray)
result from
Commonest S.
tissue/bone
Aureus
 Infection/ Likely Suggested Treatment Comments
organism Preferred Alternative
DIABETIC FOOT INFECTIONS
Antibiotics should not be used unless there are local or systemic symptoms of infection.
Local treatment including surgical debridement is important.
Antibiotic selection should be based on the most recent C&S report.
Mild Infections: Cloxacillin 500mg Cephalexin Duration of
PO q6h 500mg PO q6h treatment: 1-2 weeks
Presence of > 2
markers of OR OR
inflammation β-lactamase Clindamycin 300-
(purulence or inhibitors, e.g. 450mg PO q6
erythema, pain, Amoxycillin/
tenderness, warmth, Clavulanate
or induration) with 625mg PO
any cellulitis / q12h
erythema extending
less than 2 cm
around the ulcer;
infection is limited to
the skin or superficial
subcutaneous
tissues; no systemic
toxicity
 Infection/ Likely Suggested Treatment Comments
organism Preferred Alternative
Moderate β-lactamase Ciprofloxacin Duration of
Infections: inhibitors, e.g. 500-750mg PO treatment: usually
Ampicillin/Sulbact q12h 2-4 weeks. Modify
Features of mild am 1.5-3g IV q8h OR according to
infection, no systemic Clindamycin 300- clinical response
toxicity or metabolic OR 450mg PO q6h If proven
instability and > 1 of 2nd or 3rd gen. osteomyelitis: at
the following: Cephalosporins, If antibiotic- least 4-6 weeks.
cellulitis extending e.g. resistant
more than 2 cm Cefuroxime organisms are However, a shorter
around an ulcer, 750mg-1.5g IV q8h likely, treat as duration (3 weeks) is
lymphangiti severe infection sufficient if the
streaking, spread OR entire infected bone
beneath the Ceftriaxone 1-2g is removed
superficial fascia, q24h
deep tissue PLUS/MINUS
abscess, gangrene, Metronidazole
or involvement 500mg IV q8h
of muscle, tendon,
joint, or bone
 Infection/ Likely Suggested Treatment Comments
organism
Preferred Alternative
Severe Infections: Piperacillin/ Imipenem/ Add Vancomycin 1g
Tazobactam 4.5g Cilastatin 500mg IV q12h, if high
Infection plus IV q6-8h IV q6h risk for MRSA
systemic toxicity or
metabolic instability OR Duration of
(e.g. fever, chills, 3rd gen. treatment: as in
tachycardia, Cephalosporins, moderate
hypotension, e.g. infection
confusion, vomiting, Ceftazidime 2g IV
leukocytosis, q8h
metabolic acidosis,
severe PLUS
hyperglycemia, or Metronidazole
azotemia above 500mg IV q6h
baseline)
 Infection/ Likely Suggested Treatment Comments
organism Preferred Alternative
NECROTIZING FASCITIS
Type 1 Cloxacillin 2g IV 3rd gen. Cephalosporins Early aggressive
Polymicrobial q4-6h PLUS surgical
infection. Primarily PLUS Metronidazole 500mg IV debridement essential
occurs in patients who Metronidazole q8h
are 500mg IV q8h OR
immunocompromised PLUS β-lactamase inhibitors,
or have certain Gentamicin e.g.
chronic diseases such 5mg/kg IV q24h Ampicillin/Sulbactam 1.5g
as diabetes IV q8h
OR
Amoxycillin/Clavulanate
1.2g IV q8h
PLUS/MINUS
Gentamicin 5mg/kg IV
q24h

Type 2 Benzylpenicillin Suspect Group A Strep

Group A strep 2-4 mega units IV if Gram stain shows
q4h Gram positive cocci in
PLUS chains.
Clindamycin Early aggressive
600mg IV q8h surgical debridement
essential.
 Infection/ Likely Suggested Treatment Comments
organism Preferred Alternative
SOFT TISSUE INFECTION SECONDARY TO GAS PRODUCING ORGANISM
e.g. Clostridium *Benzylpenicillin 2-4 3rd gen. *For Clostridium sp.:
spp, Gram -ve org mega units IV q4h Cephalosporins Benzylpenicillin
PLUS PLUS 4 mega units q6h is
Metronidazole Gentamicin preferred
500mg IV q8h 5mg/kg IV q24h
PLUS/MINUS Early aggressive
Gentamicin 5mg/kg Depends on culture surgical debridement
IV q24h & sensitivity essential

SUPPURATIVE WOUND INFECTIONS, SURGICAL OR TRAUMATIC

Surrounding cellulitis Cloxacillin 500mg Change Ab Topical antibiotics are
and/or PO/IV q6h accordingly after C not recommended for
systemic symptoms & S result treatment of wound
are present: infections as it may
result in the emergence
Gram negative Gentamicin 5mg/kg of resistant organisms
organisms IV q24h
Patient tetanus
OR immunisation status
As a monotherapy: should be assessed in
Cefuroxime 1.5g IV all cases
q8h
 Infection/ Suggested Treatment Comments
Likely Preferred Alternative
organism
Muscular, Skeletal and Soft Tissue Trauma, Crush Injuries and Stab Wounds
Cloxacillin 2g IV q6h Cefuroxime 1.5g as a For severe penetrating
PLUS loading dose, injuries,
Gentamicin1 5mg/kg IV followed by 750mg especially those
q24h IV q8h involving joints
PLUS PLUS and/or tendons,
Metronidazole 500mg IV Metronidazole antibiotics must be
q8h 500mg IV q8h given for at least 5 days
Duration: Not less than 5 Duration: Not less
days than 5 days

Compound Fractures
Cloxacillin 1g IV q6h
OR
Cefuroxime 1.5g IV q8h

If wound soiling or PLUS

tissue damage is Gentamicin1 5mg/kg IV
severe and/or q24h
devitalized tissue PLUS
is present: Metronidazole 500mg IV
q8h
Duration: 5-10 days
Benzylpenicillin
• Group:
▫ Penicillin, Natural
• Adverse Reactions
▫ Hypersensitivity
▫ GI disturbances
▫ Eosinophilia, Haemolytic anaemia,
▫ Convulsion, Epilepsy
▫ Interstitial nephritis
Cloxacillin
• Group:
▫ Penicillin, Penicillinase-Resistant
• Adverse Reactions
▫ Agranulocytosis
▫ Hepatotoxicity
▫ Immune hypersensitivity reaction
▫ Myelosuppression
▫ Neutropenia
▫ Pseudomembranous enterocolitis
Ampicillin/Sulbactam (Unasyn®)
Amoxycillin/Clavulanate (Augmentin®)
• Class
▫ Aminopenicillin/ β-lactamase inhibitors
• Adverse Reactions
▫ GI disturbances
▫ Skin rashes, itching
▫ Blood disorder
▫ Anaphylaxis
Piperacillin/ Tazobactam (Tazocin®)
• Class
▫ Penicillin, Extended Spectrum
• Spectrum
• Adverse Reactions
▫ Allergic reaction
▫ Diarrhoea
▫ Nausea & vomiting
▫ Headache
▫ Injection site reactions
▫ Rash, pruritus
▫ Anaphylaxis
Cephalexin
• Class
▫ 1st Generation Cephalosporin
• Adverse Reactions
▫ COMMON
▫ Diarrhea
▫ SERIOUS
▫ Stevens-Johnson syndrome, toxic epidermal necrolysis
▫ Pseudomembranous enterocolitis
▫ Anaphylaxis
▫ Interstitial nephritis, renal failure
▫ Angioedema
Cefuroxime (Zinacef)
• Class
▫ 2nd Generation Cephalosporin
• Adverse Reactions
▫ COMMON
▫ Eosinophilia
▫ SERIOUS
▫ Erythema multiforme, Stevens-Johnson syndrome
▫ Thrombocytopenia
▫ Anaphylaxis , Hypersensitivity reaction
▫ Interstitial nephritis
Ceftriaxone (Rocephin®)
• Class
▫ 3rd Generation Cephalosporin
• Adverse Reactions
▫ COMMON
▫ Induration at injection site
▫ Diarrhea
▫ Eosinophilia , Thrombocytosis
▫ SERIOUS
▫ Erythema multiforme, Stevens-Johnson syndrome
▫ Pseudomembranous enterocolitis
▫ Renal failure
Clindamycin
• Group
▫ Lincosamide
• Adverse Reactions
▫ Morbilliform eruption, rash
▫ Abdominal pain, diarrhea, nausea
▫ Pseudomembranous enterocolitis
▫ Agranulocytosis
▫ Jaundice
Gentamicin
• Class
▫ Aminoglycoside
• Adverse Reactions
▫ Vestibular & auditory toxicity
▫ Renal toxicity
▫ Neuromuscular blockade
▫ Nausea, vomitting
▫ Rash
▫ Blood disorder
Vancomycin
• Reserve for methicillin-resistant Staph. aureus
• Class
▫ Glycopeptide
• Adverse Reactions
▫ COMMON
▫ Nausea and vomiting
▫ SERIOUS
▫ Drug-induced erythroderma
▫ Thrombocytopenia
▫ Drug hypersensitivity syndrome
▫ Ototoxicity
▫ Nephrotoxicity
Ciprofloxacin
• Class
▫ Fluoroquinolone
• Adverse Reactions
▫ Nausea, diarrhoea, vomiting
▫ Abdominal pain, flatulence
▫ Anorexia
▫ Dizziness, headache
▫ Agitation, sweating
▫ Anxiety, insomnia, confusion, depression
▫ Tinnitus, visual disturbances
Metronidazole
• Class
▫ Nitroimidazole (Anaerobic infections)
• Adverse Reactions
▫ GI disturbances
▫ Urticaria
▫ Angiodema
▫ Drowsiness, dizziness, headache
▫ Skin rash, pruritus
▫ Peripheral neuropathy
▫ Anaphylaxis
Question
• What is the first-line treatment of acute
osteomyelitis?

• Please give 2 example of antibiotic which

contain β-lactamase inhibitors

• What is the antibiotic for MRSA in diabetic foot

infection?
ANTI-TUBERCULOSIS AGENTS
(WHO Treatment of Tuberculosis Guidelines
4th Edition)
Tuberculosis of Spine & Joint
Extrapulmonary TB
•NON INFECTIOUS
•No need isolation
Anti tuberculosis drugs
First line drugs (Essential Drugs)
• Isoniazid (H)
• Rifampicin ( R )
• Pyrazinamide (Z) Oral
• Ethambutol (E)
• Streptomycin (S) Injectable

Second line drugs (Reserved Drugs)

• Amikacin / Kanamycin
• Ofloxacin / Ciprofloxacin
• Cycloserine
• Clarithromycin/ Azithromycin
• Ethionamide
• Para amino salicylic acid
Recommended doses of first-line anti-
tuberculosis drugs for adults
Isoniazid
• Class: Isonicotinic acid

• Adverse Reactions
▫ COMMON
▫ Neuropathy
▫ Psychiatric sign or symptom
▫ SERIOUS
▫ Agranulocytosis, Anemia, Thrombocytopenia
▫ Hepatitis, Hepatotoxicity, Injury of liver
▫ Rhabdomyolysis
▫ Seizure
Rifampicin
• Class: Rifamycin

• Adverse Reactions
▫ COMMON
▫ Dermatologic: Abnormal color, Sweat
▫ Heartburn, Loss of appetite, Nausea, Saliva discoloration
▫ Increased liver function test
▫ Tear discoloration
▫ Discolored urine
▫ Influenza-like illness
▫ SERIOUS
▫ Thrombocytopenia, High-dose therapy
▫ Hepatotoxicity
▫ Nephrotoxicity
Pyrazinamide
• Adverse Reactions
▫ COMMON
▫ Hyperuricemia
▫ Nausea, Vomiting
▫ Arthralgia (40%)
▫ SERIOUS
▫ Hepatotoxicity
▫ Anemia
Ethambutol
• Adverse Reactions
▫ COMMON
▫ Hyperuricemia
▫ Nausea and vomiting
▫ Mania
▫ SERIOUS
▫ Neutropenia, Thrombocytopenia
▫ Anaphylactoid reaction
▫ Peripheral neuropathy
▫ Opthalmic: Blindness AND/OR vision impairment
level, Optic neuritis (1-6%)
Streptomycin
• Class: Aminoglycoside

• Adverse Reactions
▫ COMMON
▫ Rash, Urticaria
▫ Eosinophilia
▫ Facial paresthesia
▫ Fever
▫ SERIOUS
▫ Erythroderma
▫ Anaphylaxis
▫ Nephrotoxicity
▫ Respiratory tract paralysis
Treatment regime not different
from treatment for other site of
TB infection except…….
Duration of treatment for
Joint or Spine TB
9-12 months
2-3 months of Intensive phase
(3-4 drugs daily)
+
7-10 months of continuation phase
(2-3 drugs daily or alternate day)
Example of treatment regime

2 months of Ethambutol+ Rifampicin

+ Isoniazid + Pyrazinamide
then
7 months of Isoniazid +Rifampicin
Beware of
• Side effects of the individual drugs
• Presence of coexisting diseases e.g
Hepatitis, HIV etc
• Drug-drug interactions
• The most important interactions with anti-
TB drugs are due to rifampicin.
• Rifampicin induces pathways that
metabolize other drugs, thereby reducing
the concentration and effect of those
drugs
• Rifampicin ↓ the concentration and effect of the
following drugs (dosing adjustment is needed)
— anti-infectives (including certain antiretroviral drugs, mefloquine,
azole antifungal agents, clarithromycin, erythromycin,
doxycycline)— hormone therapy, including ethinylestradiol,
norethindrone, tamoxifen, levothyroxine;
— methadone
— warfarin
— cyclosporin
— corticosteroids
— anticonvulsants (including phenytoin);
— cardiovascular agents including digoxin (among patients with
renal insufficiency), verapamil, nifedipine, diltiazem, propranolol,
metoprorol, enalapril, losartan
— theophylline
— sulfonylurea
Question
• Please give example of first-line and second-line
anti TB agents (each 2)

• What are the duration of treatment for joint &

spine TB?

• Rifampicin will increase the effect of warfarin,

True/ False?
ANTI-CANCER AGENTS
Orthopaedic Cancers
• Osteosarcoma
• Ewing’s Sarcoma
▫ a maglinant tumour of bone occuring in children &
young adults. Distinguished from osteosarcoma by
J.Ewing in 1921,it commonly arise in the femur but is
liable to spread to other bones and to the lung.
• Chondrosarcoma
▫ a malignant tumor composed of chondroblasts, cells
that produce cartilage
• Metastatic Bone Cancer
▫ Bone is the third most common site of metastatic
disease. Cancers most likely to metastasize to bone
include breast, lung, prostate, thyroid and kidney.
Osteosarcoma
• A cancerous (malignant) bone tumor that usually
develops during the period of rapid growth that
occurs in adolescence, as a teenager matures
into an adult.
• Usually in the metaphysis of the long bones of
the body and esp. around the knee and the
proximal end of the humerus
Common chemotherapy medicines in
orthopaedic cancers include:
• Cisplatin
• Carboplatin
• Cyclophosphamide
• Ifosfamide
• Doxorubicin (Adriamycin)
• Methotrexate

All are protocol base

Cisplatin
• Class: Platinum Coordination Complex
• Precaution: Do not use infusion sets or needles
containing aluminium
• Adverse Reactions
▫ COMMON
▫ Anemia (11% ), Leukopenia (27% ),
Thrombocytopenia (16% )
▫ SERIOUS
▫ Nausea, Vomiting (frequent)
▫ Myelosuppression (25% to 30% )
▫ Immune hypersensitivity reaction
▫ Encephalopathy, Seizure
▫ Ototoxicity
▫ Nephrotoxicity (28% to 36% )
Carboplatin
• Class :Platinum Coordination Complex
• Precaution: Do not use infusion sets or needles
containing aluminium
• Adverse Reactions
▫ COMMON
▫ Alopecia (2% to 50% )
▫ Hypocalcemia (29% to 31% ), Hypokalemia (20% to 28% ),
Hypomagnesemia (29% to 43% ), Hyponatremia (29% to 47% )
▫ Abdominal pain (17% ), Diarrhea (6% ), Nausea (75% to 80% ),
Vomiting (65% to 81% )
▫ Anemia (21% to 90% ), Leukopenia (26% to 71% ), Neutropenia
(16% to 67% ), Thrombocytopenia (35% to 62% )
▫ Raise of liver enzymes
▫ Blood urea abnormal (14% to 22% ), Serum creatinine raised (6%
to 10% )
▫ SERIOUS
▫ Myelosuppression
▫ Hypersensitivity (2% )
Cyclophosphamide
• Class: Alkylating Agent
• Adverse Reactions
▫ COMMON
▫ Anemia (11% ), Leukopenia (27% ),
Thrombocytopenia (16% )
▫ SERIOUS
▫ Nausea, Vomiting (frequent)
▫ Myelosuppression (25% to 30% )
▫ Immune hypersensitivity reaction
▫ Encephalopathy, Seizure
▫ Ototoxicity
▫ Nephrotoxicity (28% to 36% )
Ifosfamide
• Class: Alkylating Agent
• Rescue Agent: MESNA
• Adverse Reactions
▫ COMMON
▫ Alopecia
▫ Nausea and vomiting (58% )
▫ SERIOUS
▫ Metabolic acidosis (31%)
▫ Myelosuppression
▫ Neurotoxicity (12%)
▫ Nephrotoxicity (6%)
Doxorubicin (Adriamycin)
• Class: Anthracycline

• Adverse Reactions
▫ COMMON
▫ Alopecia (92.4% )
▫ Nausea (15.5% ), Vomiting (up to 36.8% )
▫ SERIOUS
▫ Cardiomyopathy, Acute, Congestive heart failure, Late
onset, Left ventricular failure, acute, Myocardial
infarction, Myocarditis, Pericarditis
▫ Pancreatitis, Ulceration of colon
▫ Leukopenia (3.7% ), Neutropenia, Thrombocytopenia
▫ Hepatitis
▫ Anaphylaxis
Methotrexate
• Class: Antimetabolite
• Adverse Reactions
▫ COMMON
▫ Alopecia (0.5% to 3% ), Photosensitivity, Rash
▫ Diarrhea (1% to 3% ), Nausea and vomiting (greater than
10% )
▫ Leukopenia (1% to 3% ), Thrombocytopenia (3% to 10% )
▫ Dizziness (1% to 3% )
▫ SERIOUS
▫ Pericardial effusion, Thromboembolic disorder
▫ Gastrointestinal hemorrhage, Stomatitis (2% to 10% )
▫ Cirrhosis of liver (0.1% ), Hepatic fibrosis (7% ), Hepatitis,
Hepatotoxicity, Liver failure
▫ Encephalopathy, Neurotoxicity, Seizure
▫ Nephrotoxicity
Question
• Please give one example of anti-cancer drug in
orthopedic cancer and its side effect (2).
ANTICOAGULANT
- AHA Management of Deep Vein Thrombosis & Pulmonary
Embolism 1996
- CPG Management of Venous Thromboembolism 2003
Venous Thromboembolism (VTE)
• Deep vein thrombosis (DVT), particularly of the
lower limbs, occurs either spontaneously or in
patients admitted to hospital either for a surgical
or medical problem.

• A study done in University Hospital Kuala

Lumpur reported an incidence of 76.5% in
orthopaedic patients undergoing surgery.

• Up to 50% of patients with asymptomatic DVT

may go on to have pulmonary embolism (PE).
Prevention Strategy in Surgical Patient
Risk Stratification Recommendation
Low risk Early ambulation

Moderate risk Low-dose heparin (5000 U bid) or

LMWH or
intermittent pneumatic compression

High risk LMWH or

moderate-dose warfarin or
adjusted-dose heparin
Unfractionated Heparin(UFH)
• Management of IV UFH

• Adverse Reactions
▫ Haemorrhage, cutaneous necrosis, thrombocytopenia,
anaphylaxis, hyperkalemia
Low Molecular Weight Heparin (LMWH)

• Dose for treatment of Acute VTE

Enoxaparine (Clexane)
▫ Prophylaxis of DVT (surgical patient)
 moderate risk, 20mg SC 2 hrs before surgery then
20mg every 24hrs for min 7-10 days
 high risk, 40mg every 24 hrs for at least 6 days until
patient ambulant, max 14 days
▫ Treatment of DVT
 1.5mg/kg every 24 hrs, usually for 5 days and until
adequate oral anticoagulation established.
▫ Adverse Reactions
 Haemorrhagic symptoms, haematomas & skin
necrosis at injection site, allergic reactions
Tinzaparine (Innohep)
▫ Prophylaxis of DVT (surgical patient)
 moderate risk, 3,500 anti-Factor Xa IU SC 2hrs
before surgery and postoperatively; then od for 7-10
days
 high risk (total hip replacement), 4,500 anti-Factor
Xa IU SC or 50 IU/kg 2hrs before surgery then od
until patient mobilized
▫ Treatment of DVT
 175 anti-Factor Xa IU/kg SC od for at least 6 days
▫ Adverse Reactions
 Skin necrosis, erythema, ↑liver function test, major
bleeding, hematoma, pancytopenia
Comparison of UFH & LMWH
UFH LMWH
Laboratory monitoring APTT (problematic) No need
Administration method IV or S/C S/C (prefilled syringe)
Bolus then continuous (can be treated at home)
infusion Once or twice daily
(inpatient)

Heparin induced High Low

thrombocytopenia
Osteoporosis High Low
Cost Low High
Fondaparinux (Arixtra)
• Dosing
▫ Prevention of VTE in orthopedic surgery
 2.5mg od SC, administered 6 hr following surgical
closure provided homeostasis has been established.
5-9 days (usual duration), extended course up to 24
days (hip fracture patients)
• Advantage –no animal source
• Adverse Reactions
▫ Pruritus, rash, injections site hemorrhage, fever,
bleeding, nausea, vomiting, thrombocytopenia
Warfarin
• Dosing (prophylaxis and treatment)
▫ 2 - 5 mg ORALLY/IV od; adjust dose based on the
results of INR; usual maintenance, 2 - 10 mg
ORALLY/IV od
• Monitor Parameter: International Normalised Ratio
(INR)
▫ Target 2-3
• Adverse reactions
▫ haemorrhage
▫ alopecia
▫ gastrointestinal disorders
▫ hypersensitivity reactions
▫ skin necrosis
▫ ‘purple toes’
 Caution!

Warfarin
Drug
Interactions
Dabigatran (Pradaxa®)
• New oral anticoagulant – no need INR monitoring
• Dosing (Prevention of VTE in patients undergone
TKR or THR surgery)
▫ TKR: Initially ADULT 110mg (ELDERLY, 75mg) within 1-
4 hrs after surgey, then 220mg (ELDERLY, 150mg) od
for 6-10 days
▫ THR: : Initially ADULT 110mg (ELDERLY, 75mg) within
1-4 hrs after surgey, then 220mg (ELDERLY, 150mg)
od for 28-35 days

• Adverse Reactions
▫ Bleeding, anaemia, haematoma, haemorrhage,
haematuria, wound secretion
Question
• Please state two differences between UFH &
LMWH?

• What is the route of administration for

Fondaparinux?

• How to monitor the efficacy and safety use of

Warfarin?

• Please give 3 adverse reactions of Warfarin

THANK YOU!