Non-Opioid Analgesics Celecoxib Acetaminophe n Aspirin •Mechanism not full determined •May inhibit prostaglandin synthase (possibly COX-2) •Metabolized in liver •Excreted in urine •HL: 1-4 hours •Does not affect inflammation or platelet function •Use with caution in patients with hepatic dysfunction Adverse Metabolites: •N-acetyl- benzoquinoneimine can bind to renal proteins, damaging to kidney medulla •N-acetyl- benzosemiquinoneimine can bind to hepatic proteins, leading to centrilobular necrosis ADVERSE EFFECTS: •rash •SJS/TEN •liver failure •pneumonitis •Salicylic acid derivative •Irreversibly inhibits COX-1 through acetylating the serine residue at position 530, and COX-2 at position 516 •Inhibits platelet aggregation by inhibiting TXA 2 •Often used in combo with opioid analgesics •Reduces platelet function •Oral •Rapid and wide distribution •Rapidly hydrolyzed to active metabolite (salicylic acid•Excreted in urine •HL: 15-20 min (aspirin); 6 hours (salicylic acid) ADVERSE EFFECTS: •GI ulcer •bleeding Pain Pharmacology Non-Steroidal Anti- Inflammatory Drugs •Selective COX-2 inhibitor •Oral •Metabolized in the liver by CYP2C9 •Predominately excreted in feces •HL: 11 hours •Contraindicated in “sulfa-allergic” patients •CYP2D6 inhibitor; CYP2D6 substrate ADVERSE EFFECTS: •myocardial infarction (MI) •SJS/TEN •thrombotic events •cerebrovascular accident Salicylate Poisoning •stimulates respiratory center in brainstem (hyperventilation and respiratory alkalosis) •replaces 2-3 mEq/L of plasma HCO 3 - (metabolic acidosis) •Increases fatty acid metabolism (ketone body generation) •Impairs renal function (accumulation of Inhibits α-ketoglutarate dehydrogenase Uncouples oxidative phosphorylation Mild Moderate Severe mg/kg 300-500 mg/kg children/ elderly nausea, vomiting, tinnitus, dizziness Adults lethargy Metabolic acidosis Tachypnea and hyperpnea Sweating Dehydration Ataxia Respiratory alkalosis Metabolic acidosis Hypotension Convulsions Renal failure Coma Fluids (oral or IV) Activated charcoal Fluids (IV) Urine Activated charcoal Fluids (IV) Dialysis Salicylate Poisoning Treatment •Medical Emergency •Children with viral infection (including flu and chickenpox) •Acute non-inflammatory encephalopathy •Hepatic dysfunction •Various metabolic derangements •Inhibition of mitochondrial oxidative phosphorylation Clinically Important Aspirin Interactions •Protein bound drugs (aspirin acetylates serum albumin) •β-adrenergic antagonists, ACE inhibitors ( blood pressure response) •Uricosuric agents ( effect of) •Acidyfying agents ( salicylic acid excretion) •Anticoagulants, thrombolytics, alcohol ( risk of bleeding) •Alkalinizing agents (salicylic acid excretion) •Other salicylates Common Aspirin-Herb Interactions •White willow (bark source of salicylates) •Dong Quai •Evening Primrose •Gingko Biloba •Dan Shen Pill •Policosanol NSAID Warning •May cause an increased risk of serious CV thrombotic events, myocardial infarction, and stroke, which can be fatal •Risk may be increased in those with CV disease or have risk factors for CV disease •Can also cause an increased risk of serious GI adverse events that can be fatal especially in the elderly (bleeding; ulceration; perforation of the stomach, intestines) NSAID Gastropathy •COX-1 is expressed constitutively throughout the GI tract •PGE2 and PGI2 produced by COX-1 exhibit cytoprotective effects on the GI mucosa •Reducing gastric acid secretion by parietal cells •Increasing mucosal blood flow •Stimulating the release of viscous mucous •Peptic Ulcer Disease, regardless of route, Other NSAID Adverse Effects •Elevated blood pressure, especially in elderly and in conjunction with β- blockers or ACE inhibitors •Fluid retention in patients with CHF •Drowsiness and confusion •Acute renal failure or renal insufficiency •Reversible inhibition of platelet aggregation •Anaphylaxis in aspirin-sensitive Selective COX-2 Inhibitors •Most tissues do not constitutively express COX-2 •COX-2 is induced by LPS, TNFα, IL-1, and others •COX-2 generates pro- inflammatory prostaglandins Aspirin-Induced Reye’s Syndrome Salicylate Poisoning •Pharmacokinetics: peak [plasma] in 30 minutes, 80-90% albumin bound, first- order kinetics •Toxicokinetics: high dose aspirin, peak [plasma] in 4-6 hours, 75% albumin binding, zero-order kinetics “mild to moderate pain”
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Non-Opioid Analgesics
Celecoxib
AcetaminophenAspirin• Mechanism not full determined• May inhibit prostaglandin
synthase (possibly COX-2)• Metabolized in liver• Excreted in urine• HL: 1-4 hours• Does not affect inflammation or
platelet function• Use with caution in patients with
hepatic dysfunction
Adverse Metabolites:• N-acetyl-benzoquinoneimine can
bind to renal proteins, damaging to kidney medulla• N-acetyl-benzosemiquinoneimine
can bind to hepatic proteins, leading to centrilobular necrosis
• Salicylic acid derivative• Irreversibly inhibits COX-1 through acetylating the serine
residue at position 530, and COX-2 at position 516• Inhibits platelet aggregation by inhibiting TXA2
• Often used in combo with opioid analgesics• Reduces platelet function• Oral• Rapid and wide distribution• Rapidly hydrolyzed to active metabolite (salicylic acid)• Excreted in urine• HL: 15-20 min (aspirin); 6 hours (salicylic acid)
ADVERSE EFFECTS:• GI ulcer• bleeding• tinnitus• Reye’s syndrome
Pain Pharmacology
Non-Steroidal Anti-Inflammatory Drugs
• Selective COX-2 inhibitor• Oral• Metabolized in the liver by CYP2C9• Predominately excreted in feces• HL: 11 hours• Contraindicated in “sulfa-allergic”
• Medical Emergency• Children with viral infection (including flu and chickenpox)• Acute non-inflammatory encephalopathy• Hepatic dysfunction• Various metabolic derangements• Inhibition of mitochondrial oxidative phosphorylation
• White willow (bark source of salicylates)• Dong Quai• Evening Primrose• Gingko Biloba• Dan Shen Pill• Policosanol
NSAID Warning
• May cause an increased risk of serious CV thrombotic events, myocardial infarction, and stroke, which can be fatal• Risk may be increased in those with CV disease or have risk factors
for CV disease• Can also cause an increased risk of serious GI adverse events that
can be fatal especially in the elderly (bleeding; ulceration; perforation of the stomach, intestines)
NSAID Gastropathy
• COX-1 is expressed constitutively throughout the GI tract• PGE2 and PGI2 produced by COX-1 exhibit cytoprotective effects on
the GI mucosa• Reducing gastric acid secretion by parietal cells• Increasing mucosal blood flow• Stimulating the release of viscous mucous• Peptic Ulcer Disease, regardless of route, especially in 1st month
Other NSAID Adverse Effects
• Elevated blood pressure, especially in elderly and in conjunction with β-blockers or ACE inhibitors• Fluid retention in patients with CHF• Drowsiness and confusion• Acute renal failure or renal insufficiency• Reversible inhibition of platelet aggregation• Anaphylaxis in aspirin-sensitive patients
Selective COX-2 Inhibitors• Most tissues do not
constitutively express COX-2• COX-2 is induced by LPS, TNFα,
IL-1, and others• COX-2 generates pro-
inflammatory prostaglandins
Aspirin-Induced Reye’s Syndrome
Salicylate Poisoning
• Pharmacokinetics: peak [plasma] in 30 minutes, 80-90% albumin bound, first-order kinetics• Toxicokinetics: high dose aspirin, peak [plasma] in 4-6
hours, 75% albumin binding, zero-order kinetics
“mild to moderate pain”
Opioid Analgesics• Opioids activate endogenous pain modulating systems and produce
analgesia by mimicking the action of endogenous opioid compounds at receptors in the periventricular and periaqueductal gray matter in the brain and spinal cord, thus altering transmission and perception of pain
Morphine
Fentanyl
• Prototypical opioids• μ and κ receptor effects• Schedule II controlled substance• IV, subcut• 1st pass metabolism in liver and gut wall• Metabolized in the liver• Low plasma protein binding: 20-35%• Moderate muscle tissue binding: 55%• Excreted in urine• Higher incidence of nausea and
hallucinations than other opioids
ALTERNATIVE METABOLITES:• Metabolized by UGT2B7 to morphine-3-
glucuronide or morphine-6-glucuronide• N-demethylated to inactive normorphine
• Transdermal patch: permeates in the skin, establishing a depot in the stratum corneum; fever or heat may increase absorption• Iontophoretic system: acute postoperative pain in
hospitalized patients; patient controlled; uses mild electric current; increases over time
• μ (mu): supraspinal and spinal analgesia, sedation, inhibition of respirations, slowed GI transit, modulation of hormone and neurotransmitter release• δ (delta): supraspinal and spinal analgesia, modulation of hormone and
neurotransmitter• κ (kappa): supraspinal and spinal analgesia, psychotomimetic effects, slowed
GI transit
Mild to Moderate Moderate to Severe
Opioid Analgesics
Codeine Hydrocodone Meperidine
Propoxyphene
MorphineHydromorphone
MethadoneFentanyl
MeperidineLevorphanolOxycodone
Oxymorphone
Meperidine• Diphenylheptanes• μ and κ receptor effects• Schedule II controlled substance• IV, subcut• Extensive 1st pass metabolism• Relatively high plasma protein binding: 60-
80%, principally albumin and α1-acidic glycoprotein, evidence that ratio of bound to free drug is correlated with plasma [α1-AGP]
• Excreted in urine• Higher incidence of nausea and
hallucinations• HL: 3 hours
• N-demethylated to normeperidine• Exhibits approximately half the analgesic
potency of meperidine• Twice the CNS stimulant potency (can cause
seizures, myoclonus)• May accumulate in renal/hepatic impairment
Major Drug Interactions with Opioids
• Sedative-hypnotics: CNS depression (particularly respiratory depression)• MAO Inhibitors: incidence of hyperpyrexic coma,
some reports of hypertension• Antipsychotic Tranquilizers: sedation, variable effects
on respiratory depression, accentuation of CV effects (anti-muscarinic and α-blocking actions)
Major Adverse Effects of Opioid Analgesics
• Mood changes: dysphoria, euphoria• Somnolence: lethargy, drowsiness• Stimulation of CTZ: nausea, vomiting• Respiratory depression: decreased respiratory rate• Decreased GI motility: constipation• Increase in sphincter tone: biliary spasm, urinary retention• Histamine release: urticaria, pruritis• Tolerance: larger doses for same effect• Dependence: Withdrawal symptoms
Drug Abuse
• Dependence: state that develops as a results of adaptation (tolerance) produced by resetting of homeostatic mechanisms in response to repeated drug use; pharmacokinetic tolerance; pharmacodynamic tolerance• Addiction: compulsive, relapsing drug use despite negative
consequences, at times triggered by cravings that occur in response to contextual cues• Diacetylmorphine is metabolized to morphine by carboxyesterases• Codeine is metabolized to morphine by CYP2D6
Pentazocine• Benzomorphan (only clinically useful member)• Schedule IV substance, high incidence of dysphoria
• plus acetaminophen for fibromyalgia• Atypical opioid; codeine analog• Partial μ activity• Weak 5-HT and NE reuptake properties• Central GABA, catecholamine and 5-
HTergic activities• Extensively metabolized in liver by
CYP2D6 and CYP3A4• Can be metabolized by CYP2D6 to M1 (O-
desmethyltramadol) which has a higher μ affinity and is 6 times for potent• Can be metabolized by CYP2B6 and CYP
“address neuroendocrine disturbance, including central sensitization”
• Serotonin (5-HT) and norepinephrine (NE) inhibit pain• SSRI’s and SNRI help sleep and depression• increased risk of suicidal thinking and behavior in children, adolescents, and young adults (in
short-term studies with major depressive disorder and other psychiatric disorders)• SNRI efficacy established by 2 randomized, double-blind, placebo-controlled, fixed-dose
studies in adults with diagnosis of fibromyalgia on ACR criteria
• SSRIs• Selectively block the reuptake of 5-HT at nerve terminal
• 5-HT and NE reuptake inhibitor• FDA-approved for fibromyalgia• Oral• Metabolized in liver by CYP1A2 and
CYP2D6• Predominately excreted in urine• HL: 9-19 hours
• Concurrent therapy with MAO inhibitors (Serotonin syndrome; neuroleptic malignant syndrome [NMS]-like reactions• Mydriasis: uncontrolled
narrow-angle glaucoma
Serotonin Syndrome
• Caused by overabundance of serotonin at nerve terminals• Onset within hours• hypertension• hyperreflexia• tremor• clonus• hyperthermia• diarrhea• mydriasis• agitation• coma
Pregabalin
• Binds with high affinity to the α2-δ site of the voltage-gated Ca2+ channels• Selective modulation of Ca2+
channels influence neurotransmitter release• FDA-approved for fibromyalgia• Oral• Negligible hepatic metabolism• Excreted in urine• HL: 6 hours
•Muscle relaxant•Similar structure to TCAs•Decreases pain and improves sleep
Gabapentin
• Reduces pain and improves sleep• Also used for partial onset or
generalized seizures
Tramadol AEDs
Pramipexole
•DA3 receptor agonist•Also used for restless leg syndrome
•pain modulators
Complementary/Alternative Medicine
SAMe
• S-adenosylmethionine• precursor of cysteine, taurine, and glutathione• studied for treatment of depressive disorders,
osteoarthritis, and liver disorders• deemed beneficial in fibromyalgia
5-HTP
• 5-hydroxytryptophan• precursor of 5-HT (and N-acetyl-5-
methoxyserotonin which is melatonin)• Supplements may be associated with
eosinophila-myalgia syndrome
Pharmacology of Osteoporosis
Bisphosphonates• Stable inorganic pyrophosphate analogs• Highly negatively charged; incorporated by endocytosis• Reduces both reabsorption and formation of bone• Poor oral bioavailability; food impairs absorption• Decreases bone turnover• Stabilizes or increases BMD by• filling in remodeling space and prolonging secondary mineralization• maintaining bone microarchitechture• reducing trabecular perforation in cancellous bone• decreasing cortical porosity
ADVERSE EFFECTS:• osteonecrosis of jaw (related to nitrogen groups and high IV dosing)• esophagitis or esophageal cancer (minimized by taking with full
glass of water and standing)• atrial fibrillation
Antiresorptive
Alendroate Etidronate
Zoledronate
• Second generation• Binds to bone hydroxyapatite• Inhibits osteoclast-mediated bone resorption• Oral• Not metabolized• Excreted in urine• HL: 2 hours• Onset: 1 month• Duration: 3 weeks – 7 months• 47% decrease in vertebral fracture incidence• 50% decrease in non-vertebral fracture incidence• 8% increase in BMD at spine• 3.5% increase in BMD at hip
fracture incidence• 4.3-5.1% increase in BMD at spine• 3.1-3.5% increase in BMD at hip
• alopecia• esophageal disorders• duodenal ulcer• bone pain• osteonecrosis of jaw
Selective Estrogen Receptor Modulators
Raloxifene
• High affinity for ERα and ERβ• Exhibits estrogen agonist activity on bone and
circulation of lipoproteins• Reduces bone reabsorption• Increases bone mineral density• Oral; poor bioavailability• Extensive 1st pass metabolism• Metabolized in liver• HL: 32 hours• Excreted in feces• Effective for post menopausal women• 33-55% decrease in vertebral fracture incidence• 1.6% increase in BMD at spine and hip• Hormone replacement therapy no longer
recommended for treatment due to adverse effects
ADVERSE EFFECTS:• hot sweats• cramps• deep vein thrombosis• venous thromboembolism• cerebrovascular accident• pulmonary embolism
from thyroid• Pharmaceutical calcitonin derived from
salmon• Calcium regulator• Decreases number of osteoclasts• Prevents resorptive activity of bone• Stimulates osteoblastic activity• Nasal or parenteral route• Metabolized in kidney and blood• HL: 43 minutes• Not first line• 33% decrease in vertebral fracture
incidence• 1-1.5% increase in BMD at spine• 0.58% increase in BMD at hip
factor κ B) ligand• Inhibits osteoclast formation, function, and
survival• 9.4-11.8% increase in BMD at spine• 4.0-6.1% increase in BMD at hip
ADVERSE EFFECTS:• back pain• extremity pain• hypercholesterolemia• musculoskeletal pain• cystitis
Denosumab
Teriparatide• Rhu PTH• Only approved anabolic agent for osteoporosis• Para = parathyroid hormone• Binds to the PTH receptor with the same affinity as the
intact endogenous hormone• Increases osteoclast and osteoblast activity• Subcutaneous (1X daily); rapid and extensive absorption• Reserved for patients that do not respond to SERMs• Metabolism and elimination studies have not been done• 65% decrease in vertebral fracture incidence• 54% decrease in non-vertebral fracture incidence• 9-13% increase in BMD at spine• 3.5% increase in BMD at hip
ADVERSE EFFECTS:• leg cramps• dizziness• angina• associated severe cardiovascular effects
Anabolic
Pharmacology of Osteoporosis
Prevention• Adequete calcium and vitamin D intake• Weight-bearing exercise• Smoking cessation• Limit alcohol intake• Calcium and vitamin D supplementation to prevent drug-induced osteoporosis
RALOXIFENE:• Estrogen replacement therapy to effect estrogen receptors on bone• Most suitable for women over 70 years of age who are at moderate risk and have infrequent
menopausal symptoms and are at moderate-to-high risk for breast cancer
• Second most frequent cause of secondary osteoporosis• 30-50% chronically have fractures• Control differentiation, activity, and apoptosis of
bone cells• Excess shifts osteoblast-adipocyte balance
toward enhanced adipogenesis, inhibits osteoblast differentiation and function, and increases osteoblast and osteocyte apoptosis• Associated with long term prednisone therapy• Increase adipogenesis affects bone reformation
•Abrupt discontinuation of intrathecal baclofen• seizure• high fever• altered mental status• exaggerated rebound spasticity• muscle rigidity • May advance (in rare cases) to
rhabdomyolysis, multiple organ-system failure, and death
Cyclobenzaprine
• Acts primarily at the brainstem• Exact mechanism unclear• Influences both α and γ motor systems by
decreasing tonic somatic motor activity• Oral • Extensive hepatic metabolism by both oxidative
(CYPs 1A2, 3A4, and 2D6) and conjugative pathways• Indicated for muscle spasm• Full effect may not occur for 1-2 weeks
ADVERSE EFFECTS:• strong antimuscarinic effects
Diazepam
• Blocks spinal GABAA receptors• Increases interneuron inhibition of primary
motor afferents in the spinal cord• Useful for chronic spasm due to cerebral palsy,
stroke ,and spinal cord injury or acute spasm due to muscle injury• Rectal gel can cause euphoria, rash, diarrhea,
incoordination
Tizanidine
• α-adrenergic receptor agonist in the spinal cord• Presynaptic and postsynaptic inhibition of reflex
motor output• Greatest effect on polysynaptic pathways• For spasm due to multiple sclerosis, stroke, or
amyotrophic lateral sclerosis• Contraindicated with concomitant ciprofloxacin
plasma and liver cholinesterase• Prolonged response• 2-8 hours of paralysis possible
Botulinum Toxin A
• abobotulinumtoxinA or onabotulinumtoxinA• Zn-protease• Hydrolyses fusion proteins that assist in exocytosis of Ac in
cholinergic neurons, most importantly motoneurons, causing paralysis• Injected into selected muscles can reduce pain caused by
severe spasm• Utility in more generalized spastic disorders• Weakness develops 2-4 days after muscle injection• Total paralysis of injected muscle occurs within 10 days
Disease Modifying Anti-Rheumatic Drugs
Synthetic
Methotrexate
• Inhibits dihydrofolate reductase• Causes extracellular release of
adenosine (mechanism of action in rheumatoid arthritis is unknown)• Oral, IV, IM, subcut• Metabolized in liver to active
• Prednisone• Potent anti-inflammatory• Temporary control on serious
flare-ups• Low-dose oral and local intra-
articular for symptomatic relief• Adverse effects with long-term
use
Contraindications
• Aurothioglucose• Antimalarials• Cytotoxins
Disease Modifying Anti-Rheumatic Drugs“relieve pain and inflammation, prevent joint destruction, and maintain function”
Biologics
TNF α inhibitors
• Based on proteins made by living cells• For patients refractory to synthetic DMARDs
ADVERSE EFFECTS:• influenza-like symptoms• development of autoantibodies• reactivation of tuberculosis, invasive fundal infections, and
other opportunistic infections• lymphoma (reported with TNF-inhibitors)
Drug-Vaccine Interactions
•Biologics are associated with Immunosuppression• Bacillus of Calmette and Guerin Vaccine • Measles Virus Vaccine, Live • Mumps Virus Vaccine, Live• Poliovirus Vaccine, Live • Rotavirus Vaccine, Live• Rubella Virus Vaccine, Live
Disease Modifying Anti-Rheumatic Drugs“relieve pain and inflammation, prevent joint destruction, and maintain function”
• CD4 T-cells play a critical role in rheumatoid arthritis• Patients with rheumatoid arthritis have abnormal
production of TNFa, IL-1, IL-6, TGFb, IL-8, FGF, and PDGF
Abatacept
• Cytotoxic T lymphocyte antigen immunoglobulin (CTLA4-Ig)• Inhibits T-cell activation by
binding CD80 and CD86• IV • HL: 13 days• Benefits seen within 15 days
Anakinra
•Competitively inhibits IL-1 from binding its receptor•Subcutaneous•Metabolic profile undetermined•HL: 4-6 hours•Benefits seen within 3 months
B-Cell Depleters
• Based on proteins made by living cells• For patients refractory to synthetic DMARDs
ADVERSE EFFECTS:• influenza-like symptoms• development of autoantibodies• reactivation of tuberculosis, invasive fundal infections, and
other opportunistic infections• lymphoma (reported with TNF-inhibitors)
Drug-Vaccine Interactions
•Biologics are associated with Immunosuppression• Bacillus of Calmette and Guerin Vaccine • Measles Virus Vaccine, Live • Mumps Virus Vaccine, Live• Poliovirus Vaccine, Live • Rotavirus Vaccine, Live• Rubella Virus Vaccine, Live
• B cells produce rheumatoid factors, anti-citrullinated peptide antibodies, and other autoantibodies
Rituximab
• Selectively depletes B cells bearing CD20• IV• Metabolic profile undetermined• HL: 19 hours• Benefit seen within 14 days
inhibiting xanthine oxidase• Oral• Metabolized in liver by UGT and non-
CYP 450s• Equal excretion in feces and urine• HL: 5-8 hours• Onset: rapid• Duration: 24 hours• Effective if uric acid level is < 6
mg/dL
ADVERSE EFFECTS:• abnormal hepatic enzymes• acute gout• sudden death due to myocardial
infarction
Uricostatics Uricosurics
Probenecid• Oral• Metabolized in liver• Excreted in urine• HL: 3-8 hours• Effective if uric acid level is < 6 mg/dL
ADVERSE EFFECTS:• rash, GI tract disorder, loss of appetite• nausea, vomiting, headache• aplastic anemia, leucopenia• neutropenia, thrombocytopenia• acute gout
Sulfinpyrazone• Pyrazolone derivative• Oral• Rapidly metabolized in liver to active
metabolite• Excreted in urine• Inhibited by probenecid• HL: 1-9 hours• Effective if uric acid level is < 6 mg/dL• Usually well tolerated• Low incidence of adverse effects
ADVERSE EFFECTS:• nausea, dyspepsia, GI pain, blood loss• reactivation of peptic ulcer disease
• Competitively inhibits active reabsorption of urate at proximal renal tubule
Acute Gout“crystal-induced arthritis”
NSAIDs
Glucocorticoids
Colchicine
• Speed of initiation more important than choice• Indomethacin• Ibuprofen• Naproxen• Ketorolac• Meloxicam• Meclofenamate• Sulindac• Celecoxib
• Aspirin and other salicylates should not be used
Meropenem• Broad spectrum• IV• Does not require cilastatin
ADVERSE EFFECTS:• nausea, vomiting, diarrhea
Imipenem + Cilastatin• Potent broad spectrum• IV• Cilastatin inhibits renal dihydropeptidase I (DHP I)• Imipenem is inactive without Cilastatin
ADVERSE EFFECTS:• nausea, vomiting, diarrhea
Antibiotics for Joint Infections“osteomyelitis, septic arthritis, and Lyme arthritis”
Lyme Arthritis• Monoarticular, affects knee in 80% of cases• Usually weeks to years after initial infection• Most patients respond to antibiotics• Small subset develop inflammatory joint disease persisting longer than 1 year• Oral antibiotics given as 10-day or 21-day regimen to increase rate of resolution
of erythema migrans and prevent late-stage extracutaneous manifestations• Parental antibiotics given as 14-day or 28-day courses when CNS is involved
Preferred Oral Therapy
Doxycycline
• Tetracyclic antidepressant• Bacteriostatic• Inhibits protein synthesis• Effective against wide range of Gram (+) and
• Aminopenicillin• Activity against Gram (+) and enhanced
activity against Gram (-):• HACEK group• Borrelia burgdorferi
• Given to pregnant and pediatric patients
Preferred Parenteral Therapy
Ceftriaxone
• Once-per-day outpatient IV administration• Indicated for patients with:• Neuroborreliosis (except facial nerve palsy)• 3rd degree heart block due to Lyme disease• Lyme arthritis from course of oral antibiotics that
failed
Second Line Oral Therapy
Cefuroxime axetil
• Second generation cephalosporin• Crosses blood-brain-barrier (BBB)• FDA-approved• Expensive• Prodrug de-esterified to cefuroxime• Metabolized in intestinal mucosa and
Local Anesthetics•Direct action on Na+ channels to inhibit influx of Na+ ions into neuron:• reduces depolarization of membrane• increases threshold for electrical excitation in nerve• delays propagation of nerve impulse• decreases rate of rise of action potential, thereby inhibiting generation and
conduction of nerve impulses
COCAINE:• Ester of benzoic acid and the complex alcohol 2-carbomethoxy, 3-hydroxy-
tropane• Has intrinsic vasoconstrictive activity that aids in hemostasis
Pharmacokinetics• ABSORPTION• Vasoactivity, total administered dose, infection site inflenced by specific
drug; duration depends on time in contact with nerve tissue• DISTRIBUTION• Distributes into all body tissues (rate and degree depends on individual
drug• METABOLISM• Esters are hydrolyzed mainly by plasma pseudocholinesterase and hepatic
esterases• Amides are metabolized mainly in liver by microsomal enzymes
• Blocks sodium ion channels required for the initiation and conduction of neuronal impulses• IV, epidural, intracameral, IM, oral, topical• Metabolized in the liver to active metabolites
(monoethylglycinexylidide; glycinexylidide)• Eliminated by the kidneys• HL: 2 hours (IV); 80 – 150 minutes (topical)
• Blocks sodium ion channels required for the initiation and conduction of neuronal impulses• IV• Metabolized in liver• Eliminated by kidneys• HL: 75 minutes
portion and intermediate chain• Metabolized mainly in liver by microsomal
enzymes
Esters• Contain an ester link between aromatic
portion and intermediate chain• Hydrolyzed mainly by plasma
pseudocholinesterase and hepatic esterases
“regional anesthetics block all types of nerve fibers”
Adverse Effects
Other Effects
• Respiratory arrest• Hypoventilation• Allergic reactions• Chondrolysis seen with lidocaine and bupivacaine, which are not indicated for articular injection• MetHb (affects hemoglobin function): cyanosis, dyspnea, dizziness, lethargy
Local Anesthetics“pKa of most local anesthetics is between 8 and 9”
“Larger percent at pH 7.4 will be ionized, cationic and most active at receptors”“Non-ionized form is important for rapid penetration of membranes”
the lower the pKathe greater the lipid solubilitythe greater the rate on onset
the lower the pKathe more local anesthetic is present in
non-ionized form
The un-charged (base) form diffuses more readily into the nerve than the charged
(acid) form • Potency correlates with lipid solubility• Locals with a pKa closest to physiological pH will have a higher concentration of non-ionized base
that can pass through the nerve cell membrane, and generally a more rapid onset•Highly lipid-soluble locals have a longer duration of action (less likely to be cleared by blood flow)
Local Anesthetics
Peripheral Nerve Block
• injection in or around individual peripheral nerves or nerve plexi• Wrist; digits; brachial plexus; superficial cervical
plexus; lumbar plexus; popliteal nerve; toe/foot• Advantageous in the emergency department• Requires less total local anesthetic medication• Injection site less painful than for infiltration• Onset more delayed than direct infiltration• Lidocaine or bupivacaine• Complications: nerve injury or systemic local
anesthetic toxicity
“Myelinated fibers are blocked by locals more readily than unmyelinated fibers”
Infiltration/Instillation
• Injection directly into tissue/wound edges• Often less painful than certain blocks• Can be so superficial as to only include skin• Can permit cleansing, debridement, suture repair• Can provide satisfactory anesthesia without
disrupting normal bodily functions• Duration doubles with epinephrine• Lidocaine, procaine, bupivacaine used most
frequently• Relatively large amounts must be used to
anesthetize relative small areas
Topical Local Anesthetics
•Deadens nerve endings in skin• Reduces discomfort of local procedures• May eliminate or decrease need for local infiltration• Can be applied painlessly• Does not distort wound edges• May provide good hemostasis if includes
vasoconstrictor (not cocaine)• Work better on head and neck than extremities• Slower onset• Less efficacious than injectable locals
COMBINATIONS:• TAC: Tetracaine, Adrenaline, and Cocaine• LET: Lidocaine, Epinephrine, and Tetracaine• EMLA: Lidocaine and PrilocaineOpioids
•Alleviates discomfort associated with injection of local anesthetics• Treats pain not amenable to local anesthesia• Reduces dose of sedative-hypnotics
EXAMPLES:• Tramadol with bupivacaine• Bupivacaine with fentanyl
“administered as percent values”
Bier Block
• Intravenous regional block• Injecting local anesthetic solution into
the venous system of an extremity after exsanguination by compression and/or gravity and after application of a tourniquet • appropriate for procedures, surgeries, and
manipulations of the extremities requiring anesthesia of < 45 – 60 min• Lidocaine typically used• Bupivacaine is contraindicated due to
reports of cardiac arrest and death
• Dependent on patient’s pathophysiologic state and nature of the anticipated surgery• Judged by safety, best procedure performance, and acceptability
Epinephrine
• Enhances quality of the block•Hastens onset• Prolongs duration of local anesthetics•Unnecessary if already using cocaine