musculoskeletal pharmacology
TRANSCRIPT
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
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 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”
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 HCO3
- (metabolic acidosis)• Increases fatty acid metabolism (ketone body generation)• Impairs renal function (accumulation of damaging acids)• Inhibits α-ketoglutarate dehydrogenase• Uncouples oxidative phosphorylation
Mild Moderate Severe
150-300 mg/kg 300-500 mg/kg
children/elderlynausea, vomiting, tinnitus, dizziness
Adultslethargy
Metabolic acidosisTachypnea and hyperpnea
SweatingDehydration
Ataxia
Respiratory alkalosisMetabolic acidosis
HypotensionConvulsionsRenal failure
Coma
Fluids(oral or IV)
Activated charcoalFluids (IV)
Urine alkalinization
Activated charcoalFluids (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 (cumulative effect)
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, 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
ADVERSE EFFECTS:• rash• constipation• hiccups• cardiac arrest• orthostatic hypotension• circulatory depression• shock• syncope•myoclonus• dyspnea• respiratory depression
Pain Pharmacology
• Phenylpiperidienes• μ receptor effects• Schedule II controlled substance• IM, buccal, transdermal• Metabolized in liver by CYP3A4• Excreted in urine
ADVERSE EFFECTS:• cardiac dysrhythmia• chest pain• hypertension• hypotension• apnea• hypoventilation• respiratory depression
Fentanyl Transdermal System
• 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
Drug Seeking Behavior
• Chronic pain sufferers (with limited opioid prescriptions• Addicts• Dealers
Opioid Receptor Pharmacology
• 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
Opioid Overdose
• Cool skin• Flaccid muscles• CNS depression (κ)• Miotic pupils (κ)• Decreased respiratory effort (μ, δ)• Hypotension (δ)• Decreased GI motility (μ,κ)
Embeda
• Morphine sulfate: μ opioid receptor agonist, extended release outer shell• Naltrexone hydrochloride: μ opioid receptor antagonist, inner core• Designed to limit abuse; swallowing slowly releases morphine;
chewing or crushing releases naltrexone
Naloxone
• Opioid receptor antagonist• Rapid acting/short duration• Children < 5 years old: given IV or IM
Opioid Withdrawal
• Agitation, nausea and vomiting, diarrhea, diaphoresis, tachycardia, hypertension, shivering, yawning, tremor
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
3A4 to M2 (N-desmethyltramadol)
ADVERSE EFFECTS:• nausea• vomiting• dyspepsia• constipation• dizziness• somnolence
Fibromyalgia Pharmacology
Antidepressants Centrally Acting Analgesics
Amitriptyline Fluoxetine Paroxetine
Duloxetine Milnacipran
• Tricyclic• Blocks reuptake of 5-HT and NE
“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
ADVERSE EFFECTS:• nausea• dry mouth• constipation• hyperhidrosis• insomnia• decreased appetite• somnolence• agitation
• 5-HT and NE reuptake inhibitor• FDA-approved for fibromyalgia• Oral• Principally metabolized via
glucuronide conjugation and, to a lesser extend, N-dealkylation• Excreted in urine• HL: 8 hours
ADVERSE EFFECTS:• nausea• dry mouth• constipation• hyperhidrosis• vomiting• palpitations• headache• hypertension
Serotonin-Norepinephrine Reuptake Inhibitors
Selective Serotonin Reuptake InhibitorTricyclic Antidepressants
Contraindications
• 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
ADVERSE EFFECTS:• sedation• dizziness• weight gain• blurred vision• dry mouth• peripheral edemaCyclobenzaprine
•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
ADVERSE EFFECTS:• abdominal pain• constipation• diarrhea• flatulence• indigestion• vomiting• headache
• First generation• Less potent• No nitrogen groups
• Third generation• Administered once-a-year• Contains nitrogen aromatic ring
group• Onset: 4 days• Duration: 30 days• 70% decrease in vertebral fracture
incidence• 25% decrease in non-vertebral
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
Calcitonin• Potent synthetic peptide hormone secreted
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
ADVERSE EFFECTS:• flushing• rhinitis• nausea• acute allergic reaction
Denosumab• Humanized IgG2 monoclonal antibody (mAB)• Inhibits RANK (receptor activator nuclear
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
Drug-Induced Osteoporosis• Corticosteroids• Anticonvulsants: phenytoin, barbituates, carbamazapine• Heparin (long term)• Immunosuppressants: cyclosporine, tacrolimus• Antineoplastics: Pt compounds, cyclophosphamide, ifosfamide,
methotrexate• Aromatase inhibitors: exemestane, anastrozole (aromatase converts
precursors into estrogen)• Hormonal therapies: GnRH agonists, LHRH agonists, excessive TH• Lithium
Glucocorticoids
• 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
Muscle Relaxants (Antispastics)
• Decrease muscle spasm associated with painful conditions• Back pain, sciatica, herniated discs, spinal stenosis, myofascial pain• Examples: benzodiazepines, cyclobenzaprine, carisoprodol, metaxalone,
chlorzoxazone, methocarbamol, tizanidine, orphenadrine
Spasmolytic Agents• Spasticity: upper motor neuron disorder characterized by
muscle hypertonicity and involuntary jerks• Multiple sclerosis, cerebral palsy• Examples: baclofen, tizanidine, dantrolene, diazepam
Antispastic Agents
Baclofen
• p-chlorophenyl-GABA• GABAB agonist• Facilitates spinal inhibition of
motor neurons• Indicated for severe spasticity
due to spinal cord lesions• Oral, intrathecal• Minimal hepatic metabolism• Excreted in urine
ADVERSE EFFECTS:• transient sedation• weakness, constipation
Baclofen Withdrawal
•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
or fluvoxamine
Carisoprodol
• Brand name: Soma• Precise mechanism unclear• Blocks interneuronal activity in descending
reticular formation and spinal cord• Oral• Metabolized in the liver • HL: 8 hours• Available in preparations with aspirin or codeine
• Metabolized by CYP2C19 to Meprobamate• Class IV controlled substance• anxiolytic• CNS depressant similar to benzylpiperazine• HL: 11 hours
ADVERSE EFFECTS:• dizziness, headache, somnolence• seizure, drug/abuse/dependence
Central Acting
Dantrolene
Direct Acting
• Hydrantoin derivative• Blocks RyR1 Ca2+ release in sarcoplasmic
reticulum of skeletal muscle• Reduces actin-myosin interaction• Weakens skeletal muscle contraction
• Oral for spasms due to cerebral palsy, spinal cord lesion, and multiple sclerosis
ADVERSE EFFECTS:• muscle weakness, diplopia, constipation• fatal and non-fatal liver disease
Muscle Relaxants (Neuromuscular Blockers)
Neuromuscular Blockers
Non-Depolarizing1. One molecule of a non-depolarizing neuromuscular blocker binds
a single nACh receptor (on the a site) 2. Competitive inhibition of normal channel activation.
• Do not block VG- sodium channels on the muscle membrane, and direct electrical stimulation of muscle contraction is still possible
• Highly polar; do not cross blood-brain-barrier (BBB)• Long-acting:• Doxacurium• d-Tubocurarine• Pancuronium
• Short to intermediate acting:• Mivacurium• Atracurium
Depolarizing1. 2 molecules of succinylcholine must bind to each a site of the
nACh receptor. 2. Prolonged open state of nAChR ion channel (initial depolarization
usually causes fasciculations*)3. Succinylcholine is hydrolyzed by plasma pseudocholinesterase
(not acetylcholinesterase); this takes longer4. Persistent presence of succinylcholine causes VG-sodium channel
to remain in a prolonged inactive state5. Muscle is temporarily refractory to presynaptic release of ACh
“surgical relaxation and control of ventilation”
Succinylcholine
• Also called diacetylcholine or suxamethonium• Composed of two acetylcholine molecules• Metabolized by plasma pseudocholinesterase
to succinylmonocholine and choline• Short duration of action• Can be influenced by pharmacogenetics
Pharmacogenetics
• E2E2 homozygous atypical• Genetically determined atypical
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
polyglutamate metabolites• Excreted in urine
ADVERSE EFFECTS:• ulcerative stomatitis• nausea, chills, fever, malaise• abdominal distress, undue fatique• leucopenia, dizziness• decreased resistance to infection•myelosuppresion• hepatotoxicity, pulmonary fibrosis• interstitial pneumonitis• SJS, cardiotoxicity, nephrotoxicity
Overdose:• Leucovorin (folinic acid) rescue
Antimetabolites
Contraindications
• Alcoholism, alcoholic liver disease• Chronic liver disease• Preexisiting blood dyscrasias• Evidence of immunodeficiency
syndromes
• Those who are pregnant, may become pregnant, or are breastfeeding; inhibits folic acid• Those with hypersensititivity
Leflunomide
• Inhibits dihydro-oratate dehydrogenase• Oral prodrug• Rapidly metabolized to active
cyanoacetic acid metabolite• Excretion in feces and urine• HL: 2 weeks (metabolite)• Benefit seen in 1-3 months
ADVERSE EFFECTS:• alopecia• rash• diarrhea
Sulfasalazine
• Sulfonamide• Mechanism unclear• Sulfapyridine may suppress activity of
NK cells and impair lymphocyte transformation• Oral• Metabolized in colon and liver to active
metabolites• Excretion in feces and urine• HL: 10-15 hours (sulfapyridine)
ACTIVE METABOLITES:• Sulfapyridine: sulfapyridine moiety may
suppress the activity of NK cells and impair lymphocyte transformation • Mesalamine (5-ASA): anti-inflammatory;
metabolized by NAT-1 to N-acetyl-5-ASA
ADVERSE EFFECTS:• pruritis, rash, abdominal pain• indigestion, loss of appetite• nausea, stomatitis, vomiting• dizziness, headache, fever• discolored urine, oligozoospermia• aplastic anemia, hepatoxicity• SLE, kidney disease
Hydroxychloroquine
• Antimalarial• Inhibits chemotaxis of
eosinophils• Inhibits neutrophil motility• Impairs complement-dependent
An-Ab reactions• Oral (rapid and complete
absorption)• Metabolized in liver• Slowly eliminated by kidneys
ADVERSE EFFECTS:• disorder of cornea• drug-induced pigmentation• nausea, vomiting, anorexia• diarrhea, headache• angioedema, agranulocytosis• torsades de pointes• fulminant hepatic failure• drug-induced myopathy• neuropathy, retinopathy• hearing loss
HCQ-Induced Myopathy
• Rare, but underappreciated cause of muscle weakness• Proximal muscle weakness• Normal CK levels • Characteristic ultrastructural
changes on muscle biopsy
Azothioprine
• Imidazolyl derivative of 6-mercaptopurine• Suppresses cell-mediated
hypersensitivities• Causes alterations in Ab
production• Metabolism of 6-MP involves
polymorphic TMPT• HL: 5 hours• Benefit seen in 2-3 months
“relieve pain and inflammation, prevent joint destruction, and maintain function”
Disease Modifying Anti-Rheumatic Drugs
Synthetic
“relieve pain and inflammation, prevent joint destruction, and maintain function”
Aurotherapy Chelators Bridging Therapy
Auranofin
• Oral• Mechanism unknown• No longer frequently used• Benefits seen in 4-6 months
ADVERSE EFFECTS:• rash, stomatitis• bone marrow suppression• GI intolerance• photosensitivity• proteinuria
Aurothioglucose
• Intramuscular• Benefits seen in 3-6 months
ADVERSE EFFECTS:• photosensitivity, dysgeusia• rash, bone marrow suppression• white spots on lips or in mouth• proteinuria• bleeding, brusing
Gold Sodium Thiomalate
Gold Toxicity
• fall in Hb• leukopenia below 4000 WBC/mm3• granulocytes below 1500/mm3• decrease in platelets below 150,000/mm3• proteinuria• hematuria• pruritus• maculopapular rash• stomatitis or persistent diarrhea
Penicillamine
• β,β-Dimethylcysteine• Not used casually• Severe rheumatoid arthritis
refractory to NSAIDs• May improve lymphocyte
function by reducing IgM rheumatoid factor• Used with Wilson’s Disease
ADVERSE EFFECTS:• rash, taste disorder, nausea• vomitting, myelosuppression
NSAIDs
• Not recommended as monotherapy• May not alter progression• Anti-inflammatory• Inexpensive• Can cause decrease in renal
function• May be contraindicated in
hypersensitive patients
COMMONLY USED NSAIDS•Proprionic acids (ibuprofen)• Carboxylic derivatives• Acetic acid derivatives• Salicyclic acid derivatives:• Diflunisal• Choline Mg2+ salycylate• Fenamates• COX2 Inhibitors
Glucocorticoids
• 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
• Smallpox Vaccine• Typhoid Vaccine• Varicella Virus Vaccine• Yellow Fever Vaccine
Infliximab
• Chimeric human-mouse IgG1 kappa mAb• IV• Distribution and metabolic profile
unknown• HL: 8-12 days• Benefits seen in days to 4
months
• Monoclonal antibodies against TNF and TNFR
Adalimumab
• Human IgG1 mAb• Subcutaneous• Distributed into synovial fluid• Metabolic and elimination profiles
unknown• HL: 10-20 days• Benefits seen in 8-26 weeks
Golimumab
• Human IgG1 kappa mAb• Subcutaneous with methotrexate• Benefits seen within 3 months
Certolizumab
• Pegylated recombinant humanized Fab’ fragment of a TNF mAb• Subcutaneous• Metabolic profile undetermined• HL: 14 days
Etanercept
• Soluble p75 TNF receptor fusion protein• Subcutaneous• Distribution and metabolic
profiles unknown• HL: 102 hours• Benefits seens in 2-4 weeks
ADVERSE EFFECTS:• injection site reaction• abdominal pain• vomiting, headache, rhinitis
SERIOUS ADVERSE EFFECTS:• basal cell carcinoma• squamous cell carcinoma of the
skin• necrotizing fasciitis• anemia• thrombocytopenia• autoimmune hepatitis• immune hypersensitivity reaction
Biologics
T-Cell Modulators
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
• Smallpox Vaccine• Typhoid Vaccine• Varicella Virus Vaccine• Yellow Fever Vaccine
Uricostatics/Uricosurics“stop acute attack, prevent recurrent attacks, and lower excess uric acid”
Chronic Gout“deposits of monosodium urate”
• Medications lower uric acid levels for patients with frequent attacks• Patients who have tophi, renal disease, deforming or erosive
arthritis, or renal stones
Allopurinol• Structural analog of hypoxanthine• Decreases serum and urine uric acid by
inhibiting xanthine oxidase (XO) and reutilizing hypoxanthine and xanthine • Oral• Metabolized in liver to active metabolite
(oxypurinol)• Excreted in feces and urine• HL: 1-3 hours (allopurinol); 15-30 hours
(oxypurinol)• Onset: 1-2 days• Duration: 1-3 weeks
METABOLITES:• Allopurinol: competetively inhibits XO at low
concentration; noncompetitively inhibits XO at high concentration;• Oxypurinol: noncompetitively inhibits XO
ADVERSE EFFECTS:•maculopapular eruption• immune hypersensitivity• agranulocytosis• aplastic anemia• eosinophilia• myelosuppression• hepatotoxicity
Febuxostat• Decreases serum uric acid by
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
• Oral prednisone• ACTH• Intra-articular injections
helpful with monoarticular flare-ups• Triamcinolone• Methylprednisolone• Betamethasone
• Antigout• Appears to disrupt cytoskeletal
functions through inhibition of β-tubulin polymerization into microtubules• Oral• Metabolized partially in liver• Excreted in feces• HL: 27-31 hours
ADVERSE EFFECTS:• diarrhea, nausea, vomiting•myelosuppression
Drug-Induced Increases in Serum Urate
• Loop and Thiazide Diuretics: potential for increased gouty attacks from hyperuricemia• Cyclosporin A• Pb (for saturine gout): nephropathy• Low dose acetylsalicylic acid• Alcohol
Antibiotics for Joint Infections
Septic Arthritis
Gram (-) Cocci/Bacilli
“osteomyelitis, septic arthritis, and Lyme arthritis”
Osteomyelitis
Ceftriaxone
• Third generation cephalosporin• Cell wall synthesis inhibitor• Covers most pathogens that
cause septic arthritis• Single daily infusion• Alternative: Cefotaxime
ADVERSE EFFECTS:• rash, GI effects, biliary sludging• increased liver function tests• blood dyscrasias
Gram (+) Cocci
Vancomycin
• Glycopeptide• Cell wall synthesis inhibitor• High affinity to D-Ala-D-Ala
terminus of cell wall precursors• Effective against MRSA coagulase
(-) negative staphylococci
ADVERSE EFFECTS:• nephrotoxicity• “red man” syndrome
Enterobacter
Enterococci
• Ciproflaxacin• Ceftriaxone• Meropenem
• Ampicillin + Gentamicin
P. aeruginosa• Ceftriaxone• Ciproflaxacin• Piperacillin + Gentamicin• Meropenem
S. aureus• Methicillin Sensitive• Nafcillin• Cefazolin• Cephalexin
• Methicillin-Resistant, or S. epidermidis• Vancomycin• Clindamycin
Mixed Infections• Ticarcillin-clavulanate• Clindamycin + Ciproflaxacin• Imipenem + Cilastatin
Carbapenems for Osteomyelitis
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
Gram (-):• Acinetobacter• Enterobacteriaceae• Borellia burgdoferi
• Oral• Metabolized in liver• Excreted in urine• HL: approximately 16 hours• Contraindicated in children younger than 8
years (TCAs cause gray teeth)
ADVERSE EFFECTS:• photosensitivity• drug-induced GI disturbance• increased serum blood urea nitrogen (BUN)
Amoxicillin
• 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
blood by nonspecific esterases
ADVERSE EFFECTS:• diarrhea, nausea, vomiting• vaginitis, SJS/TEN• hepatotoxicity, anaphylaxis
Local Anesthetics
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
• EXCRETION• Excreted principally in urine
Mild Moderate Severe
Visual disturbanceTongue numbnessLightheadedness
ApprehensionRestlessness
Perioral paresthesiaMuscle twitching
Slurred speechExcitabilityDrowsiness
SeizuresCR depression
Coma
CNS Effects Cardiovascular Effects
•Hyperkalemia facilitates cardiotoxicity• palpitations• vasodilation• hypertension• hypotension• ventricular dysrhythmias• myocardial depression• bradycardia• cardiovascular collapse
Lidocaine
• 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)
ADVERSE EFFECTS:• hypotension, edema, erythema at infection site• petechiae, skin irritation, constipation, headache• nausea, vomiting, confusion, dizziness, paresthesia• cardiac arrest, cardiac dysrhythmia, seizure•methemoglobinemia
Chloroprocaine
• Blocks sodium ion channels required for the initiation and conduction of neuronal impulses• IV• Metabolized in liver• Eliminated by kidneys• HL: 75 minutes
ADVERSE EFFECTS:• dizziness• cardiac arrest, ventricular arrhythmia, anaphylaxis• chondrolysis of articular cartilage• CNS depression/stimulation, seizure• hypoventilation, respiratory arrest
Amides• Contain an amide link between aromatic
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
Selecting a Local Anesthetic
BupivacaineRopivacaine
LidocainePrilocaine
ProcaineChloroprocaine
Tetracaine BenzocaineCocaine
± epinephrine
Local Anesthetics