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