• Process that begins following sub-lethal injury to tissue
• Ends with permanent destruction or complete healing of tissue 
• Elicits a series of events (Humoral and Cellular)

1. Rubor (Redness)
2. Calor (Increased heat)
3. Tumor (Swelling)
4. Dolor (Pain)
5. Function laesa (Loss of function)

• Localization of injury
• Removal of noxious agent(s)
• repair or physical damage
• Restitution of function in the injured tissue

• not beneficial
• Examples: Rheumatoid arthritis, tuberculosis, gout, psoriases, mastitis, etc. 

• Generated at site of injury
• usually exist as precursors or sequestered in cells

• Release of lysosomal enzymes, Arachidonic aced and synthesis of various Eicosanoids 

• produced and released within the body
• Examples: Prostaglandins, Prostacyclines, Leukotreines, Thromboxanes
• Prostaglandins have effects on blood vessels (cause redness), nerve endings (cause pain), and blood cells

1. Increase permeability of microvasculature
2. Activation of leukocytes

• occurs in a time-related sequence

1. Injury and damage to tissue
2. Histamine, Bradykinins and Neuropeptide release
3. influx of inflammatory cells 
4. Release of Neutrophils
5. Neutrophil membrane stimulation results in oxygen derived free radicals 
6. molecular oxygen is reduced to form a superoxide anion
7. production of hydroxyl radicals and hydrogen peroxide occurs
8. Interactions of all these substances results in formation of chemotactic substances
9. chemotaxis further perpetuates the inflammatory process

• Cell adhesion molecules
• Prostaglandins
• leukotrienes
• platelet-activating factors (PAF)

Neutrophils move into injured tissue due to 2 signals:

1. acPGP - a protein fragment from collagen due to MMP cleavage
2. IL-8 released from macrophages

• substances regulating the directed movements of cells 
• Endogenous: chemokines and other cytokines, certain prostanoids, and the fragments of certain proteins (fibrin)
• Exogenous: certain bacterial oligopeptides

1. Relief of symptoms and maintenance of function
2. slowing of tissue damage

1. Non-Steroidal Anti-inflammatory agents (NSAIDs)
2. Steroidal Anti-inflammatory agents: Corticosteroids
3. Disease Modifying Antirheumatic Drugs (DMARSs)

• Relief of pain and inflammation
• Aspirin, ibuprofen, Diclofenac, Piroxicam, Celecoxib, Naproxen

• long term control 
• Hydrocortisone, betamathasone, prednisolone, triamcinolone, flurocortisone, dexamethasone

• ↓ symptoms, slow bone damage in arthritis and ↓ inflammation
• Abatacept, Azathiprine, Cyclophosphamide, Methotrexate, Rituximab

1. phospholipase activates arachidonic acid (inhibited by corticosteroids)
2. release of arachidonic acid can stimulate 2 pathways: prostaglandin and Leukotriene 
   • Prostaglandin pathway leads to inflammation (blocked by cox inhibitors)
   • Leukotriene pathway leads to asthma (blocked by ???)
   • asthmatic patients can be sensitive to COX inhibitors b/c when this pathway is blocked all arach. acid goes through the leukotriene pathway

• variety of actions
• these agents or their analogs are used to induce or mimic their biological effects (vasodilator effects of PGE₂)
• NSAIDs and other anti-inflammatory drugs used to inhibit their biological actions (e.g. Prevention of inflammation  and prostaglandin, prostacycline and cytokine production)

Stimulates and sensitizes pain receptors 

- pain is felt at a lower threshold

(Cervidil; Prepidil; Prostin E₂)

1. Abortion: 12-20th week, acts directly on myometrium stimulating gravid uterine contraction, as in natural labor
2. Cervical ripening (gel, topical). Used prior to induction. Softens cervix and facilitates dilation

Misoprostol (Cytotec)

1. Prevention of gastric ulcers in susceptible patients taking NASIDs
2. Enhance gastric mucosal defense mech and healing in acid-related disorders via ↑ production of mucus and secretion of bicarbonate
3. Gastroprotective

- act on smooth muscle and platelet aggregation

- TXA₂ :produced and released from platelets (from PGG₂₎

- _{Stimulates platelet aggregation}

- cause vasoconstriction

- production inhibited by ASA and NSAIDs 

• Constitutive (physiologic) effects:
• Platelets - production of TXA₂ 
• Kidney - regulate renal blood flow in response to changes in blood volume and fluid & electrolyte transport
• Gastric mucosa - maintain mucosal integrity

• Constitutive (physiologic):
• Brain (COX-3) Vasodilation (blocked by tylenol)
• reproductive tract
• Inducible (pathologic)
• Inflammation and pain
• by a # of inflammatory mediators

ASA

Ibuprofen, ketoprofen, fluriprofen

naproxen

ketolorac

rofecoxib

celecoxib

valdecoxib

• Inhibition on COX iso-enzymes
• Irreversible binding; acetylation
• selectivity for COX-1 > COX-2
• inhibit the production of cyclooxygenase products

• absorption: stomach and GI (no IV prep)
• high pH and food delay gastric absorption (leads to gastric ulcers)
• Highly plasma protein bound

• Peripheral, inhibit formation of eicosanoid mediators (PGs)
• Reduce mild to moderate pain intensity (not effective for more severe types of pain)
• antagonize actions of kinins (bradykinins)

• potent pain producing substances, eliciting pain by stimulating nociceptive afferents in the skin and visceral

• Peripheral, blocks eicosanoid mediators
• antagonize actions of kinins (bradykinins)
  • inhibits granulocyte adherence to damaged vasculature
  • stabilizes lysosomes
  • inhibits migration of polymorphonuclear leukocytes and macrophages into the site of inflammation

• Reduce elevated temperature:
• Inhibition of COX isoenzymes, reducing hypothalamic PGE₁, enhancing peripheral vasodilation and profuse sweating
• inhibition of IL-6, which is released from macrophages during episodes of inflammation, thus decreasing the pyretic activity

• a single 80 mg a day dose produces a slightly prolonged bleeding time. Bleeding time is doubled if continued for 1 week or dose is greater than 325 mg
• irreversible binding to platelet COX
• antiplatelet effects last 7-10 days, with a single 80 mg dose

• mild to moderate analgesia (pain)
• antipyretic (fever)
• anti-inflammatory
  • rheumatic fever, arthritis (RA, OA)
  • Transient ischemic attack (TIA), unstable angina, coronary artery thrombosis with MI and thrombosis after coronary artery bypass

Allergy

Hypersensitivity

GI tracy irritation

↑ bleeding time

during pregnancy

Reye's syndrome

• cross sensitivity with all salicylates and NSAIDs (including methyl salicylate (oil of wintergreen) and tartazine)

Due to:

1. irritation of gastric mucosa by undissolved tablet (physical)
2. inhibition of PGE₂ causes increased gastric acid and pepsin secretion and decreased mucus secretion
3. ↑ H+ penetrates mucosa and damages blood vessels

• Anti-hypertensives
• lithium
• anticoagulants
• methotrexate
• ethanol
• digoxin
• cyclosporine
• NSAIDs & Acetaminophen
• sulfoylureas
• anticonvulsants

• Angiotensin converting enzyme inhibitors (ACEI): Captopril, enalapril, lisinopril
• Diuretics: furosemide, hydrochlorothiazide
• β-blockers: propranolol, metroprolol, atenolol

• NSAIDs: gastric bleeding, gastric damage, platelet function inhibition
• Hypoprothrombin effects of anticoagulants is ↑ by specific NSAISs (esp ASA), also due in part to protein binding displacement
• ASA (> 3g/day) reduces prothrombin levels

• both damage gastric mucosal barrier
• separate their ingestion by 12 hours

• combined use associated with ↑ incidence of Nephrotoxicity 
• acetaminophen-ASA combination: avoid long term use: may cause renal damage (alone acetaminophen effects liver)
• NSAIDs inhibit intrarenal PG production
• ↓ renal blood flow, GFR and urine volume
• Naproxen ↓ renal plasma flow by 10%

Adverse effects of ASA on bleeding time

• prolonged bleeding time
• inhibits TXA₂ formation

• restricted use in last 3 months (3rd trimester)
  1. may ↑ duration of pregnancy (about 1 week)
  2. fetal PGE₁ normally maintains the patency of ductus arteriosus in the fetus to supply oxygenated maternal blood to fetus
  3. ASA ↓ fetal PGE₁ causing the closure of the ductus, resulting in decreased birth weight and increased mortality (ductus normally closes just before birth)

Chronic, high dose given late in pregnancy:

• increases duration of labor (by 7-12 hrs)
• complicated deliveries
•  increased risk of maternal and fetal hemorrhage
• increased bleeding at episiotomy 

• seen in children with viral infection (who have been given ASA)
• chicken pox; influenza
• 20-30% mortality

• antipyretic and analgesic
• no effect on platelet aggregation
• non-ulcerogenic
• NOT associated with Reye syndrome
• minimal or no effects on peripheral COX isoenzymes (renally safe)
• acts in CNS on COX-3 isoenzyme
• safe during pregnancy
• NOT an NSAID!!

acts centrally

COX-3 isoenzyme

• analgesic; anti-pyretic
• alternative for patients allergic to ASA, having bleeding disorders, ulcers

- oral: rapid and almost complete absorption

- high carb diet may ↓ absorption

- available in IV form

• evenly distributed, crosses placenta and mild
• t1/2 = 2-4 hrs, Cmax = 0.5-2 hrs
• time to peak effect = 1-3 hrs
• duration = 3-4 hrs

• occurs 90-95% in the liver
• conjugation with glucuronic acid
• Toxic intermediate metabolite:
  • hepatotoxic, nephrotoxic
  • accumulate in overdosage after 1º metabolite pathway is saturated
  • Therefore, do not give to pts with liver dysfunction

• excessive use can damage liver, due to one of its metabolites (NAPQI), not the drug
• by far the most common cause of acute liver failure in the US
• toxicity occurs if hepatic glutathione is depleted; overdose; or when taken with other enzyme inducers
• antidote = Acetylcysteine (NAC)

• toxic metabolite of acetaminophen
•  In the liver, CYP 2E1 and 3A4 convert paracetamol to NAPQI (when 1º pathway is saturated)
• causes hepatic cell death

• antidote for acetaminophen toxicity
• acts as a precursor for glutathione helping body regenerate enough to prevent liver damage

Ethanol induces CYP2E1 levels →

Increased toxic metabolite production (NAPQI)

1. osteoarthritis (80-90%)
2. Rheumatoid (15-18%)
3. Gout (1-2%)

• Piroxicam
• non-selective COX inhibitor
• effective for treatment of arthritis 
• well absorbed, once a day dosing
• 30% pts report adverse effects
• GI, gastric ulcers may form
• Dizziness and rash

• great symptomatic (anti-pain/analgesic) effects
• not good anti-inflammatory effects

• used for acute gouty arthritis, rheumatoid arthritis and spondylitis 
• used when ASA is ineffective or not tolerated
• side effects: 
  • CNS effects: dizziness, headache, confusion
  • Ocular: blurred vision
• chemically related to SULINDAC

• chemically inert
• inhibits macrophages which may be responsible for inflammation
• erratically absorbed orally
• intramuscular route preferred
• highly plasma protein bound
• excreted through kidneys

• Cyclophosphamide (Cytoxan)
• ↓ bone erosion of arthritis
• prevents further progress of disease
• used only in pts where other anti-inflammatory drugs have failed
• side effects: vast and limit use
  • dental: mucositis, glossitis, ulcers

• an anti-metabolite
• suppresses patient immunity, therefore an anti-inflammatory
• used only in adults with severe rheumatoid arthritis
• side effects: nausea, GI discomfort, mucositis, headache
• may cause hepatotoxicity and immunodeficiency 

• effective in acute, severe rheumatoid arthritis 
• ↓ pain, stiffness, and swelling
• a metal chelator - adheres to metals and aids in their metabolism
• 1/3 of pts have side effects:
  • pruritis, dermatitis, GI upset, loss of taste, renal failure

1. deformation
2. loss of function

Abatacept

Rituximab

• A DMARD
• immune modulator that prevents T-cell activation, thus preventing inflammation
• given as IV infusion
• ↑ chance of infections
• may lead to hypersensitivity and anaphylaxis
• used in monotherapy and combination with DMARDs in moderate-severe R. arthritis

• a monoclonal AB
• targets and depletes B lymphocytes
• acts by cytotoxicity and apoptosis
• ↓ inflammatory response
• treatment of moderately severe R. Arthritis with methotrexate
• Rash occurs in 30% of pts
• cardiovascular events occur rarely

• Given systemically
• used in 60-70% of pts with R. Arthritis 
• cause relief of pain within 24 hrs (so bridge with NSAIDs)
• slow bone erosion and prevent new bone erosion
• Cushing's disease may develop
• may result in 2º fungal infections an increase in blood sugars

• a metabolic disease due to deposits of Urate crystals in joints
• Related to Hyperuricemia
• Patients have joint swelling, usually starting at the big toe (bottom up)
• acute, painful condition

• NSAIDs (Indomethacin and ibuprofen)
• allopurinol
• colchicine
• probenecid
• febuxostat
• steroids

3 ways to treat:

1. *Anti-inflammatory drugs (NSAIDS, Colchicine)* always use 1st
2. Inhibit formation of uric acid (allopurinol, febuxostat)
3. ↑ excretion of uric acid (Probenecid)

• prevents formation of uric acid by inhibiting the enzyme xanthine oxidase
• used along with colchicine or NSAIDs
• drug of choice for gout (as adjunct with NSAIDs)
• side effects: Nausea, vomiting, diarrhea
• Hepatic toxicity may occur

• Converts into uric acid in the body

• used to be drug of choice for gout, now is used after NSAIDs
• Has anti-inflammatory activity
• often causes diarrhea and vomiting

• A Uricosuric agent, which promotes the loss of Urate through urine
• causes GI irritation and rash

• a Xanthine oxidase inhibitor (like allopurinol)
• Prevents formation of uric acid
• recently FDA approved
• Side effects: Headache, diarrhea, Nausea

Osteo: less inflammation, so can use tylenol for pain

Rheumatoid: more inflammation, so tylenol is not effective 

• Acute pain: Nociception
• Chronic pain: (aberrations of normal physiologic pathways) Hyperalgesia, Allodynia, Spontaneous pain spasms

• Acute pain pathway
• an excessive noxious stimulus giving rise to an intense and unpleasant sensation

• a chronic pain pathway
• an increased amount of pain associated with a mild noxious stimulus

• a chronic pain pathway
• pain evoked by a non-noxious stimulus

• chronic pain pathway
• without precipitation stimulus (Neuropathic)

• consist of mostly Aδ fibers and C fibers

• Fast Pain fibers
• Conduct Intense, sharp, stinging pain
• lightly myelinated, 5-30 m/sec
• functions: pain localization and withdrawal reflexes
• ascending pathway, projects to: reticular formation, thalamus and sensory cortex

• Slow Pain fibers
• unmyelinated, 0.5-2 m/sec
• Conduct dull, burning, aching pain
• functions: autonomic reflexes, pain memory & discomfort
• ascending pathway, projects to: thalamus, periaqueductal gray matter, and limbic 

• touch fibers
• can inhibit the spinothalamic neurons via the release of enkaphalins (opioid peptide)
• Mediates the analgesic effects produced by several types of tissue stimulations:
  • Acupuncture, TENS (transcutaneous electrical nerve stimulation)
  • when rubbed (stimulated) they over ride Aδ ad C pain fibers

• Juice extracted from poppy
• mood altering, creates euphoric feeling
• alters noxious feeling of pain

• peptides with opioid-like activity
• widely distributed in brain (found in distinct areas associate with pain)
• also produced by non-neuronal cells (endocrine & exocrine glands and immune cells)

small peptides - 5 amino acids

(met- & leu-enkaphalins)

• G-protein coupled receptor family
• activation causes inhibition of adenylate cyclase
• Presynaptic nerve: inhibit opening of Ca channels
  • Result: inhibition of n.t. release
• Post-synaptic nerve: OPEN K+ channels
  • Result: hyperpolarization of post synaptic membrane, inhibition of firing

• causes inhibition adenylate cyclase
• produces a spectrum of activity:
• Analgesia, sedation, pupillary constriction, Bradycardia
• withdrawal relief
• suggests there are receptor sub-types

• specific receptors in brain and spinal cord
• mu (μ), sigma (σ), kappa (κ), & epsilon (ε)

mainly responsible for most of the analgesic effects, and most of the unwanted effects (respiratory depression, euphoria, sedation and depression, ↓ GI motility)

• most analgesic opioids are υ receptor agonists

contribute to analgesia at the spinal level and may elicit sedation and euphoria.

• Produce relatively few unwanted effects
• do not contribute to dependence
• ↓ GI motility

• morphine-like drugs
• high affinity for mu receptors
• lower affinity for delta and kappa receptors
• Strong agonists: morphine, Fentanyl meperidine
• Weak agonists: codeine, hydromorphone, diamorphine, oxycodone, hydrocodone, dihydrocodeine

• Pentazicine - mu antagonist, kappa agonist
  • do not give with morphine, will cause more pain due to competition and less efficacy at pain reduction
• Buprenorphine - mu partial agonist, kappa antagonist
• most drugs in this group cause dysphoria rather than euphoria

• antagonize both mu and kappa receptors
• little effect of their own
• used to treat opioid (heroin, morphine, codeine) over dose 
• Naloxone (Narcan)
• may also be used for nicotine and alcohol addiction

• strong to weak effects
• strong (morphine) for severe pain (MI)
• weak (Codeine) are as effective as NSAIDs

• sedation via kappa stimulation
• euphoria, with large doses or when pain is suddenly removed

• antitussive effect by depressing cough center (in medulla)
• dose required is sig smaller than the analgesic dose
• dextromethorphan (DM in OTC cough meds)
• Codeine is effective as antitussive

• ↑ tone of GI s.m.
• marked ↓ propulsive contractions and motility
• constipation
• Diphenoxylate (lomotil): opioid-like with no analgesic effects used to treat diarrhea

• constipation -extension of pharm effects
• myosis - pinpoint pupils, esp w/ overdose
  • diagnositc
• nausea & emesis, urinary retention, ↓ CVS, biliary colic, histamine release from mast cells (except with demerol), prolong labor, ↓ fetal respiratory fxn

• naturally occurring (10-20% dried opium)
• PKs: 
  • oral: well absorbed, extensive 1st pass effect
  • other routes: IM, IV, SC, epidural, intrathecal
  • 90% 1st pass effect
  • does not cross BBB easily

• weak analgesic (mild pain)
  • raises pain threshold
  • activates mu & kappa (to lesser extent)
  • Prodrug: metabolized to morphine
  • used in combo with NSAIDs and tylenol
• antitussive effect

• Oral route of admin
• well absorbed 
• subjected to 1st pass 
• metabolized to morphine (prodrug)
• excretion:
  • mainly in urine (caution with renal failure pts)
  • some excreted in bile; enterohepatic cycling (circulation)

constipation

drowsiness

trembling

• alcohol
• CNS depressants (causes further respiratory depression)
• anti-histamines (hydroxyzine)

• cross sensitivity with:
  • codeine, oxyocdone dihydrocodone, hydromorphone
• Alternatives: 
  • Meperidine (demerol) - affected by 1st pass effect
  • Propoxyphen 
  • Darvon (propoxyphen + tylenol)

• centrally acting analgesic
• not chemically related to opioids but has opioid like activity
• used for moderate to severe pain
• Brand name: ultram, Ultracet (tramadol + Tylenol)

1. Opioid like synthetic product: similar to codeine, activates u receptors, has active metabolite that is 200x greater affinity for u receptors
2. Aminergic: inhibits the reuptake of NE and 5HT 
3. Others: antitussive

• hepatic metabolism, MI active metabolite
  • formation of Mi dependent on CYP2D6
  • t1/2: tramadol (6.3hrs); MI (7.4 hrs)
  • [peak]: tramadol (2 hrs); MI (3 hrs)
  • onset of action = 1 hr

• Seizures (lowers seizure threshold)
• hallucinations, visual...

• CNS depressants
  • alcohol, antidepressants, opioids, sedatives
  • carbamazepines

• 12 x more potent than codeine
• Percocet = oxycodone + acetaminophen (same as 2 tylenol #3)
• 2 percocet = 120 mg codeine  
• also combined with aspirin (percodan)

•  5ml hydrocodone + 500 mg acetaminophen = Vicodin
• 7.5 mg hydrocodone + 750 acetaminophen = Vicodin Es
• also combined with ibuprofen: Vicoprofen (not often use b/c not enough ibuprofen), Combunox

• Antidepressants: tricyclics more effective than SSRI
• Anti-epileptics/anticonvulsants
• local anesthetics

• highly potent pain-producing substance
• selectively stimulates nociceptive and temp. sensitive nerve endings
• clinical uses: topical analgesics

• acts on membrane receptors coupled to cation channels
• activation results in ↑ Ca permeability, ↑ intracellular Ca
• causes release (depletion) of substance P n.t. from afferent and spinal neurons
• relieves neuropathic pain (shingles, herpes)
• cases severe pain 1st day then pain free for 7 days