Inflammatory & Related Disorders Pharm

  1. 3 locations where the autocoid histamine are present at high levels:
    • Lungs
    • Skin
    • GI tract
  2. Info about histamine
    • Autocoid, released from mast cells & basophils by type I hypersensitivity rxns, drugs, venom, trauma
    • Histamine receptors: serpentine family, 7 transmembrane spanning domains with G protien coupled receptors w/ 2nd messagners
  3. Histamine receptors: H1 Activation:
    • capillary dilation = via NO = decreased BP
    • increased capillary permeability
    • increased bronchiolar SM contraction (IP3, DAG)
    • increased activation of peripheral nociceptors: increased pain and pruritis
    • decreased AV nodal conduction
  4. Histamine receptors: H2 Activation
    • increase gastric acid secretion = increase GI ulcers
    • increased SA nodal rate, + inotropism & automaticity
  5. Antihistamine: H1 Antagonists: General
    • Mechanism: competitive antagonist of histamine (may be ineffective @ hi levels of histamine)
    • Metabolism: hepatic, and can cross the placental barrier, various PK and PD
  6. Antihistamine: H1 Antagonists: 1st generation
    • Drugs: diphenhydramine, dimenhydrinate, chlorpheniramine, meclizine
    • Clinical uses: allergy, motion sickess, sleep aid, n/v in pregnancy (meclizine)
  7. Antihistamine: H1 Antagonists: 2nd Generation **
    • Drugs: Loratidine, fexofenadine, desloritadine, cetrizine
    • Clinical use: allergy
    • Toxicity: far less sedating than 1st gen. bc less CNS entry, no muscarinic block either
  8. GI Drugs: PUD**:H2 Antagonists
    PUD tx is ON THE EXAM
    Drugs: Cimetidine, ranitidine, famotidine, nizatidine

    (take H2 blockers before you DINE, thing "table for 2" to remember H2

    • Mechanism: reversible block of H2 receptors = decreased H+ secretion by parietal cells
    • Clinical use: peptic ulcer, gastritis, mild esophageal reflux
    • Toxicity: Cimetidine, potent P450 inhibitor, antiandrogenic effects (PRL release, gynecomastia, impotence, decreased libido in males), crosses BBB (confusion, headaches, dizziness), and placenta
    • Cimetidine & Ranitidine - decrease renal excretion of creatinine
    • other H2 blockers are free of these effects
  9. GI Drugs: PUD: PPI
    • Drugs: Omeprazole, '-prazoles'
    • Mechanism: irreversible, direct inhibitors of the K/H+ antiport pump in gastric parietal cell
    • Clinical Use: peptic ulcer, gastritis, peptic ulcer, esophageal reflux, ZES, erradiation regimine of h. pylori
  10. GI Drugs: PUD: Misoprostol
    • Mechanism: PGE1 analogue, increases production and secretion of gastric mucous barrier, decreases acid secretion, increased bicarb secretion
    • Clinical use: prevention of NSAID-induced peptic uclcers, maintenance of patency of ductus arteriosis, induce labour
    • Toxicity: diarrhea, abortifactant
  11. GI Drugs: PUD: Sucralfate/Bismuth
    • Mechanism: binds to ulcer base, physical protection, allow bicarb secretion to reestablish pH gradient in mucous layer
    • Clinical use: ulcer healing, traveler's diarrhea

    • Triple Therapy of h. pylori ulcers:
    • 1. Metronidazole
    • 2. Amoxicillin (or Tetracycline)
    • 3. Bismuth
    • can also use a PPI:

    Please MAke Tummy Better!
  12. GI Drugs: Antacids: Aluminum hydroxide, Mg Hydroxide, Ca Carbonate
    • Mechanism: can affect absorption, bioavailability, or urinary excertion of other drugs by latering gastric and urinary pH or delaying gastric emptying
    • Overuse causes:
    • Aluminum Hydroxide: constipation, hypophosphatemia; proximal muscle weakness, osteodystrophy, seizures (aluminimum amount in the feces)
    • Magnesium Hydroxide: diarrhea, hyporeflexia, hypotension, cardiac arrest (Mg = must go to the bathroom)
    • Calcium Carbonate: hypercalcemia, rebound acid (can chelate and decrease effectiveness of other drugs - like tetracycline)
    • all cause hypokalemia
  13. GI Drugs: PUD: Muscarinic Antagonists
    • Drugs: piprenizine, propatntheline
    • mechanism: block M1 receptors of the ECL cell (decreases histamine secretion) and M3 receptors on parietal cell (decreases H secretion)
    • Clinical use: PUD (rarely)
    • Toxicity: tachycardia, dry mouth, difficulty focusing eyes
  14. GI Drugs:Infliximab
    • Mechanism: monoclonal antibody to TNF, proinflammatory cytokine
    • Clinical use: Crohn's disease, RA
    • Toxicity: respiratory infection (including reactivation of latent TB), fever hypotension

    INFLIXimab INFLIX pain on the TNF
  15. GI Drugs: Sulfasalazine
    • Mechanism: combo of sulfapyridine (antibacterial) and 5-aminosalicylic acid (anti-inflammatory), activated by colonic bacteria
    • Clinical use: ulcerative colitis, Crohn's disease
  16. GI Drugs: Metoclopramide
    • Mechanism: D2 receptor antagonist, increases resting tone, contractility, LES tone, motility, does no influence colon transport time
    • Clinical use: diabetic and post-surgical gastroparesis
    • Toxicity: increases parkinsonian effects, restlessness, drowsiness, fatigue, depression, nausea, diarrhea, drug interaction with digoxin and diabetic agetns, contraindicated in pts with small bowel obstruction
  17. GI Drugs: Serotonin Action: Ondansetron
    • Mechanism: 5-HT3 antagonist, powerful central-acting antiemetic
    • Clinical use: control vomiting postoperatively and chemo-induced vomiting
    • Toxicity: headache, constipation

    You will not vomit with ONDANSetron, so you can go ON DANCing
  18. GI Drugs:Antiemetics
    • Drugs:
    • 5HT3 antagonist Ondansetrone, graniestron
    • DA antagonist: prochlorperazine, metoclopramide (+ GI motility)
    • H1 antagonist: diphenhydramine, meclizine, promethazine
    • Muscarinic antagonist: scopolamine (vomiting centre)
    • Cannabinoids: dronabinol
    • NK1-receptor antaonst: aprepitant (NK1 is a receptor for substance P)
  19. Serotonin General Info
    • Autocoid made and stored in GI cells, neurons, platelets
    • Metabolized: MAOA
    • Metabolite: 5HIAA = marker for carcinoid
    • All are G-protein coupled except for 5HT3, which is directly coupled to an ion channel
  20. 5HT1 Serotonin Receptor
    • Location: CNS (usually inhibitory), smooth muscle (excitatory or inhibitory)
    • Drugs: Busprione (partial 5HT1a agonist = anxiolytic), Sumatriptan (5HT1d agonist = on cerebral blood vessels to decrease migrain pain, may cause asthenia, chest/throat pressure/pain)
  21. 5HT2 Serotonin Receptor
    • Location: CNS (excitatory)
    • Activation in periphery = VD, contraction of GI/bronchial, uterine smooth muscle, platelet aggregation
    • Drugs:
    • Olanzapine & atypical antipsychotics are 5HT2a antagonist = decrease sxs of psychosis
    • Cyprohepatidine antagonist used in carcinoid, GI tumours, postgastrectomy, anorexia nervosa, marked action in seasonal allergies
  22. 5HT3 Serotonin Receptor
    • Location: area postrema (medullary centre that controls vomiting), peripheraly snesory and enteric nerves
    • Mechanism: activation opens ion channels (no 2nd messangers)
    • Drugs: ondansetron & other '-setrons'
    • Antagonists = decrease emesis in chemo/radiation/postop
  23. Migrane Drugs: Ergot Alkaloids
    • Drug: Ergotamine
    • Mechanism: partial agonist at alpha and 5HT2 receptos in vasculature and in CNS, VC = decrease pulsation in cerebral vessels during a migraine attack
    • Clinical use: acute migraine attacks
  24. Migraine Drugs: -triptans
    • Drug: sumatriptan
    • Mechanism: 5HT1b/d receptor agonist, causes VC, inhibition of trigeminal activation and vasoactive peptide release, half life < 2 hours
    • Clinical use: acute migraine, cluster headache attacks
    • Toxicity: coronary vasospasm (contraindicated in pts with CAD or Prinzmetal's angina), mild tingling

    a SUMo wrestler TRIPs ANd falls on your head
  25. Migraine Drugs: Others:
    • Analgesics: ASA (+/- caffeine, or butabarbital), other NSAIDs, acetaminophen (+- caffeine), oral/injectable opioid-analgesics, butorphanol (spray)
    • Prophylazis: propranolol, verapamil, amitriptyline, valproic acid
  26. Ergonovine
    • Mechanism: uterine smooth muscle contraction
    • Use: intramuscularly after placental delivery
  27. Arachidonic Acid Products
    Phospholipase A2 takes the lipid membrane to form arachidonic acid that goes down Lipoxygenase or Cyclooxygenase (COX1/COX2)

    • Lipoxygenase pathway --> leukotrienes
    • COX pathway --> prostacyclin, prostaglandins, thromboxane A2

    see page 387 in FA for diagram
  28. What are ecosanoids, where are they found, and how do they work?
    • Ecosanoids: are cell-regulating polyunsaturated fatty acids that are made from arachidonic acid and released by the action of phospholipase A2 from lipid cell membranes (see p. 387 in FA for diagram)
    • Location: low concentration in most cells, but made and released 'on demand' in response to stimuli: IgE-mediated reactions, inflammatory mediators, trauma, heat, toxins
    • Ecosanoids interact w/ G-protein coupled receptors that have 2nd messangers
  29. Leukotrienes (LTs)
    • Formed via hyroperoxides, from the action of lipoxygenase on arachadonic acid
    • LTB4: inflammatory mediator = neutrophil chemoattractant that activates PMNs = increases free radical formation = cell damage
    • LTA4, LTC4, LTD4: anaphylaxis & bronchoconstriction
    • LT are 'targets' for:
    • 1. Glucocorticoids = decrease phospholipase A2 activity = antiinflammatory and immunosuppresive action
    • 2. Zileuton = inhibits lipoxyenase = decreases LT asthma tx
    • 3. Zafirlukast = LT receptor antagonists asthma tx
  30. Prostaglandins
    • Formation: endoperoxides from COX
    • COX1 = constitutive (housekeeping), expressed in most tissues, including platelets & stomach, where it makes thromboxane and cytoprotective PGs
    • COX2 = expressed in brain and kidney, and sites of infection....constitutive in the kidney
  31. Types of PGs:
    • PGE1: Misoprostol (analogue) - tx of NSAID-induced ulcers Alprostadil (analogue)- maintains PDA patency (PDA can be closed by indomethicin), VD (male impotence)CONTRAINDICATED IN PREGNANCY; unless used as abortifacient (misoprostol + mifepristone)
    • PGE2: Dinoprostone: urterine smooth muscle contraction, cervical ripeningPGE2alpha: Carboprost (aborticacient), Lantanoprost (glaucoma tx - decreaese IOP), urterine and bronchiolar smooth muscle contraction
    • PGI2 (Prostacyclin): epoprostenol, platelet stabilizer, VD, use: pulmonary htn
    • Mechanism: stimulation of adenylyl cyclase = increased cAMP = increase internal Ca pumps = decreased free Ca = platelet stabilization
    • PGE2 PGF2alpha: increase in primary dysmenorrhea, therapeutic effects of NSAIDS may be due to inhibition of their synthesis
  32. Thromboxanes (TXAs)
    • TXA2: platelet aggregator - inhibition of synthesis underlyies protective roel of ASA post-MI
    • Mechanism: Activation of TXA2 receptor = stimulation of PLC = increased PIP2 hydrolysis = increased IP3 = increase Free Ca = platelet aggregation
  33. Aspirin
    • Mechansim: irreversibly inhibits COX by covalent binding, that decreases the synthesis of thromboxane & PG
    • Clinical use: low dose (<300mg/day) = decreased platelet aggregation, int dose (300 -2400 mg/day) =antipyretic and analgesic, high does (2400 - 4000 mg/day) = anti-inflammatory
    • Toxicity: GI upset, Salicylism (verticog, decreased hearing), hypersensitivity: "triad" of asthma, nasal polyps, rhinits, bronchoconstriction, increased bleeding time chronic use = renal failure, interstitial nephritis, upper GI bleed, Reye's syndrome (in children post-viral hepatoencephalopathy), Low/mod doses: hyperuricemia, hi doses: uricosuria
    • Drug interactions: ethanol (GI bleeding), OSUs & warfarin (greater effects), urocosurics (decreased effects)
  34. Aspirin OD and Management
    • Extension of the toxicities described before + vasomoto collapse, respiratory and renal failure
    • Antidote: none in particular
    • Management: gastric lavage (+- gastric charcoal), ventilation, symptomatic management of acid/base elyte imbalances, hydration status = increase urine vol & alkalinize to facilitate salicylate renal elimination
    • Note: ASA has zero order elimination at toxic doses
  35. Aspirin & Acid/Base / Elyte Balance
    • Dose dependent actions:
    • High therapeutic: mild uncoupling of phosphorylation = increased respiration = decreased pCO2 = respiratory alkalosis = renal compensation = increased bicarb elimination = compensated respiratory alkalosis (pH = nl with low bicarb and low pCO2)
    • Toxic doses: inhibits respiratory centre = decreases respiration = increased pCO2 = respiratory acidosis (low pH, low bicarb, normalization of pCO2) + inhibition of Kres cycle & severe uncoupling of oxidative phos (low ATP) = Metabolic acidosis, hyperthermia, hypokalemia
  36. NSAIDs
    • Drugs: Ibuprofen & naproxen (prioprionic acid), indomethicine & ketorolac (acetic acid)
    • Mechanism: reversibly inhibit both COX1 & 2, blocks PG synthesis
    • Clinical use: antipyretic, analgesic, anti-inflammatory, indomethicin used to cose PDA, antiplatelet effects
    • Toxicity: renal damage, fluid retnetion, aplastic anemia, GI distress, ulcers
  37. NSAIDs vs. ASA:
    • Analegesia: ketoralac > ibuprofen/naproxen > ASA
    • GI irritation < ASA
    • minimal effeects on acid-base, no uric acid elimination effects
    • allergy: common, possible cross reactivity with ASA
    • Renal: chronic use can cause nephritis, nephritic syndrome, acute fiailure (decreased PGE2 and PGI2)
  38. COX-2 Inhibitors: Celecoxib
    • Mechanism: reversibly inhibits specifically COX2 that is found in inflammatory cells and vascular endothelium that mediates inflammation and pain: spares COX1 (protects gastric mucosa)
    • Clincal use: rheumatoid and osteoarthritis
    • Toxicity: increased risk of thrombosis, sulfa allergy, less GI mucosa toxicity (lower incidence of ulcers & bleeding), prothrombitic effects via inhibition of endothelial cell function (MI/strokes)
  39. Acetaminophen
    • Mechanism: reversibly inhibits COX (mostly in CNS), inactivated peripherally
    • Clinical use: antipyretic, analgesic, lacks anti-inflammatory properties, used instead of aspirin to prevent Rye's syndrome in children w/ viral infection, safe for asthmatics (no bronchoconstriction)
    • Toxicity: OD = hepatic necrosis (centrilobular necrosis); acetaminophen metabolite deplets glutathione and forms toxic tissue adducts in liver, N-acetylcysteins is antidote - regenerates glutathione
  40. Comparison of OTC Analgesics
    • Acetaminophen = NSAID w/o anti-inflammtory activity
    • Aspirin = NSAID w/ antiplatelet activity
  41. Bisphosphonates
    • Drugs: Etidronate, pamidronate, alendronate, risedronate
    • Mechanism: inhibit osteoclastic activity; reduces formation & resorption of hydroxyapatite
    • Clininical use: Malignancy-associated hypercalcemia, Paget's disease of bone, postmenopausal osteoporosis
    • Toxicity: corrosive esophagitis, nausea, diarrhea
  42. **Gout Drugs**: Colchicine
    • Use: Acute gout
    • Mechanism: binds & stabilizes tubulin to inhibit polymerization, impairing leukocyt chemotaxis & degranulation
    • Toxocity: GI side efects (PO adiminstration), loner use: hematuria, alopecia, myelosuppression, gastritis, peripheral neuropathy

    Note: Indomethicin (NSAID) is less toxic and is also used for acute gout
  43. Microtubule Inhibitors:
    • Phase: M phase
    • Drugs:
    • Griseofulvin (antifungal)
    • Cochicine
    • Vincrisine (cancer Rx)
    • Vinblastin (cancer Rx)
    • Paclitaxel (cant break down the spindle
  44. Gout Drugs: Probenecid
    • Use: chronic gout
    • Mechanism: inhibits the reabsorption of uric acid in PCT, also, inhibits secretion of penicillin and other acidic drugs, but ineffective if GFR < 50mL/min
    • Toxicity: uricosuric agent = could precipitate a uric acid stone if used acutely, ASA may decrease the effects
  45. Gout Drugs: Allopurinol
    • Use: Chronic gout
    • Goal: reduce uric acid pool
    • Mechanism: inhibits xanthine oxidate = decreased the conversion of xanthine to uric acid, tumour lysis-associated urate nephropathy prevention in lymphoma and leukemia, increases azathioprine and 6 mercaptopurine
    • Toxic effects: rash, hypo [xanthine] stones
  46. Things not to do whilst treating gout:
    dont use allopurinol or probenecid for acute gout episode

    Don't give salicyltes, but all the highest doeses depress uric acid clearance, even high doses (5-6 g/day) have minor uricosuric activity
  47. TNF-Alpha Inhibitors: Etanercept
    • Mechanism: recombinant form of human TNF receptor that binds TNF
    • Clinical use: rheumatoid arthritis, psoriasis, ankylosing spondylitis

    EtanerCEPT is a a TNA decoy reCEPTor
  48. TNF-Alpha Inhibitors: Infliximab
    • Mechanism: anti-TNF antibody
    • Clinical use: Crohn's disease, rheumatoid arthritis, ankylosing spondylitis
    • Toxicity: predisposes to infections (reactivation of latent TB)
    • Notes: INFLIXimab INFLIX pain on TNF
  49. TNF-Alpha Inhibitors: Adalimumab
    • Mechanism: directly binds TNF-alpha receptor sites
    • Clinical use: rheumatoid arthritis, psoriasis, anklyosing spondylitis
  50. Antirheumatic Drugs: Disease Modifying Antirheumatic Drugs (DMARDs)

    Hydroxychloroquine + other **
    • Mechansim: stabilizes lysosomes and decreases chemostaxis
    • Side effects: GI distress, visual dysfunction (cinchonism), hemolysis in G6PD deficiency
    • Clinical use: mild RA
  51. DMARD: Methotrexate **
    • Mechanism: cytotoxic to lymphocytes
    • side effects: hematotoxicity due to inhibition of DHF reductase
    • Clinical use: moderate-severe RA
  52. DMARD: Sulfasalazine
    • Mechanism: sulfapyridine = decreased B cell functions; 5-ASA possibly inhibits COZ
    • Side effects: hemolysis in G6P Deficiency
    • Clinical use: mild RA
  53. DMARD: Etanercept
    • Mechanism: binds TNF; recombinant form of TNF receptor
    • Side effects: infection
    • Clinical use: moderate-severe RA
  54. DMARD: Infilximab
    • Mechanism: monoclonal antibody to TNF
    • Side effects: infection
    • Clinical use: moderate-severe TNF
  55. NSAIDs and Rheumatoid Arthritis:
    • may be used in initial treatment of RA
    • need high doses = side effects
    • can decrease pain and swelling but don't help with course of disease or bone deterioration
  56. DMARDs and Rheumatoid Arthritis:
    • slow disease progression
    • can be started at the same time as NSAIDs if sxs are severe bc DMARDs take 2 wks to 6 mo to start working
  57. Glucocorticoids
    • Drugs: hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone
    • Mechanism:
    • Cellular: decrease leukocyte migration, increase lysosomal mb stability = decrease phagocytosis, decrease capillary permeability
    • Biochemical: decreases production of leukotrienes & PGs by inhibitionof phospholipase A2 and expression of COX2, decrease platelet-activating factor, decrease interleukins
    • Clinical use: Addison's, inflammation, immune suppression, asthma
    • Toxicity: Iatrogenic cushings syndrome, suppression of ACTH, hyperglycemia (increased gluconeogenesis = increased insulin demand), osteoporosis (vertebral fx, aseptic hip necrosis), increase GI acid & pepsin release = ulcers, E-lyte imbalance (Na/water retention, edema, htn, hypokalemia, hypocalcemia), decreased skeletal growth in chidlren, decreased: wound healing, increased infections/glaucoma/catarcts (sorbitol), mental dysfn
  58. To minimize steroidal toxicity:
    • 1. Alternate-day therapy
    • 2. Dose-tapering to avoid cortical suppression
  59. Asthma Drugs: General
    mechansims are NB
    • Bronchconstriction is mediated by:
    • 1. inflammatory processees
    • 2. sympathetic tone

    Therapy is directed at these 2 pathways: to reduce bronchial hyperactivity and protect against cellular infiltration

    Aerosolic forms = low potential for sytemic toxicity, but can cause anxiety, muscle tremors, CV toxicity w/ overuse
  60. Asthma Responses:
    Early Response
    Late Response
    Early response: 30 - 60 min, bronchospasm due to release of histamine and leukotrienes

    Late Response: infiltration of eosinophils & lymphocytes into airway = bronchoconstriction, inflammation and mucous plugging
  61. Asthma Drug: Non-specific Beta Agonist
    • Drug: Isoproterenol
    • Mechanism: relaxes bronchial smooth muscle (B2)
    • Side effect: tachycardia (B1)
  62. Asthma Drug: B2-Agonist
    • Drug: Albuterol, metaproterenol, tertbutaline (short acting)
    • Mechanism: relaxes bronchial smooth msucle (B2)
    • Clinical use: acute exacerbation, prophylaxis of exercise-induced astham
  63. Asthma Drug: B2-Agonist
    • Drug: Salmuterol
    • Mechanism: long-lasting agent
    • clinical use: prophylaxis of asthma attacks, decrease nighttime attacks, reduces doses of other meds
    • Side effect: tremor, arrhythmias
  64. Asthma Drug: Methylxanthines
    • Drug: Theophylline
    • Mechanism: (likely) bronchodilatoin by inhibiting phosphodiesterase = decreasing cAMP hydrolysis = higher cAMP levels
    • Metabolism: P450 and blocks action of adenosine (which is a bronchoconstrictor)
    • Clinical use: limited bc of narrow therapeutic index (cardio- and neurotoxicity)
    • Drug interactions: increased toxicity by erythromycin, cimetidine, fluoroquinolones
    • aminophylline: IV, used in bronchospasm or status asthmaticus
  65. Asthma Drug: Muscarinic Antagonist
    • Drug: Ipratropium
    • Mechanism: compettive block of muscarinic receptors = prevention of bronchoconstriction
    • Clinical use: asthma and COPD
    • DOC for bronchospasm caused by B-blockers
    • Toxicity: minor atropine-like effects
  66. Asthma Drug: Cromolyn/Nedocromil
    • Mechanism: prevents release (degrandulation) of mediators from mast cells= less histamine, PAF, LTC4
    • Clinical use: only asthma prophylaxis, not effective during asthma attack
    • Toxicity: rare, some throat irritation / cough which can be relieved by B2 agonist
  67. Asthma Drug: Corticosteroids
    • Drugs: Beclomethasone, prednisone
    • Mechanism: inhibits synthesis of virtually all cytokines, inactivates NF-KappaB (transcription factor that induces the production of TNF-alpha + other inflammatory agents)
    • Clinical use: first line therapy for chronic asthma
    • Surface acting drugs: beclomethasone, fluinsolid = for acute attacks and prophylaxis
  68. Asthma Drug: Antileukotrienes
    usually an adjunct to B-agonist
    • Drug: Zileuton
    • Mechanism: 5-lipoxygenase pathway inhibitor: blocks conversion of arachidonic acid to leukotrienes, rapid onset(1-3 hours), often used as an adjuvant to steroids

    • Drug: Zafirlukast, Monetlukast
    • Mechanism: blocks leukotriene recepors, especially good for ASA-induced asthma, xcise and antigen induces asthma

    • Careful w/ NSAIDs: block the COX pathway, could shunt the substances down the leukotriene pathway and cause bronchoconstriction
Card Set
Inflammatory & Related Disorders Pharm
Inflammatory & Related Disorders Pharm