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3 locations where the autocoid histamine are present at high levels:
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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
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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
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Histamine receptors: H2 Activation
- increase gastric acid secretion = increase GI ulcers
- increased SA nodal rate, + inotropism & automaticity
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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
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Antihistamine: H1 Antagonists: 1st generation
- Drugs: diphenhydramine, dimenhydrinate, chlorpheniramine, meclizine
- Clinical uses: allergy, motion sickess, sleep aid, n/v in pregnancy (meclizine)
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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
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GI Drugs: PUD**:H2 Antagonists
PUD tx is ON THE EXAM
Drugs: Cimeti dine, raniti dine, famoti dine, nizati dine
(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
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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
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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
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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!
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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
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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
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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
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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
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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
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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
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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)
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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
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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)
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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
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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
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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
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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
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Migraine Drugs: Others:
- Analgesics: ASA (+/- caffeine, or butabarbital), other NSAIDs, acetaminophen (+- caffeine), oral/injectable opioid-analgesics, butorphanol (spray)
- Prophylazis: propranolol, verapamil, amitriptyline, valproic acid
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Ergonovine
- Mechanism: uterine smooth muscle contraction
- Use: intramuscularly after placental delivery
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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)
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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)
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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
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Comparison of OTC Analgesics
- Acetaminophen = NSAID w/o anti-inflammtory activity
- Aspirin = NSAID w/ antiplatelet activity
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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
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**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
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Microtubule Inhibitors:
- Phase: M phase
- Drugs:
- Griseofulvin (antifungal)
- Cochicine
- Vincrisine (cancer Rx)
- Vinblastin (cancer Rx)
- Paclitaxel (cant break down the spindle
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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
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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
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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
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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
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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
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TNF-Alpha Inhibitors: Adalimumab
- Mechanism: directly binds TNF-alpha receptor sites
- Clinical use: rheumatoid arthritis, psoriasis, anklyosing spondylitis
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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
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DMARD: Methotrexate **
- Mechanism: cytotoxic to lymphocytes
- side effects: hematotoxicity due to inhibition of DHF reductase
- Clinical use: moderate-severe RA
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DMARD: Sulfasalazine
- Mechanism: sulfapyridine = decreased B cell functions; 5-ASA possibly inhibits COZ
- Side effects: hemolysis in G6P Deficiency
- Clinical use:
mild RA
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DMARD: Etanercept
- Mechanism: binds TNF; recombinant form of TNF receptor
- Side effects: infection
- Clinical use: moderate-severe RA
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DMARD: Infilximab
- Mechanism: monoclonal antibody to TNF
- Side effects: infection
- Clinical use: moderate-severe TNF
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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
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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
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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
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To minimize steroidal toxicity:
- 1. Alternate-day therapy
- 2. Dose-tapering to avoid cortical suppression
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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
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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
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Asthma Drug: Non-specific Beta Agonist
- Drug: Isoproterenol
- Mechanism: relaxes bronchial smooth muscle (B2)
- Side effect: tachycardia (B1)
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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
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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
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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
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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
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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
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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
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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
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