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Pharmacology II
Respiratory Pharmacology
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Now 3rd line of defense
Good absorption from GI tract
Mild respiratory stimulants/weak bronchodilators
Improve ciliary action
Block micro vascular permeability
Good in preventing asthma

Biochemical actions of Methlxantines
   Prostaglandin antagonism
   Stimulation of catecholamine release
   Antagonizes adenosine receptors
      -promotes relaxation of airway smooth muscles
   Enhances histamine release
   Attenuates the late response to allergens
   Control inflammation…reduces the release of mediators from:
      -Mast cells
      -inhibit phosphodiesterases
         Results in higher levels of c-AMP
   Phosphodiesterase inhibitors ® ­ c-AMP ® Bronchodilation

Methylxanthines vs b -agonists
   Slower onset
   Lower peak effect
   Less suitable for acute therapy

   Caffeine (1,3,7-trimethyxanthine)
      Marked CNS effects
   Central Nervous System Stimulant
   Respiratory stimulant

   Use: Central nervous system stimulant; used in treatment of idiopathic apnea of prematurity
   Mechanism of action: Increases levels of cyclic-AMP by inhibiting phosphodiesterase; methyl
      xanthine, CNS stimulant which increases medullary respiratory center sensitivity to
      carbon dioxide, stimulates central inspiratory drive, and improves skeletal muscle
      contraction (diaphragmatic contractility)
      Distribution: Vd:
         Neonates: 0.8-0.9 L/kg
         Adults: 0.5-0.7 L/kg
      Protein binding: 17%
         Neonates: 600-100 hours
         Adults: 3-6 hours
      Time to peak serum concentration: Oral: Within 1-1.5 hours
   Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 145
   Drug interactions: CYP1A2, 2E1, and 3A3/4 enzyme substrate
      May antagonize the cardiovascular effects of adensosine
      Increased effects/levels of caffeine: Cimetidine, oral contraceptives, disulfiram,
         phenylpropanolamine, quinolones
      Increased effects/levels of theophylline, beta-agonists (increased positive inotropic
         And chronotropic effects)

Theobromine (3,7-dimethylxanthine)
   -Found in tea, chocolate and cocoa

Theophylline (1,3-dimethylxanthine)
Theo-dur, Slo-phylline, Aerolate, Asbron, Marax, Quadrinal, Quibron, Respbid, Slo-bid, T-phyl,
Theo-24, Theo-dur, Theolair, Theo-x, Uniphyl, Uni-dur
   -Oxtriphylline-a choline salt of theophylline

Several trials have shown no benefit by adding theophylline to the concurrent use of:

Theophylline dervivative

Use: Bronchodilator in reversible airway obstruction due to asthma, chronic bronchitis, and emphysema;
   For neonatal apnea/bradycardia
Mechanism of action: Causes bronchodilation, diuresis, CNS and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenine
Monophosphate (cAMP) which in turn promotes catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis and induces release of epinephrine from adrenal medulla cells
Absorption: Oral: 100% of a dose is absorbed, depending upon the formulation used
   Distribution: Vd: 0.45 L/kg; distributes into breast milk (approximates serum concentration);
      crosses the placenta
   Metabolism: In the liver by demethylation and oxidation
   Half-life: Highly variable and dependent upon age, liver function, cardiac function, lung disease,
      and smoking history
Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 922-925
Adverse reactions: See table Anesthesiology & Critical Care Drug Handbook, pg. 926
Drug interactions: Cytochrome P-450 1A2 enzyme substrate and cytochrome P-450 2E enzyme
   substrate (minor)
   Decreased effect/increased toxicity: Changes indiet may affect the elimination of theophylline;
      Charcol-broiled foods may increase elimination, reducing half-life by 50%
         See Anesthesiology & Critical Care Drug Handbook, pg. 927

Theophylline usage with:
      -Catacholamine induced dysrythmias
      -Extensor-type seizures
      -Verapamil usage may lead to ¯ theophylline levels
      -Long term use of barbiturates leads to ­ hepatic metabolism of theophylline

Anticholinergics in acute asthma:
   The Parasymatholitics
   The Muscarinic antagonists
   The Anti-muscarinics

Muscarinic receptor stimulation ® ­ c-GMP ® ­ bronchoconstriction and ­ secretions

Also useful in COPD:
   Inhibit and antagonize the effects of Acetylcholine at the muscarinic receptors
   Somewhat less potent than b 2-agonists in reversing asthmatic bronchospasm
   Block vagal cholinergic tone (contraction) of airway smooth muscle
   Good in elederly and neonates

   ­ airway caliber…lasts up to 5 hours
   Blocks the formation of c-GMP
   2,000 year usage

   Side effects:
      -dry mouth
      -urinary retention
      -loss of visual accomodation
      -­ viscosity of secretions

   Anticholinergic Agent
   Anticholinergic Agent, Ophthalmic
   Antispasmodic Agent, Gastrointestinal
   Ophthalmic Agent, Mydriatic

   Use: Preoperative medication to inhibit salivation and secetions; treatment of sinus bradycardia;
      management of peptic ulcer; treatment of exercise-induced bronchospasm; atidote for
      organophosphate pesticide poisioning; produce mydriasis and cycloplegia for
      examination of the retina and optic disc and accurate measurement of refractive
      errors; uveitis
   Mechanism of action: Blocks the action of acetylcholine at parasympathetic sites in smooth
      smooth muscle, secretory glands and the CNS; increases cardiac output, dries
      secretions, antagonizes histamine and serotonin
      Onset of action:
         IV: 2-4 minutes
         IM: 30 minutes
      Absorption: Well absorbed from all dosage forms
      Distribution: Widely distributes throughout the body; crosses the placenta; trace
         amounts appear in breast milk; crosses the blood-brain barrier
      Metabolism: In the liver
      Half-life: 2-3 hours
      Elimination: Both metabolites and unchanged drug (30% to 50%) are excreted in to
   Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 103
   Adverse reactions: > 10%
      Dermatologic: Dry, hot skin
      Gastrointestinal: Impaired GI motility, constipation, xerostomia
      Local: Irritation at injection site
      Respiratory: Dry nose, throat
      Miscellaneous: Diaphoresis (decreased)
   Drug interactions:
      Antacids (decreased absorption)
      Increased risk of adverse anticholinergic effects with concomitant administration of
         Phenothiazines, amantadine, antiparkinsonian drugs, glutethimide, meperidine,
         Tricyclic antidepressants, antiarrhythmic agents with anticholinergic activity
         (eg, disopyramide, quinidine, procainamide), select antihistamines, and
         other anticholinergic agents; antipsychotic effectiveness of phenothiazines
         may be decreased; may alter response to beta-adrenergic blockers

   Glycopyrrolate (Robinul)
   Anticholinergic Agent
   Antispasmodic Agent, Gastrointestinal

   Use: Adjunct in treatment of peptic ulcer disease; inhibit salivation and excessive secretions of the
      respiratory tract preoperatively; reversal of neuromuscular blockade; control of upper
      airway secretions
   Mechanism of action: Blocks the action of acetylcholine at parasympathetic sites in smooth
      Muscle, secretory glands, and the CNS (minimal CNS penetration)
         Onset of action: Within 50 minutes
         Peak effect: Within 1 hour
      IM: Onset of action: 15-30 minutes
      IV: Onset of action: 1 minute
      Absorption: Oral: poor and erractic
      Bioavailability: ~ 10%
      Elimination: Excreted mainly as unchanged drug in feces via biliary elimination and in
   Usual dosage: See Anesthesiology & Critical Care Drug Handbook, pg. 433
      Children and Adults: Neuromuscular blockade:Reversal: Block adverse muscarinic
         effects of anticholinesterase agents:
            IV: 0.2 mg for each 1 mg of neostigmine or 5 mg of pyriodostigmine
               Administered or 5-15 mcg/kg of gylcopyrrolate with
               25-70 mcg/kg of neostigmine or 0.1-0.3 mg/kg of
               pyridostigmine (agents usually administered simultaneously
               but glycopyrrolate may be administered first if bradycardia
               is present)
   Adverse reactions: See Atropine
   Drug interactions: See Atropine

   Ipratroprium bromide (Atrovent)
   Anticholinergic Agent

   Quartenary ammonium compound…preferred agent of this group…selective…few side effects
   Doesn’t readily enter the CNS
   Good for the maintenance phase, not for the acute situation
   Action is directed at the large central airways

   Use: Anticholinergic bronchodilator in bronchospasm associated with COPD, bronchitis, and
   Mechanism of action: Blocks the action of acetylcholine at parasympathetic sites in bronchial
      smooth muscle causing bronchodilation
      Onset of bronchodilation: 1-3 minutes after administration
      Peak effect: Within 1.5-2 hours
      Duration of action: Up to 4-6 hours
      Absorption: Not readily absorbed into systemic circulation from the surface of the
         Lung or from the GI tract
      Distribution: Inhalation: 15% of dose reaches the lower airways
   Usual dosage: See Anesthesiology and Critical Care Drug Handbook, pg. 496
   Adverse reactions: Poorly absorbed from the lung, so systemic effects are rare
   Drug interactions: Drug interactions with systemically administered drugs not likely because
      of the limited systemic absorption and low plasma drug concentrations seen with oral
      inhaled administration
      Increased effect with orally inhaled albuterol
      Potential for increased toxcity with anticholinergics or drugs with anticholinergic
         Properties (eg, dronabinol)

The most potent anti-inflammatory agents currently available for the treatment of asthma
Inhibit or modify the inflammatory response
   -suppress most steps of the inflammatory cascade
b 2-adrenergic receptors:
   -Poteniates and enhances the effects of b 2-agonists
   -The degree of recruitment and activation of inflammatory cells
   -Mediator release
   -Micro vascular…capillary permeability
   -Mucous production
   -Irritability and hyper-responsiveness
Other corticosteroid actions
   Has no effect on relaxing airway smooth muscles. Possibly widens airway caliber after
      prolonged use
      -6-12 hours needed for airway improvement
      -1 week needed for maximal improvement
Prevents the late asthmatic response
Essential component:
   -Failure to administer, has been cited and implicated in deaths, from acute asthma
Corticosteroid side effects of concern:
   -dermal fragility
   -Osteoporosis (demineralization)
   -Adrenal supression:
      ? supplement during surgery
   -Thrush…hoarseness…use spacer

Corticosteroid (examples)
Beclomethasone (Beclovent, Beconase, Vanceril, Vancerase)
Budenoside (Rhinacort, Pulmicort)
Dexamethasone (Respihaler, Decadron, Dexacort, Turbinaire)
Flunisolide (Aerobid)
   Bad taste
Fluticasone propionate (Flovent)
Adrenal Corticosteroid
Anti-inflammatory Agent
Corticosteroid, rectal
Corticosteroid, systemic
Corticosteroid, topical (low/medium potency)

Use: Management of adrenocortical insufficiency; relief of inflammation of corticosteroid-responsive
   dermatoses (low and medium potency topical corticosteroid); adjunctive treatment of
   ulcerative colitis
Mechanism of action: Decreases inflammation by suppression of migration of polymorphonuclear
   Leukocytes and reversal of increased capillary permeability
   Absorption: Rapid by all routes, except rectally
   Metabolism: In the liver
   Half-life, biologic: 8-12 hours
   Elimination: Renally, mainly as 17-hydroxysteroids and 17-ketosteroids
Usual dosage: See Anesthesiology and Critical Care Drug Handbook, pg. 462
Adverse reactions: See Anesthesiology and Critical Care Drug Handbook, pg. 463
Drug interactions: CYP2D6 and 3A3/4 enzyme substrate
   Decreased effect:
      Insulin decreased with hypoglycemic effect
      Phenytoin, phenobarbital, ephedrine, and rifampin increase metabolism of hydrocortisone
         and decreases steroid blood level
   Increased toxcity:
      Oral anticoagulants change prothrombin time; potassium depleting diuretics increase risk
         Of hypokalemia
      Cardiac glucosides increase risk of arrthymias or digitalis toxcity secondary to
(Prelone, Pediapred)
Triamcinolone acetonide (Azmacort, Nasacort)

Non-steroidal Anti-inflammatory Agents:
Cromolyn sodium (Intal)
not used in OR
   No toxic effects:
      -Stabilizes mast cells. Minimizes release of:
      -Inhibits inflammatory responses in:
      -Reduces esoinophil influx into the airway
      -Reduces microvascular permeability
      Metered dose inhaler is less effective than nebulized cromolyn, theophylline,
         or inhaled steroids
      ¯ effective than albuterol in exercise –induced situation

Nedocromil sosdium (Tilade)
Anti-inflammatory…mast cell stabilizer
New derivative of Cromolyn
-offers better anti-asthmatic protection
-Ineffective at reversing bronchospasm…must be used in advance
-Bad taste
It’s use is prophylactic, mostly in children
May inhibit phosphodiesterase, thereby lead to increasing intracellular c-AMP
Both offer:
   -Outstanding safety records
   -No direct bronchodilating actions
   -Mechanism of action…not well understood
   -Protection against:
      Mediator release
      The early and late bronchoconstriction
      Airway hyper-responsiveness

Leukotriene research:
   Focusing on:
      -inhibiting leukotriene synthesis
      -blocking leukotiene action by using receptor antagonists. This approach diminishes
         the symptoms of inflammatory airway disease
Leukotrienes-1,000 times more potent than histamine
   Implicated with upper and lower lung inflammation…early and late allergic response
      -Increased mucous production
      -Eosinophil influx into the lung
         Disrupts airway epithelium
      -Smooth muscle hypertrophy
      -Airway edema
      -Activation of Mast cells and Eosinophils during anaphylaxis ® Leukotriene synthesis
         Four types:
         -C4 (LTC4)…potent bronchoconstrictor…more so than histamine…slow onset
            …10 minutes
         -D4 (LTD4)…potent bronchoconstrictor…rapid onset…2-7 minutes
         -E4 (LTE4)…recruits esoinophils into the airway… "self perpetuator"
         -B4…prolongs bronchoconstriction

         -The first marketed leukotriene receptor antagonist
      Zafirlukast (Accolate)
         -A receptor antagonist
      Zileuton (Zyflo)
         -An enzyme inhibitor which interferes with leukotriene synthesis
      Montelukast (Singulair)
      Pulmozyme (Dornase alfa)
         -Recombinant DNA preparation

   Mediator blockade:
   Approach attempts to block inflammation at certain points along the response path
         -Acts on the TH2 lymphocyte inflammation reaction
      Cytokine blockers
         -Interfere with Interlukin-4 (an inflammatory agent)
         -Also serves to dampen the TH2 lymphocyte response
-interfere with the intracellular adhesion molecule (ICAM-1)
(ICAM-1 activates eosinophils and encourages their migration to the lung’s
   endothelial surface where they adhere)

   Other areas of research:
      -Neuropeptide inteference
         To diminish anti-inflammatory reaction
      -H1-receptor antagonism
      -Bradykinin inhibitors
      -Methotrexate therapy…as an anti-inflammatory…to reduce steroid use

Anesthesia Management
   MAC or regional preferred
   Continued bronchodilators and Steroids up to induction
   Mask vs LMA vs intubation
      -Keep the ET tube away from carina!!!
      -Havepatient’s inhalers nearby
   Goal is to depress airway reflexes to prevent bronchoconstriction or laryngospasm

Histamine releasers
D-tubocurarine (Curare)
Metocurine (Metubine)
   Synergistic with Pavulon
Atracurium (Tracrium)
   ? Bronchospasm inducer
   Could be tougher to reverse
Contrast Media

Non histamine releasers
   Mild bronchodilator
   -Diprivan vs Generic (sulfites)
Methohexital (Brevital)

Magnesium sulfate in Acute Asthma
Bronchodilator…< Albuterol
Blocks smooth muscle contraction
Role in acute situation is controversial
Blood levels need watching

Heliux/Oxygen mixture:
      Resistance to gas flow
      Gas density
      Turbulent flow
      Lung ventilation
   -Therapeutic within 1 hour of usage

Use with caution in asthmatics who bronchoconstrict with aspirin (cross-sensitivity)
Avoid in NSAID-sensitive patients

Good bronchodilator
May increase secretions
Prevents increases in airway resistance…sympathomimetic agent

Good for smokers too!
1 to 1.5 mg/kg before intubation
4% LTA
   -provides topical anesthesia
   -tests anesthetic depth before intense airway instrumentation
   -transtracheal for bronchoscope use or for awake visualization of the vocal cords

Inhalation agents
All good bronchodilators…some more irritating
   -once the preferred agent
   -gaining acceptability
   -breath holding

Reactive airway: Induction and Maintenance of Anesthesia
Intravenous induction
Intravenous lidocaine (induction/emergence)
Oral airway (lidocaine ointment)
Oral lidocaine spray
Establish sufficient depth of anesthesia
Relaxant-non histamine releaser
Ventilation (1:2.5 to 1:3)
Consider deep extubation

Usually in child – may not be deep enough
Deepen the anesthetic:
   -IV meds
Beta agonists, epinephrine…Steroids, etc.

Intubation in acute situations
Try intensive bronchodilator therapy
Progressive exhaustion…real possibility
Life saving in certain instances

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Last Updated 04/10/00 12:26:58 PM
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