Go To Respiratory Pharmacology Page 1
METHYLXANTHINES
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:
-Neutrophils
-Eosiniphils
-Basophils
-Mast cells
Actions:
-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
Methylxanthines
Examples:
Caffeine (1,3,7-trimethyxanthine)
Marked CNS effects
Central Nervous System Stimulant
Nonamphetamine
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)
Pharmacodynamics/Kinetics:
Distribution: Vd:
Neonates: 0.8-0.9 L/kg
Adults: 0.5-0.7 L/kg
Protein binding: 17%
Half-life:
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
-Choledyl
-Diphylline
-Lufyllin
Several trials have shown no benefit by adding theophylline to the concurrent
use of:
-Beta-2-agonists
-Corticosteroids
Bronchodilator
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
Pharmacodynamics/Kinetics:
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:
-Halothane
-Catacholamine induced dysrythmias
-Ketamine
-Extensor-type seizures
-Verapamil
-Verapamil usage may lead to ¯
theophylline levels
-Barbiturates
-Long term use of barbiturates leads to
hepatic metabolism of theophylline
ANTICHOLINERGICS
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
Bronchodilators
Block vagal cholinergic tone (contraction) of airway smooth
muscle
Good in elederly and neonates
Atropine
airway caliber…lasts up to 5
hours
Blocks the formation of c-GMP
2,000 year usage
Side effects:
-dry mouth
-tachycardia
-urinary retention
-agitation
-loss of visual accomodation
- viscosity of
secretions
Anticholinergic Agent
Anticholinergic Agent, Ophthalmic
Antispasmodic Agent, Gastrointestinal
Bronchodilator
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
Pharmacodynamics/Kinetics:
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
urine
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)
Pharmacodynamics/Kinetics:
Oral:
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
Urine
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
Bronchodilator
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
Emphysema
Mechanism of action:
Blocks the action of acetylcholine at parasympathetic sites in bronchial
smooth muscle causing bronchodilation
Pharmacodynamics/Kinetics:
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)
CORTICOSTEROIDS
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:
-Up-regulates
-Poteniates and enhances the effects of b
2-agonists
Reduces:
-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)
Hydrocortisone
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
Pharmacodynamics/Kinetics:
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
hypokalemia
Methyprednisolone
Prednisolone
Prednisone (Prelone, Pediapred)
Triamcinolone acetonide (Azmacort, Nasacort)
NON-STEROIDALS…CROMONES
Non-steroidal Anti-inflammatory Agents:
Cromolyn sodium (Intal)
not used in OR
No toxic effects:
-Stabilizes mast cells. Minimizes release
of:
Histamine
Leukotrienes
-Inhibits inflammatory responses in:
Macrophages
Neutrophils
Eosinophils
-Reduces esoinophil influx into the airway
-Reduces microvascular permeability
Disadvantages:
Metered dose inhaler is less effective than
nebulized cromolyn, theophylline,
or inhaled steroids
Expensive…$700.00/year
¯ 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
NEW STUFF
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
BAD GUYS
-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
Anti-Leukotrienes…Examples:
Pranlukast
-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
Examples:
Interferon-g
-Acts on the TH2
lymphocyte inflammation reaction
Cytokine blockers
-Interfere with
Interlukin-4 (an inflammatory agent)
-Also serves to dampen the
TH2 lymphocyte response
Antibodies
-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
Succinylcholine
Morphine
Meperidine
Thiopental
Bronchoconstrictor
Contrast Media
Mannitol
Protamine
Non histamine releasers
Sufentanil
Alfentanil
Fentanyl
Remifentanil
Propofol
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
Heliux/Oxygen mixture:
-Reduces:
Resistance to gas flow
Gas density
Turbulent flow
-Increases:
Lung ventilation
-Therapeutic within 1 hour of usage
Ketorolac
Use with caution in asthmatics who bronchoconstrict with aspirin
(cross-sensitivity)
Avoid in NSAID-sensitive patients
Ketamine
Good bronchodilator
May increase secretions
Prevents increases in airway resistance…sympathomimetic agent
Lidocaine
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
Halothane
-once the preferred agent
Sevoflurane
-gaining acceptability
Isoflurane
-irritating
Enflurane
-irritating
Desflurane
-irritating
-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
Laryngospasm/Bronchospasm
Usually in child – may not be deep enough
Deepen the anesthetic:
-IV meds
-Inhalants
CPAP
Beta agonists, epinephrine…Steroids, etc.
Intubation in acute situations
Try intensive bronchodilator therapy
Progressive exhaustion…real possibility
Life saving in certain instances
Go To Respiratory Pharmacology Page 1
Last Updated 04/10/00 12:26:58 PM
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