| Cromolyn
(Intal)&
Nedocromil (Tilade)
- Overview
- must
be used prophylactically
- aerosols
(metered-dose inhalers)
- inhibit:
- antigen-
- exercise-induced
asthma
- bronchial
reactivity
- no
direct effect on airway smooth muscle tone
- will not reverse
asthmatic bronchospasm
return to main menu
- Cromolyn: (Intal)
- poorly
absorbed
- administered
by microfine powder inhalation or aerosol
- absorption:
approximately 10%
- no
bronchodilating activity
- Nedocromil: (Tilade)
- poorly
absorbed; low bioavailability;
- aerosol
form only
return to main menu
return to main menu
- Clinical Use:
- Cromolyn (Intal) pre-treatment:
- blocks
bronchoconstriction due to
antigen inhalation
- blocks
aspirin-induced
bronchoconstriction
- blocks
bronchoconstriction induced by
environmental agents (causes
of occupational asthma):
- toluene
diisocyanate
- wood dusts
- soldering fluxes
- piperazine
hydrochloride
- certain enzymes
- Reduces
bronchodilators medication
requirements and symptomatic
severity in patients with
perennial asthma
- Cromolyn (chronic
treatment) appears to decrease
the bronchial hyperreactivity:
- airway protection against
inflammatory, chemical anaphylaxis
mediators
- more effective in reducing
seasonal increases in bronchial reactivity
(allergic asthma) but less effective when
compared with inhaled corticosteroids.
- Cromolyn
(Intal): -- effective in reducing
symptoms of:
- allergic rhinitis
- hay fever
return
to main menu
- Adverse/Side
effects: cromolyn --
localized effects (sites of
deposition)
- throat
irritation
- cough
- mouth dryness
- wheezing
- chest tightness
- Nedocromil: (Tilade)
- equal potent
to standard doses of
inhaled corticosteroids
(in moderate asthmatics)
- Improved
asthma control: addition
of nedocromil to standard
dosage of inhaled
corticosteroids
return to main menu
Methylxanthines
-- (theophylline: some utility in asthma treatment;
theobromine;caffeine: major sources (tea, cocoa, coffee)
- Chemistry
- theophylline:
1,3-dimethylxanthine
- theobromine: 37
dimethylxanthine
- caffeine:
1,3,7-trimethylxanthine
- Most commonly used
theophylline preparation is aminophylline (theophylline-ethylenediamine complex)
- dyphylline
(synthetic theophylline analog): less
potent; shorter acting
- Metabolic
products:
- demethylated
xanthines (not uric acid)
- excreted in the
urine
return to main menu
- Proposed mechanisms of action: no mechanism has been established to
account for bronchodilation methylxanthine
effects.
- high concentrations (may
not be reached in vivo):
phosphodiesterase inhibition
- results in
increased intracellular cAMP
which may account for:
- cardiac
stimulation
- smooth
muscle relaxation
- inhibition of adenosine
cell surface receptors (modulators of
adenylyl cyclase activity)
- adenosine:
isolated airway smooth muscle
contraction
- histamine release
from lung cells
- both effects
antagonist by theophylline
- other xanthine
agents without
adenosine-antagonistic
characteristics are more potent
than theophylline in
bronchoconstriction inhibition
- Anti-inflammatory action:
- low-dose theophylline: inhibit late
response to antigenic challenge
return to main menu
Pharmacodynamics
- Overview
Pharmacodynamics:
- Multiple methylxanthine effects:
- CNS
- kidney
- cardiac/skeletal
muscle
- smooth
muscle
- theophylline: smooth
muscle effects dominate
- caffeine: CNS effects
most prominent
return to main
menu
- Central Nervous System
Effects:
- increased
alertness; reduced fatigue
- in
more sensitive individuals: caffeine --
nervousness/insomnia
- very high
methylxanthine doses: medullary
stimulation, convulsions
- Primary side effect
in patients for requiring
aminophylline (large doses) 4
control of asthma: nervousness
& tremor
return to main
menu
- Cardiovascular Effects:
- direct
positive chronotropic
- direct
enhanced myocardial contractility
- Mechanism
of Effects:
- low doses: increased
catecholamine release
secondary to inhibition
of presynaptic adenosine
receptors
- high doses:
cAMP-mediatedspace for
(secondary to
phosphodiesterase
inhibition) enhanced
calcium influx
- Reduced
blood viscosity: unknown mechanism
- pentoxifylline (Trental):
management of
intermittent claudication.
- Gastrointestinal
Tract Effects:
- methylxanthines:
enhanced secretion of gastric
acid and digestive enzymes
- coffee
(decaffeinated) -- stimulates
secretion; secretagogue not
caffeine
- Renal
Effects:
- weak diuretics--
not therapeuticly important
- increased
glomerular filtration
- reduced
tubular sodium
reabsorption
- Skeletal Muscle Effects:
- enhanced
skeletal muscle contraction
- may
improve contractility; responsible for reversing
diaphragmatic fatigue in COPD patients.
- in patients with
airflow obstruction improved
diaphragm skeletal muscle
contraction may enhance
ventilatory response to hypoxia
and reduce dyspnea
return to main
menu
Methylxanthines: Clinical Use
- Theophylline: most effective xanthine
bronchodilator
- Relieves airway obstruction:
- in acute asthma
- reduces symptoms
severity;
- in chronic
asthma:reduces off-time from work
or school in chronic asthma
- Theophylline:Less
effective bronchodilator compared to
inhaled beta2-agonists
- slower onset of
action
- some modest
anti-inflammatory effect
- relatively limited
usefulness in acute asthma,
compared other drugs, theophylline:
- decreased
frequency and severity of
symptoms in chronic
asthma
- Theophylline
base: slightly water-soluble; often
administered as salts containing various
amounts of theophylline base:
- aminophylline: 86%
theophylline (by weight)
- oxtriphylline: 64%
theophylline (by weight)
return to main menu
return to main menu
return to main menu
- Oral theophylline, although effective, may not be
dominant in maintenance treatment:
- improves
long-term asthma control as monotherapy or when added to
inhaled corticosteroids
- minor side effects --
insomnia
- risk
of accidental/intentional overdosage-- consequence:
death/severe toxicity
return to main menu
|
