Pharmacology of the respiratory tract · Pharmacology of the respiratory tract. Pathophysiology of...
Transcript of Pharmacology of the respiratory tract · Pharmacology of the respiratory tract. Pathophysiology of...
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Pharmacology of the respiratory tract
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Pathophysiology of Asthma
• Asthma is a complex disease characterized by airway
inflammation, which leads to airway
hyperresponsiveness, which causes symptomatic
bronchoconstriction.
• Unlike the reversible component of
bronchoconstriction that characterizes the acute
asthmatic reaction, the airway remodeling induced by
chronic inflammation may be irreversible.
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Asthma
Asthma is both an obstructive lung
disease and an inflammatory disease
•the obstructive component is
characterized by bronchoconstriction
•inflammatory component is marked
by airway edema, goblet-cell
hyperplasia, mucus secretion, and
infiltration by a wide variety of
immune and inflammatory cells that
release a number of associated
cytokines.
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COPD
• RAO: recurrent airway obstruction
• COPD: chronic obstructive pulmonary disease
• COPD describes a spectrum of disorders that results
in obstructive lung disease. COPD is caused by an
abnormal inflammatory response to an inhaled
environmental insult.
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COPD
• COPD is divided into two frequently overlapping
diseases: emphysema and chronic bronchitis.
• Pulmonary emphysema refers to alveolar
enlargement caused by destruction of alveolar
walls, whereas chronic bronchitis is a clinical
diagnosis made on the basis of a chronic cough.
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Physiology of Airway Smooth Muscle Contraction
• In the airways, sympathetic (adrenergic) tone causes
bronchodilation and parasympathetic (cholinergic)
tone causes bronchoconstriction.
• Airway smooth muscle cells express β2-adrenergic
receptors. β2-adrenergic receptors are activated by
adrenalin, which is secreted by the adrenal medulla and
causes bronchodilation.
• Airway smooth muscle cells express muscarinic
receptors, especially the excitatory M3 subtype of
muscarinic receptors. Upon stimulation, these receptors
induce bronchoconstriction.
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Mast cells and leukotrienes
• Acutely, mast-cell degranulation produces
bronchoconstriction and airway inflammation. Histamine
released by the mast cells promotes capillary leakage, leading
to airway edema.
• Mast cells also release leukotriene C4 (LTC4), which is
subsequently converted into LTD4 and LTE4. These three
leukotrienes, called cysteinyl leukotrienes, are central to the
pathophysiology of asthma because they induce marked
bronchoconstriction.
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Respiratory pharmacology
Bronchodilatators
Respiratory antiinflammatory drugs
Antitussives
Mucolytics, expectorants
Drugs Acting on the Respiratory System
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Bronchodilators
Constriction: Acetylcholine
Dilation: cAMP(β2-agonists, xanthine
derivatives)
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Bronchodilators
Indications:
• anaphylaxis
• allergic bronchitis
• asthma (Fe), RAO (horse)
• pulmonary edema
• pneumonia
• pleural effusion
• pneumothorax
• tracheal collapse and hypoplasia?
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Bronchodilators
1. Sympathomimetics
2. Anticholinergic substances
3. Xanthine derivatives
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BronchodilatorsSympathomimetics
Act mainly on β2-receptors
ATP cAMP
bronchodilation
adenylate cyclase
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BronchodilatorsSympathomimetics
1. Non specific sympathomimetics
2. Specific sympathomimetics (β2 receptor agonists)
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Adrenaline
bronchodilation at β2 receptors (+other receptors!)
only life threatening cases (e.g. anaphylaxis)
D: 0,1-0,5 mg/dog, cat IV., IM., intratracheal
Isoproterenol ~ adrenaline
Ephedrine (Bronchopect A.U.V.): directly and indirectly acting sympathomimetic
several, mild side effects
bronchodilator (+other indications!)
tachyphylaxis
D: 1-2 mg/kg orally BID-TID
Non specificSympathomimetics
Receptor/ligand Adrenaline Ephedrine Isoproterenol
β1 + + +
β2 + + +
α1 + + -
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SpecificSympathomimetics
β2 agonists
• Bronchodilators at β2 receptors (+ variable β1 receptorial effect)
• SE: tachycardia, restlessness, tremors, decreased uterine contraction
• contraindications: congestive heart failure
• decreased mast cell degranulation
• Short acting (1-4 hours)
• Long acting (6-12 hours)
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SpecificSympathomimetics
Short acting β2 agonist
• salbutamol (=albuterol,Ventolin®)
• significant veterinary experience
• β2:β1 ratio approx. 650:1
• per os (30 mins), inhalation (5 mins) 1-4 hours
• inhalosol: 100-200 µg/cat
400-800 µg/horse
• per os 20-60 µg/kg dog, cat
8 µg/kg horse
• parenteral?
• levosalbutamol (levalbuterol)
• side effects, contraindications
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SpecificSympathomimetics
Long acting β2 agonists
• terbutaline (Bricanyl®)
• less specific
• 6-8 hours
• D: 0,312-0,625 mg / cat and 0,625-5 mg / dog po. TID
• subcutaneous, intravenous injection, inhalation??
• feline asthma, organophosphate toxicosis: 5-7 „puffs” (auscultation! 240/min)
• horse RAO?
• clenbuterole (Ventipulmin A.U.V., Spiropent®)
• less specific
• 6-8 hours
• less effective in companion animals
• frequently in horse (1-3 µg/kg po.), but! prohibited in…
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Specific Sympathomimetics
Long acting β2 agonists
• salmeterol (Serevent®)
• most specific (50000:1)
• longest duration (10 mins-12 hours)
• most expensive
• 200 µg/horse
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Adverse effects of adrenergic agonists
o adverse effects are minimized by inhalant
delivery
o β1-receptor activity causes cardiac effects
(tachycardia, arrhythmias) - ephedrine,
isoproterenol
o β2-adrenoreceptor agonists cause skeletal
muscle tremor
o α-adrenoceptor activity causes
vasoconstriction and hypertension
o tachyphylaxis
Bronchodilators
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BronchodilatorsParasympatholytics
Acetylcholine antagonists (M3-receptors)
bronchodilation + decreased mucous secretion
side effects: tachycardia, mydriasis, decreased „mucociliary clearence”, paralytic ileus (Eq)
indications: asthma (Fe!)
horse RAO
organophosphate toxicosis
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BronchodilatorsParasympatholytics
Atropine
tertiary amin, mainly sc., iv.
0,02-0,04 mg/kg for bronchodilation ??
0,2-2 mg/kg in organophosphate toxicosis
side effects: see before + CNS signs (cat!)
Glycopyrrolate
longer action, much safer
Ipratropium (Atrovent®)
quaternary amin, only inhalasol safe,
does not cross BBB
mucociliary clearence?
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BronchodilatorsMethylxanthine derivatives
Caffeine, theophyllin, theobromin
1. Mech.: phosphodiesterase inhibitor cAMP level increases bronchodilation
2. Various pharmacological effects!
3. Pharmacokinetics: good absorption, enterohepatic circulation ( activated carbon)
4. Side effects: small therapeutic index! (CV, GI, diuresis)
5. Indications, dosage:
bronchitis, pneumonia etc.
IV., PO (retard tablets)
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BronchodilatorsMethylxanthine derivatives
Derivatives of theophyllin
aminophyllin (Diaphyllin®)
propentophyllin (Karsivan A.U.V.)
bronchodilator
vasodilator: brain, muscles, kidney
pentoxyfillin
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Methylxanthines
o Therapeutic uses
o Methylxanthines are used to treat acute or chronic
asthma that is unresponsive to β-adrenoceptor
agonists; they can be administered prophylactically.
o These agents are used to treat chronic obstructive
lung disease (COPD) and emphysema.
o Adverse effects
o The adverse effects of methylxanthines include
arrhythmias, nervousness, vomiting and
gastrointestinal bleeding.
Bronchodilators
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Respiratory antiinflammatories
Indications: asthma, RAO
1. Inhalational glucocorticoids
2. Chromones
3. Leukotriene antagonists
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Inhalational glucocorticoids
Most effective antiinflammatories
Inhibition of the expression of several genes decreasing citokine production
IL-4, IL-5!
Eosinophilic apoptosis
Decreased mucous production! Increasing diameter!
Systemic application possible
but: several side effects (HT-HP axis, stomach, liver etc.)
Mainly in inhalation!
less frequent side effects
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Inhalational glucocorticoids
Inhalosol dosage form! (dose dependent side effects)
15-20% airways
80-85% pharynx first pass!
beclomethasone, fluticasone (17-α-substitution)
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Inhalational glucocorticoids
Beclomethasone (14x dexamethasone)
500-1500 g/horse BID
Fluticasone (23x dexamethasone)
100-200 g/cat BID
2000 g/horse BID
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Chromones
Inhibition of mast cell degranulation=
„Mast cell stabilizers”
Per os, inhalosol
Rare (asthma)
Na-chromoglycate, nedocromil
Per os, inhalation, nasal spray, eye drop
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Leukotriene synthesis inhibitors, leukotriene antagonists
Final products of the lipoxygenase pathway
Arachidonic acid cysteinil leukotrienes (LTC4, LTD4, LTE4)
• bronchoconstriction!
• mucous production
• edema
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Leukotriene synthesis inhibitors, leukotriene antagonists
Leukotriene synthesis inhibitors
zileuton, fenleuton
per os
Leukotriene antagonists
zafirlukast, montelukast
per os
feline asthma: 0,5-1 mg/kg SID, BID
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Leukotriene Pathway-Modifying Agents
• Inhibition of 5-lipoxygenase by the drug zileuton reducesthe biosynthesis of leukotrienes.
• A second strategy involves inhibition of the cysteinylleukotriene receptor CysLT1. Montelukast, zafirlukast,and pranlukast are CysLT1 receptor antagonists.
• A third strategy involving inhibition of the protein thatactivates 5-lipoxygenase (5-lipoxygenase-activatingprotein or FLAP) is being actively explored.
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Treatment of allergic bronchitis, RAO and feline asthma - summary
1. Glucocorticoids
• continously!
beclomethasone, fluticasone BID
2. Bronchodilators – continously or occasionally
advantage!
E.g. HORSE
beclomethasone+salmeterol
beclomethasone+ipratropium
CAT
fluticasone + salbutamol/etc.
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Treatment of allergic bronchitis, RAO and feline asthma - summary
OTHER agents in feline asthma
1. Antihistamines
• cyproheptadine
2. Na-chromoglycate
3. Leukotriene antagonists
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• Antitussive: any medicine used to suppress or relieve
coughing
• Mucolytic: destroying or dissolving mucus
• Expectorants are drugs that loosen and clear mucus
and phlegm from the respiratory tract.
Antitussives, mucolytics and expectorants
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Antitussives
Impulse from the trachea or bronchi (irritation, inflammation, mechanical, ACE inhibitors etc.)
Afferent sensory neurons
Cough centre
(medulla oblongata)
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Antitussives
Peripherial antitussives
mucolytics, expectorants
bronchodilators
coating substances
local anesthetics
Central antitussives
morphine derivatives
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Antitussives
Codeine vs morphine
better bioavailability orally
10 times lower analgesic potency
similar antitussive
rare side effects cat!: excitation, convulsions, sedation, constipation
D: 1-2 mg/kg BID-QID
Dihydrocodeine (Hydrocodin®)
more effective, cat Ø!
Hydrocodone (Vicodin®)
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Antitussives
Butorphanol (Butomidor A.U.V., Alvegesic A.U.V.)
most effective, but…sedation
oral product?
Tramadol
dog 5 mg/kg every 6 hours
Dextrometorphan (Atussin A.U.V., Robitussin Antitussicum®, Rhinathiol®)
δ-receptor, non addictive, non analgesic
safe also in cats
D: 1-2 mg/kg po. TID-QID
reliable?
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Antitussives
Veterinary experience
butorphanol
tramadol
cat?
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Mucolytics and expectorants
Mucolytic expectorant
Indications: bronchitis, bronchopneumonia, tracheitis, rhinitis, sinusitis, RAO as adjunctive therapy
Mechanism: dissolution of the dense, sticky mucus inside the respiratory tract „productive coughing”
Clinical signs can be more pronounced! ( antitussives!)
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Mucolytics
N-Acetylcysteine (ACC®, Fluimucil®)
breaking up disulphide bonds in mucoproteins dissolution of viscous mucus
bad taste, odour!
per os inhalation
AB penetration
50 mg/kg per os BID, TID
+ antidote of paracetamol (iv.)
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Mucolytics
Carbocystein (Mucopront®)
similar action, oral absorption little better
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Expectorants
directly on the mucous membrane of airways, or indirectly by stimulating gastric mucous membrane
volatile oils (eucalyptus, thymus, turpentine)
pl. Mixtura pectoralis FoNo
Salts (pl. NH4Cl, NaI)
Ipecacuanha
Guaifenesin
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ExpectorantsBromhexin (Bisolvon A.U.V., Ventipulmin A.U.V.)
3 actions: 1. breaking up mucopolysaccharides, dissolving mucus
2. increasing secretion of serous glands
3. enhancing ciliary movement
Enhancing permeation of Ig-s and AB-s!
IgA, IgG levels increased
Indications: rhinitis, sinusitis, tracheobronchitis (but: purulent discharge!)
Side effects?
D: 2 mg/kg per os, sc. BID
Ambroxol : metabolite of bromhexine
Dembrexine: horse, longer half-life (iv. po.)
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ExpectorantsGuaifenesin (sulphaguaiacol, Bronchopect A.U.V., Robitussin expectorans®)
Does not change amount of mucous secretion
Enhances ciliary movement! (MC )
Can be combined with antitussives
Veterinary usage??