Pharmacology of the respiratory tract

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.

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.

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.

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.

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.

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.

Respiratory pharmacology

Bronchodilatators

Respiratory antiinflammatory drugs

Antitussives

Mucolytics, expectorants

Drugs Acting on the Respiratory System

Bronchodilators

Constriction: Acetylcholine

Dilation: cAMP(β2-agonists, xanthine

derivatives)

Bronchodilators

Indications:

• anaphylaxis

• allergic bronchitis

• asthma (Fe), RAO (horse)

• pulmonary edema

• pneumonia

• pleural effusion

• pneumothorax

• tracheal collapse and hypoplasia?

Bronchodilators

1. Sympathomimetics

2. Anticholinergic substances

3. Xanthine derivatives

BronchodilatorsSympathomimetics

Act mainly on β2-receptors

ATP cAMP

bronchodilation

adenylate cyclase

BronchodilatorsSympathomimetics

1. Non specific sympathomimetics

2. Specific sympathomimetics (β2 receptor agonists)

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 + + -

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)

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

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…

Specific Sympathomimetics

Long acting β2 agonists

• salmeterol (Serevent®)

• most specific (50000:1)

• longest duration (10 mins-12 hours)

• most expensive

• 200 µg/horse

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

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

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?

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)

BronchodilatorsMethylxanthine derivatives

Derivatives of theophyllin

aminophyllin (Diaphyllin®)

propentophyllin (Karsivan A.U.V.)

bronchodilator

vasodilator: brain, muscles, kidney

pentoxyfillin

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

Respiratory antiinflammatories

Indications: asthma, RAO

1. Inhalational glucocorticoids

2. Chromones

3. Leukotriene antagonists

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

Inhalational glucocorticoids

Inhalosol dosage form! (dose dependent side effects)

15-20% airways

80-85% pharynx first pass!

beclomethasone, fluticasone (17-α-substitution)

Inhalational glucocorticoids

Beclomethasone (14x dexamethasone)

500-1500 g/horse BID

Fluticasone (23x dexamethasone)

100-200 g/cat BID

2000 g/horse BID

Chromones

Inhibition of mast cell degranulation=

„Mast cell stabilizers”

Per os, inhalosol

Rare (asthma)

Na-chromoglycate, nedocromil

Per os, inhalation, nasal spray, eye drop

Leukotriene synthesis inhibitors, leukotriene antagonists

Final products of the lipoxygenase pathway

Arachidonic acid cysteinil leukotrienes (LTC4, LTD4, LTE4)

• bronchoconstriction!

• mucous production

• edema

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

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.

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.

Treatment of allergic bronchitis, RAO and feline asthma - summary

OTHER agents in feline asthma

1. Antihistamines

• cyproheptadine

2. Na-chromoglycate

3. Leukotriene antagonists

• 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

Antitussives

Impulse from the trachea or bronchi (irritation, inflammation, mechanical, ACE inhibitors etc.)

Afferent sensory neurons

Cough centre

(medulla oblongata)

Antitussives

Peripherial antitussives

mucolytics, expectorants

bronchodilators

coating substances

local anesthetics

Central antitussives

morphine derivatives

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®)

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?

Antitussives

Veterinary experience

butorphanol

tramadol

cat?

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!)

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.)

Mucolytics

Carbocystein (Mucopront®)

similar action, oral absorption little better

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

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.)

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??