RESPIRATORY DRUGS

Part 1 (NON-ASTHMA DRUGS)

a. Respiratory stimulants (analeptics)

b. Respiratory depressant

c. Cough suppressant (antitussives)

d. Nasal decongestants
 RESPIRATORY DRUGS (cont’d)

Part 2 (ASTHMA DRUGS)

a. Bronchodilators
b. Anti-inflammatory drugs
c. Others
 RESPIRATORY STIMULANTS
(ANALEPTICS)
 Stimulates respiration by increasing activity of
carotid chemoreceptors (PO2) or respiratory
centre (PCO2) or both
 No longer in popular use. Only occasionally
used, in ventilatory failure due to chronic
obstructive disease, but not in ventilatory
failure due to severe asthma or overdose of
CNS depressants
 Largely replaced by mechanical ventilation
 RESPIRATORY STIMULANTS
(ANALEPTICS)

 Doxapram (main member used)

 Stimulates both the carotid

chemoreceptor and respiratory centre

 Serious side effects restricts use (tremor,

dizziness, convulsion, hypertension)
 ANTITUSSIVES
(COUGH SUPPRESSANTS)

 Codeine (opiate with little addiction)

 Dextromethorphan
(non-opiate codeine analogue)
 Indicated in painful, unproductive and
intolerable cough (eg. bronchial carcinoma)

 Suppress cough centre in CNS (diff. receptors)

 ANTITUSSIVES (cont’d)
(COUGH SUPPRESSANTS)
 Advantages of Dextromethorphan over codeine

a. No inhibition of ciliary
activity
b.
c. No
Noinhibition of secretions
constipation
d. No liability to addiction

 Not used in cough of asthma and chronic

bronchitis-sputum thickening/retention
 NASAL DECONGESTANTS

:Nasal Congestion
• Results from oedema of nasal mucosa

• Occurs mainly in
- Flu (URTI)
- Rhinitis
(allergic or non-allergic)
 RHINITIS
(The inside story)
 NASAL DECONGESTANTS
Mechanisms of Action
Vasoconstriction (α 1(receptor activation •
.)e.g., phenylephrine(

Block of vascular permeability (anti-histamines •

or H 1blockers); ))e.g., chlorpheniramine

-Inhibition of release of mediators (by anti •

allergic drugs) ))e.g., inhaled steroids

Disadvantages of Nasal Decongestants

• Tachyphylaxis
• Rebound congestion
 ASTHMA

Inflammatory lung condition manifesting as •

.recurrent reversible bronchoconstriction

.May be extrinsic or intrinsic •

.Major medical problem in Kuwait •

(?Incidence on increase world-wide (pollution •

 CONTROL OF AIRWAY CALIBRE

Bronchodilation
Bronchoconstriction

Histamine Adrenaline

Leukotrienes PGE2

Acetylcholine EpDRF

PGD2 NO

Neuropeptides

Adenosine
Etc
 CONTROL OF AIRWAY CALIBRE

Bronchoconstriction Bronchodilation
 Ach ***  Catecholamines ***
(adrenaline)
 PGF2α PGD  NANC (VIP? NO?)
 Substance P?  PGE2
 Neurokinins?
 ANTIGEN-INDUCED DEGRANULATION OF MAST CELL
AND THE RELEASE OF ALLERGIC MEDIATORS
allergen

IgE antibody

Mast cell FcєRI

Mediator release
-histamine
Mast Cell
-PAF
-leukotrienes
-PGD2

Degranulating mast cell

 MEDIATORS OF ASTHMA
Phase Symptoms Mediator
Extrinsic asthma
Acute Attack Bronchoconstriction Histamine (stored)
(phase I) Leukotrienes C4, D4, E4
Prostanoids (PGF2α, PGD)
PAF
Kinins
Etc.
Neuronal (reflex)
Ach
Neurokinin A
Substance P
Etc.
 MEDIATORS OF ASTHMA (cont’d)

Phase Symptoms Mediator

Delayed Bronchoconstriction LTB4 PAF,

or Bronchial inflammation Interlukins
chronic Hyper-reactivity of (eg IL-2, IL-3, IL-5),
(phase II) bronchial tissues TNF, GM-CSF etc
 CHARACTERISTICS OF ASTHMA

 Bronchoconstriction

 Bronchial hyper-reactivity

 Blood and bronchial eosinophilia

 Increase in mucus secretion

 Bronchial inflammation (oedema & cell influx)
 Dual phase
 THE TWO PHASES OF ASTHMA AND
THE EFFECT OF ANTIASTHMA DRUGS
 Learning Objectives
Understand the limited use and adverse effects the .1
.analeptics

List the advantages of dextromethorphan over .2

.codeine as an antitussive

Describe, with examples, the various ways by which .3

.nasal decongestants may act, and the limitations in their use

Understand how airway calibre is controlled .4

and whyβ.-blockers are contra-indicated in asthma

Understand the pathophysiology of asthma and the .5

basis for the effects of drugs in the two phases of asthma
 ANTI-ASTHMA DRUGS
Bronchodilators

Anti-inflammatory Agents
- Corticosteroids
- Anti-rheumatics
- Immunosupressors

Others
- DSCG, Nedocromil, etc.
 BRONCHODILATORS
4 Groups

a.β 2( Agonists (eg. Salbutamol

(b. Xanthine Derivatives (eg, Theophylline

(c. Muscarinic receptor antagonists (Ipratropium

d. Anti-Leukotriene Drugs
• Cyst-LT receptor antagonists (eg, Zafirlukast)
• LT synthesis inhibitors (eg, Zileutin)
 BETA ADRENOCEPTOR AGONISTS
Drugs Receptor Specificity
α, ß 1, ß2
Adrenaline +++ +++ +++
Nor-adrenaline +++ + +
Isoprenaline - +++ +++
Salbutamol - + +++
Terbutaline - + +++
Remiterol - + +++
Fenoterol - + +++
Salmeterol Long- - + +++
formoterol acting
 Mechanism of Action ofβ 2-receptor agonists

β 2-receptor

G-protein

Adenylate cyclase

ATP cAMP AMP-’5

cAMP-dep protein kinase

Myosin LC kinase Myosin LC kinase-P

MUSCLE REAXATION
 CLINICAL USE OF ß2 AGONISTS
 Most widely used antiasthma drugs
 Drug of choice for acute attack
 Salbutamol and terbutaline most used
 Given by inhalation, but also orally
 Instant effect (lasts 3-5h; 12h for some)
 Also used in chronic bronchitis
ADVERSE EFFECTS OF ß2 AGONISTS

 Muscle tremor

 ß1 -mediated tachycardia
 May mask deterioration of asthma
 XANTHINE DERIVATIVES

 Theophylline (aminophylline)-prototype

 Enprofylline

 Proxifylline
Actions of Xanthine Derivatives
 Bronchodilators
 Stimulate heart & CNS (use is beverage)
 Has anti-inflammatory effect

Mechanisms of Action
 Inhibition of phosphodiesterases?
 Antagonism of adenosine receptors?
 Release of adrenaline?
 Mechanism of Action ofβ 2-agonists
and PDE Inhibitors

β 2-receptor
PDE
Inhibitors
G-protein

Adenylate cyclase

PDE AMP-’5
ATP cAMP

cAMP-dep protein kinase

Myosin LC kinase Myosin LC kinase-P

Myosin-P Myosin
MUSCLE REAXATION
MUSCLE CONTRACTION
 CLINICAL USE OF XANTHINE DERIVATIVES
IN ASTHMA

 Theophylline most widely used

 Given orally or by slow I.V. infusion
 Theophylline metabolized by liver, caution in
liver disease, Enprofylline preferred
 Caution in heart disease (stimulates heart)

 Used in moderate to severe asthma

 Narrow therapeutic range, blood level to be
monitored
Adverse Effects of Theophylline
 Nausea and vomiting (at therapeutic dose)
 Anorexia
 Tremor
 Cardiac arrest (rapid I.V. injection)
 Drug interaction
 Nervousness
 Seizure (children)

• Enprofylline has less side effects-does not stimulate CNS

 MUSCARINIC RECEPTOR
ANTAGONISTS IN ASTHMA
 Ipratropium bromide is mainly used
 Blocks muscarinic receptors on bronchial
smooth muscle to produce relaxation
 More effective in reflex asthma
 Often used in conjunction with other
bronchodilators
 Given by aerosol, not absorbed orally
 Safe and well tolerated
 LEUKOTRIENE ANTAGONISTS

Cyst-LT receptor antagonists

(Block Cyst.-LT receptor (common for LTC4, LTD4 and LTE4 •
.Bronchodilating effect slightly less than for salbutamol •
.Examples - zafirlukast, montelukast etc •

Leukotriene synthesis inhibitors

Inhibits enzymes 5-LO or FLAP in LT synthesis •

Affects synthesis of Cyst-LT and LTB4 •
.Have both bronchodilating and anti-inflammatory effects •
Example - Zileutin •
Anti-inflammatory Agents

- Corticosteroids
- Immunosupressors
- Others
 STEROIDS (GLUCOCORTICOIDS)
IN ASTHMA
 Powerful anti-inflammatory and
immunosuppressive actions

 Drugs of last resort in chronic asthma

 No bronchodilator effect

 Effect takes up to 6h to start

 STEROIDS IN ASTHMA

 Members most frequently used are

- Beclomethasone (aerosol)
- Budesonide (aerosol)
- Prednisolone (systemic, oral)
- Hyrocortisone (systemic, IV)
 Mechanism of Action of Steroids
in Asthma

 Inhibit the synthesis and/or release of

inflammatory mediators

 Induce synthesis and release of

anti-inflammatory mediators.

May blocks the ability of inflammatory cells

to respond to chemotactic and other stimuli
 Mechanism of action of Steroids

Steroid

Steroid -receptor complex

inhibition induction
GENE

Cytokine Annexins
s(IL-1, TNFa, IL-5, IL-4, GM-CSF) (lipocortins)

Adhesion molecules (ICAM-1,VCAM-1) PLA2

Enzymes (COX2, cPLA2, iNOS)

 CLINICAL USE OF STEROIDS IN
ASTHMA
 Inhalation is preferred route of adm. (less
side effects); oral in severe chronic asthma.
 Often combined with bronchodilators
 Given I.V. in acute severe asthma
 Very useful as prophylaxis (first line drug)

 Caution in children
 ADVERSE EFFECTS OF STEROIDS
Aerosol:
 Oropharyngeal candidiasis
 Dysphonia
Systemic:
 Adrenal insufficiency (if withdrawn rapidly)
 Osteoporosis
 Lowered resistance to infection
 Cushing’s syndrome
 Hyperglycemia
 DISODIUM CROMOGLYCATE IN
ASTHMA
 Prophylactic anti-asthma drug
 No bronchodilator effect
 Affects all forms of asthma
 More effective in children than adults
 Drug of choice in children
 Effective against both early & late phases
 DISODIUM CROMOGLYCATE IN
ASTHMA (cont’d)
 Poorly absorbed, given by inhalation
 Has some anti-inflammatory effect
 May also act by inhibiting neuronal reflex and
stabilization of mast cells
 No side effects except cough by particle
irritation
 OTHER ANTI-ASTHMA DRUGS
KETOTIFENHT antagonist.
• Effect due mainly to anti-inflammatory action.
• Effective orally.
• Effect develops after 2-3 weeks

NEDOCROMIL SODIUM
• Similar to DSCG in many respects.

METHOTHREXATE/CYCLOSPORIN-A

MONOCLONAL ANTI-IGE (Omalizumab)

OXYGEN
 Learning Objectives
Classify bronchodilators and describe the mechanism of .1
.action of each group

Understand the central role of cAMP as second messenger .2

in bronchodilation by bothβ.2-agonists and PDE inhibitors

-Describe the precautions, adverse effects and contra .3

.indications of theophylline in asthma

Describe the mechanism of action of steroids and the .4

.adverse effects associated with its use in asthma

.Understand the pharmacology of disodium cromoglycate .5

Appreciate the therapeutic options in steroid resistant .6

.asthma and in status asthmaticus
 MECHANISM OF ACTION OF
ß2 AGONISTS IN ASTHMA

Activation of ß2 receptors on bronchial smooth muscles

G-protein mediated activation of adenylyl cyclase

Conversion of ATP to cAMP

Activation of cAMP-dependent protein kinases

Phosphorylation/inhibition of myosin light chain kinase

Muscle relaxation
(Similar mechanism on mast cells inhibit mediator release)