W6 Respiratory Pharmacology 3 Flashcards
Muscarinic receptors
What is the aim of muscarinic receptor antagonists
- M3 has the biggest effect in bronchial smooth muscles
- To block postsynaptic M3 receptors
Muscarinic receptor antagonists: Mechanisms
M2 reduces amount of Ach released- inhibits contraction
M3 leads to contraction
–Although effects are limited by lack of selectivity leading to antagonism of M2 autoreceptors–
Muscarinic antagonists used are non-specific
- Therefore
– Limited effect on smooth muscle contraction
– Bronchodilatory effect (?) - BUT
– reduces mucus build up (M3 increases gland secretion)
– may increase muco-cillary clearance - No effect on late phase of asthma
What are the types of Muscarinic receptor antagonists? (2)
Generally Most use in COPD (rather asthma) but see guidelines
- Ipratropium
* Derivative of N-isopropylatropine
* Onset of action 30 mins; lasts 3-5 hours
* Not selective for M receptor subtypes - Tiotropium
* longer-acting
* once daily dosing
* More lipophilic
Muscarinic receptor antagonists: What are the Unwanted effects? (4)
Adverse effects
* Minimal when inhaled
* Anti-muscarininc side effects –
Common
1. dry mouth (M3 effects on salivary
glands)
2. GI tract effects
Uncommon include
3. Exacerbation of angle closure
glaucoma
4. Urinary retention
- Asthma
– May be used as an adjunct to Beta
2 agonists and steroids
– Bronchospasm (precipitated by
beta antagonists) - COPD (esp LAMA)
– See practice guidelines
Xanthines: Mechanisms
MoA= Not clear…
* Phosphodiesterases (PDEs) - enzymes
regulate intracellular levels cAMP (and
cGMP)
– Phosphodiesterase (PDE) metabolises cAMP
* Methylxanthines inhibit PDE,
– maintaining high cAMP levels
What are the types of Xanthines? (2)
- Theophyline
– Quite insoluble
– Narrow therapeutic index
– Many drug-drug interactions
(CytP450) - Aminophyline
– More soluble than theophyline
Xanthines
Both Orally (modified release formulas)
Aminophyline IV in acute severe asthma
What are the unwanted effects of Xanthines?
- Used for relief of bronchospasm in COPD
- Stem from effects on other systems
– Eg CNS, CVS
– Nervousness, insomnia - Narrow therapeutic Window
– Serious CVS CNS
– Cardiac dysrhythmia (can be fatal)
– Seizures (at only slightly above therapeutic range)
– Monitor - PK
– Absorption from gut unpredictable / varies between individuals - Inconjunction Variable plasma half life – use as modified release
- Metabolised by P450 enzymes in liver
– Plasma concentration decreased by drugs that induce P450 enzymes - Eg carbamazepine, phenytoin
– Plasma concentration increased by drugs that inhibit P450 enzymes - Eg erythromycin
Leukotriene receptor antagonists:
What is their mechanism?
Drugs: Leukasts
* Cysteinyl leukotrienes (e.g. LTD4) act on CysLT1 receptor in respiratory mucosa
– Airway inflammation & hyper-reactivity
* Montelukast & Zafirlukast antagonise the CysLT1 receptor
What are Leukotrienes?
Where are they formed?
- Arachidonic acid metabolites
- Leukotrienes
- Synthesized from arachidonic acid and bind to receptors on target tissues
- Formed in various cells, mostly LEUKocytes including activated mast cells and eosinophils
- Activation of cysteinyl leukotriene receptor
- Leukocyte recruitment
- mucus secretion
- vascular permeability / airway oedema
- smooth muscle contraction
Leukotriene receptor antagonists: (LTRA)
How does it work?
- Prevents bronchoconstriction mediated by LTs
- Inhibit early & late phase responses to irritants in asthma
- Generally taken orally with inhaled corticosteroid
- Not used widely
- Relax airways in mild asthma
– Not as effective as salbutamol
– Or ICS - Additive
- Few side effects
– GI effects
Histamine H1 receptor antagonists/ anti histamines
- Mast cell degranulation and release of histamine – important in early phase
of allergic asthma in particular / some exercise induced asthma and other
types - Histamine binds to H1 receptor
- Mucus secretion / SOME (Bronchoconstriction)
- BUT: Histamine H1 receptors proven to be of little clinical benefit in asthma
- May be mildly effective in mild atopic asthma but not routinely used
- May inhibit triggers
What are the functions of Anti-inflammatory Drugs?
- Used to reduce severity and frequency of asthma attacks
- Limit progression of disease by inhibiting remodelling
- Reduce night-time asthma attacks by preventing late-phase
Glucocorticoids
- Main drugs used for their anti-inflammatory
properties in asthma - Not bronchodilators (don’t relieve early phase)
- Prevent the progression of chronic asthma
- Effective in acute severe asthma
- Wide range of effects
- Add-on inhalational therapy in asthma when
bronchodilator is used more than once daily
Glucocorticoids: Mechanisms
Therapeutic effects:
Immunosuppression
– IL-10 –Decreases cytokine formation–
decreases recruitment and activation of inflammatory T cells
ie inhibits responses responsible for production of IgE and its receptors and for recruiting eosinophils – A process that begins in early phase and causes late phase of asthma – inhibiting late phase
Anti-inflammatory
– induces pathways that
* inhibits phospholipase A2
* decreased inflammatory mediators (Prostanoids & leukotrienes)
− also suppress COX-2 induction thus ↓inflammatory prostanoid production
– can reduce severity of early phase response and prevent late phase response
Glucocorticoids: Mechanisms
* Inhibit inflammatory cascade (previous 2 slides)
* Upregulate Beta 2 adrenoreceptors
– Potentiate effect
– Remember regular use of Beta 2 adrenoreceptor agonists (LABA) should be accompanied by ICS
* Eventually reduce number of mast cells
– May have some effect on early phase
Names of Corticosteroid formulations
- Pulmonary system: Generally inhaled
- Inhaled:
-Beclometasone dipropionate (BDP)
-Budesonide
-Fluticasone propionate (2 x potent as BDP)
-Mometasone - Oral: (severe acute asthma)
-Prednisolone
-Given as a single dose in the morning to mimic the body’s
cortisol secretion - IV:(severe acute asthma)
-Hydrocortisone See guidelines
Glucocorticoids-steroid hormone produced in adrenal glands:
Are unwanted effects common?
What are the unwanted effects? (6)
-
Uncommon with inhaled
– Systemic effects only in high doses
– Spacers minimise - **Oropharyngeal candidiasis **(thrush)
– Suppress T-lymphocytes important
against fungal infection
– Spacer devices reduce - Regular high doses
– Adrenal suppression esp in
children (inadequate production of cortisol) -
Latrogenic Cushings
– (moonface, increased abdominal fat,
hypertension) - Osteoporosis
- Increased risk of pneumonia in elderly with COPD
-
Poor absorption from GI tract
– Fluticasone / mometasone unwanted effects less likely
Mast cell stabilisers: Chromoglicate and Neodocromil (cromones)
- Not in common use
- Poor/variable efficacy shown in antigen-, exercise-, and irritant-induced
asthma (especially in children)
– Not bronchodilator - Weak anti-inflammatory effects
– Reduce immediate & late-phase responses
– Reduce bronchial hyper-reactivity - Mechanism unclear
– Mast cell stabilisation plays no part cf. oral anti-histamines
– Depress signals from irritant receptors
– May inhibit cytokine release
Immunotherapies
- Omalizumab (XolairTM)
-Monoclonal antibody
-Anti-IgE antibody –
-Once binds to IgE these are
removed from circulation
-IgE receptors also reduced
Reduces mediator release from
mast cells
Gradually reduces
inflammation(3 to 4 months)
Prophylaxis severe persistent
asthma
VERY expensive!!
Sub cut every 2-4 weeks
Risk of anaphylaxis with injection
What is a Cough?
Response to irritation
* The cough reflex links an afferent sensory stimulus to an efferent
motor response.
* A cough - a forceful movement of respiratory muscles to affect
the reflex
* Cough: two roles
1. The final pathway of mucociliary clearance
2. Part of the defence mechanisms against inhaled particles and
noxious substances
* Cough: an essential reflex response of the airways under both physiological and pathophysiological conditions
Causes of cough (4)
- Irritants-smokes, fumes, dusts, etc.
- Diseased conditions like COPD, tumors of thorax, etc.
- Pressure on respiratory tracts
- Infections
What are the components in a cough reflex(5)
- Cough receptors
- Afferent nerves
- Cough centre (medulla)
- Efferent nerves
- Effector muscles
What are the phases of cough? (5)
- Irritation: A stimulus irritates the upper
airways and results in a reflex action leading
to cough - Inspiration: Occurs to achieve optimum
thoracic gas volume -thus allowing the
most efficient use of the expiratory muscles - Compression: With the glottis closed, the
abdominal muscles and the thoracic cage
actively contracts, leading to high
intrathoracic pressures - Expulsion: The glottis opens and a high airflow results. The force of expression is
increased by collapsing the airways following the explosive decompression caused by glottic opening - Relaxation: At the end of the cough,
the intrathoracic pressure decreases
as the expiratory muscles relax and a
transient bronchodilatation occurs
Mechanism of ACE inhibitors (General Scheme)
(bradykinin)
ACE metabolises bradykinin
Bradykinin is a potent vasodilator peptide that
exerts its vasodilatory action through stimulation of
specific endothelial B2 receptors. It causes arterioles to
dilate (enlarge) via the release of prostacyclin, nitric
oxide, and endothelium-derived hyperpolarizing factor
and makes veins constrict
ACE inhibitors block the breakdown of bradykinin, and increase bradykinin levels, which can contribute to the vasodilator action.
* Accumulation bradykinin induces sensitization of airway sensory nerves via rapidly adapting stretch receptors and C-
fiber receptors that release neurokinin A and substance P.
Bradykinin – chemical irritation of c fibres (sensory neurons) of
respiratory tract – through release of proinflammatory peptides
(substance p and histamine) – these stimulate (hyper stimulate)
the cough reflex
Cough
How can it be described?
How long does a subacute/chronic cough last?
Cough
* Coughs can be -
* dry or chesty
* classified as acute, subacute or chronic.
* An acute cough has been present for less than three weeks and can be divided into infectious and non-infectious causes.
* A subacute cough resolves over three to eight weeks.
* Chronic, or persistent, coughs are those present for more than eight weeks.
Chronic Cough-
What is it caused by?
- Chronic coughs can be caused by:
- Environmental irritants
- Conditions within the lungs
- Conditions in the upper airways
- Conditions within the chest cavity
- Digestive causes
- Common causes of coughs within the lungs, include:
- Asthma
- COPD (emphysema and chronic
bronchitis) - Less common causes include:
- Cancer
- Congestive heart failure with chronic fluid build-up in the lungs.
Cough drugs
What are antitussives?
Opiod receptors.
* ‘Cough suppressants’
* All in clinical use are opioid analgesics
* Suppress cough in doses below those required for pain relief
* Action is poorly defined
* Suppress cough centre
* Common examples
– pholcodine, codeine, dextromethorphan
Cough drugs
Increase bronchial secretion or reduce its viscosity to facilitate removal by coughing
* Expectorants, Secretion enhancers:
– Sodium citrate, potassium iodide, guaiacol, tolu
balsam, ammonium salts
- Mucolytics include:
– Acteylcysteine - Actively breaks disulphide bonds in mucus, thinning it
- Inhaled
– Mucolytics can be useful in COPD, cystic fibrosis
COPD: Treatment efficacy of ICS
How effective are ICS in treating asthma and COPD?
What are the SE of ICS?
Inhaled corticosteroids
=Very effective in asthma BUT may only reduce exacerbations in COPD
-Side effects (less with inhaled but dose-dependent and may
still be swallowed)
1. Adrenocortical suppression
2. Bone mineral density reduced – osteoporosis
3. Candidiasis of the mouth and throat
4. Resistance in certain individuals
Phosphodiesterase type 4 inhibitors
- COPD eg Roflumilast
- Inhibition of PDE results in cAMP accumulation
- PDE isozyme 4 found in airways smooth muscle and
inflammatory cells
– Involved with inflammation in COPD
- PDE isozyme 4 found in airways smooth muscle and
- Inhibiting PDE4:
– Reduced cytokines released from neutrophils
–Reduced accumulation of T-cells in lungs
– Reduced cell death of airway cells
Treatment of acute exacerbations: Oxygen
- Long-term – guidance on giving up smoking!
Acute:
* ALWAYS use low-strength O2 in COPD, e.g. 24%
* (Respiratory drive affected by PACO2 in arterial blood and medulla and PAO2 in Carotid Bodies )
* COPD patients become tolerant to prolonged CO2 retention & respiratory drive is maintained by low levels of O2
* High-strength O2 will cause respiratory arrest
