Respiratory Pharmacology Flashcards
What is Asthma?
Reversible airflow obstruction increases in airway resistance involving bronchoconstriction + inflammation
Decreases in FEV1 (forced expiration volume in first second)
Value of < 70% means increased airway resistance
If asthma, then reversed using Beta2-agonist
What is COPD?
Airflow limitation that is not fully reversible
Both chronic bronchitis + emphysema
Loss of lung function
80-90% deaths related smoking
Diseases of late onset in life (elderly)
High energy demand + difficulty eating, e.g. use inhaler before meal, leading to weight loss
Describe the phases of asthmatic attack
What are the two categories for asthma therapy?
1) relief of symptoms (bronchodilators) - block early phase if asthma attack caused by bronchoconstriction
2) prevention of attack (anti-inflammatory agents) - prevents late phase caused by release of cytokines
What are bronchodilators?
Reverse bronchospasm + rapid relief
Beta2 adrenoceptor agonists e.g. salbutamol
- 1st choice
- Increase FEV1
- Given by inhalation
Longer acting agents (salmeterol) given for long-term prevention
Where are Beta2-adrenoceptors + function?
On smooth muscle and mast cell
Increase in cAMP prevents release of histamine
Affects on mucus secretion
What is Desensitisation?
Caused by long-term use of Beta-adrenoceptor agonists which leads to tolerance/desensitisation
Due to internalisation of the receptor
Prevented by steroids
Examples of Long-acting beta-adrenoceptor agonist
Salmetorol
Formoterol
Indacaterol
Dont know why they are long acting
Current theory = absorbed into lipid bilayer of cells - slowly released over time to activate
Adverse effects of beta2-adrenoceptor agonists
Tremor
Palpitations
Hypokalaemia
Due to high doses of drugs e.g. nebulisers
Example of Phosphodiesterase inhibitor
Roflumilast (PDE4) inhibitor (DAXAS)
For COPD
Reduces inflammation
Can enhance Beta-adrenoceptor effects
Function of Muscarinic M-receptor antagonist
Block parasympathetic bronchoconstriction
e.g. ipratropium (non-selective antagonist)
Inhaled (fewer systemic effects)
Inhibits mucous secretion
Tiotropium = long-acting, due to slow dissociation from receptor
Aclidinium = long-acting but newer
What are the side effects of Muscarininc M-receptor?
They are non-selective so they block muscarinic receptors all over body
Dry mouth
Nausea/headache
Constipation
Urinary retention
Blurred vision
Atrial fibrillation + Tachycardia + Palpitation
What are Xanthines + example?
Bronchodilators (not as good as b2-adrenoceptor agonist)
E.g. theophylline
2nd line use
Orally inhaled (or IV aminophylline in emergencies)
What is Aminophylline?
Mix of theophylline + ethylenediamine (2:1 ratio)
Improves solubility
Measure plasma theophylline 4-6 hrs after infusion (iv)
Monitor plasma levels - toxicity
What are the side effects of Theophylline?
Tremor
Palpitations
Nausea
CNS stimulations
Drug interactions:
- inhibit of metabolism increases toxicity (cimetidine)
- induce metabolism reduces plasma levels
What are anti-inflammatory agents?
Preventative - do not reverse an attack
Target late phase of asthma response
e.g. Corticosteroids
What receptors do steroids act on?
Act at intracellular or glucocorticoid receptor
Examples of Inhaled steroids
Beclometasone
Bidesonide
Ciclesonide
Fluticasone
Mometasone
Example of an oral steroid
Prednisolone
e.g. acute asthma attack
Example of an IV steroid
Hydrocortisone
e.g. life threatening asthma
What genes are switched on/activated by glucocorticoids when steroid has bounded?
Annexin A1
Beta2-adrenoceptors
IkB (Inhibitor of NF-kB)
MKP1 (inhibits MAP kinase)
Anti-inflammatory cytokines e.g. IL-10, 1L-12
What genes are switched off/repressed by glucocorticoids when crosslinked with steroid?
Inflammatory cytokines - e.g. IL-2, IL-3, IL-6, TNFα
Chemokines
Inflammatory enzymes - e.g. iNOS, COX-2
Inflammatory peptides - e.g. endothelin-1
How can genes be repressed when steroid binds to glucocorticoid receptor?
What is Annexin A1?
Involved in the up-regulation of anti-inflammatory genes
Act through formyl peptide receptors (FPR)
- inhibits histamine release from mast cells
- inhibits cPLA2 - PGs
How do steroids affect Beta2-adrenoceptor?
Increase transcription of B2-AR
Protect against downregulation of B2-ADR after long term use (desensitisation)
Benefits of co-administration
What are the side effects of corticosteroids?
Throat infections/oral candidiasis with inhaled steroids
Osteoporosis
Adrenal suppression in children
- use lowest effect dose of steroid
- monitor height
Indigestion
Chicken pox severe (avoid contact) - immune response
Withdrawal effect (reduce oral steroids gradually if more than 3 weeks)
Patients with severe asthma + COPD have poor response to steroids (Steroid resistance)
What are the reasons for the resistance?
Genetics
GR receptor modification
Decreased nuclear translocation of GR
Increases efflux of steroids
How are leukotrienes made?
Function of Leukotriene mediator
They have a role in inflammation + asthma
Stimulate mucus secretion
Cause bronchoconstriction
Role in airway remodelling
Linked to hyperresponsiveness
Link with exercise-induced asthma
Function of Cysteinylleukotriene receptor antagonist
Block LT receptors - block inflammatory actions of cystLTs
e.g. montelukast
Leukotriene receptor antagonist block production of leukotrienes + LTB4
Antagonist block bronchoconstriction
Zileuton = Suppressor of leukotriene synthesis + LTB4
What are the side effects of CystLT receptor antagonist?
Headache
Rash
Nausea
Jaundice
Mood disorders/suicidal thoughts (from montelukast)
What is Omalizumab?
Used for severe allergic asthma that cannot be controlled by steroids
It’s a monoclonal antibody against free IgE - Prevents IgE from binding to immune cells preventing allergen-induced mediator release (e.g. histamine)
S.C. Injection every 2-4 weeks
How can drug-induced asthma occur?
Affects 15% of asthmatics
Drugs involved are NSAIDS, Beta-AR + drug allergies
NSAIDS inhibit COX
- more arachidonic acid leukotriene production
- leads to inflammation/spasm + bronchoconstriction
B-adrenoceptor antagonist
- non-selective (propranolol)
- selective (atenolol)
Drug allergy (e.g. penicillins, cephalosporins, dipyridamole, tramadol)
Example of a cromone
e.g. sodium cromoglicate
Preventative (mast cell stabilisers)
- Prevent + relieve swelling of the airways
- buildup of mucus + asthma
Benefit in exercise-induced asthma
Given by Inhalation
Function of mucolytics
Break up thick mucus
e.g. carbocysteine, erdosteine, mecysteine, dornase alfa
Act as an antioxidants
Used in COPD
Dornase alfa (recombinant deoxyribonuclease) breaks down extracellular DNA from dying neutrophils
- used in CF to reduce mucus viscosity
What is a Cough?
What are Anti-tussive agents?
Stops coughing
e.g. Codeine (opioid) + dextromethorphan (non-opioid)
- act in cough centre
- little bit better than placebo
- codeine is avoided in children under 18 years
- dextromethorphan avoided in children under 6 years
e.g. Levodropropizine
- inhibit release of sensory neuropeptides
- compared to Codeine + dextromethorphan
What is Cystic Fibrosis?
Inherited disorder of ion transport in epithelial cells
Affects respiratory, hepatobiliary, gastrointestinal, reproductive tracts, pancreas
Defect in chloride transporter leading to reduced Na+ and H20 transport
- Thicker secretions w/obstruction + destruction of exocrine glandular ducts
- recurrent infections
Discuss the disease characteristics of CF
Pancreatic exocrine insufficiency
- reduced/absent secretions
Patients living longer - but developing other complications:
- diabetes
- liver disease
- osteoporosis
How can we manage CF?
Aim is to clear viscous mucus from airways to treat respiratory infections, improving respiratory function
Physiotherapy
Antibiotics
Corticosteroids
Bronchodilators
Dornase Alfa administered using Nebuliser
- synthetic version of enzyme which cleaves extracellular DNA
- ‘Digests’ extracellular DNA released from dying neutrophils in the airway which contributes to increased mucus viscosity
