Week 8 & 10 - Asthma and COPD Flashcards
List methods for delivery of drugs to nose and lungs
- Liquid
- e.g. sprays(fine mist) or drops
- Nose: mist impacts nasal mucosa
- Lungs: vapour droplets inhaled into lungs (local) - Gels
- Creams
- has fine nozzle = delivered into nasal cavity - Ointments
- Solids
- Lungs: aerosol which is dispersed (systemic)
Nose:
Local treatment = cold, flu, hay fever, allergies
Systemic = smoking, diabetes, vaccines
Drug can get caught in mucus + if swallowed = systemic effects / decreased drug absorption
Nose + lungs = highly vascularised = bypass 1st pass metabolism
Nose + lungs have large SA for absorption
Drugs are easy to administer
Lungs have low enzymatic active compared to nose = less degradation of drug
Explain what influences formulation choice
- Solubility
- formulate as suspension / powder if solubility is issue
- needs to dissolve in 25-250 micro litre - Lipophilicity/hydrophilicity and molecular size
- more lipophilic = more readily absorbed
- more hydrophilic = decline in absorption
- larger molecular size = decline in absorption - Ionisation
- Disease state
- if nose completely blocked = can’t spray nothing into it
Explain why formulations are suited for this route
Inhaled particles (lungs):
- can be liquid droplets or solid particles
- Lungs: particles need to be 1 to 5 micrometers (AERODYNAMIC)
- if larger will impact in airways = won’t reach alveolar sacs
- if smaller = exhaled again
Explain the different asthma technologies (nebuliser, PDMI, DPI)
- Nebulisers
- jet nebuliser = most common
- are given in single dose sterile ampoules
- turns liquid into mist (drug is dissolved)
- can give high doses
- easy to administer- compressed gas enters + is vaporised
- vapour particles pass through baffles + particle size is reduced + passed out of mouthpiece
- Inhalers
2a. PMDI
- drug is in solution / suspension, propellant = liquid
- nozzle = specific volume of drug released
- need to shake PDMI to ensure drug dose is correct (drug is evenly distributed)
- propellant evaporates + leaves drug droplets2b. DPI
- drug is solid
- only excipient is diluent (lactose which is swallowed)
- affected by humidity = agglomeration
- can deliver high doses
- used mixed powder to reduce agglomeration (small particles = high electrostatic potential = agglomerate)
1. capsule is pierced + powder released when patient inhales (sufficient pressure) - Spacers
- only used in PDMIs
- help people struggling with coordination (acutation-inhalation)
- for elderly, children, those with disabilities
Describe excipients for inhaled + nasal formulations
- Propellants
- Diluents (lactose)
- Antimicrobial preservatives
- Co-solvents (ethanol)
- Solubilising + stabilising agents
Explain the cause and development of asthma
Asthma = chronic inflammation + narrowing of airways BUT is reversible
- Inhaled allergens cross epithelial cells + activate mast cells (by cross linking surface bound IgE molecules)
- mast cells release histamines
- histamines activate Gq protein coupled H1 receptors = muscle contraction
- this release bronchoconstrictors mediators - Allergens also bind to dendritic cells (APC) when cross epithelial cell
- causes stimulation of CD4+ T lymphocyte = production of Th cells = stimulated B cells which produce IgE antibodies
- IgE antibodies sensitise mast cells
- TH cells also produce IL-5 = eosinophil production + inflammation + stimulate mast cell proliferation - Breakdown of AA (LOX pathway) produces LTC4, LTD4, LTE4 = bronchoconstrictoirs
- LTs activate Gq protein coupled receptors on bronchial smooth muscles
- ↑ intracellular CA2+ = contraction (myosin is phosphorylated) - Adenosine activates Gi protein coupled receptor = decrease in CAMP = muscle contraction
- Acetylcholine active Gq protein couple M3 receptors (parasympathetic nerves) causes bronchoconstriction
- ↑ intracellular CA2+ = smooth muscle contraction
Cause: genetics, other atopic disorders (e.g. eczema)
Symptoms: wheezing, difficulty breathing, persistent cough
Define the aims of treatments for acute and chronic asthma / COPD
AIMS:
- control / improve symptoms
- prevent exacerbations
- minimise side effects
- reduce need for rescue medication
- improve lung function (spirometry - FEV1 / FVC ~ 80%)
- FEV1 = volume of air exhaled in 1st second
- FVC = volume of air forcibly exhaled
- promote adherence + self-care
- improve QoL
COPD:
- stop / reduce amount smoke
- prevent infected exacerbations
- maintain nutritional intake (many COPD patients experience weight loss)
List non-pharmacological methods for improving asthma
- Avoid allergens + triggers
- Stop smoking
- Lose weight if obese
- Avoid exercise in cold air
- Avoid NSAIDs + beta-blockers
- Breastfeeding
Explain the types of therapy used to treat acute / chronic asthma
- Inhaled
- Inhalers (PDMI, DPIs)
- Reliever
- SABA e.g. salbutamol
- relieve symptoms quickly, short acting, use PRN
- Preventer
- corticosteroid e.g. beclamethasone
- use 2x a day, act on inflammation
- Controller
- LABA e.g. salmeterol
- slow onset, long acting, use 2 a day
- Nebulisers
- inhale mist - Oral
Systemic effects: oral > nebuliser > inhaled
What is the management plan for acute severe + chronic asthma?
Chronic:
- Treatment reviewed every 3 to 6 months (step up / down treatment)
- Require SABA (reliever)
If have infrequent wheezing:
- Add preventer (low dose ICS)
If worsening symptoms:
- Add controller (LABA) to low dose ICS
If no improvement:
- Stop LABA + give higher dose ICS
Acute:
- PEF is worsening
- Persistent hypoxia (low O2 reaching tissue)
- Exhaustion / drowsiness
- Blood pH = 7.4
- In hospital: steroids 5/7 days, steroid inhaler
PEF:
- take best of 3 (morning + night) and record in PEF diary
- >80% = normal
- <50% = acute severe asthma
Monitoring:
- PEF
- O2 saturation (94 - 98%)
- HR / RR
- White cell count
What is the management plan for COPD?
- Stable COPD but still breathless / exacerbations = SABA PRN
2a. Still breathless BUT NO asthmatic symptoms = LABA / LAMA
2b. Still breathless WITH asthmatic symptoms = LABA + ICS
3b. Still breathless = LAMA, LABA, ICS (triple therapy)
Asthmatic symptoms = waking up coughing, night time waking
List the 9 classes of drugs used to treat asthma / COPD
- B2 agonist (beta 2)
e.g. salbutamol, salmeterol - Corticosteroids
e.g. beclamethasone, prednisolone - Leukotriene Antagonist
e.g. Monteluekast - PDE inhibitors / methylxanthines
e.g. theophylline, roflimulast - Cromones
- Immunosuppresants
- Anti IgE monoclonal antibodies
- Muscaranic antagonist / antimuscarnic bronchodilators
e.g. imatropium (SAMA), titropium (LAMA)
1st line treatment in COPD - Biologics
How does B2 agonist manage asthma?
- Bind to Gs protein receptor = activate adenyl cyclase = ↑ in CAMP levels = protein kinase A is inactivated = ↓ intracellular Ca2+ (removed via Ca channels) = myosin NOT phosphorylated
- Cause bronchial smooth muscle relaxation
- Enhance mucocillary clearance
Examples:
SABA:
- reliever
- quick relief, quick onset (mins) short lasting (4-6 hr)
- e.g. salbutamol
LABA:
- controller
- slow onset (10-20 min), long lasting (12 hr)
- salmeterol
Disadvantages:
- receptor desensitisation (prolonged exposure)
- after dilation may get restriction of airways
How does corticosteroids manage asthma?
- Inhibits COX
- Reduce airway inflammation, bronchial hyper response, oedema, mucus secretion
- Can be used with LABA or LAMA
- Can be inhaled, oral, IV
- oral isn’t recommended long term - Use if: FEV1 = <50% , unresponsive to SABA, LABA / LAMA
- Bind to glucocorticoids receptor = inhibit inflammatory cells + suppress expression of inflammatory mediators
+ inhibit transcription of interleukin genes = reduced IL cytokines = allergic response doesn’t occur
Examples: Prednisolone (40-50mg - 5 days), Beclemethasone
Side effects: immunosuprression, thinning of skin, moon face (oral), oral candidiasis (inhaled)
Doses:
- < 400micrograms - low dose
- 400 to 800micrograms - moderate dose
- > 800micrograms - high dose
Children and young people < 17:
- <200micrograms - paediatric low dose
- 200 to 400 micrograms - paediatric moderate dose
- > 400micrograms - paediatric high dose
How does leukotrienes antagonist manage asthma?
- Mast cells produce leukotrienes (when allergen activates cell)
- Block leukotrienes from binding to Gq protein coupled receptor = ↓ muscle contraction (↓ Ca2+)
- Examples: montelukast, zafirlukast
How does cromones manage asthma?
- Mast cell stabilisers
- Inhibits release of histamine from mast cells
Example: nedocromil
Side effects: nausea, bitter taste, dyspepsia
How does immunosuppressants manage asthma?
Examples: Methotrexate, Ciclosporin
- Prevent inflammation
- Rarely used, are steroid sparing agents
How does anti IgE monoclonal antibodies (e.g. Omalizumab) manage asthma?
- Inhibits binging of IgE to mast cells = prevents inflammation response
- i.e. release of histamines - SC injection (every 2 to 4 weeks)
- No improvement after 16 weeks = stop
- USE: over 12
How does muscaranic antagonist / antimuscarnic bronchodilators manage asthma?
- M.antagonist block effect of acetylcholine on M3 (muscarinic receptors)
- ach bind to M3 receptors coupled to Gq proteins = ↑ intracellular Ca2+ = contraction of smooth muscle (as myosin is phosphorylated) - ↓ intracellular Ca2+ = bronchial smooth muscle relaxation
Examples: ipatropium bromide (SAMA) - las, tiatropiuym (LAMA) - last 24hr
How does Phosphodiesterase (PDE) inhibitors / Methylxanthines manage asthma?
- Prevents breakdown of cAMP (into 5-AMP)
= ↑ cAMP = ↓ Ca2+ = muscle relaxation - Can be given orally or IV
- Weak bronchodilators
- Mucociliary clearance
- Monitor plasma cells - narrow therapeutic level
COPD:
- Patients that smoke = higher dose as cigarette smoke produce liver enzymes which break drug down
- if stop smoking reduce = will be toxic
- Romfluilast - increase B2 agonist effect
- acts on cytokines, reduces inflammation + swelling of airways
- used if symptoms worsen despite other treatment
- taken once a day
Example: Theophylline (oral), Aminophylline (iv - hospital), Roflumilast
Side effects: vomitting
How do cysteinyl leukotriene receptor blockers manage asthma?
Cysts-leukotrienes = IL-3, IL-5
- released by eosinophils during asthma attack
- cause airway inflammation
How do biologics (monoclonal antibodies) manage asthma?
- Omalizumab (binds to IgE receptors = decrease histamine releases from mast cells)
- Meoplixumab (binds to IL-5 = reduced eosinophil production)
- Imatinib (inhibits) tyrosine kinase = mast cells inhibited = decreased hyper responsiveness)
How does mucolytic drugs treat COPD?
Breakdown mucus in airways = easier to breath (no mucus plugs)
- reduces sputum viscosity
- Used if have chronic productive cough
- Doesn’t work in everyone
Example:
- Carbocisteine
- Mecysteine
How does oxygen treat COPD?
- Required if have severe COPD (FEV <35%)
- i.e. severe airway obstruction, O2 < 92%, oedema - 24 - 28% oxygen
- Long term therapy (>15 hr daily)
- Used for acute exacerbations
Mechanism:
- Improves hypoxia
- Reduces work if breathing
HAZARD:
- Smoking (O2 cylinder is flammable)
- Too much O2 can cause respiratory distress / depression
How does antibiotics treat COPD?
Treat infective exacerbations ONLY
- Take sputum sample, send to lab for analysis to determine specific treatment
- Start with broad spectrum then FOCUS (use specific antibiotic when sample tested)
- If have recurrent infections = have long term antibiotic
- Can cause GI disturbances (if taking multiple)
Given if:
- ↑ breathlessness
- ↑ sputum volume
- change in sputum colour
Examples:
- Amoxicillin 500mg tds 5/7 (1st line)
- choices differ in hospitals + community (check local area)
- Azithromycin 250mg tds (long term treatment)
COPD vs Asthma
COPD
- Developed in middle aged
- Gradually progressive disease
- Trigger / cause = smoking (tobacco)
- Inflammatory cell = neutrophils
- causes protease release = membrane degrades = alveolar wall destruction (elastin lost) = mucus hyper secretion
- CD8+ T Lymphocytes
Asthma
- Childhood / adult development
- Reversible, and has episodes of attacks and stability
- Trigger = allergens
- Inflammatory cell = eosinophils
- CD4+ T lymphocytes
Chronic inflammation of airways
Trigger causes release of inflammatory mediators
Risk factors of COPD
- Smoking
- Age
- Occupation
- Have existing lung impairment
Vaccines Encouraged
- Influenza
- Streptococcus
- COVID
