Lec 42-asthma Flashcards
Definition
- Asthma is a common long term condition that affects the airways
- Central to all definitions is the presence of symptoms (more than one of wheeze, n breathlessness, tight chest, cough and of variable airflow obstruction)
- More recent descriptions of asthma in both children and adults have included airway hyper-responsiveness and airway inflammation as components of disease
Demographics
- 8 million people- over 12% of the population- have been diagnosed with asthma at some point
- Asthma UK states around 5.4 million people receive treatment for the disease
- In 2012, 12,565 females per 100,000 and 12,033 males per 100,000 had asthma. Asthma occurred slightly more frequently in females than males throughout the years 2004-12
- Around 1,200 people a year are recorded as dying from asthma in 2012 (1.1% of total lung disorders
Symptoms
-More than one of the following symptoms: wheezing, breathlessness, chest tightness and coughs (particularly if worse at night or early morning)
-Triggers= irritate, tighten and inflame airways: Common cold; allergies to pollen; air pollution
-The airway lining becomes inflamed causing build up of sputum. This makes the airways even narrower, so harder to get air in and out of the lungs
+Exercise-induced-asthma
+History of atopic disorder
+Family history of asthma and or atopic disorder
Diagnosis
- The amount of air you breathe out is measure by
- Spirometry- measures the total amount of air you can breathe out from your lungs and how fast you can blow it out (presence and severity of airflow obstruction
- Peak flow meter measure how fast you can breathe out after you have taken a full breath in
2 phases of asthma
- Immediate phase reaction: on first exposure to Ag
- Late phase reaction: more sustained occurring 3-12 hours after early reaction
Eosinophils
-Major cells in the LPR Primarily a secreting cell- -Eosinophil granular associated proteins \+Major basic protein (MBP) \+Eosinophil cationic protein \+Eosinophil-derived neurotoxin \+Eosinophil peroxidase -Platelet activating factor (PAF) -Peptido leukotrienes (LTC4,LTD4 , LTE4) -Free radicals species
Inflammatory mediators
-Histamine
-COX products
-Lipooxygenase products
+Bronchoconstriction: powerful response in asthmatics
+Increased vascular permeability: Very potent PAF> LTD4» Histamine
+Increased mucous secretion: v.potent
-Bradykinin
-Platelet activating factor PAF
Drug treatment of asthma
- Asthma is common, incurable but eminently treatable
- Asthma is an inflammatory disorder- the inflammatory basis is an important target
- Relivers (bronchodilators): rapid symptomatic relief in an acute attack
- Preventers- prophylactic therapy to suppress immune component of asthma
- Non-pharmacological and alternative medicine- no convincing data of benefit
Aim in chronic asthma
- Control of symptoms- preferable no chronic symptoms e.g. no nocturnal dyspnoea, best possible pulmonary function with minimal side effects
- Stable long term control- no exacerbations
- Minimal nocturnal symptoms
- Minimal use of relievers
- Peak expiratory flow rate (PEFR) maintained at 80% best. circadian variation on PEFR <20%
- Minimal limitation on exercise
Pathway for drug treatment for asthma
1)Diagnosis and assessment
-Consider monitored initiation of treatment with low dose ICS
2)Evaluation: symptoms, lung function
NB should have short acting B2 agonist prn- consider moving up scale if use 3 or more times a week
-Regular preventer (Low dose ICS)
-Initial add on therapy: add inhaled LABA to low dose- ICS (normally as combo inhaler)
-Additional add on therapies: No response to LABA stop and increase dose of ICS; if benefit from LABA but no control- continue and increase ICS to medium dose; If benefit from LABA but control still inadequate- continue LABA and ICS and consider trial of other therapy (LTRA-MONTELUKAST, theophylline-phosphodiesterase inhibitor)
-High dose therapy: Increasing ICS to high dose; addition of 4th drug (LTRA, theophylline, B-agonist tablets, LAMA) and refer to specialist
-Continuous or frequent use of oral steroids: use daily steroid tablet in the lowest dose to provide adequate control; maintain high dose; consider other treatment to minimise use of steroid tablets (refer to specialist)
Chronic asthma: Step 1- mild intermittent asthma
-Short acting inhaled B2-bronchodilator (SABA) on prn basis (But no evidence against regular dosing)
-Asthma is not controlled at any step is using SABA
+>3 x a week
+Having symptoms 3x a week or more
+Waking at least once a week
-Same strategy for adults and children under 5 years but evidence base best in adults
-Inhaled B-agonist 30 min before exercise is treatment of choice for exercise induced asthma
B-agonsit in asthma
- Bronchodilation- B-receptor on bronchial smooth muscle.M`jor effect. Most quickly effective agents availeble. act as function antagonist
- Cholinergic nerves- some reduction of Ash release (post-ganglionic nerves)
- Mucous secretion- some decrease in viscosity leading to increased clearance
- Mast cells- B-receptors stabilise. No proven anti-inflammatory action. Little change in hyper-reactivity
Adverse effects
- Skeletal muscle tremor- diagnostic use
- Cardiac stimulation- direct B2 and indirect reflex due to peripheral B2-vasodilaiton
- Impaired ventilation/perfusion ratio
- Hyperkalaemia
- Increased glucose metabolism
- Increased lipolysis
- CNS stimulation- variable typically sleep disturbance
Choice of agent (B2)
-All B2-agonist are effective
-Pharmacological differences account for differing profile of action
+Degree of B2-selectivity
+Binding affinity: duration of action
+Binding kinetics: onset of action
-Systemic effects can be clinically significant
+Vascular B2: vasodilation. reflex tachycardia
+In high doses break through B1-agonism
Short acting B2-selective agonist
-None are catecholamines (rapid metabolism)
-Rapid onset of action (<10 minutes, leak 30-90 min) and relatively short duration 4-8 hours when given by MDI
-Some may be used orally for prophylaxis
-Relatively free of CVS effects by inhaled route
+Salbutamol
+Terbutaline
Systemic administration B-agonists
- Some active orally. Increase SE profile and little evidence of benefit (unless unable to use inhaler)
- Parenteral administration used in severe or life threatening asthma
- Caution in hyperthyroidism, CVS disease, diabetes
- Risk of hypokalaemia- may be serious with systemic administration
Chronic asthma Step2: regular preventer therapy
-Low dose inhaled corticosteroids \+Beclomethasone (BEC) 200mcg BD \+Budesonide- 200mcg BD \+Fluticasone- 100mcg BD \+Mometasone- 200mcg BD -NB for dry powder inhaler
CFC free inhalers- HFA propellants
BECLOMETHSAONE (BEC)
-Qvar: extra-fine particles and more potent than traditional CFC containing inhalers and 2x more potent than clenil
-Clenil modulite: Is same potency as dry powder and CFC BEC inhalers
NB: QVAR and CLENIL are NOT interchangeable and should be Rx by brand
-Dose conversion advice in BNF
-Steroid card issued with high dose BEC
Alternative step 2 strategies
- Cromones: DSG ineffective in children, nedocromil not effective <5years
- Long active Beta-Agonist (LABAs)- have effect but should not be used without steroid therapy- so not step 2
- Leukotriene antagonists- have some effect. May be useful in children particularly <5
- Theophylline- may have beneficial effect but side effects. Caution
Glucocorticoids
First used early 1950 by systemic route
-Most powerful agents for asthma therapy
-Major systemic actions
-No direct bronchodilator activity: no immediate relief from symptoms
-6 hours before benefit and even with injection Max benefit only after 12-24 hours
INHALED administration of topically active steroids
+At suitable dosage minimises systemic actions- step 2 ‘standard dose’ regimens
+Now a major component in asthma therapy
Inhaled Administration
-Agents must have potent topical action
-BEC and budesonide equipotent
-No convincing evidence of advantage for any individual agent
-Deposition in oropharyngeal tract is a problem (Candidiasis, dysphoria can occur even at low dose)
+May minimise by use of spacers or prior administration of B-agonist
+Rinse mouth after use. particularly in higher dose schedules
Inhaled steroids- ADRs
-HPA suppression
+No significant risk BDP <800mcg dd adult or 400mcg dd child
-Bone resorption- some controversy
+Modest effects down to 500mcg dd in adults
-Carbohydrate metabolism/ Lipid metabolism
+Effect minor and not significant <800mcg dd
-Growth retardation: possible above 400mcg dd in children- usually short term. Monitor growth and use lowest possible dose
Mode of action in asthma (ICS)
-Major effect in suppression of cytokine synthesis and release and so recruitment of inflammatory cells (particularly eosinophils)
-Affect many components of inflammatory response
+Inhibit PLA2
+Inhibit macrophage activation
+Depress Ab synthesis
+Depress activation and recruitment of T cells and eosinophils
+Depress release of peptide-LTs
+(Little immediate direct effect upon mast cells)
Step 3: initial add on therapy
- Check compliance before action
- Add inhaler LABA to low dose ICS (combination inhaler)
Long acting B-agonist (LABA)
-Slow onset of action, prolonged action
-Not normally for acute attacks and used on a regular BD schedule for control
-Prolonged functional antagonism at bronchial smooth muscle. DO not replace steroids- no evidence for anti-inflammatory action
-Very potent (salmeterol 4x more than salbutamol)
+Salmeterol (serevent)
+Eformoterol
+Bambuterol- 24 hr drug (pro-drug)
Compound preparations (ICS+ LABA)
-Several different combination
-Fostair (BEC and formoterol 100/6)
+Can be used BD at step 3
-Seretide (fluticasone/ salmeterol)
-Symbicort (budesonide/formoterol)
+Used BD at step 3
+Also can used BD plus PRN as a combined prophylaxis and acute therapy
Step 4: additional add on therapies
- STOP LAVA if no response and increase ICS to medium dose
- If benefit from LABA but no control continue LABA and increase ICS
- IF benefit from LABA but NO control LABA + ICS + LT antagonist or theophylline or LAMA
Step 5: High dose therapies
-Increase ICS to high dose
-Add 4th agent
+LT antagonist
+M/r theophylline
-LAMA
-Oral slow release B-agonist tablet
Other step 4 candidates: methylxanthines
-Clinical use theophylline or as aminophylline. effective orally only
-Bronchodilator over plasma range 30-100 mcMol/ml
(side effects at 100mcMol and serious at 200)
-Small Vd- little individual dose variation
-Clearance by hepatic metabolism- variable
+Increased by enzyme induction (rifampicin, phenobarbital, phenytoin, carbamazepine)
-Impaired by hepatic disease and inhibitors of metabolism (the pill, erythromycin, CCB)
-Low therapeutic index and variable clearance
+Plasma levels achieved not easy to predict
Undesirable products (side effects of methylxanthines)
-Oral MR products minimise changes in plasma levels but show variable release
SIDE effects
-Cardiac stimulation- can be marked (inotropic and chronotropic) . High risk when by parenteral route- rare now
-Gastric irritation- increased release of gastric acid and digestive enzymes
-CNS disorganises - insomnia, anxiety, nervousness and tremor. Seizure a risk- in children around upper dose range
-NOT normally used in chronic asthma in children unless other therapies have failed- specialist advice only
Mode of action Theophylline
- Mode of action in asthma is still not fully explained
- Phosphodiesterase inhibition- likely to be involved but are plasma concern . too low
- Adenosine antagonist- but an analogue enprofylline is active yet not an antagonist
- Inhibition of inflammatory cells- weak and not enough to explain action
- Potentiation of diaphragm contractility- useful action unique to these agents
Leukotriene antagonist (LT)
-Montelukast and zafirlukast
-Cysteinyl leukotriene receptor (cysLT1) antagonist
-Long acting and orally active. OD therapy
-Licensed for prophylaxis of asthma
+Montelukast for add on therapy in adults and children
+Zafirlukast for therapy of asthma adults and children >12
Clinical use (of LTA)
-Inhibit EPR and LPR
-Additive with inhaled and oral corticosteroids and with B-adrenoceptor agonists
-Not licensed as steroid sparing agents- additive with steroids. Don’t replace and given with steroids
-Inhibit aspirin induced and exercise asthma
-Main SE are GI disturbances including pain and headache
-Both can induce Churg-Strauss syndrome-utoimmune condition that causes inflammation of small and medium-sized blood vessels
+Vasculitis and eosinophilia- common background asthma
+Rare but fatal normally seen on steroid withdrawal. Monitor patients during steroid down-dosing
New LAMA agents
-Aclidinium bromide
+Competative selective muscarininc receptor antagonist, with longer residence time at M3 receptors which mediate contraction of smooth muscle in the airways; induce bronchodilation
+Once absorbed it is rapidly broken down in the plasma, resulting in minimal systemic anti-cholinergic side effects
-Glycopyrronium bromide
-Umeclidinium
Chronic asthma- step 6: continuous and frequent use of oral steroids
-Add oral steroids with Aim of controlling asthma on the lowest possible oral steroid use
-Risk of systemic effects in therapy >3moths or more frequent than 3/4 times per year
+Monitor BP
+BLood sugars and ChE
+Add long acting bisphosphonate if longer 3 moths to counter osteoporosis (Bone mineral density)
+Monitor growth retardation and cataracts in children
-Minimise use of steroid tablets
+High dose inhaled steroids important- 2000mcg/day
+Role for trial of LABA M/r theophylline and LT antagonist for 6 weeks. Stop if no improvement or no reduction of steroid dose
Oral and parenteral steroids
-Oral- prednisone the standard agent
+equi-effective of parenteral route- route of choice
+Acute asthma: daily dosage 40-50mg- usually single dose in the morning
+Children 20mg (2-5yrs) and 30-40mg (>5yrs)
+USed only when other therapies have failed
+No need to taper off dose if therapy duration <3weeks
-Parenteral-hydrocortisone preffered
+400mg dd as 100mg doses every 6hrs. Children 4mg/kg 4 hrs
+rare to continue beyond 3 days
Anti-cholinergic
-Oldest drugs for asthma e.g. stramonium
-All are muscarinic antagonist- none are selective for muscarininc receptor sub-types
-Reduce cholinergic tone to bronchial SM and sub mucous glands
-Atropine highly effective but marked systemic effects
+Dryness of mouth; dilation of pupils; cycloplegia; dryness of skin; constipation; urinary retention
-Airway selectivity is achieved by inhaled administration
The anti-cholinergic
-Ipatropium bromide
-Oxitropium bromide
+both are Quaternary compounds with poor absorption across mucous membranes
+When inhaled, actions are local in the respiratory tract
+Slow onset of action but prolonged duration- ipatropium 8 hrs and oxitropium up to 12 hrs
-No value as add-on in chronic asthma
-Value in acute asthma
Cromoglycate/nedocromil
-Derived from original research on khellin from seeds of Amni Visnaga
-Not branchedilators
-Very safe with few side effects
-Little clinical value
+possible alternative to low-dose inhaled steroids (step 2)
+have some value in exercise induced asthma
+May be considered for occupational asthma
+No value in acute asthma
-Often termed mast cell stabilisers. Decrease mediator release from by Ca dependant mechanism. Not the only mode of action
Non-pharmacological management- Evidence value
-Primary prevention \+Breast feeding in infants- may also protect development of early asthma \+Avoidance of tobacco smoking \+Weight reduction -Secondary prevention \+Avoid house dust mites- measure to reduce \+Immunotherapy where clear Ag -Alternative medicine \+Buteyko breathing technique
Non-pharmacological- NO evidince of value
-Primary prevention \+Nutritional supplementation \+Immunotherapy \+Fish oil; and fatty acid electrolytes -2nd prevention \+air pollution -Complementary/Alternative medicine \+Acupuncture \+Herbal medicine \+Hypnosis \+Ionisers \+exercise programmes
Asthma in children: Chronic asthma <5
1) inhaled SABA (continue PRN at all steps)
2) Regular preventer: ICS or LT antagonist
3) Initial add on preventer
+If on ICS 200-400mcg dd add LT antagonist
+If on LT antagonist add ICS 200-400 msg
4) Persistent poor control refer to speacialist
Chronic asthma in children >5
1) inhaled SABA
2) Regular
Chronic asthma in children >5
1) inhaled SABA
2)Regular: ICS
>12= 200-800mcg/day BEC
5-12 = 200-400 mcg/day BEC
3) initial add on preventer: LABA
4+5) additional add on therapies: continue with LABA if benefit and increase ICS
-If no benefit with LABA: LT antagonist; M/r theophylline
6) Continuous/frequent use of oral steroids- at lowest dose
Acute asthma (Risk factors)
-In UK 200 deaths per annum- majority chronically severe asthma
-Risk factors for acute asthma
+More than 3 drugs for control
+Previous acute attacks or poor control
+Brittle asthma- wide variation in PEFR (Type 1) or sudden severe attacks when apparently controlled (Type 2)
+Psychiatric illness or treatment
+Alcohol or drug abuse
+Social factors e.g. isolatio , poverty, stress, abuse
Acute severe asthma (diagnosis inc life threatening)
ANY OF
-Respiratory rate >25/min (>30/min child over 5; >50 in under 5)
-Pulse rate >110/min (>125/min child over 5; >140 under 5)
-PEFR (Peak Expiratory flow Rate)33-50% of best
-Breathlessness- affects speech. Can’t complete sentences
LIFE THREATENING
-Cyanosis
-Weak respiratory effort
-PEFR <33% of best
-Fatigue, confusion, exhaustion
-Bradycardia or exhaustion common
-CHILD tachycardia symptom of severe falling rate at pre-terminal event
Therapy of acute asthma
- High flow O2; all patients
- High dose of B-agonist: inhaled when possible; Nebulised salbutamol or terbutaline in life threatening. IV used when inhaled impossible
- Steroid: oral if possible (40-50mg OD adults) or IV hydrocortisone Max 100mg QDS when oral impossible
- Ipatropium Br: Add to nebuliser in life threatening or if bronchodilator response is poor
- Life threatening: IV Mg sulphate, IV aminophylline. Needs some senior medical decision
Acute in children <2 yrs
- Additional problems: recurrent cough and Wheeze often associated with upper respiratory viral infections> May not indicate worsening of asthma
- Diagonsis relies on symptoms- few functional tests. Conditions may suddenly worsen
- Can use oral steroids in hospital setting
- Inhaled ipatropium Br in combo with inhaled B-agonist can be considered
Monitoring in acute asthma
- HR
- Pulse rate
- Maintain SpO2 >94-98%
- Peak expiratory flow 15-30 minutes after starting treatment
- Blood has measurements
- Chart PEF before and after giving B2-agonist and at least 4 times daily throughout hospital stay
