Lec 42-asthma Flashcards

(49 cards)

1
Q

Definition

A
  • 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
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2
Q

Demographics

A
  • 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
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3
Q

Symptoms

A

-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

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4
Q

Diagnosis

A
  • 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
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5
Q

2 phases of asthma

A
  • Immediate phase reaction: on first exposure to Ag

- Late phase reaction: more sustained occurring 3-12 hours after early reaction

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6
Q

Eosinophils

A
-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
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7
Q

Inflammatory mediators

A

-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

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8
Q

Drug treatment of asthma

A
  • 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
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9
Q

Aim in chronic asthma

A
  • 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
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10
Q

Pathway for drug treatment for asthma

A

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)

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11
Q

Chronic asthma: Step 1- mild intermittent asthma

A

-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

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12
Q

B-agonsit in asthma

A
  • 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
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13
Q

Adverse effects

A
  • 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
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14
Q

Choice of agent (B2)

A

-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

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15
Q

Short acting B2-selective agonist

A

-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

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16
Q

Systemic administration B-agonists

A
  • 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
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17
Q

Chronic asthma Step2: regular preventer therapy

A
-Low dose inhaled corticosteroids 
\+Beclomethasone (BEC) 200mcg BD 
\+Budesonide- 200mcg BD 
\+Fluticasone- 100mcg BD 
\+Mometasone- 200mcg BD 
-NB for dry powder inhaler
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18
Q

CFC free inhalers- HFA propellants

A

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

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19
Q

Alternative step 2 strategies

A
  • 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
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20
Q

Glucocorticoids

A

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

21
Q

Inhaled Administration

A

-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

22
Q

Inhaled steroids- ADRs

A

-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

23
Q

Mode of action in asthma (ICS)

A

-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)

24
Q

Step 3: initial add on therapy

A
  • Check compliance before action

- Add inhaler LABA to low dose ICS (combination inhaler)

25
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)
26
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
27
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
28
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
29
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
30
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
31
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
32
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
33
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
34
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
35
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
36
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
37
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
38
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
39
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
40
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 ```
41
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 ```
42
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
43
Chronic asthma in children >5
1) inhaled SABA | 2) Regular
44
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
45
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
46
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
47
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
48
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
49
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