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CAL

  • A disease state characterised by airflow limitation that is not fully reversible.
  • The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases [cigarette smoke]
  • Chronic bronchitis and emphysema.

Clinical Features

  • Productive cough
  • Dyspnoea
  • Recurrent low-grade infective exacerbations
  • Respiratory failure (leading cause of death)

CAL.PNG

Factors that can contribute to the development of CAL

  • Number 1: cigarette smoke
  • Occupational dust and fume exposure
  • Air pollution
  • Alpha – 1 antitrypsin deficiency
    • Serum protein found in liver
    • Inhibits neutrophil elastaseƒ
  • Genetic predisposition
  • Recurrent respiratory infections in childhood
  • Bronchial hyper-responsiveness

NB: 15-20% of smokers develop chronic CAL. 50% of smokers have some airway limitation

Inflamm and CAL.PNG Damaged alveoli.PNG

  • No proteinases have succeeded in clinica trials
  • Attachments between alveoli are deleted in emphysema etc, no longer able to keep the airway open during inspiration = breathlessness
  • Damaged alveoli: holes appear, looks like lacework

Bronchoconstriction in CAL

  • May be partially reversible in many patients.
  • Airway hyper-responsiveness may develop after exposure to tobacco smoke or environmental irritants.
  • Chronic inflammation is associated with an increase in the amount of smooth muscle in the airway wall.
CAL Asthma
Affects Elderly Affects All Ages
Progresses Slowly Episodic Course
Inflammation Inflammation
Partially Reversible Completely Reversible
  • Asthma - CD4, mast cells, eosinophils
  • CAL - neutrophils, CD8, macrophages
  • Overlap between asthma and CAL = asthmatic bronchitis
    • So a lot of the drug treatment between them is similar, but we apply it differently

Efferent pathways of the airway

  • Which receptors are present in the airway smooth muscle and what do they do?
    • Beta 2 adrenergic receptors – Circulating adrenaline stimulates it, little sympathetic innervation
      • Cause bronchodilation
    • Muscarinic (M1,2,3) receptors – Parasympathetic nerve endings; Ach
      • Causes bronchoconstriction
      • M1/3 is postsynaptic. M2 are presynaptic. M2 exerts a negative feedback effect on ACh release. M2 actually therefore decreases bronchoconstriction. So we target M1/3.
      • Thus the lung has very little sympathetic innervation
    • Non-adrenergic non cholinergic nerves (NANC)
      • Inhibitory -NO (relaxant in airway)
      • Stimulant -Substance P (increase vascular permeability and mucin secretion), neurokinin A (potent spasminogen)

Lung receptors.PNG NK antagonists should in theory work, but no drug trials have worked yet. Therapy focuses on B2 agonists and M1/3 antagonists

Treatment

  • Stop smoking
  • Pharmacological management
    • Bronchodilators – reliever medication
      • -β2adrenoceptor agonists, Xanthines (not frontline, only used in exceptional case), muscarinic receptor antagonists (more used in CAL because they inhibit mucus secretion which is pathognomonic of CAL)
    • Symptom controllers
      • Long acting β2 adrenoceptor agonists
    • Anti-inflammatory drugs
      • Glucocorticoids, oral steroids, leukotriene receptor antagonists
  • Adjunct therapy
    • Antibiotics
    • Vaccine for flu etc
    • Oxygen therapy

Smoking & CAL.PNG

  • Smoking causes 1) impaired muco-ciliary escalator, 2) mucus gland hypertrophy, 3) altered structure of alveolar macrophage, & 4) lung cancer & CVD
  • Never too late to stop smoking - is the key thing to tell patients

β-adrenergic agonists: reliever medication

  • Dilate bronchial smooth muscle by a direct action on β2 adrenergic receptors.
  • Antagonise bronchoconstriction of the smooth muscle irrespective of the spasmogen involved – physiological antagonism.
  • Inhibit the release of inflammatory mediators by mast cells. (Weak mast cell stabilisers)
  • Short-acting (SABA): SALBUTAMOL and TERBUTALINE
    • duration of action 4-6 hours, maximum effect 30 min (by inhalation)
    • resistant to uptake and to enzymatic degradation, excreted largely unchanged in urine
  • Long-acting: SALMETEROL
    • duration of action ~ 12 hours; but delayed onset of action (less effective for acute problem; more effective for treating CAL but more expensive)
  • Side-effects
    • Tremor and some tachycardia
    • Patient overuse leads to tolerance and desensitisation.
    • Should be used on an ‘as need basis’ during the early stages of disease.
    • Co-morbidity with cardiovascular disease --> Drug interactions (cardiac disease often treated with betablockers)
      • Eg beta blocker. Beta blockers are contraindicated in asthmatics. Not true for CAL, but can result in drug interactions.
      • Selective B2 agonist and selective B1 antagonist should work, but they're less selective at high doses -- so try another drug type

Muscarinic receptor antagonists: Ipratropium Bromide

  • Ipratropium antagonises bronchial constriction caused by parasympathetic stimulation
  • More effective in CAL then for asthma.
  • Onset of action is slow, maximum effect after 30-60 minutes; duration of action 3 – 5 hrs.
  • Used in combination with a short acting β2 adrenoceptor agonist.

M receptors.PNG

  • M receptors all stimulated by ACh. M2 causes negative feedback on ACh. M1/3 cause bronchoconstriction.

XANTHINES e.g. THEOPHYLLINE

  • Bronchodilators, used when β2 agonists ineffective (Not frontline drugs!!)
  • Well absorbed, given orally, using slow-release preparations
  • -> sustained blood levels up to 12 hours
  • Mechanism of action:
    • Theophylline inhibits phosphodiesterase (which metabolises cAMP) thus --> increased intracellular cAMP which could inhibit the activation of inflammatory cells; bronchodilation.
    • cAMP acts as a relaxant in the airway
  • However, effective concentration exceeds therapeutic dose - so we don't really know how these effects work
  • Side-effects:
    • poor therapeutic index (TI = Effective concentration/Toxic concentration)
    • need for individual monitoring of blood levels - titrate dose to individual patient - is invasive
    • CNS stimulation: reduced fatigue, improvement in mental & motor tasks, tremor, nervousness, sleep interference
    • Cardiac stimulation: positive inotropic & chronotropic effects ---> cardiac arrythmias
    • Diuresis: increased GFR
    • Gastrointestinal symptoms: nausea vomiting anorexia
    • Drug Interactions: oral contraceptives, erythromycin, calcium channel blockers, cimetideine.
      • All these drugs can inhibit the CYP450 that is involved in the metabolism of theophylline --> builds up --> we should reduce dose or not use

Glucocorticoids: Steriodal antiinflammatory drugs

  • Anti-inflammatory and immunosuppressant
  • Not bronchodilators
  • May reduce bronchial hyper-reactivity
  • Can result in a significant increase in FEV1 in responsive CAL patients.
  • Inhaled glucocorticoids
    • Beclomethasone, Beudesonide, Fluticasone
  • NB: if b2 agonists don't work, then most probably gluccocorticoids will not work either.
    • But even though they don't improve FEV1, they can reduce exacerbations
    • At the moment they are being prescribed, but keep abreast of literature (it's controversial)

Glucocorticoids: immunosupprressant

  • Inhibition of the influx of inflammatory cells in the lung.
  • Inhibition of the activation of macrophages and mediator release from eosinophils.
  • Reduction in the formation of inflammatory cytokines
  • Reduction in the synthesis of IL-3 (which regulates mast cells)

This is what makes them useful for inflammatory conditions, but causes side effects

Glucocorticoids: Antiinflammatory actions

  • ƒInhibit the induction of COX - 2
  • Inhibit the formation of arachidonic acid by inducing the synthesis of Lipocortin
  • Lipocortin inhibits phospholipase A2 and the subsequent formation of both prostaglandins and leukotriennes

Eicosanoid byosynthesis.PNG


See table on the actions of eicosanoids in inflammatory reactions

Glucocorticoids: Side effects

  • Oral Thrush and hoarseness
  • Suppression of the immune system
  • Systemic effect- bruising, dermal thinning, adrenal suppression and altered bone metabolism leading to osteoporosis (esp. elderly)
  • Impaired wound healing
  • Development of diabetes and peptic ulcers
  • Cushing’s Syndrome
  • Side effects more likely with oral glucocorticoids [prednisolone]
  • Growth problems in children (not a problem in CAL - elderly)

Leukotriene receptor antagonists and synthesis inhibitors

  • Antagonists:
    • Leukotrienes are potent bronchoconstrictors that amplify the inflammatory process
    • Competitive antagonists of LTC4, LTD4, LTE4
    • Eg. Montelukast, Zafirlukast
  • Inhibitors:
    • Leukotriene synthesis inhibitors block the formation of LTB4, LTC4, LTD4, LTE4
    • Inhibitors of 5-lipoxygenase
    • Eg. Zileuton

Exacerbations

  • CAL is often associated with exacerbations or worsening of symptoms such as cough, sputum production and dyspnea.
  • Management includes bronchodilators, glucocorticoids and antibiotics (for bacterial infections) and 02 therapy in the case of respiratory failure; flu vaccine to prevent viral exacerbations

COPD management.PNG

Memorise this table ^^ Aspirin sensitive asthma: COX inhibitor shunts production to LTs = worse for asthma

Cough

  • Cough removes foreign material and mucous secretions from the bronchi and bronchioles protective reflex
  • Unproductive cough: no mucous secretion, serves no protective purposes.
  • Cough should be treated with antitussives only if it is unproductive or excessive.
  • Common Causes:
    • Acute and chronic respiratory infection
    • Asthma
    • CAL
    • Irritant; eg cigarette smoke
  • No antitussive use in CAL - mucus secretion, might make bronchitis worse
  • Most antitussives are weak opioids - can cause respiratory depression. So not indicated in asthma either.

Anti-tussives

  • All opioids have antitussive actions in doses below those required for pain relief.
    • Weak analgesic and addictive properties.
  • Opioids inhibit the action of excitatory neuropeptides such as SP and increase the stimulation threshold of neurons in the cough centre. *EG.
    • Codeine
    • Dextromethorphan
    • Pholcodine
  • Don't give anti-tussives in asthma and CAL