RESPIRATORY PHARMACOLOGY

S+S OF RESPIRATORY CONDITIONS(ASTHMA AND COPD)

•SOB•Cough•Wheezing•Tight chest

2 AGONISTS

Mechanism of action: Bronchodilator1. Bind β2 receptor2. Activate adenylyl cyclase via GPCR (αs subunit)3. Increases cAMP levels4. This activates PKA5. Phosphorylates and hence inactivates myosin light

chain kinase6. This decreases smooth muscle cell contraction

Short acting (e.g. salbutamol) and long acting (salmeterol)Short acting go through the membrane channelLong acting interact with (and are taken into) membrane therefore “hang around” for longer

Side effects – think of too much dilationPeripheral vasodilation, Headache, Tremor, Tachycardia

Desensitisation: Repeated over activation of β2 receptors eventually leads to increased phosphodiesterase (PDE)

PDE inactivates cAMP so less cAMP and drugs will have less of an effect

β2 receptor

AC

↑ cAMP

Activates PKA

P and decreases MLCK

↓ SMC contraction

ANTICHOLINERGICS

•Mechanism of action: Bronchodilator1. Drug blocks M3 muscarinic receptor2. This decreases PLC3. PLC normally converts PIP2 into IP3 and DAG.

Decreased PLC decreases this process4. IP3 normally causes calcium induced calcium

release from endoplasmic reticulum. Decreased IP3 decreases this process

5. Less calcium is released for use in muscle contraction therefore less contraction of smooth muscles occur

* calcium causes contraction by binding to calmodulin and activating myosin light chain kinase•Short term (e.g. ipratropium) and long acting (e.g. tiotropium)•Side effects – (think what blocking other cholinergic receptors will do. Decreased rest and digest)Dry mouth, constipation, cough, headache, nausea, paradoxical

bronchospasm, urinary retention, glaucoma

M3 receptor

↑ PLC

PIP2 → ↓IP3

DAG

M3 receptor

↓ PLC

↓PIP2 → ↓

↓ IP3

DAG

No drug:

With drug:

CICR from E.R

↓ CICR from E.R

METHYXANTHINE •Mechanism of action:

In normal functioning, phosphodiesterase breaks down cAMP into 5’AMP which contracts smooth muscle (less cAMP means less PKA so less phosphorylation of MLCK, hence myosin is active and causes contraction)

Methylxanthines act as phosphodiesterase inhibitors, increasing cAMP, increasing PKA, increasing phosphorylation of MLCK, less contraction. Therefore bronchodilation

•Oral tablets, or IV if acute asthma attack•Side effectsInsomnia, nausea, vomiting, cardiac arrhythmias, seizuresVery severe so need to monitor serum levelsTherapeutic range – 10-20μg/mlNeed to consider what dose to start them on carefully (e.g. may need

lower doses in heart failure, cirrhosis and older patients)

β2 receptor

AC

↑ cAMP

5’ AMP

PDE

LEUKOTRIENE ANTAGONISTS

•Mechanism of actionLeukotrienes contribute to airway inflammation and

bronchospasmLeukotriene antagonists oppose thisThe cysteinyl-leukotrienes act at their cell-surface receptors

CysLT1 and CysLT2 on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation.

•Used as a preventor•Cysteinyl leukotriene receptors (CysLT1 & CysLT2) have been cloned•Montelukast & Zafirlukast block CysLT1 receptors:Reduces exercise-induced symptoms in asthmaReduce inflammatory response in early & late phases of asthmaAdditive effect with other drugsNo evidence of effect on remodelling (chronic asthma)•Side effects: Abdominal pain, headache, thirst, restlessness

GLUCOCORTICOIDS

•Mechanism of actionCorticosteroid. Diffuses across lipid membrane, bind receptor in cytoplasm and

enters nucleusActivated intracellular glucocorticoid receptor (GR) interacts with nuclear DNA

and influences gene expressionInhibition production of pro-inflammatory products (e.g. Th2 cytokines, IL-3, IL-5,

vasodilators PGE2 and PGI2, LTs). They do this by interacting with transcription factors and therefore preventing transcription of targeted pro-inflammatory genes

Up-regulate expression of anti-inflammatory products (e.g. up-regulate beta2-adrenoceptors). They know where these genes because they recognise the GRE (glucocorticosteroid response element) in the promoter region

•Beclomethasone (inhaled), Fluticasone (inhaled), Prednisolone (oral), Hydrocortisone (IV, in emergency)•Side effectsCushingoid symptoms – central adiposity, moon face, buffalo humpUlcers Skin: striae, thinning, bruising HypertensionInfections Necrosis, avascular necrosis of the femoral head Glycosuria Osteoporosis Immunosuppression Diabetes

Glucocorticoid

cytoplasm

MAST CELL STABILISERS•Mechanism of action“Stabilise” membranes of mast cells, preventing histamine release

?Suppress ‘irritant receptors’ on sensory C-fibres

•Only really used in children and in inhaler form•Side effectsBitter taste, paradoxical bronchospasm (rare)

IG-E ANTIBODIES•Mechanism of action:Monoclonal anti-IgE antibodyCompetes with IgE to bind to mast cellsPrevent binding to mast cells therefore decrease the mediators released by mast cells

•Useful to prevent allergic asthma•Omalizumab •Very expensive•NICE approved use (April 2013) in specific patients if:continuous or frequent treatment with oral corticosteroids (defined as 4 or more courses in the previous year), and

only if the manufacturer makes it available with the discount agreed in the patient access scheme

OVERVIEW OF MAST CELL STABILISERS AND IG-E ANTIBODIES (REMEMBER THESE ARE ONLY USED IN ASTHMA)

Allergen exposure

Plasma cells activated – WBC that produce immunoglobulins

IgE production

Mast cell degranulation. Release histamines, prostaglandins and leukotrienes

S+S of asthma

Mast Cell Stabilisers

IgE Antibodies IgE binds receptors on

mast cells

ASTHMA TREATMENTAcute Management – think O SHIT

O – high flow oxygen. Sufficient to maintain sats 94-98%

S – Salbutamol. Nebulised, every 15-30 minutesH – IV hydrocortisone. Move onto

prednisolone QDS after initial attackI – Ipratropium bromide. Used normally if initial response to bronchodilators is poorT – Theophylline

Chronic ManagementNICE guideline steps

Step 1 – As needed short acting β agonists. Mild intermittent asthmaStep 2 - Add low dose inhaled corticosteroids. Regular preventer therapyStep 3 – Add long acting β agonists. Initial add on therapyStep 4 – Increase dose of corticosteroids. Persistent poor controlStep 5 – additional therapies to minimise steroid use. Constant use of steroid

COPD TREATMENT•Smoking cessation advice – only real way to prolong life•Bronchodilator therapyshort-acting ß2-agoinst (salbutamol) short-acting anticholinergic (ipratropium)•Combination therapylong-acting ß2-agonist (salmeterol, formoterol)inhaled steroid (beclomethasone, fluticasone)long-acting anticholinergic (tiotropium)•Oral theophyllineonly if short and long-acting bronchodilators ineffective or inappropriate

•Home oxygen