Lecture 3: Pharmacology of Asthma Flashcards
What is the major site of action for B2 adrenoreceptor agonists?
Bronchial smooth muscle
What are the beta 2 adrenorecpeptor agonists?
- Salbutamol
- Salmeterol
- Formoterol
What do the beta 2 adrenoreceptor agonists do?
Relax smooth muscles - bronchodilataion, so improve airflow into the lungs
How do beta adrenoreceptor agonists cause bronchodilation?
- Inhibit MLCK to inhibit contraction
- Phophorlyates and switches off the receptor for IP3 - less calcium avaialble for contraction
- promotes caclium efflux to inhibit contraction - increased by protein kinase A
- Inhibit proliferation to reduce airway remodelling
How is airway cell proliferation inhibited?
MAP kinase pathway is able to mediate the proliferation and the growth of airway smooth muscle. PKA is able to inactivate RAF 1 kinase and can reduce activity of MAP kinase - this should reduce contratilility of airways over time.
What is the function of IP3?
Interacts with IP(1,4,5)P3 receptor in the sarocopplasmic reticulum to mobilise calcium
How do the beta adrenoreceptor agonists work?
- Activate protein Gs
- Gs promotes the stimulation of adenylyl cyclase
- This enzyme catalyses the formation of cyclic AMP
- cAMP activates protein kinase A which can
target different proteins and cause bronchodilation.
What does protein kinase A do in mast cells?
Phosphorylate components that provide an anti inflammatory action - they inhibit the release of inflammatory mediators.
What does protein kinase A do in bronchial smooth muscle?
Protein kinase A phosphorylates and inactivates myosin light chain - the enzyme responsible for contraction so bronchodilation and imprpved airflow into the lung
what are the two types of beta 2 adrenoreceptor agonists?
- Long acting
- Short acting
Why is the structure of salmeterol a long acting beta adrenoreceptor?
Have lipophillic groups attatched which interact with exo-sites on the receptor - this locks the ligand onto the receptor binding site
What groups does salmeterol have?
Aryalkyl group
How does salmeterol differ from salbutamol?
Same structure as salbutamol with added arylalkyl groups - 11 amino acids long
What is the structure of salbutamol similar to?
Adrenaline - which is non selective so salbutamol is an improvement of adrenaline
What are the groups in salbutamol?
Tertiary butyl group - improves selectivity making it selective for beta 2 receptors
What is more potent? (Salmeterol or salbutamol)
Salmeterol
What is the action time of salmeterol?
12 hours
What is the action time of salbutamol?
4 hours
what are the other actions of beta 2 adrenorecptor agonists?
- Cholinergic transmission
- Inhibition of inflammatory mediation release
- Vascular permeability
- Mucociliary clearance
What is cholinergic transmission?
This involves the inhibition of cholinergic acetylecholine release from parasympathetic nerves, so inhibits bronchoconstriction
What are the effects of beta 2 adrenoreceptors on inflammatory mediators?
Cause inhibition of inflammatory mediator release from T cells and mast cells.Causes mast cell stabilisation, lymphocute activation. This results in reductions in plasma histamine, PAF, chemotactic factors, i.e IL-1 and eosinophil cationic protein.
What are the anti-inflammatory effects of beta 2 adrenoreceptor activation?
- Decrease neuropeptide release from sensory nerves
- Decrease cytokine release from T lymphocytes
- Decrease mediator release from eosinophils, neutrophil, epithelial cells
- Reduce the amount of fluid that comes out of capillaries in airway tissue
But theres a low expression of beta 2 receptors on these cells so dont get a big stimulation
What is desensitisation?
Loss in response to the agonist over time
What is the major problem with beta 2 adrenorecptors?
Relatively short action
What causes desensitisation?
- Phosphorylation of the occupied receptor by a specific receptor kinase - B-adrenoceptor kinase
- Internalistaion of the receptor
- Phosphorylation of the occupied receptor by protein kinase A eg. Negative feedback
How does salmeterol have less desesitisation?
- Its a partial agonist so doesnt stimulate the receptor as much as adrenaline
- Less internalisation of the beta 2 adrenoreptor
- Less phosphorylation of the receptor by beta arenoreceptor kinase
What are the routes of administration for beta 2 adrenoreceptor agonists?
- Inhaled
- Oral
- Intravenous and intramuscular
Describe the inhaled route?
- A metered dose inhaler is commonly used
- Only 10% of the drug enters the lung
- For people who cannot use metered inhalers, others include nebulisers and dry powder inhalers.
Describe Intravenous and intramuscular route
- Necessary for acute asthma (risk of death).
- Given as a drip or as a bolus injection.
- Most commonly used with terbutaline.
What are the systemic delivery issues with B2 adrenoreceptor agonists?
- Elicit vasodilation relaxation of vascular smooth muscle
- Increased blood flow and a fall in blood pressure - reflex increased tachycardia and cardiac output
- Increased metabolic processes, including increased glucose, fatty acids, ketone bodies and high-density lipoprotein.
- Increase in tremor in skeletal muscle – associated with a relaxation of slow contracting skeletal muscle
What steroid drugs are used for asthma treatment?
Glucocorticoids
What do glucocorticoids do in asthma?
Dampen down many aspects of the inflammation linked with asthma
Name steroids used by inhalation for asthma
- Beclamtasone
- Budesonide
- Fluticasone
What is the standard oral steroid?
Prednisolone for more severe asthma
What are the intravenous steroids?
Hydrocortisone and methylprednisolome
What is the mechanism of action of steroids?
- Glucocorticoids easily enter cells due to its structure being lipid based
- Bind to glucocorticoid receptors in the cytosol
- The receptor goes into the nucleus where it has both positive and negative effects on the transcription of new gebes and generation of different proteins
- Positive effect is that it is able to induce the protein lipoprotein, and stimulate the expression of beta 2 adrenorecptors, this enhances the effect of the agonist that activates the beta 2 receptor
- Negative effects on the production of the number of cytokines. Inhibits the expressioj of inflammatory molecules eg nitric oxide synthase and COX2. Also inhibits the expression of adhesion molecules on epithelial cells
What is lipocortin?
a protein - an endogenous inhibitor for the enzyme phopholipase A2. This enzyme generates arachandonic acid from plasma membrane lipids as a starting point to the luekotreince pathway or the COX pathway.
What inflammatory cells do corticosteroids target?
- Eosinophils
- T lymphocyte
- Mast cells
- Macrophages
- Dendritic cell
What structural cells do corticosteroids target?
- Epithelial cells
- Endothelial cells
- Airway smooth muscle
- Mucus gland
How is glucorticoid carried in the body?
As transcortin
What are leukotrienes produced by?
- Eosinophils
- Basophils
- Macrophages
What is the effect of glucocorticoids in the asthma environment
- Synthesis and secretion of leukotreines is inhibited
- Platelet agregating factor (PAF) synthesis is inhibited
- PGE1 synthesis blocked (vascular endothelium).
- Bradykinin formation inhibited (plasma)
- O2 free radicle formation inhibited
What is the effect of glucosteroids on cell migration factors?
- Platelet aggregating factor formation is inhibited
- LTB4 formation is blocked
- HIstamine formation blocked
- PGD2 formation blocked
What is LTB4?
A strong chemotactic molecule – so stops attracting white blood cells to the airways
What is LTB4?
neutrophil chomoattractant
How do steroids effect alveolar macrophages?
Steroids inhibit migration, and inhibit IgG and complement decreased - reduction in cytokine synthesis
How do steroids effect mast cells?
Decrease histamine release
How do steroids effect endothelial cells?
Decrease adhesive response, reduction in vascular permeability
How do steroids effect basophils?
Local influx inhibited
What are the primary effector systems?
- Alveolar macrophages
- Mast cells
- Endothelial cells
- Basophils
What are the secondary recruiter systems?
- Neutrophils
- Eosinophils
- Lymphocytes
- Monocytes
- Platelets
How do steroids effect neutrophils?
IgG receptor decreased, increased apoptosis of neutrophils, decreased adherence to endothelium
How do steroids effect Eosinophils?
Decreased mediator leased and increased apoptosis
How do steroids effect lymphocytes?
Increased apoptosis and decreased differentiation, reduction in T4 helper cells, reduction in B-cell cycle.
How do steroids effect monocytes?
Migration inhibited, cell death incraesed, reduced production, reduced IgE receptor
How do steroids effet platelets?
Platelet kinetic normalised
How do steroids provide long duration relief?
By increasing force expiratory volume (FEV) over hours
What are the common side effects of prednisolone?
- Weigh gain
- Water retention
- Sweating or rashes
- Increased appetite
- Mood changes
- Numbness or tingling in arms or legs
- Shortness of breath
- Blurred vision
- Dizziness
- Moon face
- Headache
- Sleep problems
- Suppressed immune system
What is leukotiene B4?
Neutrophil chemoattractant for neutrophils in the inflammatory environemnt
What is the effect of leukotriene C4 and D4?
Negative pro inflammatory effects in asthma patients
- Cause bronchoconstriction
- Increased bronchial reactivity
- Mucosal edemia
- Mucous hypersecretion
Name leukotriene D4 receptor antagonists
- Zafirlukast
- Montelukast
What is the enzyme involved in leukotriene synthesis?
5-lipoxygenase
What is zileuton?
A drug that inhibits lekotriene synthesis. These agents are less effective than inhaled corticosteroids, but similar efficacy in reducing frequency of asthma exacerbations. Shown to be particularly effective in aspirin-induced asthma
What is a major side effect of zileuton?
Liver toxicity
What are the side effects of montelukast?
Eosinophilia and Churg Strauss Syndrome (eosinophilic granulomatosis in small blood vessels)
What is montelukast?
A CysLT1 receptor antagonist
What is LTD4?
A bronchoconstrictor
How are leukitrienes synthesised?
- Start with phopholipase A2 (PLA2), which is able to generate acrachidonic acid
- Arachadonic acid gets converted by 5-LO to make LTA4.
- LTA4 is converted to LTC4,LTD4, LTE4 ( these intect with CysLT1 receptors) or LTB4 – this has important chemotactic effects
What are the CysLT1 receptor antagonists?
- Montelukast
- Zafiorulokast
- Pranlukast
How does LTD4 work?
- LTD4 binds to the receptor
- Leads to activation of Gq
- This stimulates the enzyme, phospholipase C
- Phospholipase C catylyses the conversion of the phospholipid Ptd(Ins)4,5P2 (PIP1) into diacylglycerol (DAG) and Ins(1,4,5)P3 (IP3), which diffuses into the cytoplasm.
- When it reaches the SR, it binds to the Ins(1,4,5)P3 receptor, which is a receptor calcium channel.
- This results in opening of the channel and calcium flows from a high concentration (in the SR) into the cytoplasm.
- Combines with calmodulin and this complex activates myosin light chain kinase, an enzyme that transfers phosphate from ATP on myosin light chain. To cause the contraction
How do LTD4 receptor antagonists prevent bronchoconstriction?
Prevent LTD4 from binding to its receptor
Name xanthines
- Theophylline
- Enprofylline
What is the mechanism of action of Xanthines?
- Adenosine receptor antagonist: These drugs can block the inhibitory action of adenosine upon adenylyl cyclase (via its receptors), and thus allow intracellular cyclic AMP to accumulate and promote relaxation;
- Phosphodiesterase inhibitor: (blocks reduction in intracellular cyclic AMP) and relax smooth muscle; (c) effects via catecholamines (increases catecholamine release); (d) other effects, xanthines have been shown to antagonise the actions PGE2 and PGF2a.
What is phosphodiesterase?
An enzyme that breaks down cAMP
What are the effects of theophylline in asthma?
- smooth muscle relaxation.
- inhibit anaphylactic release of mediators (mast cells).
- suppress oedema by clocking mucosu secretion from goblet cells
- central stimulation of ventilation (disadvantage as breathing may become shallower).
What effect do IV routes of theophylline have?
Increase arrhythmia, palpitations, and tachycardia at doses above 30mg/l.
What are the side effects of oral theophylline?
- Anorexia (high levels of cAMP promote lypolisis)
- Vomiting
- Mild CNS stimulation.
What is step 1 therapy for asthma?
Mild intermittaent asthma - Inhaled shorting acting b2 agonist
What is step 2 therapy for asthma?
- Regular preventer therapy
- Add inhaled cortocosteroid
- Start at the dose appropriate to disease severity
What is step 3 therapy for asthma?
- Add on therapy
- Initially add long acting beta agonist and assess effect. If ineffective or inadeute, double the dose of inhaled corticosteroid and LABA stopped if it is not adding to control of asthma symptoms
What is step 4 therapy for asthma?
- Persistent poor control
- Consider trial of increased dose of inhaled cortocosteroid or addition of 4th agent (LTRA, theophyline or oral beta agonist
What is step 5 therapy for asthma?
- Continous or frequent use of oral corticosteroids
What produces IL-13?
TH2 cells
What does IL-13 activate?
Esionophils and mast cells in the allergic response
What is mepoluzimab?
anti-IL-5 antibody
What is omalizumab
Anti-IgE antibody
What is lipocortin?
a protein - an endogenous inhibitor for the enzyme phopholipase A2. This enzyme generates arachandonic acid from plasma membrane lipids as a starting point to the luekotreince pathway or the COX pathway.
