Flashcards in *Pharmacology 2 (lecture 2) Deck (100)
What are the 2 main categories of drugs that are used to treat asthma?
What do relievers act as?
What do controllers/ preventers act as?
Anti-inflammatory agents that reduce airway inflammation
What are the possible types of reliever medication for asthmatics? (3)
Short acting B2-adrenoceptor agonists (SABAs)
Long acting B2-adrenoceptor agonists (LABAs)
CysLT1 receptor antagonists
What are the possible types of controllers/ preventers available for asthma?(3)
Humanised monoclonal IgE antibodies
What drug acts as both a bronchodilator and anti-inflammatory drug?
What is step 1 of the guideline approach for treating asthma?
If it is very intermittent asthma then prescribe a SABA
What is step 2 of the guideline approach for treating asthma?
If SABA is needed more than once a day, add a regular, inhaled glucocorticoid (Inhaled corticosteroid, ICS)
What is step 3 of the guideline approach for treating asthma?
If control is inadequate, add a long-acting B2-adrenoceptor agonists (LABA)
monitor benefit and if good continue LABA
If of benefit but not adequate, increase dose of ics
if no response, stop LABA and increase dose of ICS
If control is still inadequate, trial other therapy (e.g. cysLT1 receptor agonist or theophylline)
What is step 4 of the guidelines approach for treating asthma?
If asthma is persistent and poorly controlled, increase dose of ICS. Add a fourth drug (e.g. Cyslt1 receptor antagonist, theophylline, oral b2 agonist)
What is step 5 of the guideline approach to treating asthma?
If control is still inadequate, introduce oral glucocorticoid - refer patient to specialist care
Comparison of the pharmacokinetics of aerosol and oral therapy for asthma?
Aerosal = slow absorption from lung surface and rapid systemic clearance
Oral = good absorption (with exceptions) and slow systemic clearance
Comparison of the dose of aerosol and oral therapy for asthma?
Aerosal = low dose delivered rapidly to target
Oral = high systemic dose necessary to achieve an appropriate concentration in the lung
Comparison of the systemic concentration of the drug between aerosol and oral therapy for asthma?
Aerosol = low
Oral = high
Comparison of the incidence of adverse effects between aerosol or oral therapy for asthma?
Aerosol = low incidence of adverse effects
Oral = high (but depends on drug)
Comparison of the distribution of the drug between aerosol and oral therapy for asthma?
Aerosol = reduced distribution in severe airway disease
Oral = unaffected distribution by airway disease
Comparison between compliance with aerosol and oral treatment?
Aerosol = good with bronchodilators, less so with anti-inflammatory drugs
Oral = good
Comparison between ease of administration of aerosol and oral drugs for asthma?
Aerosol = difficult for small children and infirm people
Oral = good
Comparison between effectiveness of aerosol and oral drugs for asthma?
Aerosol = good in mild to moderate disease
Oral = good even in severe disease
What is a spasmogen?
A substance causing contraction of smooth muscle e.g. histamine
What does binding of an agonist to a B2-adrenoceptor cause?
Binding of the agonist causes the B2-adrenoceptor to activate GS increasing the activity of adenylyl cyclase
Adenylyl cyclase converts ATP to cAMP which binds to Protein kinase A (PKA) activating it
PKA phophorylates MLCK (inhabiting it) and myosin phosphatase (activating it)
This causes relaxation of the bronchial smooth muscle = bronchodilation
(this therefore opposes the action anything that causes constriction of airway smooth muscle)
What are the classifications of B2-adrenoceptor agonists? (3)
Ultra long acting
What is an example of a short acting B2-adrenoceptor agonist?
What are 3 other names for this?
What is the first line treatment for mild, intermittent, asthma?
What are some examples of ways that SABAs are administered?
Usually inhalation (metered dose/ dry powder devices)
Oral is sometimes used in children
IV is given as an emergency sometimes
How quickly do SABAs act?
When do they have their maximal effect?
How long does relaxation persist for?
5 minutes for onset
30 minutes = peaks
Relaxation persists for 3-5 hours
What effect do SABAs have?
They increase mucus clearance and decrease mediator release from mast cells and monocytes
What are some side effects that can occur with SABAs when given via the inhalation route? (4)
Why can the drug sometimes affect the heart?
B1 adrenoceptors are on the heart
What causes the B2-agonist tremor?
Skeletal muscles sometimes carry B2-adrenoceptors
Why can hypokalaemia sometimes occur due to SABA?
Due to the effect on the sodium/ potassium ATPase
What are 2 examples of long acting B2-adrenoceptors?
Can LABAs be used for the acute relief of bronchospasm?
What type of asthma are LABAs particularly useful for?
Nocturnal asthma (act for approximately 8 hours)
Can LABAs be used as a monotherapy?
No, they must always be used as an add on therapy in asthma inadequately controlled by other drugs
What drug must LABAs always be used with?
what are therefore produced for this purpose?
Combination inhalers - relatively costly however)
What are 2 examples of combination inhalers?
Symbicort (Bedesonide and Formoterol)
Seratide (fluticasone and salmeterol)
What is used to reduce the potentially harmful stimulation of cardiac b1-adrenoceptors?
Selective B2-adrenoceptor agonists - non-selective agonists are redundant
What drugs should never be used in asthmatic patients?
B2-adrenocepetor antagonists (due to the risk of bronchospasm)
What happens to B2-adrenoceptors (and most G protein coupled receptors) when they are persistently activated?
They become desensitised and endocytose = loss of function
Why does the long term use of LABs cause a decrease in clinical outcome?
The receptor begins to lose sensitivity to the agonist and therefore can also lose sensitivity to adrenaline
What 2 kinases are involved in b2-adrenoceptor phosphorylation = reduced sensitivity to B2-adrenoceptor agonists?
G protein receptor kinase (GRKs)
What does phosphorylation of the B2-adrenoceptor by PKA or GRK cause?
Reduced G-protein coupling = PKA
loss of G-protein coupling/ endocytosis = GRK
Can PKA phosphorylate the B2-adrenoceptor when no agonist is bound?
Can GRK phosphorylate the b2-adrenoceptor when n agonist is bound?
No, agonist must be bound
What acts as a scaffold protein that links the desensitised B-adrenoceptors to "endocytic machinery" that internalises the receptor?
What presses the pathway by which B2-adrenoceptors are internalised by repeated activation?
What do Cysteinyl leukotriene receptor antagonists act on?
Act competitively at the CysLT1 receptor
What are leukotrienes?
What are 3 examples of cyteinyl leukotrienes?
What are CysLTs derived from?
What do they cause (3)?
Derived from mast cells and infiltrating inflammatory cells causing smooth muscle contraction, mucus secretion and inflammation (delayed phase)
What are 2 examples of CysLT1 receptor antagonists?
When are CysLT1 receptor antagonists best used?
As an add on therapy against early and late bronchospasm in mild persistent asthma and in combination with other medications, including inhaled corticosteroids in more severe conditions
What 2 types of bronchospasm are CysLT1 receptor antagonists particularly useful for?
How are CysLT1 receptor antagonists administered?
By the oral route
What type of alma are CysLT1 receptor antagonists not recommended for?
Acute severe asthma
side effects of CysLT1 receptor antagonists?
(generally well tolerated)
What are 2 examples of Methylxanthines?
What 3 types of beverages are methylxanthines naturally present in?
Coffee, tea and chocolate-containing beverages
How do Methylxanthines work?
Have an uncertain mechanism of action - might involve inhibition of isoforms of phosphodiesterases (i.e. PDE) that inactivate caMP
If there is more cAMP there will be more activation of PKA = more phosphorylation of MLCK and myosin phosphatase = more relaxation
This mechanism is only seen at high doses and people aren't convinced that this is how it works clinically
How do methylxanthines work/
they combine bronchodilator and anti-inflammatory action = inhibit mediator release from mast cells and increase mucus clearance
What effect do methyxanthines have on the diaphragm?
They increase diaphragmatic contractility and reduce fatigue = may increase lung ventilation
What type of drugs may they potentiate the action of?
How are methylxanthines administered?
Via the oral route as sustained release preparations
What is the major disadvantages of methylxanthines? (2)
They have a very narrow therapeutic window and exert adverse effects at supra-therptuic concentrations
They also have numerous interactions with CYP450s, particularly antibiotics that inhibit CYP450s
What are some of the adverse effects of methylxanthines? (3)
side effects at therapeutic concentrations?
What are the 2 major classes of (cortico)steroid hormones that are released into the circulation?
(not pre-stored, but synthesised and released on demand)
What is the main glucocorticoid in man?
What are some examples of the processes that cortisol regulates?
Inflammatory responses decreased
Immunological responses decreased
Liver glycogen deposition increased
glucose output from the liver increased
glucose utilisation decreased
protein catabolism increased
bone catabolism increased
gastric acid and pepsin secretion increased
What is the main mineralocorticoid?
What is the function of aldosterone?
Regulates the retention of salt (and water) by the kidney
What is the problem with endogenous steroids being used in the treatment of inflammatory conditions?
They may possess both glucocorticoid and mineralocorticoid actions - the latter are unwanted in the treatment of inflammatory conditions
What type of steroids are used to treat asthma?
Synthetic derivatives of cortisol (e.g. beclometasone, budesonide, fluticasone) with little, to no, mineralocorticoid activity are very frequently used for their anti-inflammatory effect in the treatment of asthma
Why are glucocorticoids ineffective in relieving bronchospasm when given acutely?
They have no direct bronchodilator action
What is the preferred route of administration of glucocorticoids?
Inhalation route (to minimise adverse systemic effects) - given orally in severe asthma
What do glucocorticoids signal via? Specifically?
Nuclear receptors (class 1)
What does lipophilic mean?
Able to dissolve in fats
How do glucocorticoids enter the cell?
By diffusion across the plasma membrane
What do glucocorticoids do once they are in the cytoplasm?
They combine with GR alpha producing dissociation of inhibitory heat shock proteins e.g. HSP90
The activated receptor translocates to the nucleus (aided by importins)
What happens to glucocorticoids once they are in the nucleus?
Activated receptor monomers assemble into homodimers and bind to the glucocorticoid response elements (GRE) in the promoter region of specific genes
Transcription of specific genes is either switched-on (transactivated) or switched off (transrepressed) to alter mRNA levels and the rate of synthesis of mediator proteins
What are the 2 ways in which glucocorticoids can affect genes?
By acting at glucocorticoid response elements
By modifying the structure of chromatin (via deacetylation of histones)
What genes does glucocorticoids tend to increase transcription of and what genes does it tend to decrease transcription of?
Increase = transcription of genes coding inflammatory proteins
Decrease = transcription of genes encoding inflammatory proteins
In terms of histones, what is expression of inflammatory genes associated with?
How do glucocorticoids switch off gene transcription?
Acetylation of histones by histone acetyltransferases
Acetylation unwinds DNA from histones allowing transcription
(glucocorticoids recruit histone deacetylases to activated genes and switch off gene transcription)
What affects do glucocorticoids have in relation to inflammation in bronchial asthma? (4)
They decrease formation of Th2 cytokines (e.g. IL-4 and IL-5) and cause apoptosis
Prevent production of IgE
Reduce the number of mast cells and decrease IgE receptors
Prevent allergen-induced influx of eosinophils into the lung and cause apoptosis of eosinophils
What is the purpose of glucocorticoids in the treatment of asthma?
Suppress the inflammatory components by preventing inflammation and resolving established inflammation
Are glucocorticoids effective in the short term?
No, they do not alleviate early stage bronchospasm caused by alergens or exercise but long term treatment is effective (particularly in combination with a LABA)
How are glucocorticoids often given in mild/ moderate asthma?
By inhalation from a metered dose inhaler (to minimise many unwanted systemic effects)
How long does it tae for the efficacy of glucocorticoids to develop in asthma?
What are the most common adverse effects of glucocorticoids in asthma?
What is this due to?
Dysphonia (hoarse and weak voice)
Oropharyngeal candidiasis (thrush)
Due to deposition of steroid in the oropharynx
What type of steroid is given in chronic, severe or rapidly deteriorating asthma?
Oral prednisolone (may be used in combination with an inhaled steroid to reduce the oral dose required and minimise unwanted systemic effects) - bronchodilator drugs are co-administered
What is a second line drug that is infrequently used in the prophylaxis of allergic asthma (particularly in children)?
How do cromones work?
Uncertain molecular mechanism of action that unloads a weak anti-inflammatory effect
A decrease in the sensitivity of irritant receptors associated with sensory C-fibres that trigger exaggerated reflexes and reduction of cytokine release are potential mechanisms
What is an example of a cromone?
How is sodium cromoglicate delivered?
By inhalation (little systemic absorption)
(efficacy make take several weeks to develop)
What type of patients are cromones most effective in?
Children and young adults compared to older patients
What is an example of a monoclonal antibody directed against IgE?
How does omalizumab work?
It binds IgE via Fc to prevent attachment to Fce receptors therefore suppressing mast cell response to allergens
Reduces the expression of Fce receptors on various inflammatory cells
How are monoclonal IgE antibodies given?
What 2 molecules do monoclonal antibodies for the treatment of asthma get directed towards?
Example of monoclonal antibody directed against IL-5