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Drugs: from molecules to man > Asthma 2 > Flashcards

Asthma 2 Flashcards

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Organic Chemistry 101 flashcards
1
Q

What are the different names for glucocorticoids?

A

corticosteroids, glucocorticosteroids and glucocorticoids

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2
Q

What are the targets of transactivation and transrepression by a particular nuclear hormone receptor?

A

The targets of transactivation and transrepression by a particular nuclear hormone receptor, are different genes and the recognition sequences on DNA for transactivation and transrepression are different

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3
Q

What is the difference between hydrocortisone and cortisol?

A

Cortisol and hydrocortisone are chemically the same. When we are referring to it acting as a hormone then cortisol is the preferred name. When it is administered as a drug, hydrocortisone.

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4
Q

What type of receptor is a glucocorticoid receptor?

A

A nuclear hormone receptor

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5
Q

What effects do glucocorticoids produce in asthma?

A

Anti-inflammatory

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6
Q

how many of the genes in the human genome do glucocorticoids modulate the expression of?

A

About 1%

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7
Q

What are some of the important anti-inflammatory effects of glucocorticoids?

A
  • Decreased activation, proliferation and migration of immune system cells
  • Decreased expression of pro-inflammatory cytokines
  • Decreased expression of cyclo-oxygenase 2 (therefore decreased prostaglandin production)
  • Increased expression of anti-inflammatory mediators (some interleukins, annexin 1)
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8
Q

Why are glucocorticoids slow and what does this make them effective as?

A

Because their effects require changes in protein expression, they are slow. This means that glucocorticoids are effective as preventers of asthma attacks, but not as relievers

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9
Q

What are common drugs used in inhaler formulation?

A
  • Beclometasone (also known as beclomethasone)
  • Budesonide
  • Fluticasone
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10
Q

When are prednisolone and dexamethasone used?

A

Prednisolone is commonly used when the medication is given in tablet form and is the drug recommended for this purpose by NICE. Dexamethasone is also suitable and is used more in other countries. It offers the advantage of having a longer duration of action

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11
Q

What does a MART combine and what do patients use this as?

A
  • combines a fast onset, long acting beta agonist with a corticosteroid in a single inhaler
  • The patient uses this as both their ‘preventer’ treatment and their ‘reliever’
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12
Q

What do examples of MARTs include and what advantages do MART inhalers offer?

A
  • Examples include Fostair (formoterol + beclomethasone) and Symbicort (budesonide and formeterol).
  • MART inhalers offer advantages in terms of convenience, better control and can result in lower doses of glucocorticoids being needed
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13
Q

What are common problems for people to experience when using glucocorticoids and how can the incidence of these problems be reduced?

A
  • It is common for people to experience a sore throat or hoarse voice (dysphonia), and oral thrush is quite common due to immunosuppression
  • Caused by excessive activation of glucocorticoid receptors
  • The incidence of these problems can be reduced by using a spacer device and by rinsing the mouth after using an inhaler
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14
Q

What severe side effect may high doses of glucocorticoids have and why?

A
  • Cushing’s syndrome

- because they regulate a wide range of genes

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15
Q

What are the two main mechanisms Cushing’s syndrome can arise through?

A
  • Tumour that results in excess glucocorticoid production by the adrenal cortex
  • Given drugs with glucocorticoids
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16
Q

What is one of the master control systems for the production of glucocorticoids?

A

The pituitary gland

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17
Q

What are the two main types of action of adrenal steroids?

A 
- Glucocorticoid 
 Metabolic effects 
 Anti-inflammatory 
 Immunosupressive 
- Mineralocorticoid 
 Water and electrolyte balance 
- Mediated by different NHRs
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18
Q

What is the natural steroid produced by the adrenal cortex and is it a glucocorticoid or mineralocorticoid?

A
  • Cortisol (hydrocortisone)/ corticosterone
     Classified as glucocorticoids
     But they actually are non-selective between mineralocorticoid and glucocorticoid
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19
Q

What type of steroid is aldosterone?

A

Mineralocorticoid only

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20
Q

Why is aldosterone necessary if we have cortisol that acts on both glucocorticoid and mineralocorticoid receptors?

A

Because in many cells the mineralocorticoid receptor is ‘protected’ from cortisol by an enzyme

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21
Q

If we gave patients a high dose of hydrocortisone what would we see?

A
  • Anti-inflammatory (desirable)
  • Immunosuppression (usually undesirable)
  • Metabolic effects (undesirable)
  • Effects at mineralocorticoid receptors (undesirable)
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22
Q

What are the unwanted effects of systemic glucocorticoids (Cushingoid features)?

A
  • Moon shaped puffy face
  • Thinning of skin
  • Poor wound healing
  • Buffalo hump of back
  • Increased abdominal fat
  • Hypertension
  • Muscle wasting
  • Osteoporosis
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23
Q

How can you use drug delivery to reduce glucocorticoid side effects?

A
  • One of the main strategies for reducing side effects is to deliver the drugs as efficiently as possible to their site of action
  • Inhalation is therefore used for glucocorticoids
  • In severe cases glucocorticoids may also be given in tablet form or even intravenously
24
Q

What is the selectivity of aldosterone, hydrocortisone, prednisolone and dexamethasone?

A
  • Aldosterone has high activity at mineralocorticoid receptor (natural ligand)
  • Hydrocortisone has moderate activation at both glucocorticoid and mineralocorticoid receptors (natural ligand)
  • Prednisolone has more activity for glucocorticoid than mineralocorticoid
  • Dexamethasone shows a high level of selectivity for the glucocorticoid receptors over the mineralocorticoid receptors
25
Q

What is the duration of action for hydrocortisone, fludrocortisone, prednisolone and dexamethasone?

A
  • Hydrocortisone and fludrocortisone have short durations of actions
  • Prednisolone has a medium duration of action
  • Dexamethasone has a long duration of action
26
Q

What does changing the structure of the corticosteroids have a significant impact on?

A

Selectivity and duration of action

27
Q

Which is more beneficial in treating asthma: transactivation or transrepression and why?

A

Although some anti-inflammatory effects are produced via transactivation, the majority of the unwanted effects of the glucocorticoids also occur via this mechanism. However, in theory tranrepression produces anti-inflammatory effects without much side effect liability so transrepression is more useful

28
Q

What can we change the structure of so it is selective for the glucocorticoid receptor and what effects will this get rid of?

A

We can change the structure of dexamethasone so it is selective for the glucocorticoid receptor. This will get rid of the mineralocorticoid effects but we will still get immunosuppression and metabolic effects

29
Q

What does transactivation take place through and what effects may you see?

A
  • Through dimeric forms of the receptor
  • Some anti-inflammatory effects
  • Metabolic effects
  • Skin thinning
30
Q

What does transrepression take place through and what effects may you see?

A
  • Through monomeric forms of the receptor

- Some anti-inflammatory effects

31
Q

What are SEGRAMs?

A
  • Selective glucocorticoid receptor agonist/ modulator
     Designed to favour transrepression pathway
     Should have a more favourable side effect profile
     BIASED AGONISM – favours one pathway over the other (happens with GPCRs)
32
Q

What are potential problems with the control of adrenal steroid synthesis?

A
  • Release from adrenal cortex under control of cascade of hormones:
  • Hypothalamus releases corticotropin releasing factor (CRF )
  • CRF travels to the anterior pituitary which stimulates the release of adrenocorticotropic hormone (ACTH)
  • ACTH travels to adrenal cortex where it stimulates the production and release of hydrocortisone and corticosterone
  • This system is kept in check by glucocorticoid receptors in the anterior pituitary and hypothalamus that provide negative feedback when activated by hydrocortisone and corticosterone
  • The negative feedback system also responds to exogenous steroids (therefore, production of CRF and ACTH will be damped if given an artificial drug e.g. dexamethasone)
  • So if the patient suddenly stops dexamethasone treatment, suddenly not having any steroid in circulation will cause you to go into adrenal insufficiency
33
Q

What is the medical advice for patient’s taking high dose steroids?

A
  • Don’t stop unless under supervision
  • If you do stop, come off it very slowly to give body time to produce their own steroid
  • Carry around a steroid treatment card – gives information in case they are in an accident, gives patient medical advice
34
Q

What is the hypothalamic pituitary adrenal axis (HPA) and what is the problem with taking corticosteroids?

A
  • Production of hydrocortisone and corticosterone under tight set of controls
  • Under normal conditions this keeps hydrocortisone levels stable
  • When someone is put under stress we see increased levels of hydrocortisone (increases availability of glucose)
  • Doesn’t cause too much of a problem in short term stress
  • People with major depressive disorder are seen to have a high level of hydrocortisone and an impaired negative feedback system. It is thought that the high levels of hydrocortisone is one of the mechanisms that underly major depressive disorder
  • Corticosteroids have negative effects on the hippocampus and prefrontal cortex. We see increases apoptosis in depression and decreased neurogenesis.
  • See increased rate of depression with people with Cushing’s syndrome (increase cortisol/ long term treatment with GC) frequently -> depression
35
Q

What does phospholipid A2 give rise to?

A
  • One of the key players in inflammatory signalling is an enzyme called phospholipid A2. This enzyme releases arachidonic acid from membrane phospholipids
  • Arachidonic acid is then further metabolised to a group of 20 carbon signalling molecules called the eicosanoids. The eicosanoids can be subdivided into various classes. The most important are the leukotrienes and prostaglandins
36
Q

What are the leukotrienes key players in?

A

Asthma

37
Q

What are leukotrienes produced by and what do they do?

A
  • Produced by mast cells, eosinophils, basophils and macrophages
  • Agonists at cysteinyl-leukotriene (CysLT) receptors (GPCRs)
  • Contract bronchial smooth muscle
  • Stimulates mucus secretion
  • Increases microvascular permeability
  • These effects contribute to the pathology of asthma so blocking them with leukotriene receptor antagonists (LTRAs) will produce beneficial effects
38
Q

What are Lukast drugs, what do they do and when are they used?

A
  • The LTRAs all end in -lukast: e.g. montelukast
  • They act on leukotriene receptors
  • These drugs are given orally and used as add-on treatments in asthma that have not responded to SABA drugs and glucocorticoids. They are quite effective in exercise-induced asthma and also seem to have an effect in aspirin-induced asthma
  • The lukasts are actually bronchodilators but their effect is not as great as the SABA drugs, which is why they tend to be used in an add-on preventer context
39
Q

What are the unwanted effects of Lukast drugs?

A

Their unwanted effects are usually quite manageable: abdominal pain and GI tract upsets, plus headaches. However, they sometimes produces psychiatric effects ranging from depression to hallucinations

40
Q

What does acetylcholine do during an asthma attack?

A

parasympathetic neurons increase their release of this transmitter and this leads to both bronchoconstriction and increased mucus production.

41
Q

What is an ancient asthma remedy and why is it no longer used?

A
  • Antagonising muscarinic receptors is a logical and old intervention. The leaves of the thorn apple plant (Datura stramonium) which contain hyoscine and atropine are known to have been used as an asthma remedy in ancient India
  • Atropine and hyoscine are non-selective muscarinic antagonists and readily pass into the systemic circulation as they are tertiary amines. This causes a host of side effects mediated by the actions of these compounds in the parasympathetic nervous system. Due to these problems atropine and hyoscine are no-longer used to treat asthma
42
Q

What compounds that are structurally related to atropine and hyoscine are still used to treat asthma and what do they do?

A

ipratropium and tiotropium are still used in asthma (and COPD). They are bronchodilators and reduce mucus production but are generally not using as first-line relievers in asthma.

43
Q

What is Ipratropium bromide, when is it used, how is administered and what does it’s structure allow it to do?

A
  • Ipratropium bromide is a short acting muscarinic antagonist (SAMA) used as an add-on in severe asthma ad also is used in COPD. It is administered via an inhaler or nebulizer.
  • Although like atropine, ipratropium does not select between mACh receptor subtypes, its structure allows it to avoid many of the systemic effects of atropine: because it is a quaternary amine and has a permanent positive charge, it is not easily absorbed into the systemic circulation
44
Q

What is Tiotropium bromide, how is it administered and when is it used?

A
  • Tiotropium bromide is a long acting muscarinic antagonist (LAMA) and is also administered via inhalation.
  • Similar to ipratropium it is a quaternary amine, minimising its systemic effects. It is used in severe asthma and also in COPD
45
Q

What are unwanted effects of muscarinic antagonists?

A
  • Dry mouth
  • Constipation
  • Headache
  • Nausea
  • Dizziness
  • Cardiac arrhythmias
46
Q

What type of drugs are theophylline and caffeine?

A

members of the alkylxanthine class of drugs.

47
Q

What is Theophylline?

A

Theophylline was once one of the first-line bronchodilator drugs (until the 1990s) and is still used in severe cases. It can be administered orally in sustained capsules or IV for a life-threatening acute asthma attack (also known as status asthmaticus). When given as an injection, ,it is very often complexed with ethylenediamine to improve its solubility

48
Q

What is aminophylline?

A

a formulation of theophylline with improved solubility

49
Q

What are the mechanisms of theophylline and why may this cause cardiac side effects?

A
  • It acts as a nonselective inhibitor of phosphodiesterases. These enzymes breakdown cAMP and the increase in cAMP that theophylline causes may promote bronchodilation and reduce inflammation
  • It is also an antagonist of adenosine receptors. This may also help promote bronchodilation (adenosine is a bronchoconstrictor) but it also causes some of the cardiac side effects of theophylline (adenosine is important in the heart and can be useful in the treatment of paroxysmal supraventricular tachycardias)
50
Q

What are the side effects of theophylline?

A
  • Nausea and vomiting
  • Anxiety
  • Headache
  • Sleep disturbances
  • Tachycardia and other dysrhythmias
  • Convulsions
    • These are more common at higher doses
51
Q

What makes the use of theophylline even more difficult?

A

it has quite a lot of interactions with other drugs. Some will increase its plasma concentration (by inhibiting or competing for enzymes that metabolise theophylline) while others will decrease its levels because they induce these enzymes. It’s plasma levels are also increased if the patient has liver disease (as it is 70% metabolised in the liver).

52
Q

What is NICE?

A
  • NICE is the national institute of health and care excellence
  • It was formed in 2005 by a merger of the national institute for clinical excellence and the health developmental agency
  • It is a government funded organisation with a wide variety of roles, ranging from promoting healthier life-styles to defining quality standards for health care.
  • One of it’s primary functions is to assess the evidence about different drugs and other medical interventions and on the basis of this evidence, to provide guidance about the most cost-effective ways of treating patients within the NHS
53
Q

What was one of the reasons NICE was set up?

A
  • One of the reasons NICE was set up was to end to ‘health-care postcode lottery’ where the drugs that were available to you depended on individual decisions made by your local NHS hospital trusts
  • Since 2005 NHS trusts are legally required to fund any treatments recommended by NICE
54
Q

Give features of NICE and healthcare rationing

A
  • NICE has finite resources. Some drugs or procedures are very expensive and will only give a marginal benefit to patients.
  • However, when you are desperately ill, any small improvement in your life quality or expectancy will seem like good value for money so NICE sometimes has to make very hard and controversial decisions about which treatments are approved for NHS use and which are rejected
55
Q

What is Omalizumab?

A
  • Omalizumab (trade name Xolair) is a humanized monoclonal antibody against immunoglobulin E (IgE). Once bound by omalizumab, IgE is rapidly removed from the circulation
  • IgE is one of the main players in type I hypersensitivity responses and reducing its circulating levels using omalizumab can be an effective treatment in a number of allergic disorders including allergic asthma, hay-fever and food allergies. Using omalizumab to treat patients with severe asthma can have many benefits
56
Q

How does NICE decide whether a drug is good value for money and what happened for omalizumab with this?

A
  • NICE uses something called the QALY (quality adjusted life year)
  • Once QALY is equivalent to one year of perfect health. The effect of a drug can be measured in terms of the increase in QALYs it produced
  • If someone’s condition means that they have a quality of life that is 50% of normal, the starting point for that person in 0.5 QALYs. A drug might give them 5 years of lige at 80% of normal before their death. This drug would therefore have produced an effect of (80-50%) x 5 = 1.5 QALYs
  • The number of QALYs produced by a treatment can be used to compare it to another treatment or control
  • NICE calculates the cost per QALY of drugs and has an upper limit of £30,000 for a drug to be deemed cost-effective
  • In the case of Omalizumab the cost per QALY was too high and NICE stopped the NHS from prescribing it to people under 12. After protests from action groups and a lot of press coverage, NICE reached a final decision to allow omalizumab for patients aged over 6 years old. One of the factors that influenced this decision was a confidential ‘patient access scheme’ agreement it had reached with the manufacturers of omalizumab to reduce the cost of the drug to the NHS.

Drugs: from molecules to man (22 decks)

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