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a chronic disease characterised by narrowing of the peripheral airways in hte lung, varying in severity over short periods of time either spontaneously or in response to treatment. is predominantly inflammatory. involved in paroxysmal obstruction of airways. primarily reversible but can be irreversible if untreated.

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bronchial asthma

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asthma drugs - Details

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A chronic disease characterised by narrowing of the peripheral airways in hte lung, varying in severity over short periods of time either spontaneously or in response to treatment. is predominantly inflammatory. involved in paroxysmal obstruction of airways. primarily reversible but can be irreversible if untreated.

Bronchial asthma

Volume of air that can be exhaled from the lungs in one second, following maximum inspiration

FEV1

Maximum flow rate developed by the lungs after a maximal inspiration

PEFR

Poorly reversible. narrowing of peripheral airways in the lung. a combination of chronic bronchitis and emphysema. predominantly inflammatory. produce similar symptoms to asthma. cant be treated with anti-inflammatory drugs. primarily caused by smoking and exposure to environmental pollutants (some genetic factors)

COPD - chronic obstructive pulmonary disease

Destruction of tissues around alveoli

Emphysema

Persistent cough with mucus production

Chronic bronchitis

Classified as allergic, extrinsic, an exaggerated immune reaction to an antigen

Classification of asthma - atopic

Classified as non-allergic, intrinsic

Classification of asthma - non-atopic

Severe acute asthma attack, not readily reversed, can be fatal without emergency treatment

Status asthmaticus uk

Rings of cartilage dissapate as move down from trachea to tertiary bronchi. bronchioles have no cartilage support but have smooth muscle.

Anatomy of the airways

More glands. more muscle. infiltration of immune system cells.

Pathological changes to the submucosal layer in the airway wall in asthma

Basement membrane becomes thicker, loss of epithelium (especially ciliated cells), goblet cells may increase in number. there is hypertrophy of submucosal gland and hyperplasia (increased such as goblet cells). mucus plugs may also form.

Pathological changes to the basement membrane in airway wall in asthma

Two phases: 1) early phase: bronchospasm, associated with the asthma attack 2) later phase: inflammation, delayed inflammatory phase can often compromise the airways more

Asthma attacks - frequently biphasic

1) dendritic cell show antigens to other cells in immune system (APCs) 2) interaction of an APC with a T helper cell 3) T cell releases cytokines (interleukins) activating other components of the immune system such as eosinophils and mast cells, triggering B lymphocytes to differentiate into plasma cells and started producing IgE antibodies. 4) antibodies then attach to mast cells and eosinophils.

Role of leukocytes

- granules that contain pr-formed early mediators e.g. histamine, proteases. proteoglycans and chemotactic factors (the black bubbles) - later mediators derived from membrane lipids e.g. leukotrienes, prostaglandins, thromboxanes and prostacyclins. - when an IgE antibody on surface of mast cells become cross linked by an antigen, it triggers the mast cell to degranulate and release large quantities of preformed mediators such as histamine - leukotriene B4 and prostaglandin D2 are produced from membrane lipids

Mast cell in asthma

Some of cells attracted in by chemotactic signals released by mast cells include eosinophils and macrophages. these cells release a variety of toxic proteins, such as major basic protein. this protein damages the respiratory epithelium causing structural changes (epithelial desquamation). also release various growth factors that cause hyperplasia's seen in asthmatic respiratory epithelium and signalling molecules that can sensitise the epithelium to further allergen challenges.

Allergen-induced release of mediators from sensitized mast cells and eosinophils

Respiratory epithelium was squamous before ciliated, so this is reverted due to the actions of major basic protein causing structural changes to the respiratory epithelium

Epithelial desquamation

Early mediator, contraction of airways smooth muscle, increased vascular permeability, increased bronchial secretions

Effect of histamine on bronchial asthma

Early mediator, infiltration of lung tissue by neutrophils and eosinophils, encourage migration of immune system cells.

Chemotactic factors

Later mediators, contraction of airways smooth muscle, increased vascular permeability, increased bronchial secretions. the late phase is similar ot early phase

Leukotrienes c4 d4 e4 and porstaglandin d2

Later mediator, from eosinophils, causes cell death and epithelial desquamation

Major basic protein

- relievers are for those with 2 or less asthma attacks a week - beta 2 adrenoceptor antagonists - theophylline - mAChR antagonists

When should relievers/bronchodilators be used and give examples

- more than 2 asthma attacks a week - long acting beta 2 agonists - glucocorticosteroids - monoclonal antibodies - leukotriene antagonists

When should preventors/prophylactic agents be used and give examples

SELECTIVE - because non-selective (propanolol) will interfere with beta adrenoceptor agonists such as salbutamol, which is needed for its therapeutic bronchodilator effects. non-selective will bind to both beta 1 and 2.

Should asthmatics be given selective or non selective beta adrenoceptor drugs

BAD - want to avoid the side effects of beta 1 adrenoceptors because they have major effects in the heart and metabolism, e.g. increased rate of SA node and release of renin (blood pressure effects). dobutamine.

Affects of beta1 selectivity of drugs to treat asthma. examples of beta 1 selective drugs.

1) SA node - increased rate 2) ventricular myocardium - increased force 3) propulsive smooth muscle of gut - relaxed 4) renal juxtaglomerular cells - release of renin 5) adipocytes - lipolysis 6) hepatocytes - glycogenolysis

Effects of beta 1 adrenoceptors on the body

1) airway smooth muscle - relaxed 2) uterus - relaxed 3) all blood vessels - dilated 4) skeletal muscle - tremor and glycolysis

Effects of beta 2 adrenoceptors in the body

Good affinity for alpha and beta adrenoceptors. increasing the size of this substituent increases selectivity for beta receptors and then for beta 2 receptors. replacing one of the catechol -OH groups by -CH2OH or changing its ring position reduces inactivation by neuronal and non-neuronal uptake.

Adrenaline as a natural ligand for beta adrenoceptors bronchodilators and how to make it more selective to beta 2

Drugs given to relieve asthma attacks. relative lipophilicity of 1

Beta agonist bronchodilators

Beta 2 adrenoceptor selective agonist. relative duration of 36 hours, fairly lipid soluble. many use in addition to terbutaline.

Salbutamol

Beta-agonist. relative lipophilicity of 3200 (longer chain gives lonmger duration). twice a day to prevent symptoms. only recommended to be given in combination with glucocorticoids. it doesn't dissociate from the agonist binding site rapidly so will continously activate (has a catechol-like end that binds to the site).

Salmeterol

Drug dissolves into membranes and slowly leaks out, thus remaining in the tissues for longer.

Lipohilicity

Acts via g protein which stimulates adenylyl cyclase. resulting increase of cAMP activates protein kinase A, which has two main effects: 1) myosin light chain kinase is negatively modulated 2) cellular calcium levels fall. together these effects result in relaxation of the smooth muscle in the airway. activation of beta 2 receptors in mast cells also prevents them from degranulating.

How do beta 2 adrenoceptor agonists act via the Gs G protein.

1) Tremor: peripheral effect involving interference with muscle spindle function 2) Tachycardia: activation of cardiac beta-adrenoceptors 3) Nervous tension: effect on CNS 4) Hypokalaemia: stimulation of Na/K ATPase in skeletal muscle - minimise using inhalation - MDI and a spacer or a nebulizer.

Unwanted effects of beta-agonist bronchodilators and how can we minimise them

(symbicort) maintenance and reliever therapy: budesonide and formoterol

What is (S)MART

- is a alkylxanthine (related to coffee) - diff between caffeine and theophylline is the methyl group on caffeine - adult dose range for oral theophylline = 125-300 mg - oral or IV - narrow therapeutic window (2 doses can be toxic) - plasma or saliva assay done to help determine dose regimen - half life affected by cardiac/liver disease, smoking and many drugs

Theophylline - basic knowlegde

Two main pharmacological effects: 1) they inhibit the enzymes responsible for the breakdown of cAMP (phosphodiesterase) 2) they may impact on both the inflammatory processes and the bronchoconstriction seen in asthma - theophylline is considered a general antagonist of adenosine receptors, this is likely to contribute to its mechanism of action because adenosine (when not blocked) causes bronchoconstriction.

Mechanism of theophylline in asthma

Phosphodiesterase break down cAMP. if theophylline inhibits the breakdown there will be a build up of cAMP. cAMP suppresses inflammation so the increase in cAMP will have an increase in suppressed inflammation

Why does theophylline have an impact on inflammation

- a water soluble complex of theophylline and ethylenediamine - oral formulation (sustained release) or IV infusion - patient with acute severe asthma has nebulised terbutaline and an IV infusion of aminophylline.

Aminophylline in asthma treatment

- it shares a metabolic pathway in the liver with a vast number of drugs so if you are taken one of these drugs or smoking it can affect plasma levels - congestive heart failure and liver disease can also increase its half-life. meaning that you have to use assays to establish the right dosage for a particular patient.

Why is the half life of theophylline affected by cardiac/liver disease, smoking and many drugs

CYP1A2: important for the metabolism of a lot of drugs; antidepressants, antipsychotic drugs, paracetamol, verapamil and propanolol - metabolism inhibited by: verapamil, caffeine, amiodarone, grapefruit juice, many herbal teas - metabolism induced by: tobacco, broccoli, cauliflower and grilled meat.

Discuss the metabolism of theophylline

- nausea and vomiting - headache - fainting - tachycardia - cardiac dysrhythmias - fatal - convulsions - fatal - because of the issue with dosage with theophylline and the side effects found, it is no longer a first-line treatment for asthma.

Unwanted effects of theophylline in asthma

- an alkylxanthine - in chocolate - bronchial dilating effect - problems with metabolism can lead to toxicity

Theobromine - basic facts

Reversal of the effects of a drug by an agent which, rather than acting at the same receptor, causes a response in the tissue or animal which opposes that induced by the drug.

What is functional antagonism

M3 - muscarinic acetylcholine receptors (M3 produces contractions which lead to asthma)

Which receptors are best to target in asthma with antagonists

- muscarinic receptors on goblet cells, increasing the secretion of mucus - muscarinic receptors that cause constriction of smooth muscle

Relative to asthma, what two sites does acetylcholine work at in the bronchial tract

- binds to M1 and M3 subtypes of mAChR, these receptors are coupled to the phospholipase C signalling system via Gq.

What type of receptor does acetylcholine bind to relative to asthma within the bronchial tract

NO - it can cause some useful therapeutic effects i.e. bronchodilation and decreased mucus secretion HOWEVER it would have several side effects e.g. blocking M2 receptors in the heart causing tachycardia. it is a tertiary amine and can exist in an uncharged form, this uncharged form is very lipid soluble and so can cross through various membranes and barriers in the body, it would enter the systemic circulation and cause unpleasant effects. NB: atropine must become +ve (protonated) in order to mimic ACh and bind to mAChR agonist binding site.

Is atropine suitable to treat asthma

- ACh not good at crossing bio membranes because it is permanently positively charged. - atropine has an ester bond and a nitrogen that can become protonated and bind to mAChR. But in its uncharged form it can cross bio membranes easily

Structural differences between atropine and acetylcholine

- close structural analogue of atropine; but has an added ethyl group to the nitrogen so is a quaternary amine with a +Ve charge (can't cross bio membranes - key to keeping ipratropiums effects to the lungs, and not allowing it into the circulation) - is a non-selective mAChR antagonist that is benefical in asthma, usuall in combination with other drugs. - given by an MDI - reduces irritant pathways (involve cholinergic neurons) - reduces bronchoconstriction, mucus secretion and cough

Ipratropium relative to asthma

- dry mouth - rare cases of urinary retention, blurring of vision and constipation - antagonism at OTHER mAChR receptors

Unwanted effects of ipratropium

- leukotrienes increased in asthma (produce bronchoconstriction) - important mediator in atshma - produced by mast cells, eosinophils, basophils and macrophages - agonist at cysteinyl-leukotriene (CysLT) receptors - contracts bronchial smooth muscle - stimulates mucus secretion - increases microvasular permeability

Leukotriene antagonists relative to asthma

- phospholipase A2 releases arachidonic acid from membrane phospholipids. - Arachidonic acid then further metabolised into a group of 20 carbon signalling molecules called the eicosanoids - eicosanoids can be further subdivided into various classes, most important of which are the leukotrienes and prostanoids

Describe the process of production of leukotrienes via phospholipase A2

- 'lukast' - e.g. montelukast

What do the names of all competitive antagonists at (cysteinyl - leukotriene) CysLT receptors end in

- given orally - add on, prophylactic therapy in mild to moderate asthma - reduces exercise induced asthma - reduces aspirin induced asthmma

Montelukast relative to asthma

- aspirin can induce attacks - aspirin inhibits the enzyme cyclooxygenase; which is important for the synthesis of prostanoids from arachidonic acid. if enzyme is inhibited, then arachidonic acid is diverted to leukotriene production instead (causes bronchoconstriction)

Why are asthmatics sensitive to aspirin

- abdominal pain, nausea - head ache - psychiatric effects - generally well tolerated with few side effects out of the oral cavity and bronchial tract

Unwanted effects of montelukast in asthma

Mineralcorticosteroids and glucocorticosteroids are synthesized in the adrenal cortex using cholesterol as a starting point.

Where are adrenocorticosteroids synthesized

Aldosterone for water and electrolyte balance

Example of mineralcorticosteroid

Hydrocortisone

Example of glucocorticosteroid

Modulation of protein and carbohydrate metabolism

What does low concentrations of glucocorticosteroids illicit

Suppression of inflammation and immune responses

What does high concentration of glucocorticosteroids illicit

- a superfamily of receptors for lipophilic substances i.e. the substances that bind to and activate these receptors all have in common a lipophilic nature - substances: steroid hormones, corticosteroids, sex hormones, thyroid hormones, fat soluble vitamins A and D - mechanism: bind agonist and regulate transcription of DNA to mRNA, this in turn changes protein expression (Slow)

Nuclear hormone receptors + basic mechanism

N-terminal domain//DBD//Hinge region//LBD//C terminal domain - n-terminal is end of protein and is loosely folded - DBD is DNA binding domain which recognises specific DNA sequence - LBD is ligand binding domain which recognises a specific agonist - C terminal tail is the opposite end to the n-terminal domain

NHR structure

Endogenous steroids = hydrocortisone, corticosterone, aldosterone - both hydro and cortico act on GCRs and MCRs (so salt + water balance + the immune system) - aldosterone has purely mineralcorticoid effects

Natural steroids

- up regulation of the anti-inflammatory protein annexin 1 (also known as lipocortin). significane here being annexin 1 inhibits phospholipase A2 which is involved in the production of arachidonic acids from membrane phospholipids. - these acids ultimatley result in production of leukotrienes (bad for asthma - cause bronchoconstriction) - down regulation of the enzyme cyclo-oxygenase. significance here is that COX-2 is involved in the release of prostanoids from arachidonic acid. - both these effects decrease inflammatory eicosanoid signalling

Anti-inflammatory effects of glucocorticosteroids in the lung

Increase capillary permeability and mucus secretion, and bronchoconstriction

Effect of leukotrienes in asthma

Increase capillary permeability

Effect of prostaglandin E in asthma

Bronchoconstrictor

Effect of prostaglandin F2a in asthma

Bronchoconstrictor

Effect of thromboxane A2 in asthma

They prevent cytokine release from T helper cells (activated lymphocytes). this will impinge on the activation of other immune system cells.

How to glucocorticosteroids affect the immune system in asthma

- immunosupressant - can be both desirable and undesirable - metabolic effects - but its wanted effect is that it is anti-inflammatory

Unwanted effects of hydrocortisone

- cushings syndrome: buffalo hump, hypertension, muscle wasting, osteoperosis, moon face, increased abdominal fat, thinning of skin, poor wound healing

Unwanted effects of systemic glucocorticoids

4 ring structure

What is the basic structure of a steroid

2) hydrocorisone (mainly mineral effect) and fludrocortisone 2) prednisolone 3) dexamethasone (mainly gluco effect)

Order hydrocortisone, dexamethasone, fludrocortisone and prenisolone in order of duration of action from short to long

- anti-inflammatory effects of the glucocorticoids must be mediated by transrepression - side of effects seem to be mediated by transactivation

Basic NHR revision - how are some of the anti-inflammatory effect and side effects of glucocorticoids mediated

Used in long term prohylaxis/prevention

What is the most common use of glucocorticosteroids in asthma

- prescribed to patients who can't control their asthma well - general structure: long acting beta agonist reliever (LABA) and steroid

When are combination inhalers prescribed and what is their general structure

A combination drug used in asthma when patients can't control their asthma well. it is made up of a LABA and a steroid. these are: formeterol and beclomethasone.

What is fostair used as and what makes up this drug

Seretide is a combination drug used for patients who can't control their asthma well. it is made up of a LABA and a steroid. these are salmeterol and fluticasone.

What is seretide used for and what makes up this drug

Symbicort is a combination drug used in patients with asthma that is not well controlled. it is made up of a LABA and a steroid. these are formeterol and budesonide

What is symbicort used for and what makes up this drug

- local immunosupression cam evoke opportunist overgrowth of candida albicans (oral thrush) - local effects of the vocal cords can result is dysphonia (hoarseness) - reduce incidence of unwanted effects by using a spacer or rinsing mouth after inhaler use

Unwanted effects of inhaled glucocorticosteroids

Due to the negative feedback loop of how hydrocortisone and corticosterone are produced endogenously, with an exogenous steroid prescription, the endogenous process comes to a halt. therefore is the exogenous steroid is then abruptly discontinued, the patient can experience acute adrenal insufficiency (Addison crisis), which can be fatal. so if the steroid administration must be stopped, then this must be a gradual process so that the adrenal cortex has time to restart endogenous steroid production.

Why is there a problem with the control of adrenal steroid synthesis as a serious side effect of steroids

Omalizumab - based on monoclonal antibody technology and thus requires a complicated purification process, therefore very expensive. but mechanism is to stop IgE binding to mast cells and eosinophils so is effective in moderate/sever asthma.

What is an antibody based treatment of asthma and what is general mechanism of it

Hydrocortisone Hydrocortisone has both gluco- and mineralo-corticoid activities and is NATURALLY occuring

What is a naturally occuring adrenocorticosteroid that has mineralcorticosteroid affects

Used for its anti-inflammatory effects Glucocorticoids such as beclometasone are used to prevent asthma attacks and do so through their anti-inflammatory actions. They also have immunosuppressive and metabolic effects but these are considered to be undesirable side effects. Bronchodilation is an effect of reliever drugs rather than preventers.

What is beclamtasones primary use in asthma

IgE (immunogloblin E) 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. For example, many people are able to move off high-dose glucocorticoid therapy and thus avoid the Cushingoid side-effects associated with it.

Omalizumab - what does it bind to

- reliever/bronchodilator - short acting beta adrenoceptor agonist

Terbutaline

Gs Salbutamol is of course an agonist at beta 2 adrenoceptors, which in bronchial smooth muscle, are coupled to Gs. Gs stimulates adenylate cyclase resulting in increased production of cAMP. In turn, cAMP activates protein kinase A Activation of protein kinase A results in relaxation of bronchial smooth muscle. The mechanism behind this relaxation is not fully delineated, but involves a) negative modulation of myosin light chain kinase and b) reduction in intracellular calcium levels.

Does Gs or Gq interact with beta 2 adrenoceptor

In the bronchial tract, muscarinic receptors (M1 and M3) are coupled to the PLC/IP3 pathway via Gq.

In the bronchial tract, muscarinic receptors interact with what G signalling pathway

Aldosterone is a mineralcorticoid and has no useful actions in asthma. other steroids useful in the treatment of asthma are beclometasone, fluticasone, and budenoside

What are aldosterones affects in asthma

asthma drugs

asthma drugs based on uni of manchester sem1year1 content