Respiratory Pharmacology PDF

Respiratory Pharmacology A review of pulmonary disease (asthma) and its treatment.  Respiratory pharmacology Topics covered: Regulation of respiration Disorders of respiratory function (asthma, COPD) and principles of inflammation Drugs affecting respiration...

Respiratory Pharmacology A review of pulmonary disease (asthma) and its treatment.  Respiratory pharmacology Topics covered: Regulation of respiration Disorders of respiratory function (asthma, COPD) and principles of inflammation Drugs affecting respiration Bronchodilators - long & short term acting agents Anti-inflammatory agents  Is asthma serious? www.asthma.org.uk Imagine being paralysed by fear as you struggle to breathe, unable to speak, unable to ask for help. That's what an asthma attack feels like There are 5.4 million people with asthma in the UK. In Northern Ireland 182,000 people (1 in 10) are currently receiving treatment for asthma. This includes 36,000 children and 146,000 adults Every 10 seconds someone is having a potentially life-threatening asthma attack in the UK. Every day, the lives of three families are devastated by the death of a loved one to an asthma attack, and tragically two thirds of these deaths are preventable. In the past 10 years (2014-2024), more than 12,000 people died in UK due to asthma  Respiration Airway resistance measured by FEV1, and more commonly by PEFR  Respiratory System Respiration controlled by 1. Respiratory centre in the medulla (chemoreceptors and pO2) pCO2 in arterial blood at carotid bodies 2. The CNS - cortex 3. Vagal afferents from the lungs Afferent neurons (otherwise known as sensory neurons). The opposite activity of direction or flow is efferent Breathing can be regulated by voluntary control  link between cortex and motor neurons in the respiratory muscles  Respiratory System In normal control of airways: AFFERENT PATHWAYS - 3 types of sensory receptor 1. Slowly adapting stretch receptors 2. Rapidly adapting irritant receptors (myelinated vagal fibres) 3. Unmyelinated sensory C-fibres Physical or chemical stimuli act on irritant receptors in upper airways C-fibre receptors found in the lower airways Activation of both causes cause coughing, bronchoconstriction and mucus secretion. Cold air and irritants such as ammonia, sulfur dioxide, cigarette smoke. Stimuli can also be internal (inflammatory mediators – see later notes on asthma).  Respiratory System In normal control of airways: EFFERENT PATHWAYS Parasympathetic (cholinergic) innervation predominates - vagus nerve M3 receptors - bronchoconstriction + mucus secretion from glands M2 receptors are auto-receptors Parasympathetic neurons dominant in maintaining tone Sympathetic (adrenergic) – noradrenaline (NA) releasing sympathetic nerves innervate bronchial blood vessels and glands, but NOT human airway smooth muscle! However, β2-adrenoceptors are abundantly expressed on human airway smooth muscle. What effect would circulating adrenaline have? New b2 selective adrenergic agonists (salbutamol) used as common treatment for acute asthmatic symptoms Noradrenaline/adrenaline cause increased heart rate (do you know which receptor is responsible for this)  Respiratory System EFFERENT pathways contd. 3. NANC mediators (non-adrenergic non-cholinergic). These can be inhibitory or stimulatory Possible inhibitory mediators = NO & VIP Possible stimulant mediators = Substance P & bradykinin - bronchoconstriction, mucus secretion, increased vascular permeability, cough and vasodilatation You should read relevant ‘Chemical Mediators’ sections in Rang & Dale for fuller account of cholinergic, noradrenergic and NANC transmission NANC Fibres Stimulatory Inhibitory Constriction Dilation NANC fibres release neuropeptides including bradykinin (bronchoconstriction) and NO (dilation)  Respiratory System Respiratory stimulants Used only in emergency and under expert care. E.g. post-op respiratory depression or acute resp. failure. Main drug = doxapram (stimulates carotid chemoreceptors, which in turn, stimulate respiratory centre in the brain) Respiratory depressants Many drugs which have a depressant action on CNS can cause some degree of resp. depression. These include: benzodiazepines general anaesthetics opioids ethanol Most of the above only have depressive effect in sig. high doses. Do you know clinical significance of drugs above?? Disorders of respiration  Disorders of respiratory function Bronchoconstriction: The muscles that surround the bronchial tubes controlled by ANS. Inflammation: hallmark of asthma. When inflammation occurs, the bronchial tubes shed their inner lining (epithelial cells) which leads to swelling and irritable airways. This decreases the diameter of the airways and reduces the airflow through the bronchial tubes Increased Mucus: Excessive amounts of thick mucus are secreted into the bronchial tubes. Airway Hyper-responsiveness: The inflamed airways become highly sensitive and react to stimuli that have no effect in normal persons The early phase of asthma is described as an immediate response to a trigger In the late phase of asthma, symptoms begin 4 to 8 hours after exposure to the trigger and may last as long as 24 hours or on occasion even longer N.B. Some people may experience only an early phase response while others may experience both an early phase and a late phase response  Asthma Asthma Defined as a chronic inflammatory disorder Symptoms result from chronic airway inflammation, hyper-responsiveness, constriction and obstruction Even in patients with normal airflow (which for mild asthmatics = most of time), their lungs are hyper-reactive or hyper-sensitive (or both = hyper-responsive) to a variety of natural stimuli (e.g., cold air, exercise, chemical fumes) Reversibility of airways obstruction in asthma contrasts with COPD  Airway hyperresponsiveness in asthma Asthma is characterised by: inflammation of the airways bronchial hyper-reactivity reversible airways obstruction  Disorders of respiratory function ASTHAMA AS AN INFLAMMATORY DISEASE Primary symptoms are due to bronchoconstriction BUT… the underlying cause is an inflammation of the airways Inflammation involves a variety of processes including infiltration by a variety of inflammatory cells including Th2 lymphocytes etc…(see later slide(s)). Th2 cytokines - attract other inflammatory cells, especially eosinophils, to mucosal surface - IL-5 primes eosinophils to produce cysteinyl leukotrienes, and to release granule proteins that damage the epithelium - hyper-responsiveness - Promote IgE synthesis and responsiveness (IL-4 and IL-13 'switch' B cells to IgE synthesis and cause expression of IgE receptors on mast cells and eosinophils; they also enhance adhesion of eosinophils to endothelium) IL-4 & IL-13 and inflammation Mechanism for acute exacerbation of asthma in atopic individuals exposed to allergen The effectiveness of omalizumab emphasise importance of IgE in the pathogenesis of asthma Suppress Th2 cell activity Fig. 46.1 Principles of Pharmacol. Golan et al.  Disorders of respiratory function All individuals continually inhale a range of environmental allergens  phagocytosed by antigen presenting cells in the airway Generally ignored by TH cells and generate low level IgG & moderate TH1 response mediated by interferon-g. In contrast an exaggerated TH2 response occurs in asthma generating the characteristic inflammatory response & bronchoconstriction  Pharmacotherapy 2 categories of anti-asthma drugs (not mutually exclusive) bronchodilators (relievers) anti-inflammatory agents (controllers/preventers) Bronchodilators reverse the immediate bronchospasm; Anti-inflammatory agents inhibit inflammatory components Step 1 - Very mild disease may be controlled with inhaled short-acting bronchodilator alone Step 2 - a regular inhaled glucocorticoid should be added Step 3 - add a inhaled long-acting bronchodilator; minimising need for increased doses of inhaled glucocorticoid. Step 4 - Consider theophylline and leukotriene antagonists, as they exert a glucocorticoid- sparing effect, one or other is added in for patients with more severe asthma and/or the dose of inhaled glucocorticoid increased to the maximum recommended Step 5 - If the patient's condition is still poorly controlled, it may be necessary to add a regular oral glucocorticoid (e.g. prednisolone) Glucocorticoids inhibit T-cell activation, and thus the inflammatory response  Disorders of respiratory function BRONCHODILATORS Sympathetic B2-adrenergic receptors activation results in dilation – (raises cAMP concentrations and inhibits smooth muscle contraction by inactivating myosin light chain kinase) Adrenaline is highly effective but reserved for special circumstances due to non- selective activity – what other types of receptors does it stimulate? B2 selective adrenergic agonists very effective e.g. salbutamol , salmeterol. In addition to relaxing bronchial muscle the b-adrenoceptor agonists inhibit mediator release from mast cells and stimulate cilia activation β2-adrenoceptor agonists are usually given by inhalation of aerosol, powder or nebulised solution, but some may be given orally or by injection Two categories β-adrenoceptor agonists used in asthma treatment: 1. Short acting agents (physiological antagonists) and 2. Long acting agents  Disorders of respiratory function Short acting agents: Salbutamol, terbutaline Given by inhalation, duration of effect within 30 min, up to 5 hrs Newer drug binds stronger to B2 than B1 receptors thus causes fewer cardiac effects than older less selective agonist drugs. N.B. at high doses these drugs cause cardiac stimulation - why and what will effect be?  Disorders of respiratory function Long acting agents Used for prevention/control – NOT PRN - Cannot be used for acute flares Agents such as salmeterol and formoterol are long-acting β-agonists (LABA’s) Engineered with lipophilic side-chains: 12-24 hr duration of action Given by inhalation Possibly allosteric regulators of β2 receptor Neither β-agonists agents tackle the underlying inflammation Short-acting drugs (salbutamol or terbutaline, usually by inhalation) to prevent or treat wheeze in patients with reversible obstructive airways disease. Long-acting drugs (salmeterol, formoterol) to prevent bronchospasm (e.g. at night or with exercise) in patients requiring long-term bronchodilator therapy Prolonged use may lead to receptor desensitisation or down-regulation  Salbutamol Pharmacokinetics Route – inhalation, PO Absorption – slow by inhalation. Rapid if given PO Distribution – delivered directly to lungs Primary metabolism – Hepatic (CYP450) Primary excretion – Renal Onset of action – Inhalation 5-15 min, peak effect 0.5-2 h. PO – 30 minutes Duration of action: Inhalation 2-6 hours; PO 8-12 hours  Xanthine drugs There are three pharmacologically active, naturally occurring xanthine-based drugs: theophylline, theobromine and caffeine - mild stimulants and bronchodilators Theophylline is main therapeutic drug of this class - numerous side-effects (tachycardia, agitation, seizures) and narrow therapeutic window Actions of drug’s in asthma still unclear: - Non-specific inhibition of phosphodiesterase enzymes (unclear, drug levels required for this are not in therapeutic range) - Also inhibit leukotriene synthesis, and reduce inflammation - Adenosine receptor antagonism Adenosine - putative mediator of the inflammatory process You should read relevant chapter in Rang & Dale on ‘Chemical Mediators’ for fuller account on adenosine transmission  Xanthine drugs - Pk Theophylline is well absorbed from the GIT. Protein binding is 40%. Aminophylline is a salt that yields theophylline Metabolised by the CYP450 system in the liver, and the elimination half-life is about 8 hours, but varies widely. The half-life of theophylline is increased in liver disease and is decreased in heavy cigarette smokers – why? Can be given i.v. or orally (as a sustained-release preparation, BUT NOT by inhalation) - add-on therapy to glucocorticoids and long-acting β2 agonists The use of theophylline is complicated by the fact that it interacts with various drugs, has a narrow therapeutic index - requires TDM  Theophylline Pharmacokinetics Route – PO, parenteral Absorption –Rapid Distribution – 40% protein bound. Remainder distributed well in fluids less so in lipids Primary metabolism – Hepatic (CYP1A2, CYP2E1, CYP3A3) Primary excretion – Renal Onset of action –peak effect ~ 1 h Duration of action: ~6-10 hours  Muscarinic receptor antagonists Activation of bronchial muscarinic (cholinergic) receptors (M3) causes constriction (see earlier notes) Muscarinic antagonist atropine can be used as a bronchodilator and to reduce secretions, but non-specific and crosses BBB The main compound used as a bronchodilator is ipratropium - a derivative of atropine that does not cross BBB but competitively inhibits mACh receptors in bronchial smooth muscle Does not discriminate between muscarinic receptor subtypes M2 are autoreceptors – what is potential overall effect here of antagonism of M2 receptors? Also inhibits the augmentation of mucus secretion that occurs in asthma ABCD'S of anticholinergic side effects: Anorexia, Blurry vision, Constipation/ Confusion, Dry mouth, Sedation  Muscarinic receptor antagonists Given by inhalation Highly polar – how will this affect its absorption?? What effects on muscarinic receptors other than those in the bronchi?? Effect occurs after approximately 30 minutes and persists for 3-5 hours Ipratropium is also combined with salbutamol [trade name Combivent] for the management of asthma Drugs decrease formation of cyclic guanosine monophosphate (cGMP) - less intracellular calcium release - lowered contractility of smooth muscle In practice drugs are safe and well tolerated Tiotropium is a long-acting antimuscarinic bronchodilator that has been developed and shows benefit specifically for COPD patients Generally these drugs are more useful in COPD than asthma  Ipratropium Pharmacokinetics Route – Inhalation, intranasal Absorption – Minimal systemic Distribution – Mainly protein bound Primary metabolism – Hepatic (CYP450) Primary excretion – Renal & faeces Onset of action – 5-15 mins, peak effect ~ 1.5-2 h Duration of action: 3-6 hours Cysteinyl leukotrienes  Cysteinyl leukotriene receptor antagonists CLTs are potent inflammatory mediators + cause bronchoconstriction CLTs are synthesised in many inflammatory cells in the respiratory system, including eosinophils and are responsible for mediating numerous asthmatic effects All the CLTs act on the same high-affinity cysteinyl LT receptor termed CysLT1 The 'lukast' drugs (montelukast & zafirlukast) antagonise CysLT1 on target cells such as bronchial smooth muscle Lukast drugs: inhibit exercise-induced asthma inhibit early and late responses to inhaled allergen relax the airways in mild asthma Less effective than salbutamol but their action is additive with β2-adrenoceptor agonists Cysteinyl leukotriene receptor antagonists ‘Aspirin-sensitive’ asthma Cysteinyl leukotriene receptor antagonists Both drugs are given orally, montelukast once daily, zafirlukast B.I.D. Unwanted side-effects with lukast drugs are minimal Synthesis of CLTs can be blocked by inhibition of the 5-lipoxygenase enzyme by the drug zileuton - inhibiting the synthetic pathway of CLT metabolism CLT antagonists are less effective than glucocorticoids but have virtually no side effects, so they are often used to treat children Act in part as BOTH controllers and preventers  Zafirlukast Pharmacokinetics Route – PO Absorption – Rapid – but decreased with food Distribution – 99% protein bound Primary metabolism – Hepatic (CYP2C9. CYP3A4) Primary excretion – mostly bile, 10% renal Onset of action – 1 week Duration of action: unknown  Disorders of respiratory function Anti inflammatory agents are controllers Main one = glucocorticoids – NOT bronchodilators Also used - human monoclonal anti IgE antibody (omalizumab) Endogenously glucocorticoid release controlled by: Corticotrophin = hormone secreted by pituitary gland. It controls synthesis & release of glucocorticoids from adrenal cortex Corticotrophin release is controlled by a corticotrophan releasing factor (CRF) in the hypothalamus and also by the level of circulating glucocorticoids in the blood (-ve feedback mechanism to hypothalamus and pituitary) Inhaled glucocorticoids = major preventative agent in asthma treatment  Disorders of respiratory function An important action is that they decrease formation of Th2 cytokines ALSO - GCs up-regulate β2 adrenoceptors levels The main compounds used are beclometasone, budesonide, fluticasone, mometasone and ciclesonide. Given by inhalation with a metered-dose or dry powder inhaler, the full effect on bronchial hyper-responsiveness being attained only after weeks or months of therapy, because …… (controller not reliever) Primary effect is to alter gene expression (usually decreasing pro-inflammatory genes) HDAC (histone deacetylase) – reason for lack of effect of GCs in COPD??  Disorders of respiratory function GCs also induce the transcription of several anti-inflammatory proteins – Annexin-1 Annexin-1 inhibits the activity of phospholipase A2 enzyme, thus decreasing the release of free arachidonic acid from phospholipids Decrease bone marrow production of eosinophils and enhance their removal from the circulation Serious unwanted effects are uncommon with inhaled steroids Detrimental effects of prolonged high dose steroid use, especially if patient requires oral steroids  Disorders of respiratory function glucocorticoids can initiate/decrease transcription of many genes Increase Decrease T’scription T’scription Genes coding for Genes coding for many pro- B2 adrenergic receptor inflammatory proteins & a no. of anti-inflammatory IL-4,5,6,13 proteins IL-10, IL-12 TNFa HDAC Glucocorticoids also induce apoptosis in a no. of inflammatory cells esp. eosinophils and TH2 lymphocytes. Overall glucocorticoids reduce the no. of inflammatory cells in airways and reduce damage to airway epithelium.  Beclomethasone Pharmacokinetics Route – Inhalation Absorption – minimal systemic Distribution – delivered directly to lungs Primary metabolism – Liver (CYP450: 3A substrate) and lungs Primary excretion – mostly faeces, less than 10% renal Onset of action – 1 week Duration of action: half-life 15 hours  Maintenance and reliever therapy (MART) Maintenance and reliever therapy (MART) is a form of combined ICS and LABA treatment in which a single inhaler, containing both ICS and a fast-acting LABA Used for both daily maintenance therapy and the relief of symptoms as required MART is only available for ICS and LABA combinations in which the LABA has a fast-acting component To be taken (inhaled) on a daily basis  Dupilumab (Dupixent) MAB approved for use by NHS in October 2021 (FDA approved Oct 2018) ….. FDA approved for Excema in March 2017 ‘First-in-class’ medication for asthma functioning as an Interleukin-4 (IL-4) and Interleukin-13 (IL-13) receptor antagonist Dupilumab binds to the alpha subunit of the interleukin-4 receptor (IL-4Rα), making it a receptor antagonist. This alpha subunit is also found on the IL-13 receptor Decreases levels of Th2 bio-markers (but seems to need both IL-4 and IL- 13 activity to do this)  Other monoclonal antibodies The main ones for asthma are: benralizumab (Fasenra) – IL-5 omalizumab (Xolair) - IgE mepolizumab (Nucala) – IL-5 reslizumab (Cinqaero) – IL-5 Not suitable for everyone with asthma and can only be prescribed by an asthma specialist. Reserved for only the most severe cases  Disorders of respiratory function Possible drug interactions Consider effects of these drugs on asthmatics: Beta blockers used for of cardiac arrhythmias, cardio-protection after MI and hypertension NSAIDs e.g. aspirin ACE inhibitors  Further work/reading Questions on BBL to test basic knowledge Chapter 28 Rang & Dale, 10th Edition or Chapter 29 Rang & Dale, 9th Edition British Thoracic society guidelines: http://www.brit-thoracic.org.uk/ Chronic Obstructive Pulmonary Disease COPD refers to chronic bronchitis and emphysema Cigarette smoking is the main cause (trigger abnormal inflammatory response in lung) Emphysema loss of elasticity of the lung tissue and air becomes trapped in the lungs Currently, COPD is the third/fourth leading cause of death in the United States ($42.6 billion in health care costs and lost productivity) Limitation of airflow is poorly reversible and usually gets progressively worse over time Increased neutrophils Emphysema - https://www.youtube.com/watch?v=Fuf-pdmT_Q4&feature=youtu.be Chronic Obstructive Pulmonary Disease Presenting features: Attacks of morning cough (during the winter) progresses to chronic cough. The diagnosis of COPD requires lung function tests Pulmonary hypertension is a late complication Tracheotomy and artificial ventilation The most important processes causing lung damage are: 1. Oxidative stress produced by high concentrations of free radicals in tobacco smoke 2. Cytokine release due to inflammation e.g. in response to tobacco smoke 3. Impaired activity of antiprotease enzymes in the lung  COPD – management Stopping smoking – only intervention that can improve the rate of progression of COPD Currently no cure for COPD Importantly - patients should be immunised against influenza, because superimposed infections with these organisms are potentially fatal Bronchodilators - long-acting bronchodilators are worthwhile, if modest, advance in treatment. Anticholinergics appear to be superior to β2 agonists in COPD Glucocorticoids are generally ineffective, in contrast to asthma Theophylline can reduce symptoms (problems with ADR’s) – this drug can possibly upregulate HDAC activity Long-term O2 therapy administered at home prolongs life (though dangerous if still smoking!)  COPD – management One of the most common symptoms of COPD is shortness of breath - breathing requires effort Studies in many countries have found that people who live in large cities have a higher rate of COPD compared to people who live in rural areas α1-antitrypsin protects the lungs from damage caused by protease enzymes Evidence has shown that cigarette smoke can lead to oxidation of methionine 358 of α1-antitrypsin - one mechanisms by which cigarette smoke can lead to emphysema