Bronchodilators, mucolytics and steroids

Question 1

What are bronchodilators?

Answer 1

medications which relieve bronchoconstriction caused by conditions that affect air passageways and alveoli

Question 2

What are the classifications of adrenoceptors?

Answer 2

• α- and β-adrenoceptors are G-protein coupled receptors; comprise different subtypes:
○ α1 – blood vessels, gut, liver, bladder, sweat glands, iris
○ α2 – pre-synaptically on all adrenergic nerve terminals, post-pancreas
○ β1 – heart muscle, gut, juxtaglomerular apparatus
○ β2 – bronchioles, skeletal muscle, pancreas, mast cells, liver, uterus
○ β3 – adipose tissue, heart
• They act through a second-messenger mechanism:
○ α1-receptors activate phospholipase C (PLC) producing inositol trisphosphate (IP3) and diacylglycerol (DAG)
○ α2-receptors inhibit adenylate cyclase thus decreasing cyclic adenosine monophosphate (cAMP)
○ All subtypes of β-receptors stimulate adenylate cyclase thus increasing cAMP

Question 3

What are the effects of adrenoceptors?

Answer 3

• α1-receptors – vasoconstriction, pupil dilatation, decreasing peristalsis and decreasing voiding, sweating and hepatic glycogenolysis
• α2-receptors – autoinhibition of transmitter release (noradrenaline (NA) and acetylcholine receptor release from autonomic nerves)
• β1-receptors – increased cardiac rate and force, relaxation of gastrointestinal (GI) smooth muscle (decreasing peristalsis), renin release and lipolysis
• β2-receptors – bronchodilatation, vasodilatation, relaxation of uterine smooth muscle, hepatic glycogenolysis, increased insulin secretion, fine muscle tremor
• β3-receptors – lipolysis

Question 4

What are some adrenoceptor agnoists?

Answer 4

Selective drugs exist for all four main adrenoceptor subtypes: α1, α2, β1, β2
• Selective α1-agonists – phenylephrine and oxymetazoline
• Selective α2-agonists – clonidine
• Selective β1-agonists – dobutamine
• Selective β2-agonists – salbutamol, formoterol, terbutaline and salmeterol used mainly in asthma

Question 5

What are beta2-adrenoceptor agonists used for and how do they work?

Answer 5

drug of choice for an immediate phase of an asthmatic attack
• Dilate bronchi by a direct action on the β2-adrenoceptors in the bronchial smooth muscle= relaxation
• Inhibit mediator release from mast cells and decrease mucus production

Question 6

Describe the main short acting beta2-adrenoceptor agonists

Answer 6

salbutamol and terbutaline - typically administered by inhalation (aerosol, powder, nebuliser) but can be given intravenously (IV) in severe attacks. rapid onset of action (within a few minutes) and the effect lasts for 3-5 hours. Common adverse effects include fine muscle tremor, headache, palpitations, hypotension due to peripheral vasodilatation, hypokalaemia and an increase in blood glucose levels

Question 7

Describe long acting beta2-adrenoceptor agonists

Answer 7

can produce effects for up to 12 hours:

• Used to improve respiratory function in patients with COPD (e.g. salmeterol, eformoterol)

Question 8

Why are drugs acting on β1 and β2 receptors not recommended for use in asthma?

Answer 8

may lead to cardio-acceleration, anginal attack and a myocardial infarction (MI) (e.g. adrenaline, isoprenaline)

Question 9

What are the effects of β-antagonists for asthmatics?

Answer 9

(e.g. propranolol) cause wheezing in asthmatics (no effect on airway function in normal individuals) and can precipitate an acute asthma attack

Question 10

What are the classifications of muscarinic receptors?

Answer 10

• M1 receptors: act in the brain on higher cerebral function, and peripherally on the parietal cells of the gastric mucosa to increase acid secretion
• M2 receptors: act in the myocardium and decrease heart rate and the force of contraction
• M3 receptors: visceral smooth muscle, pupil constriction, increase gut motility and secretion of digestive juices, promote voiding and defecation, and secretions from exocrine glands (lacrimation, salivation, sweating)
Physiological roles for M4 and M5 receptors are unknown

Question 11

Describe the second messenger system of muscarinic receptors

Answer 11

• Muscarinic acetylcholine receptors (mAChRs) are G-protein coupled receptors
• M1, M3 and M5 receptors activate phospholipase C = form two secondary messengers (IP3 and DAG) = intracellular increase of calcium and excitation
M2 and M4 receptors inhibit adenylate cyclase = decrease production of the second messenger cAMP leading to inhibition

Question 12

Describe the general function of muscarinic antagonists

Answer 12

Generally referred to as parasympatholytic because they selectively reduce or abolish the effects of the PNS:
• Inhibition of secretions – salivary, lacrimal, bronchial and sweat glands
• Heart rate – modest tachycardia
• Eye – pupil dilation, unresponsive to light (blurred vision)
• GI tract – reduced GI motility (constipation)
• Other smooth muscle – bronchial, biliary, urinary tract smooth muscle dilatation (bronchodilation, smooth muscle relaxation, decreased voiding)
• CNS – high doses cause agitation and disorientation

Question 13

Muscarinic antagonists used specifically as an anti-asthmatic are ——— (non-selective) and ——— (M3 receptor selective) by inhalation

Answer 13

Muscarinic antagonists used specifically as an anti-asthmatic are ipratropium (non-selective) and tiotropium (M3 receptor selective) by inhalation

Question 14

How do muscarinic antagonists work?

Answer 14

· Stop activity of acetylcholine in the smooth muscle preventing contraction and producing relaxation
· Can be useful as an adjunct to another therapy (when β2-agonist alone is inadequate) to help with bronchodilation and reduce mucus secretion
· Not absorbed well into circulation = minimal action on muscarinic receptors in locations other than the bronchi
· Maximum effect is after 30 minutes (lasts for 3-5 hours)
· Side effects may include dry mouth, urinary retention, facial flushing, constipation and pupil dilation

Question 15

Bronchodilators, administered by ——–, represent the first-choice treatment to relieve an acute asthma

Answer 15

Bronchodilators, administered by inhalation, represent the first-choice treatment to relieve an acute asthma

Question 16

Describe anticholinergics

Answer 16

SAMA and LAMA anticholinergics block the action of acetylcholine in bronchial smooth muscle

Question 17

Describe SAMA and LAMA

Answer 17

• Short-acting muscarinic antagonist (SAMA): blocks the action of Ach = inhibit nerve impulses responsible for involuntary muscle movements and various bodily functions (e.g. ipratropium; inhaled)
  
  • Long-acting muscarinic antagonist (LAMA): blocks the action of Ach = inhibit nerve impulses responsible for involuntary muscle movements and various bodily functions (e.g. aclidinium, glycopyrronium (inhaled), tiotropium and umeclidinium)

Question 18

Describe SABA and LABA and how do they work

Answer 18

• Short-acting beta-agonists (SABAs): provide quick relief (rescue inhalant) of asthma symptoms - periods of acute symptoms and exacerbations (e.g. salbutamol (most common) and terbutaline)
  
  • Long-acting Beta-agonists (LABA): daily (maintenance inhalant) to relax the muscles lining the airways that carry air to the lungs - prophylactic control of persistent asthma. (e.g. formoterol, indacaterol, salmeterol and vilanterol)

SABAs and LABAs stimulate β2-adrenergic receptors in the smooth muscle of bronchi and bronchioles = stimulate the enzyme adenyl cyclase = increase production of cyclic AMP = bronchodilation. Adverse effects can include dry mouth, throat irritation, tremor, palpitations and headache

Question 19

What are the 3 pharmacologically active naturally occurring methylxanthines?

Answer 19

Theophylline (coffee, tea), theobromine (cocoa) and caffeine (coffee, tea)
**Methylxanthine used in clinical medicine includes aminophylline and theophylline

Mode of Action and Common Side Effects:
• Mode of action not fully understood but methylxanthine appears to produce bronchodilation through enzyme inhibition Side effects: nausea, vomiting, diarrhoea, gastro-oesophageal reflux, headache, insomnia, irritability, anxiety, tremor and palpitations

Question 20

What are mucolytic agents?

Answer 20

Mucolytic agents generally lower (alter) the viscosity of mucus and enhance its transport by activating ciliated epithelium (mucociliary clearance)

Question 21

What is Bromhexine Duro-Tuss Chesty Cough Liquid

Answer 21

• Reduce excess mucus associated with colds, flu, other respiratory tract infections
• Oral mucolytic agent administered as a liquid or tablet formulation
Mode of Action and Common Side Effects:
• Acts on mucus secreting cells to alter the structure of viscous mucus
Adverse effects: nausea, vomiting, diarrhoea, allergy and severe skin reactions

Question 22

Describe Acetylcysteine Mucomyst

Answer 22

• Used in bronchopulmonary disease (cystic fibrosis (CF)), anaesthesia, antidote for paracetamol overdose
Mode of Action and Common Side Effects:
• Reduces viscosity by interfering directly with the chemical composition of mucus
Adverse effects: stomatitis, nausea and bronchospasm

Question 23

Describe Dornase alfa Pulmozyme

Answer 23

• Used to manage respiratory complications of CF
Mode of Action and Common Side Effects:
• Enzyme breaks down the DNA of the decaying neutrophils
• Side effects: voice alteration, pharyngitis, laryngitis and rash

Question 24

What are glucocorticoids?

Answer 24

Synthesised and released by the adrenal cortex. Regulated by hypothalamic corticotropin-releasing factor and pituitary adrenocorticotropic hormone (ACTH)

Question 25

The main actions of corticosteroids are —– effects on metabolism, water and ——- balance, —– feedback effects (adenohypophysis and hypothalamus) and anti-inflammatory and ——— effects

Answer 25

The main actions of corticosteroids are enteral effects on metabolism, water and electrolyte balance, negative feedback effects (adenohypophysis and hypothalamus) and anti-inflammatory and immunosuppressive effects

Question 26

Early administration of corticosteroids —– the —– inflammatory response by inhibiting —– cell degranulation, decrease in ——– ——–, vasoconstriction, reduced exudation, decrease number and activity of —— and ——–

Answer 26

Early administration of corticosteroids reduce the acute inflammatory response by inhibiting mast cell degranulation, decrease in inflammatory mediators, vasoconstriction, reduced exudation, decrease number and activity of leucocytes and macrophages

Question 27

Late administration of corticosteroids decrease in number and activity of ——– cells and ——–, decrease ——- and —— inflammation but also decrease ——

Answer 27

Late administration of corticosteroids decrease in number and activity of mononuclear cells and fibroblasts, decrease angiogenesis and chronic inflammation but also decrease healing

Question 28

Corticosteroids can be administered (3)

Answer 28

orally, topically or parenterally

Question 29

Corticosteroid is therapeutically useful for ———– therapy and ——— but can have unwanted ——- actions. Prolonged use can cause suppression of response to —– and —— glucocorticoid synthesis as well as osteoporosis and Iatrogenic Cushing’s syndrome

Answer 29

Corticosteroid is therapeutically useful for anti-inflammatory therapy and immunosuppression but can have unwanted metabolic actions. Prolonged use can cause suppression of response to infection and endogenous glucocorticoid synthesis as well as osteoporosis and Iatrogenic Cushing’s syndrome

Question 30

Corticosteroids in asthma

Answer 30

• Not bronchodilators = not useful in treatment of acute asthma
• Clinical effects take time to develop (full therapeutic effect after several days of therapy)
• Important role in reducing airway inflammation (oedema, mucus production, bronchoconstriction) in prophylaxis if taken continuously
• Medications can be inhaled (beclomethasone, budesonide, ciclesonide, fluticasone furoate or fluticasone propionate), given orally (prednisolone, dexamethasone) or IV (dexamethasone, hydrocortisone)
Mode of Action and Common Side Effects:
• Inhibit the activation of macrophages and mediator release from eosinophils, and reduce the formation of various inflammatory mediators
• Adverse effects can cause infection of candida albicans in the pharynx (thrush) due to immunosuppression of the pharyngeal mucosa, dysphonia, bruising, sodium and water retention, oedema, hypertension, hypokalaemia, hyperglycaemia, diabetes, dyslipidaemia, osteoporosis, and psychiatric effects