Pharmacology

Question 1

Postganglionic cholinergic fibres stimulation causes (3)

Answer 1

Bronchial smooth muscle contraction on airway smooth muscle cells
Increased mucus secretion on goblet cells
Mediated by M3 muscarinic ACh receptors

Question 2

Postganglionic noncholinergic fibres stimulation causes

Answer 2

Bronchial smooth muscle relaxation mediated by nitric oxide (NO) and vasoactive intestinal peptide (VIP)

Question 3

Sympathetic division stimulation causes (4)

Answer 3

Bronchial smooth muscle relaxation via β2-adrenoceptors
Decreased mucus secretion mediated by β2-adrenoceptors
Increased mucociliary clearance mediated by β2-adrenoceptors
Vascular smooth muscle contraction, mediated by α1-adrenoceptors

Question 4

Smooth muscle contraction results from

Answer 4

Phosphorylation of regulatory myosin light chain (MLC) in presence of elevated intracellular Ca2+ and ATP

Question 5

Smooth muscle relaxation results from

Answer 5

Dephosphorylation of MLC by myosin phosphatase

Question 6

Activities of myosin light chain kinase (MLCK) and myosin phosphatase oppose/for each other

Answer 6

Oppose

Question 7

The presence of elevated Ca2+ (2)

Answer 7

The rate of phosphorylation exceeds the rate of dephosphorylation
Relaxation thus requires return of intracellular Ca2+ concentration to basal level achieved by primary and secondary active transport

Question 8

Chronic Asthma Pathological changes (5)

Answer 8

Increased smooth muscle mass
Accumulation of interstitial fluid (oedema)
Increased secretion of mucus
Epithelial damage (exposing sensory nerve endings)
Sub-epithelial fibrosis

Question 9

Epithelial damage (exposing sensory nerve endings) causes

Answer 9

Increased sensitivity of the airways to bronchoconstrictor influences
Based on hypersensitivity and hyper-reactivity

Question 10

How to detect hyper-responsiveness

Answer 10

Provocation tests with histamine and methacholine

Question 11

Drugs in Asthma Treatment Categories (6)

Answer 11

Short acting β2-adrenoceptor agonists (SABAs)
Long acting β2-adrenoceptor agonists (LABAs)
CysLT1 receptor antagonists
Glucocorticoids
Cromoglicate
Humanised monoclonal IgE antibodies

Question 12

Aerosol Therapy for Asthma (9)

Answer 12

Slow absorption from lung surface
Rapid systemic clearance
Low dose delivered rapidly to target
Low systemic drug concentration
Low adverse effects
Distribution reduced in airway diseases
Good with bronchodilators but not anti-inflammatory drugs
Difficult for children and infirm people
Only good in mild to moderate disease

Question 13

Oral therapy in Asthma (8)

Answer 13

Good oral absorption
Slow systemic clearance
High systemic dose needed to achieve drug concentration in lung
High systemic concentration
High adverse effects
Distribution unaffected by airway disease
Good compliance and administration ease
Good even in severe disease

Question 14

SABAs and LABAs are

Answer 14

β2-Adrenoceptor Agonists

Question 15

SABAs (6)

Answer 15

Example is salbutamol
First line treatment for mild asthma
Administrated by inhalation, oral or IV
Acts rapidly in 5 minutes
Relaxes smooth muscle, increases mucus clearance and decrease mediator release from mast cells and monocytes
Few adverse effects - Fine tremor, tachycardia, hypokalaemia

Question 16

LABAs (3)

Answer 16

Example is Salmeterol,Formoterol
Not for acute relief but useful in nocturnal asthma
Must always be co-administered with a glucocorticoid

Question 17

Cysteinyl leukotriene (CysLT1) receptor antagonists (6)

Answer 17

Example is Montelukast
Blocks CysLT1 receptor preventing CysLT release from mast cells and inflammatory cells
Causes bronchial smooth muscle relaxation
Administered orally
Not for acute severe asthma relief
Few adverse effects - Headache, GI upset

Question 18

Methylxanthines (7)

Answer 18

Theophylline, Aminophylline
Inhibits phosphodiesterase PDE3 inactivating cAMP and cGMP
Causes smooth muscle relaxation, anti-inflammatory effect and increases mucus clearance
Improves lung ventilation by causing diaphragmatic contractility reducing fatigue
Administrated orally
Very narrow therapeutic window
Many adverse effects - nausea, vomiting, headache, seizures, hypotension, dysrhythmia

Question 19

Glucocorticoids (6)

Answer 19

Beclometasome (mild) and predinisolone (severe)
Prevents and resolves inflammation by decreasing number of inflammatory cells, cytokine mediators, mucus secretion, and endothelial cell leak
No acute bronchodilator action but acts as long term or prophylaxis in mild/moderate asthma
Delivered via inhalation to minimize adverse effects like dysphonia (hoarse, weak voice) and thrush
In severe asthma glucocorticoids are taken orally with inhaled steroid to minimize systemic effects
Must be taken regularly to avoid disease progression which is irreversible

Question 20

Cromoglicate (Cromones) (6)

Answer 20

Sodium Cromoglicate
Delivered via inhalation
More effective in children than older adults
No effect on bronchial smooth muscle
Stabilises mast cells that forms a weak anti-inflammatory effect
Reduces short and late term asthma attack but efficacy requires several days to block late phase reaction so requires frequent dosing

Question 21

Monoclonal antibodies directed against IgE (3)

Answer 21

Example is Omalizumab
Suppresses mast cell response to allergens
Administered via IV
Con is very expensive

Question 22

Muscarinic ACh Receptors in Airways (2)

Answer 22

Decreasing parasympathetic neuroeffector transmission with muscarinic receptor antagonists is a vital COPD treatment
Muscarinic receptor antagonists act as antagonists of bronchoconstriction caused by smooth muscle M3 receptor activation in response to ACh released from postganglionic parasympathetic fibres

Question 23

M1 location and function

Answer 23

Ganglia

Facilitate fast neurotransmission mediated by ACh acting on nicotinic receptors

Question 24

M2 location and function

Answer 24

Postganglionic neurone terminals

Act as inhibitory autoreceptors reducing release of ACh

Question 25

M3 location and function

Answer 25

Airway smooth muscle and goblet cells | Mediate contraction and mucus secretion to ACh

Question 26

Short acting muscarinic antagonist (SAMA) (6)

Answer 26

Ipratropium Administered via inhalation Quaternary ammonium group decreases absorption and systemic exposure causing few adverse effects Non-selective blocker of M1, M2 and M3 receptors Decreases bronchospasm and mucus secretion Only in asthma

Question 27

Long acting muscarinic antagonists (LAMAs) (6)

Answer 27

Tiotropium, Glycopyrronium, Aclidinium, Umeclidinium Administered via inhalation Quaternary ammonium group decreases absorption and systemic exposure causing few adverse effects Decreases bronchospasm and mucus secretion Only in asthma LABA/LAMA combinations are scientifically logical and are likely to be most effective when both drugs are deposited in the same location in the airways

Question 28

Ultra LABAs (3)

Answer 28

Indaceterol, olodaterol Not for acute bronchospasm relive Once daily dosing is effective

Question 29

Phosphodiesterase-4 (PDE4) inhibitor (4)

Answer 29

Rofumilast Suppresses inflammation and emphysema Taken orally in severe COPD Few adverse effects (GI tract)

Question 30

Glucocorticosteroids (3)

Answer 30

Affect in combination with β -adrenoceptor agonists and/or muscarinic receptor antagonists in COPD patients is debatable Benefits patients who develop frequent and severe exacerbations when given with LABAs Glucocorticoid unresponsiveness in COPD patients may be due to oxidative/nitrative stress

Question 31

Rhinitis and Rhinorrhoea Treatments (6)

Answer 31

``` Glucocorticoids H1 Receptor Antagonists (Anti-Histamines) Muscarinic Receptor Antagonists Sodium Cromoglicate (Cromones) CysLT1 receptor antagonists Vasoconstrictors ```

Question 32

Glucocorticoids in Rhinitis (7)

Answer 32

Beclometasome, Predinisolone, Fluticasone Reduce vascular permeability, recruitment and activity of inflammatory cells and the release of cytokines and mediators Applied topically as spray to nasal mucosa Effective as monotherapy Can be combined with anti-histamine in moderate/severe rhinitis Given orally (short term) in very severe cases Effective in SAR, PAR, NARES and vasomotor rhinitis

Question 33

H1 Receptor Antagonists (Anti-Histamines) (6)

Answer 33

``` Cetirizine, Ioratidine, Fexofenadine Causes vasodilation, increased capillary permeability, sensory nerve activation, mucus secretion Effective in allergic rhinitis only Less effect on congestion Taken orally or spray Effective as monotherapy ```

Question 34

Muscarinic Receptor Antagonists in Rhinitis (4)

Answer 34

Ipratropium Reduces rhinorrhoea in PAR and SAR only Administered intranasally Minor adverse effects (dryness of nasal membrane)

Question 35

Sodium Cromoglicate in Rhinitis (3)

Answer 35

Stabilizes mast cells Administered nasally Maintenance treatment with onset action of 4 to 7 days but full effect takes weeks

Question 36

CysLT1 receptor antagonists in Rhinitis (3)

Answer 36

Montelukast Taken orally Effective in PAR and SAR

Question 37

Vasoconstrictors in Rhinitis (5)

Answer 37

Oxymetazoline Mimics effect of noradrenaline by activating α1-adrenoreceptors to decrease swelling in vascular mucosa Taken intranasally Short term effectiveness in reducing congestion Taking more than a few days causes a rebound upon discontinuation

Question 38

Mucolytics (2)

Answer 38

Oral carbocisteine , erdosteine | Reduces sputum viscosity and aide sputum expectoration in COPD