Pharmacology Flashcards
How does the parasympathetic division causes changes in the respiratory system?
Stimulation of cholinergic and noncholinergic fibres
- Stimulation of postganglionic cholinergic fibres causes:
- bronchial smooth muscle contraction
- mediated by M3 muscarinic ACh receptors on ASM cells
- increased mucus secretion
- mediated by M3 muscarinic ACh receptors on goblet cells
- bronchial smooth muscle contraction
- Stimulation of postganglionic noncholinergic fibres causes
- bronchial smooth muscle relaxation mediated by nitric oxide and vasoactive intestinal peptide
Where cell bodies of preganglionic and postganglionic located in the parasympathetic division of the resp. system?
- Cell bodies of the preganglionic fibres are located in the brainstem
- Cell bodies of the postganglionic fibres are embedded in walls of the bronchi and bronchioles
Adrenaline kickstarts a chain of reactions to relax bronchial smooth muscle. What is the end result of these chain reactions?
- Inhibits myosin light chain kinase to inhibit contraction
- Stimulates myosin phophatase to facilitate relaxation
Is there sympathetic innervation of bronchial smooth muscle in humans?
NO
Post-ganglionic fibres supply:
- submucosal glands
- smooth muscle of blood vessels
What does stimulation of sympathetic division cause in the resp. system?
- Bronchial smooth muscle relaxation via B2-adrenoreceptors on ASM cells activated by adrenaline released from the adrenal gland
- Decreased mucus secretion mediated by B2-adrenoreceptors on goblet cells
- Increased mucociliary clearance mediated by B2-adrenoreceptors on epithelial cells (mucociliary escalator)
- vascular smooth muscle contraction by a1-adrenoreceptors on vascular smooth muscle cells
How does smooth muscle contraction occur?
- Increased intracellular Ca2+
- Calmodulin –> Ca2+-calmodulin
- Inactive MLCK –> Active MLCK
- ATP degrades to ADP and Phosphate
- Inactive myosin cross bridge becomes phosphorylated
- Phosphorylated myosin cross bridge binds with actin
Actin and myosin filaments of muscle ‘slide’ across each other to genrate force- contraction.
If contraction results from phosphorylation of the regulatory myosin light chain in the presence of elevated Ca2+ and ATP; what causes relaxation?
Relaxation results from dephosphorylation of myosin light chain by myosin phosphatase
In the presence of elevated intracellular Ca2+ the rate of phosphorylation exceeds the rate of dephosphorylation so relaxation requires return of intracellular Ca2+ concentration to basal level
This is achieved by primary and secondary active transport
Define asthma
Is a recurrent and reversible (in the short term) obstruction to the airways in response to substances (or stimuli) that: -are not necessarily noxious -normally do not affect non-asthmatic subjects
What are some of the common causes of asthma?
-allergens (in atopic individuals) e.g. dust mite faeces & pollen -exercise (cold, dry air) -respiratory infections (e.g. viral) -smoke, dust, environmental pollutants etc.
What is the incidence of asthma?
Affects 5-10% of the population in industrialized countries
List four symptoms of asthma
- Tight chest
- Wheezing
- Difficulty in Breathing
- Cough
What pathological changes to the bronchioles occur from long standing inflammation associated with chronic asthma?
- Increased mass of smooth muscle -hyperplasia & hypertrophy
- Accumulation of interstitial fluid -oedema
- Increased secretion of mucus
- Epithelial damage (exposing sensory nerve endings)
- Sub-epithelial fibrosis
What effect does asthma have on PEFR and FEV1?
- Decreases FEV1
- Decreases PEFR
Airway narrowing by inflammation and bronchoconstriction increase airway resistance which decreases FEV1 and PEFR
What are the two wings of bronchial hyper-responsiveness?
- Hypersensitivity
- Hyper-reactivity
Explain what is meant by ‘bronchial hyper-responsiveness’.
Epithelial damage exposes sensory nerve endings which contributes to increased sensitivity of the airways to bronchoconstrictor influences and may cause neurogenic inflammation by the release of various peptides
Hyper-Responsiveness
As seen in the graph, this increases the extent of the response and so increases the % decrease in PEFR
Hyper-sensitivity
As seen in the graph, this means a lower concentration of the antigen is required for a response
What type of hypersensitivity reaction is the immediate phase of an asthma attack?
Tyoe 1
What type of hypersensitivity reaction is the late phase of an asthma attack?
Type IV
What is one major caues of asthma thought to be?
An immune inbalance between TH1 and TH2 lymphocyte-mediated responses
Describe the events that occur subsequent to TH2 lymphocyte activation.
- Activated TH2 cells activate B cells by binding to them and by IL-4 production
- B Cells mature to IgE secreting Plasma cells
Meanwhile
- Activated TH2 cells also release IL-5
- Which causes eosinophils to differentiate and activate in response to IL-5 released from TH2 cells
Meanwhile
- Activated TH2 cells also release IL-4 and IL-13
- Causes mast cells in airway tissue to express IgE receptors
- This stimulates calcium entry into mast cells and release of Ca2+ from intracellular stores evoking:
- release of secretory granules which release histamine and LTC4 and LTD4
- ^they cause airway smooth muscle contraction
- release of substances (e.g. prostaglandin 2) that attract cells causing inflammation such as mononuclear cells & eosinophils
- release of secretory granules which release histamine and LTC4 and LTD4
What are the indications for a SABA? Also name one.
SABAs are first line treatment for someone suspected to have asthma
- They have asthma symptoms
- FEV1/FEV <70%
Salbutamol
What is the mechanism of action of a SABA?
They act as physiological antagonists of all spasmogens
- Inhibits muscle contraction by increasing intracellular cAMP which activates protein kinase
- this inhibits muscle contraction by phosphorylating and inhibiting myosin-light-chain kinase
NB: reduction in intracellular Ca2+ conc. and activation of large conductance potassium channels are also involved
When is a LABA indicated? Name one.
Used in asthma that is poorly controlled in people who are already on SABA and ICS. Must always be co-administered with ICS. Combination inhalers are preferable.
Useful for nocturnal asthma
Salmeterol
What is the mechanism of action for a LABA?
Act as physiological anatagonists of all spasmogens
- Activation of B2-adrenoreceptors relaxes smooth muscle by increasing intracellular cAMP which activates protein kinase
- This inhibits muscle contraction by phosphorylating and inhibiting myosin-light-chain kinase
NB: reduction in intracellular Ca2+ concentration and activation of large conductance potassium channels are also involved
When would an LTRA be indicated? Name one.
If a person is on SABA, ICS and LABA and there is benefit from LABA but control is still inadequate continue LABA and ICS and consider trail of LTRA
Montelukast
What is the mechanism of action of LTRA?
LTRAs act competitively at CysLT1 receptor
CysLT1s are derived from mast cells and inflammatory cells causing:
- smooth muscle contraction
- mucus secretion
- oedema
Describe the role of glucocorticoids in the body.
The main glucocorticoid hormone is cortisol (hydrocortisone) which regulates numerous essential process:
- inflammatory responses decrease
- immunological responses decrease
- gluconeogenesis increase
- glucose output from liver increases
- glucose utilization decreases
- protein catabolism increases
- bone catabolism increases
- gastric acid and pepsin secretion increases
Why are synthetic derivaties of cortisol rather than cortisol itself are used in the treatment of asthma?
Synthetic derivaties of cortisol such as beclometasone have little or no mineralocorticoid activity.
Why is is the inhalational route of glucocorticoid administration favoured in the treatment of mild and moderate asthma?
To avoid systemic effects.
Outline the molecular mechanism of action of the glucocorticoids
- Glucocorticoids enter cells by diffusion
- Combine with GRalpha
- Dissociation of inhibitory heat shock proteins
- Activated receptor translocate to nucleus
- Within nucleus activated receptor monomoers assemble into homodimers
- Bind to glucocorticoid response elements in promoter region of specific genes
- Transcription of specific genes is either ‘switched on’ or ‘switched off’ to:
- alter mRNA levels
- alter rate of synthesis of mediator proteins
Give examples of the cellular effects that underlie the anti-inflammatory action of glucocorticoids
INFLAMMATORY CELLS
Eosinophil numbers decrease due to apoptosis
T-Lymphocytes produce less cytokines
Mast cells decrease in numbers
Provide a brief account of the clinical use of glucocorticoids in asthma.
Indications/Place in Step-Up Therapy
No use in acute
Long term treatment effective
Administration
Inhalation to avoid systemic effects
Efficacy develops over several days
Adverse Effects
Dysphonia (hoarse and weak voice)
Oropharyngeal candidiasis (thrush)
