Flashcards in Pharmacology Deck (115):
Stimulation of post-ganglionic cholinergic fibres in the parasympathetic pathway is mediated by ___ Muscarinic Ach Receptors on ASM
What does post-ganglionic stimulation of cholinergic fibres cause?
bronchial smooth muscle contraction
increased mucous secretion
Stimulation of post-ganglionic non-cholinergic fibres causes bronchial smooth muscle contraction - true or false?
false - causes relaxation by Nitric Oxide and Vasoactive intestinal peptide
Peptides involved in parasympathetic non-cholinergic fibres?
Nitric Oxide (NO)
Vasoactive Intestinal Peptide (VIP)
Which nerve provides parasympathetic stimulation to the airway smooth muscle?
Vagus - CN X
There is no sympathetic innervation of bronchial smooth muscle in humans - true or false?
Stimulation of sub-mucosal glands and smooth muscle of blood vessels by post-ganglionic sympathetic fibres causes...(4)
- bronchial smooth relaxation via b2-adrenoceptors
- decreased mucous secretion mediated by b2-adrenoceptors on goblet cells
- increased mucociliary clearance mediated by b2-adrenoceptors on epithelial cells
- vascular smooth muscle contraction mediated by a1-adrenoceptors
contraction stimulated by a1-adrenoceptors
vascular smooth muscle
relaxation stimulated by b2 adrenoceptors
bronchial smooth muscle
Activation of the M3 receptors leads to activation of which G protein?
Gq/11 activates ____ which converts PIP2 to ____ and ____
PLC, IP3, DAG
IP3 stimulates calcium release from the _______ _______ via the ____ receptor
sarcoplasmic reticulum, IP3
Calcium induced calcium release is mediated by which receptor in smooth muscle?
Cellular depolarisation causes the closure of voltage gated calcium channels - true or false?
causes VGCC to open and allow calcium to influx allowing contraction of the smooth muscle
Calcium binds and activates _______, this allows the subsequent activation of _______. Active MLCK allows phosphorylated ______ cross bridge binding to ______ via the breakdown of ATP
Calmodulin, MLCK, myosin, actin
What is calmodulin?
calmodulin is a cytoplasmic Ca receptor which undergoes a conformational change when bound to Ca
In the presence of high IC Ca, the rate of phosphorylation exceeds the rate of dephosphorylation of MLCK by myosin phosphatase - true or false?
How is IC calcium removed from the cell for smooth muscle relaxation?
primary and secondary active transport
Primary Active Transport
utilises energy in the form of ATP to drive a process of moving the ion from a low concentration to a high concentration
Secondary Active Transport
utilises energy from another process where the energy is not required to move another ion i.e. a symporter
In order to counteract the action M3 causing contraction, _______ activates b2 adrenoceptors which activates the G-protein ___.
Activation of the Gs protein stimulates the enzyme...
adenylate cyclase produces _____ which is broken down by _____
What does cAMP activate?
PKA phosphorylates and stimulates MLCK - true or false?
PKA phosphorylates and thus inhibits MLCK
PKA phosphorylates and stimulates...
Overall, activation of PKA causes what?
bronchial smooth muscle relaxation
cAMP is degraded to what by PDE?
What is the incidence of Asthma in industrialised countries?
How can asthma be defined?
recurrent and reversible obstruction to airways in response to substance or stimuli that are not necessarily noxious and do not normally affect non-asthmatics
Examples of asthma attack causes
Asthma is not just bronchospasm, it is....
intermittent attacks of bronchoconstriction; tight chest, wheezing, difficulty in breathing and coughs
Pathological changes that occur in the bronchioles of chronic asthmatics as a result of long standing inflammation (5)
- increased mass of smooth muscle (hyperplasia/trophy)
- accumulation of interstitial fluid
- increased secretion of mucous
- epithelial damage exposing sensory nerve fibres
- sub-epithelial fibrosis
Airway narrowing due to inflammation and bronchoconstriction increases the ______ _______ and decrease the ____ and _____
airway resistance, FEV1, PEFR
Which fibres are exposed in chronic asthma?
What are the components of hyper-responsiveness in asthma?
hypersensitivity and hyperreactivity
Which substance can be used to provoke asthma via H1 receptors?
Which substance can be used to provoke asthma via M3 receptors?
What type of reaction is the early phase asthma attack?
type I hypersensitivity (bronchospasm)
What type of reaction is the late phase asthma attack?
type IV hypersensitivity (bronchospasm and inflammatory)
What response is normal following exposure to an allergen?
low levels of Th1 involving IgG and macrophages
Cell-mediated response following exposure to an allergen
low levels Th1
Preferred allergen response pathway in asthmatics
Th2 anti-body mediated response
Antigen presenting cell presents allergen to ____ T cells which differentiate into ___ cells.
In asthmatics, Th2 cells activate ____ cells which mature into ______ cells which secrete ____.
B, Plasma, IgE
What do Th2 cells secrete that enhances the B cell response?
What interleukin do Th2 cells secrete to activate eosinophils?
activates mast cells which express IgE receptors in response to ILs
activates B cells and also mast cells to express IgE receptors
Cells which have IgE receptors to help activate them
eosinophils and mast cells
During activation, IgE receptors dimerise and allow Ca entry into the mast cells - true or false?
Mast cells release...
preformed histamine and other agents including leukotrienes LTC4 and LTD4.
Substances (PAF and LTB4, PGDs) that attract pro-inflammatory mediators and cells
airway smooth muscle contraction
Cells that cause inflammation in asthma
Key cells in the immediate phase of an asthma attack
mast cells and mononuclear cells
mast cells and mononuclear cells produce
- spasmogens, CysLTs, Histamine -> bronchospasm
- chemotaxins and chemokines -> late phase
Late phase asthma attack involves...
infiltration of cytokine releasing Th2 and monocytes, activation of inflammatory cells in particular eosinophils
During the late phase, mediators and CysLTs cause ______ _______, hyper-responsiveness, bronchospasm, ________, cough and ________.
airway inflammation, wheezing, mucous
During the late phase, eosinophils and major basic and cationic proteins cause epithelial damage, ______ _______, hyper-responsiveness, bronchospams, wheezing, ______ and mucous
airway inflammation, cough
Step 1 Asthma treatment
Step 2 Asthma treatment is given when...
SABA use is more than once daily
Step 2 asthma treatment
Step 3 Asthma treatment
Add LABA with ICS
If LABA is not effective increase ICS dose, discontinue LABA
If still not adequate consider other therapies i.e. monteleukast or theophylline
Step 4 asthma treatment
persistent poorly controlled, increase ICS and add 4th drug i.e. Monteleukast, theophylline, oral b2-agonist
Step 5 asthma treatment
introduce oral glucocorticoid and refer to specialist
B2-adrenoceptor agonists act as phsyiological ______ of all spasmogens.
b2 agonists activate Gs --> AC which converts ATP to _____ which activates _____
Types of b2-agonist
SABA, LABA, ultra long acting
Examples of SABA
SABAs are the _____ line treatment in ______, _________ asthma and are used as relievers when ______
first, mild, intermediate, required
SABAs are usually administered orally or nebulised - true or false?
usually in MDI, oral and IV or nebulised is used in severe and life-threatening asthma
Overall effects of SABAs (3)
bronchial smooth muscle relaxation
increased mucus clearance
decreased mediator release from mast cells and monocytes
Adverse effects of SABAs
Examples of LABAs
What are LABAs not recommended for?
acute relief of bronchospasm
Why are LABAs not recommended for monotherapy?
desensitisation to b-agonist by reducing the number of receptors
Examples of CysLT1 Receptor Antagonists
LTC4, LTD4 and LTE4 are derived from ______ cells and infiltrate inflammatory cells causing smooth muscle ______, mucous _______ and _______.
mast, contraction, secretion, oedema
Examples of xanthines
theophylline and aminophylline
Suggested mechanism of action of methylxanthines
inhibition of PDE III and IV
What sort of mechanisms are exhibited by methylxanthines?
bronchodilator and anti-inflammatory
Theophylline activates HDAC which may ______ the activity of glucocorticoids
Adverse effects of methylxanthines
Reason for methylxanthines being problematic
drug interactions involving CYP450s, particularly antibiotics that inhibit CYP450
Glucocorticoids are produced in the ______ ________ of the adrenal cortex
Glucocorticoids are essential in regulating: (5)
decreased inflammatory responses
decreased immunological responses
increased liver glycogen deposits
increased glucose output from the liver
Site of production of mineralocorticoids
Action of glucocorticoids
In particular glucocorticoids decrease the formation of....
Glucocorticoids prevent the production of IgE and influx of...
eosinophils and mast cells
common side affects of inhaled glucocorticoids
hoarse and weak voice, thrush
When might oral prednisolone be given?
when there is an exacerbation or severe asthma
Cromones are often described as _____ ____ ______ even though this is not their mechanism of action. An example is _______ _______
mast cell stabilisers
cromones are more effective in...
children and young adults
sodium cromoglicate is used to reduce _____ phases of an attack but efficacy may take several weeks to develop a block to _____ ______ attack
Monoclonal antibodies used in asthma
IgE - Omalizumab
IL-5 - Mepolizumab
Preferred pharmacological target in the treatment of COPD?
M1 and M3 muscarinic receptors
Why is it preferable to avoid M2 receptors in the treatment of COPD?
the M2 receptor is a auto-regulatory receptor which provides negative feedback when stimulated.
Which immune cells are activated in COPD?
neutrophils, CD8 T cells and macrophages
ipratropium & oxitropium
tiotropium & aclidinium
Route of administration for SAMA and LAMA and why?
inhalational to avoid blocking systemic parasympathetic nervous system
B-adrenoceptor agonists used in COPD?
salbutamol, salmeterol, formoterol
PDE4 selective inhibitor which suppresses inflammation and emphysema
Rhinitis or Rhinorrhoea may be allergic or non-allergic - TRUE or FALSE?
in allergic rhinitis, what mediators may be released that contribute to the inflammatory response?
IgE, cysLTs, histamine, tryptase, prostaglandins,
non-allergic causes of rhinitis
infection, hormonal, vasomotor, non-allergic rhinitis with eosinophilia syndrome, medications
treatment targeting inflammation in rhinitis?
glucocorticoids used in rhinitis?
treatments targeting receptors in rhinitis?
H1 receptor antagonists, CysLT1 receptor antagonists
H1 receptor antagonists used in rhinitis
CysLT1 receptor antagonists used in rhinitis?
oxymetazoline is used as...
a selective a1 adrenoceptor agonist for vasomotor rhinitis