Pharmacology Flashcards
in the parasympathetic division of the ANS, what types of fibers are stimulated to regulate airway function
postganglionic cholinergic/ noncholinergic
what does the stimulation of postganglionic cholinergic fibres cause
bronchial muscle contraction and increased mucous secretion
what is bronchial muscle contraction mediated by
M3 muscarinic Ach (acetylcholine) receptors on airway smooth muscle cells
what is increased mucous secretion mediated by
M3 muscarinic Ach receptors on gland (goblet) cells
what does stimulation of postganglionic nonchlorinergic fibers do
bronchial smooth muscle relaxation
what mediates bronchial smooth muscle relaxation?
nitric oxide, vasoactive intestinal peptide (VIP)
what does the sympathetic region of the ANS innervate to regulate airway fuction?
post-ganglionic fibers supply sub-mucosal glands and smooth muscle of blood supply
what does the sympathetic nervous system not innervate in humans
bronchial smooth muscle
what does stimulation of the sympathetic nervous system cause (4)
bronchial smooth muscle relaxation, decreased mucous secretion, increased mucociliary clearance, vascular smooth muscle contraction
what mediates bronchial smooth muscle relaxation
stimulation of the B(beta)2-adrenoceptors on ASM cells by adrenaline
what mediates decreased mucous secretion
B2-ADR on gland (goblet) cells
what mediates increased mucociliary clearance
B2-ADR on epithelial cells
what mediates the contraction of vascular sooth muscle
a(alpha)1-adrenoceptors on vascular smooth muscle cells
describe how transmitters/hormones cause contraction in ASM
activate GPCR which stimulates IP3 production and therefore IP3 receptors which move calcium secreted from calcium stores
describe how depolarisation causes contraction in ASM
activates voltage activated Ca2+ channel which then activates a second Ca2+ channel
how does calcium initiate contraction
binds to from calcium compounds which then activate myosin light chain kinase. MLCK then phosphorolates a myosin cross bridge which glides across actin to produce contraction
what does relaxation of ASM result form
dephosphorylation of myosin light chain by myosin phosphatase
what happens to the rates of de/phosphorylation in the presence of elevated intracellular calcium
phosphorylation exceeds dephos…
what does relaxtion require in terms of Ca+ concentration and how is this achieved
return to basal level via primary and secondary active transport
what is the activity of MLCK and myosin phophatase dependent on, give and example
extracellular signals e.g adrenoline and B(eta)2-adrenoceptor
define asthma
intermittent attacks of bronchoconstriction: recurrent and reversible (in the short term) obstruction to the airways in response to substances or stimuli
note asthma’s prevalence
5-10% of the population in industrialised countries
list common causes of asthma
allergens, exercise (cold, dry air), respiratory infections, smoke, dust, environmental pollutants
what pathological changes occur in chronic, poorly controlled asthma as a result of long standing inflammation
increased mass of smooth muscle (hyperplasia and hypertrophy), accumulation of interstitial fluid (oedema), increased secretion of mucus, epithelial damage (exposing sensory nerve endings), sub epithelial fibrosis
what is bronchial hyper-responsiveness
hyper sensitivity and hyper reactivity as a result of epithelial damage that has exposed sensory nerve endings
when can an immune response cause asthma
when there is an imbalance between TH1 and TH2 lymphocyte-mediated responses
in the development of allergic asthma what does the initial presentation of the allergen result in
an adaptive immune response
describe the induction phase of the adaptive immune response that leads to allergic asthma (2 steps)
antigen presentation; antigen presented to T CD4 cell
colonial expansion and maturation; TH0 cells differentiate into TH1 and 2 cells (preferably TH2 which produce a cytokine environment). TH2 cells activate B cells that mature to IgE secreting P cells
describe the effector phase of the adaptive immune response that leads to allergic asthma (2 steps)
Eosinophils differentiate and activate in response to IL-5 released from TH2 cells.
Mast cells in airway tissues express IgE receptors in repsonse to IL-4 and IL-3 released from TH2 cells
how is calcium involved subsequent to TH2 lymphocyte activation
cross link IgE receptors stimulates calcium entry into mast cells and release of Ca2+ from intracellular stores
what does the entry and release of calcium evoke (2)
release of secretory granules containing histamine and the production and release of other agents (leukotrienes) that cause ASM contraction
release of substances that attract cells that cause inflammation into the area
describe the phases of an asthma attack
immediate (mainly bronchospasms) late/delayed (mainly inflammatory response)
what are the products of mast cells and mono nuclear cells that result in bronchospasms and early inflammation in the immediate phase of an asthma attack
spasmogens, CysLTs, histamine
what is produced by mast cells and mono nuclear cells in the immediate phase that evokes the late/delayed phase
cytokines, chemotaxis
what inflammatory cells in particular is activated in the late phase
eosinophils
what pathologically happens in the late phase (*)
airway inflammation, epithelial damage, airway hyper responsiveness, bronchospasm, wheezing, mucous oversecretion, cough
what are the two categories of drugs used to treat asthma and
relievers and controllers/preventors
how to relievers work and give 3 examples
act as bronchodilators; short acting Beta2-adrenoceptor agonist (SABAs), LABAs, CysLT1 receptor antagonist
how to controllers/ preventors work and give 3 examples
anti-inflammatory agents; glucocorticoids, cromoglicate, humanised monoclonal IgE antibodies
what are controllers/preventors NOT used to treat
acute asthma attacks- long term usage reduces frequency of them
what should be used to treat an acute asthma attack
B2- agonist (can be supplemented with relievers)
why is the oral route avoided
to avoid adverse affects
what are the advantages of administering drugs through the inhalation route
smaller dose needed to acquire appropriate concentration in lungs
Explain how B2-adr agonists treat asthma as bronchodilators
act as physiological antagonists of all spasmogens (substance that induces spasms). Cause ASM relaxation via formation of protein kinase A which phosphorylates MLCK and myosin phosphatase + reduce intracellular Ca conc + activate potassium channels
name two SABAs
salbutamol and turbutaline
what are SABAs used to treat
mild intermittent asthma
name two LABAs
salmeterol and formoterol
what are LABAs used to treat and what do they not treat
nocturnal asthma (last 8 hours) don’t treat acute attacks
describe how LABAs should be used
not as monotherapy, must always by co-administered with a glucocorticoid
how do Cysteinyl leukotriene (CysLT1) receptor antagonist work
act competitively at the CysLT1 receptor. Cyslts (e.g LTC4, LTD4 and LTE4) which are derived from mast cells and infiltrating inflammatory cells cause ASM contraction, mucous secretion and oedema
how are CYsLT1 receptor agonists administered
orally
how do Xanthines work
combine bronchodilator and anti-inflammatory actions, inhibit mediator release from mast cells, increase mucous clearance
describe the role of glucocorticoids in the body
class of hormone- main hormone cortisol (hydrocortisone)- regulate numerous essential process e.g. inflammatory and immunological responses
why are synthetic derivatives of cortisol, rather than cortisol itself are used in the treatment of asthma
as have little or no mineralcocorticoid activity (regulation of retention of salt and water by kidney)
name an example of a CystLT receptor agonist
montelukast
name an example of a Xanthine
theophylline
why is the inhalation route of glucocorticoid administration favoured in the treatment of mild or moderate asthma
minimise adverse effect
how do glucocorticoids signal
via nuclear receptors specifically GRalpha
how do glucocorticoids enter cells
are lipophillic so enter through diffusion across cellular membrane
describe the molecular mechanism of glucocorticoid action within the cytoplasm
in cytoplasm bind with GRalpha which dissociates heat shock proteins. ctivated nucleus then translocates to nucleus via importins.
describe the molecular mechanism of glucocorticoid action within the nucleus
activated receptor monomers assemble into homodimers and bind to GLUCOCORTORICOID RESPONSE ELEMENTS (GRE) in the promoter region of specific genes
what does the transcription or inhibition of specific genes result in
alter mRNA levels, rate of synthesis of mediator proteins
what does the transcription or inhibition of specific genes result in that is specific to treating asthma
increase transcription of anti-inflammatory proteins and decrease transcription of inflammatory proteins
what are the four effects of glucocorticoids that are relevant to bronchial inflammation in asthma
prevent IgE production, decrease number of mast cells, prevent allergens, decrease formation of TH2 cytokines,
how and what inflammatory cells do corticosteroids affect
decrease in number; eosinophils, mast and dendritic
decrease cytokines from; T-lymphocytes and macrophages
how do corticosteriods affect epithelial cells
decrease cytokine mediators
how do corticosteriods affect endothelial cells
makes them less leaky
how do corticosteriods affect ASM cells
increases beta 2 receptors
decreases cytokines
how do corticosteriods affect mucous gland cells
decreases secretion
summarise what glucocorticiodes do and dont do
suppress the inflammatory component of asthma, do not alleviate early stage bronchospasms caused by allergens or exercise
describe cromoglicate
second line drug now infrequently used for the treatment of of allergic asthma particularly in children. no direct effect on bronchial smooth muscle. delivered by inhalation. can reduce both phases of an asthma attack but could take weeks to develop efficiency.
describe omalizumab
monoclonal antibodies directed against IgE. Prevents binding of IgE (by binding to IgE) to receptors which suppresses mast cell response to allergens. requires IV administration. expensive
what components of the inflammation cascade can be blocked by monoclonal antibodies
TSLP, IL-4, IL-5, IL-13 and IgE
what does PRN mean
as required
what is a LAMA
long acting muscarinic antagonist
why are inhaled steroids used throughout treatment
as they act on eosinophils
when are LAMAs and LABAs used
in the 3rd step- moderate persistent
what may corticoidsteroids cause in COPD
pneumonia
what has a higher therapeutic ratio oral/inhaler drugs for lungs
inhaler
when can inhaled steroids be used alone
in asthma (not COPD)
what does ICS stand for
inhaled cortical steroids
what is the carina
the bifurcation of the trachea
how small must particles be to get past the carina
5 microns
how small must particles be to get past the 7th generation splitting of the bronchioles
2 microns
what is the role of spacers
reduce velocity and size of particles, stops need to coordination, improves lung deposition
what type of inhaler must always be used with a spacer
meter dose
how are dry powder inhalers administered
breath actuated
name a pro and con of dry powder inhalers
pro- dont need coordination
con- bug particles
when in asthma is cromoglycate most effective
raised IgE/ exercise
what does LTD4 do in the inflammatory cascade
amplify it
how is montelukast administered
never on its own, always with inhaled steriods, orally
how are corticoid steroids administered in COPD
never as monotherapy- as ICS/LABA combo
what is the action of cromones
anti inflammatory, mast cell stabilizer
when are cromones used
to treat asthma (cromoglycate)
how are cromones administered
inhalation only
when are leukotriene receptor antagonists used
only for asthma
what does the binding of omalizumab to IgE receptor cause
inhibits TH2 response and associated mediator release from basophils/mast cells
what does mepolizumab do
blocks the effect of the TH2 cytokine LT-5
what does LT-5 do
is responsible for eosinophilic inflammation in asthma
what does smart stand for
single maintenance and reliever therapy (combined inhalers
what is tachyphylaxis
when body adapts during use of B2 agonists to have less B2 receptors
what do B2 agonists do
stimulate bronchial smooth muscle- bronchodilators
what do you not treat with LABA
an acute attack, only use high doses of salbutamol for that
name a LAMA
tiotropium
what are the two bronchodilators
B2 antagonists, muscarinic antagonists
how is methylxanthine administered
orally with inhaled steroid
what is methylxanthine used for
maintenance therapy in asthma and COPD. useful for nocturnal dips
describe methylxanthine
non steroid, non specific, anti inflammatory + bronchodilator
what do mucolytics do
thin the mucous
what type of steroids should and shouldn’t be used to treat acute asthma
should= systemic shouldn't= inhaled
when should a respiratory stimulant be used in asthma
NEVER
what is more effective than the ICS/LABA combo used to treat COPD
ICS/LABA/LAMA combo
when should the LABA/LAMA combo be used
when the inflammation is non eosinophilic
what type of steroids should and shouldn’t be used to treat acute COPD
should= systemic shouldn't= inhaled
what does smoking activate
macrophages
how is bronchoconstriction by smooth muscle initiated
M3 receptor activation by ACh
what releases ACh
postganglionic parasympathetic fibres
what do M1 muscarinic receptors do
facilitate fast neurotransmission mediated by ACh
what do M2 muscarinic receptors do
act as inhibitory autoreceptors reducing release of ACh
what do M3 muscarinic receptors do
mediate contraction of ASM to ACh
what do muscarinic receptor facilitate
ganglionic transmission- nicotinic stimulation
what does blockage of nicotonic stimulation stop
stops ACh ptoduction
what muscarnic receptor adds to the blockage of M3 by reducing release of ACH
M1
via what mechanism do M2 receptors work and their role in COPD management
negative feedback, stimulated by ACh and then triggers M1 and M3, so blockage counterproductive in COPD treatment
which muscarinic receptor is targeted (blocked) first in the management of COPD
M3
what do drugs ending in ium usually do (e.g. ipatropium (sama), and other LAMAs)
act on a ACh receptor- are competitive muscarinic receptor antagonists
why are Quaternary structures beneficial in MAs
as positively charged and cant cross biological membranes to enter into blood stream and cause adverse effects (stop effects of parasympathetic system)
what is first used to treat an acute constriction
B2 agonists
why are muscarinic antagonists more effective for COPD
more effective but slower, decrease mucous secretion
what reflex do MAs also repress
the cough (vago-vagal) reflex stimulated by the vagus nerve
why are M3 selective blockers superior to ipratropium
functionally selective, Ip blocks all
give an example of an M3 blocker and explain how they are selective
tiotropium, glycopyrronium, due to kinetics of drugs stay in M3 receptor longer
what is salbutamol
a SABA
what do B-adrenoceptor agonists do and dont do
bronchodilators but dont act on underlying inflammation
what combination of drugs is best at increasing FEV1
B2 agonist and muscarinc antagonist
when are LABA/LAMA combinations most effective
when deposited in same location in the airways (inhaled)
what in LABA/LAMA treats underlying inflammation and immunosuppresses
neither of them
what do muscarinic antagonist do when in combo with a LABA
block activation by ACh preventing contraction
what do B2 agonists do when in combination with a LAMA
cause relaxation by binding to B2-adrenoreceptor
what can be administered with LABA/LAMA combos to treat COPD
glucocorticoids- in moderately severe conditions
what is rhinitis
acute or chronic inflammation of the nasal mucosa
what are the three types of rhinitis
allergic (clear trigger), non-allergic, mixed (both allergic and non allergic features)
what are the symptoms of rhinitis
rhinorrohea (runny nose), sneezing, itching, nasal congestion and obstruction
what causes nasal congestion
dilated blood vessels in nasal mucosa
what are the classifications of allergic rhinitis
seasonal, perennial, episodic
what condition is allergic rhinitis very strongly linked to
asthma
what are the similarities between allergic rhinitis and asthma
inhalation of allergen increases IgE levels which binds to receptors on mast cells and eosinophils. re-exposure causes granulation. calcium flood into cell releasing inflammatory mediators
what does non allergic rhinitis NOT involve
IgE dependent event
what can cause non allergic rhinitis
infection, hormones, vasomotor, drug induced, eosinophilia syndrome
what may occupational rhinitis involve
both allergic and non allergic components
what do rhinitis and rhinorrhoea both involve
increased mucosal blood flow, increased blood vessel permeability = increased volume of nasal mucosa and difficulty breathing in
what are the 4 targets of treatments for rhinitis and rhinorrhoea
anti-inflammatory, mediator receptor blockade, nasal blood flow, anti-allergic
what is used as anti-inflammatory treatment in rhinitis and rhinorrhoea
glucocorticoids (rhinitis with immunological basis)
what is used as mediator receptor blockade treatment in rhinitis and rhinorrhoea
H1 receptor antagonists, CysLT1 receptor antagonists
what is used as nasal blood flow treatment in rhinitis and rhinorrhoea
vasoconstrictors- decongestant, doesn’t remove mucous just reduces blood flow
what is used as anti-allergic treatment in rhinitis and rhinorrhoea
sodium cromoglicate- immunosuppressant
what is the mechanisms of glucocorticoids
reduce vascular permeability, recruitment and activity of inflammatory cells and release of cytokines and mediators, suppress recruitment of inflammatory cells in nasal mucosa
how are glucocorticoids administered in rhinitis and rhinnorhoea
nasal spray for several weeks
what is the mechanism for anti histamines
competitive antagonists that reduce effects of mast cell derived histamine
what are the effects of the mast cell derived histamine
vasodilatation and increased capillary permeability, activation of sensory nerves, mucous secretion
what is the mechanism of anti-cholinergic drugs
muscarinic receptor antagonists
what is the mechanism of CysLT1 receptor antagonists
reduce the effect of CysLTs upon the nasal mucosa
what is the mechanism of a vasoconstrictor
mimic the affect noradrenaline
