Pharmacology Flashcards
Where are cell bodies of the parasympathetic preganglionic fibres located?
brainstem
Where are cell bodies of parasympathetic postganglionic fibres located?
Walls of the bronchi and bronchioles
What nerves carries preganglionic fibres to the bronchial and bronchi walls?
Vagus nerve (CN X)
Stimulation of postganglionic cholinergic fibres cause what?
Bronchial smooth muscle contraction (ASM airway smooth muscle cells)
Mucus secretion from goblet cells
Which neurotransmitter is used in stimulation of postganglionic cholinergic fibres?
ACh (acetylocholine)
What are the receptors which the ACh binds to on the smooth muscle cells and goblet cells?
M3 muscarinic ACh receptors
what does Stimulation of postganglionic noncholinergic fibres cause?
Relaxation of smooth muscle cells (ASM)
What neurotransmitters are involved in the noncholinergic pathway?
Nitric oxide (NO)
Vasoactive intestinal peptide (VIP)
There is sympathetic innervation of bronchial smooth muscle in humans true or false?
false
How does the sympathetic system act on bronchial smooth muscle cells?
Nicotinic acetylcholine receptor (nAChR) which are located on the adrenal grand, chromaffin cells when stimulated release adrenaline into circulation which act on smooth muscles
Which receptors does the adrenaline act on in both goblet and smooth muscle cells?
beta2 adrenoceptors
What does sympathetic stimulation cause on the airways?
- ASM cells relaxation
- decreased mucus secretion on goblet cells
- increased mucociliary clearance on epithelial cells
- vascular smooth muscle contraction- alpha 1 adrenoceptors
How does the release of Ca2+ cause contraction of smooth muscles?
- Ca2+ activates calmodulin to Ca2+ calmodulin
- Inactive MLCK is activated by Ca2+ calmodulin to form active MLCK
- Active MLCK and phosphate group (formed from hydrolysis of ATP) Cause inactive myosin cross bridge to phopshyrlated cross bridge (binds to actin)
What enzyme is responsible for phosphorylation of Myosin light chain (MLC) (contraction)?
Myosin light chain kinase (MLCK)
What enzyme is responsible for dephosphorylation of myosin Light chain (relaxation)?
Myosin phosphatase
What is asthma?
recurrent and episodic condition of the obstruction to the airways in response to substances or stimuli
What are the main causes of asthma?
- Allergens
- Exercise (cold,dry air)
- Resouratiry infections
- smoke, dust and environmental pollutants
What effects does chronic asthma have on the airways?
- increased mass of smooth muscle (hyperplasia + hypertrophy)
- accumulation of intestitial fluid (oedema)
- increased secretion of mucus
- epithelial damage (exposes sensory nerve endings)
- Sub-epithelial fibrosis
What is acute severe asthma called?
status asthmaticus
What effect does air narrowing have on airway resistance?
ii. what does this cause
Increases it
ii. FEV1 and PEFR values decrease
Epithelial damage from chronic asthma exposes what type of sensory nerve endings?
C fibres- irritant receptors
What does epithelial damage lead to in the airways?
Hypersensitivity (X axis)
Hyper-reactivity (Y axis)
What is inhaled with provocation tests which real hyper-responsiveness?
Broncho constrictors (spasmogens)
e.g. histamine (activates ASM H1 receptors)
Methacholine (activates ASM M3 receptors)
What does an asthma attack consist of ?
- immediate phase- Bronchospasm Type 1 hypersensitivity reaction
- Delayed phase ( inflammatory reaction) Type IV hypersensitivity reaction
what type of Th cells are part of the antibody-mediate response involving IgE in response to an allergen? (atopic)
TH2 cell- strong response
T helper cell
What type of Th cells are part of cell-mediated immune response involving IgG and macrophages (nonatopic)?
TH1 cell- low level response
T helper Cell
What cell matures in TH2?
ii. what environment needs to be present for to occur?
TH0
ii. cytokine environment
How do TH2 cells activate B lymphocytes?
- directly binds to B cells
2. releases Interleukins which bind to B cells (IL 4)
What do B lymphocytes mature to?
IgE secreting plasma cells
Interleukin 5 (IL 5) which are released from TH2 cells cause what?
Activation of eosinophils
Mast cells express what in response to to IL 4 and IL 13 from TH 2 cells?
IgE receptors
when the specific allergen becomes present and links to the antibodies covering the mast cell, what is stimulated?
calcium entry into mast cells causing the release of calcium from intracellular stores
when calcium enters the mast cells and calcium is released from intracellular stores what 2 things occur?
- release of substances that cause airway smooth muscle contraction (spasmogens)
- release of chemotaxins and chemokines that attract cells that cause inflammation (eosinophils)
What are the spasmogens released from mast cells?
Histamine
Leukotrienes ( LTC4,LTD4)
both also released by eosinophils.
What chemotaxins and chemokines are released?
LTB4
Platelet -activating factor (PAF)
Prostaglandins (PGD2)
which group of substances released from a mast cell is responsible for the immediate phase response of an asthma attack?
spasmogens
what group of substances released from a mast cell is responsible for the delayed phase response of an asthma attack?
chemotaxins and cytokines
How do relievers treat asthma?
act as bronchodilators
How do controllers treat asthma?
Act as anti-inflammatory agents
Give examples of relievers?
Short acting beta 2 adrenoceptor agonists (SABAs)
Long acting Beta 2 adrenoceptor agonists (LABAs)
CysLT1 receptor antagonists-block cysLTs (LTC4, LTD4, LTE4) derived from mast cells and so cause smooth muscle relaxation, decreased mucus secretion and decreased oedema
Methylxanthines
Give examples of controllers?
Glucorticoids
Cromoglicate
Humanised monoclonal IgE antibodies
methylxanthines
Describe the differences between aerosol and oral therapy for asthma?
Pharmacokinetics:
Aerosol- slow absorption from lung surface and rapid systemic clearance
Oral- Good absorption and slow
systemic clearance
Dose: Aerosol: Low
Oral: High
systemic concentration of drugs:
aerosol - Low
Oral- high
Incidence of adverse effects:
Aerosol- Low
Oral- high
distribution of drug:
aerosol- reduced in severe airway disease oral- unaffected by any airway disease
Compliance:
aerosol: good with bronchodilators not good with anti-inflammatory.
Oral: Good with both
Ease of administration:
aerosol- difficult for small children and infirm people.
Oral: Easy
Effectiveness:
aerosol- only effective in mild to moderate diseases.
Oral: very effective
When are SABAs used?
first line treatment for mild/intermittent asthma
How are SABAs administered?
inhalation via metered dose/dry powder device
can be administered:
Oral(children)
IV (emergency)
How long does it take SABAs to act on bronchial smooth muscle?
Very rapid ( maximal effect within 30 mins) feel effect in 5 mins
lasts for 3-5 hours
What is the main effect of SABAs?
ii. what are the adverse effects?
Increase mucus clearance and decrease mediator release from mast cells
ii. Very few- fine tremor most common. Can have tachycardia, cardiac dysrhythmia and hypokalaemia
What is the main type of SABA?
salbutamol
When are LABAs used?
Useful for noctural asthma (lasts for 8 hours)
Should you use LABAs for acute relief of bronchospasm??
NO- slow to act especially salmeterol
Can LABAs be used as a monotherapy for asthma?
ii. if not then what should it be co-administered with?
No- can worsen asthma increase risk of death
ii. Always a glucocorticoid
Give examples of LABAs.
Salmeterol
Formoterol
What should you use to reduce potentially harmful stimulation of Cardiac B1 adrenocopetors?
Selective Beta 2 adrenoceptor agonists
What happens if you use non selective beta adrenoceptor agonists?
increase risk of bronchospasm
When are CysLT1 receptor antagonists used?
Add on therapy (inhaled corticosteroids
used for early and late bronchospasm in mild persistent asthma
Effective against antigen and exercised induced bronchospasm
What are the effects of cysLts?
ii. what are the adverse effects?
relax bronchial smooth muscle
ii. well tolerated can have headaches and GI upset
How do you administer CysLts?
ii. when shouldn’t you administer them?
Orally
Acute severe asthma
Give examples of CysLt1 receptor antagonist.
montelukast
zafirlukast
Give examples of Methylxanthines
Theophylline
Aminophylline
What effects do methylxanthines have?
Inhibit mediator release from mast cells
increase mucus clearance
increase diaphragmatic contractility
reduce fatigue- increases lung ventilation
When are methylxanthines used?
ii. what are they co-administered with?
second line therapy
ii. B2 adrenoceptor agonist
and
glucorticoids
How are methylxanthines administered?
orally
What are the adverse effects of methylxanthines?
Supratherapeutic concentrations: Dysrhythmia, seizures and hypotension
therapeutic concentrations: Nausea, vomiting, abdominal discomfort and headache
What are the two main steroid hormones synthesised by the adrenal cortex?
- Glucorticoids (zona fasiciculata)
2. Mineralocorticoids (zona glomerulosa)
What are the effects of glucocorticoids?
Decreases inflammatory and immunological responses
increases Liver glycogen deposition, gluconeogenesis and glucose output from liver
Increases protein and bone catabolism
what is the main glucocorticoid in the body?
cortisol
What is the main mineralocorticoid which regulates salt retention via the kidney?
aldosterone
Which type of steroid hormone is not wanted to treat inflammatory conditions?
mineralocorticoid
When are glucocorticoids ineffective against bronchospasm?
ii. when is it mainly used?
When given acutely- no direct bronchodilator effect
ii. treatment in prophylaxis of asthma
How are glucocorticoids administered?
inhalation- minimises adverse systemic effects
What do glucorticoids bind to?
ii. specifically which receptor?
Nuclear receptors (class 1)
ii. GR alpha- bind to glucorticoid response elements
What are the two main effects of clinically administered glucocorticoids in asthma treatment?
- prevent inflammation
2. resolve established inflammation
How should glucocorticoids be administered?
Long term treatment- especially in combination with LABA
mild moderate asthma- inhalation from a metered dose inhaler
chronic/severe asthma- oral prednisolone with an inhaled steroid to reduce the oral dose required
What are the main glucocorticoids used in an inhaler?
Beclometasone
budesonide
fluticasone
What are the adverse effects of glucocorticoids in asthma?
Dysphonia
thrush
both caused by deposition of steroid in oropharynx
When are cromones administered?
second line drug used prhophylactically in allergic asthma
used infrequently- used to be used a lot for children due to lack of adverse effects
What is an example of a cromone?
sodium cromoglicate
Give an example of a monoclonal antibody directed against IgE
omalizumab
given IV
Give an example of a monoclonal antibody directed against IL 5?
Mepolizumab
very expensive- started being used against asthma associated with severe eosinophilia
what are the 4 main effects of glucocorticoids that are particularly relevant to inflammation in bronchial asthma?
- decrease formation of Th2 cytokines and cause apoptosis
- prevent production of IgE
- reduce number of mast cells and decrease Fc receptor expression
- prevent allergen-induced eosinophil influx into lungs and cause apoptosis
what are the 4 smaller structural effects of glucocorticoids that are particularly relevant to inflammation in bronchial asthma?
- decrease production of cytokine mediators from epithelial cells
- reduces leaking from endothelial cells
- increase B2-receptor expression in airway and smooth muscle
- reduced mucus secretion
What are the two subtypes of COPD?
- chronic bronchitis
2. emphysema
What are the symptoms of chronic bronchitis?
- Inflammation of bronchi and bronchioles
- cough
- Clear mucoid sputum
- Infections with purulent sputum
- Increasing breathlessness
What are the symptoms of emphysema?
Distention and damage to alveoli
Destruction of acinal pouching in alveolal sacs
loss of elastic recoil
What is the build up which leads to COPD?
- smoking (air pollution)
- Stimulation of resident alveolar macrophages
- Cytokine production
- Activation of neutrophils, CD8+, Increased macrophage numbers
- release of free radicals
What is the main characteristic of COPD?
increased resistance to airflow during expiration
Muscaranic receptor antagonists act against bronchoconstriction caused by which smooth muscle receptor?
M3 receptor
Where are M1 muscarinic receptors found?
ii. what is their role?
Ganglia
Facilitate fast neurotransmission mediated by ACh acting on nictonic receptors
Where are M2 muscarinic receptors found?
ii. what is their role
Postganglionic neurone terminals
act as inhibitory autoreceptors reducing release of ACh
Where are M3 muscarinic receptors found?
ii. what is their role?
post junctional muscarinic end plate receptors found on smooth muscle effector submucosal glands
contraction of airway smooth muscle
increased secretion of submucosal glands
What are the two types of competitive Muscarinic receptor antagonists used to treat COPD?
ii. how are they administered?
- SAMA
- LAMA
ii. Inhalation
Give an example of SAMA?
Ipratropium (non selective)
Given examples of LAMA
Tiotropium (selective M3)
Glycopyrronium (selective M3)
aclidinum (selective M3)
contraction of airway smooth muscle
increased secretion of submucosal glands
reduces absorption and systemic exposure
what 3 effects do muscarinic antagonists have in the treatment of COPD do?
- relaxes bronchospasm caused by irritant stimuli (which initiate a vagal reflex that liberates ACh)
- blocks ACh-mediated basal tone
- reduces mucus secretion
Why are selective M3 blockers superior to ipratropium?
Block of M3 and M1 is good
Block of M2 is not as release of ACh from post-ganglionic neuronse is increased by autoreceptor antagonism
Which LABAs should not be used in acute bronchospasm?
Indacterol
olodaterol
What is the best way to treating COPD?
Combination of B2 agonist and muscarinic antagonist
(Muscarinic antagonist- prevent contraction of airways)
(Beta 2 agonists cause relaxation of airways)
When are LABA and LAMAs combinations at the most effective?
Deposited in the same location in the airways
What is administered in combination inhalers for COPD?
Glucocorticoids and Beta agonist or muscarinic antagonist
What is Rofumilast?
a selective PDE4 inhibitor - suppresses inflammation and emphysema in animals
oral treatment for severe COPD with chronic bronchitis
What is rhinitis
common disease involving acute or chronic, inflammation of the nasal mucosa
What are the main symptoms of rhinitis?
rhinorrohea- runny nose
sneezing
itching
nasal congestion and obstruction ( swelling o nasal mucosa largely due to dilated blood vessels- mainly cavernous sinusoids
What types of rhinitis are there?
- allergic- involved IgE dependent events
- non-allergic- not involve IgE dependent events
- mixed
What are the subtypes of allergic rhinitis?
- seasonal
- perennial
- episodic
what is a triple inhaler? (for COPD)
LABA/LAMA/glucocortidcoid
(eg formoterol/tiotropium/ciclesonide)
not lisenced for use
What are the causes of Non allergic rhinitis?
- infection
- hormonal imbalance
- Vasomotor disturbances
- Non allergeic rhinitis with eosinophilila syndrome (NARES)
- Drug induced (aspirin)
What does occupational rhinitis involve?
allergic and non allergic components
What do both rhinitis and rhinorrhoea involve?
Increased mucosal blood flow
increased blood vessel permeability
or both
this causes increases volume of nasal mucosa- difficulty breathing
What is the mechanism of Glucocorticoids for rhinitis treatment?
reduces vascular permeability
recruitment and activity of inflammatory cells
What type of rhinitis are Glucocorticoids mainly used to treat?
seasonal allergic rhinitis
perennial allergic rhinitis
can be also used for NARES and vasomotor rhinitis
How are Glucocorticoids administered for rhinitis?
Topically as a spray - effective as a monotherapy takes several weeks to reduce all symptoms
can be given orally in short term
What can Glucocorticoids be combined with to treat severe-moderate rhinitis
Anti-histamines
What is the mechanism for anti-histamine (H1 receptor antagonists) for treatment of rhinitis?
Competitive antagonist- reduces effect of histamine from mast cells
What are the effects of histamine?
- vasodilatation and increased capillary permeability
- Activation of sensory nerves
- mucus secretion from submucosal glands
What type of rhinitis do anti-histamines treat?
Mainly allergic
How are Antihistamines adminsitered?
ii. when are they administered?
orally or intranasal spray
effective as monotherapy
ii. first or second - primarily second due to reduced sedation
Give examples of second generation anti-histamines
Loratidine
fexofenadine
What is the mechanism for anti-cholinergic drugs for treating rhinitis?
Blocks ACh released from post-ganglionic parasympathetic fibres activates M receptors on nasal glands causing a watery secretion that contributes to rhinnorhoea
What type of rhinitis do anti-cholinergic drugs treat?
Reduces rhinorrhoea in PAR and SAR - has no effect on other symptoms though
How are anti-cholinergics administered?
intranasally
Give an example of an anticholinergic drug.
ipratropium
When do you use sodium cromoglicate?
maintenance treatment of allergic rhinitis
via nasal administration- less effective than nasal corticosteroids
When should you use CysLt1 for rhinitis?
PAR and SAR
Give an example of CysLT1
Montelukast
What is the mechanism of vasoconstrictors?
Directly/indirectly mimic noradrenaline- cause vasoconstriction via activation of alpha 1 adrenoceptor
What is oxymetazoline?
selective alpha 1 adrenoceptor agonist- intranasally administered- only short term too long and nasal congestion can occur
what does Chronic agonist induced stimulation of airway beta-2 receptors results in?
Beta-2 receptor up regulation and enhanced receptor coupling to G protein -adenylyl cyclase
