Hazbun lecture 2 Flashcards
3 main treatment strategies in asthma
bronchodilation
anti-inflammation
inhibition of mast cell degranulation
3 types of drugs for bronchodilation
B2 adrenergic agonist
methylxanthines
anticholinergic
2 types of drugs for anti-inflammation
Glucocorticoids
anti-leukotriene agents
2 types of drugs for inhibition of mast cell degradation
cromolyn type drugs
Omalizumab (xolair)
B2- adrenergic agonist (sympathomimetic amines) primary and secondary activity.
Primary- bronchodilation of smooth muscle
secondary- inhibition of release of mediators from mast cells.
How does the inhibition of release of mediators from mast cells affect the body?
it increases microciliary transport to mucus and inhibits microvascular leakage
What are the steps to muscle contraction?
LTC4 or LTD4 interacts with CYSLT-1R (or histamine interacts with H1R)
This activates the GQ pathway and PLC, which leads to an increase in IP3
This leads to an increase in calcium, which binds to calmodulin
Leads to activation of myosin LC kinase (phosphorylates myosin LC)
myosin interacts with actin, after phosphorylation. It contracts
Steps to muscle relaxation (B2 agonist effect)
B2 agonist activates G2 protein, increasing cyclase
This decreases calcium and increases cAMP
PKA gets activated and phosphorylates myosin LC kinase
leads to muscle relaxation
recognize SABA chemical structures and chemical properties
Has a ter-butyl group
has a salicylic alcohol group in the middle
has an alcohol phenyl ring on the far left
contraction vs relaxation of the muscle difference in MLCK (myosin LC kinase)
In contraction the MLCK activates myosin LC, phosphorylating it. It then interacts with actin
in relaxation, activation of PKA phosphorylates MLCK and muscle relaxes
name of 2 SABAs and their differences
Albuterol and terbutalin.
Albuterol has optimal B2 selectivity, terbutalin has more potent B2 selectivity (but has increased palpitations)
LABA chemical structures and properties
Has CH2 chains in between two phenyl rings.
Name two LABA s and explain their differences
Formoterol and Salmeterol
Formoterol has the highest receptor affinity, it has increased lipophilicity and is resistant to MAO and COMT. LOOK UP STRUCTURE AND REMEMBER
Salmeterol has greater water solubility and moderate lipophilicity. It has long CH2 groups sandwiched between two phenyl rings
Also resistant to MAO and COMT
When are LABAs contraindicated?
you CAN NOT use LABAs as a monotherapy, being deaf is a side effect
why do LABAs act longer than SABAs
SABAs are resistant to COMT with a slight MAO resistance
LABAs are resistant to COMT and MAO
why is inhalation the route of choice for acute attacks
drug delivery directly to the site of action and fewer adverse effects compared to B2 agonists given orally
Adverse effects of B2 adrenergic agonists
- tachycardia and palpitations
a) Less of this if the drug is more selective for B2
b) High doses of B2 selective agents may stimulate B1 receptor in heart
C) There may be some reflex tachycardia due to vasodilation by B2 - Skeletal muscle tremors
effect of glucocorticoids on bronchial smooth muscle
decreases hyperresponsiveness of bronchial smooth muscle that occurs in asthma
What infection risk is associated with taking glucocorticoids
Candidiasis (fungal infection) thrush
Risk of systemic side effects for gllucocorticoids? Why?
Low, this is because it is inhaled, oral has a lot of systemic side effects
example of ICS+LABA combination
Advair- Fluticasone+salmeterol
Does theophyline cause bronchoconstriction or relaxation? How?
Theophyline inhibits PDE4 in the muscle contraction/relaxation pathway. This increases levels of cAMP
leads to relaxation
Theophyline antagonizes the broncho-constriction produced by adenosine by blocking the adenosine 1 receptor
Why is theophyline not used anymore?
Narrow therapeutic range and lots of drug-drug interaction
How does cromolyn treat asthma
Inhibits mast cell degranulation
Compare the structures of the two cromolyns Cromolyn sodium (intal) and nedocromil sodium (tilade)
Cromolyn sodium (Intal) has 4 phenol rings, an OH in the middle with an Na+ on each side
nedocromil sodium (tilade) has 3 phenol rings with an Na+ on each side
Are cromolyn drugs inhaled or orally administered?
Inhaled via microfine powder of aerosol
Why can’t cromolyn drugs be taken orally
They are insoluble salts
Cromolyn action compared to B2 adrenergic agonists
Cromolyn blocks bronchoconstriction, reducing symptomatic severity and bronchodilator use while B2 induces bronchodilation
What are the wo types of inflammation associated with asthma and monoclonal-based therapy
Type 2 low inflammation and type 2 high inflammation
What is the difference between type 2 high inflammation and type 2 low inflammation?
Type 2 low inflammation is neutrophilic and harder to treat and is likely to have adverse effects
Type 2 high is eosinophilic and easier to treat
name the 5 major pathways targeted by biologics (monoclonal antibodies)
IgE antagonists- omalizumab (xolair)
IL-5 pathway- reslizumab &mepolizumab
IL-5 alpha receptor- benralizumab
IL-4 receptor alpha antagonist- dupliumab
thymic stromal lymphopoietin (TSLP)- tezepelumab
All approved for type 2 high inflammation
rationale for xolairs (omalizumab) therapeutic use
causes a 96% reduction in free IgE
How does xolair cause a reduction of IgE
Xolair inhibits binding of IgE antibodies to the FcER1 receptor on mast cells and basophils.
This inhibits mast cell degranulation, suppressing inflammation.
Name two different anti-leukotriene drugs
ZYFLO (Zileuton)
Zafrilukast/montelukast (Accolate)
explain the differences in the mechanism of action between zileuton and zafrilukast
zileuton is a selective inhibitor of 5-lipoxygenase
Zafrilukast/montelukast is a selective and competitive inhibitor of CysLT-1 receptor
Remember the structures of Zafrilukast and Zileuton
How does singulair work and how does its chemical structure contribute to its action?
Singulair has similar structure to LTD-4 so it mimics this LTD4 and binds CysLT-1 receptor, inhibiting the late phase of bronchoconstriction
adverse effects of singulair and associated box warning
Box warning- agitation and mental health issues
headache, nausea, diarrhea
difference between ipratropium and tiotropium
Ipratropium is a SAMA
Tiotropium is a LAMA
Know the structure of Tiotropium and Ipratropium
why is it useful the both ipratropium and tiotropium are quaternary ammonium compounds
Limits systemic absorption, decreasing side effects
mechanism of action of tiotropium and ipratropium
Both ipratropium and tiotropium block the binding of AcH to muscarinic receptor, preventing contraction
What drugs are allowed as monotherapy in COPD but not asthma
LABA (formoterol, salmeterol, indacterol)
In COPD, neutrophils are activated and release proteases called
MMP9 and elastase
WHat inhibits MMP9 and elastase
a-1 anti trypsin
effect of a-1 anti trypsin deficiency
leads to excessive proteolytic damage to lung tissue
How can we treat a-1 anti trypsin deficiency
We can treat this by replacement therapy
What is a drug that can improve lung function in CF
Ivacaftor (kalydeco)
Mechanism of action of kalydeco (ivakaftor)
Kalydeco helps potentiate the chloride current channel in CFTR, allowing the channel to function better
What is the del 508 mutation? what does it lead to?
Del 508 mutation leads to CF and makes the protein unstable affecting protein traffic
What are 3 drugs used to treat genotypes of cystic fibrosis
Orkambi
symdeco
trikafta
Orkambi is used to treat what genotype of F508del
Homozygous for F508del
Symdeco is used to treat what genotype of F508del
Homozygous for F508del or one F508del plus one 154 residual function mutation
Trikafta is used to treat what genotype of F508del
One copy of F508del or atleast one copy of 177 mutations
what drugs are used for alleviating complications/symptoms from CF
Mucolytics- reduce mucus thickness
bronchodilators (albuterol)
antibiotics
Thick mucus in CF obstructs pancreatic enzyme flow, how do we treat this
PERT (Pancreatic enzyme replacement therapy)
Asthma pulmonary targets for treatment
bronchodilation
anti-inflammation
inhibition of mast cell
inhibition of eosinophilia
COPD pulmonary targets for treatment
bronchodilation
protease inhibitor
CF pulmonary targets for treatment
Protein folding/channel corrections
PERT
bronchodilation and antibiotics
