Hazbun lecture 2 Flashcards by Matti Daniel

3 main treatment strategies in asthma

bronchodilation
anti-inflammation
inhibition of mast cell degranulation

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3 types of drugs for bronchodilation

B2 adrenergic agonist
methylxanthines
anticholinergic

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2 types of drugs for anti-inflammation

Glucocorticoids
anti-leukotriene agents

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2 types of drugs for inhibition of mast cell degradation

cromolyn type drugs
Omalizumab (xolair)

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B2- adrenergic agonist (sympathomimetic amines) primary and secondary activity.

Primary- bronchodilation of smooth muscle
secondary- inhibition of release of mediators from mast cells.

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How does the inhibition of release of mediators from mast cells affect the body?

it increases microciliary transport to mucus and inhibits microvascular leakage

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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

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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

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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

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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

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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)

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LABA chemical structures and properties

Has CH2 chains in between two phenyl rings.

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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

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When are LABAs contraindicated?

you CAN NOT use LABAs as a monotherapy, being deaf is a side effect

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why do LABAs act longer than SABAs

SABAs are resistant to COMT with a slight MAO resistance
LABAs are resistant to COMT and MAO

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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

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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

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effect of glucocorticoids on bronchial smooth muscle

decreases hyperresponsiveness of bronchial smooth muscle that occurs in asthma

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What infection risk is associated with taking glucocorticoids

Candidiasis (fungal infection) thrush

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Risk of systemic side effects for gllucocorticoids? Why?

Low, this is because it is inhaled, oral has a lot of systemic side effects

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example of ICS+LABA combination

Advair- Fluticasone+salmeterol

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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

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Why is theophyline not used anymore?

Narrow therapeutic range and lots of drug-drug interaction

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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