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Drugs > Lectures 20-22 > Flashcards

Lectures 20-22 Flashcards

1
Q

What is bronchial asthma?

A

a chronic disease characterised by narrowing of the peripheral airways in the lung, varying in severity over short periods of time either spontaneously or in response to treatment.

Predominantly an inflammatory disorder.

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2
Q

what is FEV1?

A

forced expiratory volume, volume you can expire in 1 second.

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3
Q

what is peak expiratory flow rate?

A

peak speed you can blow air out your lungs at.

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4
Q

what is COPD?

A

chronic obstructive pulmonary disease.
similar symptoms to asthma.
irreversible.

a combination of chronic bronchitis and emphysema. also predominately inflammatory.

common in smokers.

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5
Q

what is chronic bronchitis?

A

persistent cough with mucus production.

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6
Q

what is emphysema?

A

destruction of tissues around alveoli.

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7
Q

what is the hygiene hypothesis?

A

being exposed to dirt and allergies at a young age gives you a smaller chance of getting asthma later in life.

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8
Q

describe allergic factors

A

genetic factors and environmental factors.

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9
Q

describe the types of asthma

A

intrinsic/non atopic/non allergic - triggered by non allergic factors like stress, cold, excercise.

extrinsic/atopic/allergic - caused by allergies.

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10
Q

describe the anatomy of the airways.

A

in a cross section of the trachea there is a C shaped ring of cartilage.
this holds the trachea open.

further down there is less cartilage and more smooth muscle. allows regulation by relaxing and contracting.

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11
Q

what do alveoli do?

A

increase surface area and allow for gaseous exchange.

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12
Q

describe the changes to the airways in asthmatic people.

A

hypertrophy of smooth muscle, allows the airways to contract more than normal.

oedema.

lose ciliated epithelium, get more goblet cells. can’t beat mucus away effectively. (epithelial desquamation).

basement membrane gets thickened.

mucus builds up.

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13
Q

what is bronchoconstriction?

A

smooth muscle contracts and narrows the airways,

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14
Q

describe an asthma attack.

A

biphasic - early phase is due to bronchoconstriction.

later phase is due to inflammation.

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15
Q

describe the process of an allergen entering the lungs.

A

allergen binds to a antigen presenting dendritic cell.

this interacts with Th2 lymphocytes and activates them.
They release signalling molecules which summon more cells:
interleukin 5 & 9 activate the eosinophils and mast cells.
interleukin 4 activates B lymphocytes.

B lymphocytes differentiate into antibody producing plasma cells.
they can produce Ig E antibodies, which can bind to eosinophils and mast cells.
These can now interact with the allergens.

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16
Q

describe a mast cell and what happens when it binds to an allergen.

A

nucelus in the centre, cell membrane surrounding outside, granules in the cytoplasm.

the granules contain pre formed mediators (ie histamines, proteases). These are released early when it responds.

Later on it produces mediators often derived from lipids.
ie leukotrienes, prostaglandins, thromboxanes.

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17
Q

describe what happens when eosinophils bind to an allergen.

A

they release major basic protein, causes the epithelium to lose its structure.
causes the loss of ciliated epithelium (epithelial desquamation).

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18
Q

what is the effect of releasing histamines?

A

contraction of airways smooth muscle, also vasodilator so causes an increase in permeability of blood vessels to immune system cells which allows them to get into the tissue.

also increases mucus secretion.

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19
Q

what is the effect of releasing chemotactic factors?

A

signalling cells which tell other immune system cells to move into the lung tissue.

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20
Q

what is the effect of releasing leukotrienes (C4, D4, E4) and prostaglandin (D2)?

A

bring about contraction of smooth muscle, increased permeability of blood vessel wall, increased mucus secretion.

also going to see epithelial desquamation and cell death caused by the major basic proteins.

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21
Q

what are the main divisions of anti asthma drugs?

A 
relievers/bronchodilators:
beta2 adrenoceptor agonists.
leukotriene antagonists.
theophylline.
mAChR antagonists.

preventers/prophylactic agents:
glucocorticosteroids.
monoclonal antibodies.
leukotriene antagonists.

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22
Q

what are the agonists for beta adrenoceptors?

A

non selective agonists in relative potency:
isoprenaline>adrenaline>noradrenaline.

beta1 - dobutamine
beta2 - salbutamol

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23
Q

describe propranolol in relation to asthma.

A

non selective antagonist to beta adrenoceptors.

bad look at past lectures.

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24
Q

describe the effect of B1 adrenoceptor agonists.

A

increased heart rate, increased force of contraction.

B1 not that present in bronchioles.

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25
Q

describe the effect of B2 adrenoceptor agonists.

A

relax bronchioles smooth muscles.

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26
Q

describe adrenaline and asthma

A

naturally occurring alpha and beta agonist.

if you change the end methyl group it becomes more selective for beta vs alpha.
if you increase it more it becomes selective to only beta2.

by altering the catechol group you can alter how it is metabolised/broken down.

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27
Q

describe salbutamol and asthma.

A

altered adrenaline.
lipophilic rating - 1

no longer catechol, longer methyl group.
short acting relievers.

similar to terbutaline.

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28
Q

describe formoterol.

A

long action - 12 hours.

lipophilic rating - 8

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29
Q

describe salmeterol.

A

lipophilic rating - 3200
very beta2 selective.

very long duration of action.
other end binds to an exosite, and the catechol end (not a catechol now) can repeatedly bind and unbind, gives long duration.

huge methyl chain.
Its lipophilicity also means that it dissolves into membranes and slowly leaks out, thus remaining in the tissues for longer.

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30
Q

learn the Gs pathway.

A

lecture 20 end.

previous lectures somewhere?

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31
Q

what are the side effects of B agonist bronchodilators?

A

tremor - B2 receptors in muscle.

tachycardia - B in cardiac muscle

nervous tension

hypokalaemia - stimulation of Na/K pump in skeletal muscle.

32
Q

How do you counter side effects of Beta agonists?

A

if you administer straight to the lungs and dont take orally you reduce side effects.
ie use MDI (metered dose inhaler).

33
Q

Why is an MDI not that effective?

A 
hard to correctly use.
even if correctly used.
10% reaches the lung.
50% impacts in mouth.
90% swallowed into circulation.
34
Q

What are alternatives to MDI?

A

spacer bro.
more efficient.

nebuliser.
gas mask type thing.
not any more efficient than spacer.
more expensive, less portable.

35
Q

describe alkylxanthines.

A

bronchodilators.

caffeine and theophylline.

36
Q

how do alkylxanthines act?

A

inhibiting phosphodiesterase enzymes.
(These break down cyclic nucleotides).

PDE III and IV are inhibited.

and

Also act as adenosine antagonists. Adenosine can cause bronchoconstriction.

37
Q

Describe theophylline

A

very narrow therapeutic window (2:1)

can be given orally.

half life affected by smoking, drugs etc.

plasma or sailva assay to help determine dosage.

38
Q

how is theophylline metabolised?

A

by CYP1A2 enzyme, also metabolises lots of other drugs like verapamil, paracetamol. If also taken they will compete for the enzyme.

inhibited by caffeine, verapamil, grapefruit juice.

induced by tobacco, broccoli, cauliflower and grilled meat.

39
Q

What are the side effects of theophylline?

A

vomiting, headache, fainting, tachcardia, dysrhthmias, convulsions.
can lead to death.

IT’S A BIT SHIT.

40
Q

What is functional antagonism?

A

the actions of a drug on one receptor opposes the effects of another drug on a different receptor.

ie B2 agonists and theophylline

41
Q

describe ACh receptors.

A

nicotinic in skeletal muscle.

muscarinic in parasympathetic NS. ie lots in bronchioles.

42
Q

name some muscarinic ACh agonists and antagonists.

realtive potency

A

antagonists:
atropine > tubocurarine

agonists:
ACh/metacholine/muscarine&raquo_space; nicotine

43
Q

what are the effects of muscarinic receptors in the respiratory tract?

A

At muscarinic receptors on goblet cells it increases the secretion of mucus and it also causes constrictions of smooth muscle - broncoconstriction.

44
Q

what muscarinic ACh receptors are present in respiratory smooth muscle/goblet cells?

A

M1 and M3.

signal through IP3 pathway, Gq pathway.

45
Q

How does the IP3 pathway work?

A

3rd lecture
if not lecture 21

intracellular calcium leads to contraction basically.

46
Q

why is atropine not used?

A

gets into the systemic circulation easily.
this effects all muscarinic subtypes in the body, non selective.

also a tertiary amine.
uncharged form crosses through the membranes of lungs and into the blood.

47
Q

what is the systemic circulation?

A

is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart

48
Q

describe ipratropium.

A

reduces irritant pathways, bronchoconstriction, mucus secretion and cough.

don’t get into systemic circulation, they are quarternary amines. This gives a permanent positive charge, so can’t cross through membranes.

given by inhalation.

non selective to M receptors. still hits M2 in heart.

similar to tiotropium but Tio has longer action.

49
Q

what are side effects of ipratropium?

A

antagonism at other mACh receptors, dry mouth, occasionnally blurry vision and constipation.

ITS PRETTY DAMN GOOD.

50
Q

what are the leukotrienes?

How do they work?

A

20carbons, derived from fatty acids. Act on GPCR.

Produced by mast cells, eosinophils, basophils and macrophages
Important mediator in asthma.
Agonist at cysteinyl-leukotriene (CysLT) receptors.
Contracts bronchial smooth muscle.
Stimulates mucus secretion.
Increases microvascular permeability.

cause PLA2 (phospholipase A2) to be activated, this cuts off membrane lipids.

cuts off phospholipids to arachidonic acid to leukotrienes.

51
Q

what are montelukast and zafirlukast?

A

competitive antagonists at CysLT receptors.
given orally.
reduce excercise and aspirin induced asthma.

can be relievers or preventers.

52
Q

what are the side effects of montelukast and zafirlukast?

A

nausea, abdominal pain, headaches, potential psychiatric side effects.

53
Q

what is a consequence of taking aspirin?

A

overproduction of leukotrienes and less prostanoids.

somebody prone to asthma may have an asthma attack provoked.

inhibiting cycloxygenase prevents prostanoids being made. aspirin inhibits it?

54
Q

what are adrenocorticosteroids?

A

steroid hormones secreted by the adrenal cortex.

either mineralcorticosteroids or glucocorticosteroids.

both water and electrolyte balance.

bind to nuclear hormone receptors - NHR.
pretty slow so used for prevention not relief.

55
Q

give an example of a mineralocorticosteroid.

A

aldosterone - water and electrolyte balance.

56
Q

give an example of a glucocorticosteroid.

A

hydrocortisone (cortisol)
at low conc - modulation of protein and carbohydrate metabolism.

at high conc - suppression of inflammation and immune responses.

corticosterone.

also shows activity of mineralocorticosteroid.

57
Q

describe nuclear hormone receptors.

A

ligands are all very lipophilic, ie sex hormones, corticosteroids.

all similar structure.

bind agonist and regulate transcription of DNA, thus changing protein expression.
pretty slow.

58
Q

what is the structure of NHRs?

A

DNA binding domain.

ligand binding domain.

59
Q

how do glucocorticosteroids act an anti-inflammatory agents in the lung?

A

glucocorticosteroids down regulate the production of cyclo-oxygenase (COX-2).

(COX-2 breaks arachidonic acid into prostalandin endoperoxides.)
reduce the production of prostalandins.

also upregulate annexin 1, which down regulates phospholipase A2.
this reduces production of everything, both leukotrienes and prostaglandins.

60
Q

what do prostaglandins do?

A

increase capillary permeability and bronchoconstrictor.

61
Q

what do leukotrienes do?

A

increase capillary permeability and mucus secretion; bronchoconstrictor.

62
Q

what are the unwanted effects of glucocorticoids?

A

hypertension, moon face, redistribution of fat to abdomen, thinning of skin, osteoperosis.

chusingoid features.
Cushing’s syndrome.

63
Q

how can alpha or beta isomers effect the mineralcorticosteroid or glucocorticosteroid selectivity?

A

alpha type inactive at both receptors.

alpha has functional group at top facing back.

64
Q

what is selectivity?

A

ability to bind tighter at one receptor compared to another.

usually a ratio.

65
Q

good and bad GC effects?

A

good - anti flammatory.

bad - cushing’s syndrome.
Happen through transactivation which requires dimerisation.

66
Q

how do NHR enter the cell?

A

We start off with the steroid outside the target cell. However, its lipid solubility allows it to slip easily through the membrane. Once inside the cell it can interact with glucocorticoid receptors (GCR). These receptors are normally bound to proteins called Heat Shock proteins (HSP), but interaction with the steroid causes the HSPs to dissociate. The standard mechanism is then for the receptors to dimerize (two monomers join) and enter the nucleus via a nuclear pore. Monomeric receptors can also enter the nucleus.

67
Q

what is transactivation?

A

After translocation to the nucleus, the NHR dimer binds to a section of DNA known as a hormone responsive element (HRE) (in the case of the GCR, Glucocorticoid responsive element). It is then able to recruit coactivator proteins and RNA polymerase and promote the transcription of mRNA and thus expression of proteins. Proteins that have their expression regulated by GCs in this manner include the anti-inflammatory mediator, annexin 1. However, a large number of proteins involved in the unwanted effects of the GCs are upregulated in this fashion.

68
Q

what is transrepression?

A

the transcription of mRNA is promoted by a transcription factor. GCR binding to this transcription factor inhibits transcription. This mechanism (transpression) involves receptor MONOMERS and does not involve the receptor binding to DNA. It has been shown using mutant versions of the GCR which cannot dimerize (and so can’t bind to a GRE), that anti-inflammatory effects are still maintained. This means that at least some of the anti-inflammatory effects of the glucocorticoids must be mediated by transrepression. As many of the side effects seem to be due to transactivation, we might be able to make better drugs if we could find ones that favoured transrepression pathway over the transactivation one. Pharmaceutical companies are actively researching this possibility. However, some people think it might not be so simple.

69
Q

how can you prevent the bad effects of GCs?

A

deliver by inhaling straight to the lungs, less gets into the systemic system.

if given orally you get Cushing’s syndrome.

70
Q

give 3 examples of glucocorticosteroids used through inhalatoin.

A

prophylaxis - all preventers

beclomethasone.
budesonide.
fluticasone.

71
Q

what are unwanted effects of inhaled GCs?

How can they be reduced?

A

Local immunosuppression
can evoke opportunist
overgrowth of Candida
albicans (oral thrush).

Local effects on the vocal
cords can result in
dysphonia (hoarseness).

The incidence of these unwanted effects can be reduced by
using a spacer device - or by rinsing the mouth after inhaler use.

72
Q

problems with control of adrenal steroid synthesis?

A

Production of endogenous steroids by the adrenal cortex is under the control of the hypothalamic/pituitary axis: the hypothalamus releases CRF which stimulates the anterior pituitary to produce ACTH. This in turn stimulates the adrenal cortex to produce glucocortioids. To ensure the plasma levels of GCs stay in the correct range, there is negative feedback by the GCs on the hypothalamus and pituitary. This works well until we introduce exogenous steroids into the equation. We then have a situation where there is continuous negative feedback on the hypothalamus and pituitary. This will eventually cause endogenous GC production to come to a halt. The consequence of this is that if the exogenous steroid is then abruptly discontinued, the patient can experience acute adrenal insufficiency (Addisonian crisis), which can be fatal.

shuts down pathway if given for a long period of time.
okay if still taking steroids but once you stop u r fucked.

73
Q

what is a steroid treatment card?

A

alert anyone that they must not be taken off the steroids.

74
Q

what is omalizumab?

A

monoclonal antibody based therapy.
prevents IgE binding to mast cells and eosinophils.

very expensive.
not prescribed to children.

75
Q

A drug with high selectivity for glucocorticoid receptors is?

A

dexamethasone

76
Q

A mutation in Drosophila leads to a phenotype called ‘ether a go-go’. The equivalent human gene to that underlying the ‘ether a go-go’ phenotype is:

A

hERG

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