Lecture 3 - Pharmacology of asthma

Question 1

what are example of B2-adrenoreceptor drugs?

Answer 1

salbutamol, salmeterol, formoterol which relaxes smooth muscles for symptomatic relief

Question 2

explain the mechanism by which beta arena receptors cause relaxation of smooth muscle

Answer 2

Beta adrenoceptor agonists activate Gs which in turn promotes the stimulation of adenylyl cyclase. This enzyme catalyses the formation of cyclic AMP. cAMP activates protein kinase A, which can

Inhibit MCLK
Promote calcium efflux by increased protein kinase A.
Inhibit the MPK pathway by phosphorylating and inhibiting Raf-1 kinase

The net effect is relaxation of the bronchial smooth muscle and therefore bronchodilation

Question 3

Explain what long acting beta-adrenoreceptor agonist have?

Answer 3

the long acting beta-adrenoreceptor agonist have lipophilic groups attached which interact with exo-sites on the receptor. this locks the ligand onto the receptor binding site.

Question 3

describe the difference between salmeterol vs salbutamol

Answer 3

Highly potent 10-11M vs 10-6M at receptor (need to use less)

Binds for longer/more strongly to the receptor.

Longer action 12hr vs 4hrs

Less desensitisation – we will come back to this

Question 4

what are other actions of beta-adrenoreceptors?

Answer 4

Cholinergic transmission.

Inhibition of inflammatory mediator release.

Vascular permeability.

Mucociliary clearance

Question 5

explain what effects B2-agonsist (salbutamol) have.

Answer 5

decrease mediator release via mast cells, eosinophils and neutrophils and epithelial cells

dearest cytokine release vis T lymphocytes

decrease neuropeptide release via sensory nerve

Question 6

what’s a major problem with B2-adrenoreceptor agonist?

Answer 6

short action - desensitisation (loss in response to the agonist over time)

Question 7

what three mechanisms is desensitisation brought about by?

Answer 7

Phosphorylation of the occupied receptor by a specific receptor kinase, termed b-adrenoceptor kinase (b-ARK)

Internalisation of the receptor.

Phosphorylation of the occupied receptor by protein kinase A; e.g. negative feedback.

Question 8

what does evidence suggest about salmeterol?

Answer 8

longer acting - due to partial agonist :

Less phosphorylation of the receptor by Beta adrenoceptor kinase (b-ARK)

Less internalisation of the Beta -2 adrenoceptor

The same amount of cAMP/PKA dependent phosphorylation of the receptor

Question 9

what are routes of administration of the B2-adrenoreceptor drugs?

Answer 9

Inhaled route. A metered dose inhaler is commonly used. Only 10% of the drug enters the lung. For people who cannot use metered inhalers, others include nebulisers and dry powder inhalers.

Oral route. Side-effects make this route a last option. However, some argue that this path is more effective for small airway bronchodilation.

Intravenous and intramuscular. Necessary for acute asthma (risk of death). Given as a drip or as a bolus injection. Most commonly used with terbutaline.

Question 10

what are the systemic delivery issues with B2-adrenoreceptor agonist?

Answer 10

b2-adrenoceptor agonists elicit vasodilation relaxation of vascular smooth muscle.

Increased blood flow and a fall in BP - reflex increased tachycardia and cardiac output.

Increased metabolic processes, including increased glucose, fatty acids, ketone bodies and high-density lipoprotein.

Increase in tremor in skeletal muscle.

Question 11

what are steroid treatments for asthma treatment?

Answer 11

Glucocorticoids: dampen down many aspects of the inflammation linked with Asthma

Widely used by inhalation (e.g. beclametasone,
budesonide, fluticasone) as prophylactic therapy.

Standard oral steroid is prednisolone

Intravenous steroids are hydrocortisone and methylprednisolone.

Question 12

what are the effects of steroid on mediators ?

Answer 12

LTC4, LTD4, LTE4 (eosinophils, basophils, and macrophages). Synthesis and Secretion inhibited.

LTB4 formation blocked (mast cells, alveolar macrophages).

histamine formation blocked (mast cells, basophils)

Question 13

what are corticosteroids carried in the body as?

Answer 13

transcortin

Question 14

explain the effect of corticosteroids on the primary effector systems cells - alveolar macrophages and endothelial cells

Answer 14

Alveolar macrophages (migration, IgG and complement decreased- reduction in cytokine synthesis)

Endothelial cells (decrease adhesive response, reduction in vascular permeability).

Question 15

what are the effects of corticosteroid on the secondary recruiter systems cells

Answer 15

Eosinophils decreased mediator leased and increased apoptosis

Lymphocytes (increased apoptosis and decreased differentiation, reduction in T4 helper cells, reduction in B-cell cycle).

Monocytes (migration inhibited, cell death, reduced production, reduced IgE receptor).

Question 15

dwhat effects do steroids have on forced expiratory volume ?

Answer 15

steroids provide long duration relief (15-20% improvement) by increasing FEV1 over hours

Question 16

what are steroids side effects?

Answer 16

weight gain, water retention

increased appetite

shortness of breath

sweating/ rashes

blurred vision, dizziness

sleep problems

suppressed immune system

numbness or tingling in arms or legs

Question 17

what are leukotrienes? what’s is leukotriene B4?

Answer 17

lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases.

leukotriene B4 is a neutrophil chomoattractant

Question 18

what do leukotriene C4 and D4 cause - 4 factors? and what is a leukotriene D4 receptor antagonist?

Answer 18

cause bronchoconstriction, increased bronchial reactivity, mucosal edema and mucous hypersecretion

zafirlukast and montelukast.

Question 19

what enzyme is involved in leukotriene systnthesis and what drug is used for leukotriene inhibition - what are its affects?

Answer 19

5-lipoxygenase is the enzyme involved in leukotriene synthesis: inhibition by zileuton inhibits the above effects. Shown to be particularly effective in aspirin-induced asthma

Question 20

what are effects of zileuton and zafirlukast and montelukast

Answer 20

Zileuton MAJOR Side Effect: LIVER TOXICITY!!! (less often used)- zafirlukast has some hepatotoxicity, but less than zileuton

Montelukast UNIQUE Side effect: Eosinophilia and Churg Strauss Syndrome (eosinophilic granulomatosis in small blood vessels)

Question 21

explain how montelukast causes bronchial smooth muscle relaxation

Answer 21

LTD4 works through calcium to activate contraction, so when released in the asthmatic environment, more contraction and can be blocked via montelukast.

In asthmatics this leads to bronchoconstriction. Asthmatics may well have increased IP3 receptors expressed in their bronchial smooth muscle and therefore these cells respond more strongly to for example LTD4.

montelukast antagonises the CysLT1 receptor and decreases lekotrines C4, D4 and E4

Question 22

what are xanthines ?

Answer 22

These are commonly used anti-asthmatic drugs, e.g Theophylline, enprofylline.

Question 23

what are the two mechanisms of action of xanthines?

Answer 23

Adenosine receptor antagonist. These drugs can block the inhibitory action of adenosine upon adenylyl cyclase (via its receptors), and thus allow intracellular cyclic AMP to accumulate and promote relaxation;

phosphodiesterase inhibitor (blocks reduction in intracellular
cyclic AMP) and relax smooth muscle; (c) effects via catecholamines (increases catecholamine release); (d) other effects, xanthines have been shown to antagonise the actions PGE2 and PGF2a.

Question 24

what are the effects of theophylline in asthma?

Answer 24

(i) smooth muscle relaxation.

(ii) inhibit anaphylactic release of mediators (mast cells).

(iii) suppress oedema.

(iv) central stimulation of ventilation (disadvantage as breathing may become shallower).

Theophylline and not enprofylline depress respiratory centre activity in the CNS.

Question 25

what are problems associated with theophylline?

Answer 25

Oral theophylline side-effects include, anorexia, vomiting and mild CNS stimulation.

Doses should be low to avoid gastro-abdominal problems.
CNS stimulation is a problem when maintenance administration is increased too quickly.

Most serious toxicity is a risk of seizures.

Intravenous routes increase arrhythmia, palpitations, and tachycardia at doses above 30mg/l

Question 26

what are asthma therapy steps?

Answer 26

1. miled intermittent asthma - inhaled short acting B2 agonist as required
2. regular preventer therapy - add inhaled corticosteroids. dose adjusted to severity
3. add on therapy - initially add long acting beta agonist and assess effect. if ineffective, inhaled corticosteroid dose should be doubled and LABA stopped if not adding to control of asthma
4. persistent poor control - consider trial of increased dose of inhalation corticosteroid or addition of 4th agent - LTRA, theophylline, or oral beta agonsit
5. continuous or frequent use of oral corticosteroids - use lowest dose as possible. consider other theatres, refer to specialist

Question 27

what are the antibodies medication treatment for asthma?

Answer 27

Tralokinumab (anti-IL-13), lebrikizumab, (anti-IL-13). IL-13 is produced by TH2 cells and activates esoinophils and mast cells in the allergic response

Mepoluzimab (anti-IL-5 antibody)

Omalizumab (anti-IgE antibody)