pharmacology: respiratory drugs

this lecture covered the conventional drugs used to treat respiratory conditions such as asthma. there are several classes of asthma treating drugs, including adrenergic agonists, anti-cholinergics, methylxanthines, etc. which can be grouped into 2 categories: drugs that reduce inflammation, and drugs that relax bronchial smooth muscle. bronchial smooth muscle tone is increased with increased sympathetic activity; epinephrine is a sympathetic neurotransmitter that decreases asthmatic symptoms by this mechanism. since it acts non-selectively, it also acts on beta-1 receptors, causing cardiac symptoms such as palpitations, and on alpha-1 receptors, causing dry mouth and hyperglycemia. in general, the bronchodilating group of asthma drugs are the type used for anaphylaxis / status asthmaticus, while the inflammation reducing drugs are better for longer term, less acute treatments.

then there are drugs that specifically bind to beta-2 agonists, and using the same mechanism above induces dilation of bronchial smooth muscle. these include albuterol, proventil, and salmeterol-- the latter is longer acting and is used more for chronic conditions. these drugs are mainly administered by inhalation, and delivery can be improved by the use of "spacers" which allow for smaller, slower velocity to reach the lungs.

anticholinergics are another class of asthma drugs that act by competitively inhibit the acetylcholine neurotransmitter at muscarinic receptor sites, inducing sympathetic bronchodilation. as opposed to epinephrine or beta-2 agonists, anticholinergics are best used for maintenance as opposed to acute conditions. atrovent and theophylline are two examples of anticholinergics; the former is chemically similar to atropine (from the plant belladonna) and the latter is similar to caffeine.

corticosteroids are also used as asthma treatment when bronchodilators are not effective by themselves. they are potent anti-inflammatories; blocking phospholipase A2, the enzyme which mediates the release of arachidonic acid, the precursor of inflammatory mediators such as leukotrienes and prostaglandins. thus, they decrease the activity of macrophages, eosinophils and t-lymphocytes, as well as decreasing capillary permeability and thus edema systemically (not specific for bronchial tissue). the main danger of corticosteroids is disruption of the body's natural cortisol production via the HPA axis; abrupt discontinuation of corticosteroids might result in an addisonian crisis due to the body's inability to produce ACTH.

corticosteroids also suppress immunity in general, leading to increased susceptibility to infection. one of the side effects of beclovent, an inhaled corticosteroid, is an increased incidence of oral thrush. prednisone is an oral corticosteroid which, compared to inhaled steroids, has more chance of producing systemic side effects, such as hyperglycemia, fat redistribution (same as in cushing's syndrome, a condition of excess cortisol production), osteoporosis, in addition to the potential for the addisonian crisis.

leukotriene inhibitors such as zafirlukast are a newer class of asthma drugs which block leukotriene receptors D4 and E4 in bronchial smooth muscle, thereby reducing inflammation and allowing for bronchodilation. it is also used in the treatment of chronic cases as opposed to anaphylaxis. side effects include headache, Gi upset, possibly increased respiratory infections.

antitussives such as codeine block the medullary centers that are involved in the cough response. the two antitussives that we discussed, codeine and dextramethorphan, are related to morphine: codeine is broken down into morphine while dextramethorphan is a synthetic morphine derivative. besides being addictive, these drugs have other side effects, drowsiness and constipation being among the chief complaints. dextramethorphan is milder than codeine in terms of constipation and and addictive properties.


another major category of respiratory drugs are drugs used to treat allergic rhinitis. antihistamines such as benadryl block histamine H1 receptors and cross the blood brain barrier, causing drowsiness, while medications such as claritin perform the same action while being large enough to not cross the BBB. both cause dryness of mucous membranes and thus are contraindicated in asthma, when a mucolytic (n-acetyl cysteine?) and moistening agent is preferred.

nasal corticosteroids can also be used to depress the inflammatory response locally, such as beconase or rhinocort, although can result in local irritation and nosebleeds, as well as increased susceptibility to nasal candidiasis. nasal alpha agonists are also used to combat allergic rhinitis, such as phenylephrine / afrin, but are highly addicting due to the rebound symptoms that occur as soon as the medication is stopped.

questions
intro...
1. describe the different roles of the autonomic nervous system in terms of bronchoconstriction and bronchodilation.
2. what are the two general mechanisms of action for asthma drugs?
3. epinephrine indications...
4. epinephrine mechanism of action?
5. side effects of epinephrine?
6. method of delivery?

beta-2 agonists...
7. albuterol, proventil mechanism of action?
8. methods of administration and timing of action for each?
9. inhaled administration might be improved by...
10. when is use of salmeterol / serevent indicated?
11. onset and duration of action of salmeterol?
12. side effects of salmeterol?

anticholinergics...
13. anticholinergics are similar in structure to...
14. action of anticholinergics?
15. when are anticholinergics indicated?
16. example of anticholinergic?
17. what is an example of an anticholinergic that has been replaced by beta agonists / corticosteroids?
18. what class of drug does [17] belong to?
19. what other substance is [17] similar to?

corticosteroids...
20. mechanism of action?
21. acute or chronic cases?
22. main side effect?
23. secondary side effects?
24. examples of inhaled corticosteroids?

specific corticosteroids...
25. indication for beclovent?
26. 2 mechanisms of action for beclovent?
27. beclovent's effect on bronchial smooth muscle?
28. oral side effect of inhaled beclovent?
29. indications for prednisone?
30. side effects of prednisone?

leukotriene inhibitors...
31. mechanism of action?
32. two examples?
33. indications for leukotriene inhibitors?
34. zafirlukast used more commonly in which population?
35. side effects?
36. inhibits which other enzyme?

antitussives...
37. mechanism of antitussives?
38. codeine is broken into...
39. side effects?
40. what does the DM in robitussin DM stand for?
41. what class of drug is DM?
42. how do DM antitussives compare to narcotic analgesic tussives in terms of side effects?

antihistamines...
43. MAO of benadryl?
44. benadryl relationship with BBB?
45. why is benadryl contraindicated for asthma?
46. example of a non-drowsy antihistamine?
47. MAO of [46]?
48. how is [46] non-drowsy?
49. common side effect of [46]?

nasal sprays...
50. two examples of nasal corticosteroids?
51. mechanism of action?
52. side effects?
53. two examples of nasal alpha-agonists?
54. most significant side effect?

answers
1. sympathetic= bronchodilation. parasympathetic= bronchoconstriction.
2. bronchodilators and inflammation suppressors.
3. emergent treatment of asthma, status asthmaticus, anaphylaxis.
4. beta-2 adrenergic receptor stimulation leads to increased cAMP levels leads to smooth muscle relaxation and bronchodilation.
5. B-1 agonist effects include tachycardia, anxiety, arrhythmias, palpitations. alpha-1 agonist effects include dry mouth and hyperglycemia.
6. subcutaneous, IV, IM, inhalation, endotracheal tube.

7. beta-2 agonist causes increased cAMP levels resulting in bronchial smooth muscle dilation.
8. periorally-- 30 minutes onset and 4-8 hour duration. inhaled-- 15 mins onset and 2-3 hour duration.
9. spacer which allows for smaller, slower velocity particles.
10. for long term treatment of asthma.
11. 20-30 min onset, 12 hour duration.
12. headache, cough.

13. atropine from belladonna.
14. competitively antagonize AcH at muscarinic receptor sites, resulting in sympathetic bronchodilation.
15. maintenance as opposed to acute cases.
16. ipratropium / atrovent.
17. theophylline.
18. methylxanthine / xanthines bronchodilators.
19. caffiene.

20. inhibition of phospholipase A2 which blocks the release of arachidonic acid, the precursor of inflammatory mediators. also inhibits histamine and kinin activity.
21. chronic.
22. starts to shut off the HPA feedback loop for cortisol production
23. increased susceptibility to infections, hyperglycemia, bone loss, insomnia.
24. beclomethasone / beclovent , vanceril.

25. when asthma can not be controlled by bronchodilators.
26. decreasing activity for inflammatory cells (macrophages, eosinophils, t lymphocytes), decreases capillary permeability.
27. no direct effect on smooth muscle.
28. oral thrush.
29. COPD, worsening asthma.
30. fat redistribution, hyperglycemia / diabetes, osteoporosis, addisonian crisis.

31. blocking leukotriene receptors (E4, D4) in bronchial smooth muscle.
32. zafirlukast / accolate, montelukast / singulair.
33. chronic asthma, prophylaxis.
34. pediatrics.
35. headache, GI upset, increased respiratory infections in older populations.
36. cytochrome p450 enzymes.

37. decreases sensitivity of medullary cough centers.
38. morphine.
39. drowsiness, constipation, GI upset, dependence.
40. dextromethorphan.
41. morphine derivative.
42. DM less addictive, less constipation.

43. blocking H1 receptors.
44. readily crosses BBB.
45. because benadryl will dry and thicken secretions and asthma needs moistening and mucolytics.
46. claritin / loratadine.
47. same as [43].
48. doesn't cross BBB.
49. dry mouth. dryness of mucous membranes.

50. beclomethasome / beconase
budesonide / rhinocort
51. decreases inflammatory mediators in nasal mucosa.
52. irritation, nose bleeds, sore throats, candidiasis.
53. phenylephrine / afrin
oxymetazoline / long acting afrin
54. rhinitis medicosum: rebound effect after taking nasal alpha agonists.