1. Muscarinic Antagonists
and other bronchodilators
Ch. 7

2. Where does Acetylcholine come from?
In the presynaptic neurons the following combine, in the presence of the enzyme acetyltranferase, to make Ach
Acetyl – CoA
Choline
Remember that Ach is the chemical nerve transmitter for both synapses in the para-sympathetic limb, and the ganglion in the sympathetic limb. Anti-muscarinic equals anti-cholinergic. These drugs are not anti-nicotinic

3. Where does Acetylcholine come from?
When the nerve impulse reaches the ganglion, there is an influx of Ca++
1000 to 50,000 molecules of Ach per vesicle are released into the junction
Remember that Ach is the chemical nerve transmitter for both synapses in the para-sympathetic limb, and the ganglion in the sympathetic limb. Anti-muscarinic equals anti-cholinergic. These drugs are not anti-nicotinic

4. Parasympathetic Receptors NTs and Termination
Acetylcholine (ACh) stimulates Muscarinic 3 (M3) receptors
Action of ACh is terminated primarily by the enzyme acetylcholinesterase
Secondarily, ACh activates M2 receptors on the presynaptic ganglion, which inhibits the release of ACh

5. Muscarinic Receptors Lung innervated by the vagus nerve
M1: parasympathetic ganglia (along with nicotinic receptors)
M2: heart, and postganglionic parasympathetic nerves
M3 airway smooth muscle, submucosal glands
scan page 100 here
Pg in Rau
M1 is in parasympathetic ganglia (along with nicotinic receptors), and nasal submucosal glands
Vagus Nerve-10th Cranial nerve. Vagrant nerve, has para-sympathetic innervation throughout heart, lungs, stomach, liver and intestine
M4 and M5; later

6. Blocking Muscarinic Receptors
M3 receptors on smooth muscle and mucous glands
M1 receptors on the postganglionic nerve
M2 receptors on the end of the postganglionic nerve
All of our bronchodilators currently blockade all 3, including M2
M3 receptors on smooth muscle and mucous glands will prevent smooth muscle contraction and decrease mucous production (that’s good!)
M1 receptors on the postganglionic nerve, will inhibit nerve transmission from the preganglionic nerve to the postganglionic nerve (that’s good too!)
M2 receptors on the end of the postganglionic nerve will actually enhance acetylcholine release - blocks the inhibitory effect. (this is bad as it promotes bronchoconstriction!)
If we can avoid blocking the M2 we could prolong the effect of our anti-muscarinic agents

7. Remember the Cholinergic Effects
SLUG or SLUD

8. Remember the Cholinergic Effects
For us in the lung:
Increase in secretion production (exocytosis)
Bronchial smooth muscle contraction
M3 receptor stimulation produces chain effect, end result of which is an influx of Ca++ into the cell causing muscle contraction
cGMP is a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. It also relaxes smooth muscle tissues. In blood vessels, relaxation of vascular smooth muscles lead to vasodilation and increased blood flow.
cGMP production leads to Calcium influx, leads to bronchoconstriction etc.

9. Anticholinergic Advantage
Parasympatholytics have shown long term improvement in baseline FEV1 in COPD patients
No such improvement found using adrenergics, although still used
Unknown etiology, although may be from blocking Vagally mediated bronchoconstriction
Baseline FEV1-measurement of lung function, meaning we actually improve our patients, not just treat symptoms
Receptors are also more proximally in the airways, adrenergic receptors may have been destroyed by disease progression
Also an advantage while treating asthmatic bronchoconstriction
In broncho-constriction you may not be able to get beta 2s to the effector site as they are blocked by constriction, so must use other drugs or other pathways.

10. Combination Therapy
Ventolin and Atrovent, when taken together, have a greater effect than either alone.
AKA = synergism
Why?
No one knows for sure, may be related to different time of onset, or times of peak effect

11. Xanthines – 2nd or 3rd line agents?
Theories of action
inhibition of phosphodiesterase?
this is what breaks down cAMP (we’ll talk about this later)
but it is not that good at it
antagonism of adenosine?
adenosine can agonize A1 and A2 receptors
but they don’t have that much to do with bronchodilation
More properly called Methylxanthines-Chapter 8 in Rau
Theophylline, caffeine
Small group of drugs
Pg Rau
2. Adenosine-a nucleoside that can stimulate A1, A2. A1 receptor stimulation inhibits cAMP which can cause smooth muscle contraction. So blocking A1 stimulation could block bronchial smooth muscle contraction

12. Xanthines – 2nd or 3rd line agents?
Theories of action
catecholamine release?
no conclusive evidence
move calcium so it can’t be used in muscle contraction?
Catecholamines-Like Epinehrine, evidence is contradictory

13. What does Phosphodiesterase do? A bit of a review
When beta two receptor is activated by an agonist…
Stimulates Adenyl Cyclase
Adenyl Cyclase helps to convert adenosine triphosphate (ATP) into cyclic adenosine 3’, 5’ monophosphate (cAMP);
phosphodiesterase breaks down the “good” cAMP
So Xanthines inhibit phosphodiesterase

14. What does Phosphodiesterase do? Continued
Cyclic AMP
increases the inactivation of protein kinase A, which leads to less myosin + actin interaction
lowers intracellular calcium (Ca)
Ultimately causing smooth muscle relaxation
Also results in inhibition of mast cell degranulation

15. Categorized a bronchodilator, but…
Bronchodilating effects are weak
Not a first line drug for asthma or COPD
Minimal to no improvement in pulmonary function studies
But may show clinical improvement
True benefit may come from other effects
But there are benefits for use in COPD
Not for use in acute exacerbations
Use Adrenergics and anticholinergics first, followed by long-acting β2 agonists

16. Non-Bronchodilatory Benefits
Increased diaphragm strength-from improved muscle contractility
CNS Stimulation-increased ventilatory drive
Increased diaphragm strength-from improved muscle contractility
Improved endurance, decreased fatigue
? Improved skeletal muscle function

17. More Non-Bronchodilatory Benefits
Anti-Inflammatory Effects
Improved Cardiac function (common comorbidity)
Diuresis (think caffeine but more potent)
Less mucosal swelling and edema, decreased secretion production, decrease in airway reactivity , prevention of fibrosis
Look more at inflammatory response. Will be discussed more in corticosteroid module
Improved Cardiac function (common comorbidity)
Increased myocarcial contractility
Diuresis (think caffeine but more potent)
Improves cardiac function
Decreases edema, improving lung compliance

18. Side effects: think Caffeine and more
neonates previously given theophylline for apnea of prematurity, now given caffeine (safer xanthine)
Side effects of theophylline…
headache, vertigo, diarrhea, nausea, vomiting
anorexia
nervousness, insomnia, irritability, tremor,
hyperglycemia
low electrolytes (hypokalemia, hypercalcemia, hypomagnesemia, hypophosphatemia)
cardiac arrhythmias leading to hypotension,
seizures, death
Cardiac arrhythmias secondary to electrolyte abnormalities?

19. End of Show

20. Stop Here if this is Friday

21. What happens at the Muscarinic Three Receptor When Activated
Activation of phospholipase
Phospholipase helps to breakdown phosphoinositides to
inositol triphosphate (IP3)
diacylglycerol (DAG)
This increases intracellular calcium (Ca++)
Ultimately causing smooth muscle contraction
Also results in gland exocytocis - submucosal gland produces secretions
May be more complicated then I want to go. Think on it
Calcium always causes muscle contraction. Inhibiting cGMP blocks the Ca cascade and muscle tightening

22. Anticholinergics
Atropine is the naturally occurring alkaloid found in the Atropa Belladona (nightshade plant) and the Datura species
Dantura plants burned and inhaled as early as the 17 century in India
Atropine used as an adjunct to sympathomimetics in the 1980s
Q. What’s another way to inhale a drug besides burning?
A. The Atropine was nebulized
Rework

23. ipratropium (Atrovent)
Available for use in a nebulized formula in 1987
Short-acting (4 to 6 to 8hrs) anti-cholinergic (anti-muscarinic)
non-selectively blocks the M1, M2, and M3 receptors
Q. Which one of these is the worst to antagonize if you’re goal is to help an an Asthmatic?
A. M2
indications: bronchoconstriction due to COPD and also to Asthma, etc
Generalize

24. Revised-Eric Lau (slide 10 Beta 2) Bronchodilation: the hypothetical Nonadrenergic, noncholinergic (NANC) (continued)
(from the last slide)
Brochoconstriction may be caused by afferent C-fibers leading back to the CNS
C-fibers stimulated by a noxious substances (causes bronchoconstriction)
C-fibers release a neuropeptide (a tachykinin) known as substance P
Results in more bronchoconstriction and cough
As well as vasodilation, increased vascular permeability, mucous gland secretion, mucocilliary activity
Currently no pharmacological agents targeted toward NANC

25. ipratropium inhaled Inhaled dosages and [ ]s
MDI 20 mcg/puff, 1-2 puffs
soln 0.25 mg/mL
nebules (many)
0.25 mg/ml in 1mL of drug
0.125 mg/ml in 2mL “ “
0.25 mg/ml in 2mls “ “

26. ipratropium; dosages and routes
Dosage Frequencies (three examples)
Taken at same times as salbutamol (i.e. q4h, qid, prn)
Taken tid (when salbutamol taken qid)
Taken as “maintenance” bronchodilator on its own, with salbutamol as a “rescue” (COPD)
Other formulations
nasal spray

27. Atrovent (ipratropium): side effects
less side effects (cardiac, vasoactive) as it is fully ionized limiting systemic absorption
dry mouth
cough, pharyngitis
nervousness, irritation,
hypersensitivity reactions (laryngospasm, uticaria, etc)
headache, vertigo, diarrhea, nausea and vomiting
worsening of narrow angle glaucoma when it gets into the eyes (intraoccular pressure can rise)
should use t-piece when nebulizing to older patients

28. Atrovent (ipratropium): drug times
Onset min; CPS = ______
Peak min; CPS = ______
Duration 4 to 6 to 8 hrs; CPS = ______

29. Ventolin and Atrovent together: Combivent
Indicated for COPD maintenance
salbutamol and ipratropium combined
*MDI 100 or 120 mcg (sulfate) with 20mcg
Nebules 2.5mg with 0.5mg all in a 2.5ml soln
bromide?
sulphate?
“Salts” or “formulations”
not synonymous
* discontinued in 2007

30. Spiriva (tiotropium) Mode of action: Concentrations and Dosages
More selective for M3 receptors dissociates from M2 faster
6 – 20X more affinity for M3 than ipratropium
Concentrations and Dosages
18 mcg qday
Form and Delivery
“Handihaler” (DPI) capsules are crushed and inhaled
Repeat inhalation (of the single capsule) 2 or 3 times with reduced IC
Action Times (onset, and duration)
30 min, 3hrs (peak)
Half life of 35 hrs – improves FEV1 to max peak at one-week

31. 4 Steps for the “HH”

32. Theophylline (a xanthine)
As a anti-inflammatory drug
Very small therapeutic index, therefore target the following blood levels
55-65 mmol/L
10-12 mcg/mL
Salts of theophylline
pure (100% theophylline) e.g. Theodur given orally
aminophylline (85%) given IV
oxtriphylline (Choledyl) (65%) given orally
regular tabs or extended release capsules