Muscarinic Antagonists and other bronchodilators Ch 7 1

Muscarinic Antagonists and other bronchodilators Ch. 7 1

Where does Acetylcholine come from? § In the presynaptic neurons the following combine, in the presence of the enzyme acetyltranferase, to make Ach § Acetyl – Co. A § Choline 2

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 3

Parasympathetic Receptors NTs and Termination § Acetylcholine (ACh) stimulates Muscarinic 3 (M 3) receptors § Action of ACh is terminated primarily by the enzyme acetylcholinesterase § Secondarily, ACh activates M 2 receptors on the presynaptic ganglion, which inhibits the release of ACh 4

Muscarinic Receptors § Lung innervated by the vagus nerve § M 1: parasympathetic ganglia (along with nicotinic receptors) § M 2: heart, and postganglionic parasympathetic nerves § M 3 airway smooth muscle, submucosal glands § scan page 100 here 5

Blocking Muscarinic Receptors § Blocking… § M 3 receptors on smooth muscle and mucous glands § M 1 receptors on the postganglionic nerve § M 2 receptors on the end of the postganglionic nerve § All of our bronchodilators currently blockade all 3, including M 2 6

Remember the Cholinergic Effects § SLUG or SLUD 7

Remember the Cholinergic Effects § For us in the lung: § Increase in secretion production (exocytosis) § Bronchial smooth muscle contraction § M 3 receptor stimulation produces chain effect, end result of which is an influx of Ca++ into the cell causing muscle contraction 8

Anticholinergic Advantage § Parasympatholytics have shown long term improvement in baseline FEV 1 in COPD patients § No such improvement found using adrenergics, although still used § Unknown etiology, although may be from blocking Vagally mediated bronchoconstriction 9

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 10

Xanthines – 2 nd or 3 rd line agents? Theories of action 1. inhibition of phosphodiesterase? § this is what breaks down c. AMP (we’ll talk about this later) § but it is not that good at it 2. antagonism of adenosine? § adenosine can agonize A 1 and A 2 receptors § but they don’t have that much to do with bronchodilation 11

Xanthines – 2 nd or 3 rd line agents? Theories of action 3. catecholamine release? § no conclusive evidence 4. move calcium so it can’t be used in muscle contraction? 12

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 (c. AMP); § phosphodiesterase breaks down the “good” c. AMP 13

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 14

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 15

Non-Bronchodilatory Benefits § Increased diaphragm strength-from improved muscle contractility § CNS Stimulationincreased ventilatory drive 16

More Non-Bronchodilatory Benefits § Anti-Inflammatory Effects § Improved Cardiac function (common comorbidity) § Diuresis (think caffeine but more potent) 17

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 18

End of Show 19

Stop Here if this is Friday 20

What happens at the Muscarinic Three Receptor When Activated § Activation of phospholipase § Phospholipase helps to breakdown phosphoinositides to 1. inositol triphosphate (IP 3) 2. diacylglycerol (DAG) § This increases intracellular calcium (Ca++) § Ultimately causing smooth muscle contraction § Also results in gland exocytocis - submucosal gland produces secretions 21

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 1980 s § Q. What’s another way to inhale a drug besides burning? § A. The Atropine was nebulized 22

ipratropium (Atrovent) § Available for use in a nebulized formula in 1987 § Short-acting (4 to 6 to 8 hrs) anti-cholinergic (antimuscarinic) § non-selectively blocks the M 1, M 2, and M 3 receptors § Q. Which one of these is the worst to antagonize if you’re goal is to help an an Asthmatic? § A. M 2 § indications: bronchoconstriction due to COPD and also to Asthma, etc 23

Revised-Eric Lau (slide 10 Beta 2) Bronchodilation: the hypothetical Nonadrenergic, noncholinergic (NANC) (continued) 1. (from the last slide) 2. 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 24

ipratropium inhaled Inhaled dosages and [ ]s § MDI 20 mcg/puff, 1 -2 puffs § soln 0. 25 mg/m. L § nebules (many) § § § 0. 25 mg/ml in 1 m. L of drug 0. 125 mg/ml in 2 m. L “ “ 0. 25 mg/ml in 2 mls “ “ 25

ipratropium; dosages and routes § Dosage Frequencies (three examples) § Taken at same times as salbutamol (i. e. q 4 h, 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 26

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 27 patients

Atrovent (ipratropium): drug times § § § Onset 5 - 15 min; CPS = ______ Peak 60 - 90 min; CPS = ______ Duration 4 to 6 to 8 hrs; CPS = ______ 28

Ventolin and Atrovent together: Combivent § Indicated for COPD maintenance § salbutamol and ipratropium combined § § § *MDI 100 or 120 mcg (sulfate) with 20 mcg Nebules 2. 5 mg with 0. 5 mg all in a 2. 5 ml soln bromide? sulphate? “Salts” or “formulations” § not synonymous § * discontinued in 2007 29

Spiriva (tiotropium) § Mode of action: § More selective for M 3 receptors dissociates from M 2 faster § 6 – 20 X more affinity for M 3 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 § http: //www. spiriva. com/consumer/taking-spiriva/spirivacapsules-and-handihaler. jsp § Action Times (onset, and duration) § 30 min, 3 hrs (peak) § Half life of 35 hrs – improves FEV 1 to max peak at one-week 30

4 Steps for the “HH” 31

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/m. L § 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 32