Respiratory Pharmacology Week 4

1. Respiratory PharmacologyWeek 4

2. Receptors • Adrenergics: • Beta 1 (heart, when stimulated cause contraction, increased HR)---Isoperternal, Epinephrine • Beta 2 (lungs, when stimulated cause dilation)----Albuterol/Xopenex • Alpha 1 (blood vessels/brain/kidney, when stimulated cause vessel constriction)—Racemic Epinephrine • Alpha 2 (Sphincters, GI tract, inhibits insulin release; stimulation causes constriction) Stimulated by neurotransmitter Epinephrine/ norepinephrine *Stimulation of a receptor= agonist *Blocking of a receptor = antagonist

4. Receptors • Cholinergic: • Nicotinic (found in the CNS and the peripheral nervous system. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles; stimulation of these receptors causes muscular contraction) • Blocked with Nicotinic acetylcholine receptors can be blocked by curare; used for anesthesia and mechainical ventilation • Muscarinic (found primarily in lung; G-protein-coupled receptors that activate other ionic channels via a second messenger cascade. sub types; M1-M5) • responds to the binding neurotransmitter acetylcholine

5. Airway Receptors • Adrenergic receptors • Also known as sympathetic and sympathomimetic receptors • Sympatholytics = block response • Stimulated by epinephrine or norepinephrine • Antiadrenergic drugs block receptors for norepinephrine or epinephrine (usually to slow the heart rate or decrease blood pressure)

6. Airway Receptors • Cholinergic receptors • Also known as parasympathetic or parasympathomimetic receptors • Stimulated by acetylcholine • Blocked by ant-cholingergics • In airway anti-musacarinic (anti-cholinergic) = bronchodilation • Anti-nicotinics= neuromuscular paralysis

7. ACh • Airway smooth-muscle cells are innervated by postganglionic parasympathetic nerves. Acetylcholine (ACh) release from these nerves triggers the contraction of airway smooth muscles. This activity is predominantly mediated by smooth-muscle M3 receptors, but activation of postsynaptic M2 receptors is also likely to contribute to this response/AChalso leads to the activation of pre-junctional M2 muscarinic Ach receptor (mAChR) autoreceptors, which mediate the inhibition of AChrelease • M2 receptive for cholinersterase (we block all M receptors, so also the “good” M2)

9. Adrenergic Receptors • The adrenergic receptors which subserve the responses of the sympathetic nervous system have been divided into two discrete subtypes: alpha adrenergic receptors (alpha receptors) and beta adrenergic receptors (beta receptors). 

10. Adrenergic Receptors • The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenergic receptors. • Blood vessels: α1 couples to Gq, which results in increased intracellular Ca2+ which results in smooth muscle contraction. α2, on the other hand, couples to Gi, which causes a decrease of cAMP activity, resulting in e.g. smooth muscle contraction. • Heart/Lung: β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

11. Beta Receptors • Beta Receptors Beta receptors have been further subdivided into beta1 and beta2 receptors.  • beta3and beta4 receptors have recently been isolated, cloned and characterized.  The beta3 receptor may be involved in regulating the metabolism of fatty acids.  This receptor could be the site of antiobesity drugs in the future.  The functions of the beta4 receptor remain to be discovered.  • The classification of beta receptors is based on the interaction of a series of drugs with these receptors. 

12. Beta Receptors • Beta Receptor Systems • Most tissues express multiple receptors.  However, the receptor mainly utilized by the sympathetic nervous system to affect myocardial function in the normal heart is the beta1 receptor; while in vascular and nonvascular smooth muscle it is the beta2 receptor.

13. Beta Receptors

15. Beta Blockers • Beta Blockers used as anti arrthymia agents for A-fib, A-flutter • beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction and hypertension Ex: Labetalol, Esmolol. Metoprolol…

16. Airway Receptors • Cholinergic receptors • Muscarinic drugs stimulate acetylcholine receptors specifically at parasympathetic nerve-ending sites • Anticholinergic drugs block receptors for acetylcholine

17. How Bronchodilators Work • Receptor sites • Alpha sites – cause vasoconstriction and vasopressor effects, increasing blood pressure • Beta1 sites – cause increase in heart rate and myocardial contractility

18. How Bronchodilators Work • Receptor sites • Beta2 sites – cause relaxation of bronchial smooth muscle, stimulate mucociliary activity, and have mild inhibitory effects on inflammatory mediator release

20. Autonomic System • We give drugs that: • 1. increase sympathetic nervous system response (increase BP/HR/bronchodilate) • 2. drugs that increase the parasympathetic response (induce bronchoconstriction, slow heart, increase muscle contraction) • 3. drugs that block the sympathetic nervous system response (decrease HR/BP) • 4. drugs that block the parasympathetic response (prevent bronchoconstriction)

21. Autonomic System • Sympathetic nervous system: fight or flight. Half of ANS system • Parasympathetic nervous system: rest and digest, other half of ANS system • Sympathetic agonist: simulate fight/flight • Parasympathetic agonist: simulate rest/digest • Antagonists block response • Sympathetic agonist have similar response as parasympathetic antagonist

22. Sympathomimetic • Mimic, imitate, increase sympathetic nervous system response. • Sympathetic agonists • Albuterol, Xopenex, Racemic Epinephrine, Serevent, Brovona, Foradil • Most cardiac stimulators

23. Sympatholytic • Decrease the sympathetic nervous system response. Block or decrease sympathetic nervous system response • Sympathetic antagonists • Drugs that block beta receptors to decrease heart rate/BP • Contraindicated with Asthma/COPD

24. Parasympathomimetic • Mimic, imitate, increase parasymoathetic nervous system response • Parasympathetic agonists • Methocholine (induces bronchoconstriction) • Medications to slow heart/BP

25. Parasympatholytics • Block parasympathetic response • Parasympathetic antagonist • Example: Atrovent (block AcH), Atropine (increase HR), Spiriva

26. Autonomic Nervous System • You DO NOT control ANS (automatic) • ANS controls functions of organs automatically, many drugs that affect the ANS affect many organscausing side effects (such as Albuterol/Xopenex) • ANS drugs affect: Heart, blood vessels, pancreas, ureters, bladder, eyes, pupils, lungs, salivary glands

27. Autonomic Nervous System • Do not confuse ANS with the PNS and the CNS • Central nervous system • Brain and spinal cord • Neurons end on other neurons • Peripheral Nervous System • Outside of the skull and spinal cord • Neurons end on organs and muscle (non smooth muscle)

28. Autonomic Nervous System • Do not confuse the ANS with the Voluntary nervous system • Voluntary means willing • You DO control your voluntary nervous system • You control your skeletal muscles to move your body (includes the diaphragm)

30. Sympathomimetics • Substances that mimic effects of the sympathetic nervous system • Part of the autonomic nervous system (not under conscious control) • Activated by “fight or flight” response

31. Sympathomimetics • Neurotransmitters include: • Epinephrine • http://www.youtube.com/watch?v=-gUC7ZQTp34 • Norepinephrine • Catecholmines • Dopamine • Fight or Flight response allows for: • Bursts of energy • Increased heart rate • Increased blood to brain • Increased Oxygen through BRONCHODILATION

32. Sympathomimetics • Sympathomimetic drugs given by aerosol to the lungs MIMIC fight or flight neurotransmitters and cause DIRECT bronchodilation • Examples of Sympathomimic bronchodilators: • Fast Acting: Albuterol, Xopenex, Racemic Epinephrine • Long Acting:Serevent, Brovona

33. Sympathomimetics • Sympathomimetic drugs bind to Beta 2 receptor sites on bronchial smooth muscle cells producing an adrenergic agonist response 1. Once attached to a β2 receptor in bronchial smooth muscle the drug then attaches to the intracellular Gsprotien which stimulates adenlycyclase to form cAMP from ATP which then decreases Ca2+↓ and Myosin resulting in SM relaxation . 2. Also activate β receptors on mast cell mb. , thus used in prophylaxis of allergic asthma .

34. Sympathomimetics • Sympathomimetic drugs can enter the blood stream and also stimulate Beta 1 receptors increasing systemic side effects such as increased HR • These drugs are given for patients with reversible airflow obstruction such as Asthma and COPD

35. Parasympatholytic • Substances that reduce the activity of the parasympathetic nervous system • The PNS is part of the ANS and is often referred as the rest and digest phase. • The primary neurotransmitter in this phase is: • Acetycholine (Ach)

36. Parasympatholytic • The Ach response causes: • Decrease in HR • Decrease in BP • Skeletal muscle contraction • Bronchial smooth muscle constriction • Ach causes: M3 muscarinic receptor reaction in blood vessels, as well as the lungs causing bronchoconstriction. • Drugs that are parasympatholytic BLOCK M3 response and thus indirectly allow for bronchodilation

37. Parasympatholytic • Examples of Parasympatholytics bronchodilators: • Fast Acting: Atrovent/Atropine • Long Acting: Spiriva • Parasymptholytic bronchodilators are referred to as anticholinergics, they are Ach antagonists • Ach enters bronchial smooth muscle cells through muscanaric receptors • Atrovent works by blocking all M receptors resulting in the formation of Cyclic guanosine monophosphate

38. Parasympatholytic • cGMP inhibits constriction and mucus production • cGMP acts as a secondary messenger much like cAMP but instead of converting ATP, cGMP prevents neurotransmitters from entering the bronchial smooth muscle cell • Unlike sympathometic bronchodilators, Atrovent/Spiriva do not cross the blood brain barrier and thus have essentially no systemic side effects (both are derivatives of Atropine, but are quaternary amines) • Slower bronchodilator effects and less intense than adrenergics

41. How Bronchodilators Work • Adrenergic bronchodilators • ATP converts to cyclic 3’5’-adenosine monophosphate (cAMP) • cAMP produces bronchodilation

42. How Bronchodilators Work • Anticholinergic agents • Parasympathetic stimulation of the muscarinic sites leads to production of guanosine triphosphate (GTP) • GTP converts to cyclic guanosine monophosphate (cGMP) • http://www.youtube.com/watch?v=g_H5PWlr3lk

43. How Bronchodilators Work • Anticholinergic agents • Anticholinergic agents block the parasympathetic stimulation at the muscarinic site

44. How Bronchodilators Work • Xanthines • In the presence of phosphodiesterase, cAMP denatures to form GMP • Xanthines inhibit the action of phosphodiesterase, prolonging bronchodilation

45. Adrenergic Bronchodilators • Short acting bronchodilators • Includes catecholamines • Indicated for relief of acute reversible airflow obstruction • Also known as “rescue” bronchodilators • Primary drugs Albuterol and Xopenex

46. Adrenergic Bronchodilators • Short acting bronchodilators • Rapid onset (3-5 minutes) • Rapidly metabolized, resulting in short duration of action (3-8 hours) • Common side effects: increased HR, trembling, nervousness • If HR increases by 20+ stop treatment

47. Adrenergic Bronchodilators • Long acting bronchodilators • Indicated for maintenance bronchodilation and control of bronchospasm • Used to control nocturnal symptoms • Slower onset • Long duration of action, generally 12 hours • Include Serevent, Brovona, Foradil

48. Catecholamines Ultra short

49. Short Acting Bronchodilators

50. PAGE 98 CH 6 • Responsible for dose, onset, peak, duration, names for: • Albuterol • Xopenex • RacemicEpi • ALL LABAs