Introduction to Sympathetic ANS Pharmacology -ญ‐ Part 1

Introduction to Sympathetic ANS Pharmacology -‐ Part 1 Hi everyone. I’m sorry that I’m extraordinarlly late on getting this noteset to you guys. I spent this past weekend hiking in Tahoe, and I’m at a conference in San Francisco. For a clearer explanation, see the last page of the noteset. If you’re going to print this noteset, don’t print the last page. A lot of the later learning objectives are covered in the ANS Sympathetics II lecture and in Oduche’s noteset, and we cover some of the same material in this noteset, as Dr. Kadowitz was a bit all over the place. Because of the lecturer, much of the material I’m using for the LO’s comes from Katzung’s 12e text. If you have an questions or comments, email me! [email protected] 1. Describe the anatomy of the sympathetic nervous system. a. The sympathetic division of the autonomic nervous system is made up of general visceral efferent cell bodies in the lateral horns of the spinal cord that extend from T1 to L2 spinal levels. b. Preganglionic neurons of the sympathetic system are usually short, synapsing at the paravertebral chain ganglia or the prevertebral ganglia, with long post ganglionic nerves going to the organs that they innervate. i. Paravertebral chain ganglia are made up of the cervical ganglia, thoracic and lumbar ganglia and pelvic ganglia. Remember dissecting these along the spine during the thorax/abdomen block of anatomy? Yeah, neither do I. ii. Sympathetic preganglionic neurons also synapse directly on chromaffin cells of the adrenal medulla. This is an exception to the short pre-‐ganglionic, long post-‐ganglionic nerve rule for sympathetics. c. Remember, of course, that the sympathetic nervous system promotes fight or flight responses. It diverts blood flow away from the GI tract while enhancing blood flow to skeletal muscles and lungs. It also dilates bronchioles of the lungs (think inhalers), increases heart rate and contractility, dilates pupils to allow for more light, causes vasodilation of coronary vessels of the heart, constricts intestinal sphincters, inhibits peristalsis and stimulates orgasm (Point & Shoot). 2. Describe the biosynthetic steps and regulation of the biosynthesis of catecholamines. a. Catecholamines are synthesized from tyrosine largely in the adrenal medulla and released from the chromaffin cells under control of sympathetic nerves. The final step forming epinephrine occurs only in the adrenal medulla | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e E a s i e r ” Introduction to Sympathetic ANS Pharmacology -‐ Part 1 i. Tyrosine hydroxylase hydroxylates tyrosine to form dihydroxyphenylalanine (DOPA). ii. DOPA is decarboxylated by aromatic amino acid decarboxylase to form DOPAMINE. iii. Dopamine is ß-‐hydroxylated by dopamine ß-‐hydroxylase to form norepinephrine. iv. Norepinephrine can be methylated by phenylethanolamine-‐N-‐
methyltransferase to form epinephrine. The rate-‐limiting step in the formation of neurotransmitters is the conversion of tyrosine to DOPA by tyrosine hydroxylase. Metyrisine (or alpha-‐methyl DOPA) inhibit this step. In the image to the left (Katzung’s 12e, Figure 6-‐5), an alternative pathway is shown as well as the physiological pathway described above. The pathway forming tyramine and octopamine to finally form norepinephrine is not physiologically significant in humans. However, both tyramine and octopamine accumulate in patients taking monoamine oxidase inhibitors (MAOIs). | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e E a s i e r ” Introduction to Sympathetic ANS Pharmacology -‐ Part 1 3. Explain the actions of the transmitters of the sympathetic ANS. a. Preganglionic neurons release acetylcholine, which acts at nicotinic (excitatory) receptors on postganglionic neurons. b. Postganglionic sympathetic neurons release catecholamines. Note that dopa and tyrosine do not have significant NT functions. i. Dopamine – precursor for norepinephrine, when released systemically it produces peripheral vasodilation. 1. Thus, dopamine is an extraordiarily important agent in the treatment of cardiogenic shock and cardiovascular collapse, when renal and mesenteric profusion are compromised by increased peripheral vasoconstriction. See the drugs list below for more information on this. ii. Norepinephrine is the primary transmitter released by sympathetic nerves iii. Epinephrine is the circulating hormone form of norepinephrine. It is released from the adrenal medulla. Remember: the adrenal medulla has direct synapses between preganglionic sympathetic neurons (releasing acetylcholine) and its chromaffin cells, thus the release of epinephrine into systemic circulation is under direct sympathetic ANS control. 4. Describe the role and responses mediated by adrenergic receptors. (See table 6-‐2 in Katzung). a. Alpha receptors i. α1 – found on postsynaptic effector cells. produces vasoconstriction of smooth muscle, pupillary dilation, and contraction of GI & bladder sphincters. 1. Molecular result of ligand binding: formation of IP3 and DAG, resulting in increased intracellular Ca2+ ii. α2 – According to Kadowitz’s slides, this one is found on postsynaptic effector cells and produces peripheral vasoconstriction in blood vessels. According to Katzung, it’s found on presynaptic adrenergic nerve terminals, platelets, lipocytes and smooth muscle. 1. Molecular result of ligand binding: inhibition of adenylyl cyclase & decreased cAMP | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e E a s i e r ” Introduction to Sympathetic ANS Pharmacology -‐ Part 1 iii. α3 – this neurotransmitter receptor is found on presynaptic nerve terminals. When activated, it decreases CNS sympathetic activity and inhibits the release of norepinephrine. b. Beta receptors i. ß1 – this receptor is found especially in myocardial tissue but also in lipocytes and the brain. 1. When activated, it is inotropic (increases myocardial contractility) and chronotropic (increases heart rate). When activated in high doses, it can cause arrhythmias. 2. It stimulates adenylyl cyclase and increases intracellular cAMP. ii. ß2 – this neurotransmitter is found in postsynaptic effector cells of smooth muscle and cardiac muscle. Its activation stimulates adenylyl cyclase, but in some conditions can activate cardia Gi. iii. ß3 – these are found on postsynaptic effector cells, especially lipocytes. They stimulate adenylyl cyclase, increasing cAMP. 1. ß3 is also found in cardiac tissue, but its function is poorly understood. However, its activation does not appear to result in stimulation of rate or force. c. Dopamine receptors i. D1 (DA1) – located in the brain but also in effector tissues, especially smooth muscle of the renal vascular bed. When activated, D1 stimulates adenylyl cyclase and increases cAMP. ii. D2 – located in the brain & in smooth muscle. D2 causes inhibition of adenylyl cyclase & increased potassium conductance. 5. Describe how adrenergic hormones and receptors regulate cardiovascular function. a. Norepinephrine’s actions are described in LO7 below. b. Epinephrine causes increases in heart rate and contractility, but because it also causes increased vasodilation in skeletal muscle, it acts to decrease peripheral resistance. Thus, mean arterial pressure is not significantly affected by epinephrine. c. Dopamine acts at D1 receptors to produce vasodilation of mesenteric and renal vascular beds. At high doses, dopamine will produce cardiac effects by acting on ß1 receptors (increasing contractility and rate) and alpha2 receptors (vasoconstriction), and thus it is a useful drug in cardiogenic shock / cardiovascular collapse and helps support blood pressure, while maintaining perfusion of the kidneys and GI tract. | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e E a s i e r ” Introduction to Sympathetic ANS Pharmacology -‐ Part 1 6. Describe the function of the adrenergic nerve terminal. a. Adrenergic neurons transport the precursor amino acid tyrosine into the nerve terminal and then they synthesize the catecholamine transmitter. Catecholamines are stored in membrane-‐bound vesicles, transported into the vesicle by vesicular monamine transporter or VMAT (reserpine alkaloids inhibit VMAT!!!!) i. In most preganglionic sympathetic fibers, norepinephrine is the final product. In the adrenal medulla and certain areas of the braine, epinephrine is the final product. In dopaminergic neurons, catecholamine synthesis stops at dopamine. ii. VMAT transports primarily dopamine from the cytosol into the vesicle, but it can also carry norepi or epi into the granule. iii. Once inside the vesicle, dopamine ß hydroxylase converts dopamine to NE. b. Another transporter of the adrenergic nerve terminal is the norepinephrine transporter or NET. This little guy carries norepi and molecules like norepi (read: catecholamines) back into the cell from the synaptic cleft (i.e., it’s a reuptake transporter and is partly responsible for ending synaptic transmission). i. NET is inhibited by cocaine and tricyclic antidepressants. 7. Describe how neuronally released norepinephrine regulates vascular and cardiac function. a. Norepinephrine when slowly infused produces direct effects on both vascular and cardiac muscle. i. It is a powerful vasoconstrictor, increasing peripheral vascular resistance and mean arterial pressure. ii. In the absence of reflex control (e.g., in a heart transplant patient), it is also stimulatory producing increases in heart rate and contractility. However, in a subject with intact reflexes (read: intact baroreceptor reflex), negative feedback causes decreased sympathetic outflow to the heart and a powerful increase in vagal parasympathetic discharge. iii. Thus, in a “normal” patient, the net effect of norepi infusion produces increases in peripheral resistance, increases in arterial pressure, and a consistent slowing of the heart rate. 8. Discuss the actions of drugs that alter adrenergic neuronal function. | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e E a s i e r ” Introduction to Sympathetic ANS Pharmacology -‐ Part 1 a. The laundry list of drugs “covered” in this lecture is covered in Oduche’s noteset on Part 2 of the lecture. He did a good job. Check it out. 9. Describe the inactivation pathways for catecholamines and which drugs affect them. a. Oduche also covered the inactivation pathways in his noteset. | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e E a s i e r ” Introduction to Sympathetic ANS Pharmacology -‐ Part 1 The primary reason I’m so late on turning this in: Best! [email protected] | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e E a s i e r ”

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