What autonomic nervous system (ANS) receptor does this medication target? What is the mechanism of action when these receptors are stimulated?

Transcription

1 CASE 5 A 12-year-old girl is brought to the emergency room with difficulty in breathing. On examination she is found to have dyspnea with audible wheezes and is diagnosed with asthma. The patient is given an inhaled medication (albuterol), which provides immediate relief of the bronchial constrictive symptoms. What autonomic nervous system (ANS) receptor does this medication target? What is the mechanism of action when these receptors are stimulated? What neurotransmitter normally activates these receptors?

2 48 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 5: AUTONOMIC NERVOUS SYSTEM Summary: A 12-year-old girl with an acute asthma exacerbation is given albuterol, a β-agonist sympathomimetic agent. ANS receptor target: β 2 receptors. Mechanism of action: Activation of adenylyl cyclase, increase in cyclic adenosine monophosphate (camp), and relaxation of bronchial smooth muscle, leading to bronchodilation. Neurotransmitter: Norepinephrine (NE). CLINICAL CORRELATION A good understanding of the autonomic nervous system is imperative in treating many medical conditions, such as asthma. Different cells throughout the body have different ANS receptors with differing agonist and antagonist properties, and medications targeting specific receptors can selectively relieve symptoms in particular organs while minimizing side effects that would be mediated by other receptors. The sympathetic β 2 receptor agonist albuterol selectively produces bronchial dilation and thus provides relief from bronchial constrictive disorders such as asthma. However, with some receptors it is not possible to achieve selective targeting because the same receptor is found in diverse organs, and many commonly used drugs act on more than one receptor. For example, propranolol, which is used to treat various cardiac and cardiovascular problems, blocks both β 1 and β 2 receptors. It would be contraindicated in patients with asthma because by blocking β 2 receptors, it would cause bronchial constriction and worsening of a patient s asthma. Many medications have side effects involving the ANS, but these effects can be predicted if one knows the distributions of different autonomic receptors in the body. APPROACH TO AUTONOMIC NERVOUS SYSTEM Objectives 1. Know the organization of the autonomic nervous system (ANS). 2. List the major neurotransmitters of the ANS. 3. Know the receptor types in the ANS. Definitions Parasympathetic nervous system: Division of the autonomic nervous system associated with resting visceral functions (e.g., digestion), defined anatomically by efferent preganglionic axons exiting the CNS via cranial nerves and sacral spinal nerves S 2 to S 4.

3 CLINICAL CASES 49 Sympathetic nervous system: Division of the autonomic nervous system associated with physiological responses to stress, defined anatomically by efferent preganglionic axons exiting the CNS via thoracic and lumbar spinal nerves T 1 to L 3. Enteric nervous system: Division of the autonomic nervous system associated with direct control of gastrointestinal functions, defined anatomically by embedment within the gastrointestinal tract. DISCUSSION Bronchial smooth muscle, like most smooth muscle, cardiac muscle, and glands, is innervated by the ANS. The ANS mediates important homeostatic and emergency functions in a largely involuntary manner. It has three major divisions: the sympathetic, parasympathetic, and enteric nervous systems. The sympathetic and parasympathetic divisions have efferent (output) systems that evoke or modulate contractile, secretory, and metabolic responses throughout the body. The enteric division is a relatively independent nervous system embedded in the gastrointestinal (GI) tract and contains sensory neurons, interneurons, and motor neurons. Although the enteric system can function autonomously, its activity usually is modulated by the sympathetic and parasympathetic systems. The ANS also has central integrative components in the hypothalamus and brainstem autonomic nuclei that receive input from visceral and somatic afferents as well as from more rostral brain regions. In the sympathetic and parasympathetic systems, the final efferent pathway consists of central preganglionic neurons, which synapse onto peripheral postganglionic neurons, which then synapse onto effector cells in target organs. In the sympathetic system, the preganglionic cell bodies are in the intermediolateral column of the spinal cord between levels T 1 and L 3 (thoracolumbar). The postganglionic cell bodies are in either the nearby paravertebral ganglia or the more distant prevertebral ganglia. Each preganglionic sympathetic fiber synapses with many postganglionic neurons across several ganglia, often producing widespread effects. Sympathetic postganglionic neurons usually send very long axons to effector targets. In the parasympathetic system, the preganglionic cell bodies reside in nuclei of the medulla, pons, midbrain, and spinal segments S 2 through S 4 (craniosacral) and send long axons to synapse with relatively few postganglionic neurons in terminal ganglia, which are close to or embedded in the walls of their target organs. Sympathetic and parasympathetic systems usually have opposite effects on visceral targets. Massive activation of the sympathetic system enhances the capacity for immediate physical activity (eg, exercise and fight or flight responses) and enables adaptive responses to physiologic emergencies such as hemorrhage, whereas more localized activation mediates discrete homeostatic reflexes. Parasympathetic activity enhances the functions of organs active during quiescent states

4 50 CASE FILES: PHYSIOLOGY (rest and digest functions) and often mediates actions opposite to those of the sympathetic system in homeostatic reflexes (eg, baroreceptor reflex, pupillary reflex). All preganglionic fibers (sympathetic and parasympathetic) release acetylcholine (ACh) at synapses in autonomic ganglia; the ACh binds to nicotinic receptors and excites postganglionic neurons. Nearly all sympathetic postganglionic neurons release NE onto effector targets. The major exceptions are the Table 5-1 ACTIONS MEDIATED BY AUTONOMIC RECEPTORS IN SELECTED EFFECTOR SYSTEMS* SYMPATHETIC ACTIVITY PARASYMPATHETIC ACTIVITY EFFECTOR ACTION RECEPTOR ACTION RECEPTOR Heart Sinoatrial node Tachycardia β 1, β 2 Bradycardia M Contractility Increase β 1, β 2 Decrease M (atria) Blood vessels Skin, viscera Constriction α 1, α 2 Skeletal muscle Dilation β 2 Sweat glands Secretion, M general Secretion, α 1 palms Bronchial muscle Relaxation β 2 Contraction M Eye Radial muscle, iris Contraction α 1 Sphincter, iris Contraction M Gastrointestinal tract Motility Decrease α 2, β 2 Increase M Secretion Decrease β 2 Increase M Urinary bladder Detrusor Relaxation β 2 Contraction M Trigone, sphincter Contraction α 1 Relaxation M Male sex organs Ejaculation α 1 Erection M * For a more complete list see Katzung (2004).

5 CLINICAL CASES 51 sympathetic fibers innervating most sweat glands, which release ACh (binding to muscarinic receptors), and the cells in the adrenal medulla, which are homologous with sympathetic postganglionic neurons but release epinephrine and some NE into the bloodstream. The major classes of receptors for NE and epinephrine are α 1 (important in blood vessels), α 2 (often on presynaptic terminals of sympathetic postganglionic axons), β 1 (important in the heart), and β 2 (concentrated in bronchial smooth muscle). All parasympathetic postganglionic neurons release ACh, which binds to muscarinic receptors on effector cells. Autonomic effects are often modulatory and are mediated by second messengers. Both muscarinic receptors and adrenergic receptors are metabotropic receptors that often are linked positively or negatively by G proteins to adenylyl cyclase or phospholipase C, which alter camp or Ca 2+ levels in target cells. Table 5-1 lists some of the important autonomic effectors and the physiologic actions of each type of autonomic receptor found in them. COMPREHENSION QUESTIONS [5.1] Which of the following is promoted by parasympathetic activity? A. Airway constriction B. Ejaculation C. Pupillary dilation D. Vasoconstrictor response to hemorrhage E. Secretion of sweat [5.2] Which type of receptor located on sinoatrial (SA) nodal cells mediate an increase in heart rate? A. α B. β C. Muscarinic D. Nicotinic [5.3] Which of following fibers release NE? A. Preganglionic fibers innervating the adrenal medulla B. Postganglionic fibers causing bradycardia C. Postganglionic fibers causing constriction of the iris D. Postganglionic fibers causing arteriolar constriction E. Sympathetic fibers innervating eccrine sweat glands Answers [5.1] A. Parasympathetic fibers release ACh onto muscarinic receptors that cause contraction of bronchiolar smooth muscle. All the other listed effects are produced by sympathetic activation. [5.2] B. Sympathetic fibers release NE onto β 1 and β 2 receptors, which activate adenylyl cyclase, increasing the currents that generate the pacemaker

6 52 CASE FILES: PHYSIOLOGY potential. The other listed receptors are not present in the SA node or decrease heart rate (muscarinic receptors). [5.3] D. Sympathetic fibers release NE onto α 1 receptors in arterioles, which constrict these resistance vessels. The other listed fibers all release ACh, including sympathetic fibers that innervate eccrine sweat glands. PHYSIOLOGY PEARLS The sympathetic and parasympathetic nervous systems are neural systems controlled by integrative regions in the brain, whereas the enteric nervous system has afferent, integrative, and efferent components that allow it to function autonomously (the term autonomic comes from Greek words meaning self-governing ). Massive activation of the sympathetic nervous system is vital for preparing for and responding to physiologic emergencies such as fight or flight situations and hemorrhage. Activation of more restricted parts of the sympathetic nervous system mediates discrete autonomic reflexes such as the baroreceptor reflex and ejaculation. The parasympathetic nervous system exerts more localized control over visceral functions such as digestion, micturition, and many sexual responses. ACh is released by all preganglionic fibers (sympathetic or parasympathetic) and binds to ganglionic nicotinic receptors that rapidly depolarize postganglionic cells. ACh is released by parasympathetic postganglionic fibers and binds to muscarinic receptors on effector cells, which often are coupled through G proteins to phospholipase C (positively) or adenylyl cyclase (negatively). NE usually is released by sympathetic postganglionic fibers and can bind to β 1 or β 2 receptors which are positively coupled to adenylyl cyclase. NE also can bind to α 1 receptors, which are coupled to phospholipase C, or to α 2 receptors, which are negatively coupled to adenylyl cyclase. REFERENCES Katzung BG. Introduction to autonomic pharmacology. In: Katzung BG. Basic and Clinical Pharmacology. New York: McGraw-Hill; 2004: Richerson GB. The autonomic nervous system. In: Boron WF, Boulpaep EL. Medical Physiology. Philadelphia, PA: Elsevier Science; 2003: Weisbrodt NW. Autonomic nervous system. In: Johnson LR. Essential Medical Physiology. San Diego, CA: Elsevier Academic Press; 2003: