Introduction to Autonomic Pharmacology PDF

Introduction to Autonomic Pharmacology Michael Parker Ph.D. Dept. of Pharmacology Ext. 21357 Email: [email protected] Two major systems control body function: nervous system and the endocrine system. Endocrine system: chemical transmitters are hormones which are released...

Introduction to Autonomic Pharmacology Michael Parker Ph.D. Dept. of Pharmacology Ext. 21357 Email: [email protected] Two major systems control body function: nervous system and the endocrine system. Endocrine system: chemical transmitters are hormones which are released into the circulation where they find and bind to receptors on the effector tissues. The endocrine system regulates slower, more generalized adaptations. Hormones in the circulation act at distant sites over periods of minutes to hours or even days. Nervous system: signals are transmitted at points of contact between neurons and effector tissues (neurons, muscle, glands etc.), these contacts are called synapses. A chemical transmitter is released from presynaptic neuron terminals where it diffuses across the synaptic cleft and binds to receptors on the postsynaptic cell either activating or inhibiting the activity of that cell. Through locally released neurotransmitters the nervous system is responsible for rapid adjustments to changes in the organism’s environment. Nervous system The efferent (outgoing signals) portion of the nervous system can be divided into two main divisions: Autonomic nervous system (ANS) and the Somatic nervous system. The autonomic nervous system operates without conscious control and regulates visceral functions necessary for life. Primarily effects 3 tissue types: Smooth muscle, Cardiac Muscle and exocrine glands. Other types of tissue effected include: nerves and endothelium. The somatic nervous system regulates consciously controlled voluntary movements. Both the somatic and autonomic systems receive sensory or afferent (incoming signals) information which provide sensation and can modify efferent outputs. (reflex arcs). Some basic differences between the Somatic and Autonomic Nervous systems are: Somatic vs. Autonomic Nervous Systems Somatic nervous system: Autonomic nervous system: Regulates consciously controlled functions Regulates autonomic functions without direct o Movement conscious control o Respiration o Heart o Posture o Glands Cell bodies within the cerebrospinal axis o Visceral organs result in spinal efferent nerves o Smooth muscle In the periphery it consists of Spinal efferents form synapses in peripheral ganglia o Nerves (myelinated) Ganglia o Neuromuscular junction (NMJ) o Preganglionic nerves No ganglia: Peripheral synapses occur on o Postganglionic nerves (generally non- skeletal muscle myelinated) o NMJ o Plexuses (complex networks of synapses) Interruption of spinal efferent nerves results in Some spontaneous activity independent of intact paralysis and atrophy innervation Drugs that mimic or block the effects of transmitters at efferent and afferent neuronal synapses can be used to selectively modify the autonomic functions of many tissues such as cardiac 1 muscle, smooth muscle, exocrine glands, vascular endothelium, and presynaptic nerve terminals. Due to the complexity and integration of the autonomic nervous system, many drugs that are used for other purposes can have unwanted effects on autonomic function. Therefore, in order to fully understand the desirable and unwanted effects of drugs affecting the autonomic nervous system it is necessary to thoroughly comprehend the structure and function of the autonomic nervous system. Anatomic divisions of the Autonomic Nervous system There are two main anatomic divisions of the autonomic nervous system the sympathetic and parasympathetic. Remember, this distinction is anatomical not functional, however, most of the time the two divisions function in opposition to each other. Efferent neurons leave the CNS and enter the periphery bundled in nerves (i.e. the Vagus) on their approach to the target or effector tissue. Efferent projections consist of two neurons between the CNS and the effector tissue; preganglionic neurons and postganglionic neurons. Preganglionic neuron cell bodies are located in central nuclei; the axonal projections from these neurons exit the CNS from either the brain stem or spinal cord and terminate in motor ganglia (collection of neuron cell bodies). All preganglionic neurons are cholinergic (that is they synthesize and release acetylcholine (ACh)). ACh is released at synapses within the ganglia where it binds to and activates nicotinic acetylcholine receptors located on the postsynaptic neuron. Postganglionic neurons, in turn, send their axonal projections from the motor ganglia to the target organs where they modify the function of that tissue. Innervation of Effector Tissue Parasympathetic Medulla M: Parasympathetic: “craniosacral” ACh Cardiac and smooth muscle, gland cells, nerve terminals ACh M: Sympathetic: Sweat glands NE α, β: Sympathetic: Sympathetic Cardiac and smooth “thoracolumbar” muscle, gland cells, nerve DA D1: Sympathetic: Renal vascular smooth muscle Spinal cord ACh Nm: Somatic: Skeletal muscle Voluntary motor nerve The Peripheral Nervous System Sympathetic (Thoracolumbar) division Preganglionic sympathetic axon fibers arise mainly from the intermediolateral columns of the spinal cord and exit from the CNS through thoracic and lumbar nerves, thus the name thoracolumbar. These axons synapse with neurons lying outside the cerebrospinal axis in sympathetic ganglia. Sympathetic ganglia are found in three locations: paravertebral, prevertebral and terminal. There are 22 pairs of paravertebral ganglia which are connected by nerve trunks and form the lateral chains on either side of the vertebral column. The 2  prevertebral ganglia are located on the ventral surface of the vertebral column and include the celiac, superior mesenteric, aorticorenal and inferior mesenteric ganglia. There are a few terminal ganglia which tend to lie near the organ they innervate like the urinary bladder, the rectum and the cervical ganglia. o The majority of sympathetic ganglia have a great deal of interconnectivity, and the preganglionic axons are short, this structure allows for full and rapid activation of the sympathetic system. The majority of sympathetic postganglionic fibers release norepinephrine (NE) and are termed adrenergic. However, there are some sympathetic fibers that release different neurotransmitters. For example, sympathetic fibers innervating sweat glands release ACh which binds to muscarinic receptors and postganglionic neurons innervating renal vascular smooth muscle release dopamine (DA). In addition to the primary neurotransmitter many of these sympathetic fibers release other chemically active transmitters, or co-transmitters, like ATP, neuropeptide Y (NPY) and Substance P. A unique sympathetic connection is found in the adrenal medulla. The adrenal medulla is actually a modified sympathetic ganglion whose preganglionic sympathetic fibers form synapses on the adrenal chromaffin cells within the adrenal medulla. These neurons release acetylcholine which binds to nicotinic receptors (like those found in ganglia) on the surface of the chromaffin cells resulting in the secretion of epinephrine (85%) and norepinephrine (15%) into the circulation. Parasympathetic (Craniosacral) division Preganglionic parasympathetic fibers arise from the midbrain, the medulla oblongata and the sacral region of the spinal cord. These fibers exit the CNS from either the Cranial nerves (III, VII, IX, or X) or the sacral spinal roots. Most of these fibers terminate on ganglion cells distributed diffusely or in networks within the walls of the innervated organs (e.g. cardiac ganglia). Some of the preganglionic parasympathetic fibers terminate in ganglia just outside of the organs they innervate (e.g. ciliary or submandibular). The anatomy of the parasympathetic system is designed so that individual target organs can be activated independently. In the same fashion as the sympathetic system preganglionic fibers release ACh which binds to nicotinic acetylcholine receptors. In contrast to the sympathetic system parasympathetic system postganglionic fibers the vast majority release ACh (a few exceptions) which binds to muscarinic receptors on the target organ and elicit a response. Somatic nervous system The somatic nervous system is distinct from the Autonomic nervous system because its primary purpose is to regulate consciously controlled functions like movement, respiration and posture. Neurons arising from the cerebrospinal axis synapse directly on skeletal muscle at a specialized synaptic structure known as the neuromuscular junction (NMJ). There are no ganglia in this system. The long, myelinated neurons forming direct contacts on muscle tissue allow for discreet and rapid responses necessary for voluntary movement. The cell bodies of somatic motor neurons are in the ventral horn of the spinal cord. The axon of a single neuron forms multiple branches which innervate more than 100 individual muscle fibers; this is referred to as a motor unit. The somatic neurons are cholinergic and secrete ACh on postsynaptic muscle cells which express nicotinic acetylcholine receptors (nAChRs). ACh binds to and activates the postsynaptic nAChRs which stimulate muscle contraction. While the somatic system is distinct from the autonomic system, some agents used to modify autonomic function may affect receptors at the NMJ. 3  The enteric nervous system (ENS) This is often considered a third division of the autonomic nervous system. It is a complex web of neurons found in the wall of the gastrointestinal (GI) tract. This web of neurons is divided into two plexuses the myenteric plexus and the submucosal plexus. Although the parasympathetic and sympathetic systems innervate and modulate the ENS, it can maintain proper GI function autonomously. Cell bodies within the plexuses control smooth muscle motility and the activity of secretory cells. Sensory information arising from the walls of the GI tract is relayed to the parasympathetic and sympathetic nervous systems which can then act to modulate GI activity. However, be clear about the fact that the ENS can function normally in the absence of any parasympathetic or sympathetic innervation. Reflex Arcs As mentioned above both the somatic and autonomic nervous systems receive sensory or afferent neuron inputs. The afferents projecting from the effector tissue into the CNS provide sensation which can directly modify the function of effector tissues through reflex arcs. For example, the effector tissue receives a stimulus (e.g. hot stove) the afferent neuron synapses in the spinal chord either directly with the efferent motor neuron or an interneuron which then stimulates the appropriate response from the effector tissue (e.g. pull your hand away). This is an example of a somatic nervous system reflex, the same situation occurs in the autonomic nervous system with the integration occurring at higher levels of the CNS in the medulla oblongata and the hypothalamus. For example, baroreceptors in the carotid sinus (also in the aortic arch) can detect changes in blood pressure and through reflex arcs within nuclei of the medulla alter the autonomic output controlling the heart and blood vessels thus rapidly compensating for potentially life threatening changes in blood pressure. Neurotransmission in the Autonomic nervous system Aside from anatomical divisions the autonomic nervous system can be divided into groups based on the neurotransmitters used (cholinergic, adrenergic, dopaminergic). A large number of peripheral nervous system fibers release acetylcholine and are termed cholinergic. The cholinergic neurons in the autonomic and somatic nervous systems include: 1. All preganglionic neurons (both parasympathetic and sympathetic) 2. All somatic motor neurons 3. Postganglionic parasympathetic fibers (not all some use nitric oxide or peptides) 4. Postganglionic sympathetic fibers that innervate sweat glands a. Receptors at the postsynaptic side of these synapses are activated by ACh and are called acetylcholine or cholinergic receptors. The cholinergic receptors are either muscarinic (M, g-protein coupled) or nicotinic (N, ion channel) Important Cholinergic receptors in the peripheral nervous system: Receptor Location Mechanism Major function M1 Nerve endings Gq ↑ IP3 and DAG: M2 Heart/nerve ending Gi ↓ cAMP: activates K+ channels slow AV/SA node, ↓ neuro-transmitter release M3 Effector cells: smooth Gq ↑ IP3 and DAG: contraction/secretion/ NO muscle/glands/endothelium release NN (neuronal) ANS postganglionic Na+-K+ ion channel Depolarization evokes Action Potential neurons NM (muscle) Neuromuscular Junction Na+-K+ ion channel Depolarization evokes Action Potential 4  Neurons that release norepinephrine (NE) or epinephrine (Epi) are termed adrenergic. Most sympathetic post ganglionic neurons are adrenergic. Postsynaptic receptors at these synapses are called adrenergic receptors. Within the sympathetic nervous system there are neurons that release dopamine (DA) these are referred to as dopaminergic neurons and they bind to dopaminergic receptors on postsynaptic effector tissues. Important Adrenergic receptors in the peripheral nervous system: Receptor Location Mechanism Major function α1 Effector tissues: smooth muscle Gq ↑ IP3 and DAG ↑[Ca+2] Contraction/secretion glands α2 nerve endings/smooth muscle Gi ↓ cAMP ↓ transmitter release/ contraction of some smooth muscle β1 Cardiac muscle/kidney Gs ↑ cAMP ↑ Heart rate, ↑ force; ↑ renin release β2 Smooth muscle/liver/heart Gs ↑ cAMP Relax smooth muscle; ↑ glycogenolysis; ↑ heart rate, force β3 Adipose cells Gs ↑ cAMP ↑ Lipolysis D1 Smooth muscle Gs ↑ cAMP Relax renal vascular smooth muscle Drugs can modify the autonomic function by either activating (agonists) or blocking (antagonists) the function of all of these postsynaptic receptors. At both adrenergic and cholinergic presynaptic terminals drugs can also alter function at many steps involved in synaptic transmission. Sympathomimetics Agents that cause the same physiological responses as endogenous catecholamines Norepinephrine, epinephrine or dopamine are referred to as sympathomimetics. There are many drugs in this class with a variety of mechanisms. Direct acting sympathomimetics: albuterol, epinephrine, phenylephrine etc. directly activate adrenergic receptors as agonists. Indirect acting sympathomimetics: tyramine, amphetamine, cocaine, tranylcypromine, antidepressants too indirectly increase catecholamine (NE, DA) release through multiple different mechanisms. Function of the Autonomic nervous system The integration of the two divisions of the autonomic nervous system is vitally important to the survival of an organism. The autonomic nervous system regulates the activity of systems that are not under voluntary conscious control like respiration, digestion, circulation, temperature, metabolism, secretions or sweating. The sympathetic and parasympathetic systems work in tandem; synergistically or antagonistically. The parasympathetic system maintains the body’s ability to rest, recover and gain energy; also known as “rest and digest.” During times of stress the sympathetic system provides the energy required for extremes in physical activity known as the “fight or flight response.” Under normal or resting conditions there is some sympathetic activity (referred to as tone), however at rest parasympathetic tone predominates. 5 a. The sympathetic division is normally continuously active, although the amount of activity varies from moment to moment allowing for continuous adjustments in organ function in response to a changing environment. The sympathetic system is not absolutely required for sustaining life, but its absence would be acutely felt in a stressful situation. The sympathetic division can be activated in toto as an all or none response (highly interconnected) and is designed to cope with stressful situations. The “fight or flight response” is triggered when a perceived threat or stress (hypoglycemia, exercise, trauma etc.) stimulate norepinephrine release from neurons in the locus ceruleus which increases sympathetic outflow and ultimately results in the release of NE directly on target organs and the secretion of epinephrine and norepinephrine from the adrenal medulla into the circulation. In addition, cholinergic (sweat) fibers are also stimulated. The presence of NE and EPI in the general circulation and NE release from nerve terminals simultaneously activates sympathetic effector tissues resulting in the following effects:  Increases blood pressure, heart rate and respiration  Increases blood supply to skeletal muscle, brain, lungs and heart  Decreased blood supply to viscera  Pupil dilation  Bronchiole dilation  Piloerection  Energy: stimulation of glycogenolysis, gluconeogenesis and lipolysis  Reduced blood flow to GI, kidney and Skin  Sweat (cholinergic) b. The parasympathetic division is responsible for rest and recovery and generally has the opposite effects of the sympathetic division. At rest parasympathetic tone predominates and is indispensable for maintaining life. It operates through distinct actions to regulate basic bodily functions like digestion and excretion. Activation of the entire parasympathetic division at one time would not result in a favorable outcome as is the case with poisons like the organophosphates (e.g. sarin or Malathion; cholinesterase inhibitors). Activation of the parasympathetic division causes the following symptoms:  Lowers blood pressure  Lowers heart rate  Diverts blood to skin, GI and kidneys  Contracts pupils and bronchioles  Increases peristalsis  Empties the urinary bladder and rectum  Increases salivary gland secretion The below responses are for you to review the drugs and how they contribute to the physiologic outputs of the effector organs. Do not memorize but use as a reference. Functional regulation of different organ systems: The symptoms described above for the sympathetic and parasympathetic nervous systems are diverse and widespread due to the variety of adrenergic and cholinergic receptors in conjunction 6 with the receptors’ widespread and differential expression patterns. The following outlines the effects of sympathetic and parasympathetic activation of different organ systems and the receptors that mediate these responses. (So agonists of theses receptors will have the following actions). 1. Eye Pupillary response Sympathetic contracts radial muscle—dilation (mydriasis) α1 Parasympathetic contracts circular/sphincter muscle constriction (miosis) M3 Lenticular response (accommodation) Sympathetic Relaxes ciliary muscle--- far vision β2 Parasympathetic Contracts ciliary muscle--- near vision M3 Aqueous humor Sympathetic Increased secretion of aqueous humor from ciliary epithelium; Increases intraocular pressure β2 Decreased production of aqueous humor (Ciliary epithelium) (lowers IOP) α2 Parasympathetic Contraction of ciliary muscle increases the pressure on the trabecular meshwork, opening its pores, increasing the outflow of aqueous humor into the canal of Schlemm resulting in a decrease in intraocular pressure M3 2. Heart Sinoatrial node Sympathetic Accelerates heart rate (+ly chronotropic) β1 Parasympathetic Decelerates heart rate (-ly chronotropic) M2 Atria Sympathetic Increase contractility and conduction velocity β1 Parasympathetic Decrease contractility and shortened action Potential duration M2 Atrioventricular node Sympathetic Increased automaticity and conduction velocity β1 Parasympathetic Decreased conduction velocity; AV block M2 Ectopic pacemakers (can cause irregular beats) Sympathetic Accelerates heart rate β1 Parasympathetic no effect 7 Contractility Sympathetic Increases force of contraction (+ly inotropic) β1 Parasympathetic Decreases in atria only M2 3. Blood vessels Skin and splanchnic vessels Sympathetic Contracts α1 Parasympathetic no effect Skeletal muscle vessels Sympathetic Relaxes β2 Parasympathetic no effect Endothelium Sympathetic No effect Parasympathetic Relaxes vasodilation M3 (Release of nitric oxide or EDRF (endothelium derived relaxing factor) from endothelium diffuses to muscle where it activates guanylyl cyclase increasing cGMP inhibiting Ca+2 release from the SR and preventing muscle contraction. This can only be caused by circulating cholinergic agonists since there is no cholinergic innervation.) 4. Lung Bronchiolar and Tracheal smooth muscle Sympathetic Relaxes, bronchodilation β2 Parasympathetic Contraction, bronchoconstriction M3 5. Gastrointestinal tract Smooth muscle walls Sympathetic Relaxation; this relaxation might be due to a presynaptic α2, β2 inhibition of ACh release in the parasympathetic terminals Parasympathetic Contraction—increased peristalsis M3 Smooth muscle sphincters Sympathetic Contraction α1 8  Parasympathetic Relaxation M3 6. Genitourinary smooth muscle Bladder wall Sympathetic Relaxation β2 + β3 Parasympathetic Contraction M3 Sphincter Sympathetic Contraction α1 Parasympathetic Relaxation M3 Uterus Sympathetic Relaxes (non-pregnant this dominates) β2 Contracts (only in pregnant state) α1 Parasympathetic variable effects Male sexual organ Sympathetic Ejaculation α1 Parasympathetic Erection (NO release) M3 7. Skin Eccrine (Thermoregulatory) Sweat glands Sympathetic increases M3 Parasympathetic no effect Apocrine (Stress) Sweat glands Sympathetic increases α1 Parasympathetic no effect 8. Metabolic functions Liver Sympathetic Stimulates Gluconeogenesis and glycogenolysis β2 Parasympathetic no effect Pancreas 9  Sympathetic Islets (B cell) Decreased secretion α2 Islets (B cell) Increased secretion β2 Generally speaking activation of the autonomic nervous system (trauma, hypothermia etc) will activate α2s and decrease insulin secretion Parasympathetic Acini (increased secretion) M3 Fat cells Sympathetic Lipolysis β3 Parasympathetic no effect Kidney Sympathetic Increased renin secretion β1 Kidney Sympathetic Dilation of renal blood vessels D1 (maintains blood flow) Parasympathetic no effect 9. Autonomic nerve endings Presynaptic receptors These act to decrease neurotransmitter release; thus regulating themselves and the opposing autonomic division. Sympathetic terminals Autoreceptor: α2 (Decreased NE release) Heteroreceptor: M2 Parasympathetic terminals Autoreceptor: M2 (Decreased ACH release) Heteroreceptor: α2 Central nervous system connections with the autonomic nervous system: There is some control at the level of the spinal cord since after a spinal injury some autonomic function is still intact. However, there is control higher than the level of the spinal cord including the medulla oblongata and the hypothalamus, which is considered the principal loci of autonomic integration. Afferent sensory input reaches these integrating centers in the CNS which respond by sending reflex efferent motor signals to the appropriate tissues. These reflex arcs are extremely important compensatory mechanisms which can be triggered by drug action and thus must be considered when administering autonomic drugs. Baroreceptors in the heart: An important example of autonomic reflex arcs is found in the heart. There are receptors in the carotid sinus (baroreceptors) which detect changes in mean arterial pressure. A slow infusion of norepinephrine (NE, agonist of alpha and beta adrenergic receptors) in a patient can directly cause vasoconstriction and stimulate the heart (increases rate and contractile force). However, vasoconstriction leads to increased peripheral resistance and thus an increase in mean arterial pressure. This increase in mean arteriole pressure is detected by baroreceptors which in turn trigger 10 a decrease in sympathetic outflow and an increase in parasympathetic outflow to the heart. Therefore, the net effect of a NE infusion is an increase in peripheral vascular resistance and mean arterial pressure with a concomitant slowing of the heart (bradycardia) due to increases in parasympathetic output to that organ. Therefore, because of this reflex the action of NE on the heart is the exact opposite of what would be expected from a direct activation of the heart with NE. Consequently, when determining the physiologic responses from the use of autonomic drugs the compensatory effects of the reflex arcs must be considered. 11