Central Autonomic Nervous System Review Exam #1 PDF

Central Autonomic Nervous System - The autonomic nervous system along with the endocrine system involuntarily coordinates the regulation and integration of bodily functions. o Endocrine system: sends signals to target tissues via blood borne hormones. o Nervous system: sends signals via transmission...

Central Autonomic Nervous System - The autonomic nervous system along with the endocrine system involuntarily coordinates the regulation and integration of bodily functions. o Endocrine system: sends signals to target tissues via blood borne hormones. o Nervous system: sends signals via transmission of electrical impulses over nerve fibers terminating at effector cells. Therefore, all autonomic biological processes are regulated by the following: 1. Hormones - 2. Neurotransmitter 3. Local Mediators Autonomic drugs: Produce their effect by mimicking or altering the functions of the autonomic nervous system. o By stimulating or blocking the actions of autonomic nerves - The nervous system is divided in two anatomical divisions: o Central Nervous System: § Brain § Spinal Cord o Peripheral Nervous System: Neurons located outside of the brain and spinal cord – that is any nerves that enter or leave CNS. § Efferent Neurons Carry messages from the brain and spinal cord to peripheral tissues. Can be voluntary (somatic) or involuntary (autonomic) § Afferent Neurons Carry messages from peripheral tissues to the CNS. Provide sensory input to modulate the function of the efferent division. - The efferent division is further divided into: o Somatic Efferent Neurons § Involved in voluntary control of actions (ej. Movement of Skeletal muscle) § Receptors: Nicotinic o Autonomic system (aka. visceral, vegetative or involuntary) § Regulates vital bodily functions without conscious participation of the mind. § Composed of efferent neurons that innervate smooth muscle - - Brain anatomy: o In the brain the grey matter is superficial and white matter is underneath, in the spinal cord it is inversed. o Outer brain is more advanced brain. o Internal brain is the primitive. o Most cranial nerves are found in the brain stem (III-XII), EXCEPT for II (optic nerve). o In the spinal cord: § Anterior = Efferent § Posterior = Afferent § Cervical disk – 8 § Thoracic disk – 12 § Lumbar disk – 5 § Sacral disk – 5 Anatomy of the ANS Typically, a two-neuron structure is found in the autonomic nervous system Afferent neurons: The afferent neurons of the ANS are important in the reflex regulation, and in signaling the CNS to influence the efferent branch of the system to respond. o - Efferent neurons: The ANS carries nerve impulses from the CNS to the effector organs by two types of efferent neurons: o 1st - preganglionic neuron: its cell body is located within the CNS with its cell body in the lateral horn of the gray matter of the spinal cord or in the brainstem they emerge from the brainstem or spinal cord and make a synaptic connection in ganglia *(an aggregation of nerve cell bodies located in the peripheral nervous system) its axon in an autonomic ganglion where it synapses with one or more postganglionic neurons 2nd - postganglionic neuron: § The cell body originating in the ganglion - § Nonmyelinated and terminates on effector organs The efferent ANS is divided into the sympathetic, parasympathetic, and enteric nervous system: oSympathetic neurons: (thoracolumbar division) § Preganglionic neurons come from thoracic and lumbar regions (T1 to L2) of the spinal cord (Lateral horns) § The preganglionic neurons are shorter, and highly branched, allowing many interactions § the postganglionic and axons extend to tissues § Anatomically designed to produce widespread physiological activity § 3 trayectory neurons: in eye and adrenal medulla § Receptors: adrenergic oParasympathetic neurons: (craniosacral division) § Preganglionic neurons in brain stem § arise from: cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus) the sacral region (S2 to S4) of the spinal cord § Synapse in ganglia near or on the effector organs. § Preganglionic fibers are long, and the postganglionic are short and innervate most of the organs in the thoracic and abdominal cavity § Anatomically designed to produce respond on an organ basis § Receptors: cholinergic, more specifically muscarinic (M3) - Functions of the sympathetic nervous system Primarily, adjust in response to stressful situations, such as trauma, fear, hypoglycemia, cold, and exercise - Effects of stimulation of the sympathetic division: o Increase heart rate and blood pressure, to mobilize energy stores of the body, o Increase blood flow to skeletal muscles and the heart o Diverting flow from the skin and internal organs. - Fight or flight response: o Changes experienced by the body during emergencies o Triggered by direct sympathetic activation of the effector organs and stimulation of the adrenal medulla to release epinephrine and lesser amounts of norepinephrine o Hormones released by the adrenal medulla directly enter the bloodstream and promote responses in effector organs that contain adrenergic receptors - Functions of the parasympathetic nervous system Involved with maintaining homeostasis within the body. Acts to oppose or balance the actions of the sympathetic division dominant over the sympathetic system in “rest and digest” situations discrete parasympathetic fibers are activated separately and functions to affect specific organs - Role of the CNS in the control of autonomic functions It requires sensory input from peripheral structures, provided by afferent impulses, originating by autonomically innervated structures Responds to the stimuli by sending out efferent reflex impulses via the ANS Reflex arcs: Translation of afferent impulses into reflex responses without involving consciousness. Chemical signaling between cells - Hormones: o Specialized endocrine cells secrete hormones into the bloodstream, exerting effects distributed target cells in the body. - Local Mediators: (Ej. Histamine and Prostaglandins) o Chemicals that act locally o Do not enter the blood and are not distributed throughout the body. Neurotransmitters o All neurons are distinct anatomic units, and no structural continuity exists between them. o Communication occurs through: 1. Release of specific chemical signals from the nerve terminals, triggered by the arrival of the action potential at the nerve ending 2. An increase in intracellular Ca2+ initiates fusion of the synaptic vesicles with the presynaptic membrane and release of their contents. 3. The neurotransmitters rapidly diffuse across the synaptic cleft, or space (synapse), between neurons. 4. They combine with specific receptors on the postsynaptic (target) cell. - [Note: A receptor is defined as a recognition site for a substance. It has a binding specificity and is coupled to processes that eventually evoke a response. Most receptors are proteins.] - - o Types of neurotransmitters: § Most commonly six signal compounds are invloved in therapeutic drugs: 1. norepinephrine (and the closely related epinephrine) 2. acetylcholine 3. dopamine 4. serotonin 5. histamine 6. γ-aminobutyric acid (GABA) o Acetylcholine and norepinephrine are the primary chemical signals in the ANS § released on nerve stimulation o Acetylcholine: § If transmission is mediated by acetylcholine, the neuron is termed cholinergic § Mediates the transmission of preganglionic nerve impulses across autonomic ganglia in both the sympathetic and parasympathetic nervous systems. § Neurotransmitter at the adrenal medulla § Transmission from the autonomic postganglionic nerves to the effector organs in the parasympathetic system o Norepinephrine and epinephrine: § When norepinephrine or epinephrine is the transmitter, the fiber is termed adrenergic § Mediates the transmission of nerve impulses from autonomic postganglionic nerves in sympathetic nervous system. Effector Receptors Innervation: o Most effector organs receive dual innervation (constitutive innervation) o Both working in opposition (balanced) the one exerting the greater function will prevail Specific effects: 1. Bloods vessels o Mainly innervated by sympathetic system, maintain, smooth muscle tone 2. Heart o Sympathetic system: Beta 1 receptor § Positive chronotropic (heart rate) – frequency of contraction § Positive inotropic (force of contraction) § Positive dromotropic (conductivity) o Parasympathetic system § Negative inotropic § Negative dronotropic 3. Cardiovascular reflex o Mainly due to stretch receptors (carotid body) effects on cardiovsacular center at Medulla oblongata 4. Eye (Pupil, Lens) o Sympathetic system (mydriasis) § Dilator innervation contracts – dilator pupillae (radial fibers) § Sympathomimic would contract the dilator o Parasympatheic system (miosis) § Sphinter innervation contracts - Constrictor pupillae (circular fibers) § At rest the suspensory ligaments of cilliary body exerts tension flattening the lens § Under parasympathetic stimuli the cilliary body contracts decreasing tension on the lens thickening the lens due to elasticity accommodating for near vision § Parasympatholitic drug would inhibit acetocholine relaxing the sphinter 5. Lung: (Bronchial tree is dually innervated) o Sympathetic system: Beta 2 Agonist receptor § Bronchodilation o Parasympatehtic system § Bronchoconstriction 6. Gastrointestinal tract o Dual effects but act on local neural regulators § Enkephalins – Counter act substance P § Substance P – Sensations mediation § Vasoactive intestinal peptide o Paraympathetis – Bowel Movements o Sensations - Sympathetic 7. Salivary glands o Dual stimulation produce secretion with different characteristics § Sympathetic stimuli Thick and mucinous § Parasympathetic stimuli Watery 8. Adrenal medulla o Behaves as a sympathetic ganglion producing primarily epinephrine, then norerpinephrine. o Impulse initiates at hypothalamus Adrenergic Agonist Agents - The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. - Sympathomimetic - adrenergic drugs that act directly on the adrenergic receptor (adrenoceptor) by activating it. - Sympatholytics - block the action of the neurotransmitters at the receptors II. THE ADRENERGIC NEURON - Adrenergic neurons release norepinephrine as the primary neurotransmitter. - They are found in the central nervous system (CNS) and also in the sympathetic nervous system - Serve as links between ganglia and the effector organs. - The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs A. Neurotransmission at adrenergic neurons - Norepinephrine is primary neurotransmitter for post ganglionic sympathetic adrenergic nerves. - It is synthetized inside the nerve axon, stored within vesicles, then released when an action potential travels down the nerve. - The process involves five steps: 1. Synthesis of norepinephrine: - Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) - This is the rate-limiting step in the formation of norepinephrine. DOPA is decarboxylated to form dopamine. 2. Storage of norepinephrine in vesicles: - Dopamine is transported into synaptic vesicles. - Dopamine is hydroxylated to form norepinephrine. - Note: Synaptic vesicles contain dopamine or norepinephrine, as well as other cotransmitters. - In the adrenal medulla, norepinephrine is methylated to yield epinephrine - On stimulation, the adrenal medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation. 3. Release of norepinephrine: - An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron - The increase in calcium causes vesicles to fuse with the cell membrane and expel (exocytose) their contents into the synapse - Drugs such as guanethidine block this release 4. Binding to receptors: - Norepinephrine released from the synaptic vesicles diffuses across the synaptic space - Binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. - The membrane receptors trigger a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as transducers between the neurotransmitter and the action generated within the effector cell. - Adrenergic receptors use the cyclic adenosine monophosphate (cAMP) second- messenger system and the phosphatidylinositol cycle to transduce the signal into an effect. - Norepinephrine also binds to presynaptic receptors that modulate the release of the neurotransmitter. 5. Removal of norepinephrine: - Norepinephrine may: 1) Diffuse out of the synaptic space and enter the general circulation 2) Be metabolized to O-methylated derivatives in the synaptic space 3) Be recaptured by an uptake system that pumps the norepinephrine back into the neuron The uptake by the neuronal membrane involves a sodium or potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine. Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine’s effects. 6. Potential fates of recaptured norepinephrine: - Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may: 1) Be taken up into adrenergic vesicles and be sequestered for release by another action potential 2) Persist in a protected pool in the cytoplasm 3) Be oxidized by monoamine oxidase (MAO). The inactive products of norepinephrine metabolism are excreted in urine as vanillylmandelic acid, metanephrine, and normetanephrine. B. Adrenergic Receptors: - In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically - Two families of receptors, designated α and β, identified by their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol 1. α1 and α2 Receptors:*****KNOW THESE BY HEART***** - The α-adrenoceptors are responsive to the naturally occurring catecholamines epinephrine and norepinephrine - For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol. - The α-adrenoceptors are sub-divided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs. a. α1 Receptors: These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects: Constriction of smooth muscle Vasoconstriction Increased peripheral resistance Increased Blood Pressure Mydriasis – Dilator muscle Increased closure of internal urinary bladder sphincter b. α2 Receptors: Control adrenergic neuromediator and insulin output respectively - These receptors are located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas and on certain vascular smooth muscle cells Inhibition of Insulin release Feedback inhibition of norepinephrine release. Reducing sympathetic neuromediator output when there is high sympathetic activity. [Note: In this instance, these receptors are acting as inhibitory autoreceptors.] 2. β Receptors: Isoproterenol > epinephrine > norepinephrine - The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3, based on their affinities for adrenergic agonists and antagonists - β1 receptors have approximately equal affinities for epinephrine and norepinephrine - β2 receptors have a higher affinity for epinephrine than for norepinephrine, particularly responsive to epinephrine released by the adrenal medulla. 3. Distribution of receptors: - Tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate The heart contains predominantly β1 receptors. III. Mechanism of action of the adrenergic agonists 1. Direct-acting agonists: - These drugs act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla. - Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, and phenylephrine. 2. Indirect-acting agonists: - Include amphetamine, cocaine, and tyramine, may block the uptake of norepinephrine (uptake blockers) - Are taken up into the presynaptic neuron, causing the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron - The norepinephrine then traverses the synapse and binds to the α or β receptors. - Examples of uptake blockers and agents that cause norepinephrine release include cocaine and amphetamines, respectively. 3. Mixed-action agonists: Some agonists, such as ephedrine and its stereoisomer, pseudoephedrine, have the capacity both to stimulate adrenoceptors directly and to release norepinephrine from the adrenergic neuron. Not important right now. IV. DIRECT-ACTING ADRENERGIC AGONISTS - Direct-acting agonists bind to adrenergic receptors without interacting with the presynaptic neuron. - The activated receptor initiates synthesis of second messengers and subsequent intracellular signals. As a group, these agents are widely used clinically. - There are five catecholamines: 1. Epinephrine – naturally occurring neurotransmitter 2. Norepinephrine - naturally occurring neurotransmitter 3. Dopamine - naturally occurring neurotransmitter 4. Dobutamine – Synthetic compound 5. Isoproterenol – Synthetic compound A. Epinephrine - Epinephrine is synthesized in the adrenal medulla and released, with small quantities of norepinephrine, into the bloodstream. - Epinephrine interacts with both α and β receptors. - At low doses, β effects (vasodilation) on the vascular system predominate - At high doses, α effects (vasoconstriction) are strongest. 1. Actions: a. Cardiovascular: The major actions are on the cardiovascular system increasing cardiac output and oxygen demand: Strengthens the contractility of the myocardium (positive inotropic: β1 action) Increases its rate of contraction (positive chronotropic: β1 action) Constricts peripheral arterioles in the skin, mucous membranes, and viscera; increased renal blood flow (α1 effects) Dilates peripheral vessels going to the liver and skeletal muscle (β2 effects) b. Respiratory: Bronchodilation by acting directly on bronchial smooth muscle (β2 action). Rapidly relieves dyspnea (labored breathing) and increases tidal volume (volume of gases inspired and expired). Inhibits the release of allergy mediators such as histamines from mast cells. c. Hyperglycemia: Increased glycogenolysis in the liver (β2 effect) Increased release of glucagon (β2 effect) Decreased release of insulin in pancreas (α2 effect). d. Lipolysis: Initiates lipolysis of adipose tissue (β3) 2. Biotransformation: Epinephrine is metabolized by two enzymatic pathways: MAO and COMT Final metabolites found in the urine are metanephrine and vanillylmandelic acid. 3. Therapeutic uses: a. Bronchospasm: Primary drug used in the emergency that bronchoconstriction has resulted in diminished respiratory exchange: § acute asthma § anaphylactic shock β2 agonists, such as albuterol, are favored in the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory effect. b. Glaucoma Open Angle 2% sol – Decreases IOP by increasing uveoscleral outflow c. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of symptoms in Type I hypersensitivity reactions in response to allergens. d. Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest regardless of the cause. e. Anesthetics: Solutions contain 1:100,000 parts epinephrine, to increase the duration of the local anesthesia, due to vasocontricting effects 4. Pharmacokinetics: Rapid onset but a brief duration of action (due to rapid degradation). The preferred route is intramuscular (anterior thigh) due to rapid absorption In emergency situations, is given intravenously (IV) or subcutaneously for the most rapid onset of action Oral administration is ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes 5. Adverse effects: CNS disturbances: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor. Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of blood pressure. Cardiac arrhythmias: Epinephrine can trigger cardiac arrhythmias Pulmonaryedema: Epinephrine can induce pulmonary edema *Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions, because cocaine prevents reuptake of catecholamines into the adrenergic neuron. Thus, epinephrine remains at the receptor site for longer periods of time B. Norepinephrine - When given in therapeutic doses, the α-adrenergic receptor is most affected, there is no β clinical effects. 1. Actions: a. Cardiovascular: Vasoconstriction: Rise in peripheral resistance due to intense vasoconstriction of most vascular beds. § including the kidney (α1 effect). § Both systolic and diastolic blood pressures increase b. OjO: Norepinephrine causes greater vasoconstriction than epinephrine, because there is no compensatory vasodilation via β2 receptors.*Remember no β clinical effects Baroreceptor reflex: Norepinephrine stimulates cardiac contractility in isolated tissues. § HOWEVER, in vivo little cardiac stimulation is noted. § Due to the increased blood stimulating the baroreceptors. § This reflex bradycardia is sufficient to counteract the local actions of norepinephrine on the heart Interaction with atropine: (for tx of acute hypotension in a hemodynamically unstable px) When atropine, is given before norepinephrine, stimulation of the heart by norepinephrine causes tachycardia. When atropine, is given after norepinephirne, it acts as a pre-treatment for acute hypotension c. Therapeutic uses: Norepinephrine is used to treat shock, because it increases vascular resistance and, therefore, increases blood pressure. d. Pharmacokinetics Norepinephrine may be given by IV for rapid onset of action. The duration of action is 1 to 2 minutes following the end of the infusion period. It is poorly absorbed by subcutaneous injection Destroyed in the gut if administered orally. Metabolism is similar to that of epinephrine. e. Adverse Effects Blanching and sloughing of skin du eto extreme vasoconstriction C. Isoproterenol - Direct-acting synthetic catecholamine that stimulates both β1- and β2-adrenergic receptors. - Rarely used therapeutically 1. Actions: a. Cardiovascular: β1 Increased cardiac output - Via (+chronotropic) and (+ inotropic) Tx of atrioventricular (AV) block or cardiac arrest Decreased peripheral resistance. b. Pulmonary: Bronchodilation 2. Therapeutic uses: Used to stimulate the heart in emergency situations. D. Dopamine - Occurs naturally in the CNS in the basal ganglia and adrenal medulla. - Can activate α- and β-adrenergic receptors. Higher doses - Vasoconstriction by activating α1 receptors, Lower doses - Stimulates β1 cardiac receptors. - D dopaminergic receptors: D1 § In the peripheral mesenteric, renal, cerebral and coronary vascular beds § Binding of dopamine produces vasodilation D2 § Found on presynaptic adrenergic neurons § Binding of dopamine inhibits with norepinephrine release. 1. Actions: a. Cardiovascular: Stimulatory on the β1 receptors of the heart, + inotropic and + chronotropic effects Activates α1 receptors, resulting in vasoconstriction. b. Renal and visceral: Dilates renal and splanchnic arterioles by activating dopaminergic receptors 2. Therapeutic uses: Drug of choice for cardiogenic and septic shock Raises the blood pressure by stimulating the β1 receptors Enhances perfusion to the kidney and splanchnic areas § Increased blood flow to the kidney enhances the glomerular filtration rate and causes sodium diuresis. Tx of hypotension and severe congestive heart failure 3. Adverse effects: Nausea, hypertension, and arrhythmias, short-lived. E. Fenoldopam - Agonist of peripheral dopamine D1 receptors, and it has moderate affinity for α2 receptors - Rapid-acting vasodilator to treat severe hypertension in hospitalized patients - Administered via IV infusion - Adverse side effects: Headache, flushing, dizziness, nausea, vomiting, and tachycardia F. Dobutamine - Direct acting β1 receptor agonist - Increases cardiac rate and output with few vascular effects ( + inotropic) - Used in Congestive Heart Failure to increase Cardiac Output (CO) G. Oxymetazoline - Stimulates both α1- and α2-adrenergic recepors. - Primarily used in the eye or the nose as a vasoconstrictor - Found in many over-the-counter short-term nasal spray decongestant products, as well as in ophthalmic drops for the relief of redness of the eyes H. Phenylephrine - Binds primarily to α1 receptors. - Vasoconstrictor - Raises both systolic and diastolic blood pressures. - Used topically on the nasal mucous membranes and in ophthalmic solutions for mydriasis I. Clonidine - α2 agonist - Used in essential hypertension to lower blood pressure (diminish central adrenergic flow) J. Beta 2 Agonist (Bronchodilators) – Used with Steroids - Metaproterenol - Albuterol - Terbutaline (also, off label uterine relaxant for suppression of premature labor) - Salmeterol - Formoterol V. INDIRECT-ACTING ADRENERGIC AGONISTS - Indirect-acting adrenergic agonists cause norepinephrine release from pre-synaptic terminals - or inhibit the uptake of nor-epinephrine A. Amphetamine - Central stimulatory action - Increase blood pressure by α1-agonist action - β-stimulatory effects on the heart B. Tyramine - Not a clinically useful drug - Found in fermented foods, such as aged cheese and Chianti wine C. Cocaine - Blocks the Na+/K+-activated ATPase (required for cellular uptake of norepinephrine) on the cell membrane of the adrenergic neuron. - Consequently, norepinephrine accumulates in the synaptic space, resulting in enhancement of sympathetic activity and potentiation of the actions of epinephrine and norepinephrine. - Like amphetamines, it can increase blood pressure by α1-agonist actions and β-stimulatory effects. VI. MIXED-ACTION ADRENERGIC AGONISTS - Mixed-action drugs induce the release of norepinephrine from presynaptic terminals, and they activate adrenergic receptors on the postsynaptic membrane - Enhanced sympathetic system may cause: Arrythmia, Headaches, Hyperactivity, Insomnia, Nausea, Tremors A. Ephedrine and pseudoephedrine - Directly stimulate both α and β receptors - Ephedrine: § Raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation § Enhances contractility and improves vasomotor in Myasthenia Gravis - Pseudoephedrine: § Primarily used orally to treat nasal and sinus congestion § Alternative drug for shock tx § May be used to treat acute hypotension in hospital settings