Introduction toAutonomic Pharmacology By M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science
Introduction to Autonomic Pharmacology Introduction Nomenclature Neurochemistry of ANS Cholinergic Transmission Adrenergic Transmission Nonadrenergic, Noncholinergic (NANC) Receptor Subtypes, Mechanisms & Functions Regulation of ANS ANS Interaction (the Eye)
Introduction Autonomic Nervous System (ANS) controls involuntary body functions. Sympathetic Fight or Flight Parasympathetic Rest & Digest Enteric nervous system (ENS) is a highly organized collection of neurons in the walls of the GI tract.M.H.Farjoo
A highly simplified diagram of the intestinal wall and some of the circuitry ofthe enteric nervous system (ENS). The ENS receives input from both thesympathetic and the parasympathetic systems and sends afferent impulses tosympathetic ganglia and to the central nervous system. Many transmitter orneuromodulator substances have been identified in the ENS.ACh, acetylcholine; AC, absorptive cell; CM, circular muscle layer; EC,enterochromaffin cell; EN, excitatory neuron; EPAN, extrinsic primary afferentneuron; 5HT, serotonin; IN, inhibitory neuron; IPAN, intrinsic primary afferentneuron; LM, longitudinal muscle layer; MP, myenteric plexus; NE,norepinephrine; NP, neuropeptides; SC, secretory cell; SMP, submucosalplexus.
Nomenclature Synapse is the junction across which a nerve impulse passes from an axon to another neuron. Nerve fibers carrying the signal into a Synapse are: presynaptic. Nerve fibers carrying the signal out of a Synapse are: postsynaptic.M.H.Farjoo
Nomenclature Cont,d Junction is the connection between a neuron and a non neuronal cell (muscle, gland etc). Nerve fibers carrying the signal into a junction are prejunctional. Cells responding to the neuronal signal are postjunctional.M.H.Farjoo
Nomenclature (Cont,d) Ganglion is a group of nerve cells forming a nerve center, especially one located outside the brain or spinal cord. Nerve fibers carrying the signal into a ganglion are: Preganglionic. Nerve fibers carrying the signal out of a ganglion are: Postganglionic.M.H.Farjoo
Nomenclature (Cont,d) The neurons transmitting the neuronal message out of the CNS to the periphery are efferent fibers. The neurons transmitting the neuronal message from periphery to the CNS are afferent fibers. The fibers that control voluntary movements are somatic nerves.M.H.Farjoo
Schematic diagram comparing some anatomic andneurotransmitter features of autonomic and somatic motornerves. Only the primary transmitter substances are shown.Parasympathetic ganglia are not shown because most areof vessels Smooth muscle residing in skeletal musclein or near the wall of the organ innervated. Cholinergicnerves are shown in blue; noradrenergic in red; anddopaminergic in green. Note that some sympatheticpostganglionic fibers release acetylcholine or dopaminerather than norepinephrine. The adrenal medulla, amodified sympathetic ganglion, receives sympatheticpreganglionic fibers and releases epinephrine andnorepinephrine into the blood. ACh, acetylcholine; D,dopamine; Epi, epinephrine; M, muscarinic receptors; N,nicotinic receptors; NE, norepinephrine.
Neurochemistry of ANS Sympathetic and Parasympathetic are anatomic terms. They do not depend on the type of transmitter released nor on the kind of effect (excitatory or inhibitory). A large number of peripheral ANS fibers release acetylcholine; they are Cholinergic fibers. Almost all efferent fibers leaving the central nervous system are cholinergic. Most parasympathetic postganglionic and a few sympathetic postganglionic fibers are cholinergic.M.H.Farjoo
Neurochemistry of ANS Cont,d Receptors that respond to acetylcholine are Cholinoceptors. Most postganglionic sympathetic fibers release norepinephrine (noradrenaline); they are noradrenergic or Adrenergic. Receptors that respond to catecholamines such as norepinephrine are Adrenoceptors.M.H.Farjoo
Neurochemistry of ANS Cont,d Dopamine is released by some peripheral sympathetic fibers. Adrenal medullary cells release a mixture of epinephrine and norepinephrine. Most autonomic nerves also release several cotransmitters in addition to their primary transmitters.M.H.Farjoo
Schematic illustration of a generalized cholinergic junction (notto scale). Choline is transported into the presynaptic nerveterminal by a sodium-dependent choline transporter (CHT).This transporter can be inhibited by hemicholinium drugs. Inthe cytoplasm, acetylcholine is synthesized from choline andacetyl Co-A (AcCoA) by the enzyme choline acetyltransferase(ChAT). Acetylcholine is then transported into the storagevesicle by a second carrier, the vesicle-associated transporter(VAT), which can be inhibited by vesamicol. Peptides(P), adenosine triphosphate (ATP), and proteoglycan are alsostored in the vesicle. Release of transmitter occurs whenvoltage-sensitive calcium channels in the terminal membraneare opened, allowing an influx of calcium. The resultingincrease in intracellular calcium causes fusion of vesicles withthe surface membrane and exocytotic expulsion ofacetylcholine and cotransmitters into the junctional cleft (seetext). This step can be blocked by botulinum toxin.Acetylcholines action is terminated by metabolism by theenzyme acetylcholinesterase. Receptors on the presynapticnerve ending modulate transmitter release.SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.
Cholinergic Transmission Release of transmitter is dependent on calcium and occurs by the action potential. The acetylcholine release is blocked by botulinum toxin.M.H.Farjoo
Cholinergic Transmission Cont,d Acetylcholinesterase splits acetylcholine into choline and acetate thereby terminates the action of the transmitter. The half-life of acetylcholine in the synapse is within seconds. Acetylcholinesterase is also found in RBC. Butyrylcholinesterase (pseudocholinesterase) has a lower specificity for acetylcholine and is found in blood, plasma, liver & glia.M.H.Farjoo
Schematic diagram of a generalized noradrenergic junction (not toscale). Tyrosine is transported into the noradrenergic ending orvaricosity by a sodium-dependent carrier (A). Tyrosine is converted todopamine (see Figure 6–5 for details), and transported into the vesicleby the vesicular monoamine transporter (VMAT), which can be blockedby reserpine. The same carrier transports norepinephrine (NE) andseveral other amines into these granules. Dopamine is converted to NEin the vesicle by dopamine--hydroxylase. Physiologic release oftransmitter occurs when an action potential opens voltage-sensitivecalcium channels and increases intracellular calcium. Fusion ofvesicles with the surface membrane results in expulsion ofnorepinephrine, cotransmitters, and dopamine--hydroxylase. Releasecan be blocked by drugs such as guanethidine and bretylium. Afterrelease, norepinephrine diffuses out of the cleft or is transported intothe cytoplasm of the terminal by the norepinephrine transporter(NET), which can be blocked by cocaine and tricyclicantidepressants, or into postjunctional or perijunctional cells.Regulatory receptors are present on the presynaptic terminal.SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associatedmembrane proteins.
Adrenergic Transmission Metyrosine can inhibit adrenergic transmission. A carrier for catecholamines located in the vesicle wall (vesicular monoamine transporter, VMAT) is inhibited by the reserpine. Reserpine causes depletion of transmitter stores.M.H.Farjoo
Adrenergic Transmission (Cont,d) Norepinephrine transporter, NET carries norepinephrine back into the cell from the synaptic cleft (uptake 1). NET is inhibited by cocaine and TCAs, resulting in increased transmitter activity in the synaptic cleft.M.H.Farjoo
Metabolism of catecholamines by catechol-O-methyltransferase (COMT) andmonoamine oxidase (MAO).
Adrenergic Transmission (Cont,d) Tyramine, amphetamines, and ephedrine, can release stored transmitter from noradrenergic nerve endings. These drugs are poor agonists (some are inactive) at adrenoceptors, but they are excellent substrates for monoamine transporters. They are taken up into noradrenergic nerve endings by NET where they displace norepinephrine. Amphetamines also inhibit monoamine oxidase that result in increased norepinephrine activity.M.H.Farjoo
Nonadrenergic, Noncholinergic (NANC) Gut, airways, bladder contain nerve fibers which is neither cholinergic nor adrenergic. Peptides are the most common transmitter found in NANC fibers. NOS, CGRP, GRP, 5HT, cholecystokinin, VIP, d ynorphin, enkephalins, NPY, somatostatin, and substance P is also found. Some neurons contain as many as five different transmittersM.H.Farjoo
Major Autonomic Receptor TypesReceptor Name Result of Ligand BindingCholinoceptors Muscarinic M Formation of IP and DAG, increased Ca2+ Opening of potassium channels, inhibition of Muscarinic M adenylyl cyclase Muscarinic M Like M receptor-ligand binding Muscarinic M Like M receptor-ligand binding Muscarinic M Like M receptor-ligand binding Nicotinic NN Opening of Na K channels, depolarization Nicotinic NM Opening of Na K channels, depolarization
Major Autonomic Receptor TypesReceptor Name Result of Ligand BindingAdrenoceptors Alpha Formation of IP and DAG, increased Ca2+ Alpha Inhibition of adenylyl cyclase, decreased cAMP Beta Stimulation of adenylyl cyclase, increased cAMP Beta Stimulation of adenylyl cyclase, increased cAMP Beta Stimulation of adenylyl cyclase, increased cAMP
Major Autonomic Receptor TypesReceptor Name Result of Ligand BindingDopamine receptors D ,D Stimulation of adenylyl cyclase Inhibition of adenylyl cyclase; increased D potassium conductance D Inhibition of adenylyl cyclase D Inhibition of adenylyl cyclase
Sympathetic ParasympatheticOrgan Action Receptor Action ReceptorEye Iris radial muscle Contracts a Iris circular muscle Contracts M Ciliary muscle [Relaxes] b Contracts MHeart Sinoatrial node Accelerates b ,b Decelerates M Ectopic pacemakers Accelerates b ,b Decreases Contractility Increases b ,b M (atria)Blood vessels Skin, splanchnic vessels Contracts a Skeletal muscle vessels Relaxes b [Contracts] a Relaxes M Endothelium Releases EDRF M ,M
Sympathetic ParasympatheticOrgan Action Receptor Action ReceptorBronchiolar smooth muscle Relaxes Contracts MGastrointestinal tract Smooth muscle Walls Relaxes Contracts M Sphincters Contracts Relaxes M Secretion Increases MGenitourinary smooth muscle Bladder wall Relaxes Contracts M Sphincter Contracts Relaxes M Uterus, pregnant Relaxes Contracts Contracts M Penis, seminal vesicles Ejaculation Erection M
Regulation of ANS The ANS is regulated in three different ways: Presynaptic Regulation Postsynaptic Regulation Physiologic reflexesM.H.Farjoo
Presynaptic Regulation Some receptors are located on the presynaptic neurons and are activated by the neurotransmitter released from the same neuron. The presynaptic receptors that respond to their own neurotransmitter are called Autoreceptors. Autoreceptors are usually (not always) inhibitory. Somatic motor fibers, have excitatory nicotinic autoreceptors.M.H.Farjoo
Presynaptic Regulation Cont,d The α2 receptor is an inhibitory autoreceptor which diminishes further release of norepinephrine. The presynaptic receptors activated by the transmitters of other neurons are called Heteroreceptors. Heteroreceptors usually have a modulating effect on neurotransmitter release. Presynaptic regulation by a variety of endogenous chemicals occurs in all nerve fibers.M.H.Farjoo
Postsynaptic Regulation Up- and down-regulation of the receptors occurs in response to decreased or increased activation, respectively. An extreme form of up-regulation occurs after denervation of some tissues (denervation supersensitivity).M.H.Farjoo
Physiologic Reflexes In heart In the absence of reflexes (in a patient with heart transplant) norepinephrine increases heart rate and contractile force. with intact reflexes, the net effect of norepinephrine is an increase in arterial pressure, and slowing of heart rate.M.H.Farjoo
Autonomic and hormonal control ofcardiovascular function. Note that two feedbackloops are present: the autonomic nervoussystem loop and the hormonal loop. Thesympathetic nervous system directly influencesfour major variables: peripheral vascularresistance, heart rate, force, and venous tone. Italso directly modulates renin production (notshown). The parasympathetic nervous systemdirectly influences heart rate. In addition to itsrole in stimulating aldosteronesecretion, angiotensin II directly increasesperipheral vascular resistance and facilitatessympathetic effects (not shown). The netfeedback effect of each loop is to compensatefor changes in arterial blood pressure.Thus, decreased blood pressure due to bloodloss would evoke increased sympathetic outflowand renin release. Conversely, elevatedpressure due to the administration of avasoconstrictor drug would cause reducedsympathetic outflow, reduced renin release, andincreased parasympathetic (vagal) outflow.
ANS Interaction (the Eye) Contraction of the ciliary muscle, which occurs with cholinesterase inhibitor is called cyclospasm. Ciliary muscle contraction also facilitates outflow of the aqueous humor a very useful result in patients with glaucoma. Alpha adrenoceptors mediate contraction of the dilator muscle fibers in the iris and result in mydriasis. Beta-adrenoceptors on the ciliary epithelium facilitate the secretion of aqueous humor. Beta blockers provide another therapy for glaucoma.M.H.Farjoo
Structures of the anterior chamber of theeye. Tissues with significant autonomicfunctions and the associated ANSreceptors are shown in this schematicdiagram. Aqueous humor is secreted bythe epithelium of the ciliary body, flowsinto the space in front of the iris, flowsthrough the trabecular meshwork, andexits via the canal of Schlemm (arrow).Blockade of the adrenoceptors associatedwith the ciliary epithelium causesdecreased secretion of aqueous. Bloodvessels (not shown) in the sclera are alsounder autonomic control and influenceaqueous drainage.