Physiologic considerations of Sympathetic system

Classify Nervous system Central Nervous system - Brain; Spinal cord Peripheral Nervous system ( efferent) Somatic ( Voluntary control) Autonomic ( Involuntary control) Sympathetic Parasympathetic

Name the neurotransmitters (NT) in somatic ANS and the respective receptors Nerve fibre Organ supplied NT Receptor Somatic Skeletal muscle Acetylcholie (Ach) Nicotinic (Nm) Parasympathetic & Ganglia & Ach Nicotinic ( Nn) Sympathetic Preganglionic Adrenal medulla Postganglionic Visceral organs Ach Muscarinic parasympathetic (M) Postganglionic Visceral organs Nor adrenaline (NA) , sympathetic Adrenal medulla (into Visceral organs Adrenaline (Ad) , blood circulation)

List the steps involved in neuronal transmission Impulse conduction Transmitter release Transmitter action of Postjunctional membrane Post junctional activity Termination of transmitter action

How the action of NT is terminated? Ach- action terminated by metabolism by the enzyme acetyl cholinesterase (AChE) present in the synaptic cleft. There is an enzyme pseudocholinesterase ( PChE) in the plasma, liver, the physiological function of which is not known. Since the Ach released by the nerve ending is immediately metabolized hence no Ach in blood circulation for PChE to metabolize it. NA: action is terminated by axonal uptake and subsequently vesicular uptake or metabolism by Monoamino oxidase (MAO) enzyme in the axonal cytoplasm. NA in the synaptic cleft can diffuse into blood and metabolized by liver enzyme catecholamine-omethyltransferase (COMT)& MAO. Ad & NA released by adrenal medulla are metabolized by COMT & MAO in liver.

Axonal Uptake

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State the physiological importance of Autonomic responses Cholinergic responses meant for Rest & Digest ( Digestion & Absorption of nutrients) Adrenergic responses meant for Fight or Flight - Pupillary dilatation (1) to see properly ; cardiac output (1) to maintain blood supply to myocardium, brain and skeletal muscle; bronchodilatation for more Oxygen supply; skeletal muscle function supported by increased blood supply (2vasodilatation) and energy production (2 glycogenolysis)

 State the chemical transmitters involved in adrenergic functions Noradrenaline (Norepinephrine) is the neurotransmitter secreted by the sympathetic nerve endings to the synaptic cleft to act at 1 & 2 & 1receptors. Adrenaline is the hormone released by the adrenal medulla (a modified ganglion without postsynaptic fibres). Adrenaline from blood will act at 2 receptors which are not located with sympathetic nerve terminals and also can diffuse into the synaptic cleft and act at 1& 1receptors Dopamine, a precursor of both Adrenaline & Nor adrenaline is a neurotransmitter at adrenergic nerve terminals supplying splanchnic and renal vascular smooth muscle

Actions of Noradrenaline / Adrenaline at different receptors 1 Vasoconstriction Mydriasis 2 pre synaptic NE release pre synaptic Ach release Sympathetic outflow from brain medulla 1 Heart rate Myocardial contractility AV conduction 2 Vasodilatation Bronchodilatation

Bladder sphincter muscle, liver closure glycogenolysis GIT spincter Renal rennin Relaxation of uterine closure release smooth muscle Livergluconeogenesis Ejaculation male genital D1 receptors- vasodilatation of mesenteric and renal blood vessels

Flight & Fight - Adrenergic Responses

Pharmacology of Adrenergic Receptor Agonists

Classify adrenergic receptor agonists (drugs) / sympatho mimetic (SM) drugs SM drugs are basically classified based on structure Catecholamines & Noncatecholamines What is the therapeutic significance of this structural difference? Catecholamines are inactive by oral rout as metabolized by GIT MAO & COMT so only injected; Even when injected by IV route has few minutes of action because of metabolism by liver MAO & COMT; where as Non cate cholamines can be given by oral route and when injected have long duration of action. Can still cross BBB unlike catecholamines. Noncatecholamines are once again classified on receptor specific action.

Catecholamines Adrenaline Dopamine Dobutamine

Noncatecholamines 1-Selective agonists 2-Selective agonists 2-Selective agonists

List the therapeutic uses of Adrenaline with basis 1. Anapahylactic shock: Purpose is to maintain BP Basis: In anaphylactic shock, antigen-antibody reaction leads to severe vasodilatation, there is drastic fall in BP so the perfusion to vital organs is cut off. Adrenaline when injected IV (1:10000 solution) or IM (1,1000 solution) increases cardiac output (1) thereby maintains BP and perfusion to vital organs. Anaphylactic mediators can also bring about bronchoconstriction relieved by Adrenaline (2mediated bronchodilatation). Anaphylactic reactions can result in edema of mucosa because of capillary dilatation that can be relieved by Adrenaline (1mediated vasoconstriction) 2. Cardiac arrest: Purpose is to maintain cardiac rhythmicity Electrocution and salt water drowning can stop heart suddenly due to stop in pacemaker activity. 0.1/ml Adrenaline injected into the cardiac ventricular lumen maintains rhythm city of myocardium by 1 activation. In anaphylactic shock, since blood is not in movement in blood vessels, IV injection does not help for the drug to reach myocardium. So need to inject directly into heart 3. Adrenaline when applied on mucosa (1:100,000) brings about 1 vasoconstriction decreases bleeding. Can be used in nasal bleeding

4. Used along with a local anesthetic (1:100,000) during minor surgeries: Adrenaline (1)vasoconstriction decreases the washing away of local anesthetic (LA) from the site of injection into blood circulation hence prolongs the duration of action of LA at the site of surgery. In the first two conditions, Adrenaline is a life saving drug. Whereas in the last two cases, Adrenaline is not life saving ; use otptional so one must weigh the benefits of using it over the risks ( hypertensive crisis; cardiac arrhythmias; cerebral hemorrhage)

What are the therapeutic uses of Dopamine Dopamine is used in Cardiogenic shock, septic shock to maintain BP In these conditions, because of renal vasoconstriction, renal blood flow is compromised. Dopamine at doses 5 -10 microgram/ Kg/ min infusion- 1 mediated increase in CO and maintaining BP and renal vasodilatation (D1receptor). At higher doses, Dopamine (1) renal blood vessels and precipitate acute renal failure. So dose needs to be titrated carefully. Adrenaline should not be used to maintain BP as it is further going to constrict renal blood vessels (1) and precipitate acute renal failure.

What are uses of Dobutamine Cardiogenic shock, septic shock Acute cardiac failure- to maintain BP Dobutamine acts at 1 & 1 receptors. Maintains BP. (Advantage) Dobutamine produces less of tachycardia compared to Dopamine. (Disadvantage) Dobutamine produces renal vasoconstriction , so whenever renal blood flow is drastically decreased, Dopamine is preferred over Dobutamine

Name 1 receptor selective agonists & Uses Methoxamine, Phenylephrine, Ephedrine: During spinal anesthesia, due to blockade to sympathetic outflow ( lumbar) to blood vessel, vasodilatation takes place resulting in fall of BP. These drugs (IV) route) bring about 1 mediated vasoconstriction that helps to rise BP. Pseudoephedrine, Phenyl propanolamine: used by oral route to decrease mucosal

edema of nasal mucosa in rhinitis. In rhinitis, there is inflammation of nasal mucosa and vasodilatation in nasal mucosa resulting in edema. Vasoconstriction by these drugs decrease the fluid movement from vascular compartment to extra vascular space and there by decreases edema. Xylometazoline, Naphazoline (Nasal de congestants) : used as nasal drops to decrease mucosal edema of nasal mucosa in rhinitis. Prolonged use can result in atrophic rhinitis and also rebound rhinitis on stopping List 2-Selective agonists and their therapeutic use Salbutamol, Terbutaline; Salmeterol These drugs bring about 2-receptor bronchodilatation hence used in treatment of bronchial asthma ( will be discussed during a separate class in respiratory module)

List 2-Selective agonists and uses Clonidine; Methyl dopa Used in treatment of hypertension to bring down BP Physiological regulation of BP involves baroceptor reflex pathway. Rise in BP stretches the baro receptors of carotid sinus and aortic arch which send impulses to vasomotor center (VMC) of medulla. VMC inhibits (Noradrenaline acts at 2 receptor) sympathetic flow to Heart (CO) and blood vessels (vasodilatation) both leading to BP. This is the physiological regulation of BP. This VMC inhibition of sympathetic outflow involves NA activation of 2receptors in medulla The above 2 drugs act at the same 2 receptors at VMC in place of nor adrenaline resulting in decreased sympathetic outflow and fall in BP.

Baro receptor reflex regulation of BP

Methyldopa Clonidine agonists

Medulla

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2 selective agonists Slabutamol, Terbutaline Agonist at 2 receptors in bronchial smooth muscle bronchodilatation. Used in treatment of bronchial asthma

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