Introduction to ANS Pharmacology Dr. Kaukab Azim + Dr. Hanin Osama 1

NS Central – Brain – Spinal cord Peripheral – Afferent (sensory) – Efferent (motor, autonomic ) 2

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ANS Regulates Involuntary Functions Blood pressure Heart rate Respiration Body Temperature Glandular Secretion Digestion Reproduction 4

The ANS facilitates immediated physical reactions associated with a preparation for violent muscular action. Acceleration of heart and lung action Paling or flushing, or alternating between both. Inhibition of stomach and upper intestinal action (digestion slows down or stops) Liberation of nutrients for muscular action Dilation of blood vessels for muscles Inhibition of Lacrimal gland and salivation Dilation of pupil 5

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Sympathetic SystemParasympathetic System Originates in thoracic and lumbar regions of the spinal cord (T1 – L2) Originates in brainstem (cranial nerves III, VII, IX, and X) and sacral region of spinal cord (S2 – S4) Ganglia located in paravertebral sympathetic ganglion chain Terminal ganglia located near or embedded within target tissue Short pre-ganglionic fibers Long postganglionic fibers Long pre-ganglionic fibers Short postganglionic fibers Ratio of pre-ganglionic fiber to post- ganglionic fibers is 1 : 20 Ratio of pre-ganglionic fibers to postganglionic fibers is 1 : 3 Activity often involves mass discharge of entire system Activity normally to discrete organs Primary neurotransmitter of postganglionic neurons is norepinephrine Primary neurotransmitter of postganglionic neurons is acetylcholine Predominates during emergency “fight-or- flight” reactions and exercise Predominates during quiet resting conditions Divergence coordinates activity of neurons at multiple levels of spinal cord Limited divergence 7

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4 Sympathetic Parasympathetic Pre-ganglionic Blue Post-ganglionic Pink Pre-ganglionic Red Post-ganglionic Green III VII IX X – Vagus Nervi erigentes III VII IX X VII Ciliary Pterygopalatine Submandibular Otic All preganglionic nerves secrete Ach. Ganglionic blocking drugs block transmission. (e.g.Mecamylamine) 8

AcetylcholineNorepinephrineEpinephrine Site of release All preganglionic neurons of ANS; all postganglionic neurons of parasympathetic system; Some sympathetic postganglionic neurons to sweat glands Most sympathetic postganglionic neurons; adrenal medulla (20% of secretion) Adrenal medulla (80 % of secretion) Receptor Nicotinic (Nn or Nm), Muscarinic (M1, M2, M3, M4, M5) - cholinergic α1, α2, β1 (adrenergic) α1, α2, β1, β2 (adrenergic) Termination of activity Enzymatic degradation by cholinesterase Reuptake into nerve terminals; diffusion of synaptic cleft, metabolic transformation by monoamine oxidase (within nerve terminal) or cahechol-O-methyl- transferase within liver) Metabolic transformation by catechol-O- methyl- transferase within liver 9

Location of cholinergic transmission All autonomic ganglia Voluntary muscles (neuromuscular junction) Adrenal medulla (secretion of adrenaline) Post ganglionic parasympathetic Post ganglionic sympathetic to sweat glands 10

Acetyl Choline (Ach) Synthesis: At the nerve terminals CAT (choline acetyl transferase), From Choline 50% of it, is recaptured by nerve terminals 11

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Potential targets for drugs Five key features of neurotransmitter function provide potential targets for pharmacologic therapy: synthesis, storage, release, termination of action of the transmitter, functions of the receptor. 13

Parasympathomimetic 14

Effects of Muscarinic agonists A. Cardiovascular system Slow heart rate (negative chronotropy) Decreases conduction velocity and increases refractory period Bradycardia and vasodilatation lead to drop in BP Vasodilatation of arteries and veins due to stimulation of M3 receptors in the endothelium, releasing NO 15

Continue… B. RESPIRATORY Bronchio-spasm increase secretion C. GIT Increase peristalsis Increase secretions mainly salivary and gastric Sphincters are relaxed 16

Continue… D. GU Stimulation of detrusor muscle and Relaxation of the trigone and sphincter of the bladder thus promote micturition. E. Eye Causes contraction of the smooth muscle of the iris causing miosis and of the ciliary muscle (accommodation of near vision) It will facilitate the outflow of aqueous humor into the canal of Schlemn which drains the anterior chamber 17

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Continue… F. Exocrine gland Increased their secretion, sweating, lacrimation and salivation G. CNS Ach is widely distributed in the brain It is a excitatory neurotransmitter in the basal ganglia Its effect include; increased locomotor activity tremor 19

Nicotinic agonists A.Peripheral nervous system Activation of nicotinic receptors in the autonomic ganglia result in firing action potential in postganglionic neurons The action is same on both sympathetic and parasympathetic ganglia 20

B. NMJ Application of nicotine agonist in NMJ leads to depolarization of the endplate The response vary from fasciculation of independent motor units to a strong contraction of entire motor unit. 21

MUSCARINIC ANTAGONIST Atropine Scopolamine Ipratropium Pirenzepine 22

Pharmacological action Muscarinic antagonist 1- CNS: Atropine in therapeutic doses has a minimal stimulant effect on CNS and a slower-long lasting sedative effect on the brain Scopolamine has more marked CNS effects producing drowsiness in recommended doses In high doses scopolamine and to a lesser extent atropine causes agitation, excitement, hallucination and coma 23

2- eye: Mydriasis Cycloplegia leads to loss of accommodation of near vision (eye can not focus on near objects) Reduction of lacrimal secretion, dry eyes 24

3- CVS: The initial effect is bradycardia followed by tachycardia The initial bradycardia is often with lower doses and is due to blockade of presynaptic M1 muscarinic receptors on vagal nerve, thus facilitate Ach release The tachycardia is due to blockade of M2 receptors in the SAN Therapeutic doses of atropine is abolishes peripheral vasodilatation induced by cholinomimetics. 25

4- Respiratory system: Antimuscarinic drugs are added to general anesthetics to reduce secretion in the trachea 5- GIT marked reduction in salivary secretion (dry mouth) Gastric secretion is blocked less effectively. 26

6-GU: Smooth muscle of the uterus is relaxed Bladder wall is relaxed and voiding is slower 7- sweat glands Sweat gland secretions are blocked by antimuscarinic drugs, thermoregulation is suppressed leading to increase in body temperature. 27

Nicotinic antagonists A) neuromuscular blockers : 1- depolarizing NMJ blocking drugs; the depolarizing blockers first depolarize the motor end-plate and then prevent further depolarization. E.g. Succinylcholine 2- non-depolarizing NMJ blocking drugs; compete with acetylcholine for receptors at the neuromuscular junction and clinical relaxation begins when 80–85% of the receptors on the motor end-plate are blocked. tubocurarine 28

Ganglion blocking drugs B. Ganglion blocking drugs can occur by several mechanisms: – By interfering with Ach release – By prolonged depolarization due to large dose of stimulation – By interfering with postsynaptic action of Ach. 29

ADRENERGIC AGONIST & ANTAGONIST 30

SYMPATHOMIMETICS Classification: A- According to the source: 1.Natural; NE, EP, DA 2.Synthetic; isoproternol, ephedrine, amphetamine B- chemically: 1.Catecholamines; NE, EP, DA and isoproternol 2.Non catecholamines; ephedrine, amphetamine, tyramine 31

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α1 found in the smooth muscle of many organs and they cause contraction of the blood vessels, relaxation of the GIT and glycogenlysis α2 found in presynaptic neuron,CNS, blood vessels, it inhibit transmitter release, in addition they cause platelets aggregation and blood vessel contraction. If found postsynaptically work as α1 β1 mainly in the heart,stimulation result in an increase cardiac out put and heart rate β2 present in the smooth muscle of many organs and its stimulation lead to bronchodilation, perpherial vasodilation, relaxation of the visceral smooth muscle and skeletal muscle tremor 33

PHARMACOLOGYCAL EFFECTS OF SYMPATHOMIMETIC 1- Cardiovascular system The overall effects on blood vessels depend on the relative activities of the sympathomimetics at α or β receptor. α1; increase arterial resistance β2 receptors promote smooth muscle relaxation β1: Activity of both normal (SAN) and abnormal (purkinje fibers) is increased (positive chronotropic effects). Contractility is increased (positive inotropic effects) 34

2. eye: Activation by α1 agonist causes mydriasis α1- agonists increases the outflow of aqueous humor from the eye, while β antagonists decreases the production of the aqueous humor. These effects are beneficial in treatment of glaucoma. 3. Respiratory Activation of β2 receptors in the bronchial muscle results in bronchiodilatation. 35

4. GU In human uterus the β2 receptors mediate relaxation that might be useful during pregnancy. The bladder base, urethral sphincter and prostate contain α receptors that mediate contraction and therefore promote urinary continence. 5. effects on endocrine function Insulin secretion is stimulated by β receptors and inhibited by α2 Renin secretion is stimulated by β1 and inhibited by α2 36

6- Metabolic effect Activation of β3 receptors in fat cells leads to increased lipolysis. Sympathomimetics enhances glycogenolysis in the liver that leads to increased glucose release into the circulation (mediated mainly by β2) Activation of β2 receptors promotes uptake of potassium into cells, leading to fall in extracellular potassium.. Carbohydrates metabolism in the muscle and liver is enhanced 37

α-blocker Selective α1 (prazosin): – Vasodilation – Hypotension Selective α2 (yohimbine) – Increase nor adrenaline release and cause sympathomimetic effect – Can block α2 in blood vessel and cause vasodilatation 38

Non selective α-blockers – Phenoxybenzamine, phentolamine – Vasodilatation – Reduce blood pressure 39

β-blocker Non selective: – Propranolol, labetalol Selective – Atenolol, metoprolol – Reduce HR (-ve chronotropic) – Reduce force of heart contraction (-ve ionotropic) 40