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The nervous system is divided into 2 anatomical divisions, the CNS which is composed of brain and spinal cord and the peripheral nervous system, which includes neurones located outside the CNS. The peripheral nervous system can be further subdivided into 3 major divisions: 1- Sensory neurones which involved in carrying various types of sensations to CNS. 2- Somatic neurones which involved in control of voluntary functions e.g. skeletal muscle contraction. 3- Autonomic neurones which involved in control of involuntary functions e.g. smooth mucles, cardiac muscle and exocrine gland functions. From physiological point of view ANS is subdevided into Sympathetic * Heart: . H.R. . Ventricular contraction * Smooth muscles: . Eye . Bronchi . GIT Tachycardia (1) Increase (1) Mydriasis Bronchodilatation (2) Relax wall & contract sphinters ( ) . Urinary bladder Urine retention ( ) . Blood vessels Vasoconstriction ()and * Secretions: dilatation () . Salivary . Sweat Thick viscid Increase Parasympathetic Bradycardia No effect Miosis Bronchospasm (M) Contract wall & relax sphinters Urination No effect Profuse watery No effect -Usually each organ has double nerve supply except sweat glands and ventricle have sympathetic supply only, while constrictor pupillae muscle and ciliary muscle have parasympathetic supply only. -The parasympathetic tone is usually predominating. CHEMICAL TRANSMITTERS Two chemical transmitters are identified in autonomic nerves namely Acetylcholine & Norepinephrine. I- Adrenergic Receptors: receptors for norepinephrine. Adrenergic Receptors 1 Receptors: -Activation leads to (Actions). *Smooth Muscles: 1-Eye: Contraction of dilator pupillae Active Mydriasis 2-GIT: motility. 3-Urinary bladder: Contract the sphincter. 4-Bl.Vs: Vasoconstriction (especially of skin and mm) peripheral resistence Hypertension. Adrenergic Receptors 1 receptors -Activation leads to (Actions): *Heart: Contractility (+ve Inotropic) HR (+ ve Chronotropic) all cardiac properties AV conduction (+ve Dromotropic) Atrial and ventricular conduction *Smooth Muscles: GIT motility. *Others: Renin release 2 receptors -Activation leads to (Actions): *Heart: Coronary dilatation. *Smooth Muscles: -Bronchi: Bronchodilatation. -GlT: Motility -Urinary bladder: relax wall. -Bl.Vs: Vasodilatatation of skeletal muscle Bl Vs peripheral resistence Hypotension. *Others - Glycogenolysis - Relax wall of pregnant uterus. 3 adrenoceptors (adipose tissue( lipolysis Free fatty acids. Sympathomimitics Definition: Drugs, which stimulate the adrenergic receptors. Classification: *According to chemistry: (contain catechole nucleus): 1.Catecholamines -Natural: Epinephrine, Norepinephrine and Dopamine. -Synthetic: Isoprenaline, dobutamine and hexoprenaline. 2.Non catecholamines: Ephedrine and amphetamine. *According to mechanism of action: 1.Directly acting: Most of them. 2.Indirectly acting amphetamine and tyramine. 3.Dual (mixed) acting: Ephedrine. Epinephrine(Adrenaline) *Actions: Given S.C. and acts on both and adrenergic receptors. *Systemic actions: 1)CVS: - Heart: all cardiac properties (1 effect) CO. -Blood vessels. V.C.of skin and mucous membrane vessels (1 PRBP V.D. of skeletal muscle blood vessels (2) PR BP -Blood pressure: is due to predominence of 1 effect while in small doses due to predominence of 2 effect. 2)Respiratory system: -Bronchodilatation (2) -Decongestion of bronchial mucosa (1) due to VC of broncial blood vessels. 3)Eye: -Active Mydriasisi (1) - I.O.P: due to aqueous formation (VC of ciliary body blood vessels) especially in open angle glaucoma. 4)G.I.T: motility (+). 5) Urinary Bladder: Urine retention due to relaxation of wall(2) and contraction of the sphincter (1) 6)Uterus: relaxes the pregnant uterus (2). *Anti-allergic action: It is the physiological antagonist of histamine, it produces VC while histamine produces VD but both act on 2 different sites. *Metabolic Actions: 1)Hyperglycemia due to: - hepatic gluconeogenesis and glycogenolysis (2). - insulin secretion (2) 2)lipolysis (3). *Therapeutic uses: 1. Allergy: anaphylactic shock and angioneurotic oedema. 2. Intracardiac in CPR (Cardio-Pulmonary Resuscitation). 3. Hemostatic in epistaxis (bleeding per nose). 4. With local anesthetics to - absorption -Prolong duration- toxicity – Hemostatic. *Adverse effects; 1.Tachycardia, palpitation and anginal pains. 2.Hypertension and cerebral hemorrhage. 3.Gangrene if injected with local anesthetics around fingers, toes and in circumcision. 4.Skeletal muscle tremors. *Contraindications: 1.Angina pectoris. 2.Hypertension. 3.Hyperthyroidism as thyroid hormone sensitizes the heart to catecholamines arrhythmia. 4.With Halothane (inhalation anesthetic) arrhythmia. Norepinephrine (Noradnenaline) *Actions: Directly acting sympathomimitic with predominant and 1. *CVS: -Heart:all cardiac properties (1)CO, but the tachycardia is masked by reflex bradycardia mediated via parasympathetic system. -BP: generalized VC of skin & mm PR blood pressure stimulation of baroreceptors in carotid bodies parasympathetic tone to reflex bradycardia. *Other actions: As adrenaline but with predominant actions *.Uses: As hypertensive agent in hypotensive states as in hypovelemic shock with correction of hypovolemia. Isoprenaline *Actions: Directly acting sympathomimitic on both 1 and 2 adrenoceptors. *Uses: -Acute Bronchial asthma (Inhalation). -Heart block. Dopamine *Actions: Directly acting sympathomimitic on , 1 and specific dopaminergic receptors (in renal, mesenteric, coronary and intracerebral blood vessels). *Uses: Cardiogenic, endotoxic and hypovolaemic shock (with correction of hypovolemia). Dobutamine *Actions: Directly acting selective 1 adrenergic sympathomimitc. *Uses: Cardiogenic shock due to acute myocardial infarction. Ephedrine *Actions: -Dual acting sympathomimitic on both and adrenoceptors, but mainly indirect repeated administration tachyphylaxis. 1)Sytemic actions: as Epinenephrine but weaker, slower in onset and longer. 2)CNS actions: Stronger CNS stimulant effect than Epinephrine but weaker than amphetamine. It stimulate the cortex, medullary centers and reticular activating System “responsible for aurosal state” Insomnia. *Theraputic uses: 1-Nasal decongestant. 2-Narcolepsy (hypersomnia). 3-Bronchial asthma. Amphetamine - *Actions: Indirectly acting sympathomimitic i.e. agonist on both and 1 adrenrgic receptors repeated administration tachyphylaxis. - Its actions are similar to Norepinephrine but weaker, slower and longer. - It has a prominent CNS action much stronger than ephedrine, manifested by: 1-Psychic action: euphoria and increase mental activity. 2-Anti-fatigue action: ability for work. 3-Anorexigenic action: the appetite. - Tolerance addiction usually occurs on prolonged use. *Theraputic Uses: 1-Obesity. 2-Narcolepsy. Other Sympathomimitics (1) Selective 1 adrenrgic agonists: Phenylephrine and Methoxamine : used as nasal decongestant, Mydriatic in glaucoma, in hypotensive. Midodrine is methoxamine derivative used orally in chronic hypotension. Naphazoline, xylometazoline, oxymetazoline and tetrahydrozoline: used as nasal decongestant. Pseudoepherdine : OTC oral nasal decongestant. All selective 1 agonists are containdicated in hypertention and angina pectoris. (2) Selective 2 adrenergic agonists: I- Bronchodilators: short acting (Salbutamol and terbutaline), long acting (fermoterol and salmetrol). Used in acute attack (short acting) and prophylaxis of bronchial asthma (long acting). II- Uterine Relaxants: Ritodrine. Used in contraction ring uterus and premature labor. III- Vasodilators: isoxuprine. Used in peripheral vascular diseases. All selective B2 agonists may produce serious tachycardia in excessive doses (WHY?) Sympathetic Depressants Blockers Classification: 1)Non-selective: block both 1 and 2 receptors as Phentolamine. 2)Selective:- block only 1 receptors as Prazocin. *Uses: 1-Essential hypertension. 2-Resistant heart failure. 3-Prostatic hypertrophy (Terazocin, doxazocin and tamsulosin are much better). *Side effects: -Postural hypotension with first dose (so starts with small dose at bedtime and increases it gradually) Blockers -They are competitve antagonists at 1 and/or 2 adrenergic receptors. Classification: Non-selective: block both 1 and 2 receptors e.g. Propranolol and Timolol. Selective: block 1 receptors e.g. Atenolol and Meteprolol. Combined and blocker: Labetalol Actions 1) CVS:* Heart: all cardiac properties CO. *Blood vessels: Vasoconstriction may occur initially (due to unopposed 1 action) PR initial of BP. This may blood flow to all organs except the brain. *Blood pressure: Antihypertensive effect on prolonged use in hypertensive patients due to: -CO and PR. - renin release. 2) Bronchi: Block of 2 receptors in bronchi may increase airway resistance in asthmatic patients. 3)Eye: IOP, most probably due to aqueous formation but have no effect on pupil size or accommodation. 4)Metabolic Actions: Prevent the glycogenolytic effect of catecholamines (2 effect) hypoglycaemia 5)CNS actions: -Anti-anxiety and tremors. -Propranolol is used in prophylaxis of migraine headache. 6) Other actions: Some blockers have ISA e.g. Pindolol. *Therapeutic uses: 1)Cardiovascular uses: Prophylaxis of Angina Pectoris. Essential hypertension. Tachycardia. Thyrotoxicosis to control adrenergic manifestations of T 3 and T4 (thyroid hormones increase the sensitivity of adrenergic receptors to endogenous catecholamines). Drugs without ISA e.g. propranolol are only used (WHY?). 2)Non - cardiovascular uses: CNS: -Control anxiety and tremors (Propranolol.( -Prophylaxis of migraine headache (Propranolol( Eye: Open angle glaucoma (Timolol eye drops). *Side effects: 1. Heart failure. 2. Hypotension. 3. The hypoglycemic effect of insulin without appearance of manifestations of hypoglycemia except sweating (WHY?) 4. Bradycardia. 5. Bronchospasm particularly with non-selective blockers in asthmatic patients. 6. Fatigue, depression and sleep disturbances. 7. Sudden cessation of therapy after prolonged use Rebound phenomenon (sympathetic overactivity manifested by angina pectoris, myocardial infarction or arrhythmia. So it is advised to stop treatment gradually. *Contraindication: 1. Heart failure. 2. Heart block. 3. hypotension. 4.Peripheral vascular diseases. 2. Bronchial asthma (2 blockers). 6.Diabetes Mellitus.