1.Autonomic Nervous System Dr. Yahya Ibn Ilias ( Pharmacology )

2. GENERAL ORGANIZATION AND FUNCTIONS OF THE NERVOUS SYSTEM The nervous system is divided into two parts: The central nervous system (CNS) and The peripheral nervous system (PNS). The CNS consists of the Brain and spinal cord. The PNS consists of all afferent (sensory) neurons, which carry nerve impulses into the CNS from sensory end organs in peripheral tissues, and All efferent (motor) neurons, which carry nerve impulses from the CNS to effector cells in peripheral tissues. 3. The peripheral efferent system is further divided into t Somatic nervous system and Autonomic nervous system. The effector cells innervated by the somatic nervous system are skeletal muscle cells. The autonomic nervous system innervates three types of effector cells: (1) Smooth muscle, (2) Cardiac muscle, and (3) Exocrine glands. 4. ANATOMIC DIFFERENCES BETWEEN THE SOMATIC AND AUTONOMIC NERVOUS SYSTEMS The axon of a somatic motor neuron leaves the CNS and travels without interruption to the innervated effector cell. In contrast, two neurons are required to connect the CNS and a visceral effector cell of the autonomic nervous system. The first neuron in this sequence is called the preganglionic neuron. The second neuron, whose cell body is within the ganglion,travels to the visceral effector cell; it is called the postganglionic neuron. 5. AUTONOMIC NERVOUS SYSTEM The Preganglionic neurons of the Sympathetic nervous system have their cell bodies in the thoracic and lumbar regions of the spinal cord, termed the thoracolumbar division. The Preganglionic neurons of the parasympathetic division have their cell bodies in the brainstem and in the sacral region of the spinal cord, termed the Craniosacral division. The cranial part of the Parasympathetic nervous system innervates structures in the head, neck, thorax, and abdomen (e.g., the stomach, part of the intestines, and pancreas). The cranial Parasympathetic fibers leave the CNS in the Oculomotor, Facial, Glossopharyngeal, and Vagal cranial nerves. The Sacral division of the Parasympathetic nervous system innervates the remainder of the intestines and the pelvic viscera. 6. Location of the Autonomic Ganglia The sympathetic ganglia consist of two chains of 22 segmentally arranged ganglia lateral to the vertebral column. The preganglionic fibers leave the spinal cord in adjacent ventral roots and enter neighboring ganglia, where they make synaptic connections with postganglionic neurons. Some preganglionic fibers pass through the vertebral ganglia without making synaptic connections and travel by way of Splanchnic nerves to paired prevertebral ganglia in front of the vertebral column, where they make synaptic connections with postganglionic neurons. In addition, some sympathetic preganglionic fibers pass through the splanchnic nerves into the adrenal glands and make synaptic connections on the chromaffin cells of the adrenal medulla. 7. Special Nature of the Sympathetic Nerve endings in the Adrena Medullae. Preganglionic sympathetic nerve fibers pass, without synapsing, all the way from the intermediolateral horn cells of the spinal cord, through the sympathetic chains, and finally into the two adrenal medullae. There they end directly on modified neuronal cells that secrete epinephrine and norepinephrine into the blood stream. 8. Because Sympathetic ganglia lie close to the vertebral column, Sympathetic preganglionic fibers are generally short. Postganglionic fibers are generally long, since they arise in vertebral ganglia and must travel to the innervated effector cells. There are exceptions (e.g., urinary bladder and rectum); thus, these preganglionic fibers are long and the postganglionic fibers are short. In contrast,the parasympathetic ganglia lie very close to or actually within the organs innervated by the parasympathetic postganglionic neurons. 9. Basic Characteristics of Sympathetic and Parasympathetic Function Principal transmitter agents involved are :- 1. Acetylcholine and 2. Norepinephrine 10. Chemical Divisions of the Autonomic Nervous System Divided into cholinergic and noradrenergic divisions :- 1. fibers that secrete acetylcholine are said to be cholinergic. 2. fibers that secrete norepinephrine are said to be Adrenergic, a term derived from adrenalin, which is an alternate name for epinephrine. Cholinergic :- parasympathomimetic; stimulated, activated 11. RECEPTORS ON THE AUTONOMIC EFFECTOR CELLS The receptors for acetylcholine and related drugs (cholinoreceptors) and for norepinephrine and related drugs (adrenoceptors) are different. Acetylcholine will not interact with receptors for Norepinephrine, and nor-epinephrine will not interact with cholinoreceptors. These receptors are selective not only for their respective agonists but also for their respective antagonist drugs; that is, drugs that antagonize or block acetylcholine at cholinoreceptors will not antagonize nor-epinephrine at adrenoceptors and vice versa. 12. Synthesis, Storage, Release, and Removal of Acetylcholine The initial substrates for the synthesis of acetylcholine are Glucose and Choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether Choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme Choline acetyl-transferase, Acetylcholine is synthesized from Acetyl-CoA and Choline. The Acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms. 13. Release of transmitter is dependent on extracellular calcium and occurs when an action potential reaches the terminal and triggers sufficient influx of calcium ions. The increased Ca2+ concentration "destabilizes" the storage vesicles by interacting with special proteins associated with the vesicular membrane. Conduction of an action potential through the terminal branches of an axon causes depolarization of the varicosity membrane, resulting in the release of transmitter molecules via Exocytosis. After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). Eventually (and usually very rapidly), all of the acetylcholine released will diffuse within range of an acetylcholinesterase (AChE) molecule. AChE very efficiently splits acetylcholine into choline and acetate, and thereby terminates the action of the transmitter. Most cholinergic synapses are richly supplied with acetylcholinesterase; the half-life of acetylcholine in the synapse is therefore very short. 14. Synthesis, Storage, Release, and Removal of Norepinephrine Synthesis of Norepinephrine begins with the amino acid Tyrosine. In the neuronal cytosol, Tyrosine. is converted by the enzyme tyrosine hydroxylase to Dihydroxyphenylalanine (Dopa), which is converted to dopamine by the enzyme Decarboxylase, sometimes termed dopa-decarboxylase. The Dopamine is actively transported into storage vesicles, where it is converted to Norepinephrine (the transmitter) by dopamine beta-hydroxylase, an enzyme within the storage vesicle. In the Adrenal medulla ,the synthesis is carried one step further by the enzyme phenylethanolamine N- methyltransferase, which converts Norepinephrine to Epinephrine. 15. Since the enzyme that converts dopamine to norepinephrine (dopamine beta-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, Monoamine oxidase (MAO). 16. Following processes contribute to the removal of norepinephrine from the biophase: 1. Transport back into the noradrenergic neuron (reuptake), followed by either vesicular storage or by enzymatic inactivation by mitochondrial MAO. The transport of norepinephrine into the neurons is a sodium-facilitated process similar to that for choline transport. 2. Diffusion from the synapse into the circulation and ultimate enzymatic destruction in the liver and renal excretion. 3. Active transport of the released transmitter into effector cells (extraneuronal uptake) followed by enzymatic inactivation by catechol-O-methyltransferase. 17. Varicosity of a noradrenergic neuron showing synthesis and storage of norepinephrine. Also shown is the release of norepinephrine (NE) and multiple routes for degradation. COMT, catechol-O-methyltransferase; MAO, monoamine oxidase. 18. Parasympathetic Receptors (muscarinic) M 1 : 1. CNS : motor functions 2. Autonomic ganglia : histamine release 3. Gastric glands : acid secretions 4. GI motility : increases 19. M 2 1. Visceral smooth muscle : contraction 2. CNS 3 .Heart : Cardiac output : decrease SA node: heart rate (chronotropic):decrease rate AV node : decrease conduction Atrial cardiac muscle : decrease contractility (inotropic) Ventricular cardiac muscle:decrease contractility 20. M 3 1. Blood vessels (arteries : - erectile tissues salivary glands): dilates 2. Vascular smooth muscles : relaxes 3. Eye : pupil dilator muscle relaxes and ciliary muscles contracts 4. Salivary glands : increased watery secretions 5. Respiratory : smooth muscles of bronchioles : contracts. 6. Pancrease : increase insulin secretion 7. G.I.T : motility increase, sphincter relaxes, glands secretion 8. Renal : detrusor muscle contract and sphincter : relaxes 21. Nicotinic Nm (neuromuscular junction) : Deporalization of muscle end plate : contraction of skeletal muscle Nn (neuroneuronal junction) : CNS : excitation or inhibition Adrenal medulla : catecholamine release. 22. Sympathetic Receptors Alpha 1 1. Skin : sweat gland : increase secretion , Arrector pili : stimulates 2. Blood vessels (arteries : - skin, erectile tissues, brain, viscera and renal): constricts 3. Vascular smooth muscles : contracts 4. Eye : pupil dilator muscle : contracts 5. Salivary glands : increased secretions 6. Respiratory : smooth muscles of bronchioles : contracts (minor) 7. Liver : glycogenolysis 8. Renal : sphincter : contracts 9. Reproductive : uterus : contract (pregnant) genitalia (ejaculation) 23. Alpha 2 1. Eye : decrease aqueous humor production 2. Salivary glands : decrease secretion 3. G.I.T : sphincter contraction 4. Platelets : aggregation 5. Metabolism : inhibition of lipolysis. 24. Alpha 1 and Alpha 2 1. Arteries to heart (coronary): Vasoconstriction 2. G.I.T : smooth muscle motility :Decrease, sphincter : contracts 3. Male genitalia : Contraction (ejaculation) 25. Beta 1 1. Heart : Increase cardiac output 2. Kidney : Increase renin secretion 26. Beta 2 1.Blood vesseles :- Arteries (smaller coronary, hepatic, skeletal): - dilatation Veins : dialatation 2. Vascular smooth muscles : relaxation 3. Mast cells (histamine): inhibits 4. Vascular smooth muscles : relaxation 5. Eye (ciliary muscles) : relaxation 6. Respiratory (smooth muscles of bronchioles): relaxation (major) 7. G.I.T (sphincter) : contracts 8. Liver : Gluconeogenesis 9. Renal (bladder, sphincter): relaxation 10. Reproductive (uterus) : relaxation 27. Adrenergic drugs (Sympathomimetics) 28. Direct sympathomimetics : They act directly as agonists on alpha and /or beta adrenoceptors adrenaline, NA, isoprenaline (Iso), phenylephrine, methoxamine, xylometazoline, salbutamol. Indirect sympathomimetics : They act on adrenergic neurone to release NA, which then acts on the adrenoceptors tyramine, amphetamine. Mixed action sympathomimetics : They act directly or indirectly ephidrine, dopamine, mephentermine. 29. Adrenoceptor agonists are classified into three types:(based on the selectivity for the main adrenoceptor subtypes) - adrenoceptor agonists: Norepinephrine Phenylephrine ,methoxamine - adrenoceptor agonists: Adrenaline , Dopamine, Ephedrine - adrenoceptor agonists: Isoprenaline, Dobutamine, Terbutaline, Salbutamol 30. Norepinephrine (noradrenalne): 1, 2, 1 and 3, but not 2 action Epinephrine (adrenaline): 1, 2, 1 and 2 and weak 3 action Isoproterenol (isoprenaline): 1 and 2, but not action 31. Action on alpha- adrenoceptors Contraction of arterioles and veins: raise in BP (1+ 2) Contraction of radial muscules of iris: mydriasis and decreased aqueous secretion (1) Heart little action, arrhythmia at high dose (1) GIT: intestinal relaxation, contraction of sphincters Bladder trigone: contraction (1) Uterus: contraction (1) 32. Splenic capsule: contraction (1) Insulin secretion: inhibited (2 dominant) Prostate : ejaculation, urine continence (1) Salivary glands: K+ and water secretion (1) 33. Action on beta- adrenoceptors Dilatation of arterioles and veins (2): fall in BP Cardiac stimulation (1): increased heart rate, force and conduction velocity Bronchodilation (2) Eye: enhanced aqueous secretion GIT: intestinal relaxation (2) Bladder detrusor: relaxation (2) 34. Uterus: relaxation (2) Augmented insulin and glucagon secretion (2) Liver: glycogenolysis (2) Fat lipolysis (1,2,3), Kidney renin release (1) Posterior pituitary: ADH secretion (1) 35. Actions Blood Vessels :- Alpha receptors - increase arterial resistance, Beta - 2 receptors - smooth muscle relaxation Skin vessels (alpha receptors) - constrict in the presence of epinephrine and norepinephrine Skeletal muscle vessels - constrict or dilate depending on whether alpha or beta receptors are activated. Overall effects of a sympathomimetic drug on blood vessels depend on the relative activities of that drug at and receptors and the anatomic sites of the vessels affected. 36. Heart Beta-1 receptors, although beta-2 and to a lesser extent alpha receptors are involved Beta-receptor activation -- increased calcium influx in cardiac cells Pacemaker activity, both (SA node) and (Purkinje fibers), are increased (positive chronotropic effect) Conduction velocity in the AV node is increased, and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased 37. Blood Pressure NA (1, 2, 1 and 3, but not 2 action) : causes rise in systolic and diastolic BP. It does not cause vasodilation (no 2 action), peripheral resistance increases consistently due to alpha action. Isoprenaline (1 and 2, but not action): rise in systolic (1) but marked fall in diastolic (2) BP. 38. Adrenaline or Epinephrine (1, 2, 1 and 2 but weak 3 action) Given by slow i.v. infusion or s.c. injection causes rise in systolic but fall in diastolic BP (2 receptors are more sensitive than receptors). Pulse pressure is increased. Rapid i.v. inj. of Adr. Produces a marked increase in both systolic and diastolic BP (at high conc response predominates and vasoconstriction occurs) 39. Eye: mydriasis (1) 40. Respiratory Tract Bronchodilation (2) Blood vessels of the upper respiratory tract mucosa contain receptors; the decongestant action of adrenoceptor stimulants is clinically useful. 41. Gastrointestinal Tract Relaxation of gastrointestinal smooth muscle ( and ) Bladder (urinary continence):- Detrusor is relax () and trigone is constricted () (Urethral pressure normally exceeds bladder pressure, resulting in urine remaining in the bladder) Uterus : nonpregnant (contraction), pregnant (relaxation at term only) 42. Adrenaline (Ad, Epinephrine) ,- adrenoceptor agonists 43. Epinephrine is a potent stimulant of both - and-adrenergic receptor ,and its effects on target organs are thus complex. Particularly prominent are the actions on the heart and on vascular and other smooth muscle. 44. [Pharmacokinetics] 1.Bioavailability is poor with oral administration because: 1) Absorption is poor because of the vasoconstriction of Ad acting on -adrenergic receptor and rapidly metabolism in digestive tract. 2) The first pass effect of the drug is patent (obvious). 45. 2. Absorption is slow with subcutaneous injection because Ad acts on -adrenergic receptor in subcutis and leads vasoconstriction. 3. Absorption is rapid with intramuscular injection because Ad acts on -adrenergic receptor in skeletal muscle and leads vasodilatation. 46. 4. In emergencies,it may be necessary in some cases to administer Ad intravenously. 5. When relatively concentrated solution (1%) are nebulized and inhaled, the action of the drug largely are restricted to the respiratory tract ; However,systemic such as arrhythmias may occur, particularly if larger amounts are used. 47. 6. Ad is rapidly inactivated in the body . The liver, which is rich in both of the enzymes responsible for destroying circulating Ad (COMT and MAO),is particularly important in this regard . Although only small amounts appear in the urine of normal persons, the urine of patients with pheochromocytoma may contain relatively large amounts of epinephrine , norepinephrine, and their metabolites. 48. [Pharmacological effects] 1.Cardiovascular system 1) Heart: Direct effects on the heart are determined largely by 1receptors. 49. In intact heart , intraventricular pressure rises and falls more rapidly and ejection time is decreased. (1) contractility(1) ; (2) heart rate (predominantly 1) ; (3)stroke volume ; (4) cardiac output. - Increase myocardium oxygen consumption, - Systolic and diastolic BP. 50. 2) Blood vessels: (cutaneous and mucous 1 membranes) Skin vessels have predominantly alpha receptors and constrict in the presence of epinephrine . Small arteriol , precapillary sphincter , vessel constriction. The effect on vein and artery is weak . 51. Ad combines with 2 receptors, then promote smooth muscle relaxation. For splanchnic vessels (, ) Ad constricts renal and mesenteric blood vessels, the effect on cerebral and pulmonary blood vessels are weak. In vivo coronary artery vessels dilate. 52. 3) Blood Pressure: Ad is one of the most potent vasopressor drugs known. If a pharmacological dose is given rapidly by an intravenous route, it evokes a characteristric effect on blood pressure, which rises rapidly to a peak that is proportional to the dose. The increase in systolic pressure is greater than the increase in diastolic pressure, so that the pulse pressure increases. 53. 2. Smooth muscle : The effect of Ad on the smooth muscles of different organs and systems depend on the type of adrenergic receptor in the muscle. Bronchial smooth muscle: relaxation , due to stimulating beta2-adrenergic receptors . 54. Gastrointestinal smooth muscle: Relaxation of gastrointestinal smooth muscle Uterine muscle: The responses of uterine muscle to Ad vary with species, phase of the sexual cycle ,state of gestation, and dose given. During the last month of pregnancy and at parturition, Ad inhibits uterine tone and contraction. 55. Bladder: Ad relaxes the detrusor muscle of the bladder as a result of activation of receptors and contracts the trigone and sphincter muscles owing to its -agonist activity. This can result in hesitancy in urination and may contribute to retention of urine in the bladder . Activation of smooth muscle contraction in the prostate promotes urinary retention. 56. 3.Metabolic effects: Increase metabolism, activation receptors in fat cells leads to increased lipolysis. activates glycogenolysis (liver), inhibit the secretion of insulin , blood glucose. 57. Clinical uses 1. Cardiac arrest: Cardiac arrest induced by drowning, intoxication of CNS inhibitors, anaesthesia, acute infectious disease . Intraventricle injection, cardiopulmonary resuscitation. 2. Anaphylaxis: Anaphylactic shock and related immediate (type 1) IgE-mediated reactions affect both the respiratory and the cardiovascular systems. 58. 3. Bronchial asthma: Relaxation of bronchial muscle and inhibition the secretion of histamine and leukotriene from tissues and mast cells. 4. Local application : Use with local anaesthesia to constrict the regional blood vessles for reducing mucous membrane congestion. epistaxis, gingival bleeding. 59. Adverse effects Restlessness , anxiety, tremor, and insomnia , palpitation, sweating . Very high dose: severe headache , BP, the danger of cerebral hemorrhage, arrhythmia, ventricular fibrillation. 60. Contraindications Hypertension , Sclerosis of cerebral artery, Ischemic heart disease, Congestive heart failure, Hyperthyroidism, Diabetes . Use with care for old patients. 61. Ephedrine 62. Ephedrine Ephedrine is a naturally occurring alkaloid extracted from Chinese herb, that can cross the blood-brain barrier and thus exert a strong CNS-stimulating effect in addition to its peripheral actions. It has direct effect on and receptors and enhances the release of NA from adrenergic nerve endings. It activates and receptors . 63. It has both direct and indirect actions. 1) . It causes the release of NA from storage in nerve terminals. 2) . It also produces direct stimulation of adrenergic receptors. 64. High bioavailability and a relatively long duration of action. It is absorbed when taken orally, and it is resistant to COMT and MAO, so that its action is prolonged. 65. Pharmacological Actions Ephedrine increases systolic and diastolic blood pressure; heart rate is generally not increased. Ephedrine activates 1 receptor of heart , increase heart contractility and increase cardiac output. Compensatory vagus reflex tends to decrease heart rate. Ephedrine produces bronchial smooth muscle relaxation of prolonged duration when administered orally. Aside from pupillary dilation, ephedrine has little effect on the eye. It causes CNS stimulation, which can result in effects such as insomnia, nervousness, nausea. 66. Clinical Uses Ephedrine is useful in relieving bronchoconstriction and mucosal congestion associated with bronchial asthma, asthmatic bronchitis, chronic bronchitis, and bronchial spasms. It is often used prophylactically to prevent asthmatic attacks and is used as a nasal decongestant, as a mydriatic, and in certain allergic disorders. Although its bronchodilator action is weaker than that of isoprenaline , its oral effectiveness and prolonged duration of action make it valuable in the treatment of these conditions. Pressor agent: prevent hypotension induced by epidural anaesthesia or subarachnoid anaesthesia. 67. Adverse Effects Symptoms of overdose are related primarily to Cardiac and CNS effects. Tachycardia, insomnia, nervousness, nausea, vomiting, and emotional disturbances may develop. Ephedrine should not be used in patients with cardiac disease, hypertension, or hyperthyroidism. 68. Dopamine (DA )3,4-dihydroxyphenylethylamine Dopamine is a naturally occurring catecholamine. it is the immediate biochemical precursor of the norepinephrine found in adrenergic neurons and the adrenal medulla. It is also a neurotransmitter in the CNS, where it is released from dopaminergic neurons to act on specific dopamine receptors. 69. It is metabolized by COMT and MAO. Intravenous infusion, no effect on CNS, does not penetrate blood brain barrier. 70. Dopamine can stimulate D, and receptors . Dopamine causes an increase of cardiac contractility. It also causes the release of NA from nerve endings, which contributes to its effects on the heart, vasoconstriction. The effect on Dopamine receptor of kidney ,and mesentery induces dilation of renal and mesenteric blood vessels. Infusion of low dose of dopamine causes an increase in glomerular filtration rate, renal blood flow and Na+ excretion. Large dosage of Dopamine activates -receptor , leading to renal vasoconstriction 71. Uses: Some types of shock: cardiogenic and septic shock, hemorrhagic BP shock, especially with cardiac dysfunction, oliguria or anuria. Dopamine and diuretics to treat acute renal insufficiency. Adverse effects: If infused very fast, it may induce tachycardia, arrhythmia, headache and hypertension. 72. - adrenoceptor agonists Norepinephrine, NE ( Noradrenaline, NA ) 73. PHARMACOLOGICAL PROPERTIES The pharmacological actions of NE and Epi are approximately equipotent in stimulating b1 receptors. They differ mainly in their effectiveness in stimulating and 2 receptors. It has very strong receptor activating effect, has effect on 1 receptor . NE has relatively little effect on 2 receptor . 74. ABSORPTION, FATE, AND EXCRETION NE, like Epi, is ineffective when given orally and is absorbed poorly from sites of subcutaneous injection. It is rapidly inactivated in the body by uptake and the actions of COMT and MAO. Small amounts normally are found in the urine. The excretion rate may be greatly increased in patients with pheochromocytoma. 75. Pharmacological effects The effects of norepinephrine on cardiac function are complex because of the dynamic interaction of the direct effects of norepinephrine on the heart and the initiation of powerful cardiac reflexes. The net effect of norepinephrine administration on heart rate and ventricular contractile force therefore varies with the Dose of norepinephrine, Physical activity of the subject, Any prior cardiovascular and baroreceptor pathology, Presence of other drugs that may alter reflexes. 76. Clinical uses Hypotension : for patients with criticalhypotension. It is given intravenously and acts on both 1 and 2 adrenergic receptors to cause vasoconstriction. Shock: To treat patients in vasodilatory shock states such as septic shock and neurogenic shock, Hemorrhage of Upper digestive tract: Orally : It contricts blood vessels of esophagus and stomach. 77. Adverse effects NA can cause: Headache and cerebral hemorrhage from the vasopressor effects; Pulmonary edema from pulmonary hypertension; Renal insufficiency from decrease of renal blood flow; Local necrosis because leakage of NA from blood vessel. 78. Contraindications Hypertension , Atherosclerosis , Coronary heart disease, Oliguria , anuria. 79. Methoxamine 1 receptor selective adrenergic agonist, as such, it causes a dose- related increase in peripheral vascular resistance. No effect on receptors. The major cardiovascular response to the drug is a rise in blood pressure, which is associated with reflex bradycardia because of activation of vagal reflexes. Used to treat hypotensive states. 80. Phenylephrine 1 receptor agonist it activates receptors only at much higher concentration. Phenylephrine is commonly used as anasal decongestant, although occasional nasal mucosal damage has occurred from injudicious use of the nasal spray. It is also employed in ophthalmology as a mydriatic agent. Phenylephrine, however, should not be given to patients with closed-angle glaucoma before iridectomy, since further increases in intraocular pressure may result. In dentistry, phenylephrine is used to prolong the effectiveness of a local anesthetic. 81. - adrenoceptor agonists 82. - adrenoceptor agonists Classification 1,2- adrenoceptor agonists: Isoproterenol 1- adrenoceptor agonists: Dobutamine 2- adrenoceptor agonists: Salbutamol, Terbutaline 83. Isoprenaline (ISO) Isoproterenol is readily absorbed when given parenterally or as an aerosol. It is metabolized primarily in the liver and other tissues by COMT. Isoproterenol is a relatively poor substrate for MAO and is not taken up by sympthetic neurons to the same extent as are epinephrine and norepinephrine. The duration of action of Isoproterenol therefore may be longer than that of epinephrine, but it still is brief. 84. [Pharmacological effects] Cardiovascular system: 1,2 receptors strong agonist. Little effect on receptors. Intravenous infusion of Isoproterenol lowers peripheral vascular resistance, primarily skeletal muscle but also in renal and mesenteric vascular beds. Diastolic pressure falls. Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls. Cardiac output is increased because of the positive inotropic and chronotropic effects. The cardiac effects of Isoproterenol may lead to palpitations, sinus tachycardia and more serious arrhythmias. 85. Bronchial smooth muscle: 2 receptor: Relaxation of bronchial muscle, stronger than Adr. Its effects in asthma may be due in part to an additional action to inhibit antigen induced release of histamine and other mediators of inflammation. Metabolism: Activates receptors, enhances glycogenolysis, accelerates the breakdown of triglycerides to form fatty acid and glycerol, increases oxygen consumption. 86. Clinical uses 1. Cardiac arrest, heart block( to increase heart rate) 2. Asthma 3. shock Adverse effects Palpitation, tachycardia, headache and flushed skin are common. 87. Dobutamine 1. It is a direct 1 receptor agonist, and has relatively more prominent inotropic effects on the heart compared to Isoproterenol, and has a greater inotropic than chronotropic effect, increase cardiac contractility, cardiac output, without increase of heart rate. 2. It is used to treat congestive heart failure, acute myocardial infarction. 3. Side effects are BPand heart rate, arrhythmias. 88. Salbutamol 1. The 2 selective adrenergic receptor agonist has a relaxing effect on bronchial smooth muscle and show little effect on cardiac 1 receptors. 2. It is used for treatment of bronchospasmwith lack of cardiac stimulation. 89. Terbutaline 2-receptor agonist, Orally, inhalation. After inhalation, its action may persist for 3~6 hours. Used in bronchial asthma. 90. Adrenergic Receptor Blocking Agents 91. Adrenergic receptor antagonists inhibit the interaction of NE, Epi, and other sympathomimetic drugs with their receptors. 92. Adrenergic Receptor Antagonists -Adrenergic Receptor Antagonists -Adrenergic Receptor Antagonists 93. Prazosin is much more potent in blocking 1 than 2 receptors and is termed 1-selective. Whereas Yohimbin is 2-selective; Phentolamine has similar affinities for both of these receptor subtypes. Phenoxybenzamin is an irreversible antagonist that binds covalently to -adrenergic receptors. 94. Since blockade of a1 receptors inhibits vasoconstriction, Pressor responses to adrenaline may be transformed to vasodepressor effects (adrenaline "reversal") because of residual stimulation of b2 receptors in the vasculature with resultant vasodilation. 95. Alpha adrenergic blocking drugs Classification : 1. Nonequilibrium type : Phenoxybenzamine 2. Equilibrium type (competitive) A. Nonselective : Ergotamine, Ergotoxine, Dihydroergotamine (DHE), Dihydroergotoxine, tolazoline, Phentolamine, chlorpromazine B. Alpha 1 selective : Prazosin, Terazosin,Doxazosin, Tamsulosin C. Alpha 2 selective : Yohimbine 96. General effects of alpha blockers 1. Fall in BP (vasodilatation) 2. Tachycardia : fall in BP leads to stimulation of vasomotor centre and withdrawal of vagal tonic discharge ------ tachycardia 3. Urinary outflow : tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of alpha 1 receptors ------ urine flow in patients with BPH is improved. 4. GIT : intestinal motility is increased and relaxation of sphincter --- diarrhoea 97. 5. Postural hypotension : normally, when a person stands up, a large volume of blood (700ml in 70 kg man) is pooled in the veins of lower limb due to gravity --- this causes reduction of cardiac output -- cerebral ischemia and fainting should therefore develop in every person on standing. But this does not happen because of compensatory mechanism: due to reduction of cardiac out put, BP, falls ---- therefore, via sinu aortic mechanism (baroreceptor reflex), the vasomotor center is stimulated ---- sympathetic system activated ---- venomotor tone, via alpha 1 receptors, increased --- venous return to heart restored ------ cardiac output restored. Therefore, alpha blocking should lead to postural hypotension. Conclusion : alpha 1 blockers should cause : fall of BP, postural hypotension, tachycardia 98. 6. Nasal stuffiness : vasodilatation (due to alpha 1 blocking) of nasal mucosal blood vessels may produce swelling of the nasal mucosa --- nasal stuffiness 7. Impotence : alpha blockers can inhibit ejaculation 99. Alpha -RECEPTOR BLOCKING AGENTS The clinically important alpha-blockers fall primarily into three chemical groups: Haloalkylamines ( e.g. phenoxybenzamine), Imidazolines (e.g., phentolamine), Quinazoline derivatives (e.g. prazosin). Of these three classes of a-adrenoceptor antagonists, the quinazoline compounds are of greatest clinical utility. The use of the haloalkylamines and imidazolines has diminished in recent years because they lack selectivity for a1- and a2-receptors. 100. Non selective blockers Phenoxybenzamine Blocks both alpha 1 and presynaptic alpha 2 receptors, irreversibly. PBZ causes a progressive decrease in peripheral resistance, an increase in cardiac output (due,in part, to reflex sympathetic nerve stimulation), Tachycardia accentuated by enhanced release of NE (due to a2 blockade), 101. THERAPEUTIC USES A major use of PBZ is in the treatment of pheochromocytoma. PBZ is almost always used to treat the patient in preparation for surgical removal of the tumor. Major side effects : postural hypotension, palpitation, nasal blockage, inhibition of ejaculation. Pharmacokinetics : oral, im and sc inj. Is painful, excreted in urine in 24 hrs. Dose : 20-60 mg oral, 1mg/kg slow iv infusion, on rapid iv inj. Cause nausea and vomiting (lipid soluble, cross BBB) 102. Phentolamine Rapidly acting alpha blocker with short duration of action Blocks both alpha 1 and 2 receptors Uses : Phentolamine can be used in short-term control of hypertension in patients with pheochromocytoma. Dose : 5 mg iv (10mg/ml) Tolazoline : similar to phentolamine and less potent. Also blocks histamine 103. Alpha 1 selective Prazosin : highly selective alpha 1 blockers Fall in BP (venodilatation is much less than arteriolar dilatation). Because of lack alpha 2 antagonism, tachycardia is only mild. Effective orally (bioavailability 60%), highly bound to plasma protein, metabolized in liver and excreted in bile, plasma half life 2-3 hours, effect of a single dose lasts for 6- 8 hours. Uses : antihypertensive, BPH (improve urine flow) Dose : 0.5, 1, 2 mg tab, start with 0.5 1 mg at bed time 104. Prazosin can cause first dose effect ie, postural hypotension is less marked, dizziness and fainting can develop after 1st dose, but if the drug is persistent, tolerance develops. Therefore, the rule is, 1. Very low dose at first 2. Administered at night 3. The patient should be warned of the first dose effect. 105. Terazosin Chemically and pharmacologically similar to prazosin; differences are higher biovailability (90%) and longer plasma half life (12 hrs), a single dose lowers BP over 24 hrs. Uses : BPH (popular for use), antihypertensive Dose : 1, 2 and 5 mg (2-10 mg od) Doxazosin : longer acting (t1/2 18 hrs), used in HTN and BPH, dose : 1, 2 , 4 mg (1 mg od) 106. Uses of alpha blockers 1. Chronic hypertension (alpha 1 selective, less postural hypotension than others) 2. Hypertensive emergencies 3. Benign prostatic hypertrophy (BPH) 4. Pheochromocytoma (excess CAs are secreted which can cause intermittent or persistent HTN) 5. Impotence 107. Beta adrenergic blocking drugs Classification Nonselective (beta 1 and 2): Propranolol, Sotalol, Timolol Pindolol With additional alpha blocking property : labetalol, carvedilol . Cardioselective (beta1): Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol, 108. Another classification First generation (nonselective) : Propanolol, Timolol, Sotalol, Pindolol Second generation (beta1 selective) : Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol Third generation (with additional alpha blocking and / or vasodilator property) : Labetalol, Carvedilol, Nebivolol 109. Beta adrenergic blocking drugs Pharmacological Actions : The most important actions of the beta-blocking drugs are on the cardiovascular system: Beta-Blockers decrease heart rate, myocardial contractility, cardiac output, and conduction velocity within the heart. These effects are most pronounced when sympathetic activity is high or when the heart is stimulated by circulating agonists. 110. The actions of beta-blockers on blood pressure are complex. After acute administration, blood pressure is only slightly altered. This is because of the compensatory reflex increase in peripheral vascular resistance that results from a beta-blockerinduced decrease in cardiac output. Chronic administration of beta-blockers, however, results in a reduction of blood pressure, and this is the reason for their use in primary hypertension. 111. The mechanism of this effect is not well understood, but it may include such actions as Reduction in renin release, Antagonism of beta-receptors in the central nervous system, or Antagonism of presynaptic facilitatory beta- receptors on sympathetic nerves. 112. Are useful for the prophylactic treatment of angina pectoris, The chief benefit of the beta-blockers in this condition derives from their ability to decrease cardiac work and oxygen demand. The release of Renin from the juxtaglomerular cells of the kidney is to be regulated by beta-receptors; most beta-blockers decrease renin release. The glycogenolytic and lipolytic actions of endogenous catecholamines are mediated by beta- receptors and are subject to blockade by beta- blockers. 113. Beta-blocker increases airway resistance by antagonizing beta2-receptormediated bronchodilation. Although the resulting bronchoconstriction is not a great concern in patients with normal lung function, it can be quite serious in the asthmatic. The cardioselective beta-blockers produce less bronchoconstriction than do the non-selective antagonists. 114. Clinical Uses The beta-receptor blocking agents have widespread and important uses in the management of cardiac arrhythmias, angina pectoris, and hypertension. The beta-blockers also offer proven benefit in preventing the recurrence of a myocardial infarction (MI). For this purpose, it is best if beta-blocker therapy is instituted soon after the MI and continued for the long term. 115. Hyperthyroidism The beta-blockers significantly reduce the peripheral manifestations of hyperthyroidism, particularly elevated heart rate, increased cardiac output , and muscle tremors. Anxiety States The peripheral manifestations of anxiety may include a number of symptoms (e.g., palpitations) that are due in part to overactivity of the sympathetic nervous system. The beta-blocking agents may offer some benefit in the treatment of anxiety. Migraine The beta-blockers may offer some value in the prophylaxisof migraine headache, possibly because a blockade ofcraniovascular beta-receptors results in reduced vasodilation. 116. Propranolol (prototype) 1. CVS : a) Bradycardia (beta1 blocking effect on SA node, AV node and atrial muscles) b) Fall of cardiac output (fall of contractility of myocardium) c) Prolonged use reduces BP in hypertensives but in normotensive the BP is not affected): decrease renin release 2. Respiratory tract : bronchoconstriction (worsened and a severe attack may be precipitated) 3. CNS : high doses : forgetfulness, increased dreaming and nightmares. Low dose : suppresses anxiety 117. 4. Local anaesthetic : potent local anaesthetic but not used because of its irritant property 5. Metabolic : inhibits lipolysis and glycogenolysis 6. Skeletal muscle : inhibits adrenergically tremor. 118. Pharmacokinetics Absorption: Well absorbed but undergoes extensive first-pass hepatic metabolism. Distribution: CNS penetration. Crosses the placenta; enters breast milk. Protein Binding: 93%. Metabolism/Excretion: Almost completely metabolized by the liver. Half-life: 3.46 hr. 119. Adverse effects CNS: fatigue weakness, nervousness, nightmares. ENT: dry eyes , nasal stuffiness. Resp: bronchospasm , wheezing. CV: , bradycardia , orthostatic hypotension GU: erectile dysfunction GI: constipation MS: arthralgia , back pain, muscle cramps. 120. Contraindications Reversible airways disease, particularly asthma or chronic obstructive pulmonary disease (COPD) Bradycardia (