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Transcript
Adrenergic neurons release norepinephrine (NE) as the primary neurotransmitter. Found in CNS ans in sympathetic nervous system . Norepinephrine also relased from adrenal medulla Most of the postganglionic sympathetic neurons are adrenergic However; the postganglionic sympathetic nerve fibers to the sweat glands, piloerector muscles of the hair and to a very few blood vessels are cholinergic. Substance activate adrenoreceptor called sympthatomimtic and the one block it called sympatholytic Neurotransmission at adrenergic neurons: synthesis, storage, release, receptor binding of norepinephrine, removal of the neurotransmitter from the synaptic gap -hydroxylation of tyrosine is the rate limiting step , in the synthesis of norepinephrine. -norepinephrine is hydrolysed by monoamine oxidase (MAO) and Catechol-O-methyl transferase Tow type of adrenoreceptor are α (alpha) and β (beta), α (alpha) weak response to synthetic agonist but well response to natural agonist subdivided into alpha 1 and alpha 2 β (beta) : subdivided to 1β Equal affinity to epi = norepi 2β Affinity for epi > norepi 3β lipolysis Mechanisms of adrenergic receptor activation: 1. Direct receptor binding Direct interaction with receptors. 2. Promotion of norepinephrine release acting on terminals of sympathetic nerves to cause release of NE 3. Blockade of norepinephrine reuptake blocking NE reuptake cause NE to accumulate within the synaptic gap, and thereby increase receptor activation. 4. Inhibition of norepinephrine inactivation Some of the NE inside the terminals of adrenergic neurons is subject to inactivation by monoamine oxidase (MAO). Hence, drugs that inhibit MAO will increase the amount of NE available for release Classification of adrenergic drugs: 1.Direct acting: 1-non-selctive act on more than one receptors subtype 2-selctive act on one certain receptor subtype 2.Indirect-acting drugs: 3.mixed-acting sympathomimetic (1) by releasing or displacing NE from indirectly release sympathetic nerve varicosities (vesicles ) and also directly (2) by blocking the transport of NE into activate receptors sympathetic neurons (prevent reuptake) (3) by blocking the metabolizing enzymes, MAO or catechol-Omethyltransferase Catecholamines versus Noncatecholamines: Catecholamine as NE, epinephrine, dopamine, dobutamine, isoproterenol. 1. They cannot be taken orally. 2. They have a brief duration of action. 3.They cannot cross the blood brain barrier Noncatecholamines as ephedrine, phenylphrine, terbutaline 1- can be given orally . 2- longer duration of action 3- ,ore able to penetrate BBB Characteristic responses mediated by each adrenoceptors: مهم All this effect is the same that mediated by Epinephrine since it activate all this receptors On GIT decrease muscle activity and relaxation The B2 receptors of the bladder wall mediate relaxation of the wall Insulin secretion is stimulated by B receptors and inhibited by a2 receptors. Renin secretion is stimulated by B1 and inhibited by a2 receptors Desensitization of receptors: Prolonged exposure to the catecholamine and other sympathomimetic drugs reduces the responsiveness of these receptors Mechanisms: 1. sequestration of the receptors 2. down-regulation of the receptors 3. inability to couple to G protein Catecholamine act on B recptorc activate enzyme adenylcyclase inside the cell increase the level of CAMP this second massnger make other reaction responsible for the response . Note alpha2 decrase cAMP and alpha 1 increase cAMP Epinephrine (adrenaline) Norepinephrine (Noradrenaline) Isoproterenol alpha1, alpha2, beta1, beta2. And Considered the prototype of the sympathomimetic drugs. The drug cannot be given orally and Epinephrine has a short half life because of 2 processes: enzymatic inactivation (MAO and COMT), and uptake into adrenergic nerves. alpha1, alpha2, beta1. NE does not promote hyperglycemia, a response that is mediated by beta2 receptors. NE has limited clinical applications. The only recognized indications are hypotensive states and cardiac arrest. beta1, beta2 The drug has positive chronotropic and inotropic actions Mediated by B1 -Beta2 selective agonists are preferred more than Isoproterenol In treatment of asthma Therapeutic uses : 1.Cardiovascular: By activating beta1 receptors on the heart, isopreterenol can be used in 1.Can help overcome AV heart block. 2. In cardiac arrest. 3.Can increase cardiac output during shock. 2.Asthma: By activitating beta2 receptors in the lung, isoproterenol can cause bronchodilation Dopamine in low doses, acts on dopamine receptors only. At moderate doses activates beta1 receptors in addition to dopamine receptors At very high doses, dopamine activates alpha1 receptors along with beta1 and dopamine receptors Dobutamine beta1 1.Shock: by activating beta1 receptors in the heart, dopamine can increase cardiac output By activating dopamine receptors in the kidney, dopamine can dilate renal blood vessels, thereby improving renal perfusion, which in turn reduces the risk of renal failure. 2. Heart failure. Dopamine can help alleviate symptoms by activating beta1 receptors on the heart The only indication for the drug is heart failure. Phenylephrine alpha 1 it is not a catechol derivative, it is not inactivated by COMT and has a much longer duration of action than the catecholamines. Therapeutic uses: 1- Locally as nasal drops to reduce nasal congestion. 2- Parenterally to elevate blood pressure. 3- As eye drops to dilate the pupil (Mydriatic). Terbutaline beta2 noncatecholamine Terbutaline is preferred to isoproterenol and related drugs for therapy of asthma, because it is selective for B2 only without activation of B1 1.Asthma: stimulation of beta2 receptors in the bronchi, causing bronchodilation. 2. Delay of preterm labor: By activating beta2 receptors in the uterus, terbutaline can relax uterine smooth muscle Factor that determine suitable drug to be used : 1.Whether activation of alpha or beta is required 2.preffered route of administration 3.duration of action desired Therapeutic uses of alpha 1 activation: Adverse effects of alpha 1 activation: 1.Hemostasis cause vasoconstriction and arrest bleeding 1- Hypertension due to side spread vasoconstriction 2.Nasal decongestion cause vasoconstriction of dilated and engorged blood vessels of nasal mucosa this lead to stop congestion 2- Necrosis lack of blood flow secondary to excessive vasoconstriction 3.Adjunct to local anesthesia : Alpha 1 agonist combined with anesthetic agent ( lidocaine ) to a- to prolong anesthetic action b- reduction in anesthetic dose c- reduce systemic effect ( toxicity ) of anesthetic agent d-delay anesthetic absorption epinephrine is the most commonly used . 3- Bradycardia vasoconstriction elevate blood pressure barorecptors reflex cause decrease in heart rate 4.Elevation of blood pressure cause vasoconstriction and elevate blood pressure and used in hypotensive state but not primary therapy 5.Mydriasis Therapeutic uses of alpha 2 activation: Centrally acting alpha 2 agonists: Includes clonidine and methyldopa. They reduce sympathetic outflow centrally to heart and blood vessel Their activation inhibits NE release. These drugs are used as antihypertensive drugs. Therapeutic uses of Beta 1 activation: 1.Cardiac arrest activate cardiac B1 receptor initiate beat in heart that stopped baeting Adverse effects of beta 1 activation: Over stimulation of B1 tachycardia and dysrhythmia 2.Heart failure activate cardiac B1 has positive intropic effect increase force of cardiac contraction 2. Angina pectoris increased work of heart increase oxygen demand in patient with compromised coronary blood flow in risk of angina 3.Shock increase heart rate and contraction increase cardiac output and improve tissue perfusion 4.Atrioventricular heart block B1 activation enhance impulse conduction through AV node Therapeutic uses of beta 2 activation: 1.Asthma activation of B2 receptor in lung lead to bronchiodilation Adverse effects of beta 2 activation: 1.Hyperglycemia activation of B2 lead to increase liver and muscle glycogenolysis 2.Delay of preterm labor activation of B2 receptor in uterus relax uterine smooth muscles 2. Tremor activation of B2 in skeletal muscle enhance contraction . Therapeutic uses of alpha blockade 1. Essential hypertension Adverse effects of alpha adrenergic blocking agents: 1. Orthostatic hypotension 2. Reversal of toxicity from alpha 1 agonists 2. Reflex tachycardia 3. Benign prostatic hyperplasia 3. Nasal congestion 4. Pheochromocytoma. 4. Inhibition of ejaculation 5. Raynaud's disease Therapeutic uses of Beta blockade: 1.Angina pectoris Adverse effects of beta blockade: 1.Bronchoconstriction. Contraindications 1. Asthma. 2.Hypertension 2.Heart block. 2. Chronic obstructive pulmonary disease. 3.Cardiac dysrhythmias 3.Decrease peripheral blood flow causing cold extremities. 3. Peripheral vascular diseases (vasospasm). 4.Myocardial infarction 4.Decrease blood flow to the liver and kidneys 4. Combination with Ca channel blockers, particularly verapamil. 5.Hyperthyroidism 5.Increase lipids Concentration. 5. IDDM patients. 6. Migraine 6.Mask hypoglycemic symptoms. 6. Heart failure and bradycardia. 7.Pheochromocytoma 7.CNS. 7. Psychiatric disorders. 8. Glaucoma 8.Allergy: skin rash, fever. 9.Impotence (sexual dysfunction).