Metabolism of Catecholeamines PDF

Metabolism of Adrenaline & Noradrenaline Presented By Naglaa Fathy Prepared By professor of...

Metabolism of Adrenaline & Noradrenaline Presented By Naglaa Fathy Prepared By professor of Medical Biochemistry & Molecular Inas Abd Elmonem Biology Assistant professor of Medical Biochemistry & Inas Abd Elmonem Molecular Biology Assistant professor of Medical Biochemistry & Molecular Biology 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 1 Objectives Identify the Chemical structure of adrenaline & noradrenaline Outline the metabolic role of adrenaline & noradrenaline Describe the biosynthesis & catabolic pathways Recognize mode of action Differentiate different types of adrenergic receptors Differentiate between epinephrine & norepinephrine Relate the medical uses & clinical applications 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 2 Introduction Adrenaline (epinephrine) Noradrenaline (Norepinephrine) A hormone that is involved in regulating visceral An organic chemical in the catecholamine family that functions in the brain and body as both a hormone functions. (Trigger 'alarm' responses, to prepare and neurotransmitter. body for extreme efforts) The general function of norepinephrine is to mobilize Extreme efforts ( increase heart rate, increase the brain and body for action. blood pressure, dilation of bronchioles, elevation Secreted by certain nerve endings of the in blood glucose, reduced blood flow to skin and sympathetic nervous system, and by the medulla of digestive organs and increase blood flow to heart the adrenal glands. and muscles) Its release is lowest during sleep, rises during wakefulness, and reaches much higher levels during Normally produced by the adrenal glands and by situations of stress or danger, in the so-called a small number of neurons in the medulla fight-or-flight response. (it is also referred to as a oblongata. stress hormone.) 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 3  Epinephrine Norepinephrine Chemical structure 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 4  Biosynthesis & storage However, the catecholamines of the The catecholamines are secreted by adrenal medulla are released into blood, adrenal medulla, they also function as rather than a synaptic cleft, and act at classical neurotransmitters in the sites distant from the site of secretion, by autonomic nervous system. activating specific receptors. So the adrenal medulla also functions like a The adrenal medulla itself is modified conventional endocrine gland. neural tissue and its activity is regulated by a direct neural input, i.e. as modified However, the actions of the medullary sympathetic ganglion. hormones are far more rapid and short- lived than those of most hormones. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 5  Biosynthesis & storage (cont.) Adrenomedullary catecholamine biosynthesis starts with uptake of the L-tyrosine from blood by the chromaffin cell. Catecholamine biosynthesis involves the sequential activity of four enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β- hydroxylase (DBH), and phenylethanolamine- N-methyltransferase (PNMT). Tyrosine hydroxylase catalyzes the synthesis of L-dihydroxyphenylalanine (DOPA) from tyrosine. It is the rate-limiting step in the synthesis of the catecholamines 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 6  Biosynthesis & storage (cont.) Except for DBH, all these enzymes are localized in the cytoplasm of the chromaffin cell. The end products of this biosynthetic route are dopamine, norepinephrine, or epinephrine, depending on intracellular enzyme expression. Epinephrine then is translocated into chromaffin granules, where the amine is stored while awaiting release. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 7  Biosynthesis & storage (cont.) Epinephrine is mainly produced by the adrenomedullary chromaffin cells (>95%) and functions as a hormone released directly into the bloodstream. In contrast, circulating norepinephrine is mainly derived from overflow of the neurotransmitter from sympathetic nerve endings with adrenomedullary chromaffin cell production providing usually a less than 10% contribution. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 8  Release of catecholamines Generally, catecholamine secretion is triggered by the activation of the pre- ganglionic nerve, which releases acetylcholine from nerve endings in the adrenal medulla, close to chromaffin cells. Acetylcholine activates nicotinic receptors, which depolarizes chromaffin cells and allows Ca2+ to flow through the nicotinic receptors. This produces cellular depolarization, action potential discharges, as well as catecholamine secretion. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 9  Factors triggering Release of catecholamines Stress, Pain, Cold, heat, Asphyxia, Hypotension, Hypoglycemia, and Sympathetic excitation during hyponatremia increase the release of catecholamines 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 10  Metabolic Role of catecholamines Catecholamines are catabolic hormones Epinephrine: ↓ Uptake of bl. glucose ↑ Glycogenolysis ↓ Oxidation of bl. Glucose ↓ Glycogenesis ↑ Gluconeogenesis ↓ Lipogenesis ↑ Lipolysis Increase metabolic rate 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 11  Role of catecholamines(cont.) Cardiovascular: ↑ Heart rate & cardiac contractility ↑ BP Respiration: ↑ Oxygen consumption ↑ Respiratory rate GIT: Relaxation of smooth muscles of GIT motility 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 12  Differences between Epinephrine and Norepinephrine Epinephrine >> norepinephrine –in terms of increasing metabolism. Epinephrine >> norepinephrine – in terms of cardiac stimulation leading to greater cardiac output ( stimulation). Epinephrine < norepinephrine – in terms of constriction of blood vessels – leading to increased peripheral resistance – increased arterial pressure. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 13 Mechanism of Action Receptor mediated – adrenergic receptors Peripheral effects are dependent upon the type and ratio of receptors in target tissues Relative effects of epinephrine and norepinephrine on  and  adrenergic receptors. Guyton 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 14 Mechanism of Action (cont.) Alpha receptors are only found in the vascular & visceral smooth muscles. Beta receptors are in the heart, lungs, and arteries of skeletal muscles. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 15  Catabolism of catecholeamines Catecholamines are metabolized by a variety of enzymes, mainly monoamine oxidase (MAO), catechol-O methyltransferase (COMT). MAO deamination stands for the more important one of the two major pathways on catecholamine metabolism, thus they are converted to inactive metabolites. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 16  Catabolism of catecholeamines The second major enzyme of catecholamine metabolism is COMT, which catalyze O- methylation of dopamine to methoxytyramine, epinephrine to metanephrine, and norepinephrine to normetanephrine. Vanillylmandelic acid (VMA) is the major end product of human norepinephrine and epinephrine metabolism that will be excreted in urine. Except for the VMA, all catecholamines and their metabolites are metabolized into sulfate conjugates, representing other end products of catecholamine metabolism. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 17 Epinephrine Vs. Norepinephrine Epinephrine Norepinephrine Almost exclusively made in the adrenal Predominantly made in the sympathetic medulla. nervous system. More Adrenaline is released from the More Noradrenaline is released from the adrenal medulla than Noradrenaline. sympathetic nervous system than Adrenaline. Acts mainly as a hormone and is released Function mainly as a neurotransmitter at the primarily by the adrenal medulla into the synapse between neurons when released from bloodstream. Hence, we can say that sympathetic neurons (stored in vesicles). Adrenaline is carried throughout the whole Noradrenaline is released at a small body and acts at different organs on concentration as a hormone in the blood different adrenergic receptors. circulation by the adrenal medulla. Synthesized from Noradrenaline. Synthesized from Dopamine. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 18 Epinephrine Vs. Norepinephrine Epinephrine Norepinephrine Activates the alpha and beta- Activates mainly the alpha-adrenergic adrenergic, so has a wide-range receptors and acts on beta receptors receptors. to a certain degree Response: dilates blood vessels in Response: increases and maintain the skeletal muscle, increases heart blood pressure through rate and an increase in blood vasoconstriction of blood vessels and pressure, bronchodilation, increase dilates coronary arteries. in carbohydrate metabolism. The metabolic aim is to increase energy usage and availability. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 19  Metabolism of Catecholamines 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 20  Clinical correlation Therapeutic Uses of epinephrine 1) Allergic reaction: Adrenaline is drug of choice in the treatment of various acute allergic disorders by acting as a physiological antagonist of histamine. It is used in bronchial asthma, acute angioneurotic edema, acute hypersensitivity reaction to drugs and in the treatment of anaphylactic shock. 2) Cardiac uses: Adrenaline may be used to stimulate the heart in cardiac arrest 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 21  Clinical correlation Therapeutic Uses of Norepinephrine 1) Sometimes norepinephrine is used to treat septic shock, a severe infection that can lead to organ failure. This infection tends to cause dangerously low blood pressure. Norepinephrine given through an IV can help to constrict blood vessels, increasing blood pressure.- 2) Some people with ADHD or depression take medications that stimulate or increase the release of norepinephrine. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 22 Clinical correlation Pheochromocytoma Pheochromocytoma: a type of neuroendocrine tumor that grows from chromaffin cells in the adrenal glands. The clinical hallmark of pheochromocytoma is hypertension, but some patients are normotensive and may even be hypotensive. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 23 Clinical correlation Pheochromocytoma Symptoms& signs palpitations headache classic triad sweating resistant hypertension (95%) chest pain anxiety glucose intolerance increased metabolic rate 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 24  Clinical correlation Pheochromocytoma Diagnosis and Treatment Preferred tests are: HIGH plasma free metanephrines, urine metanephrines plasma catecholamine tests. However, the VMA test may still be ordered along with one or more of these tests to help detect and rule out a pheochromocytoma. Increased metabolites [VMA] in urine. Normal excretion of VMA is approximately 20 μmol/24 hours, with a range of 4 to 35 μmol/24 hours. In cases of pheochromocytoma the level may be up to 550 μmol/24 hours Treatment is surgical resection. Calcium channel Imaging blockers may be used in certain cases. 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 25 12/9/2023 Assistant prof. dr. Inas Abd Elmonem 26