Pharmacology ANS 3 - Adrenergic Receptors and Agonists

a generics neurons released nor piloff run as the primary neurotransmitter it is also known as noradrenaline these neurons are found in the central nervous system and also in the sympathetic nervous system where they serve as links between ganglia and the effector organs a PI the friend or also known as the dren alone is the main neurotransmitter excreted from the adrenal medulla and dopamine which has an important role as a neurotransmitter in the CNS so it'll be discussed in the CNS lectures now let's discuss the neurotransmission at the Adrenaline's or as I'm calling the Adrenaline's journey this journey involves synthesis of dopamine followed by an or eternal and then adrenaline then storage release and binding to receptors followed by removal of the neurotransmitter from the synaptic cleft tyrosine is transported by a carrier into the adrenergic neuron where it is hydroxylated by tyrosine hydroxylase 2 D hydroxy phenylalanine or known as dopa and this is the rate limiting step in the formation of norepinephrine dopamine o acid decarboxylase to form da pin mine in the presynaptic neuron then top and mine is transported into synaptic vesicles binem and transporter system this carrier system is blocked by reserve pine which we'll discuss later dopamine is next hydroxylated to form nor pine the fryin by the enzyme dopamine beta hydroxylase as we discussed before in synaptic transmission video when an action potential arrived to the nerve ending voltage sensitive calcium channels on the presynaptic membrane open causing an increase in the concentration of intracellular calcium elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and the release of their contents into the synaptic space drugs such as Gwyneth iodine block this release then noradrenaline diffuses across the synaptic space and binds to postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending binding to a receptor leads to a biologic response within the cell then comes the last step which is the removal of noradrenaline and actually there are multiple options for this process to be done noradrenaline may diffuse out of the synaptic cleft and enter the systemic circulation or it may be metabolized to an active metabolites that will be excreted in urine by Kadokawa methyl transferase known as calmed in the synaptic space or it may undergoes reuptake into the neuron the reuptake by the neuronal membrane involves a sodium chloride dependent or pi the fryin transporter that can be inhibited by tricyclic antidepressants such as mi Perman by serotonin or pi the frined reuptake inhibitors such as Juke sateen or by cocaine which we'll discuss later reuptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of its effects once nor piloff Rhino enters theater nergic neuron it may be taken up into synaptic vesicles by the human transporter system so it'll be ready for release by another action potential or it can be oxidized by monoamine oxidase known as mal present in neuronal mitochondria producing an active metabolites that are excreted in urine noradrenaline undergoes methylation in the adrenal medulla producing adrenaline this is the Adrenaline's journey in this lecture we'll discuss the other energy receptors or also known as addresses they are classified in the two main families of receptors alpha and beta receptors each of these receptor types has a number of specific receptor subtypes that have been identified they are classified according to their responses to the inner energy CAG inist papaya frying nor pine a frying and isoproterenol to simplify this let's check the chemical structures of these three agents and let's make a simplified representation of them the affinity for beta receptors increases as the group anjum and nitrogen gets larger so we can conclude that beta receptors are characterized by a strong response to isoproterenol with less sensitivity to a PI the friend and lesser sensitivity to nor pine affine BAE the receptors are subdivided into three major subgroups beta 1 beta 2 and beta 3 based on their affinities for energic agonists and antagonists beta 1 receptors have approximately equal affinities for pi the friend and norepinephrine and beta 2 receptors affinity for pi the friend is higher than for nor pine affine so tissues with the predominance of beta 2 receptors such as the vasculature of skeletal muscle are more responsive to the effects of circulating a pine a frien that as we discussed in the previous lecture is released by the adrenal medulla beta 3 receptors are involved in lipolysis and also have effects on the D traceur muscle of the bladder the Alpha receptors show a weak response to the synthetic agonist isoproterenol but they are responsive to the naturally occurring catecholamines a PI the friend and nor pine if Ryne they are characterized by a strong response to a pine a frying with less sensitivity to nor pi the friend and lesser sensitivity to isoproterenol they are subdivided into two main subgroups alpha 1 and alpha 2 based on their affinities for agonists and antagonists alpha 1 receptors present on the postsynaptic membrane of the effector organs and alpha 2 receptors are located primarily on sympathetic presynaptic nerve endings and control the release of norepinephrine stimulation of alpha 2 receptors causes feedback inhibition and inhibits further release of Nohr pi the friend from the stimulated energic neuron alpha 2 receptors are also found on presynaptic parasympathetic neurons nor pi the fryin release from a presynaptic sympathetic neuron can diffuse and interact with these receptors inhibiting acetylcholine release the alpha 1 and alpha 2 receptors are further divided into alpha 1 a b c and d and into alpha 2 a b and c some drugs are selectively to one subtype of these receptors for example tamsulosin is a selective alpha 1 a which is found primarily in the urinary tract and prostate gland so it is used to treat benign prostatic hyperplasia with fewer cardiovascular side-effects as it does not affect the alpha 1 B subtype found in the blood vessels we've already discussed the autonomic receptors distribution and effects and details in a previous lecture but let's summarize it again in a minute the activation of alpha 1 receptors produces vasoconstriction increased peripheral resistance increased blood pressure mid rias's and increased closure of internal sphincter of the bladder the activation of alpha 2 receptors produces inhibition of norepinephrine release inhibition of acetylcholine release and inhibition of insulin release the activation of beta 1 receptors produces dekha kar diya increased myocardial contractility an increased release of Rieman the activation of beta 2 receptors produces skeletal muscles vaso dilatation bronco dilatation increased muscle and liver glycogen alysus increased release of glucagon and relaxed uterine smooth muscle the activation of beta 3 receptors increases lipolysis in the previous lecture we discussed the energy receptors so now we'll continue and discuss the energy economists characteristics most of the energy drugs are derivatives of beta phenylethylamine there are two places available for substitutions either on the benzene ring or on the ethyl amine side chains this produces a variety of compounds with varying affinity and selectivity to alpha and beta receptors and also controls the ability to penetrate the CNS so there are two important structural features in these drugs the number and location of hydroxyl substitutions on the benzene ring and the nature of the substituents on the amino nitrogen a giorgia catalysts have been classified to two main groups catecholamines and non-critical means cadigal means are those compound that has three four Dedrick siblings een group or in other words they have two hydroxyl groups on the benzene ring of the positions three and four such as a pie the frying nor pine affine isoproterenol and op in mine having these two hydroxyl groups allows catecholamines to show the highest potency indirectly activating alpha or beta receptors and is also responsible for the rapid and activation and metabolism by com'd postsynaptically and by mao internally as well as by calmed and mao in the gut wall and by mao in the liver so catecholamines have a brief period of action when given perimeter li and they are ineffective when administered orally as they are readily metabolized the two hydroxyl groups make catechol men more polar so they do not readily penetrate into the CNS nevertheless most catecholamines may produce anxiety tremor and headaches and these effects are attributable to action on the CNS non-critical amines are those compounds lacking the catechol hydroxyl groups so they are not inactivated by calmed and they are poor substrates for mal so they have longer half-lives and duration of action than catecholamines these agents include phenylephrine ephedrine and then feta mean lack of polar hydroxyl groups makes these agents more like bit soluble permitting greater access to the CNS substitutions on the amine nitrogen have an important role in determining beta and alpha selectivity of the Adreno Jacana stand we've discussed that in details in the previous lecture the affinity for beta receptors increases as the group on the amine nitrogen gets larger so the affinities order to beta receptors isoproterenol followed by piloff rhine and then nor pine if Rhine and for alpha receptors the piloff Rhine followed by nor piloff Rhine and then isoproterenol now let's talk about the mechanism of action of the Adreno jerk agonists they either work directly indirectly or both the direct acting agonists act directly on alpha or beta receptors producing effects similar to those produced from the stimulation of sympathetic nerves or from the release of epinephrine from the adrenal medulla examples of these agents are papaya frying nor pine a frying isoproterenol and vanilla frying the indirect acting agonists work either by blocking the reuptake of norepinephrine and increases the concentration of nor pi the frame and synapse so increases its effects such as cocaine or they enhance the release of Nohr pi the friend from the site plasmic vesicles of the energic neuron such as amphetamines and the mixed action agonists such as ephedrine and it's stereo summer pseudoephedrine both stimulate Adreno scepters directly and release nor pine a friend from the attorney jack neurons as we already know the direct acting agonists bind to adrenergic receptors on effector organs without interacting with the prison abdic neuron they are widely used clinically in two lectures we'll discuss a pie the frying noir pine a frying isoproterenol da pemain dobutamine phenol dope am exhumed is Olin Siloam dazzling formula frying clonidine albuterol and turbot Allen sama trawl in format a roll and mer be green let's talk about a pine a frying noir pie the friend and isoproterenol at the same time and make a simplified comparison for their actions there are pute accuses pharmacokinetics and adverse effects the three of them are catechol means as we already know a pie the friend Arn or pine a friend or also known as the gentleman and noradrenaline respectively are naturally occurring neurotransmitters and isoproterenol or also known as isoprene alone is a synthetic compound in the adrenal medulla nor pine afferent is methylated to produce a pine Afrin which is stored in gramophone cells along with noir pine if rhine on stimulation the adrenal medulla releases about 80% to pi the friend and 20% more pie the frying directly to the blood on the other hand nor pine a friend is the neurotransmitter of energy curves now let's talk about their actions in the body piloff Ryan interacts with both alpha and beta receptors at low doses beta effects predominate that means vasodilation in skeletal muscles blood vessels whereas at high doses alpha effects predominate which represent the vasoconstriction of the blood vessels the PI the friend strengthens the contractility of the myocardium and it also increases heart rate by acting on beta 1 receptors in the heart therefore cardiac output increases so the myocardium will need more oxygen to work upon the fryin activates beta 1 receptors in the kidney causing Rieman release which is an enzyme involved in the production of a potent vasoconstrictor called angiotensin 2 the pie the friend causes vasoconstriction in the skin mucous membranes and viscera by acting on alpha-1 receptors which slightly increases peripheral resistance and it dilates vessels going to the liver and skeletal muscle by acting on beta 2 receptors and that significantly decreases peripheral resistance and the some of that of course is a decrease in the peripheral resistance renal blood flow is also decreased so an increase in heart rate and a decrease in the peripheral resistance means an increase in systolic blood pressure coupled with a slight decrease in diastolic blood pressure what about noir pine if Rhine well it is supposed to work on alpha and beta receptors as it is the neurotransmitter of energy nerves but actually it works mostly on alpha receptors with slight effect on beta receptors so we can conclude that nor Piatt friend causes an intense vasoconstriction by acting on alpha one receptors while no compensatory vasodilation via beta 2 receptors on blood vessels supplying skeletal muscles leading to a rise in peripheral resistance both systolic and diastolic blood pressures increase to overcome this intense increase in the blood pressure the body has to make an action so what would it be it is the baroreceptor reflex when Noor piloff Ryan increases blood pressure this simulates the baro receptors inducing a rise in vagal activity which is a parasympathetic activity and that produces reflex bradycardia accordingly blood pressure decreases isoproterenol stimulates both beta-1 and beta-2 adrenergic receptors it is rarely used therapeutically because of its nan selectivity its action on alpha receptors is insignificant it produces intense stimulation of the heart upon acting on beta 1 receptors just as a pie the frying it increases heart rate contractility and cardiac output it also causes vasodilation of skeletal muscle blood vessels by acting on beta 2 receptors with an insignificant effect on alpha receptors they would result in a sniffing decrease in peripheral resistance because of its cardiac stimulatory action it may increase systolic blood pressure slightly and it greatly reduces diastolic blood pressure isoproterenol is a potent bronchodilator by acting directly on bronchial smooth muscle beta 2 receptors back to a pine a frying it is also a powerful bronchodilator by acting on beta 2 receptors and lungs it also inhibits the release of allergy mediators such as histamine from mast cells while nor pi the fryin has a very weak beta to activity so it almost has no effect is a bronchodilator a PI the friend has a significant hyperglycemic effect as it increases glycogenolysis in the liver by acting on beta 2 receptors and it also increases the release of glucagon by acting on beta 2 receptors and decreases the release of insulin by acting on alpha 2 receptors upon the fryin also initiate slip will assist by acting on beta receptors of adipose tissue after talking about their actions let's talk about their therapeutic uses a PI the friend is the primary drug used in the emergency treatment of respiratory conditions and it can be a life-saving in these cases so it is the drug of choice in treatment of acute asthma and anaphylactic shock and it is also the drug of choice for the treatment of type 1 hypersensitivity reactions including anaphylaxis in response to allergens it may also be used to restore cardiac rhythm in patients with cardiac arrest it is used with local and esthetic solutions to increase the duration of local anaesthesia by producing vasoconstriction at the site of injection and this allows the local anesthetic to persist at the injection site for a longer time before being absorbed into the systemic circulation and very weak solutions of a PI the friend can also be applied topically to vasoconstrict mucous membranes and control losing of capillary blood such as nose bleeding while nor pi the friend is used to treat shock because it increases vascular resistance and that increases blood pressure but it has no other clinically significant uses the use of isoproterenol has largely been replaced with other drugs because of its non selectivity but it may be used as intravenous injection in case of cardiac arrest heart block and shock and also in management of bronchospasm during anesthesia let's now talk about their pharmacokinetics as all of them are catecholamines so as we discussed in the previous lecture they are rapidly metabolized by Mao and comped and their metabolites are excreted in urine the pie the fryin has a rapid onset and a brief duration of action the preferred route is intramuscular in the anterior thigh due to rapid absorption but in emergency cases the pine afferent is given intravenously to provide the most rapid onset of action it may also be given subcutaneously by endotracheal tube and by inhalation nor pi the friend and isoproterenol are given intravenously for rapid onset of action and finally the adverse effects a pine a friend can produce adverse CNS effects that include anxiety fear tension headache and tremor the pie the frying dose should be monitored with some patience as it can trigger cardiac arrhythmias particularly if the patient is receiving digoxin it may enhance cardiovascular actions in patients with hyperthyroidism so the dose must be reduced in these individuals it increases the release of endogenous stores of glucose so in diabetic patients dosages of insulin may have to be increased it can also induce pulmonary edema and some drug interactions may also be a problem inhalation anesthetics also sensitize the heart to the effects of a pine a frying which may lead to tachycardia non-selective beta blockers prevent versitility effects of a pie the frying on beta 2 receptors leaving alpha receptor stimulation unopposed which leads to increased peripheral resistance and increased blood pressure nor pine the friends adverse effects are similar to a pine if Rhine in addition nor pie the friend is a potent vasoconstrictor so if leakage of drug from the vessel into tissue surrounding the injection site occurs it can cause tissue necrosis so it should not be administered in peripheral veins if possible alpha receptor antagonists which we'll discuss later can be used to counteract the impaired circulation produced from nor pine if Rhine and finally the adverse effects of isoproterenol are similar to those of a pine affine so as you see you can remember these three drugs by the piloff Rhine alpha and beta nor pine a fine mostly alpha and isoproterenol mostly beta you so we're going to talk about dopamine dobutamine phenol dope am exhumed is alene Salam to Saleem phenylephrine clonidine albuterol and terbutaline sama trial and for materal myrrh be Agron let's discuss their actions there are pute accuses adverse effects and brand names dopamine as we discussed before is the immediate metabolic precursor of norepinephrine it is found naturally in the CNS in the basal ganglia where it functions as a neurotransmitter as well as in the adrenal medulla it can activate alpha and beta adrenergic receptors in addition to d1 and d2 dopaminergic receptors at low doses it stimulates beta one cardiac receptors of the heart having both positive inotropic and Poorna tropic effects whereas at higher doses it causes vasoconstriction by activating alpha 1 receptors d1 and d2 dopaminergic receptors occur in the peripheral mesenteric and renal vascular beds where a binding of dopamine produces vasodilatation thereby increasing blood flow to the kidneys and other viscera d2 receptors are also found on presynaptic genetic neurons where their activation increases nora pi the friend release dopamine is the drug of choice for cardiogenic and septic shock and is given by continuous infusion it raises blood pressure by stimulating beta 1 receptors in the heart to increase cardiac output an increased total peripheral resistance by acting on alpha 1 receptors on blood vessels in addition it enhances profusion to the kidney accordingly it enhances the glomerular filtration rate and causes diuresis so it is better than nor piloff earn which diminishes blood supply to the kidney and may cause renal shutdown it is also used to treat hypotension and severe heart failure dopamine is rapidly metabolized by Mao or calmed as it is a catecholamine an overdose of dopamine produces the same effects as sympathetic stimulation and it has some adverse effects such as nausea hypertension and arrhythmias dobutamine is a synthetic direct acting catacomb and that is a beta one receptor agonist so it increases heart rate and output it increases cardiac output and does not significantly elevate oxygen demands of the myocardium which is a major advantage over other sympathy mimetic drugs so it is used to increase cardiac output an acute heart failure as well as from a tropic support after cardiac surgery but it should be used with caution in that real fibre elation because it increases AV conduction phenotype M is an agonist of peripheral dopamine d1 receptors it is used as a rapid acting Vista deliver to treat severe hypertension in hospitalized patients acting on coronary arteries kidney arterioles and mesenteric arteries it has some adverse effects such as headache flushing dizziness nausea vomiting and tachycardia as a reflex to vasodilation oxymetazoline is a direct acting synthetic a journalist that stimulates both alpha-1 and alpha-2 adrenergic receptors it is found as nasal spray decongestants as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming colds and contact lenses agzam de saline directly stimulates alpha receptors on blood vessels supplying the nasal mucosa and conjunctiva producing vasoconstriction and decreasing congestion it is absorbed in the systemic circulation and may produce nervousness headaches and trouble sleeping local irritation and sneezing may occur with internal administration rebound congestion and dependence are observed with long-term use xylem dessaline is an alpha adrenergic agonist it is used directly in the nose as a spray or drops to improve symptoms of nasal congestion allergic rhinitis and sign news itis side effects include trouble sleeping irritation of the nose nausea and headache long-term use is not recommended due to rebound congestion independence Aniela freen is a direct acting synthetic adrenergic drug that binds primarily to alpha 1 receptors so it is a vasoconstrictor that raises both systolic and diastolic blood pressures it acts as a nasal decongestant when applied topically or taken orally large doses can cause hypertensive headache and cardiac irregularities clonidine is an alpha-2 agonist decreasing sympathetic outflow so it is used for the treatment of hypertension it can also be used to minimize the symptoms that accompany withdrawal from opiates tobacco smoking and benzodiazepines the most common side effects of clonidine are lethargy sedation constipation and xerostomia abrupt discontinuance must be avoided to prevent a rebound hypertension albuterol or also known as salbutamol and terbutaline are short-acting beta-2 agonists used primarily as bronchodilators and administered by a metered dose inhaler albuterol is the short-acting beta-2 agonist of choice for the management of acute asthma symptoms salmeterol and for mature all are long-acting beta 2 agonists a single dose by a metered dose inhaler chien device such as a dry powder inhaler provides sustained bronchi delation over 12 hours compared with less than three hours for albuterol these agents are usually combined with a corticosteroid to produce the highest effect salmeterol and for mature all are the agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medications Moe Bergeron is a beta 3 agonist that relaxes the Detra sir smooth muscle and increases bladder capacity it is used for patients with overactive bladder as we said before the indirect acting adrenergic agonists cause the release inhibit the reuptake or inhibit the degradation of a pine a fern or nor pine Afrin they potentiate the effects of a PI the Freneau nor pi the frame produced endogenously but do not have a direct effect on the postsynaptic receptors empty mean the first thing you should know about it that it has a strong stimulant effect on the CNS and it is highly addictive drug amphetamine acts by releasing intracellular stores of catecholamines such as noir pine afferent and dopamine it also inhibits mal and is a weak reuptake transport inhibitor so high levels of catecholamines are readily released into synaptic spaces leading to a marked CNS stimulation and an increase in blood pressure and heart stimulation its therapeutic use is limited due to psychological and physiological dependence but it is used in certain conditions such as attention deficit hyperactivity disorder or known as ADHD which is a condition in some young children characterized by hyperkinetic and lack the ability to be involved in any activity for longer than a few minutes it is also used in narcolepsy which is a relatively rare sleep disorder that is characterized by uncontrollable bouts of sleepiness during the day and also used in appetite suppression more information about HAMP demean and its derivatives will be discussed in the cns lectures tyramine is another agent that enhances the release of catecholamines from nerve terminals increasing their concentration in synapse and potentiating their effects actually it is not a clinically useful drug but it is important because it is found in fermented food such as aged cheese and ghee on t wine it is a normal byproduct of tyrosine metabolism normally it is oxidized by Mao in the gastrointestinal tract but it can precipitate serious the suppressor episodes and patients receiving mao inhibitors cocaine is a widely available and highly addictive drug it acts by blocking the reuptake of the catecholamines into the presynaptic terminals thus increasing the amount of catecholamines available at the synapse and this potentiates and prolongs the CNS and peripheral actions of these catecholamines the prolongation of dopaminergic effects in the brains pleasure system which is called the limbic system produces the intense euphoria that cocaine initially causes but chronic intake of cocaine depletes top.mine and that triggers craving for cocaine that temporarily relieves severe depression more information will be discussed in the CNS lectures now let's talk about the last type of the energy Karagounis --ts the mixed action Adreno joke agonists they both act by enhancing the release of stored nor pine a friend from nerve endings and also directly stimulate both alpha and beta receptors such as ephedrine and pseudoephedrine they are not catecholamines and our poor substrates for calmed and mal so they have a long duration of action they are absorbed orally and they penetrate into the CNS but pseudoephedrine has fewer CNS effects ephedrine is eliminated largely unchanged in urine and pseudoephedrine undergoes incomplete hepatic metabolism before elimination in urine a fettering produces a mild CNS stimulation it also raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation it also produces bronchi delation but it is less potent and slower acting than a pine afferent I support arenal so it can be used to prevent asthma attacks it can also be used as oral nasal decongestant veteran is primarily used orally to treat nasal and sinus congestion but it has been illegally used to produce methamphetamine so products containing pseudoephedrine have certain restrictions

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Keywords: adrenergic receptors, adrenergic system, sympathomimetic drugs, adrenergic and cholinergic pharmacology, adrenergic drugs, adrenergic agonist, receptors pharmacology, adrenergic agonists, adrenergic pharmacology, adrenergic antagonist, catecholamines, noncatecholamines, agonists, adrenergic vs cholinergic, norepinephrine, clonidine, phenylephrine, antagonists, epinephrine, pharmacology, autonomic nervous system, sympathetic nervous system, pseudoephedrine, adrenergic drugs pharmacology

Id: EYREpPzsIIE

Length: 33min 1sec (1981 seconds)

Published: Fri Sep 20 2019