Pharmacology Mod 1: Adrenergic Agonists PDF

PHARMACOLOGY 08/20/2024 MOD 1: ADRENERGIC AGONISTS Dr. M. Oliver...

PHARMACOLOGY 08/20/2024 MOD 1: ADRENERGIC AGONISTS Dr. M. Oliver Trans Group/s: TM, NC, AS, IV, MC, KC I. REVIEW Primary Primary Endogenous catecholamine catecholamin catecholamine A. ADRENERGIC AGONIST VS ADRENERGIC neurotransmitter in e hormone predominantly ANTAGONIST the peripheral released from located in the sympathetic adrenal CNS AGONIST ANTAGONIST nervous system medulla Drugs that “Adrenoblockers” Acts in innervated Secreted into STIMULATE response INHIBITS the tissues locally the blood from the adrenergic action of circulation receptors: α1, α2, β1, Epinephrine, and acts as a β2, β3 Norepinephrine, hormone, Mimics the function of and other which effects SNS: “Fight or flight” Catecholamines dependent on Response Sympatholytic its circulating ○ Increase Heart drugs concentration Rate ○ Increase Cardiac Clinical importance: Drugs acting to alter sympathetic Output and adrenergic responses are used for a myriad of ○ Increase Skeletal clinical disorders including hypertension, asthma, heart Muscle failure, and anaphylactic reactions. Vasodilation ○ Cutaneous and III. CLASSIFICATION: BASED TO ACTIONS OF Gastrointestinal SYMPATHOMIMETIC AGENTS Vasoconstriction ○ Pupillary Dilatation ○ Bronchial 7 BROAD TYPES Dilatation ○ Piloerection Smooth muscle (e.g., blood vessels supplying skin, kidney Peripheral 1 and mucous membranes) II. ADRENERGIC AGONISTS Excitatory Gland cells (e.g., salivary & Agents or drugs that act on the adrenergic system may sweat glands) mimic the actions of endogenous catecholamines, block their synthesis or release, or antagonize their Other types of smooth muscle, wall effects at the level of adrenergic receptors on cell Peripheral 2 of the gut, bronchial tree, in blood membranes Inhibitory vessels supplying skeletal muscle Drugs can be classified by: ○ Sympathomimetic drug: drug that enhances the Increases heart rate, force and adrenergic function Cardiac 3 rate, an extent of contraction and ○ Sympatholytic drug: drug that interrupts or inhibits Excitatory rate of relaxation adrenergic function Increases in the rate of glycogenolysis in liver and muscle 4 Metabolic and liberation of free fatty acids from adipose tissue Modulation (increasing or decreasing) of the secretion of Catecholamines are released from your neurons within 5 Endocrine insulin, renin and pituitary the SNS hormones ○ Part of ANS ○ Role in events related to danger or stressful Respiratory stimulation, increase situations 6 CNS in wakefulness and psychomotor ○ Controls heart rate, blood pressure, digestion, activity and reduction in appetite urination and sweating Inhibit or facilitate the release of NOREPINEPHRINE EPINEPHRINE DOPAMINE neurotransmitters 7 Prejunctional Inhibitory action: physiologically more important Pharmacology- Mod 1 Adrenergic Agonists 1 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  norepinephrine release Prototypic drug: Entacapone → effectively increasing transmitters supply MIXED-ACTING Drugs that indirectly release norepinephrine and directly Effects are blunted activate receptors but not abolished by prior treatment Prototypic drug: Ephedrine Classification of Sympathomimetic Agents or Adrenergic with reserpine or Drug Agonists. guanethidine → abrupt response Agonists: drugs that stimulates a response from the BUT NOT totally adrenergic receptors on the surface of the cell inhibited ○ Gets activated when they bind a type of neurotransmitter such as catecholamines Catecholamines and sympathomimetic drugs are Direct or indirect sympathomimetics ultimately cause classified as: activation of adrenoceptors leading to some or all of the characteristic effects of endogenous catecholamines Pharmacologic effects of direct agonist depend on: CLASSIFICATION OF CATECHOLAMINES AND ○ Route of administration SYMPATHOMIMETIC DRUGS ○ Relative affinity for adrenoceptors subtypes ○ Relative expression of this receptors subtypes in DIRECT-ACTING DIRECT ACTING SELECTIVE target tissues Drugs that act directly on Responses are not one or more adrenergic A. BIOCHEMICAL STRUCTURE OF reduced by prior receptors, may exhibit SYMPATHOMIMETICS treatment with considerable selectivity reserpine or E.g., guanethidine, which ○ ⍺1-phenylephrine depletes ○ ⍺2-clonidine norepinephrine from ○ β1-dobutamine sympathetic neurons ○ β2-terbutaline DIRECT ACTING NONSELECTIVE Drugs that has no or minimal selectivity E.g., ○ ⍺1 ⍺2-oxymetazoline ○ β1 β2-isoproterenol ○ ⍺1 ⍺2 β1 β2-epinephrine ○ ⍺1 ⍺2 β1-norepinephrine Structures and Main Clinical Uses of Important Sympathomimetic Drugs. INDIRECT-ACTING RELEASING AGENTS Releasing or displacing Parent structure: β-phenylethylamine consisting of a Responses are norepinephrine from benzene ring and an ethyl amine side chain abolished by prior sympathetic nerve varicosities Presence of OH groups at the 3rd and 4th positions treatment with of the benzene ring yield sympathomimetic drugs reserpine or Prototypic drug: Amphetamine collectively known as catecholamines (e.g. guanethidine epinephrine, norepinephrine, dopamine, isoproterenol). meaning response is UPTAKE INHIBITORS inhibited Inhibits the transport of norepinephrine into sympathetic Increases the neurons availability of norepinephrine or Prototypic drug: Cocaine epinephrine to inhibition thereby increases the stimulate adrenergic dwell time of the transmitter at the receptors by several receptor mechanisms MAO INHIBITORS Pharmacologic Blocking the metabolizing effects of indirect enzymes such as Monoamine sympathomimetic Oxidase (MAO) effects are greater under conditions of Prototypic drug: Selegiline increased sympathetic COMT INHIBITORS activity and Catechol Structure. Catechol-O-methyltransferase Pharmacology - Mod 1 Adrenergic Agonist 2 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Substitution or any changes on ethylamine side chain Conversely, the larger the substituent on the amino give rise to a new biological structure. group, the lower is the activity at α receptors. For example: ○ Isoproterenol is very weak at α receptors β2-selective agonists generally require a large amino substituent group. ○ In general, the smaller the substitution on the amino group, the greater is the selectivity for α activity ○ However, the N-methylation increases the potency of primary amines. ○ Thus, alpha activity is maximal in epinephrine and almost absent in isoproterenol 3. SUBSTITUTION ON THE ALPHA CARBON Substitutions at the alpha carbon (ephedrine and amphetamine) block oxidation by monoamine oxidase (MAO), thus prolonging the duration of action of these drugs. ○ MAO, together with COMT, are important metabolizing enzymes that increase neurotransmitter supply. Enhanced ability to displace catecholamines from storage sites in noradrenergic nerves. ○ A portion of their activity is dependent on the presence of normal epinephrine stores in the body Structures and Main Clinical Uses of Important ○ They are indirectly acting sympathomimetics Sympathomimetic Drugs. ○ Compounds with an alpha methyl substituent persist in the nerve terminals and are more likely B. IMPORTANT CONCEPTS REGARDING THE to release epinephrine from storage sites. STRUCTURE OF SYMPATHOMIMETICS ○ The duration of actions of drugs such as ephedrine and amphetamine are measured in hours rather 1. SUBSTITUTION ON THE BENZENE RING/AROMATIC than minutes. NUCLEUS 4. SUBSTITUTION ON THE BETA CARBON PRESENCE OF BENZENE ABSENCE OF BENZENE Substitution of -OH groups on the beta carbon facilitates RING RING activation of adrenoreceptors. ○ The hydroxyl group may also be important for the Presence of -OH groups The potency or ability to storage of sympathomimetics or amines in the make catecholamines cause an effect in the alpha neural vessels subject to inactivation by receptor is reduced → beta Generally decreases actions within the CNS, largely catechol-o-methyltransfe receptor activity is because it lowers lipid solubility rase (COMT), and because minimal ○ However, such substitution greatly enhances this enzyme is found in the agonist activity at both alpha and beta adrenergic gut and liver, receptors. catecholamines are not ○ Ephedrine is less potent than methamphetamine active orally as a central stimulant. It is more powerful in dilating bronchioles and increasing blood pressure Rapidly inactivated in the Increases the and heart rate. intestinal mucosa and liver bioavailability after oral before reaching the administration and C. PHYSIOLOGIC BASIS OF ADRENERGIC systemic circulation prolongs the duration of RESPONSIVENESS action. Increases the distribution AGONIST BINDING TO RECEPTOR of the molecule to the central nervous system 1 The activation of G-protein coupled receptors by (CNS). catecholamines promotes the dissociation of guanosine diphosphate (GDP) from the alpha subunit of the corresponding G-protein. 2. SUBSTITUTION ON THE AMINO GROUP The effects of amino substitution are most readily seen 2 Guanosine triphosphate (GTP) then binds to the in the actions of catecholamines on α and β receptors G-protein and the alpha subunit dissociates from the Increasing the size of alkyl substituents on the amino beta-gamma subunit. group tends to increase β receptor activity. For example: 3 The activated GTP-bound alpha subunit then ○ Methyl substitution on norepinephrine, yielding regulates the activity of its effector. Effectors of epinephrine, enhances activity at β2 receptors adrenoceptor activated alpha subunits include: ○ Isopropyl substitution, yielding isoproterenol, Adenylyl Cyclase increases beta activity further Pharmacology - Mod 1 Adrenergic Agonist 3 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  D. RECEPTOR TYPES Phospholipase C Ion channels 4 The alpha subunit of this G-protein activates the effector. Example: Activation of Phospholipase C → release of inositol triphosphate (IP3) and diacylglycerol (DAG) from the phosphatidylinositol bisphosphate → release of sequestered stores of calcium → increased concentration of cytoplasmic calcium Adrenergic agonist binding to alpha-1 receptor The alpha-1 receptors coupled through G proteins regulate various effector proteins. Each G-protein is a heterotrimer consisting of alpha, Distribution of Receptor Subtypes beta, and gamma subunits. 1. ALPHA RECEPTORS All of these sequences of metabolic signals and receptor binding have a net effect of phosphorylation and activation that targets the protein that amplify the signal into cellular growth cascade which is critical for ALPHA 1 ALPHA 2 regulating: RECEPTORS RECEPTORS ○ Fatty acid ○ Cholesterol Coupled to the ○ Carbohydrates Coupled via G inhibitory Coupled ○ Amino acids proteins of the Gq regulatory protein related ○ Metabolism family to Gi that reduces proteins ○ Autophagy phospholipase C adenylyl cyclase ○ Mitochondrial function activity ○ Cell growth. In short, with the net effect of regulating a signal Presynaptic transduction autoreceptors that Location Post synaptic temper norepinephrine release Decreases intracellular levels of cAMP → decreased Increase calcium cytoplasmic Net effect → mediates calcium → excitatory effects decreases neurotransmitter release and central vasodilation Phospholipase C hydrolyzes polyphosphoinositide → formation of inositol triphosphate (IP3) and diacylglycerol (DAG) Pharmacology - Mod 1 Adrenergic Agonist 4 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Inositol triphosphate (IP3) → release of sequestered 1.1 Actions of Epinephrine intracellular stores of calcium → increased concentration of cytoplasmic calcium → activate Actions include sweating, piloerection, and mydriasis various calcium-dependent protein kinases and other (depending on the physiological state of the subject) calmodulin regulated proteins The prominent effect of epinephrine is on the heart, Alpha 1 receptors are mainly involved in contraction of vascular system, and in smooth muscles. smooth muscle compared to alpha 2 receptors which It has direct effects on cardiovascular stability have a variety of functions. regulating blood pressure. Epinephrine also affects the following: 2. BETA RECEPTORS ○ Blood pressure ○ Vascular effects Coupled protein: Stimulatory regulatory protein Gs ○ Cardiac effects Net effect: activates adenylyl cyclase → increase ○ Non vascular smooth muscle intracellular levels of cAMP → neurotransmitter ○ Respiratory release ○ CNS ○ Second messenger system that mediates most of ○ Metabolic the actions of the β receptors ○ Miscellaneous ○ In the liver, cAMP mediates a cascade of events culminating in the activation of glycogen phosphorylase ACTIONS OF EPINEPHRINE PER SYSTEM ○ In the heart, cAMP increases the influx of calcium across the cell membrane → action potential → The mechanism of the rise in BP muscle contraction due to EPI is a triad of effects: ○ In smooth muscle, cAMP promotes relaxation ○ A direct myocardial stimulation through phosphorylation of myosin light-chain that increase the strength of kinase to an inactive form ventricular contraction due to The β3 adrenoceptor is a lower-affinity receptor stimulation of beta-adrenergic compared with β1 and β2 receptors but is more resistant receptors (increasing cardiac to desensitization. output, positive inotropic ○ β3 receptors are expressed in the detrusor muscle action) of the bladder and induce its relaxation. EXAMPLE: Hypovolemic ○ Mirabegron is a selective β3 agonist used clinically shock for the treatment of symptoms of overactive bladder For instance, a patient is (urinary urgency and frequency). hypotensive due to sepsis, BP 80/50. To increase the 3. DOPAMINE RECEPTORS BP, stimulating the beta receptors can cause a positive inotropic effect on E. ENDOGENOUS CATECHOLAMINES the cardiac muscle, increasing its driving force for an action potential–leading to a ventricular contraction improving total cardiac output. Blood ○ An increased heart rate due to Main Sites of catecholamines. Pressure beta receptors (positive chronotropic action) Epinephrine is a neurotransmitter and a hormone in the Cardiac Output = Heart sympathetic nervous system. Rate x Stroke Volume Norepinephrine is a neurotransmitter and a hormone in To increase BP, there the adrenal medulla. should also be an increase BOTH Epi and NE are important during fight or flight in HR simulated by responses. adrenergic agonist beta receptors. 1. EPINEPHRINE (EPI) OR ADRENALINE ○ Vasoconstriction in many Potent stimulant of both alpha and beta adrenergic vascular beds–especially in the receptors, thus, its effects on target organs are precapillary resistance vessels complex of skin, mucosa, and The structure of epinephrine has various effects: kidney–along with marked ○ On alpha receptors: specifically on allergic constriction of veins due to net reactions, blood pressure, and can elicit local stimulation of α-adrenergic vasoconstriction. receptors ○ On beta receptors: bronchodilation and direct In general, heart rate, cardiac cardiac effect output, stroke volume, and left ventricular work per beat are increased as a result of direct cardiac stimulation and increased venous return to the heart, which is reflected by an increase in right Structure of Epinephrine and its receptors atrial pressure. Pharmacology - Mod 1 Adrenergic Agonist 5 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Acts strictly on smaller arterioles potential is shortened and the and precapillary sphincters (veins refractory period is decreased and large arteries are also affected). Induction of automaticity in Skeletal muscles: blood flow is specialized regions of the heart — increased by therapeutic doses in large doses of EPI may cause humans, due to the powerful beta-2 premature ventricular contraction and mediated vasodilator action that is more serious ventricular arrhythmias only partially counterbalanced by a vasoconstrictor action on α receptors GI: also present in the vascular bed ○ In general, EPI relaxes GI Cerebral circulation: related to smooth muscle due to systemic BP; in usual therapeutic activation of both α and β doses, EPI has a relatively little receptors constrictor action on cerebral ○ Intestinal tone and the arterioles frequency and amplitude of Renal vasculature: spontaneous contractions are ○ Increased renal vascular reduced resistance and reduced renal Non Uterus: responses are variable (e.g., blood flow by as much as 40% vascular during the last month of pregnancy ○ Glomerular filtration rate is Smooth and at parturition, EPI inhibits uterine only slightly and variably altered Muscle tone and contraction) ○ Filtration fraction is Bladder: consistently increased ○ Beta receptors: relaxes the ○ Decreased excretion of Na+, detrusor muscles of the bladder Vascular K+, and Cl- ○ Alpha agonist activity: Effects ○ Urine volume may be contracts the trigone and increased, decreased, or sphincter muscles unchanged Prostate: activation of smooth ○ Maximal tubular reabsorptive muscle contraction in the prostate and excretory capacities are promotes urinary retention unchanged ○ Secretion of renin is increased EPI has a powerful bronchodilator Pulmonary vasculature: action most evident when bronchial ○ Arterial and venous muscle is contracted because of pulmonary pressures are disease, as in bronchial asthma, or in raised response to drugs or various ○ Very high concentration of EPI autacoids. may cause pulmonary edema Has a more profound precipitated by elevated Respiratory anti-inflammatory effects in asthma pulmonary capillary filtration System in clinical setting pressure and possibly by ○ Inhibition of antigen-induced “leaky” capillaries release of inflammatory Coronary blood flow: increased mediators from mast cells and ○ In an event of cardiopulmonary to a lesser extent from resuscitation, EPI is given to diminution of bronchial enhance the coronary blood flow secretions and congestion within to achieve a return of the mucosa spontaneous circulation following a cardiac arrest. EPI penetrates poorly into the CNS (because it is a polar compound), EPI is a powerful cardiac and thus, is NOT a powerful CNS stimulant, acting directly on the stimulant. predominant beta 1 adrenergic Effects (e.g., restlessness, receptors on the cardiomyocytes apprehension, headaches, tremors) and on the cells within the CNS are secondary to the effects of EPI pacemaker and conducting tissues on the cardiovascular system, β2, β3, and α receptors are also skeletal muscles, and intermediary present in the heart. metabolism (that is, may be the Increased contractile force result of somatic manifestations of Cardiac (inotropy) anxiety) Effects Accelerated rate of rise of isometric tension EPI elevates the concentrations of Enhanced rate of relaxation glucose and lactate in the blood (lusitropy) Inhibition of secretion of insulin Decreased time to peak tension through an interaction with α2 Increased excitability Metabolism receptors Acceleration of the rate of Glucagon secretion is enhanced via spontaneous beating activation of beta receptors of the (chronotropy) — when the HR is alpha cells of pancreatic islets increased, the duration of action Pharmacology - Mod 1 Adrenergic Agonist 6 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  It decreases the uptake of glucose Mydriasis occurs with physiological by peripheral tissues (skeletal sympathetic stimulation but NOT muscles) when EPI is instilled into the It raises the concentration of free conjunctival sac of normal eyes fatty acids in blood by stimulating EPI facilitates neuromuscular beta receptors in adipocytes, transmission, particularly that primarily in beta 3 receptors → following prolonged rapid stimulation activation of triglyceride lipase → of motor nerves via stimulation of TAG breakdown → free fatty acids alpha receptors causes a more and glycerol rapid increase in transmitter Calorigenic action of EPI (increase release from the somatic motor in metabolism) is reflected in humans neuron, as a result of enhanced by an increase of 20% to 30% in O2 influx of Ca2+ consumption after conventional EPI promotes a fall in plasma K+ doses, an effect due mainly to largely due to stimulation of K+ enhanced breakdown of triglyceride uptake into cells particularly in brown adipose tissue (via beta 3 skeletal muscle, due to activation of receptors), providing an increase in beta 2 receptors. oxidizable substrate. In clinical settings, ○ Cases of septic shock: 1.2 Epinephrine vs. Norepinephrine patients (even those who are non-diabetic) will have hyperglycemia. This is because the body senses stressful events, activating the CNS and neuroendocrine systems, which releases hormones such as catecholamines. ○ Cases of hypovolemic shock: as the body senses continuous and severe blood loss in patients (e.g., due to a gunshot wound), the body compensates by increasing the heart rate to compensate for inadequate blood volume Comparative Effects of EPI and NE. NOTE: HR, contractility and ventricular wall tension are 3 Cardiac Effects important factors that determine ○ EPI has a more chronotropic effect (increases the myocardial O2 demand. heart rate), generally increasing the cardiac output compared to NE. ○ In terms of stroke volume and coronary blood flow, Miscellaneo EPI reduces circulating plasma both EPI and NE can contribute to total cardiac us volume by loss of protein-free fluid output. to the extracellular space, thereby ○ Both EPI and NE can induce arrhythmias. increasing hematocrit and plasma Blood Pressure protein concentration ○ NE is seen to be more effective to increase systolic EPI rapidly increases the number of arterial, mean arterial, diastolic arterial, and mean circulating polymorphonuclear pulmonary pressure. leukocytes, likely due to beta Peripheral Circulation receptor-mediated de-margination of ○ EPI is more effective in increasing peripheral these cells circulation as compared to NE. EPI accelerates blood coagulation ○ In terms of total peripheral pressure, NE is and promotes fibrinolysis advantageous compared to EPI. The effects of EPI on secretory Metabolic Effects glands are not marked; in most ○ EPI significantly affects metabolic processes in the glands, secretion is usually is body — increasing O2 consumption, blood inhibited, partly owing to the reduced glucose, lactic acid, and has an eosinophilic blood flow caused by response. vasoconstriction CNS EPI stimulates lacrimation and ○ Both EPI and NE have similar effects on scanty mucus secretions from respiration and sensation. salivary glands Sweating and pilomotor activity 1.3 Pharmacokinetics of Epinephrine are minimal after systemic administration of EPI but occur after intradermal injection of very dilute PHARMACOKINETICS OF EPINEPHRINE solutions of either EPI or NE. Such effects are inhibited by alpha Ineffective via oral administration — receptor antagonists. Absorption rapidly conjugated and oxidized in the GI mucosa and liver Pharmacology - Mod 1 Adrenergic Agonist 7 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Prolong the action of local anesthetics, Slow absorption in subcutaneous presumably by decreasing local blood flow and tissue due to vasoconstriction effect reducing systemic absorption Absorption is more rapid after ○ Topical hemostatic agent on bleeding surfaces: intramuscular injection peptic and duodenal ulcers In emergencies, it may be ○ Systemic absorption of the drug can occur with necessary to administer EPI dental application. intravenously (e.g. during ○ Inhalation of EPI may be useful in the treatment of anaphylaxis) postintubation and infectious croup. Lungs: nebulization/inhalation restricted to the respiratory tract (however, in larger amounts, can Patient X 57/M was brought to ER unresponsive, BP 0, cause systemic reactions such as Asystole, gasping and was immediately intubated. arrhythmias) Immediate ACLS was done. Patient has unknown medical history and was brought by a bystander Distribution Systemic What medication should we use to achieve ROSC Rapidly inactivated in the liver by (Return of Spontaneous Circulation)? EPINEPHRINE COMT 1mg/mL: 1mL given every 3 minutes (catechol-O-methyltransferase) and MAO (monoamine oxidase) After continuous chest compression and ACLS, patient COMT and MAO are widely noted with ROSC after 4th epinephrine was given. BP was Metabolism distributed with high concentration 70 palpatory, HR 140 (sinus tachycardia on scope) RR 20 in the liver, brain, and O2 sat 88% sympathetic nervous system. Both are important metabolizing What is the receptor activated by epinephrine? β1 enzymes which effectively increase Receptor EPI supply. What is the drug classification of epinephrine? Direct Acting Non-Selective Adrenergic Receptor Agonist α1, α2, β1, β2 Kidneys: urine Excretion Clinical: pheochromocytoma A.D. 47/M known hypertensive and with dyslipidemia on 1.4 Toxicity, Adverse Effects, and Precautions of maintenance medications with good compliance. He is a Epinephrine mountain climber and had to hike at Mt. Pico De Loro. During the hike, the patient had contact with an unknown plant and developed a sudden onset of itchiness and TOXICITY, ADVERSE EFFECTS, AND generalized rashes. Patient complained of dizziness CONTRAINDICATIONS OF EPINEPHRINE followed by difficulty breathing and decided to postpone the hike and immediately went to the hospital. At ER, BP was May cause restlessness, 80/50 HR 123 RR 30 Afebrile, O2 Sat 85% patient noted throbbing headache, tremor, wheezing all over and tachycardic with noted generalized and palpitations urticaria. Mild Effects rapidly subside with quiet, rest, recumbency, and What is the diagnosis? Anaphylactic Shock reassurance. probably secondary to allergic contact dermatitis Use of large doses or What is the medication of choice for this patient? accidental rapid intravenous Epinephrine injection of EPI may result to cerebral hemorrhage from What is the adrenergic receptor stimulated? What is sharp rise in blood pressure the effect of Epinephrine in the bronchial smooth Serious Ventricular arrhythmias may muscle? β2 Receptor, Bronchial Smooth Muscle follow EPI administration Relaxation Angina may be induced by EPI in patients with coronary Patient was advised admission and full workup was done artery disease including FBS and lipid profile. Results show elevated cholesterol and triglyceride levels and was started on Patients who are receiving Atorvastatin 40mg/tablet ODHS. After 30 minutes, the non-selective 𝛽-receptor patient was complaining of severe headache and antagonists because its dizziness. Vital signs were stable however, the patient Contraindication unopposed actions on vascular presented with slurring of speech. 𝛼1-receptors may lead to severe hypertension and cerebral What is the most serious complication of epinephrine hemorrhage. use? Cerebral Hemorrhage 1.5 Therapeutic Uses of Epinephrine 2. NOREPINEPHRINE (NE) Hypersensitivity reactions, including anaphylaxis, to AKA levarterenol or l-noradrenaline or drugs and other allergens. l-𝛽-[3,4-dihydroxyphenyl]-𝛼-aminoethanol Cardiovascular: restoration of cardiac rhythm in Is a major chemical mediator liberated by mammalian patients with cardiac arrest due to various causes. postganglionic sympathetic nerves Anesthesia Pharmacology - Mod 1 Adrenergic Agonist 8 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Structurally, NE differs from EPI since it lacks the methyl substitution in the amino group. Via urine Small amounts are normally present in urine Excretion The excretion rate may be greatly increased in patients with pheochromocytoma Norepinephrine vs Epinephrine. 2.2. Toxicity, Adverse Effects, and Precautions of Norepinephrine NE constitutes 10% to 20% of the catecholamine content of human adrenal medulla. Greater elevation of blood pressure with NE Pharmacologic properties of NE compared to EPI: Excessive doses can cause severe hypertension. ○ Both drugs are direct agonists on effector cells. Indicated with patients without any complications ○ Their actions differ mainly in their effectiveness ratio such as pre existing diseases on the kidneys and GIT. in stimulating 𝛼- and 𝛽2-receptors. Care must be taken that necrosis and sloughing do not ○ They are approximately equipotent in stimulating occur at the site of intravenous injection owing to 𝛽1-receptors. extravasation of the drug. ○ NE is a potent 𝛼 agonist and has relatively little Proper infusion handling — the infusion should be action on 𝛽2-receptors. high in the limb, preferably through a long plastic ○ NE is somewhat less potent than EPI on the cannula extending centrally. 𝛼-receptors of most organs. Impaired circulation at injection sites, with or without extravasation of NE, amy be relieved by infiltrating the 2.1. ACTIONS OF NOREPINEPHRINE area with phentolamine, an 𝛼-receptor antagonist. Blood pressure must be determined frequently during the infusion, particularly during adjustment of the rate of ACTIONS OF NOREPINEPHRINE PER SYSTEM the infusion. Reduced blood flow to organs, e.g. kidney and Systolic and diastolic intestines, is a constant danger with NE use. pressures and pulse pressure increased Cardiac output is unchanged A 35/F known diabetic and hypertensive with poor or decreased compliance with medication developed pimple-like lesions Total peripheral resistance is on the back and eventually progressed to swelling of the Cardiac Effects raised back with noted pus formation now associated with fever Stroke volume is increased and chills. The patient consulted at ER and noted BP of Peripheral vascular 80/40 HR 98 RR 20 Temp 39C O2 sat 98% CBG 480 resistance increases in most vascular bed What is your diagnosis? Septic shock probably Coronary flow usually is secondary to Cellulitis, T2DM Uncontrolled increased What inotropic support can we give to improve the patient’s blood pressure? Norepinephrine Drip. NE is Renal Effect Renal blood flow is reduced much preferred in cases of septic shock What is the drug classification of norepinephrine? Direct-Acting Non-Selective Adrenergic Agonist: Constricts mesenteric vessels Gastrointestinal α1, α2, β1 Reduces splanchnic and Effects hepatic blood flow Small doses does not cause vasodilation or lower blood Effects on pressure because the blood vessels Skeletal Muscle of skeletal muscle constrict rather than dilate Summary of the Effects of Epinephrine and Norepinephrine. Causes hyperglycemia in large 3. DOPAMINE (DA) Metabolic Effect doses PHARMACOKINETICS OF NOREPINEPHRINE NE, like EPI, is ineffective when given orally Absorption Is absorbed poorly from sites of Dopamine. subcutaneous injection AKA 3,4-dihydroxyphenylethylamine Distribution Systemic Is the metabolic precursor of NE and EPI Is a central neurotransmitter particularly important in Is rapidly inactivated by COMT the regulation of movement and possesses important Metabolism (catechol-O-methyltransferase) and intrinsic pharmacological properties MAO (monoamine oxidase) Pharmacology - Mod 1 Adrenergic Agonist 9 of 18 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  In the periphery, it is synthesized in epithelial cells of the proximal tubule and is thought to exert local Activation of D1-receptors on diuretic and natriuretic effects. renal tubular cells decreases Na+ transport by cAMP-dependent and cAMP-independent mechanisms. Increasing cAMP production in DOPAMINE RECEPTORS the proximal tubular cells and the medullary part of the thick STIMULATORY to adenylyl ascending limb of the loop of D1 RECEPTOR cyclase Henle inhibits the Na+-H+ exchanger and the INHIBITORY to adenylyl cyclase Na+,K+-ATPase pump. activity, opens potassium The renal tubular actions of DA D2 RECEPTOR channels, and decreases calcium that cause natriuresis may be influx. augmented by the increase in the renal blood flow and the small 3.1 Pharmacokinetics of Dopamine increase in the glomerular filtration rate that follows its DA is a substrate for both COMT administration. (catechol-O-methyltransferase) and MAO (monoamine The resulting increase in oxidase), hence, is ineffective when orally hydrostatic pressure in the administered. peritubular capillaries and reduction in oncotic pressure 3.2 Pharmacologic Effects of Dopamine may contribute to diminished reabsorption of Na+ by the ACTIONS OF DOPAMINE PER SYSTEM proximal tubular cells. At low concentration: 1.3 Precautions, Adverse Reactions, and ○ Primary interaction of DA is Contraindications with vascular D1-receptors, especially in Excessive sympathomimetic activity the renal, mesenteric, and Nausea, vomiting, tachycardia, anginal pain, coronary beds → adenylyl arrhythmias, headache, hypertension, and peripheral cyclase → raising vasoconstriction may be encountered during DA intracellular concentration infusion. of cAMP → stimulation → Extravasation of large amounts of DA during infusion vasodilation may cause ischemic necrosis and sloughing. At higher concentrations: ○ Rarely: gangrene of the fingers or toes has ○ Exerts a positive inotropic followed prolonged infusion of the drug effect on the myocardium → DA should be avoided or used at much lower doses if acting on 𝛽1 adrenergic the patient has received a MAO inhibitor. Cardiovascular receptors Careful adjustment of dosage is necessary for those System ○ Release of NE from nerve who are taking tricyclic antidepressants. terminals → indirectly It is only used intravenously, preferably into a large affecting the heart via NE vein to prevent perivascular infiltration. ○ Activates vascular ○ Extravasation may cause necrosis and sloughing 𝛼1-receptors → of surrounding tissue. vasoconstriction ○ The use of a calibrated infusion pump to control Low cardiac output associated the rate of flow is necessary. with compromised renal ○ The drug is administered at a rate of 2 to 5 ug/kg function per min; this rate may be increased by gradually up Increases systolic blood to 20 to 50 ug/kg per min or more as the clinical pressure and pulse pressure situation dictates. Total peripheral resistance ○ During the infusion, patients require clinical usually is unchanged when low assessment of myocardial function, perfusion of or intermediate doses of DA are vital organs such as the brain, and the production given. of urine. ○ Reduction in urine flow, tachycardia, or the DA is a major CNS development of arrhythmias may be indications to neurotransmitter. slow or terminate the infusion Central Injected DA usually has no Nervous central effects → does not 1.4 Therapeutic Uses — EFFECTIVE System readily cross the blood-brain barrier. Severe acute decompensated heart failure with oliguria and low or normal peripheral vascular Infusion of low doses of DA resistance causes an increase in Cardiogenic and septic shock Kidneys The duration of action of DA is brief, and hence, the rate glomerular filtration rate, renal blood flow, and Na+ excretion. of administration can be used to control the intensity of the effect. Pharmacology - Mod 1 Adrenergic Agonist