Basic principles of pharmacology PDF

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic DRUGS AFFECTING THE ADRENERGIC NERVOUS SYSTEM YFRM202 2  Welcome to this session Attendance password: Dob...

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic DRUGS AFFECTING THE ADRENERGIC NERVOUS SYSTEM YFRM202 2  Welcome to this session Attendance password: Dobutamine YFRM202 3  Lecture Overview In this lecture you can expect to learn about direct acting adrenergic agonists. You have previously learned about indirect-acting adrenergic drugs that may mimic or inhibit the sympathetic nervous system. In this lecture you will build upon that knowledge and further explore the effects of drugs that bind to and stimulate alpha and beta receptors. Throughout this lecture it will become clear that alpha 2 agonists inhibits the effects of the sympathetic nervous system though its negative feedback mechanism on adrenergic neurons. 4  Learning Outcomes At the end of this lecture, you should be able to:  Describe the adrenergic receptors in the body, their location and actions  Describe the actions, adverse effects and clinical uses of the mixed-acting sympathomimetic agonists  Describe the actions of the catecholamines on organ systems (including selectivity for specific adrenoceptors), their clinical uses and adverse effects  Describe the mechanisms of action of non-catecholamine adrenoceptor agonist drug classes with drug examples, their clinical uses and adverse effects 5  Adrenergic transmission Rang & Dale’s Pharmacology - Page 165 Goodman & Gilman's: The Pharmacological Basis of Therapeutics – Chapter 10 – Figure 10.2 ACh is also the neurotransmitter at cells of the adrenal medulla, where it acts on NN receptors to cause release of adrenaline and NA into the circulation, which stimulates the sympathetic nervous system 6  Adrenoceptors Adrenergic receptors include alpha and beta receptors, which NA binds to: Alpha receptors: α1, α2 Beta receptors: β1, β2, β3 Rang and Dale’s pharmacology. 2024. Chapter 15. Page 205. 7  α 1(A,B,D) α 2(A,B,C) β1 β2 β3 G protein Gq Gi/Go GS GS GS Characteristics of adrenoceptors coupling Second Phospholipase C ↓ cAMP ↑ cAMP ↑ cAMP ↑ cAMP messengers activation ↓ Calcium and effectors ↑ Inositol channels trisphosphate ↑ Potassium ↑ Diacylglycerol channels 2+ ↑ Ca Agonist NA > A ≫ ISO A > NA ≫ ISO ISO > NA > A ISO > A > NA ISO > NA = A potency order Selective Phenylephrine Clonidine Dobutamine Salbutamol Mirabegron agonists Oxymetazoline Terbutaline Salmeterol Formoterol Selective Prazosin Yohimbine Atenolol (Butoxamine) — antagonists Doxazosin Metoprolol Table 15.2 Characteristics of adrenoceptors Rang and Dale’s pharmacology. 2024. Chapter 15. Page 207. 8 Table 15.1 Distribution and actions of adrenoceptors Rang and Dale’s pharmacology. 2024. Chapter 15. Page 207. 9  Tissues and effects β1 β2 β3 Smooth muscle Blood vessels — Dilate — Bronchi — Dilate — Gastrointestinal tract — Relax — Uterus — Relax — Bladder detrusor — Relax Relax Seminal tract — Relax — Iris (radial muscle) — — — Ciliary muscle — Relax — Heart a Rate Increase Increase — a Force of contraction Increase Increase — Other tissues/cells Skeletal muscle — Tremor Thermogenesis Increased muscle mass and speed of contraction Glycogenolysis Liver (hepatocytes) — Glycogenolysis — Fat (adipocytes) — — Lipolysis Thermogenesis Nerve terminals Adrenergic — Increase release — Table 15.1 Distribution and actions of adrenoceptors Rang and Dale’s pharmacology. 2024. Chapter 15. Page 207. 10 Direct-acting sympathomimetic drugs Catecholamines and non- catecholamines YFRM202 11  Direct-acting sympathomimetic drugs Drugs that act as agonists at adrenergic receptors – α and β DIRECT-ACTING NON- CATECHOLAMINES SYMPATHOMIMETICS CATECHOLAMINES Brenner & Stevens’ Pharmacology. 2023. Chapter 8. Table 8.2 Pharmacologic effects and clinical uses of adrenoceptor agonists. Page 88. 12  Catecholamines (non-selective adrenergic receptor agonists) Each catecholamine consists of the catechol moiety and an ethylamine side chain Naturally occurring catecholamines include: Noradrenaline (norepinephrine) Endogenous sympathetic neurotransmitter Adrenaline (Epinephrine) Principal hormone of the adrenal medulla Synthetic catecholamines include: Isoprenaline (US- Isoproterenol) Dobutamine Brenner & Stevens’ Pharmacology. 2023. Chapter 8. Figure 8.5. Page 87. Figure 8.5. Structures of selected adrenoceptor agonists. Catecholamines contain the catechol moiety and an ethylamine side chain. The amine nitrogen substitution (R2) determines the relative affinity for α- and β-adrenoceptors, with larger substitutions (e.g., in isoproterenol and dobutamine) decreasing the affinity for α-adrenoceptors and increasing the affinity for β-adrenoceptors. Note that dopamine has an even higher affinity for dopamine D1 receptors than for the adrenoceptors. 13  Catecholamines (non-selective adrenergic receptor agonists) Each of the catecholamines differs in terms of their affinity for the adrenergic receptors This affects the effects that they have on various organ systems The catecholamines differ slightly from each other in their clinical effects These drugs are rapidly metabolised by MAO and COMT They must thus be administered parenterally, They are used primarily to treat cardiac disorders and various types of shock Brenner & Stevens’ Pharmacology. 2023. Chapter 8. Figure 8.5. Page 87. Structures of selected adrenoceptor agonists. Catecholamines contain the catechol moiety and an ethylamine side chain. The amine nitrogen substitution (R2) determines the relative affinity for α- and β-adrenoceptors, with larger substitutions (e.g., in isoproterenol and dobutamine) decreasing the affinity for α-adrenoceptors and increasing the affinity for β-adrenoceptors. Note that dopamine has an even higher affinity for dopamine D1 receptors than for adrenoceptors. 14  Catecholamines RECEPTOR PHARMACOLOGICAL DRUG CLINICAL USE SELECTIVITY EFFECT β1 Cardiac stimulation Cardiogenic shock Dobutamine Acute heart failure (β1>β2>α) Cardiac stimulation during β2 Vasodilation heart surgery β1 Cardiac stimulation Cardiogenic shock Septic shock Dopamine β1 Heart failure ↑BP Hypotension (D>β1>α) α1 Adjunct to fluid Dopamine-1 administration in Renal vasodilation (D1) hypovolemic shock Isoprenaline β1 Cardiac stimulation Atrioventricular block (β1=β2>α) β2 Bronchodilation Bradycardia Brenner & Stevens’ Pharmacology. 2023. Table 8.2 Pharmacologic effects and clinical uses of adrenoceptor agonists. Page 88. 15  Catecholamines RECEPTOR PHARMACOLOGICAL DRUG CLINICAL USE SELECTIVITY EFFECT Noradrenaline Vasoconstriction Shock α1 (α1=α2; β1>β2) and ↑BP Hypotension Anaphylaxis β1 Cardiac stimulation Cardiac arrest Adrenaline β1 Ventricular fibrillation ↑BP Reduction in bleeding (epinephrine) α1 (α1=α2; β1=β2) β2 Bronchodilation during surgery Prolongation of the action α1 Vasoconstriction of local anesthetics Brenner & Stevens’ Pharmacology. 2023. Table 8.2 Pharmacologic effects and clinical uses of adrenoceptor agonists. Page 88. 16  Cardiac effects of catecholamines Due to their differences in affinity for the adrenergic receptors, the catecholamines differ in their cardiac effects Brenner & Stevens’ Pharmacology. 2023. Page 89 – Figure 8.6 Comparison of the cardiovascular effects of four catecholamines when a low dose of each drug is given by intravenous infusion. Arrows indicate when the infusion was started and stopped. The blood pressure recordings show systolic, diastolic, and mean arterial pressure. Peripheral resistance is expressed on an arbitrary scale, ranging from 0 to 4 units. The reflex mechanism, adrenoceptors (α1, β1, and β2), or dopamine (D1) receptors responsible for changes in the heart rate and peripheral resistance are illustrated. Norepinephrine increases peripheral resistance and blood pressure, and this leads to reflex bradycardia. Epinephrine increases heart rate while reducing peripheral resistance, and the mean arterial blood pressure increases slightly. Isoproterenol increases heart rate but significantly lowers peripheral resistance, and the mean arterial pressure declines. Dopamine increases heart rate (and increases cardiac output) while lowering vascular resistance, and the mean arterial pressure increases 17  Respiratory effects of catecholamines Stimulation of β2 receptors: ↑ Bronchial muscle relaxa on (bronchodilation) Isoprenaline (Isoproterenol) and adrenaline have potent bronchodilator effects, and have been used in the treatment of acute asthma attacks (Adrenaline nebulisers) More selective β2 agonists are now used in practice e.g. salbutamol ( Ventolin / Venteze) Image source: https://www.sciencebuzz.com/the-cellular-and-molecular-basis-of-bitter- tastant-induced-bronchodilation/ Brenner & Stevens’ Pharmacology. 2023. Page 91. Rang & Dale’s Pharmacology. 2024. Chapter 15. Table 15.4 Adrenoceptor agonists. Page 212. 18  Metabolic effects of catecholamines Catecholamines encourage the conversion of energy stores to freely available fuels Conversion of glycogen and fat to increase the plasma concentration of glucose and free fatty acids The effects on carbohydrate metabolism of liver and muscle are mediated through β2 receptors The stimulation of lipolysis and thermogenesis is produced by β3 receptors Activation of α2 receptors inhibits insulin secretion, which further contributes to hyperglycaemia Rang & Dale’s Pharmacology. 2024. Chapter 15. Page 216-217. Fig. 15.5 Regulation of energy metabolism by catecholamines. The main enzymic steps that are affected by β-adrenoceptor activation are indicated by + and − signs, deno ng s mula on and inhibi on, respec vely. The overall effect is to mobilise glycogen and fat stores to meet energy demands. TCA, Tricarboxylic acid. 19  Local anaesthetics and catecholamines Most local anaesthetics (LA) have a direct vasodilator action, which increases the rate at which they are absorbed into the systemic circulation This increases their potential toxicity and reduces their LA action Adrenaline may be added to LA solutions injected locally to cause vasoconstriction through α1 agonist effects Prevents LA diffusing away from the site of injection Action of the LA remains localised where it’s needed Prolongs LA action at the injection site Prevents side effects which would occur if the LA diffused to other sites Brenner and Steven’s pharmacology. 2023. Page 233-234. 20  Adverse effects of catecholamines Due to β2 agonism: Skeletal muscle tremor (Fine tremor after using Beta 2 agonist inhaler) Hyperglycaemia (undesirable in diabetics) Excessive cardiac stimulation that leads tachycardia and other cardiac dysrhythmias Due to α1 agonism: Excessive vasoconstriction leading to leading to tissue ischemia and necrosis Brenner & Stevens’ Pharmacology. 2024. Chapter 8. page 89 21 Non-catecholamines No catechol moity YFRM202 22  Non-catecholamine adrenergic receptor agonists The non-catecholamines differ in chemical structure to the catecholamines They don’t contain a catechol moiety Not substrates for COMT Some of the non-catecholamines are also resistant to degradation by MAO Thus, non-catecholamines are effective after oral administration and have a longer duration of action than catecholamines Brenner & Stevens’ Pharmacology. 2023. Page 90. 23 Non-catecholamine adrenergic receptor agonists Drug classes (based on selectivity for receptor) Non-selective agonists (α and β agonist –including indirect mechanisms) Selective α1 - agonists Selective α2 - agonists Selective β2 – agonists Selective β3 – agonist 24 Mixed-acting sympathomimetic drugs Indirect and direct effects YFRM202 25  Mixed-acting sympathomimetic drugs Mixed-acting Indirect effects Direct effects Increase release of NA Non-selective α and Inhibit reuptake via β receptor agonist NET Brenner and Steven’s pharmacology. 2023. Chapter 8. Page 93. 26  Mixed-acting sympathomimetic - ephedrine Ephedrine – is chemically related to amphetamine i.e its indirect sympathomimetic effects AND it is an agonist of alpha-1 beta-1 and beta-2 receptors DRUG PHARMACOLOGICAL EFFECT CLINICAL USE Nasal decongestion due to vasoconstriction (α1- Treatment of nasal Ephedrine agonist) congestion caused by colds Bronchodilation (β2- and flu agonist) Drugbank online. 2024. Ephedrine. Available at: https://go.drugbank.com/drugs/DB01364 (Date accessed: 2 October 2024) Brenner and Steven’s pharmacology. 2023. Chapter 8. Page 93. 27  Indirect-acting mechanism of ephedrine Displacers of NA: These drugs are structurally similar enough to NA that they are taken up into the presynaptic neuron by the NA transporter (norepinephrine transporter - NET) Drug enters synaptic vesicles via the vesicular monoamine transporter (VMAT), in exchange for NA, which accumulates in the cytosol NA escapes, in exchange for drug via the NET, to act on postsynaptic receptors These drugs also reduce NA reuptake via NET, so enhancing the action of the released NA Fig. 15.7 The mode of action of amphetamine, an indirectly acting sympathomimetic amine. Amphetamine enters the nerve terminal via the noradrenaline transporter (NET) and enters synaptic vesicles via the vesicular monoamine transporter (VMAT), in exchange for noradrenaline (NA), which accumulates in the cytosol. Some of the NA is degraded by monoamine oxidase (MAO) within the nerve terminal and some escapes, in exchange for amphetamine via the noradrenaline transporter, to act on postsynaptic receptors. Amphetamine also reduces NA reuptake via the transporter, so enhancing the action of the released NA. The effect is a result of adrenergic hyperstimulation centrally and peripherally hence its street name “Speed”. Rang and Dale’s pharmacology. 2024. Page 214, 222-223. Table 15.6 Drugs that affect noradrenaline synthesis, release or uptake. Page 214 28  Mixed-acting sympathomimetic - Pseudoephedrine Pseudoephedrine is structurally related to ephedrine, but have a weaker effect on the sympathetic nervous system. Alpha-receptor agonist, less strong agonist of beta-receptors, block NET (i.e. NE reuptake) Relatively resistant to metabolism by MAO and COMT, contributing to a longer duration of action Used in illicit manufacture of methamphetamine (co-formulated S2, single ingredient S6) DRUG PHARMACOLOGICAL EFFECT CLINICAL USE Nasal decongestion due to vasoconstriction(primary Treatment of nasal Pseudoephedrine α1-agonist) congestion caused by colds Bronchodilation (lesser and flu β2-agonist) Drugbank online. 2024. Pseudoephedrine. Available at: https://go.drugbank.com/drugs/DB00852 (Date accessed: 2 October 2024) SAMF. 2022. Page 573. Brenner and Steven’s pharmacology. 2023. Chapter 8. Page 93. 29  Decongestant action Pseudoephedrine Limited to short-term symptomatic relief of acute nasal congestion Topical therapy preferred Systemic formulations often co-formulated: With analgesic: Pseudoephedrine + paracetamol: Sudafed Sinus Pain With antihistamine: Pseudoephedrine + loratadine: Demazin NS S2 – one pack per customer Dose of pseudoephedrine max 60mg/dose, Pack size limit 720mg / pack SAMF. 2022. R02 Nasal preparations. Decongestants for systemic use Page 573-574. 30  Pseudoephedrine Adverse effects: Tachycardia (β1) ↑ Blood pressure (β1 and α1) CNS stimulation and insomnia Urinary retention due to contraction of the sphincter muscle of the bladder, especially in men with prostatic hypertrophy (α1) SAMF. 2022. R02 Nasal preparations. Decongestants for systemic use Page 573-574. 31  RECEPTOR PHARMACOLOGICAL DRUG CLINICAL USE SELECTIVITY EFFECT Nasal and ocular Phenylephrine Vasoconstriction decongestion - (Sudafed tabs ; Also α1 Mydriasis Mydriasis IVI preparations) ↑BP Maintenance of BP Shock Oxymetazoline Vasoconstriction Nasal and ocular (Dristan, Vicks Sinex nasal α1 sprays) decongestion Xylometazoline Nasal and ocular α1 Vasoconstriction (Otrivin nasal spray) decongestion Midodrine α1 Vasoconstriction Orthostatic hypotension Brenner & Stevens’ Pharmacology. 2023. Chapter 8. Table 8.2. Page 88. Rang & Dale’s Pharmacology. 2024. Chapter 15. Table 15.4. Page 211. 32  The α1-agonists have a vasoconstrictive effect on the nasal mucosa This reduces vascular congestion and mucus secretion, which opens the nasal passages and facilitates breathing Both topical and oral preparations are available for this purpose Treatment with topical α1-agonists must not exceed 3-5 days’ duration Prolonged vasoconstriction leads to tissue ischaemia Triggers a compensatory mechanism by the body resulting in vasodilation and ↑ mucosal gland secre on Rebound nasal congestion, also known as ‘rhinitis medicamentosa’ Brenner & Stevens’ Pharmacology. 2023. Chapter 8. Page 90 33  The α1-agonists have a vasoconstrictive effect in the arterioles of the conjunctiva, thereby reducing redness Decongestant eye drops: Phenylephrine Naphazoline(Safyr Blur®) Oxymetazoline Tetryzoline/antazoline (Spersallerg®, Gemini®) SAMF. 2022. Page 612-613. 34  Drug Main action Indications Adverse effects Clonidine α 2 partial agonist Hypertension, Drowsiness, migraine hypotension, prophylaxis, oedema and vasomotor weight gain, instability (‘hot rebound flushes’) hypertension Rang & Dale’s Pharmacology. 2024. Table 15.4 Adrenoceptor agonists. Page 212. 35  Adrenergic transmission and presynaptic feedback control The inhibitory feedback mechanism operates through α2 receptors ↓ Activation of presynaptic α2 receptors ↓ Activation of Gi protein ↓ Inhibits adenylyl cyclase ↓ Prevents the opening of calcium channels ↓ Inhibits exocytosis and release of NA Rang & Dale’s Pharmacology. 2024. Chapter 15. page 209 – Figure 15.2 Feedback control of noradrenaline (NA) release. The presynaptic α2 receptor inhibits Ca2+ influx in response to membrane depolarisation via an action of the βγ subunits of the associated G protein on the voltage-dependent Ca2+ channels G protein-coupled inwardly-rectifying K+ channels – promotes hyperpolarization of the neuronal membrane thus delaying action potentials 36  RECEPTOR PHARMACOLOGICAL DRUG CLINICAL USE SELECTIVITY EFFECT Salbutamol Bronchodilation β2 (short-acting - Asthma and COPD (albuterol) Preterm labour (Ventolin / Venteze) SABA) Bronchodilation Salmeterol β2 (long-acting - Asthma and COPD LABA) Bronchodilation Formoterol β2 (long-acting - Asthma and COPD LABA) Bronchodilation (SABA) Terbutaline β2 Asthma and COPD Relaxation of the uterus (tocolysis) Brenner & Stevens’ Pharmacology. 2023. Chapter 8. Table 8.2. Page 88. Rang & Dale’s Pharmacology. 2024. Chapter 15. Table 15.4. Page 211. 37  Skeletal muscle tremor Tachycardia Nervousness Increased susceptibility to cardiac dysrhythmias Thought to be partly due to hypokalaemia, caused by an increase in K+ uptake by skeletal muscle SAMF. 2022. Page 612-613. 38  Drug Main action Indications Adverse effects Mirabegron β 3 agonist Symptoms of Tachycardia overactive bladder Picture source: http://ars.els-cdn.com/content/image/3-s2.0-B9780124077102000291-f29-01- 9780124077102.jpg?httpAccept=%2A%2F%2A (Date accessed: 2Apr17) Rang & Dale’s Pharmacology. 2024. Chapter 15. Table 15.4. Page 211. 39  Checklist Can you...  Describe the adrenergic receptors in the body, their location and actions?  Describe the actions, adverse effects and clinical uses of the mixed-acting sympathomimetic agonists?  Describe the actions of the catecholamines on organ systems (including selectivity for specific adrenoceptors), their clinical uses and adverse effects?  Describe the mechanisms of action of non-catecholamine adrenoceptor agonist drug classes with drug examples, their clinical uses and adverse effects? Did you...  Complete The Attendance Register? 40  Resources Osmosis videos: Sympathomimetics: direct agonists Sympatholytics: alpha-2 agonists 41  References Brenner & Stevens’ Pharmacology. 2023. Chapter 8 Sympathetic neuropharmacology and adrenergic agonists. Page 83-94. Rang and Dale’s Pharmacology. 2024. Chapter 15 Noradrenergic transmission. Page 205-224. 42  Feedback Please be kind enough to take a minute and rate this lesson and provide a little feedback to help us gain a better understanding of your learning experience. Let us know what you really enjoyed and what we can do better for you. Click on the link at the bottom of the lesson page on I-learn to provide feedback for this lesson. +- (2mins) 43 44 45