Basic Principles of Pharmacology Lecture Notes PDF

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Noradrenergic transmission Indirect acting noradrenergic drugs YFRM202 2  Lecture Overview In this lecture you can expect to learn...

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Noradrenergic transmission Indirect acting noradrenergic drugs YFRM202 2  Lecture Overview In this lecture you can expect to learn about drugs affecting the sympathetic nervous system by acting inside the post-ganglionic neuron. You have previously learned about the synthesis of noradrenaline and its effects on the sympathetic nerves. In this lecture you will build upon that knowledge and further explore how these drugs may inhibit or enhance the synthesis, storage, release, re-uptake or metabolism of norepinephrine. Throughout this lecture it will become clear that these drugs have numerous indications and clinical uses. 3  Learning Outcomes At the end of this lecture, you should be able to:  Define and differentiate amongst the terms ‘Sympathomimetic’, ‘Sympatholytic’, direct-acting and indirect-acting sympathetic drugs  List drug classes with examples of drugs affecting noradrenergic neurotransmission including presynaptic feedback control of the sympathetic nervous system  Describe the mechanisms of action, indications and adverse effects of drugs that displace NA from the presynaptic neuron, including methyldopa, reserpine, amphetamines and others  Describe the mechanisms of action, indications and adverse effects of drugs that inhibit NA reuptake into the presynaptic neuron including cocaine and antidepressants  Describe the mechanisms of action, indication and adverse effects of drugs that inhibit the metabolism of NA 4  Orientation for 2024 Week 4 30th Mo 508 2 M van Sep n 10:30 - 11:15 45 (0002) Lecture Huyssteen Sympathetic nervous system Noradrenergic transmission and indirect-acting sympathetic drugs 508 2 M van 11:45 - 12:30 45 (0002) Lecture Huyssteen Sympathetic nervous system Noradrenergic transmission and indirect-acting sympathetic drugs Mo 508 2 M van 2nd Oct n 10:30 - 11:15 45 (0002) Lecture Huyssteen Sympathetic nervous system Direct-acting adrenoceptor agonists 508 2 M van 11:45 - 12:30 30 (0002) Lecture Huyssteen Sympathetic nervous system Direct-acting adrenoceptor agonists Week 5 Mo 508 2 Lecture M van 7th Oct n 10:30 - 11:15 45 (0002) (online) Huyssteen Sympathetic nervous system Direct-acting adrenoceptor antagonists 508 2 Lecture M van 11:45 - 12:30 45 (0002) (online) Huyssteen Sympathetic nervous system Direct-acting adrenoceptor antagonists We 508 2 Lecture M van 9th Oct d 13:30 - 14:15 45 (0002) (online) Huyssteen Hypertension Hypertension and the role of the Autonomic nervous system 508 2 Lecture M van Hypertension and drugs acting on the ANS to control blood 14:30 - 15:00 30 (0002) (online) Huyssteen Hypertension pressure 10th Thu Oct r YBOD200 LS Test4 Week 6 14th Mo 508 2 M van Oct n 10:30 - 11:15 45 (0002) Huyssteen Pharmaceutics - Drug Development and Safety 1 508 2 M van 11:45 - 12:30 45 (0002) Huyssteen Pharmaceutics - Drug Development and Safety 2 16th We 508 2 Lecture M van Oct d 13:30 - 14:15 45 (0002) (online) Huyssteen Legal aspects of pharmacology 508 2 14:30 - 15:00 30 (0002) 5  Orientation for 2024 Week 7 21st Mo 508 2 Oct n 10:30 - 11:15 45 (0002) Revision 508 2 11:45 - 12:30 45 (0002) Revision 23rd We 508 2 Lecture Oct d 13:30 - 14:15 45 (0002) (online) 508 2 14:30 - 15:00 30 (0002) Week 8 28th Mo Oct n 10:30-12:30 60 YFRM202 Test 3 (40 marks) We d 13:30 - 14:15 45 Feedback 14:30 - 15:00 30 Feedback 6 Learning resources Osmosis videos Post-lecture quizzes 7  Divisions of the nervous system Image source: https://ib.bioninja.com.au/options/option-a-neurobiology-and/a2-the- human-brain/autonomic-control.html 8  Drugs acting on the adrenergic nervous system Sympathomimetic Sympatholytic Drugs that increase the Drugs that block the sympathetic response sympathetic response In effect, this inhibits the In effect, this increases the parasympathetic response parasympathetic response Drugs that mimic the Drugs that inhibit the action action of NA of NA Since the sympathetic and parasympathetic divisions have opposing actions, if a drug increases the sympathetic division, it decreases the parasympathetic response, and vice versa. If a drug blocks the sympathetic division, it ends up increasing the parasympathetic response. 9  Sympathetic / adrenergic drugs α-agonists / antagonists β-agonists / antagonists DIRECT-ACTING Sympathetic drugs INDIRECT-ACTING Affect synthesis of NA Affect termination of action of MA (metabolism / reuptake) Affect storage of NA Affect release of NA Brenner & Stevens’ Pharmacology – page 84 Certain drugs may have both direct and indirect effects. The mixed-acting agonists (e.g., pseudoephedrine) have both direct and indirect actions. 10  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 11  Indirect acting sympathetic drugs Synthesis of NA Storage of NA in vesicles Release of NA into the synapse Direct-acting Interaction of the NA with post-synaptic receptors Termination of NA action Tyrosine, which can also be synthesized in the body from phenylalanine, is found in many high-protein food products such as chicken, turkey, fish, milk, yogurt, cottage cheese, cheese, peanuts, almonds, pumpkin seeds, sesame seeds, soy products, lima beans, avocados, and bananas. FIGURE 8-12 Steps involved in the synthesis and release of norepinephrine. COMT = catechol-O-methyltransferase. Picture source: The-Crankshaft Publishing: What-when-how.com: ND. Neurotransmitters (the neuron) Part 4 Available at: http://what-when-how.com/wp- content/uploads/2012/04/tmp1474_thumb1.jpg (Date accessed: 12 July 2023) Range and Dale’s pharmacology. 2024. Chapter 15. Page 208-210. Brenner & Stevens’ Pharmacology – page 60 – Figure 6.3 Drugs can act to enhance or inhibit the sympathetic nervous system by affecting the synthesis, storage, release, reuptake or binding of NA to its target receptors. Sympathetic neurotransmission and sites of drug action. Norepinephrine (NE) is synthesized from tyrosine in a three-step reaction: tyrosine to dopa (dihydroxyphenylalanine), dopa to dopamine (DA), and dopamine to NE. The conversion of tyrosine to dopa is inhibited by metyrosine. The vesicular storage of DA and NE is 12 blocked by reserpine, and the release of NE in response to nerve stimulation is blocked by bretylium. After activating postsynaptic receptors, NE undergoes neuronal reuptake, a process blocked by cocaine. Amphetamine indirectly increases the transport of NE into the synapse. Postsynaptic adrenoceptors are activated or blocked by adrenoceptor agonists or antagonists, respectively. α, α-adrenoceptors; β, β-adrenoceptors; COMT, catechol-O-methyltransferase; DAT, dopamine transponder; MAO, monoamine oxidase; (−), inhibits; (+), s mulates. 12 Drug affecting noradrenaline synthesis Displacement of NA from the presynaptic neuron YFRM202 13  Methyldopa Treatment of hypertension during pregnancy False transmitter Not metabolised by monoamine oxidase (MAO) in the neuron, ___________ α-methylnoradrenaline accumulate and displace norepinephrine (NE) from vesicle Less active on post synaptic α1 More active on pre-synaptic α2 Adverse effects: hypotension, drowsiness, diarrhoea, impotence, hypersensitivity reactions Picture source: The-Crankshaft Publishing: What-when-how.com: ND. Neurotransmitters (the neuron) Part 4 Available at: http://what-when-how.com/wp- content/uploads/2012/04/tmp1474_thumb1.jpg (Date accessed: 12 July 2023) Rang and Dale’s pharmacology. 2024. Page 214, 221. Table 15.6 Drugs that affect noradrenaline synthesis, release or uptake. Page 214 Methyldopa is taken up by noradrenergic neurons, This is the α-methyl analogue of dopa which is converted to α-methyldopamine by dopa decarboxylase and then by dopamine- β-hydroxylase to α-methylnoradrenaline, which is stored in vesicles. In addition, the false transmitter α-methylnoradrenline is not deaminated within the neuron by monoamine oxidase (MAO), so it accumulates and displaces noradrenaline from the synaptic vesicles. α-Methylnoradrenaline is released in the same way as noradrenaline, but is less active than noradrenaline on α 1 receptors and thus is less effective in causing vasoconstriction. However, it is more active on presynaptic (α 2 ) receptors, so the autoinhibitory feedback mechanism operates more strongly than normal, thus reducing transmitter release. Both of these effects (as well as a central effect, probably caused by the same cellular mechanism) contribute to the hypotensive action. 14 Drug affecting noradrenaline storage Displacement of NA from the presynaptic neuron YFRM202 15  Reserpine Blocks vesicular monoamine transporter (VMAT) - the transport of noradrenaline and other amines into Reserpine block storage vesicles VMAT NE accumulates in the cytoplasm, where it is degraded by monoamine oxidase (MAO) NA content of tissues drops, and sympathetic transmission is blocked Also depletes serotonin (5-HT) and dopamine from neurons in the brain Adverse effect: depression, parkinsonism, gynaecomastia VMAT – vesicular monoamine transporter 5-HT – 5-hydroxytryptamine / serotonin Picture source: The-Crankshaft Publishing: What-when-how.com: ND. Neurotransmitters (the neuron) Part 4 Available at: http://what-when-how.com/wp- content/uploads/2012/04/tmp1474_thumb1.jpg (Date accessed: 12 July 2023) Rang and Dale’s pharmacology. 2024. Page 214, 221. Table 15.6 Drugs that affect noradrenaline synthesis, release or uptake. Page 214 16  Indirect-acting sympathomimetic drugs 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 17  Indirect-acting sympathomimetic drugs Displacers of NA: DRUG CLINICAL USE Narcolepsy Amphetamine ADD ADD Methylphenidate ADHD ADD Atomoxetine ADHD Fig. 15.7 The mode of action of amphetamine, an indirectly acting sympathomimetic amine. Rang and Dale’s pharmacology. 2024. Page 214, 222-223. Table 15.6 Drugs that affect noradrenaline synthesis, release or uptake. Page 214 18  Indirect-acting sympathomimetic drugs Displacers of NA: Since these drugs increase the levels of NA in the synapse, NA is able to bind to and activate all adrenergic receptors (α and β) They thus have widespread effects throughout the body: They cause bronchodilation, raised arterial pressure, peripheral vasoconstriction, increased heart rate and force of myocardial contraction, and inhibition of gut motility They also have central actions: Accounts for effects such as appetite suppression, CNS stimulant effects, and significant potential for abuse Thus have very limited therapeutic uses 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 19 Drug affecting noradrenaline reuptake Reuptake inhibitors YFRM202 20  Indirect-acting sympathomimetic drugs Inhibition of NA reuptake Reuptake of released NA by NET is the most important mechanism by which its action is terminated Drugs that inhibit NET increase circulating NA levels in the synapse, which enhances sympathetic effects These drugs tend to have central effects, which is their intended therapeutic effect, but also lead to peripheral effects of sympathetic transmission Tachycardia, cardiac dysrhythmias, increased arterial pressure, and, with chronic use, cardiomyopathy and cardiac hypertrophy NET - Norepinephrine transporter Rang & Dale’s Pharmacology. 2024. Chapter 15. Page 223 21  Indirect-acting sympathomimetic drugs Inhibition of NA reuptake DRUG CLINICAL USE Local anaesthetic (Increases local NA Cocaine causing vasoconstriction) Amitriptyline (and other Tricyclic antidepressants) Antidepressants Selective norepinephrine Neuropathic pain reuptake inhibitors (sNRIs) sNRIs – selective norepinephrine re-uptake inhibitors Rang and Dale’s pharmacology. 2024. Page 214, 222-223. Table 15.6 Drugs that affect noradrenaline synthesis, release or uptake. Page 214 22  Drug affecting noradrenaline metabolism COMT or MAOI inhibitors YFRM202 COMT - catechol-O-methyl transferase MAO – Monoamine oxidase 23  Metabolism of catecholamines Catecholamines are primarily metabolised by 2 enzymes: Catechol-O- methyltransferase (COMT) Monoamine oxidase (MAO) Fig. 15.3 The main pathways of noradrenaline metabolism. The oxidative branch (catalysed by aldehyde dehydrogenase [ADH]) predominates, giving vanillylmandelic acid (VMA) as the main urinary metabolite. The reductive branch (catalysed by aldehyde reductase [AR]) produces the less abundant metabolite, 3- methoxy-4-hydroxyphenylglycol (MHPG), which is conjugated to MHPG sulfate before being excreted; MHPG sulfate excretion reflects noradrenaline (NA) release in brain. COMT, catechol- O -methyl transferase; DHMA, 3,4-dihydroxymandelic acid; DHPG, 3,4- dihydroxyphenylglycol; MAO, monoamine oxidase; NM, normetanephrine. Rang and Dale’s pharmacology. 2024. Chapter 15. Page 211. 24  Monoamine oxidase inhibitors (MAOIs) MAO inhibitors inhibit one or both forms of brain MAO (MAOA and MAOB) This results in inhibition of the metabolism of NA and serotonin (5-HT) This causes elevated cytosolic stores of noradrenaline and 5-HT in nerve terminals Clinically used as antidepressants Inhibition of type A MAO correlates with antidepressant activity Most MOA inhibitors are non-selective, e.g. phenelzine Moclobemide (Aurorix , Depnil) is specific for MAOA MAOB inhibitors are used in the treatment of Parkinson’s disease Prevent the metabolism of dopamine in the brain E.g. selegiline, rasagiline Rang & Dale’s Pharmacology. 2024. Chapter 48 Antidepressant drugs Page 642, 648, 656-657. MAO – monoamine oxidase 25  Catechol-O-methyl transferase (COMT) inhibitors COMT inhibitors are used in the treatment of Parkinson’s disease Prevent the metabolism of dopamine in the brain and in the periphery These drugs counteract the deficiency of dopamine in basal ganglia leading to the symptoms of Parkinson’s COMT inhibitors acting in the periphery: tolcapone, entacapone COMT inhibitors acting in the brain: tolcapone Rang & Dale’s Pharmacology. 2024. Chapter 40 Neurodegenerative diseases. Parkinson’s disease. Page 550. 26  Sites of action of MAOIs and COMT inhibitors in Parkinson’s disease Fig. 41.5 Sites of action of drugs used to treat Parkinson's disease. Levodopa enters the brain and is converted to dopamine (the deficient neurotransmitter). Inactivation of levodopa in the periphery is prevented by inhibitors of dopa decarboxylase (DDC) and catechol- O -methyl transferase (COMT). Inactivation in the brain is prevented by inhibitors of COMT and monoamine oxidase-B (MAO-B). Dopamine agonists act directly on striatal dopamine receptors. 3-MDopa, 3- methoxydopa; 3-MT, 3-methoxytyrosine; DOPAC , dihydroxyphenylacetic acid. Rang and Dale’s pharmacology. 2024. Chapter 40. Page 551. 27  Sites of adrenergic drug action Fig. 15.8 Generalised diagram of a noradrenergic nerve terminal, showing sites of drug action. EMT, extraneuronal monoamine transporter; MAO, monoamine oxidase; MeNA, methylnoradrenaline; NA, noradrenaline; NET, neuronal noradrenaline transporter. Rang and Dale’s pharmacology. 2024. Page 224. 28  Checklist Can you...  Define and differentiate amongst the terms ‘Sympathomimetic’, ‘Sympatholytic’, direct-acting and indirect-acting sympathetic drugs?  List drug classes with examples of drugs affecting noradrenergic neurotransmission including presynaptic feedback control of the sympathetic nervous system?  Describe the mechanisms of action, indications and adverse effects of drugs that displace NA from the presynaptic neuron, including methyldopa, reserpine, amphetamines and others?  Describe the mechanisms of action, indications and adverse effects of drugs that inhibit NA reuptake into the presynaptic neuron including cocaine and antidepressants?  Describe the mechanisms of action, indication and adverse effects of drugs that inhibit the metabolism of NA? Did you...  Complete The Attendance Register? 29  Resources Osmosis videos: Adrenergic antagonists: presynaptic antagonists This video is helpful in illustrating noradrenergic neuro transmission and the mechanism of action of reserpine. Monoamine oxidase inhibitors This video adds information about MAO inhibitors for those interested in learning more. Psychomotor stimulants This video provides additional information about the mechanism of action of amphetamines, methylphenidate and cocaine. It also explains some factors related to the abuse of these drugs 30  References Rang and Dale’s Pharmacology. 2024. Chapter 15 Noradrenergic transmission. Page 205-224. & Chapter 40 Neurodegenerative diseases (Parkinson’s disease) Page 548-553. & Chapter 48 Antidepressant drugs Page 640- 662. 31  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) 32 33 34