1. Martin Štěrba, PharmD., PhD. Associate professor Department of Pharmacology Faculty of Medicine in Hradec Kralove Pharmacology of sympathetic NS: Adrenergic agonists and antagonists 2015

2. ORGANS (effectors) Nervous system CNSPERIPHERAL N.S. AFERENT PART EFFERENT PART EFFERENT PART SKELETAL MUSCLE SYMPATHETIC PARASYMPATHETIC SOMATIC N.S. AFERENT PART EFFERENT PART (motoric) AUTONOMIC N.S.

3. postganglionic neurons may innervate more than one organ postganglionic neurons are not branched, but are directed to a specific organ Lippincott Illustrated Reviews 2014

5. ACh N N N N Adrenal medulla Ganglia without ganglia Spinal cord (thoracic and lumbar) Spinal cord (thoracic and lumbar) Brain Spinal cord (sacral) Postganglionic neurons Effector organs CNS A release into the blood NA Muscarinic receptors α, β M NMNM ACh Nurorransmitter Preganglionic neurons Ganglionic transmitter AUTONOMIC Sympathetic Parasympathetic SOMATIC Voluntary motor nerve Skeletal muscle (neuromuscular junction) ACh N M Adrenergic receptors Sweat glands Cardiac and smooth muscle, gland cells, nerve terminals… Cardiac and smooth muscle, gland cells, nerve terminals ACh

6. Synthesis, docking and release of catecholamines Synthesis of catecholamines Precursor = tyrosine (AA, active transport into sympathetic n.) Synthesis in 4-5 steps: 1)tyrosine → L-DOPA Tyrosinehydroxylase = rate limiting enzyme NOR 2)L-DOPA → dopamine DOPA-decarboxylase: -COOH cleavage 3)Dopamine transport: cytoplasm → vesicles (can be blocked by reserpine) 4)Dopamine → noradrenaline (norepinephrine, NOR) dopamine hydroxylase:  -hydroxylation 5)Noradrenaline → adrenaline (epinephrine, ADR) N-methyltranspherase: N-methylation of NOR L-DOPA is also used a drug in the treatment of Parkinson disease - as a CNS permeable dopamine precursor

7. L-TYROSINE NORADRENALINE ADRENALINE OH NH 2 COOH COOH OH OH NH 2 OH OH C H 2 NH 2 OH OH NH 2 OH OH OH N H OH CH 3 DOPAMINE Tyrosine hydroxylase Dopa-decarboxylase Dopamine-β-hydroxylase N-Methyl transferase L- DOPA

8. Dopamine Noradrenaline Uptake 1 (re-uptake) M A O metabolites presynaptic receptor R R Tyrosine DOPA inactive metabolites Dopamine outflow COMT Ca 2+ Ca 2+ uptake 2 Noradrenaline Ca 2+ tyrosine MAO Postsynaptic receptors COMT Liver

9. Dopamine Noradrenaline Uptake 1 (re-uptake) M A O metabolites presynaptic receptor R R Tyrosine DOPA inactive metabolites Dopamine outflow COMT Ca 2+ Ca 2+ uptake 2 Noradrenaline Ca 2+ tyrosine MAO Postsynaptic receptors COMT Liver Reserpine Cocaine Amphetamine Antidepresants TCA…

10. Synthesis, docking and release of catecholamines Main site of ADR synthesis – Adrenal medulla phylogenetically = ganglion ADR makes majority of catecholamine content (up to 80 %) ADR is secreted directly to blood – Regulated by glucocorticoids N-methyltransferase induction, DOPA-decarboxylase and beta-hydroxylase = adaptation on stress – Minor ADR content in synaptic neurons NOR clearly prevails

11. NOR – docking and release Docking ―In vesicles – synthesized herein + active transport from cytoplasm after reuptake from synaptic cleft ―Deposited with ATP, Ca 2+, chromogranine A, ascorbate and dopamine-  -hydroxylase Released with catecholamines dopamine-  -hydroxylase activity in plasma – marker of sympathetic activity Release – Depolarization of presynaptic membrane triggered by AP – Opening of voltage-gated Ca 2+ channels – Ca 2+ entry induces exocytosis – Facilitation of vesicle fusion with presynaptic membrane – Release of vesicular content into the synaptic cleft

12. NOR – fate in synaptic cleft Action on – Postsynaptic receptors Adrenergic effects – Presynaptic receptors Negative feedback regulation of catecholamin erelease Catecholamine uptake into the cells – uptake 1 = neuronal uptake (re-uptake) – uptake 2 = into extraneuronal cells Outflow into the circulation – Loss of neurotransmitter role and degradation

13. Dopamine Noradrenaline Uptake 1 (re-uptake) M A O metabolites presynaptic receptor R R Tyrosine DOPA inactive metabolites Dopamine outflow COMT Ca 2+ Ca 2+ uptake 2 Noradrenaline Ca 2+ tyrosine MAO Postsynaptic receptors COMT Liver Reserpine Cocaine Amphetamine Antidepresants TCA…

14. Termination of NOR action in the synaptic cleft Key role of neuronal re-uptake (uptake1) – Manage more than 90 % of NOR released – Reflect higher complexity of catecholamine synthesis (x ACh) – Thus, NOR „recycling“ is more efficient (comparing to ACh) – After NOR reuptake – part of NOR is is degraded by MAO-A docked into the vesicles No major role of degrading enzymes in the synaptic cleft – In contrast to parasympathetic system – MAO i COMT are localized predominantly within the cells

15. Autoregulation of NOR release Negative feedback regulation – By the neurotransmitter itself (NOR) – Its action on presynaptic α 2 -receptors ↓ exocytosis Result: inhibition of further NOR release Presynaptic β receptors – Rather uncertain and possibly complex role

16. Biodegradation of catecholamines Role of 2 enzymes monoaminooxidase (MAO) a catechol-O- methyltransferase (COMT) MAO – Intracellular localization - anchored to mitochondrial membrane – Outside ANS/CNS – liver and gut wall – Oxidative deamination to aldehyde (oxidized/reduced further) – 2 isoforms – both degrades NOR and dopamine MAO-A - substrate preference to 5HT (serotonin) – Targeted in the CNS by antidepressants (I-MAO-A) MAO-B - substrate preference to phenylalkylamines – Targeted in the CNS by antiparkinsonics (I-MAOB) MAO-A/B inhibitors may have important peripheral adverse effects

17. Biodegradation of catecholamines COMT – In neurons and in other tissues (in particular liver and kidney) – After uptake 2 or after outflow – Transfer methyl on the catechol hydroxyl –OH – End products in urine: e.g. Vanillyl mandelic acid examination of catecholamine production (urine) – inhibitors = antiparkinsonic agents (↓ peripheral degradation of L-DOPA)

18. Receptors for catecholamines G-protein coupled receptors - specific second messengers to transduct the signal into the cells – α-receptors α 1 and α 2 subtype affinity: noradrenaline > adrenaline > > isoprenaline – β-receptors β 1, β 2 and β 3 subtype affinity: isoprenaline > adrenaline > noradrenaline

20. α-receptors and effects α 1 -subtype – Postsynaptic localization – smooth muscle Vascular smooth muscle (esp. skin, mucosa, splanchnicus …) – Vasoconstriction:↑ peripheral vascular resistance (PVR) and ↑BP urogenitary (prostatic capsule, urethra, urinary bladder) – impact on urine flow GIT: contraction of sphincters, decreased peristalsis – Transduction of the signal into the cells G protein → IP 3 → ↑ cytosolic Ca 2+ → calmoduline → myosinkinases → phosphorylation of myosin = contraction α 2 -subtype – localization presynaptic – Signal transduction – G i protein → ↓cAMP → inhibition of Ca 2+ channels and K + channel opening → inhibition of NOR release postsynaptic – thrombocytes (inhibition of aggregation), pancreatic β-cells (inhibition of insulins secretion)..

21. β-receptors and effects All subtypes activate adenylatecyclase → ↑ cAMP β 1 -subtype – Myocardium ! ↑cAMP → activation of L-type Ca 2+ channels ↑ Ca 2+ in cardiomyocytes – Positive effects chronotropic dromotropic inotropic bathmotropic

22. β-receptors β 2 -subtype – Smooth muscle ↑ cAMP → ↓inhibition of myosin phosphorylation → ↓ tone Bronchodilation, vasodilation (skeletal muscle arteries), tocolysis, ↓ GIT motility – Skeletal muscle ↑ cAMP → tremor, ↑ strength of contraction and muscle volume – Liver glycogenolysis – pancreas Insulin secretion β 3 -subtype – Lipolysis and thermogenesis??? – Importance in humans???

23. A. Classification of sympathotropic drugs Sympathomimetics (SM, adrenergic agonists) Direct-acting sympathomimetics – Non-selective SM acting on both α and β receptors – Selective SM acting on α receptors i.e. α-sympathomimetics α 1 -selective SM α 2 -selective SM – Selective SM acting on β receptors i.e., β-sympathomimetics Non-selective β-SM β 1 - selective SM β 2 - selective SM Indirect-acting sympathomimetics

24. B. Classification of sympathotropic drugs Sympatholytics (SL) syn. antiadrenergic agents, adrenergic antagonists Direct-acting sympatholytics (SL, adrenoreceptor blockers) – α-sympatholytics (α-blockers) Non-selective α-blockers α 1 -selective blockers α 2 -selective blockers – β-sympatolytics (β -blockers) Non-selective β-blockers (with ISA or without ISA) β 1 -selective blockers (with ISA or without ISA) β-blockers with combined effects Indirect-acting sympatholytics

25. SYMPATHOMIMETICS (SM, ADRENERGIC AGONISTS)

26. SYMPATHOMIMETICS (SM)  - SYMPATHO MIMETICS  - SYMPATHO MIMETICS DIRECT INDIRECT ,  - SYMPATHO MIMETICS neurotransmiters - noradrenaline (  1,  2,  1 ) - adrenaline (  1,  2,  1,  2 ) - dopamine (D 1, D 2,  1,  1 )  1 - selective SM - phenylephrine - midodrine local decongescion - nafazoline - oxymetazoline - xylometazoline - tetryzoline  2 - selective SM -α-methyldopa -apraclonidine  1 -SM direct & indirect-acting hydroxyamphetamine  - nonselective SM - Isoproterenol (isoprenaline)  1 - selective SM - dobutamine Short-acting - fenoterol - salbutamol - terbutaline Long-acting - salmeterol - procaterol - formoterol Uterine relaxation -fenoterol -hexoprenaline  2 - selective SM Release- inducers - ephedrine - pseudoefedrine - amphetamine - metamphetamine - tyramine re-uptake blockers - TCA - cocaine Degradation inhibitors - IMAO - ICOMT

27. SYMPATHOMIMETICS (SM, ADRENERGIC AGONISTS) Mimic effects induced by discharge of SNS Chemistry: phenylethylamine or imidazoline derivatives Classification – Direct-acting Direct agonists on α/β receptors – Indirect-acting Drugs increasing concentrations of NOR synaptic cleft – Drugs with mixed effects Direct and indirect effect in one drug

28. Sympathomimetics - effects Stimulation of selected smooth muscle – vasoconstriction -α 1 receptors: sensitivity varies according to localization Marked effects: skin, mucosa and splanchnic, resistance arteries → ↑ BP Low response in: cerebral, coronary and pulmonary arteries – Dilation in skeletal muscle arteries (β 2 receptors) Inhibition of selected smooth muscle – Bronchi (bronchodilation - COPD), – GIT, arteries of skeletal muscle and pregnant uterus (tocolysis) – Mainly β 2 receptors Stimulation of the heart – 4 positive effects: β 1 (β 2 and α 1 less important – more in HF upon down-regulation of β 1 ) – Increased workload and perfusion/O 2 demands (disproportionally to work) Skeletal muscle – Fasciculation, tremor, ↑ strength and contractility, volume Metabolic effects and endocrine effects – glycogenolysis - β 2 a α 1 receptors – modulation of insulin secretion (receptors ↑β 2 a ↓α 2 ) – Renin secretion - β 1 receptors CNS effects (in lipophilic agents) – Psychostimulation, central analeptic and anorectic effects Inhibition of histamine release from mast cells (  2 -effects)

29. Sympathomimetics – effects on blood pressure Effects may be complex – Differences according to the affinity to receptors (dose matters!) – Overall response affected by activation of baroreflexes Noradrenaline (NOR) – Vasoconstriction (α 1 - receptors) ↑ systolic, diastolic as well as mean BP ↓ HR – baroreflex mediated - may mask direct β 1 -effects Adrenaline (ADR) – Vasodilatation (β 2 -effect), – vasoconstriction (α 1 -effect) – In lowest doses mild vasodilation, then ↑ systolic and mean BP Isoprenaline (isoproterenol) – Marked vasodilation (β 2 ) and tachycardia (β 1 ) – ↑ Systolic BP increases, while ↓ diastolic BP Dopamine – D 1 receptors → vasodilation:from low doses (kidney, mesenteric & coronary) –  1 receptors – moderate doses: ↑ stroke volume and CO – α 1 receptors – high doses – ↑ systolic BP without marked increase in PVR

30. Sympathomimetics Clinical indications α 1 -sympathomimetics – Decongestion of mucosa (nasal, paranasal) – Additives to local anesthetics – In hypotension treatment – For mydriasis induction α 2 -sympathomimetika – Hypertension treatment (mainly CNS effects) β 1 -sympathomimetics – Cardiogenic shock, cardiac arrest (resuscitation) – Acute heart failure with low CO and hypotension – Stress tests in cardiology β 2 -sympatomimetics – COPD (asthma) – Suppression/prevention of premature labor – anaphylactic reactions

31. Sympathomimetics Adverse effects Cardiovascular system – heart Tachycardia, palpitations, extrasystoles, other arrhythmias Myocardial ischemia – angina pain Necrosis after large doses (ADR, ISO) Reflex bradycardia (strong vasoconstriction) – Vessels hypertension, headache, peripheral ischemia, local necrosis at the site of administration CNS (mainly in lipophilic agents) – Anxiety, fear, agitation, insomnia, irritation, psychosis-like (amphetamines) Decreased effect after repeated administration – tachyphylaxis (indirect SM), tolerance (e.g. β 2 -mimetics) Rebound hyperemia – congestion after disappearance of the effect Skeletal muscle tremor

32. Sympathomimetics interactions and contraindications Proarrhythmic effects – In combination with halothane or cardioactive glycosides Increased effect – In combination with IMAO and ICOMT – In combination with tricyclic antidepressants, cocaine (re- uptake inhibition ) Risk of hypertension or arrhythmias Consider suitability in – Endocrine diseases (diabetes, hyperthyreosis) – In glaucoma

33. Direct-acting sympathomimetics α/β-non-selective agents Natural neurotransmitters and hormones Noradrenaline (NOR) Adrenaline (ADR) Dopamine (DOP) – Common pharmacokinetic features Oral administration impossible/do not penetrate to CNS – Low lipophilicity, degradation by MAO in the gut and liver, local vasoconstriction – Low oral BAV Parenteral (systemic) administration – Strong vasoconstrictors (NOR) strictly only i.v. – i.m., s.c. can be used in ADR Short T 1/2 (often administered in infusion)

34. Noradrenaline (NOR, norepinephrine) Main natural neurotransmitter of SNS Affinity to receptors – α 1,2 ˃ β 1 ˃ ˃ ˃ β 2 – In contrast to ADR - β 2 -effect almost negligible – Often significant reflex bradycardia Therapeutic use – Systemic treatment - rather rare – Hypotension states (peripheral analeptic effect) Shock states (e.g. septic shock with refractor hypotension) i.v. infusion with slow discontinuation to avoid hypotension development – Addition to local anesthetics Adverse effects – Bradycardia, hypertension, palpitation, chest pain, tremor, nausea, peripheral ischemia

35. Adrenaline (ADR, epinephrine) Mainly stress hormone (less important as neurotransmitter) Affinity to receptors – β 2 ˃ β 1 ˃ α 1,2 – Cardiovascular system and BP Low doses – β-effects (↓PVR and positive effects on the heart) Higher doses – dominate α 1 -effects on vessels (↑PVR) vasoconstriction with exception of coronary and cerebral aa. Therapeutic use – Cardiostimulant in cardiac arrest, in cardiogenic shock, as a support in resuscitation (0.01 mg/kg slowly i.v.) – Anaphylactic shock Inhibition of histamine release, bronchodilation, Prevents „capillary leak syndrome“, massive vasodilation and shock development Adrenaline pens (EpiPen) for self-administration in high risk patients – Additive to local anesthetics, decongestion, bronchospasms

36. Dopamine Neurotransmitter in CNS and enteric NS – Little role in ANS – Precursor of NOR and ADR Affinity to receptors – D 1/2 ˃ β 1 ˃ α 1,2 – D 1/2 - effect on VS: vasodilatation in kidney, coronary arteries – CVS and PB effects Increased CO and improves/keeps adequate kidney perfusion Low „renal“ doses – improvement in GF was not evidenced Therapeutic use – Acute heart failure (HF) with low CO and hypotension – Cardiogenic shock, septic shock + other shock states esp. with oliguria – i.v. infusion Adverse effects – Hypertension, tachycardia – or arrhythmias

37. Direct-acting sympathomimetics α/β-non-selective agents Other α/β-non-selective agents Ephedrine, pseudoephedrine (mixed direct-indirect effects) – often classified as indirect agent (discussed with them later) – Direct SM effects (α and β) + indirect SM effects

38. Direct-acting sympathomimetics α-sympathomimetics α 1 – selective sympathomimetics Imidazoline derivatives used for decongestion – Local use – Higher lipophilicity and chemical/metabolic stability – naphazoline, oxymetazoline, tetryzoline and xylometazoline – Therapeutic use – rhinitis, conjunctivitis – Combinations with: antihistamines, hyaluronic acid – Adverse effects rebound hyperemia „sanorinism“, mucosal atrophy, dry rhinitis In hypersensitive patients – may affect systemic BP Other synthetic agent for systemic and local use – phenylephrine – decongestion, hyperemia in ophthalmology symptomatic treatment of simple cold: systemic administration in combined preparations… – midodrine – orthostatic hypotension, incontinence due to the sphincter insufficiency, oral administration, prodrug

39. Direct-acting sympathomimetics α-sympathomimetics α 1 – sympathomimetics with both direct and indirect effects hydroxyamphetamine – Little clinical use – Used in treatment of hypotension

40. Direct-acting sympathomimetics α-sympathomimetics α 2 - sympathomimetics To treat hypertension – Mainly CNS effects – decrease central sympathetic outflow via strengthening of negative feedback → decrease in PVR (and HR) In skeletal muscle spasticity – Central myorelaxant effect In glaucoma Drugs – clonidine – α–methyldopa – apraclonidine – tizanidine

41. Direct-acting sympathomimetics α-sympathomimetics α 2 - sympathomimetics clonidine – effects CNS - vasomotor center: on α 2 + imidazoline receptors (block I 1 ) – inhibition of SNS activity →↓ PVR →↓BP – clinical use Formerly, in hypertension and drug dependence therapy Glaucoma treatment (local, inhibition of liquor formation?) – systemic adverse effects Hypotension (often orthostatic), sedation, Rebound hypertension – after sudden withdrawal, Na + retention,,,

42. Direct-acting sympathomimetics α-sympathomimetics α 2 - sympathomimetics Methyldopa (α–methyldopa) – prodrug active metabolite - α-methyl-noradrenaline – Formed in CNS and sympathetic neurons – Higher affinity towards α 2 -receptors (inhibits NOR release) – lower affinity to post-synaptic α 1 -receptors – Lag phase 2-3h (needed for bioactivation) Clinically used in hypertension – Specific populations (diabetics, in pregnancy) – Adverse effects CNS – sedation, nightmares, depression, decreased libido Orthostatic hypotension GIT – dry mouth, GIT adverse effects Rare but severe liver damage and hematological abnormalities Apraclonidin – local glaucoma treatment (like clonidine) Tizanidine – central myorelaxant (spasm, vertebrogenic pain sy.) – Postural hypotension and CNS sedation are frequent

43. β-sympathomimetics

44. Direct-acting sympathomimetics β-sympathomimetics Non-selective β-sympathomimetics Seldom therapeutic use – Unfavorable therapeutic profile: Bronchodilation (β 2 effects) is complicated by cardiac stimulation (β 1 effects) Cardiac stimulation (β 1 effects) are complicated by peripheral vasodilation (β 2 effects) Isoprenaline (isoprotenerol) – Synthetic agonist on β 1 and β 2 -receptors – Prototype for development of other β-SM – Prolonged effect – In past, used as cardiostimulant and bronchodilator – Replaced by selective SM agents

45. Direct-acting sympathomimetics β-sympathomimetics β 1 -selective sympathomimetics Dobutamine – Only weak β 2 and α 1 effects (contribution to therapeutic effects?) – Administered in i.v. infusion – Positive effects on the heart – Higher inotropic than chronotropic response (without marked tachycardia – reason unclear) – Therapeutic use Acute HF with low CO and hypotension Cardiogenic shock In cardiac surgery Stress tests in cardiology (e.g., dobutamine echocardiography) – Adv. effect: ↑ BP, headache, palpitation or angina pain

46. Direct-acting sympathomimetics β-sympathomimetics β 2 -selective sympathomimetics Used as bronchodilators and tocolytics β 2 -selectivity = mitigated cardiac adverse effects – receptor selectivity is only relative (dose & susceptibility matters!!!) – Higher risks/susceptibility to cardiac adverse effects in: HF (up-regulation β 2 -receptors) tolerance development after chronic use likely (corticoids diminishes the risks) – Higher doses needed – cardiac effects more ischemic heart disease (IHD, angina) propensity to arrhythmias Tricyclic antidepressants Slower metabolism (by MAO, not COMT) In asthma – combinations with: corticoids, ipratropium or cromoglycate Adverse effects (higher doses/susceptible patients) – CVS: palpitations, myocardial ischemia/angina, necrosis, arrhythmias – Tremor, anxiety, restlessness, peripheral vasodilation

47. Direct-acting sympathomimetics β-sympathomimetics β 2 -selective sympathomimetics: classification Short-acting – fenoterol (oral, inhal. and inf. – also as tocolytic) – salbutamol (oral, inhal.) – terbutaline (inhal. only, poor oral BAV) Long acting (T 0,5 up to 12 hours) – Night treatment, better BAV – formoterol – salmeterol – procaterol, clenbuterol

48. Indirect-acting sympathomimetics

49. Ephedrine – Originally alkaloid from plant (Ephedra sinica) Today, produced biotechnologically – effects both indirect + direct (both α and β) both periphery and CNS – Currently only limited therapeutic use In past: bronchodilator, decongestant, obesity treatment, analeptic and CNS stimulant (e.g., in narcolepsy). – Adverse effects Possibility of abuse and drug dependence development (ephedrinism) and abuse as a precursor for methamphetamine synthesis CVS: Palpitations, angina pain, hypertension and urine retention

50. Indirect-acting sympathomimetics Pseudoephedrine – Optic isomer of ephedrine with similar PD profile less CVS and CNS effect and less rebound hyperemia after systemic use – Clinical use As decongestant in cold & inflammation of upper respiratory – Vasoconstriction → ↓ edema (nasal and paranasal mucosa) – Symptomatic relieve OTC drugs (with restrictions) – combined with analgesics – Adverse effects and contraindications Contraind or cave: IHD, HF, arrhythmias, hypertension, hyperthyreosis, diabetes, epilepsy Under doping control – interactions IMAO (wash out period is necessary) – Abused as precursor for methamphetamine synthesis

51. Indirect-acting sympathomimetics Amphetamine, dexamphetamine, methamphetamine – Lipophilic agents – marked CNS effects – Indirect effects dominate over direct effects inhibit catecholamine reuptake and degradation by MAO and induces their release to synaptic cleft Besides NOR and dopamine, concerns partially also 5HT Effects: CNS stimulation, central analeptic, anorectic… – Abuse and drug dependence: psychotropic effects, chronic behavioural changes resembling psychosis (often paranoid) – Indications: narcolepsy, ADHD (attention deficit hyperactivity disorder): mainly amphetamine/dexamphetamine – Lisdexamfetamine (L-lysine-dextroamphetamine), prodrug used in ADHD Similar CNS stimulants with less marked CNS effects: -Phentermine – rather obsolete use in obesity treatment -Methylphenidate – ADHD, in past also obesity treatment

52. Indirect-acting sympathomimetics Stimulants in ADHD treatment – Appears paradoxical, but is well supported by clinical trials – The symptoms liokely develop due to weak NOR/dopamine neurotransmission in pyramidal neurones of prefrontal cortex Symptoms: attention deficit and compulsive hyperactive reactions – Stimulants enhance NOR-based signal processing and reduce dopamine deficiency-associated signal noise → improved attention and reduced hyperactivity Tyramine – Formed during fermentation process in food production – Normally no systemic effects Low systemic BAV – effective degradation by MAO in gut and liver – During antidepressant treatment (nonselective irreversible IMAO) BAV is dramatically enhanced (MAO in the liver and gut is blocked) Hypertension crisis and arrhythmias („cheese and wine reactions“) Diet restriction necessary – concerns: matured cheeses, wine, beer, bananas…

53. SYMPATHOLYTICS (SL, ADRENERGIC ANTAGONISTS, ANTIADRENERGIC AGENTS)

54. SYMPATHOLYTICS (direct) NON-SELECTIVE  - SL 11 - selective SL - prazosin - terazosin - doxazosin “uroselective“ - alfuzosin - tamsulosin without ISA - propranolol - metipranolol - timolol - sotalol  2 - selective - yohimbine with ISA - pindolol - bopindolol  - SL  - ergot alkaloids (and derivatives) - ergotamine dihydroergotamine - Synthetic non-selective SL -phentolamine - phenoxybenzamine (irreversible) SELECTIVE  - SL NON-SELECTIVE  - SL SELECTIVE  - SL - acebutolol - celiprolol others - urapidil  1 -selective SL labelatol:-  1 antagonist - non-selective  antagonist (with ISA on  2 ) carvediol-   antagonist -  non-selective antagonist  - Sympatholytics with combined effects - atenolol - betaxolol - metoprolol - bisoprolol - nebivolol - esmolol - without ISA with ISA - methylergometrine ergotametrine -

55. Direct-acting sympatholytics Block adrenergic receptors – Competitive antagonists on α or β receptors α-sympatholytics (α blockers) β-sympatholytics (β blockers) – Exception: phenoxybenzamine is irreversible antagonist and thus shows DRC effects typical rather for non-competitive antagonist Non-selective α SL or β-SL – Block all receptor subtypes of α and β receptors Selective α-SL or β-SL – Block individual α or β receptor subtypes – E.g. α 1 -selective SL or β 1 -selective SL Combined effects SL – block both α and β receptors

56. Direct-acting sympatholytics  -sympatholytics (  -blockers) Main target: vessels Non-selective α-blockers – Ergot alkaloids ergotamine,or ergotoxine + dihydroforms Oldest agents, start of development newer drugs – Synthetic phentolamine, phenoxybenzamine α 1 -selective blockers – Newer and clinically the most important – prazosin, doxazosin, terazosin α 2 -selective blockers – Marginal therapeutic importance – yohimbine

57. Direct-acting sympatholytics  -sympatholytics (  -blockers) Clinical indications Hypertension – Combination therapy (not drugs of 1st choice for monotherapy) – Mainly α 1B blockers, long acting – prazosin, doxazosin, terazosin Pheochromocytoma – To treat accompanying hypertension – To prevent ↑ BP during adenoma surgery (with β-blockers) Benign prostatic hypertrophy – Often used – Mainly drugs affecting α 1A and α 1D receptors – tamsulosin, alfuzosin Impairment of peripheral circulation – Angiospasms, Raynaud´s disease – α 1B blockers, DH derivatives of ergot alkaloids Premedication before surgery – Sometimes to prevent hypertensive reactions

58. Non-selective  -blockers (  -SL) Antagonize both α 1 and α 2 – α 1 receptor blockade  desirable effects: ↓ PVR, ↑ peripheral perfusion, ↓ systemic BP – α 2 receptors blockade  undesirable effects = tachycardia block of presynaptic α 2 -receptors in the heart → disinhibited NOR release → β 1 stimulation block of presynaptic α 2 -receptors in the vessels will not be manifested (postsynaptic α 1 -receptors are blocked) Activation of baroreflex response (rather minor importance) tachycardia = increased demands on myocardium (on perfusion vs. shortened diastole, on blood O 2 ) – Risk of hypotension

59. Non-selective  -blockers (  -SL) Ergot alkaloids Derivatives of lysergic acid (indole alkaloids) – ergotamine, dihydroergotamine – ergometrine, methylergometrine Pharmacodymics – complex and individual agents may differ significantly Non-selective α-receptor blockade (or partial agonist effects) Smooth muscle 5HT receptors – myotropic effect: important in migraine and uterotonic effect, can cause periphehral vasoconstriction – effects antimigrenic ( ergotamine ) uterotonic ( methylergometrine – postpartum hemorrhage in uterine hypotonia ) vasodilation (CNS, periphery),improvement of venolymphatic insufficiency – largely discontinued in the latter indications Risk of fibrosis upon chronic use – cardiac, pulmonary, retinal, retro-peritoneal Egotisms (in overdose) – Convulsive (seizures, muscle spasms, psychosis, mania and vomiting) – Gangrenous (dry gangrene due to the peripheral vasoconstriction, direct effects on vascular smooth muscle)

60. Non-selective  -blockers (  -SL) Ergot alkaloids Ergotamine and dihydroergotamine – antagonists/partial agonist on α-receptors – Agonist on 5HT 1B/D receptors (migraine) – Indications: treatment of acute migraine and vasomotor cephalea Errgot alcaloids are no more indicated for chronic use – due to poor benefit/risk ration (uncertain efficacy vs fibrosis issues) – now only for acute migraine treatment and in obstetrics to stop postpartum hemorrhage in uterine hypotonia Related compounds bromocryptine – D-receptor agonist – mainly in CNS – Treatment of Parkinson disease

61. Non-selective  -blockers (  -SL) Synthetic  -blockers Reversible (competitive, imidazole derivatives) – phentolamine – Also effects on H, 5HT or M receptors – Use is often complicated by Tachycardia, hypotension and nasal hyperemia – Limited clinical use Irreversible ( showing largely non-competitive antagonism character ) – Phenoxybenzamine Both alpha receptors are blocked via alkylation (covalent bond) Tachycardia requires addition of β-blocker Long-lasting significant effects in pheochromocytoma (before surgery) – Often replaced by α-selective agent (e.g. doxazosin)

62. Selective α-blockers α 1 -selective blockers 100-1000x higher affinity to α 1 receptors than to α 2 Main effect – vasodilation (arteries and veins, mainly α 1B receptors) ↓ preload and afterload ↓ PVR and drop in BP Without marked tachycardia (α 2 -receptors are nor affected), only baroreflex-mediated effect possible Without negative impact on lipidemia and glucose tolerance – In contrast: may ↓LDL, ↑HDL or improve glucose – Relax smooth muscle in urinary tract (mainly α 1A and α 1D receptors) Urethra, prostatic capsule, basis of urinary bladder  enhanced urine outflow Indications – Combination treatment of hypertension (esp. with β-blockers) Not suitable as drugs of 1st choice for initial monotherapy – Symptomatic treatment benign prostatic hyperplasia

63. Selective α-blockers α 1 -selective blockers Adverse effects – First dose hypotension (soon after 1 st dose) Hypotension, syncope (up to 50 % of patients, tolerance develops) Treatment may be initiated overnight to avoid troubles – Postural hypotension Inhibition of sympathetic mediated reflex response – Headache – Perimaleolar edema – Nasal hyperemia

64. Selective α-blockers α 1 -selective blockers With effect on both vessels and urinary tract – prazosin Short T 0,5 (cca 4 hours), repeated dosing (3x daily) Discontinued in some countries – doxazosin, terazosin Longer T 0,5 (once daily) Metabolized in the liver (inactive metabolites) With „uroselective“ effects – alfuzosin, tamsulosin – More effects on α 1A and α 1D -receptors in urinary tract – Minor CVS effects Small risk of postural hypotension Other drugs with more complex effects – urapidil (hypertension treatment) bloks α 1B -receptors– ↓ PVR and BP (without tachycardia) CNS effects – blocks 5HT 1A receptors (participates in BP lowering eff.)

65. Yohimbine – Natural alkaloid – Selective α 2 -blokade – increase NOR release Increase HR and BP – Short acting drug – Indications: Minor clinical use – in erectile dysfunction (uncertain efficacy) Selective α-blockers α 2 -selective blockers

66.  -sympatholytics ( β-blockers) Clinically extremely important class of drugs Chemic structure – Typical structure-activity relationship works here – Important similarity in branched aliphatic chain – Different lipohilicity Relatively lipophilic – propranolol, metoprolol Relatively hydrophilic – atenolol Lipohilicity determines – CNS effects, GIT absorption – „first-pass effect“ (in more lipophilic) – BAV is therefore rather lower (≈ 20-50%) – Important liver metabolisms – CYP2D6 » genetic polymorphism – interindividual variability in response » Interactions

67.  -sympatholytics ( β-blockers) Pharmacodynamics and classification cardioselectivity (β 1 selectivity) ISA („intrinsic sympathomimetic activity“) – without ISA = drug is pure antagonist Affinity to receptor but no intrinsic biological activity No activation of receptor – just occupies and block – with ISA = drug is partial agonist Affinity to receptor + some intrinsic activity (but ↓than full agonists!) Partially activates, but less then endogenous catecholamines – hence, relatively, also partially blocks the receptor Lower drop in HR and CO at rest, but more apparent effects in effort! MSA (membrane stabilizing effects) – Nonspecific „quinidine-like“ effect (blockade of Na + channels) – Little importance in normal doses (more in overdose?!) Combination with other effects – α-blockade, β 2 -mimetic effects, antioxidant action….

68. All drugs – reversible competitive antagonists  Selectivity to β-receptor subtypes – Clinically used drugs have negligible β 3 -effects – Non-selective β-blockers – block β 1 and β 2 -receptors β 2 -blockade is not desirable – only source of adverse effects – Cardioselective β-blockers More suitable and more often used β 1 -blockade is not entirely (100%) selective – always relative – Small involvement of β 2 -receptors as well – ISA Better tolerability, but lower value in some indications Not suitable in MI or HF treatment  -sympatholytics ( β-blockers)

69. Effects on heart (via β 1 -receptor blockade) β 1 -blockade → ↓ cAMP → inhibited L-type Ca channels → ↓ Ca 2+ in cardiomyocytes – negative chronotropic – SA node: ↓ rate of spontaneous firing → ↓HR dromotropic – AV node: ↓ functional refractory period of AV node inotropic – Artrial and ventricular myocardium: ↓ release from SR → ↓contractility bathmotropic – Atrial and ventricular myocardium: ↓ resting membrane potential (more negative) → ↓ excitability  -sympatholytics ( β-blockers)

70. Effects on CVS – Heart ↓ metabolic and O 2 demands ↑ diastole duration – enhanced perfusion of ischemic myocardium ↓ arrhythmogenicity – i.e. also decreased sudden death risk ↓ Pathological remodeling effects of catecholamines – Hemodynamics More affected in pts with increased sympathetic tonus – CO in heathy pts – small ↓ or no effect (in contrast to pts with hypertension or IHD) – Drugs with ISA – less effects on CO in resting conditions, but similar effects as those with ISA in effort Perfusion of the periphery – ↓ with ↓ CO and β 2 -blockade may contribute further (cave in ischemic leg disease)

71.  -sympatholytics ( β-blockers) Effects on CVS – Antihypertensive action Little impact on normal BP (in normal doses) Several mechanisms involved – ↓ CO (negative inotropy and chronotropy) – ↓ renin secretion (juxtaglomerular apparatus) – central effects – in lipophilic drugs - ↓ CNS sympathetic outflow – re-set of baroreceptor sensitivity » low risk of postural hypotension, reflex reactions work Effect develops gradually – maximum effect achieved after 2-3 weeks – In ischemic heart disease (IHD) Decreased demands on work, O 2 and perfusion Prolonged diastolic phase → optimized chances for perfusion of ischemic myocardium Improvement correlates with drop in HR ↓ angina pain, ↓ sudden death and risk of reinfarction

72.  -sympatholytics ( β-blockers) Effects on CVS – In heart failure (HF) In acute HF or acute decompensation of chronic HF – β-blockers are contraindicated!!! Sympathetic activation = acute compensatory mechanisms in HF to manage critical situation – Inhibition = further (critical) worsening of CO and ↓ organ perfusion and ↑ congestion (pulmonary edema ) In stable chronic HF = typical indication! – Inhibit chronic hyperactivaty of SNS (is maladaptive and contraproductive) – Complex mechanisms: ↓ HR, ↓ CO, ↓ O 2 demands, ↓ renin secretion, antiarrhythmic effect – improvement in symptoms and survival of HF pts – induction of treatment - careful, low doses, slow dose escalations under supervision

73.  -sympatholytics ( β-blockers) Mechanisms of main adverse effects Bronchoconstriction – in COPD pts – β 2 -blockade – Much higher risk in non-selective β-blockers – Cardioselective and ISA drugs – safer but not totally without risk! Metabolic – Risks of hypoglycemia diabetic patients (mainly type I DM) SNS/adrenaline activates glycogenolysis and gluconeogenesis – to compensate approaching hypoglycemia Other SNS/adrenaline effects (tachycardia, tremor, sweating) = warning symptoms Risks of sudden serious hypoglyceamia incidents in insulin- dependent DM (esp. with unstable glycemia) – Impact on lipid metabolism mild ↑ TAG and ↓ HDL Concerns β-blockers without ISA

74.  -sympatholytics β-blockers: clinical use CVS Hypertension – Among basic drugs of 1 st choice for initial monotherapy – Very suitable for combination treatment – Available evidence about ↓ organ damage and ↓ mortality IHD – Basic drugs of in all forma of angina (AP) with exception of variant (Prinzmetal) AP – risk of coronary spams worsening – Improvement of symptoms, morbidity and mortality – Acute forms of IHD Non-stable AP – decrease progression to MI Acute MI: reduce (by 20-40%) malign arrhythmias, sudden death, overall mortality, risk of re-infarction

75.  -sympatholytics β-blockers: clinical use CVS Chronic HF (NYHA II-IV) – Onset under supervision of cardiologists (in up 25% pts require intervention due to the transient decompensation) – Slow dose titration Low introductory doses and slow up-titration (every 2-3 weeks) Improves both symptoms and mortality (by up to 35%)! Additive benefit to other drugs (e.g. ACE-I) – But likely not a „class effect“- solid evidence only in metoprolol, carvedilol, bisoprolol Arrhythmias – SV tachycardias (e.g. AF) with rapid ventricular response (rate-control approach), symptomatic sinus tachycardia etc. – In endocrine etiology – thyrotoxicosis, feochromocytoma

76.  -sympatholytics β-blockers: clinical use Outside CVS: Glaucoma – local treatment – ↓ intraocular pressure (by ↓ production of liquor, lower problems with accommodation compared to AChE inhibitors). – mostly: timolol and betaxolol Migraine prevention – Lipophilicity is a must – Mechanism uncertain – antagonisms of vasodilatation in the CNS. Adjuvant anxiety treatment – Control of somatic symptoms associated with sympathetic hyperactivity (e.g. palpitation, tremor). – abusus in doping (sport shooting) Treatment of benign tremor (familiar disorder)

77.  -sympatholytics β-blockers: adverse effects Most common short after initiation of the treatment Bronchoconstriction – In COPD pts (mainly asthma) – Risk depends by drug selectivity, ISA, dose and severity of COPD – Can trigger even life-threatening events (status asthmaticus) CVS complications – bradycardia, AV-blockades – Exacerbation (decompensation) of HF, hypotension Peripheral perfusion impairments – Cold periphery – Worsened claudication in pts with ischemic leg disease Increased fatigue + worsened adaption in stress and physical load CNS (lipophilicity matters) – nightmares (vivid dreams), depression, – hallucinations and paresthesia (unusual)

78.  -sympatholytics β-blockers: adverse effects Metabolic – Mild dyslipidemia: ↑ TAG, ↓ HDL; total cholesterol mostly ok – In diabetics Risks of sudden severe hypoglycemia in IDDM (type I) (mask symptoms and inhibits compensatory reactions) May decrease insulin secretion on DM type II. In allergic reactions – Enhance problems (antagonize catecholamine-induced inhibition of degranulation of mastocytes → ↑ release of histamine) Rebound phenomenon – After sudden withdrawal from long-term therapy – Due to the up-regulation and hypersensitivity of β-receptors – Risk of tachycardia, angina pain, arrhythmias and hypertensive crisis

79.  -sympatholytics β-blockers: contraindications Acute HF with low CO/acute decompensation of chronic HF – Risk of: worsening of organ hypoperfusion, pulmonary edema, cardiogenic shock Serious bradycardia – sinus/AV-block of higher degree (HR˂50 BPM) – Risk of: HR worsening, HF symptoms, block of AV-conduction COPD – Mainly serious forms of asthma – Risk of: acute severe asthma attack or status asthmaticus Leg ischemic disease – Serious forms – Risk of: ischemia worsening, decreased claudication distance or critical ischemia induction Diabetes – Mainly IDDM (type I) with instable glycaemia – Risk of: sudden serious hypoglycemia or even coma Concomitant treatment (PD interaction) with – verapamil (esp. i.v.) and dilthiazem – bradycardia and AV-block, HF, cardiogenic shock/arrest – Antiarrhythmics with strong cardiodepressive action

80.  -sympatholytics β-blockers: classification Non-selective β-blockers Without ISA – propranolol 1st β-blocker (Glasgow University, prof. J. Black – Nobel Prize) Reference for other drugs, now often unavailable – metipranolol – original Czech drug (VUFB Prague) 2x daily administration – timolol – glaucoma treatment (eye drops) – sotalol β-blocker and antiarrhythmic agent (class III) Used only as antiarrhythmic indications With ISA – pindolol, bopindolol (pindolol prodrug)

81.  -sympatholytics β-blockers: classification β 1 -selective drugs Without ISA – atenolol hydrophilic, little CNS effects, renal elimination – betaxolol Medium lipophilic, high BAV, low variability in plasmatic concentrations, important liver metabolism – metoprolol Often used, lipophilic, BAV 50%, important metabolism Conventional forms - 2x daily; or SR, CR (ZOK) forms – 1 x daily – bisoprolol Medium lipophilic, high BAV, metabolism/renal elimination (1:1) HF treatment – esmolol Very short T 0,5 – acute (parenteral) use, arrhythmias treatment – nebivolol – enhance NO availability (slight vasodilation) With ISA – acebutolol – with active metabolite (longer T 0,5 )

82.  -sympatholytics β-blockers: classification Β-blockers with combined effect β 1 -blocker + mild β 2 -mimetic (ISA on β 2 ) – celiprolol vasodilation, well-tolerable, low risk of bronchospasm, Low lipophilicity, renal/hepatic elimination without metabolism Indications: hypertension and IHD β 1 -blocker + mild β 2 -mimetic (ISA on β 2 )+α 1 -blocker. – labelatol Marked vasodilation Hypertension treatment (available only for acute i.v. use) Non-selective β-blocker (without ISA)+α 1 -blocker – carvedilol Also block Ca 2+ channels and direct antioxidant effects Vasodilation and drop in PVR, no tachycardia indeed Most important agent in chronic HF treatment?

83. Indirect-acting sympatholytics Drugs that do not interact directly with adrenergic receptors Impact on synthesis, docking and release of NOR (catecholamines) Results into decrease in adrenergic transmission and effects Little clinical use Rather theoretically important – reserpine – carbidopa (inhibition of catecholamin degradation outside CNS) Inhibits L-DOPA bioactivation outside CNS in parkinsonism treatment – Nerve ending blockers – bretylium, guanethidin Inhibit reuptake of NOR, lower accumulation in sympathetic neurons, decrease in NOR neurotransmission block Na + channel (excitability of neurons)

84. Indirect-acting sympatholytics Reserpine – alkaloid from plant Rauwolfia serpentina – Formerly used as Neuroleptic (antipsychotic) agent (decrease dopamine availability in mesolimbic/mesortical system in the CNS) Antihypertensive agent (indirect SL, when no better drugs were available) – mechanisms Inhibits dopamine transport into the vesicle (irreversibly) in sympathetic neurons (long-lasting effects) Decreased NOR availability in SNS neurons → vasodilatation – Adverse effect: depression (decreased NOR a D neurotransmission i CNS) and many others