1. Alpha-adrenergic drugs J. Starkopf Department of Anaesthesiology and Intensive Care University of Tartu Estonia

2.  Arterial hypertension  Shock  Glaucoma therapy  Prostatic hyperplasia  Central nervous system  … Alpha-adrenergic drugs

3. Content of the lecture:  Adrenoreceptors  Cellular mechanism of muscle contraction  Catecholamines  Autonomic nervous system  Sympathomimetic drugs  Sympatholytic drugs  Clinical use Alpha-adrenergic drugs

4. 1948Ahlquist  and  adrenoreceptors 1967Lands et al.  1 ja  2 1970  1 and  2,  1 and  2 Adrenoreceptors

6.  GsGs Adenylate cyclase Phospholamban  GqGq ATP cAMP 5´AMP phosphodiesteraseProtein kinase A Ca 2+ Ca-pump Ca 2+ PIP 2 DAG IP 3 Protein kinase C Ca-channel Phospholipase C Cardiomyocyte Lusitropic effect Inotropic effect Cellular mechanisms of muscle contraction

7. Vasodilatation:  Tissue metabolism  Cell depolarization  Endotheluim derived factors NO Prostacyclin Bradykinin Acetylcholine Histamine Vasoconstriction:  Symphatic nerve endings  Circulating catecholamines  Angiotensin  Endothelin Blood vessels Cellular mechanisms of muscle contraction

8.  GqGq Adenylate cyclase ATP cAMP Protein kinase A Ca 2 + Ca-pump Ca 2+ IP 3 Phospholipase C Vascular smooth muscle cell VasodilatationVasoconstriction ATII  GsGs Ca 2+ + Calmoduline Myosine light chain kinase Cellular mechanisms of muscle contraction ET

9. Catecholamines

11. Autonomic nervous system Nervous and humoral mechanisms which modify the function of the autonomous or automatic organs. Innervation of smooth muscles, heart, endocrine glands.  Sympathetic nervous system  Parasympathetic nervous system  Enteric nervous system

12. SympatheticParasympathetic Nicotinergic receptors Ach Pre- ganglionar fibres Ganglions Post- ganglionar fibres Effectors NA Adrenergic (  receptors Transmitter Nicotinergic receptors Ach Muscarinergic receptors Transmitter Autonomic nervous system

15. ALPHA Heart Blood vessels Arteries Veins GI tract Genitourinary tract Metabolic and endocrine effects BETA Heart Blood vessels Veins Respiration Metabolic and endocrine effects Adrenergic-receptor differentiation (1) Vasoconstriction (skin, gut, kidney, liver, heart) (2) Vasoconstriction (1) Sphincters (1) Contraction of sphincters, contraction of uterus (2) Deacreased insulin realease from pancreas (1) Increased rate and force of contraction (2) Vasodilatation (skeletal muscle, heart, brain) (2) Bronchodilatation (2) Glycogenolysis (muscle, liver) (1) Lipolysis (2) Gluconeogenesis Autonomic nervous system

16. Adrenoreceptors in the heart  Cardiomyocytes      Sinus node      Coronary vessels ,      – positive inotropic and lusitropic effect  In normal heart: 77%   23 %    Chronic heart failure:60%   38 %      Autonomic nervous system

17. Catecholamines Endogenous:  Adrenaline  Noradenaline  Dopamine Synthetic:  Isoprenaline  Dobutamine  Dopexamine Sympathomimetic drugs Non-catecholamines Acting via adrenergic receptors:  Ephedrine  Phenylephrine  Methoxamine  Metaraminol Acting via non-adrenergic mechanisms:  PDE-inhibitors  others

18. Adrenaline Drug of choice for: Cardiac arrest Acute allergic (anaphylactic) reactions Occasionally as a bronchodilatator I/v in emergency situations; bolus – i/v infusion S/c – slower release due to local vasospasm Endogenous catecholamines

19. Adrenaline Dose:  Cardiac arrest 1 mg i/v (2…3 mg intratracheally)  Acute anaphylactic reactions 100  g …1 mg i/v  Shock 0.01…0.2  g/kg/min Cardiovascular effects on i/v infusion:  Low dosage:   effect – vasodilatation of skeletal muscle and splanchic arterioles. MAP remains stable  Higher dosage:  ,    effects – vasoconstriction (incl. renal), increase in blood pressure and cardiac output, tachycardia Endogenous catecholamines

20. Adrenaline Other effects:  Metabolic effect  Hyperglycaemia  Potassium shift (hypokalaemia)    stimulation drives K + into red blood cells and muscle cells  Mydriasis    effect; after CPR  Hypertermia in neonates Endogenous catecholamines

21. Noradrenaline  Arteriolar and venous vasoconstrictor  Acts almost exclusively at   -receptors  Infusion 0.01…0.1 (…1.0)  g/kg/min  Increase in systemic and pulmonary artery pressure  No effect on heart rate  No change in cardiac output  Renal vasoconstriction  Main indication: septic shock  Low systemic vascular resistance Endogenous catecholamines

22. Noradrenaline NB! Hypovolemia cannot be treated with noradrenaline! Endogenous catecholamines

23. Dopamine Stimulates:  DA 1 -receptors in renal and mesenteric arteries   - and  -adrenoreceptors  Overall effect is related to the dose Endogenous catecholamines …3  g/kg/minRenal and mesenteric vascular resistance , blood flow , glomerular filtration rate , diuretic effect 5…10  g/kg/min  mediated inotropic action, no vasoconstriction. Increase in CO and arterial pressure. Tachyarythmias. 10…15  g/kg/min  effect, similar to noradrenaline

24. Dopamine Endogenous catecholamines …3  g/kg/min 5…10  g/kg/min 10…15  g/kg/min DA 1  

25. Vasopressors in septic shock Some advantages of norepinephrine and dopamine:  over epinephrine  potential tachycardia  possibly disadvantageous effects on splanchnic circulation  over phenylephrine  decrease in stroke volume Endogenous catecholamines Norepinephrine is more potent than dopamine and may be more effective at reversing hypotension. Dopamine may be particularly useful in patients with compromised systolic function but causes more tachycardia and may be more arrhythmogenic.

26. Dopamine in acute renal failure Endogenous catecholamines Dopamine is a good diuretic: -Renal vasodilatation (DA) -Increased cardiac output (  ) -Increased perfusion pressure (  ) -Inhibition of aldosterone release at tubular epithelial cells -Inhibition of Na + /K + ATPase at tubular epithelial cells Large randomized trial and a meta-analysis comparing low-dose dopamine to placebo in critically ill patients found no difference in either primary outcomes (peak serum creatinine, need for renal replacement therapy, urine output, time to recovery of normal renal function) or secondary outcomes (survival to either ICU or hospital discharge, ICU stay, hospital stay, arrhythmias). Thus, the available data do not support administration of low doses of dopamine to maintain or improve renal function (31, 32).

27. Synthetic cathecholamines Isoproterenol    and    agonist, with no  -activity  Heart rate , vascular resistance , cardiac output , arterial pressure   Treatment of bradyarrhytmias Dobutamine    agonist, moderate    agonist and mild   -activity  Dose: 2.5…25  g/kg/min  Cardiac output , vascular resistance , arterial pressure   Tachycardia Dopexamine      agonist and DA 1 -agonist, moderate  Dose: 0.5…6.0  g/kg/min  Heart rate , Cardiac output , vascular resistance ,  Maintenance of splanchnic blood flow Synthetic catecholamines

28. Ephedrine  Similar effects as adrenaline  Agonist at ,   and    receptors  Heart rate , arterial pressure   Dosage:  5…15 mg i/v bolus  15…30 mg i/m  Useful to treat hypotension  Induced by sympathetic blockade during regional anaesthesia  From general anaesthesia Non-catecholamines

29. Phenylephrine  Direct acting    agonist  Minimal agonist effects at   and  receptors  Vasoconstriction, arterial pressure , heart rate   Dosage:  50…100  g i/v bolus (standard dilution 1:100)  20…50  g/min infusion  Useful to treat hypotension  From general anaesthesia Non-catecholamines

30. Drugs, which antagonize the effects of the sympathetic nervous system. They may act at  Central adrenergic neurones   2 -receptor agonists  Peripheral autonomic ganglia or neurones  Ganglion blocking drugs (e.g. hexamethonium)  Postsynaptic  - or  -receptors   -blockers   -blockers Sympatholytic drugs

31.   2 -receptor agonist,  2 :  1 > 200:1  Stimulation of brain-stem   -receptors decreases sympathetic tone  Arterial pressure , cardiac output   Synergistic analgesic effect with opioids  Treatment of delirium  Dosage:  50…100  g i/v bolus  2  g/kg/h infusion Clonidine Sympatholytic drugs

32. Phenoxybenzamine   1 -receptor antagonist,  1 :  2 > 200:1  Long half-life  Preoperative preparation of phaeochromocytoma patients (chemical sympathectomy) Phentolamine Prazosin (Minipress) Alpha-adrenergic antagonists Sympatholytic drugs Vasodilatators, used for treatment of hypertension or as urinary tract smooth muscle relaxants in patients with benign prostata hyperplasia

33. Labetalol   1 -,  1 - and  2 -antagonist  Antihypertensive  Dosage:  5…10  g i/v bolus  …. infusion Alpha-adrenergic antagonists Sympatholytic drugs

34. Clinical use  Arterial line  Central venous line, whenever possible  Dilution of the drugs - standard dose regimens  Central hemodynamic monitoring if indicated Standards!