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![Page 1: Alpha-adrenergic drugs J. Starkopf Department of Anaesthesiology and Intensive Care University of Tartu Estonia.](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649e4b5503460f94b3f094/html5/thumbnails/1.jpg)
Alpha-adrenergic drugs
J. Starkopf
Department of Anaesthesiology and Intensive CareUniversity of Tartu
Estonia
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Content of the lecture:
Adrenoreceptors
Cellular mechanism of muscle contraction
Catecholamines
Autonomic nervous system
Sympathomimetic drugs
Sympatholytic drugs
Clinical use
Alpha-adrenergic drugs
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1948 Ahlquist and adrenoreceptors
1967 Lands et al. 1 ja 2
1970 1 and 2 , 1 and 2
Adrenoreceptors
Adrenoreceptors
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Adrenoreceptors
Adrenoreceptors
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Gs Adenylate cyclase
Phospholamban
Gq
ATP cAMP 5´AMP
phosphodiesterase
Protein kinase A Ca2+
Ca-pump
Ca2+
Ca2
+
PIP2
DAGIP3
Protein kinase C
Ca-channel
Phospholipase C
Cardiomyocyte
Lusitropic effect
Inotropic effect
Cellular mechanisms of muscle contraction
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Vasodilatation:
Tissue metabolism Cell depolarization Endotheluim derived factors
NOProstacyclinBradykininAcetylcholineHistamine
Vasoconstriction:
Symphatic nerve endings Circulating catecholamines
Angiotensin Endothelin
Blood vessels
Cellular mechanisms of muscle contraction
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Gq Adenylate cyclase
ATP cAMP
Protein kinase ACa2
+
Ca-pump
Ca2+
IP3
Phospholipase C
Vascular smooth muscle cell
Vasodilatation
Vasoconstriction
ATII
Gs
Ca2+
Ca2++ Calmoduline
Myosine light chain kinase
Cellular mechanisms of muscle contraction
ET
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Catecholamines
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Catecholamines
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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
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Autonomic nervous system
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Autonomic nervous system
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ALPHAHeartBlood vessels
ArteriesVeins
GI tractGenitourinary tractMetabolic and endocrine effects
BETAHeartBlood vessels
VeinsRespiration 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
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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
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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
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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
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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
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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
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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
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Noradrenaline
NB! Hypovolemia cannot be treated with noradrenaline!
Endogenous catecholamines
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Dopamine
Stimulates:
DA1-receptors in renal and mesenteric arteries
- and -adrenoreceptors
Overall effect is related to the dose
Endogenous catecholamines
…3 g/kg/min Renal 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
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Dopamine
Endogenous catecholamines
…3 g/kg/min
5…10 g/kg/min
10…15 g/kg/min
DA1
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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.
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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 DA1-agonist , moderate
Dose: 0.5…6.0 g/kg/min Heart rate , Cardiac output, vascular resistance, Maintenance of splanchnic blood flow
Synthetic catecholamines
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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
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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
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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
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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
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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
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Labetalol 1-, 1- and 2-antagonist
Antihypertensive
Dosage: 5…10 g i/v bolus …. infusion
Alpha-adrenergic antagonists
Sympatholytic drugs
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Clinical use
Arterial line Central venous line, whenever possible Dilution of the drugs - standard dose regimens Central hemodynamic monitoring if indicated
Standards!
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