Alpha-adrenergic drugs

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

• Arterial hypertension
• Shock
• Glaucoma therapy
• Prostatic hyperplasia
• Central nervous system

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Alpha-adrenergic drugs

• Content of the lecture
• Adrenoreceptors
• Cellular mechanism of muscle contraction
• Catecholamines
• Autonomic nervous system
• Sympathomimetic drugs
• Sympatholytic drugs
• Clinical use

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Adrenoreceptors
Adrenoreceptors

• 1948 Ahlquist a and b adrenoreceptors
• 1967 Lands et al. b1 ja b2
• 1970 a1 and a2 , b1 and b2

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Adrenoreceptors
Adrenoreceptors
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Cardiomyocyte
Cellular mechanisms of muscle contraction
b1
Gs
Adenylate cyclase
Lusitropic effect
Phospholamban
Ca-pump
Ca-channel
Inotropic effect
Gq
Phospholipase C
a1
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Cellular mechanisms of muscle contraction
Blood vessels

• Vasoconstriction
• Symphatic nerve endings
• Circulating catecholamines
• Angiotensin
• Endothelin

• Vasodilatation
• Tissue metabolism
• Cell depolarization
• Endotheluim derived factors
• NO
• Prostacyclin
• Bradykinin
• Acetylcholine
• Histamine

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Cellular mechanisms of muscle contraction
Vascular smooth muscle cell
a1
ATII
b2
Gq
Adenylate cyclase
Gs
Phospholipase C
ET
IP3
Protein kinase A
Ca2
Ca-pump
Ca2
Ca2
Ca2
Calmoduline
Myosine light chain kinase
Vasodilatation
Vasoconstriction
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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
Sympathetic
Parasympathetic
Pre-ganglionar fibres
Transmitter
Transmitter
Nicotinergic receptors
Nicotinergic receptors
Ganglions
Ach
Ach
Post-ganglionar fibres
Effectors
NA
Adrenergic (a,b) receptors
Ach
Muscarinergic receptors
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Autonomic nervous system
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Autonomic nervous system
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Autonomic nervous system
Adrenergic-receptor differentiation
ALPHA Heart Blood vessels Arteries Veins GI
tract Genitourinary tract Metabolic and endocrine
effects BETA Heart Blood vessels Veins Respirati
on Metabolic and endocrine effects
(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
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Adrenoreceptors in the heart
Autonomic nervous system

• Cardiomyocytes b1gtgta1
• Sinus node b1b2
• Coronary vessels a, b2
• b1 positive inotropic and lusitropic effect
• In normal heart 77 b1 23 b2
• Chronic heart failure 60 b1 38 b2 a1 ?

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Sympathomimetic drugs

• Catecholamines
• Endogenous
• Adrenaline
• Noradenaline
• Dopamine
• Synthetic
• Isoprenaline
• Dobutamine
• Dopexamine

• Non-catecholamines
• Acting via adrenergic receptors
• Ephedrine
• Phenylephrine
• Methoxamine
• Metaraminol
• Acting via non-adrenergic mechanisms
• PDE-inhibitors
• others

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Endogenous catecholamines
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
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Endogenous catecholamines
Adrenaline

• Dose
• Cardiac arrest 1 mg i/v (23 mg intratracheally)
• Acute anaphylactic reactions 100 mg 1 mg i/v
• Shock 0.010.2 mg/kg/min
• Cardiovascular effects on i/v infusion
• Low dosage b2 effect vasodilatation of
  skeletal muscle and splanchic arterioles. MAP
  remains stable
• Higher dosage a1, b1 effects vasoconstriction
  (incl. renal), increase in blood pressure and
  cardiac output, tachycardia

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Endogenous catecholamines
Adrenaline

• Other effects
• Metabolic effect
• Hyperglycaemia
• Potassium shift (hypokalaemia)
• b2 stimulation drives K into red blood cells and
  muscle cells
• Mydriasis
• a1 effect after CPR
• Hypertermia in neonates

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Endogenous catecholamines
Noradrenaline

• Arteriolar and venous vasoconstrictor
• Acts almost exclusively at a -receptors
• Infusion 0.010.1 (1.0) mg/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

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Endogenous catecholamines
Noradrenaline

• NB! Hypovolemia cannot be treated with
  noradrenaline!

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Endogenous catecholamines
Dopamine

• Stimulates
• DA1-receptors in renal and mesenteric arteries
• a- and b-adrenoreceptors
• Overall effect is related to the dose

3 mg/kg/min
Renal and mesenteric vascular resistance?, blood
flow?, glomerular filtration rate?, diuretic
effect
510 mg/kg/min
b-mediated inotropic action, no vasoconstriction.
Increase in CO and arterial pressure.
Tachyarythmias.
1015 mg/kg/min
a-effect, similar to noradrenaline
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Endogenous catecholamines
Dopamine
3 mg/kg/min
DA1
510 mg/kg/min
b
1015 mg/kg/min
a
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Endogenous catecholamines
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

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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Endogenous catecholamines
Dopamine in acute renal failure

• Dopamine is a good diuretic
• Renal vasodilatation (DA)
• Increased cardiac output (b)
• Increased perfusion pressure (a)
• Inhibition of aldosterone release at tubular
  epithelial cells
• Inhibition of Na/KATPase 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).
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Synthetic catecholamines
Synthetic cathecholamines

• Isoproterenol
• b1and b2-agonist, with no a-activity
• Heart rate?, vascular resistance?, cardiac output
  ?, arterial pressure?
• Treatment of bradyarrhytmias
• Dobutamine
• b1agonist, moderate b2-agonist and mild
  a1-activity
• Dose 2.525 mg/kg/min
• Cardiac output?, vascular resistance?, arterial
  pressure??
• Tachycardia
• Dopexamine
• b2- agonist and DA1-agonist , moderate
• Dose 0.56.0 mg/kg/min
• Heart rate ?, Cardiac output?, vascular
  resistance?,
• Maintenance of splanchnic blood flow

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Non-catecholamines
Ephedrine

• Similar effects as adrenaline
• Agonist at a, b1and b2-receptors
• Heart rate?, arterial pressure?
• Dosage
• 515 mg i/v bolus
• 1530 mg i/m
• Useful to treat hypotension
• Induced by sympathetic blockade during regional
  anaesthesia
• From general anaesthesia

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Non-catecholamines
Phenylephrine

• Direct acting a1-agonist
• Minimal agonist effects at a2 and b-receptors
• Vasoconstriction, arterial pressure?, heart rate?
  
• Dosage
• 50100 mg i/v bolus (standard dilution 1100)
• 2050 mg/min infusion
• Useful to treat hypotension
• From general anaesthesia

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Sympatholytic drugs

• Drugs, which antagonize the effects of the
  sympathetic
• nervous system. They may act at
• Central adrenergic neurones
• a2-receptor agonists
• Peripheral autonomic ganglia or neurones
• Ganglion blocking drugs (e.g. hexamethonium)
• Postsynaptic a- or b-receptors
• a-blockers
• b-blockers

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Sympatholytic drugs
Clonidine

• a2-receptor agonist, a2 a1 gt 2001
• Stimulation of brain-stem a2-receptors decreases
  sympathetic tone
• Arterial pressure?, cardiac output?
• Synergistic analgesic effect with opioids
• Treatment of delirium
• Dosage
• 50100 mg i/v bolus
• 2 mg/kg/h infusion

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Sympatholytic drugs
Alpha-adrenergic antagonists
Vasodilatators, used for treatment of
hypertension or as urinary tract smooth muscle
relaxants in patients with benign prostata
hyperplasia

• Phenoxybenzamine
• a1-receptor antagonist, a1 a2 gt 2001
• Long half-life
• Preoperative preparation of phaeochromocytoma
  patients (chemical sympathectomy)
• Phentolamine
• Prazosin (Minipress)

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Sympatholytic drugs
Alpha-adrenergic antagonists

• Labetalol
• a1-, b1- and b2-antagonist
• Antihypertensive
• Dosage
• 510 mg i/v bolus
• . infusion

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Clinical use
Standards!

• Arterial line
• Central venous line, whenever possible
• Dilution of the drugs - standard dose regimens
• Central hemodynamic monitoring if indicated

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