Alpha-adrenergic drugs

J. Starkopf

Department of Anaesthesiology and Intensive CareUniversity of Tartu

Estonia

Content of the lecture:

Adrenoreceptors

Cellular mechanism of muscle contraction

Catecholamines

Autonomic nervous system

Sympathomimetic drugs

Sympatholytic drugs

Clinical use

Alpha-adrenergic drugs

1948 Ahlquist and adrenoreceptors

1967 Lands et al. 1 ja 2

1970 1 and 2 , 1 and 2

Adrenoreceptors

Adrenoreceptors

Adrenoreceptors

Adrenoreceptors

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

Vasodilatation:

Tissue metabolism Cell depolarization Endotheluim derived factors

NOProstacyclinBradykininAcetylcholineHistamine

Vasoconstriction:

Symphatic nerve endings Circulating catecholamines

Angiotensin Endothelin

Blood vessels

Cellular mechanisms of muscle contraction

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

Catecholamines

Catecholamines

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

Autonomic nervous system

Autonomic nervous system

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

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

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

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

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

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

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

Noradrenaline

NB! Hypovolemia cannot be treated with noradrenaline!

Endogenous catecholamines

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

Dopamine

Endogenous catecholamines

…3 g/kg/min

5…10 g/kg/min

10…15 g/kg/min

DA1

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.

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

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

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

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

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

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

Labetalol 1-, 1- and 2-antagonist

Antihypertensive

Dosage: 5…10 g i/v bolus …. infusion

Alpha-adrenergic antagonists

Sympatholytic drugs

Clinical use

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

Standards!