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Norepinephrine

• Norepinephrine is the primary neurotransmitter released by postganglionic neurons of the autonomic sympathetic system.

• Norepinephrine (Levophed) is a potent activator of a and ß₁ adrenergic receptors.

 Blood Pressure

• Potent vasopressor

  • Systolic and diastolic pressure increase

    • pulse pressure widens

  • Norepinephrine (Levophed) increases blood pressure by:

    1. vasoconstriction a₁ receptor effects

       • precapillary resistance vessels of the skin, kidney, and mucosa

       • veins

  •  Elevation of systolic pressure following norepinephrine is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart rate.

0.1-0.4 ug/kg/min IV infusion

Adaptation of Table 10-2 from: Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.199-242

 

                  Arterioles (Adrenergic Effects in RED; Cholinergic Effects in BLUE)                     

Coronary	alpha1,2; beta 2	constriction;dilatation	constriction
Skin/Mucosa	alpha1,2	constriction	dilatation
Skeletal Muscle	alpha; beta2	constriction,dilatation	dilatation
Cerebral	alpha1	slight constriction	dilatation
Pulmonary	alpha1 , beta2	constriction; dilatation	dilatation
Abdominal viscera	alpha1, beta2	constriction; dilatation	-------
Salivary glands	alpha1,2	constriction	dilatation
Renal	alpha1,2;beta1,2	constriction;dilatation	---------

Based on Table 6-1: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,( Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.110-111.

Vascular Effects

• Norepinephrine significantly increases total peripheral resistance, often inducing reflex cardiac slowing.

• Norepinephrine (Levophed) causes vasoconstriction in most vascular beds.

• Blood flow is reduced to the kidney, liver and skeletal muscle.

• Glomerular filtration rates are usually maintained.

• Norepinephrine may increase coronary blood flow (secondary to increased blood pressure and reflex activity)

• Norepinephrine (Levophed) may induce variant (Prinzmetal's) angina.

• Pressor effects of norepinephrine (Levophed) are blocked by alpha-receptor blockers.

• ECG changes following norepinephrine (Levophed) are variable, depending on the extent of reflex vagal effects.

increase, decrease

0.1-0.4 ug/kg/min IV infusion

Adaptation of Table 10-2 from: Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.199-242

Therapeutic use: Norepinephrine

• may be used in treatment of shock

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.204-213.

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Dopamine

• Dopamine is the immediate precursor of norepinephrine.

• Dopamine is a CNS neurotransmitter associated with the basal ganglia and motor control.

Cardiovascular Effects (Dopamine)

• Vasodilator:

  • At low doses, dopamine (Intropin) interactions with D₁ receptor subtype results in renal, mesenteric and coronary vasodilation.

    • This effect is mediated by an increase in intracellular cyclic AMP

  • Low doses result in enhancing glomerular filtration rates (GFR), renal blood flow, and sodium excretion.

• Positive inotropism:

  • At higher doses, dopamine increase myocardial contractility through activation of ß₁ adrenergic receptors

  • Dopamine (Intropin) also promotes release of myocardial norepinephrine.

  • Dopamine (Intropin) at these higher dosages causes an increase in systolic blood and pulse pressure with little effect on diastolic pressures.

• Vasopressor:

  • At high doses dopamine (Intropin) causes vasoconstriction by activating a₁ adrenergic receptors

Therapeutic use (Dopamine)

•  Cardiogenic and hypovolemic shock

  • by enhancing renal perfusion despite low cardiac output. Oligouria may be an indication of inadequate renal perfusion.

  • Example: dopamine may be used, in postoperative cardiopulmonary bypass patients who exhibit:

    • low systemic blood-pressure

    • increased atrial filling pressures

    • low urinary output

• Increased sodium excretion following dopamine may be due to inhibition of aldosterone secretion.

• Dopamine may inhibit renal tubular solute reabsorption(suggesting that natriuresis & diuresis may occur by different mechanisms.)

• Fenoldopam and dopexamine: newer drugs

  • may be useful in treating heart failure by improving myocardial contractility

• Dopamine (Intropin) at higher doses increases myocardial contractility by ß₁ - adrenergic receptor activation.

• Ventilation effects: -- dopamine IV infusion interferes with ventilatory responses to arterial hypoxemia

  Dopamine (Intropin) acts as inhibitory neurotransmitter at carotid bodies)

  •  Consequence: Unexpected ventilation depression in patients treated with IV dopamine (Intropin) to enhance myocardial contractility

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Dopexamine

• Dopexamine--synthetic catecholamine

• Activation of dopaminergic and beta₂ receptors

• Slight positive inotropic effect (beta2-adrenergic agonists activity; potentiation those endogenous norepinephrine secondary to reuptake blockade)

• Dopexamine enhances creatinine clearance

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Isoproterenol (Isuprel)

• Activates ß adrenergic receptors (both ß₁ - and ß₂ -receptor subtypes)

• Has limited action at a adrenergic receptors

• i.v. influsion of isoproterenol results in a slight decrease in mean blood pressure with a marked drop in diastolic pressure.

• ß₂ - adrenergic receptor-mediated reduction in peripheral resistance (reflected in the diastolic pressure effects) is primarily due to vasodilation of skeletal muscle vasculature. Renal and mesenteric vascular beds are also dilated.

• Activation of cardiac ß₁ - adrenergic receptors: increased contractility and heart rate.

• Activation of ß₂ - adrenergic receptors: Bronchial and GI smooth muscle relaxation.

• Isoproterenol and ß₂ -selective adrenergic agonists inhibit antigen-mediated histamine release.

  Isoproterenol: Limited therapeutic uses:

  • emergency settings to treat heart block or severe bradycardia

  • management of torsades de pointes (a ventricular arrhythmia)

• Isoproterenol (Isuprel) adverse effects:

  • palpitations

  • tachycardia

  • arrhythmias

  • coronary insufficiency

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Dobutamine (Dobutrex)

• Structurally similar to dopamine (Intropin).

  Pharmacological effects exerted through interaction with a and ß adrenergic receptor interactions

  • no effect on release

  • no action through dopamine receptors

   

• Pharmacological effects are due to complex interactions of (-) and (+) enantiometic forms present in the clinically used racemate with a and ß adrenergic receptors.

• Dobutamine (Dobutrex) is a positive inotropic agent usually causing limited increase in heart rate.

  • Positive inotropism is mediated through ß adrenergic receptor activation. Some peripheral a₁ activity causes modest vasoconstriction, an effect opposed by dobutamines ß₂ effects.

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.199-242

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