VASOPRESSORS

Sympathomimetic Amines
     Sympathomimetic amines are inotropic drugs that bind to cardiac B1-receptors. Stimulation of these receptors increases the activity of adenylate cyclase, causing increased formation of cyclic adenosine monophosphate (cAMP). Increased cAMP activates protein kinases, which promote intracellular calcium influx by phosphorylating L-type calcium channels. The increased calcium entry triggers a corresponding rise in Ca release from the sarcoplasmic reticulum, which enhances the force of contraction. Intravenous dopamine and dobutamine are commonly used sympathomimetic amines in the treatment of acute heart failure. Norepinephrine, epinephrine, and isoproterenol are prescribed in special circumstances, as described in the following paragraphs.

Sympathomimetic Drug Effects
                                                          Receptor Stimulation
Drug                   D1 ( ↑ Renal               Alfa                          Beta 1                       Beta 2
                          Perfusion)         (Vasoconstriction)        ( ↑ Contractility)           (Vasodilation)

Dopamine                  + (a)                  ++++ (b)                    ++++                           ++
Dobutamine              0                            +                            ++++                            +
Norepinephrine          0                        ++++                          ++++                            0
Epinephrine               0                        ++++ (b)                    ++++                           ++
Isoproterenol             0                           0                             ++++                         ++++




(a) : low dose
(b) : high dose

     Dopamine is an endogenous catecholamine and the precursor of norepinephrine. It possesses an unusual combination of actions that makes it attractive in the treatment of heart failure associated with hypotension and poor renal perfusion. There are various types of receptors with different affi nities for dopamine. At low dosages, < 2 mcg/kg/min, dopamine interacts primarily with dopaminergic receptors distributed in the renal and mesenteric vascular beds. Stimulation of these receptors causes local vasodilation and increases renal blood flow and glomerular filtration, facilitating diuresis.
     Medium dosages of dopamine, 2 to 10 mcg/kg/min, increase inotropy by stimulation of cardiac B1-receptors directly and indirectly by promoting release of norepinephrine from sympathetic nerve terminals. This action increases heart rate, cardiac contractility, and stroke volume, all of which augment cardiac output.
     At high dosages, > 10 mcg/kg/min, dopamine also stimulates systemic Alfa-receptors, thereby causing vasoconstriction and elevating systemic resistance. High-dose dopamine is indicated in hypotensive states such as shock. However, these doses are inappropriate in most patients with cardiac failure because the peripheral vasoconstriction increases the resistance against which the heart must contract (i.e., higher afterload), further impairing left ventricular output.
     The major toxicity of dopamine arises in patients who are treated with high-dose therapy. The most important side effects are acceleration of the heart rate and tachyarrhythmias.

     Dobutamine is a synthetic analog of dopamine that stimulates B 1-, B 2-, and Alfa -receptors. It increases cardiac contractility by virtue of the B 1 effect but does not increase peripheral resistance because of the balance between -mediated vasoconstriction and B 2-mediated vasodilation. Thus, it is useful in the treatment of heart failure not accompanied by hypotension. Unlike dopamine, dobutamine does not stimulate dopaminergic receptors (i.e., no renal vasodilating effect), nor does it facilitate the release of norepinephrine from peripheral nerve endings. Like dopamine, it is useful for short-term therapy ( <1 week), after which time it loses its effi cacy, presumably because of downregulation of adrenergic receptors. The major adverse effect is the provocation of tachyarrhythmias.

     Norepinephrine is an endogenous catecholamine synthesized from dopamine in adrenergic postganglionic nerves and in adrenal medullary cells (where it is both a final product and the precursor of epinephrine). Through its B 1 activity, norepinephrine has positive inotropic and chronotropic effects. Acting at peripheral Alfa -receptors, it is also a potent vasoconstrictor. The increase in total
peripheral resistance causes the mean arterial blood pressure to rise.
     With this combination of effects, norepinephrine is useful in patients suffering from “warm shock,” in which the combination of cardiac contractile dysfunction and peripheral vasodilation lowers blood pressure. However, the intense vasoconstriction elicited by this drug makes it less attractive than others in treating most other cases of shock. Norepinephrine’s side effects include precipitation
of myocardial ischemia (because of the augmented force of contraction and increased afterload) and tachyarrhythmias.

     Epinephrine, the predominant endogenous catecholamine produced in the adrenal medulla, is formed by the decarboxylation of norepinephrine. As indicated in Table 17.2, epinephrine is an agonist of Alfa-, B 1-, and B2- receptors. Administered as an intravenous infusion at low dosages, its stimulation of the B 1-receptor increases ventricular contractility and speeds impulse generation. As a result, stroke volume, heart rate, and cardiac output increase. However, at this dosage range, B2-mediated vasodilation may reduce total peripheral resistance and blood pressure.
     At higher dosages, epinephrine is a potent vasopressor because -mediated constriction dominates over B 2-mediated vasodilation. In this case, the effects of positive inotropy, positive chronotropy, and vasoconstriction act together to raise the arterial blood pressure.
     Epinephrine is therefore used most often when the combination of inotropic and chronotropic
stimulation is desired, such as in the setting of cardiac arrest. The Alfa-associated vasoconstriction may also help support blood pressure in that setting. The most common toxic effect is the precipitation of tachyarrhythmias. Epinephrine should be avoided in patients receiving B-blocker therapy, because unopposed Alfa-mediated vasoconstriction could produce signifi cant hypertension.

     Isoproterenol is a synthetic epinephrine analog. Unlike norepinephrine and epinephrine, it is a “pure” B-agonist, having activity almost exclusively at B 1- and B 2-receptors, with almost no -receptor effect. In the heart, isoproterenol has positive inotropic and chronotropic effects, thereby increasing cardiac output. In peripheral vessels, stimulation of B 2-receptors results in vasodilation and reduced peripheral resistance, which may cause blood pressure to fall.
     Isoproterenol is sometimes used in emergency circumstances to increase the heart rate in patients with bradycardia or heart block (e.g., as a temporizing measure before pacemaker implantation). It may also be useful in patients with systolic dysfunction and slow heart rates with high systemic vascular resistance (a situation sometimes encountered after cardiac surgery in patients who had previously been receiving B -blocker therapy). Isoproterenol should be avoided in patients with myocardial ischemia, in whom the increased heart rate and inotropic stimulation would further increase myocardial oxygen consumption.

Phosphodiesterase-3 Inhibitors
Milrinone is an example of a nondigitalis, noncatecholamine inotropic agent. It exerts its positive inotropic actions by inhibiting phosphodiesterase type 3 in cardiac myocytes. This inhibition reduces the breakdown of intracellular cAMP, the ultimate result of which is enhanced Ca ++ entry into the cell and increased force of contraction. Additionally, in vascular smooth muscle, phosphodiesterase-induced augmentation of cAMP results in beneficial vasodilation (in vascular tissue, cAMP inhibits myosin light chain kinase and crossbridge formation between myosin heads and
actin filaments).
     Milrinone is sometimes used in the treatment of acute heart failure when there has been insufficient improvement with conventional vasodilators, inotropic agents, and diuretics. It has the potential for serious adverse  effects, including provocation of ventricular arrhythmias, and chronic milrinone therapy is associated with increased mortality. Its use is therefore limited to hospitalized patients for short-term therapy.

Vasopressin
Vasopressin, the endogenous antidiuretic hormone secreted by the posterior pituitary, primarily functions to maintain water balance. It also acts as a potent nonadrenergic  vasoconstrictor when administered intravenously at higher-thannatural doses, by directly stimulating vascular smooth muscle V1 receptors. It has proved useful for maintaining blood pressure in patients with vasodilatory shock, as may occur in septic states. It may also be benefi cial during cardiac arrest advanced life support because it increases coronary perfusion pressure, augments blood flow to vital organs, and improves the likelihood of successful resuscitation in patients with ventricular fibrillation.