PITT Cardiology

Terminology

To get started, let's review the terminology used for drugs that affect adrenergic transmission.

Sympathomimetics: drugs that act like the neurotransmitters released by the sympathetic nervous system (like norepinephrine and epinephrine).

This drug class includes:

• Direct-acting sympathomimetics --> Drugs that directly stimulate α and β receptors.
• Indirect-acting sympathomimetics --> Drugs that cause the release of norepinephrine from nerve terminals, or block the uptake of the neurotransmitter.
• Mixed-acting sympathomimetics --> Drugs that cause the release of norepinephrine from nerve terminals AND stimulate adrenergic receptors.

Sympatholytics: drugs that oppose sympathetic nervous system actions, such as antagonists of α and β receptors.

Chronotropes: drugs that alter heart rate.

This drug class includes:

• Negative chronotropes --> Decrease heart rate.
• Positive chronotropes --> Increase heart rate.

Inotropes: drugs or agents that affect the contraction of cardiac muscle

This drug class includes:

• Negative inotropes --> Weaken cardiac contractions.
• Positive inotropes --> Strengthen cardiac contractions.

Adrenergic Drugs Used in Cardiology

As discussed in the Adrenergic Transmission module, drugs that alter adrenergic transmission elicit a broad spectrum of physiological changes. Discussed below are the actions of adrenergic drugs most commonly used in cardiology. The effects described are limited to those on the cardiovascular system.

Certainly, a variety of drugs in addition to those that act on the sympathetic nervous system are used in cardiology, including diuretics, calcium channel blockers, etc. These drugs will be discussed later in the course and in subsequent courses such as the renal block. The principal goal of this module is to reinforce basic science principles discussed in prior lectures by discussing the actions of certain adrenergic drugs.

Sympathomimetics

Epinephrine

At low doses, epinephrine serves mainly as a positive inotrope and chrontrope. However, the doses of epinephrine usually provided pharmacologically are adequate to stimulate both α and β receptors. Hence, systemic injections of epinephrine elicit increases in heart rate and contractility (by binding to cardiac β-1 receptors) and vasoconstriction (by binding to α-1 receptors in vascular smooth muscle). However, the increase in total peripheral resistance produced by epinephrine administration is only modest. This is because large doses of epinephrine activate both α-1 and β-2 receptors in muscle arterioles, and the physiological effects are offsetting (binding to α-1 receptors promotes vasoconstriction, while binding to β-2 receptors promotes vasodilation).

Systemic epinephrine is often administered prior to cardiopulmonary resuscitation (when bradycardia is present; cardiac arrest) or in patients with anaphylactic shock. It can also be used in patients with ventricular fibrillation.

Norepinephrine

The main difference in the actions of pharmacological doses of norepinephrine and epinephrine is that epinephrine binds to β-2 receptors, whereas norepinephrine does not. Both of these drugs have chronotropic and inotropic effects, but norepinephrine elicits a much larger increase in total peripheral resistance. Since afterload increases precipitously following norepinephrine administration, increases in cardiac output can be limited despite the stimulatory effects of the drug on the heart.

Because norepinephrine causes sharp increases in blood pressure, its administration activates the baroreceptor reflex. This diminishes the effects of the drug on the heart, so chronotropic effects are attenuated and the drug tends not to induce tachycardia.

Norepinephrine administration does not produce any of the physiological effects associated with β-2 agonists, such as dilation of airway smooth muscle. Systemic norepinephrine is used to treat profound hypotension.

Dopamine

Although dopamine is usually considered a neurotransmitter of the central nervous system, dopamine is also produced and secreted by some renal cells. The pharmacology of systemically administered dopamine is complex. At low does, the drug mainly binds to D1 receptors in the kidney, resulting in renal vasodilation and a decrease in total peripheral resistance. Increased renal blood flow will result in increased urine output and decreased fluid retention and decreased edema.

At higher doses, dopamine binds to β-1 receptors, producing cardiac effects. Interestingly, moderate doses of dopamine have an unusual action on the heart: a selective increase in the force of myocardial contraction occurs without a significant effect on heart rate. High doses of dopamine produce both inotropic and chronotropic effects. In addition, high doses of dopamine activate α-1 receptors, producing an increase in total peripheral resistance.

Dopamine has been used to treat heart failure patients, as it stimulates cardiac function while producing renal effects that aid to clearing the fluid accumulation resulting from the pumping mismatch between the left and right ventricles.

Isoproterenol

Isoproterenol is classified as a non-selective β-adrenergic agonist, as it binds well to both β-1 and β-2 receptors, but has higher sensitivity for β-1 receptors. Isoproterenol thus has both chronotropic and inotropic effects, and also reduces afterload by producing vasodilation of muscle arterioles (through actions on β-2 receptors in vascular smooth muscle). Isoproterenol is thus an ideal drug to treat patients with poor myocardial contractility and low heart rate, but high peripheral resistance. Clinically, it is used most often for its chronotropic effects.

Dobutamine

Dobutamine was developed as a structural analogue of isoproterenol. At pharmacological doses, it is a β-1 agonist, but at very high doses it also binds to β-2 receptors. Thus, dobutamine increases heart rate and contractility, while producing less changes in peripheral resistance than isoproterenol.

Dobutamine is a useful drug to treat patients with low cardiac contractility due to organic disease or surgical procedures. Dobutamine is also commonly used in the hospital setting as a pharmacologic stress testing agent to identify coronary artery disease. However, its use is limited by propensity to produce tachycardia.

Clonidine

Clonidine is an α-2 receptor agonist that crosses the blood-brain barrier, and is particularly effective in binding to the subtype of α-2 receptors in the brainstem. As noted in the Adrenergic Transmission module, α-2 receptors are located on presynaptic terminals of noradrenergic neurons, including those of neurons projecting to the rostral ventrolateral medulla (RVLM). Binding of clonidine to these presynaptic receptors results in a decrease in norepinephrine release at the synapse, and thus less excitation of the postsynaptic neuron. Hence, clonidine results in reduced activity of RVLM neurons, reduced sympathetic nervous system activity, and a reduction in blood pressure. Clonidine is used to reduce blood pressure in patients that are resistant to other hypertensive treatments. Since clonidine acts in the central nervous system, it has also been used off-label to treat patients with a number of neurological and psychiatric problems. Clonidine has sedative effects due to its actions in the nervous system, which is a major side effect of the drug.

The classification of clonidine as a sympathomimetic drug can be questioned, as it does not fall neatly into this category. Although the drug is an agonist for adrenergic receptors, its administration results in a decrease in sympathetic nervous system activity. Some would classify clonidine as a sympatholytic. The terminology does not apply easily to this particular drug.

Phenylephrine

Phenylephrine is an α-1 receptor agonist. Phenylephrine is commonly used as a vasopressor to increase the blood pressure in unstable patients with hypotension. Since the drug produces a sudden increase in blood pressure, it can activate the baroreceptor reflex, thereby causing a reflexive decrease in heart rate and contractility.

Sympatholytics

Prazosin / Doxazocin / Terazosin / Tamsulosin

These drugs are α-1 receptor antagonists. They all lower blood pressure by causing peripheral vasodilation and reducing total peripheral resistance. However, as discussed in the Adrenergic Transmission module, the initial drop in blood pressure produced by an α-1 receptor antagonist induces a baroreceptor reflex-mediated increase in heart rate and contractility, thereby increasing myocardial oxygen demand. Hence, these drugs are second-line treatments for hypertension, but are commonly used for other medical conditions such as benign prostatic hyperplasia.

Phenoxybenzamine / Phentolamine

These drugs are antagonists for both α-1 and α-2 receptors. They have the same vasodilatory effects as selective α-1 receptor antagonists, but also block presynaptic α-2 receptors in the periphery, including those on sympathetic efferent fibers in the heart. As a consequence, norepinephrine release from sympathetic nerve terminals increases, since the normal presynaptic feedback inhibition mediated through the α-2 receptor is blocked. As noted above, vasodilators induce a baroreceptor reflex-mediated increase in heart rate and contractility. The reflex-mediated increases in heart rate and contractility are larger following the administration of a combined α-1 / α-2 antagonist than a selective α-1 antagonist, as more norepinephrine is released from sympathetic postganglionic terminals in the heart.

Other Drugs

β receptor antagonists (β blockers) are commonly used in cardiology to treat hypertension, as they decrease cardiac output by producing negative chronotropic and inotropic effects. These drugs will be discussed in great detail later in the course.

Review

The table below summarizes the actions of the drugs discussed in this module.

Drug	Agonist or Antagonist	Receptors Affected	Effect on Total Peripheral Resistance	Chronotropic Effect	Inotropic Effect	Other Information
Epinephrine	Agonist	β1 = β2 > α	Decrease with low dose; Modest increase with high dose	Positive	Positive	Less increase in TPR than norepinephrine
Norepinephrine	Agonist	β1 > α >> β2	Increase	Positive	Positive	Produces a large increase in afterload; chronotropic effects are attenuated by the baroreceptor reflex; less risk of tachycardia than other beta-agonists
Dopamine--low dose	Agonist	Dopamine > β > α	Decrease	Little	Little	Mainly acts in kidney to increase renal blood flow
Dopamine--moderate dose			Decrease	Little	Positive
Dopamine--high dose			Increase	Positive	Positive
Isoproterenol	Agonist	β1 > β2 No α	Decrease	Positive	Positive
Dobutamine	Agonist	β1 >> β2 > α	Little, but a decrease at high dose	Positive	Positive
Phenylephrine	Agonist	Selective α1	Increase	Decrease	Decrease	Effects on heart are due to baroreceptor reflex
Clonidine	Agonist	Selective α2 (acts in brainstem)	Decrease	Decrease	Decrease	Acts in the central nervous system; decreases activity of RVLM neurons
Prazosin	Antagonist	Selective α1	Decrease	Increase	Increase	Chronotropic and inotropic effects are via baroreceptor reflex mechanisms
Phenoxybenzamine	Antagonist	Selective α	Decrease	Increase	Increase	Produces larger chronotropic and inotropic effects than Prazosin