Posted: March 4th, 2021

The use of Parasympatholytics versus Sympatholytics medications

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You must turn in the Essays below for a grade by 10/4/20.

Ace my homework – Write an essay on each of the topics. This will count for 25 % of your final grades. Ace my homework – Write a paper of 500-1000 word s on:

1. The use of Parasympatholytics versus Sympatholytics medications

2. The use of Epinephrine in the ICU and ER

3. The use of Calcium Channel Blockers including how they work, indication for administration, and the side effects associated with the consumption of this drug group.

4. The use of Diuretics in the treatment of congestive heart failure.

5. Anti Coagulation agents and Thrombolytics in the treatment of
patients post myocardial infarction.

6. The use of Vasodilators in patients with hypertensive heart disease.

BONUS: 1. The role of ACE inhibitors in the treatment of cardiac patients. Your Bonus is worth 5 points towards your final exams

General Pharmacology
Beta-Blockers
Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors. This inhibits normal sympathetic effects that act through these receptors. Therefore, beta-blockers are sympatholytic drugs. Some beta-blockers, when they bind to the beta-adrenoceptor, partially activate the receptor while preventing norepinephrine from binding to the receptor. These partial agonists therefore provide some “background” of sympathetic activity while preventing normal and enhanced sympathetic activity. These particular beta-blockers (partial agonists) are said to possess intrinsic sympathomimetic activity (ISA). Some beta-blockers also possess what is referred to as membrane stabilizing activity (MSA). This effect is similar to the membrane stabilizing activity of sodium-channels blockers that represent Class I antiarrhythmics.
The first generation of beta-blockers were non-selective, meaning that they blocked both beta-1 (β1) and beta-2 (β2) adrenoceptors. Second generation beta-blockers are more cardioselective in that they are relatively selective for β1 adrenoceptors. Note that this relative selectivity can be lost at higher drug doses. Finally, the third generation beta-blockers are drugs that also possess vasodilator actions through blockade of vascular alpha-adrenoceptors.

Heart
Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both β1 and β2 adrenoceptors, although the predominant receptor type in number and function is β1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood. Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from binding to the beta-adrenoceptor by competing for the binding site.
Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cell. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate (chronotropy). PK-A also phosphorylates sites on the sarcoplasmic reticulum, which lead to enhanced release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate myosin light chains, which may contribute to the positive inotropic effect of beta-adrenoceptor stimulation.
Because there is generally some level of sympathetic tone on the heart, beta-blockers are able to reduce sympathetic influences that normally stimulate chronotropy (heart rate), inotropy (contractility), dromotropy (electrical conduction) and lusitropy (relaxation). Therefore, beta-blockers cause decreases in heart rate, contractility, conduction velocity, and relaxation rate. These drugs have an even greater effect when there is elevated sympathetic activity.

Blood vessels
Vascular smooth muscle has β2-adrenoceptors that are normally activated by norepinephrine released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by β2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).
Compared to their effects in the heart, beta-blockers have relatively little vascular effect because β2-adrenoceptors have only a small modulatory role on basal vascular tone. Nevertheless, blockade of β2-adrenoceptors is associated with a small degree of vasoconstriction in many vascular beds. This occurs because beta-blockers remove a small β2-adrenoceptor vasodilator influence that is normally opposing the more dominant alpha-adrenoceptor mediated vasoconstrictor influence.
Therapeutic Indications for the use of Beta-Blockers
Cardiac Effects
• Decrease contractility
(negative intropy)
• Decrease relaxation rate
(negative lusitropy)
• Decrease heart rate
(negative chronotropy)
• Decrease conduction velocity
(negative dromotropy)
Vascular Effects
• Smooth muscle contraction
(mild vasoconstriction)
Beta-blockers are used for treating hypertension, angina, myocardial infarction, arrhythmias and heart failure.
Hypertension
Beta-blockers decrease arterial blood pressure by reducing cardiac output. Many forms of hypertension are associated with an increase in blood volume and cardiac output. Therefore, reducing cardiac output by beta-blockade can be an effective treatment for hypertension, especially when used in conjunction with a diuretic. Acute treatment with a beta-blocker is not very effective in reducing arterial pressure because of a compensatory increase in systemic vascular resistance. This may occur because of baroreceptor reflexes working in conjunction with the removal of β2 vasodilatory influences that normally offset, to a small degree, alpha-adrenergic mediated vascular tone. Chronic treatment with beta-blockers lowers arterial pressure more than acute treatment possibly because of reduced renin release and effects of beta-blockade on central and peripheral nervous systems. Beta-blockers have an additional benefit as a treatment for hypertension in that they inhibit the release of renin by the kidneys (the release of which is partly regulated by β1-adrenoceptors in the kidney). Decreasing circulating plasma renin leads to a decrease in angiotensin II and aldosterone, which enhances renal loss of sodium and water and further diminishes arterial pressure.
Hypertension in some patients is caused by emotional stress, which causes enhanced sympathetic activity. Beta-blockers can be very effective in these patients.
Beta-blockers are used in the preoperative management of hypertension caused by a pheochromocytoma, which results in elevated circulating catecholamines. When used for this condition, the blood pressure is first controlled using an alpha-blocker such as phenoxybenzamine, and then a beta-blocker can be carefully administered to reduce the excessive cardiac stimulation by the catecholamines. It is important that a beta-blocker is administered only after adequate blockade of vascular alpha-adrenoceptors so that a hypertensive crisis does not occur as a result of unopposed alpha-adrenoceptor stimulation.

Angina and myocardial infarction
Theraputic use of Beta-Blockers
• Hypertension
• Angina
• Myocardial infarction
• Arrhythmias
• Heart failure
The antianginal effects of beta-blockers are attributed to their cardiodepressant and hypotensive actions. By reducing heart rate, contractility, and arterial pressure, beta-blockers reduce the work of the heart and the oxygen demand of the heart. Reducing oxygen demand improves the oxygen supply/demand ratio, which can relieve a patient of anginal pain that is caused by a reduction in the oxygen supply/demand ratio due to coronary artery disease. Furthermore, beta-blockers have been found to be very important in the treatment of myocardial infarction in that they have been shown to decrease mortality. Their benefit is derived not only from improving the oxygen supply/demand ratio and reducing arrhythmias, but also from their ability to inhibit subsequent cardiac remodeling.
Arrhythmias
The antiarrhythmic properties beta-blockers (Class II antiarrhythmic) are related to their ability to inhibit sympathetic influences on cardiac electrical activity. Sympathetic nerves increase sinoatrial node automaticity by increasing the pacemaker currents, which increases sinus rate. Sympathetic activation also increases conduction velocity (particularly at the atrioventricular node), and stimulates aberrant pacemaker activity (ectopic foci). These sympathetic influences are mediated primarily through β1-adrenoceptors. Therefore, beta-blockers can attenuate these sympathetic effects and thereby decrease sinus rate, decrease conduction velocity (which can block reentry mechanisms), and inhibit aberrant pacemaker activity. Beta-blockers also affect non-pacemaker action potentials by increasing action potential duration and the effective refractory period. This effect can play a major role in blocking arrhythmias caused by reentry.
Heart failure
The majority of patients in heart failure have a form that is called systolic dysfunction, which means that the contractile function of the heart is depressed (loss of inotropy). Although it seems counterintuitive that cardioinhibitory drugs such as beta-blockers would be used in cases of systolic dysfunction, clinical studies have shown quite conclusively that some specific beta-blockers actually improve cardiac function and reduce mortality. Furthermore, they have been shown to reduce deleterious cardiac remodeling that occurs in chronic heart failure. Although the exact mechanism by which beta-blockers confer their benefit to heart failure patients is poorly understood, it may be related to blockade of excessive, chronic sympathetic influences on the heart, which are known to be harmful to the failing heart.
Different Classes of Beta-Blockers and Specific Drugs
Beta-blockers that are used clinically can be divided into two classes: 1) non-selective blockers (block both β1and β2 receptors), or 2) relatively selective β1 blockers (“cardioselective” beta-blockers). Some beta-blockers have additional mechanisms besides beta-blockade that contribute to their unique pharmacologic profile. The two classes of beta-blockers along with specific compounds are listed in the following table. Additional details for each drug may be found at www.rxlist.com. The clinical uses indicated in the table represent both on and off-label uses of beta-blockers. For example, a given beta-blocker may only be approved by the FDA for treatment of hypertension; however, physicians sometimes elect to prescribe the drug for angina because of the class-action benefit that beta-blockers have for angina.
Clinical Uses
Class/Drug HTN Angina Arrhy MI CHF Comments
Non-selective β1/β2
carteolol X ISA; long acting; also used for glaucoma
carvedilol X X α-blocking activity
labetalol X X ISA; α-blocking activity
nadolol X X X X long acting
penbutolol X X ISA
pindolol X X ISA; MSA
propranolol X X X X MSA; prototypical beta-blocker
sotalol X several other significant mechanisms
timolol X X X X primarily used for glaucoma
β1-selective
acebutolol X X X ISA
atenolol X X X X
betaxolol X X X MSA
bisoprolol X X X X
esmolol X X ultra short acting; intra or postoperative HTN
metoprolol X X X X X MSA
nebivolol X relatively selective in most patients; vasodilating (NO release)

Abbreviations:
HTN, hypertension
Arrhy, arrhythmias
MI, myocardial infarction
CHF, congestive heart failure
ISA, intrinsic sympathomimetic activity.

Side Effects and Contraindications
Cardiovascular side effects
Many of the side effects of beta-blockers are related to their cardiac mechanisms and include bradycardia, reduced exercise capacity, heart failure, hypotension, and atrioventicular (AV) nodal conduction block. Beta-blockers are therefore contraindicated in patients with sinus bradycardia and partial AV block. The side effects listed above result from excessive blockade of normal sympathetic influences on the heart. Considerable care needs to be exercised if a beta-blocker is given in conjunction with cardiac selective calcium-channel blockers (e.g., verapamil) because of their additive effects in producing electrical and mechanical depression. Although this may change with future clinical trials on safety and efficacy of beta-blockers in heart failure, at present only carvedilol and metoprolol have been approved by the FDA for this indication.
Other side effects
Bronchoconstriction can occur, especially when non-selective beta-blockers are administered to asthmatic patients. Therefore, non-selective beta-blockers are contraindicated in patients with asthma or chronic obstructive pulmonary disease. Bronchoconstriction occurs because sympathetic nerves innervating the bronchioles normally activate β2-adrenoceptors that promote bronchodilation. Beta-blockers can also mask the tachycardia that serves as a warning sign for insulin-induced hypoglycemia in diabetic patients; therefore, beta-blockers should be used cautiously in diabetics.
Cardiovascular Pharmacology Concepts
Richard E. Klabunde, PhD

Revised 01/29/16

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