PART 3: Drugs Affecting the Autonomic Nervous System
ü I: Introduction to ANS.
ü II: Adrenergic drugs.
ü III: Adrenergic antagonists.
ü IV: Cholinergic drugs.
ü V: Cholinergic antagonists.
I: introduction to autonomic nervous system
- Over view:
The autonomic nervous system (ANS), along with the endocrine system, coordinates the regulation and integration of bodily functions. The endocrine system sends signals to target tissues by varying the levels of blood-borne hormones. In contrast, the nervous system exerts its influence by the rapid transmission of electrical impulses over nerve fibers that terminate at effector cells, which specifically respond to the release of neuromediator substances.
The ANS works to regulate blood pressure, heart rate, respiration, body temperature, water balance, urinary excretion, and digestive functions, among other things. This system exerts minute-to-minute control of body responses, which is balanced by the two divisions of the ANS.
- Divisions:
The ANS is divided into two branches: the sympathetic nervous system and the parasympathetic nervous system.
Neurotransmitters in ANS
Receptors in ANS
Synthesis and storage of acetylcholine
Synthesis and storage of epinephrine.
: Adrenergic Drugs:
Overview:
Adrenergic compounds include several exogenous and endogenous substances. They have a wide variety of therapeutic uses depending on their site of action and their effect on different types of adrenergic receptors.
Adrenergic drugs stimulate the sympathetic nervous system (SNS) and are also called adrenergic agonists. They are also known as sympathomimetics, because they mimic the effects of the SNS neurotransmitters norepinephrine, epinephrine, and dopamine. These three neurotransmitters are chemically classified as catecholamines.
Adrenergic receptors: these are the sites at which adrenergic drugs bind and produce their effects. Adrenergic receptors are located in many anatomic sites. Many physiologic responses are produced when they are stimulated or blocked. Adrenergic receptors are further divided into alpha-adrenergic receptors and beta-adrenergic receptors, depending on the specific physiologic responses caused by their stimulation. Both types of adrenergic receptors have subtypes, designated 1 and 2.
The alpha1-and-alpha2- adrenergic receptors are differentiated by their location relative to nerves. The alpha1-adrengic receptors are located on postsynaptic effector cells (the tissue, muscle, or organ that the nerve stimulates). The alpha2-adrenergic receptors are located on the presynaptic nerve terminals. They control the release of neurotransmitters. The predominant alpha-adrenergic agonist response is vasoconstriction and central nervous system stimulation.
The beta-adrenergic receptors are all located on postsynaptic effector cells. The beta1-adrenergic receptors are primarily located in the heart, whereas the beta2-adrenergic receptors are located in the smooth muscle fibers of the bronchioles, arterioles, and visceral organs. A beta-adrenergic agonist response results in bronchial, gastrointestinal (GI), and uterine smooth muscle relaxation; glycogenolysis; and cardiac stimulation.
Another type of adrenergic receptor is the dopaminergic receptor. When stimulated by dopamine, these receptors cause the vessels of the renal, mesenteric, coronary, and cerebral arteries to dilate, which increases blood flow to these tissues. Dopamine is the only substance that can stimulate these receptors.
Location Receptor Response
Cardiovascular
Blood vessels alpha1 Constriction
beta2 Dilation
Cardiac muscle beta1 Increased contractility
AV Node beta1 Increased heart rate
SA Node beta1 Increased heart rate
Gastrointestinal
Muscle beta2 and alpha Decreased motility
Genitourinary
Bladder alpha1 Constriction sphincter
Uterus alpha1 Contraction
beta2 Relaxation
Respiratory
Bronchial beta2 Dilation muscles
Pupils alpha1 Dilation
Pharmacology overview:
ADRENERGIC DRUGS:
A. Catecholamines produce a sympathomimitic response and are either
- Endogenous substances such as epinephrine, norepinephrine, and dopamine.
- Synthetic substances such as isoproterenol and dobutamine.
- These three endogenous catecholamines, (epinephrine, norepinephrine, and dopamine) are also available in synthetic drug form.
B. Noncatecholamines
Compounds lacking the catechol hydroxyl groups have longer half lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine.
When any of the adrenergic drugs is given, it bathes the synaptic cleft. Once there, the drug has the opportunity to induce the response. This can accomplish in one of three ways: by direct stimulation, by indirect stimulation, or by a combination of the two (mixed acting).
ü Mechanism of action:
1- A direct-acting sympathomimetics binds directly to the receptor and causes physiologic response. Epinephrine is an example of such a drug.
2- An indirect-acting sympathomimetic is an adrenergic drug that, when given, causes the release of the catecholamine from storage sites (vesicles) in the nerve endings; it then binds to the receptors and causes a physiologic response.
Amphetamine and other related anorexiants are examples of such drugs.
3- A mixed-acting sympathomimetic both directly stimulates the receptor by binding to it and indirectly stimulates the receptor by causing the release of neurotransmitter stored in vesicles at the nerve endings. Ephedrine and pseudoeohedrine are an example of a mixed-acting adrenergic drug.
ü Drug effects:
Stimulation of alpha1-adrenergic receptors on smooth muscles results in
Ø Vasoconstriction of blood vessels
Ø Relaxation of GI smooth muscles (decreased motility)
Ø Constriction of bladder sphincter
Ø Contraction of uterus
Ø Contraction of pupillary muscles of the eye (dilated pupils)
Stimulation of alpha2-adrenergic receptors, actually tend to reverse sympathetic activity but is not of great significance either physiologically or pharmacologically.
Stimulation of beta1-adrenergic receptors on the myocardium, AV node, and SA node results in cardiac stimulation
Ø Increased force of contraction (positive inotropic effect)
Ø Increased heart rate (positive chronotropic effect)
Ø Increased conduction through AV node (positive dromotropic effect)
Stimulation of beta2-adrenergic receptors results in
Ø Bronchodilation (relaxation of the bronchi)
Ø Uterine relaxation
Ø Relaxation of GI smooth muscles (decreased motility)
ü Indications:
Their selectivity for either alpha- or beta- adrenergic receptors and their affinity for certain tissues or organs determine the settings in which they are most commonly used.
Respiratory indications:
Certain adrenergic drugs have an affinity for the adrenergic receptors located in the respiratory system and are classified as bronchodilators. They tend to preferentially stimulate the beta2-adrenergic receptors and cause bronchodilation. The beta2 agonists are helpful in treating conditions such as asthma and bronchitis. Some common bronchodilators that are classified as predominantly beta2-selective adrenergic drugs include (salbutamol, formetrol, salmeterol and terbutaline).
Indications for topical nasal decongestants
The intranasal application of certain adrenergics can cause the constriction of dilated arterioles and reduction in nasal blood flow, which thus decreases congestion. These adrenergic drugs work by stimulating alpha1-adrenergic receptors and have little or no effect on beta-adrenergic receptors. The nasal decongestants include epinephrin, pseudoephedrine, naphazoline, oxymetazoline, phenylephrine, and tetrahydrozoline.
Ophthalmic indications
Some adrenergics are applied to the surface of the eye. These drugs are called ophthalmics, and they affect the vasculature of the eye. When administered, they stimulate alpha-adrenergic receptors located on small arterioles in the eye and temporarily relieve conjunctival congestion by causing arteriolar vasoconstriction. The ophthalmic adrenergics include epinephrine, naphazoline, phenylephrine, and tetrahydrozoline.
Adrenergics can also used to reduce intraocular pressure and dilate the pupils (mydriasis), properties that make them useful in the treatment of open-angle glaucoma, as well as for diagnostic eye examinations. They produce these effects by stimulating alpha-or-beta2-adrenergic receptors, or both. The two adrenergics used for this purpose are epinephrine and dipivefrin.
Cardiovascular indications
Cardioselective sympathomimetics they are used to support the cardiovascular system during cardiac failure or shock these drugs have a variety of effects on the various alpha- and beta-adrenergic receptors, and these effects can also be related to the specific dose of the adrenergic drug. Common vasoactive adrenergic drugs include dobutamine, dopamine, ephedrine, epinephrine, fenoldopam, midodrine, norepinephrine, and phenylephrine.
ü Contraindications: The only contraindications to the use of adrenergic drugs are known drug allergy and severe hypertension
ü Adverse effects:
Alpha-Adrenergic Adverse Effects
CNS: Headache, restlessness, excitement, insomnia, euphoria
Cardiovascular: Palpitations (dysrhythmias), tachycardia, vasoconstriction, hypertension
Other: Loss of appetite, dry mouth, nausea, vomiting, taste changes (rare)
Beta-Adrenergic Adverse Effects
CNS: Mild tremors, headache, nervousness, dizziness
Cardiovascular: Increased heart rate, palpitations (dysrhythmias), fluctuations in BP
Other: Sweating, nausea, vomiting, muscle cramps
ü Drug profiles:
1- Epinephrine:
It acts directly on both the alpha- and beta-adrengic receptors of tissues innervated by the SNS.
Therapeutic uses:
a. Bronchospasm: Epinephrine is the primary drug used in the emergency treatment of respiratory conditions when bronchoconstriction has resulted in diminished respiratory function.
b. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of type I hypersensitivity reactions (including anaphylaxis) in response to allergens.
c. Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest.
d. Anesthetics: Local anesthetic solutions may contain low concentrations (for example, 1:100,000 parts) of epinephrine. Epinephrine greatly increases the duration of local anesthesia by producing vasoconstriction at the site of injection. This allows the local anesthetic to persist at the injection site before being absorbed into the systemic circulation.
At low dosages it stimulates mostly beta1-adrenergic receptors, increasing the force of contraction and heart rate. It is used to treat acute asthma and shock at these dosages. At high dosages, it stimulates mostly alpha-adrenrgic receptors, causing vasoconstriction, which elevates the blood pressure.
2- Dobutamine.
Is a beta1-selective vasoactive adrenergic drug that is structurally similar to the naturally occurring catecholamine dopamine. Through stimulation of the beta1 receptors on heart muscle (myocardium), it increases cardiac output by increasing contractility (positive inotropy), which increases the stroke volume, especially in patients with heart failure. Dobutamine is available only as an intravenous drug is given by continuous infusion.
3- Dopamine:
Dopamine is a naturally occurring catecholamine in the SNS. It has potent dopaminergic as well as beta1- and alpha1- adrenergic receptor activity, depending on the dosage.
Dopamine, when used at low dosages, can dilate blood vessels in the brain, heart, kidney, and mesentery, which increases blood flow to these areas (dopaminergic receptor activity).
At higher infusion rates dopamine can improve cardiac contractility and output (beta1-adrenergic receptor activity).
Use of the drug is contraindicated in patients who have a catecholamine-secreting tumor of the adrenal gland known as a pheochromocytoma. The drug is available only as an intravenous injectable drug and is given by continuous infusion.
Therapeutic uses:
Dopamine is the drug of choice for cardiogenic and septic shock and is given by continuous infusion.
It raises blood pressure by stimulating the β1 receptors on the heart to increase cardiac output and α1 receptors on blood vessels to increase total peripheral resistance. In addition, it enhances perfusion to the kidney and splanchnic areas.
Increased blood flow to the kidney enhances the glomerular filtration rate and causes diuresis. It is also used to treat hypotension and severe heart failure, primarily in patients with low or normal peripheral vascular resistance and in patients who have oliguria.
Nursing Implications:
Follow administration guidelines carefully
Intravenous administration
Check IV site often for infiltration
Use clear IV solutions
Use an infusion pump
Infuse drug slowly to avoid dangerous cardiovascular effects
Monitor cardiac rhythm
Monitor for therapeutic effects (cardiovascular uses)
Decreased edema
Increased urinary output
Return to normal vital signs
Improved skin color and temperature
II: Adrenergic-Blocking Drugs:
Overview:
The adrenergic blockers have the opposite effect of adrenergic agonists and therefore referred to as antagonists. They also bind to adrenergic receptors but in doing so inhibit or block stimulation by the SNS. They are also referred to as sympatholytics because they “lyse:, or inhibit, SNS stimulation. At adrenergic receptors the adrenergic blockers act, and they are classified by the type of adrenergic receptor they block-alpha or beta or, in few cases, both. Hence, they are called alpha-blockers, beta-blockers, or alpha/beta-blockers.
Pharmacology overview:
1- Alpha-Blockers:
ü Mechanism of action and drug effects:
These drugs have a greater affinity for the alpha-adrenergic receptor than do norepinephrine and can chemically displace norepinephrine molecules from the receptor.
Adrenergic blockade at these receptors leads to effects such as vasodilatation, reduced blood pressure, miosis (papillary constriction), and reduced smooth muscle tone in organs like the bladder and prostate.
ü Indications:
The alpha-blockers such as doxazosin, prazosin, and terazosin cause both arterial and venous dilation. This reduces peripheral vascular resistance and blood pressure, and these drugs are used to treat hypertension.
The alpha-adrenergic receptors are also present in the prostate and bladder. By blocking stimulation of alpha1 receptors, these drugs reduce smooth muscle contraction of the bladder neck and the prostatic portion of the urethra. For this reason, alpha-blockers are given to patients with benign prostatic hyperplasia (BPH) to decrease resistance to urinary outflow. This reduces urinary obstruction and relieves some of the effects of BPH.
Tamsulosin and alfuzosin are used exclusively for treating BPH, whereas terazosin and doxazosin can be used for both hypertension and BPH.
ü Contraindications:
Contraindications to the use of alpha-blocking drugs include known drug allergy and peripheral vascular disease and may include hepatic and renal disease, coronary artery disease, peptic ulcer, and sepsis.
ü Adverse effects:
Body System Adverse Effects
· Cardiovascular Palpitations, orthostatic hypotension, and edema.
· CNS Dizziness, headache, drowsiness, anxiety, depression, vertigo,
weakness, numbness, fatigue
· Gastrointestinal Nausea, vomiting, diarrhea, constipation, abdominal pain
2- Beta-Blockers:
ü Mechanism of action and drug effects:
The beta-adrenergic-blocking drugs (beta-blockers) block SNS stimulation of the beta-adrenergic receptors by competing with the endogenous catecholamines norepinephrine and epinephrine. The beta-blockers can be either selective or nonselective, depending on the type of beta-adrenergic receptors they antagonize.
As mentioned earlier, beta1-adrenergic receptors are located primarily in the heart. Beta-blockers selective for these receptors are sometimes called cardioselective beta-blockers or beta1-blocking drugs.
Other beta-blockers block both beta1- and beta2- adrenergic receptors, the latter of which are located primarily on the smooth muscles of the bronchioles and blood vessels. These beta-blockers are referred to as nonselective beta-blockers.
Two beta-blockers, carvedilol, and labetalol, also have an alpha receptor-blocking activity, especially at higher dosages.
Cardioselective beta1-blockers reduces myocardial stimulation, which in turn reduces heart rate, slows conduction through the atrioventricular (AV) node, prolongs sinoatrial (SA) node recovery, and decreases myocardial oxygen demand by decreasing contractility. Nonselective beta blockers also have these cardiac effects, but they block beta2 receptors on the smooth muscle of the bronchioles and blood vessels as well.
ü Indications: