Autonomic Pharmacology

This section introduces the basic aspects of drug action related to both components of the autonomic nervous system: sympathetic and parasympathetic. For both systems, synthesis, storage, and release of the chemical neurotransmitter are described to emphasize the places in the metabolic scheme where drugs can intervene. The sites of action for the adrenergic (sympathetic) and cholinergic (parasympathetic) transmitters and blockers are also described.

The autonomic nervous system controls all of the bodily functions over which the individual has no voluntary control (and which the individual might not control well given the opportunity). These functions include regulation of respiratory airway diameter, respiratory secretions, blood vessel diameter, heart rate, intestinal motility, and pupil size, among many others. It is easy to see that it might take more than the talents of a well-trained expert to keep an active person functioning day and night.

The sympathetic nervous system is the half of the autonomic system that takes a dominant role in the cardiovascular and respiratory systems when bodily activity is necessary. This includes actions such as increasing ventilation capacity, elevating blood pressure, and shunting blood flow to the skeletal muscles. Classically, the sympathetic component of the autonomic nervous system has been called the fight-or-flight system. The other half of the autonomic system is called the parasympathetic nervous system. This system is most important in maintaining the “less exciting” functions of the body, such as digestion, salivation, and urination. In some organs the two systems work in a complementary way to provide very fast and very fine control. For example, the size of the pupil responds quickly to a change in light intensity. The parasympathetic system actively functions to decrease the size of the opening while the sympathetic system relaxes, thereby causing a quick decrease in pupil size. If the light is turned down, the opposite occurs just as quickly. This is a good example of the antagonistic action of the two components of the autonomic nervous system.

Some organs, however, have only one innervation. Much of the arterial blood vessel network is controlled only by sympathetic nerves, whereas gastric secretion and gastric motility are primarily regulated by the parasympathetic system.

Sympathetic Neurotransmission

Sympathetic nerves transport impulses from the vasomotor center in the medulla of the brain through the spinal cord and out to the smooth muscle, heart muscle, and secretory cells. These tissues have receptor sites that will accept the norepinephrine released from the nerve ending. Norepinephrine, also called noradrenalin, is synthesized in the nerve ending only in the sympathetic neurons. It is stored in the terminal until an electric impulse reaches the terminal; then it is released into the synapse.

The norepinephrine molecule attaches to a receptor molecule on a cell surface in the immediate vicinity of its release. This drug-receptor combination causes a biological change, such as stimulation of the pacemaker cells in the heart to fire more frequently (increased heart rate). The effect is terminated when the norepinephrine is reabsorbed into the nerve terminal. About 90% of the released norepinephrine is taken back into the neuron, where it is either restored into granules for future release or destroyed by the enzyme monoamine oxidase (MAO).

There are two types of sympathetic receptors: alpha and beta. The alpha-receptor is found in the arterioles, and the beta-receptor is found in the arterioles, heart, and bronchioles. Stimulation of the alpha-receptor in the arteriole causes vasoconstriction, which results in increased blood pressure. Stimulation of the beta-receptor in the arteriole causes vasodilation and lowered blood pressure. Some drugs stimulate both receptors, and in those cases the effect will be determined by the degree of alpha or beta activity of the drug. One example is norepinephrine. It has 90% alpha activity and 10% beta activity, and it always causes vasoconstriction. Epinephrine is 50% alpha and 50% beta and may cause a rise or drop in blood pressure.

Stimulation of the beta-receptor in the heart results in increased heart rate (HR) (beats per minute) and increased stroke volume (SV) (number of milliliters of blood the left ventricle pumps out into the aorta every time it contracts). Incidentally, the combination of HR and SV changes is another way to express cardiac output (CO) (milliliters of blood pumped per minute):

< ?xml:namespace prefix = "mml" />beats/min(HR)×mL/beat (SV)=mL/min (CO)

This expression, cardiac output, is a common one, and it constitutes half of the blood pressure regulation equation: CO × TPR = BP, where CO is cardiac output, TPR is total peripheral resistance, and BP is blood pressure. TPR is determined by vasoconstriction or vasodilation in the arterioles. For example, vasoconstriction increases resistance; therefore TPR and BP go up.

Stimulation of smooth muscle beta-receptors will relax these tissues wherever they are found. Respiratory airway smooth muscle will decrease tension when the beta-receptor is activated by beta-acting drugs like epinephrine or isoproterenol. The functional result will be an increase in air flow because of a larger airway diameter, otherwise referred to as bronchodilation. Likewise, blood vessels respond to beta-acting drugs by dilating as well, allowing a greater rate of flow. In this case, TPR has decreased and blood pressure will drop.

Parasympathetic Neurotransmission

The center for parasympathetic control is the vagal nucleus in the medulla. The vagus nerves pass through the spinal cord and out to the heart, the smooth muscle, and exocrine glands (salivary glands and pancreas). In all of these tissues, acetylcholine (ACh) is released from the nerve terminals and combines with receptor sites to cause an effect such as bradycardia (slowing of the heart) or an increase in gastric motility. ACh is found in many parts of the central and peripheral nervous system. ACh is the only transmitter used in the parasympathetic system. It is used to transmit impulses from the nerve that comes out of the spinal cord to the nerve that finally reaches the cells in the organ being affected. This connection is called a ganglion and exists in both sympathetic and parasympathetic systems. ACh is also the neurotransmitter that makes the connection between the voluntary (somatic) nerves and the skeletal muscle.

There are two types of receptors in the central and peripheral nervous systems. ACh affects both, but some drugs affect only one and not the other. These two types of receptors are called nicotinic and muscarinic, named after the drugs that selectively stimulate them. Nicotine stimulates only those receptors in the ganglia and at the neuromuscular junction. The muscarinic receptor site is found everywhere that a parasympathetic nerve terminal synapses at a tissue. The biological effects usually attributed to the parasympathetic nervous system, such as bradycardia, salivation, and bronchoconstriction, are produced when the muscarinic receptors are stimulated. It is also possible to stimulate muscarinic receptors indirectly with a nicotinic drug by activating the parasympathetic ganglia. In a similar way, it is possible to stimulate the entire sympathetic nervous system. The neurotransmitter at the sympathetic ganglia is ACh, and it affects nicotinic receptor sites there. One of the toxic effects of ACh (and similar-acting drugs) is hypertension with tachycardia, which is the result of stimulation of the sympathetic postganglionic fibers.

To better understand the action of ACh and related drugs, let us consider the synthesis, release, and inactivation of this transmitter. ACh is synthesized inside the nerve terminal from acetyl-CoA and choline. The ACh is then stored in granules and released out into the synapse when an action potential reaches the terminal. The ACh molecule attaches to a receptor site, muscarinic or nicotinic, or to the enzyme that breaks it apart. Combination with the receptor site results in biological action, and coupling with the enzyme ends in destruction. The enzyme, acetylcholinesterase, is found at all cholinergic synaptic sites. A nonspecific variety of the enzyme is also prevalent in many other tissues. It too will break down ACh. The final action of either enzyme is the production of acetic acid and choline. The acetic acid is washed away for further metabolism, and the choline is reabsorbed into the nerve terminal for resynthesis to ACh.

Bethanecol

Bethanecol (Urecholine) is a synthetic choline ester that is not destroyed as easily as ACh by cholinesterase enzymes. It is useful in treating patients with urinary retention and paralytic ileus, and it is administered orally or subcutaneously. The side effects and toxicities for this drug are the same as those for ACh. Because the drug is not given intravenously, however, cardiac and respiratory effects are minimized.

Carbachol

Carbachol (Carcholin) is a mixed nicotinic and muscarinic drug because it releases ACh from the nerve ending, producing the expected cholinergic effects at all receptor sites. The drug has been used for treatment of glaucoma (applied topically), paralytic ileus, and urinary retention (orally and subcutaneously).

Pilocarpine

Pilocarpine (Pilocar) is a cholinomimetic that is useful in ophthalmology as an antiglaucoma agent. Cholinergic compounds decrease intraocular pressure by relieving the obstruction to the canal of Schlemm, a drainage circuit for the eye. Miosis (pinpoint pupils) is one feature of cholinergic therapy and may be beneficial to glaucoma treatment because the muscular base of the relaxed iris may contribute to the drainage block. Another use of pilocarpine (Salagen) is to promote salivary flow in patients with a ganglionic blockade.

Anticholinesterase Drugs

Before proceeding to specific anticholinesterase drugs, it is important to understand the basic mechanism of action for these compounds. Acetylcholinesterase is the enzyme responsible for destroying ACh at the various nerve junctions where it is released. The class of drugs that interfere with this function is called the anticholinesterases. These drugs attach to the enzyme and thereby block the enzymatic hydrolysis of ACh, causing ACh to accumulate outside of the nerve ending. This results in a greater response than normal to any cholinergic nerve stimulation. Some of these anticholinesterases are relatively short-acting compounds and are therapeutically important, whereas others are extremely long-lasting and potent compounds that are important only as poisons. The long-acting compounds have been used as insecticides and as nerve gases in chemical warfare. The therapeutically useful anticholinesterases are beneficial in problems related to the eye, intestine, and the skeletal neuromuscular junction (NMJ). In these applications, these drugs increase the amount of ACh available for activity, an effect that is especially important in cases in which the synthesis or release of ACh is lower than normal, as in myasthenia gravis.

There is great medical interest in the toxicology of the anticholinesterases, especially the extremely potent irreversible anticholinesterases. Toxicity due to these compounds is not uncommon and is often severe. When a toxic irreversible anticholinesterase, such as diisopropylfluorophosphate (DFP) or sarin, is ingested, inhaled, or absorbed across the skin, a great variety of toxic cholinergic effects are seen. The first effects seen after exposure to an anticholinesterase are often ocular and respiratory effects. In the eyes, marked miosis is produced quickly. In the respiratory system, bronchoconstriction and bronchial secretions combine to produce tightness in the chest and wheezing. Gastrointestinal symptoms include nausea, vomiting, cramps, and diarrhea. Other muscarinic effects are severe salivation, involuntary defecation and urination, sweating, lacrimation, bradycardia, and hypotension.

Further effects of anticholinesterases are related to nicotinic functions of ACh. These include skeletal muscle twitching, weakness, and paralysis. CNS effects include depression of the respiratory and cardiovascular control centers, leading to respiratory collapse. At the time of death, respiratory paralysis is evident, caused by a combination of bronchoconstriction, bronchosecretions, respiratory muscle paralysis from overstimulation, and CNS/control center depression. The treatment of this toxicity is closely related to preserving respiratory function. Administration of atropine, a muscarinic blocker, will effectively decrease bronchoconstriction and secretion. Another drug, pralidoxime (Protopam), is used to reactivate the acetylcholinesterase. It is most effective shortly after exposure to the toxic agent because it breaks down the anticholinesterase so it can be removed from the enzyme site. Additional measures are related to physiological support of the patient. Maintenance of an airway, artificial respiration, and oxygen administration are important therapeutic applications for these patients.²

Cholinergic Blocking Drugs

Cholinergic antagonists block the various receptor sites where ACh is a transmitter. There are specific blocking drugs for each type of ACh receptor. Atropine blocks all cholinergic action right at the muscarinic receptor site on smooth muscle, exocrine glands, and myocardium. The cholinergic antagonist curare works only at the neuromuscular junction to block the nicotinic effect of ACh, resulting in paralysis of skeletal muscle. Still another type of nicotinic blocker is the ganglionic blocker hexamethonium, which blocks both sympathetic and parasympathetic ganglia by occupying the ACh receptor there. These drugs are useful wherever sympathetic or parasympathetic tone needs to be decreased. It is possible to selectively inhibit cholinergic effects in the body to produce a desired effect or to eliminate an undesirable effect. Because of this selectiveness, cholinergic antagonists have widespread use in many areas of medicine.

Cardiovascular Reflex

The cardiovascular reflex involves many of the components of the autonomic nervous system to maintain a normal blood pressure. This mechanism is important for maintaining blood pressure within certain limits during all phases of physical activity. Even the simple act of standing from a seated position requires prompt compensation by this reflex system. If in some way this reflex is interrupted, a condition known as orthostatic hypotension will exist. A common manifestation of this condition is fainting upon standing because of inadequate blood flow to the brain. This section is devoted to the functional aspects of the reflex after a change in blood pressure.

Other Drug Classes Used in the Treatment of Hypertension

As mentioned in the previous sections, many drugs have the potential to affect blood pressure, cardiac output, heart rate, etc. Many studies have been done to establish appropriate guidelines for patients with hypertension, which is an important risk factor for heart disease and stroke. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that it takes at least two medications of different classes to treat most cases of mild hypertension, and three to four medications for those with severe hypertension.⁴ The latest Joint National Committee JNC report (2003)⁵ recommends starting patients on a two-drug regimen in which one of the drugs is a diuretic. There are many types of diuretics, all classified according to which part of the kidney is affected and what type of action is performed. Some examples are hydrochlorothiazide (HCTZ) (HydroDIURIL), furosemide (Lasix), and spironolactone (Aldactone). In addition to the diuretics and beta-blockers discussed previously, there are angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium-channel blockers, and many drugs that combine two of these classes. These drugs are commonly used for the treatment of hypertension but are also used in heart failure and other heart diseases. Recently, more focus has been put on hypertension in the context of overall cardiovascular risk and the importance of the long view. Evidence from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)⁶ shows that in addition to blood pressure lowering medications, cholesterol-lowering medications (such as the statins) should be considered as part of primary therapy in certain patients.

ACE inhibitors and ARBs affect a cascade of events that ultimately leads to an increase in blood pressure. This is known as the renin-angiotensin system. The endogenous components of this system effect vascular tone and thereby affect blood pressure. Renin is an enzyme produced by the kidneys and released in response to changes in blood pressure. When renin is circulated throughout the blood stream, it comes in contact with angiotensinogen, which is synthesized by the liver and circulates throughout the body. The angiotensinogen is then converted to angiotensin I. With the aid of ACE, angiotensin I is converted to angiotensin II, which has vasoconstricting effects. Bradykinins are inflammatory mediators that are also broken down by ACE. ACE inhibitors block the enzyme and do not allow angiotensin I to be converted or bradykinins to be broken down.⁷ Excessive bradykinins can cause many systemic effects, one of them being chronic cough. Some patients need to be taken off their ACE inhibitor for that reason. Two examples of the many ACE inhibitors commonly used are enalapril (Vasotec) and lisinopril (Prinivil). There has been a significant debate over the recommendation for first-line drugs in the treatment of hypertension. Some feel beta-blockers should be used, and others feel ACE inhibitors are a better first line medication, but most agree that both should be used in combination with diuretics. Many ongoing studies continue to address those options. The JNC guidelines primarily are responsible for publishing these recommendations, and healthcare providers should frequently check for updates by going to the National Institute of Health (NIH) website (http://www.nih.gov/) and searching for “JNC Guidelines.”

Another class of drugs known as the ARBs has helped eliminate chronic cough as well as many other side effects. ARBs work by blocking the receptor to which angiotensin II binds. Therefore angiotensin II is not able to exert its vasoconstrictive effects on the body, and the result is a decrease in blood pressure. Some examples of ARBs are losartan (Cozaar), candesartan (Atacand), and valsartan (Diovan).

Calcium-channel blockers are another class of drugs used to treat HTN, but these are unrelated to the renin-angiotensin system. There are calcium channels on the cardiac myocytes that, when activated, increase heart rate and contractility as well as vasoconstriction. Therefore when these channels are blocked, the opposite occurs: heart rate, contractility, and vasodilation decrease. In addition to the treatment of hypertension, calcium-channel blockers can be used in heart failure and other heart diseases. Some examples of calcium-channel blockers are diltiazem (Cardizem), nifedipine (Procardia-XL), and verapamil (Calan).

The ACE inhibitors, ARBs, and calcium-channel blockers have many side effects and contraindications that are not discussed here but can be reviewed in any of the texts listed in this chapter’s references. Although these drug have different mechanisms of action, they all work toward reducing blood pressure and decreasing the risk for heart damage.

Drugs Used in Obstructive Airway Disease

Patients suffering from asthma or COPD (emphysema or chronic bronchitis) may have an obstructed airway for several reasons. Acute asthmatic obstruction and some chronic airway obstructions are due to bronchial smooth muscle contraction, which results in a smaller diameter airway. Inflamed passageways, which are swollen because of edema, may also constitute an airway obstruction. A further complication seen in many respiratory diseases is the thickening and collection of secretions that cannot be eliminated from the respiratory tree and subsequently block the airway. In this section, the various drugs that can reverse smooth muscle contraction, inflammatory edema, and collection of secretions are presented.

A variety of therapeutic mechanisms are useful against this collection of obstructive conditions. The single most effective mechanism for relief of smooth muscle spasm is the aerosolized beta₂ activity that is available in some of the adrenergic agents. Other useful mechanisms aim at potentiating the beta activity of adrenergic agents, decongesting the inflamed airway, and in a broader approach, generally stabilizing cells that can release mediators of the disease, thereby lowering the severity of the disease. The following drugs will be discussed in regard to their actions in obstructive airway disease.

Drug Inhalation Devices

Most drugs administered by inhalation in respiratory disease are delivered by pressurized metered-dose inhalers (MDI) (Figure 45-1) or nebulizers. MDIs rely on pressurized chlorofluorocarbon or hydrofluoroalkane propellants to deliver very small drug particles (less than 5-micron diameter) into the airway. Each activation of the metered valve allows an accurately determined volume (dose) of propellant and drug mixture to be released at a high velocity. As of 2010, most CFC based MDIs have been removed from the market in attempts to protect the environment.⁹ A nebulizer is a machine that delivers the drug after it has been aerosolized with room air. One important advantage of a nebulizer is that the patient does not need hand/breathing coordination, which is further discussed below. The nebulizer, however, is not portable like an MDI and is more expensive than an MDI.

The delivery of drugs to the site of action in the airway by any type of inhalation is inefficient, and therefore, correct technique in MDI use is an important concern. The MDI will allow delivery of 20% of the metered drug to the airway if the patient correctly coordinates the proper rate of inhalation with activation of the device and then adequately holds his or her breath before exhalation. Unfortunately, it is estimated that 50% or fewer patients manage the drug delivery correctly. In response, patient education on correct MDI technique is an important part of therapy, and additional devices, called spacers, have been developed to allow success with variations in technique. The spacers come in various configurations, but they all provide a chamber between the patient and the MDI, which can be charged with the drug-propellant mixture that is then inhaled without concern for critical timing. Patients with poor MDI technique should benefit from the addition of a spacer (see Figure 45-1).

An alternative to the MDI, for patients who have difficulty with the inhalation technique, is the single-dose or multi-dose powder inhaler (Figure 45-2). This device offers a drug compounded into a fine powder that is delivered from a container on simple inhalation by the patient. Coordination of drug delivery is simple and not a problem because only inspiration by the patient drives powder delivery to the airway. The method offers the same or lower efficacy of drug delivery (6% to 20%) when compared with MDI. Also, a relatively high airflow is needed to suspend the powder properly. Therefore young children and the older adults may not benefit from this type of device. Overall, studies have shown that if the patient uses the correct technique, each of the delivery devices provides similar outcomes.¹⁰

Summary

This chapter describes the basic respiratory and cardiovascular physiology that underlies pharmacological considerations of drug prescription for people with heart and lung conditions. The actions of common drugs are presented. The relationship between physiology and the mechanisms of action of these drugs is highlighted. Medications for hypertension and chronic airway disease are given special consideration. Finally, drug inhalation devices are reviewed because it is important that physical therapists understand these devices and their proper use for effective outcome.