Respiratory and Cardiovascular Drug Actions



Respiratory and Cardiovascular Drug Actions


Stacy J. Laack and Arthur V. Prancan



Key Terms





















The respiratory and cardiovascular systems have many built-in mechanisms for controlling their functions during health and disease. In healthy individuals, both systems act quickly and positively to maintain proper functioning under the most complicated conditions. Even during trauma or disease, these systems often overcome distress and regain normal function. Disease sometimes alters the physiology of respiration or circulation to the extent that the homeostatic mechanisms are no longer effective. In such a case, a drug with the appropriate action becomes necessary to restore normal physiological function.


Before a drug can be used effectively, the system it is to modify must be understood. How the mechanism of the drug action relates to the biological system must be clear before an effect can be predicted.


This chapter describes much of the basic respiratory and cardiovascular physiology that underlies the action of the drugs presented, with the goal of elucidating the relationship between basic physiology and the drug mechanism of action (Table 45-1). Some of the trade names of the medications mentioned in the text will be changing, but the generic names will remain the same. Not all pharmacological interventions for the respiratory and cardiovascular systems are covered. Certainly, no attempt has been made to describe the pharmacology of other systems or disease states. For further study, any of the texts listed in the reference section at the end of the chapter are highly recommended.




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):


beats/min(HR)×mL/beat (SV)=mL/min (CO)


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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.



Adrenergic (Sympathomimetic) Drugs


Norepinephrine


As mentioned previously, norepinephrine (Levarterenol, Levophed) is a mixed-activity drug (90% alpha, 10% beta). It stimulates beta-receptors in the heart, which results in an increase of heart rate and stroke volume (increased cardiac output). In the arterioles, norepinephrine causes vasoconstriction via the alpha-receptor, resulting in increased total peripheral resistance. The total effect is an increase in blood pressure. Norepinephrine has little effect on the bronchioles. This drug is given only intravenously, and it is reserved for use in hypotensive emergencies to raise blood pressure, therefore preserving blood supply to the brain and heart. The natural sympathetic compounds are known as catecholamines.



Epinephrine


Epinephrine (Adrenalin) is also a mixed-activity drug (50% alpha, 50% beta). It is naturally produced in the adrenal medulla and can be released during sympathetic nervous system activation. When this occurs, it acts as a circulating hormone, stimulating both alpha- and beta-receptors. This drug will increase heart rate and stroke volume and may slightly increase or decrease total peripheral resistance at the arterioles. In any case, cardiac output always goes up; blood pressure may go up or down slightly.


In the bronchioles, epinephrine exerts a dramatic dilating effect that is mediated by the beta-receptor. Epinephrine can be administered by inhalant aerosol to reverse a bronchoconstrictive episode. It is also administered intramuscularly and subcutaneously to treat asthma and anaphylactic reactions to an allergic response, cardiac arrest, heart block, and as a mild vasoconstrictor to keep local anesthetics at the injection site.




Phenylephrine and Metaraminol


Both phenylephrine (Isophrin, Neo-Synephrine) and metaraminol are powerful and prolonged stimulators of alpha-receptors. The action is directly on the receptor site itself. The response to the administration of either of these drugs is a rise in blood pressure because of vasoconstriction accompanied by a reflex bradycardia, which causes a decrease in cardiac output. Reflex alterations of cardiovascular function are explained later in this chapter. The primary usefulness of these drugs is in various hypotensive states. Phenylephrine is used as a nasal decongestant, mydriatic, and for the relief of paroxysmal atrial tachycardia. Phenylephrine affords relief from tachycardia because it increases blood pressure and evokes the cardiovascular reflex that is marked by high vagal tone and bradycardia.




Amphetamine


Amphetamine (Dextroamphetamine, Dexedrine) drug has pharmacological properties related to the catecholamines because it causes release of norepinephrine from the nerve terminal. Amphetamine has both alpha- and beta-receptor activity, although indirectly, through its release of norepinephrine. The usual cardiovascular response is an increase in blood pressure often accompanied by a reflex bradycardia. Amphetamine also has potent central nervous system (CNS) activity. It is a stimulant of the medullary respiratory center, and it can antagonize drug-related central nervous system depression. Respiratory depression often accompanies overdoses of CNS depressant drugs and this effect may be overcome by amphetamine. This drug is usually used for its CNS effects and not for peripheral cardiovascular or respiratory effects.



Beta2-Receptor Stimulants


As mentioned above, there are several drugs that act primarily at the beta2 smooth muscle receptor site, causing selective actions in the bronchioles and arterioles but not in the heart (Box 45-1). These drugs will produce a bronchodilation without increasing cardiac output. This particular lack of cardiovascular effect makes them safer than drugs like isoproterenol or ephedrine in treatment of bronchial asthma. This class of drugs is currently part of the mainstay of treatment for asthma and chronic obstructive pulmonary disease (COPD).



Box 45-1   Beta2-Receptor Stimulants




*Formoterol and salmeterol are used primarily in combination with inhaled steroids for long-term use.



Alpha-Adrenergic Blocking Drugs


The alpha-adrenergic blocking class of drugs should not be used as monotherapy because of their propensity to cause fluid retention. When combined with diuretics, there is no evidence to contraindicate their use. Diuretics are drugs that act on the kidney to increase the formation of urine, therefore decreasing blood volume and fluid accumulation.






Beta-Adrenergic Blocking Drugs


The beta-blocker class of drugs is highly effective for the treatment of hypertension. They are commonly prescribed in conjunction with diuretics. The following drugs are just a few examples of the many beta-blockers available.


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Jun 11, 2016 | Posted by in RESPIRATORY | Comments Off on Respiratory and Cardiovascular Drug Actions

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