I. INTRODUCTION TO THE PERIPHERAL EFFERENT NERVOUS SYSTEM
A. T al muscle and controls motor functions of the body. Axons originate from the spinal cord and release the neurotransmitter acetylcholine (ACh) at the neuromuscular junction. Some drugs can affect both the somatic and the autonomic nervous systems because ACh is a transmitter in both systems.
B. The autonomic nervous system regulates the activity of the heart, secretory cells, and smooth muscle. Two neurons are involved in the transmission process. The first neuron originates in the central nervous system (CNS) and synapses in a ganglion outside the CNS. A second neuron then innervates the target (effector) tissue.
1. Organization (Figure 2-1)
a. Sympathetic nervous system
(1) Preganglionic neurons originate from the thoracic and lumbar portions of the spinal cord and terminate in the para- or post-vertebral ganglia, or they directly innervate the adrenal medulla. Functionally, the adrenal medulla responds as if it were a ganglion.
(2) Postganglionic neurons originate from the ganglia and innervate the effector cell.
b. Parasympathetic nervous system
(1) Preganglionic neurons originate from either the midbrain, the medulla ob-longata, or the sacral portion of the spinal cord. They terminate on postganglionic neurons. The terminals of the preganglionic neurons and ganglia are located in or close to the effector cell.
(2) Postganglionic neurons innervate the tissue.
2. Neurotransmitters are chemical substances that transmit impulses across junctions such as synapses (e.g., nerve-to-nerve, nerve-to-effector cell).
a. Sympathetic nervous system
(1) Preganglionic neurons release ACh onto nicotinic receptors of postganglionic neurons or the adrenal medulla.
(2) Postganglionic neurons release norepinephrine (NE) onto adrenergic receptors (adrenoceptors) in the effector tissue.
b. Parasympathetic nervous system
(1) Preganglionic neurons release ACh onto nicotinic receptors of postganglionic neurons.
(2) Postganglionic neurons release ACh onto muscarinic receptors in the effector cell.
3. Receptors (Table 2-1)
a. Cholinergic receptors mediate the effects of ACh. They are muscarinic or nicotinic, named after plant alkaloids responsible for the physiologic effects of poisonous mushrooms and tobacco, respectively.
(1) Muscarinic receptors have five subtypes, M1–M5. M1 receptors are found in neurons to mediate excitatory postsynaptic potential (EPSP); M2 receptors are found in the heart (to decrease excitability); M3 receptors are found in smooth muscles, sphincters, and secretory glands; M4 receptors are found in the CNS; and M5 receptors are found in the midbrain dopaminergic neurons [to increase dopamine (DA) release], cerebral arteries and arterioles, possibly peripheral blood vessels, and lymphocytes. M1, M3, and M5 receptors are coupled to Gq, whereas M2 and M4 receptors are coupled to Gi/o (Table 2-2).
(2) Nicotinic receptors have two subtypes, NM and NN. NM receptors are found in the muscle of neuromuscular junctions, whereas NN receptors are found in the neurons of the CNS and autonomic ganglia. Nicotinic receptors are part of the nonselective cation channels; activation of these receptors will open the channels to permit the passage of Na+, K+, and Ca2+, predominantly Na+. As a result, membrane is depolarized, which triggers the opening of voltage-dependent Ca2+ channels to further increase Ca2+ influx.
b. Adrenergic receptors mediate the effects of NE and epinephrine (Epi).
(1) α-Receptors: α1, α2
These receptors are found in many tissues (Table 2-1). α2-Receptors are also found in presynaptic site of the adrenergic neuron. α1-Receptors are coupled to Gq, whereas α2–receptors are coupled to Gi/o.
(2) β-Receptors: β1, β2, β3
Both β1– and β2-receptors are found in many tissues and elicit many different effects (Table 2-1). β3-Receptors are found mainly in adipocytes and some in myocardium. All three β-receptor subtypes are coupled to Gs.
TABLE 2-1. Tissue Receptors and Response to Stimulation
FIGURE 2-1. Effector neurons of the peripheral nervous system. Drugs that stimulate ($) and block (
) receptors are also shown. NN,ganglionic nicotinic receptor; NM, skeletal muscle nicotinic receptor; NE, norepinephrine; Epi, epinephrine; ACh, acetylcholine. (From Figure 2-1, NVMS Pharmacology.)
TABLE 2-2. Cholinergic Receptor Pharmacology—An Overview
II. ADRENERGIC AGONISTS (SYMPATHOMIMETIC AMINES). An overview is presented in Table 2-3.
A. Catecholamines
1. Epi, NE, and DA are endogenous substances that serve as hormones and neurotransmitters. They are also used therapeutically as drugs.
a. Chemistry and biosynthesis are illustrated in Figure 2-2.
b. Mechanism of action (Figure 2-3)
(1) Epi is a potent agonist of all adrenergic receptors (i.e., α1, α2, β1, β2, and β3).
(2) NE is a potent agonist of α1-α2-, and β1–receptors. It has little effect on β2–receptors.
(3) Dopamine
(a) DA causes the release of NE from adrenergic neurons, which activates α1-and β1–receptors.
(b) DA activates specific DA receptors.
i. D1–receptors are present in the renal, mesenteric, and coronary circulation and are activated by low concentrations of DA. Activation of these receptors evokes vasodilatation, which is blocked by DA receptor antagonists (e.g., haloperidol), but not by β-adrenergic receptor antagonists. D1–receptors are coupled to Gs, thereby stimulating cyclic AMP synthesis (more cyclic AMP, more relaxation of smooth muscle).
ii. D2–receptors are present in ganglia, adrenal cortex, and certain areas of the CNS, including the substantia nigra and pituitary gland. Activation of these receptors inhibits neuroendocrine release. D2–receptors are coupled to Gi/o, thereby inhibiting cyclic AMP synthesis (less cyclic AMP, less neurosecretion).
iii. D3–receptors are present in the nucleus accumbens located at the base of the striatum. D3–receptors are coupled to Gi/o.
iv. D4–receptors are present in the heart and CNS. D4–receptors are coupled to Gi/o.
v. D5–receptors are present in lymphocytes, hippocampus, and nucleus accumubens. D5–receptors are coupled to Gs.
c. Pharmacokinetics
(1) Absorption
(a) Catecholamines are poorly absorbed following oral administration, partly because the drugs are rapidly oxidized and conjugated.
(b) They are absorbed from the respiratory tract when nebulized and inhaled.
(c) SC absorption is slow because of vasoconstriction.
(2) Fate
(a) Distribution. Catecholamines do not cross the blood–brain barrier readily.
(b) Deactivation (see Figure 2-3)
i. Tissue uptake mechanisms remove the drug from the receptor site, thereby decreasing the number of receptors being occupied and decreasing the response.
Uptake1 is the active uptake of the drug into the presynaptic sympathetic nerve terminal. Cocaine produces a sympathomimetic effect by blocking uptake1.
Uptake2 is the uptake of catecholamines into the effector cell. Effector cell contains monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), which metabolize catecholamines to inactive products.
ii. The liver and kidneys, which are rich in MAO and COMT, inactivate circulating catecholamines.
(c) Excretion. The metabolites are excreted in the urine.
d. Pharmacologic effects. The pharmacologic response to an agonist is a function of the affinity of the agonist for the receptor, the number of receptors, and the efficacy of the agonist (see Table 2-1).
(1) Epinephrine
(a) Blood pressure effects
i. Low doses may cause little change in blood pressure. They increase skeletal muscle blood flow via activation of β2–receptors and increase heart rate and force of contraction via activation of β1–receptors. β2-Receptors have a higher affinity than do α-receptors for Epi, producing a preferential activation at low doses.
ii. Higher doses. Increasing the dose of Epi leads to the activation of α-receptors, which causes vasoconstriction and reduces the blood flow to the skeletal musculature. Because α-receptors predominate in the cutaneous, mesenteric, and renal vascular beds, the net result is an increase in blood pressure.
Activation of the α-receptors increases total peripheral resistance and counters the β2-receptor-mediated vasodilatation. In addition, the larger dose of Epi activates more β1-receptors in the heart, which increases cardiac output and contributes to the increase in blood pressure.
As the blood pressure increases, baroreceptors in the aorta arch and carotid sinus are activated. They, in turn, activate the vagus nerve and increase vagal tone on the heart to reduce the cardiac output, lowering the systemic blood pressure.
(b) Vascular effects
i. Skin. Activation of α-receptors causes vasoconstriction, decreasing blood flow.
ii. Skeletal muscle. At low concentrations, β2–receptors are activated, increasing blood flow to skeletal muscle. At higher concentrations, activation of α-adrenergic receptors reduces blood flow.
iii. Mesentery and kidneys. Activation of α-receptors leads to a decreased blood flow.
iv. Lungs. Decreased blood flow results from vasoconstriction of arteries and veins.
v. Heart. Blood flow increases, largely because of the metabolic products created by the increase in cardiac work.
(c) Cardiac effects. β1–Receptors predominate in the heart, but α1, β2, and β3-receptors are also present. Epi causes
i. Increased force of contraction (positive inotropic effect).
ii. Increased rate of contraction (positive chronotropic effect).
iii. Increased output.
iv. Increased excitability.
v. Increased automaticity.
vi. Increased potential for arrhythmias.
vii. Decreased efficiency (greater oxygen consumption).
(d) Smooth muscle effects
i. Gastrointestinal (GI) tract. Epi and NE relax GI smooth muscle via activation of α2– and β-receptors, and increase the contraction of the sphincters by activating α1–receptors. Activation of α2–receptors in the presynaptic nerve of the parasympathetic ganglia inhibits ACh release, thereby decreasing parasympathetic tone.
ii. Uterus. Contraction (mediated by α-receptors) or relaxation (mediated by β2–receptors) may occur, depending on the state of estrous cycle, pregnancy, and species.
iii. Urinary bladder. Urinary retention occurs when the fundus relaxes (as a result of β-receptor stimulation) and the trigone and sphincter contract (as a result of α1-receptor stimulation).
iv. Bronchioles. Relaxation occurs via activation of β2-receptors.
v. Eye. Mydriasis (pupillary dilation) results when α1– receptors in the radial muscles of the iris are stimulated, intraocular pressure may be reduced by a local vasoconstriction that decreases the production of aqueous humor.
vi. Spleen. Contraction (mediated by α1-receptors) increases blood erythrocyte levels, particularly in dogs.
vii. Pilomotor muscles. Contraction (mediated by α1-receptors) erects the hairs on the skin, particularly in carnivores during fear or rage reactions.
(e) Metabolic effects
i. Blood concentrations of glucose, free fatty acids, and lactic acid increase when β-receptors in the liver, skeletal muscle, and adipose tissue are stimulated.
ii. Some of the effects of Epi on plasma glucose concentrations are secondary (e.g., inhibition of insulin secretion via activation of α2-receptors and stimulation of glucagon secretion via activation of β2-adrenergic receptors).
(2) NE elicits most of the effects produced by Epi that are mediated via α1-, α2-, and β1-receptors, with the following exceptions:
(a) At similar doses, NE will increase the mean blood pressure more than Epi because it is not able to relax the skeletal blood vessels via β2-adrenergic receptors.
(b) Baroreceptor activation and vagal reflex will occur at lower doses for NE than Epi. This reflex can be strong enough to decrease cardiac output despite the direct activation of cardiac β1-receptors.
(3) DA has unique pharmacologic actions. The release of NE from the sympathetic postganglionic nerve terminal by DA contributes to its pharmacologic effects.
(a) Activation of D1-receptors causes vasodilatation of the renal, mesenteric, and coronary vasculature at low rates of infusion. Natriuresis and diuresis result from the increased glomerular filtration rate and renal blood flow.
(b) Activation of D2-receptors in the CNS decreases blood pressure and heart rate in the same manner as activation of α2-adrenergic receptors in the CNS. It is unlikely that CNS D2-receptors are activated when DA is infused, because DA does not cross the blood–brain barrier.
(c) Activation of β1–receptors, which occurs at somewhat greater concentrations, produces a positive inotropic effect on the heart.
(d) Activation of α1–receptors causes vasoconstriction; however, very high concentrations are necessary to produce this effect.
e. Therapeutic uses. Epi, NE, and DA are used parenterally or topically.
(1) Epinephrine
(a) Epi will reduce bronchospasm.
(b) Epi is used to treat hypersensitivity reactions and anaphylactic shock that is characterized by bronchospasm and hypotension.
(c) Epi reduces cutaneous blood flow, which makes it useful for prolonging local anesthetic effects.
(d) Applied topically, it can be used to control localized hemorrhage.
(e) Epi promotes the outflow of aqueous humor, making it useful for the treatment of open-angle glaucoma.
(f) Epi is used to restore cardiac activity following cardiac arrest.
(2) NE may be used to correct the hypotension induced by spinal anesthesia. It is not useful for correcting hypotension in most types of shock, because sympathetic activity is already high and further vasoconstriction may compromise the renal and mesenteric circulations.
(3) DA may be used to treat
(a) Cardiogenic shock
(b) Septic shock
(c) Acute heart failure (usually as supportive therapy)
f. Adverse effects
(1) Epinephrine
(a) Anxiety, fear, and restlessness
(b) Palpitations
(c) Cerebral hemorrhage
(d) Cardiac arrhythmias (especially in hyperthyroid patients)
(2) Norepinephrine. Adverse effects are similar to those of Epi. In addition, extravasations following IV injection may cause necrosis and sloughing at the site because of intense vasoconstriction.
(3) Dopamine. Adverse effects include those of Epi and NE, but they are shortlived because DA is rapidly metabolized.
2. Isoproterenol (Isuprel®)
a. Mechanism of action. Isoproterenol, a potent nonselective β-receptor agonist, increases cyclic AMP levels as β1– and β2-receptors activate adenylyl cyclase through coupling to Gs.
b. Pharmacologic effects
(1) IV infusion decreases mean blood pressure by reducing peripheral resistance, primarily in skeletal muscle.
(2) Cardiac output increases, owing to increases in cardiac contractility and heart rate.
(3) Smooth muscle tissues possessing β-receptors (e.g., bronchiolar and GI smooth muscle) are relaxed.
c. c. Therapeutic uses
(1) Acute bronchial constriction
(2) Complete atrioventricular (A-V) block.
d. d. Pharmacokinetics
(1) Absorption. Isoproterenol is readily absorbed parenterally or as an aerosol.
(2) Fate. It is principally metabolized by COMT and MAO, but MAO is less effective than with Epi and NE.
(3) Excretion. Metabolites are excreted in urine.
e. Adverse effects
(1) Tachycardia
(2) Arrhythmias (as a result of general stimulation of cardiac tissues).
TABLE 2-3. Adrenergic Receptor Pharmacology—An Overview
FIGURE 2-2. Biosynthesis of dopamine, norepinephrine, and epinephrine. (From Figure 2-2, NVMS Pharmacology.)
FIGURE 2-3. Site of action of drugs affecting the sympathetic nervous system. The figure depicts the events taking place at the junction of a sympathetic nerve terminal and an end-organ cell.
Tyrosine from the circulation enters the nerve terminal (1) and is converted first (2) via tyrosine hydroxylase (TH) into dopa and then (3) via dopa decarboxylase (DD) into dopamine (DA). DA enters the vesicle of the nerve terminal (4), where it is converted (5), via DA β-hydroxylase (DBH), into norepinephrine (NE), which is stored in the vesicles. Free NE in the axoplasm also enters and leaves the vesicles (4A).
In the process of nerve impulse transmission across the neuroeffector junction, the nerve terminal is depolarized (6) by action potential. The storage vesicle fuses with the plasma membrane, and NE is released into the junction (7) by exocytosis. Indirect-acting sympathomimetics can also cause NE to leave the vesicles and enter the junction (8).
Once released from the neuron, NE activates the postsynaptic α(α1, α2), β1, and β2 receptors (9, 10, 11) on the effector cell, thereby producing the response. NE also activates presynpatic α2–receptors to inhibit further NE release (12).
Several mechanisms terminate the action of NE. Most important is the reentry of NE into the nerve terminal (a process known as uptake-1) (13). Some of the NE enters the effector cell (uptake-2) (14), and some enters the circulation.
Two enzymes play a role in the metabolism of NE. The NE that enters the effector cell is methylated (15) by catechol-O-methyltransferase (COMT) to normetanephrine. The NE in the axoplasm of the nerve terminal is converted (16) by monoamine oxidase (MAO) in the neuron’s mitochondria, first to the aldehyde, and then to the glycol or to vanillylmandelic acid (VMA). The glycol and the acid are the major metabolites excreted in the urine. (From Figure 2-3, NVMS Pharmacology.)
B. Noncatecholamines
1. Phenylephrine (Neo-synephrine®)
a. Mechanism of action. Phenylephrine is an α1–receptor agonist (Figure 2-4). It also has some β-adrenergic stimulatory properties at high doses.
b. Pharmacologic effects. Phenylephrine increases blood pressure (primarily by vasoconstriction).
c. Therapeutic uses. It is administered parenterally, orally, or topically.
(1) Phenylephrine has an advantage over Epi as a vasopressor in situations where cardiac stimulation is undesirable, such as during gas anesthesia.
(2) Phenylephrine is used as a topical nasal decongestant.
(3) It is used in ophthalmology as a mydriatic agent (during examinations), to reduce posterior synechiae formation, and to relieve the pain associated with uveitis.
d. Pharmacokinetics
(1) Following IV administration, vasopressor effects begin immediately and persist for ≤20 minutes.
(2) It is metabolized by the liver (to phenolic conjugates mainly after oral ingestion, and to m-hydroxymandelic acid after IV administration), and the effects of the drug are also terminated by uptake into tissues. The biological t½ is 2–3 hours.
e. Adverse effects
(1) Phenylephrine may elicit a reflex bradycardia when administered IV.
(2) Hypertension, especially in geriatric, hyperthyroid, or hypertensive patients, may occur.
(3) Nasal irritation and rebound congestion may occur following long-term nasal use.
2. Dobutamine (Dobutrex®, see also Chapter 8)
a. Chemistry. The clinically used formulation of dobutamine is the racemic mixture of two enantiomeric forms, the negative and positive isomers.
b. Mechanism of action. Dobutamine activates α-receptors, and activates weakly β2– and α1-receptors as well.
c. Pharmacologic effects
(1) Dobutamine produces an inotropic effect, which is greater than its chronotropic effect.
(2) It increases cardiac output by increasing cardiac contractility and stroke volume.
(3) Increased myocardial contractility may increase myocardial oxygen demand and coronary blood flow.
d. Therapeutic uses. Dobutamine is used for the short-term treatment of heart failure.
e. Pharmacokinetics
(1) Dobutamine is administered by IV infusion. Upon IV infusion, the onset of action generally occurs within 2 minutes and peaks after 10 minutes.
(2) Dobutamine is metabolized rapidly in the liver and other tissues and has a plasma t½ of 2 minutes in humans. The drug’s effects diminish rapidly after cessation of therapy.
f. Adverse effects
(1) Dobutamine may increase oxygen use; therefore, it should be used with care after myocardial infarction to avoid increasing infarct size.
(2) It may induce cardiac arrhythmias.
(3) Other adverse effects may include those described for Epi [see II A 1 f (1)].
3. Ephedrine (Ephedra®)
a. Mechanism of action. Ephedrine is a mixed-acting agent (i.e., it has direct and indirect actions); however, its primary action is indirect. Thus, a significant portion of its action is indirectly from the NE release. Its direct effect is activation of α1-adrenergic receptors and β-receptors.
b. Pharmacologic effects
(1) Ephedrine increases blood pressure by causing peripheral vasoconstriction and cardiac stimulation.
(2) It causes bronchodilation by activating β2-adrenergic receptors.
(3) It causes the urinary bladder sphincter constriction by activating α1-adrenergic receptors.
c. Therapeutic uses. Ephedrine is a scheduled drug (i.e., additional regulations for its use are imposed by FDA).
(1) It is used to treat asthma-like conditions.
(2) It is used as a mydriatic.
(3) It can be used to treat primary urinary bladder sphincter incompetence. However, phenylpropanolamine has been used more commonly than ephedrine for urinary incontinence.
d. Pharmacokinetics
(1) Absorption. Ephedrine is absorbed from the GI tract and can be administered orally.
(2) Metabolism. It is resistant to metabolism by MAO and is not a substrate for COMT, so it has a prolonged action. It is metabolized very slowly in the liver and excreted mostly unchanged in the urine. Urine pH may alter excretion characteristics. In humans: at urine pH of 5, t½ is ~3 hours; at urine pH of 6.3, t½ is ~6 hours.
e. Adverse effects are similar to those of Epi.
(1) Hypertension and cardiac arrhythmias may occur with systemic use.
(2) CNS stimulation may cause nervousness, nausea, and agitation.
(3) Tachyphylaxis (i.e., diminished response following repeated administration) may occur. It is thought to be caused by a depletion of NE in the adrenergic nerve terminals susceptible to ephedrine.
4. Phenylpropanolamine (PPA®)
a. Chemistry and mechanism of action. PPA is a mixed-acting agent (i.e., it has direct and indirect actions); however, its primary action is indirect. Thus, part of its action is indirectly from the NE release. Its direct effect is activation of α1-adrenergic receptors.
b. Pharmacologic effects. The effects of PPA are similar to those of ephedrine, except PPA has little CNS stimulatory activity.
c. Therapeutic uses. PPA is used primarily for urinary incontinence. Tachyphylaxis has not been seen when it is used for this purpose.
d. Pharmacokinetics
(1) Absorption. PPA is absorbed from the GI tract and can be administered orally.
(2) PPA is resistant to metabolism by MAO and is not a substrate for COMT.
(3) The drug is partially metabolized to an active metabolite by the liver, but 80–90% is excreted unchanged in the urine within 24 hours of dosing.
(4) The plasma t½ is 3–4 hours.
e. Adverse effects are similar to those of ephedrine. In addition, anorexia may occur.
5. Terbutaline (Brethine®) is an orally effective β-receptor agonist used as a bronchodilator. It can be administered SC as well. It is the bronchodilator of choice for animals with heart disease, hyperthyroidism, or hypertension; however, it should be administered with caution because high doses may stimulate α-receptors. Terbutaline can be administered parenterally or orally.
a. Pharmacokinetics
(1) No information is available for dogs and cats. Terbutaline has a high pKa (10.1); as a result, most of terbutaline is in ionized form at physiological pH. In humans, < 50% of oral dose is absorbed because of the high pKa value for this drug; peak bronchodilation occurs within 3 hours and lasts for ≤8 hours. It is well absorbed following SC administration, peak bronchodilation occur within 1 hour, and lasts for ≤4 hours.
(2) In horses, terbutaline should not be administered orally, since < 1% is being absorbed via this route. When administered IV, bronchodilation lasts for ~30 minutes. Thus, terbutaline should be administered as constant infusion when given IV.
(3) Terbutaline is excreted mainly as the parent drug in the urine (60%), the rest as metabolites (sulfate conjugate).
b. Adverse effects. Tachycardia, tremors, and excitation may be seen, particularly at high doses. Sweating may be seen in horses.
6. Albuterol (Torpex®)
a. Mechanism of action. Albuterol is a selective β2–agonist, which causes bronchodilation.
b. Therapeutic uses. Albuterol is used as an aerosol and oral tablets, mainly in dogs, cats, and horses as a bronchodilator and for its effects on bronchial smooth muscle to alleviate bronchospasm or cough.
c. Pharmacokinetics
(1) Albuterol has a high pKa (9.3), thus most of the compound is in ionized form in the blood and other tissues at physiological pH. The absorption following oral administration is limited because of the high pKa value for this drug. The absorption following inhalation is rapid and complete; bronchodilation occurs within 5 minutes of inhalation.
(2) Duration of bronchodilation generally persists for 1–7 hours after inhalation and ≤12 hours after oral administration.
(3) Albuterol is extensively metabolized in the liver, principally to the inactive metabolite, albuterol 4’ — O-sulfate, which is excreted into urine. Plasma t½ is 3–5 hours after oral administration.
7. Isoxsuprine (Vasodilan®)
a. Pharmacologic effects and mechanism of action. Isoxsuprine is a selective β2–adrenergic agonist, which causes vasodilatation in skeletal muscle. In horses with navicular disease, isoxsuprine raises distal limb temperatures. Isoxsuprine also relaxes uterine smooth muscle and may increase heart rate and contractility. At high doses, isoxsuprine can decrease blood viscosity and reduce platelet aggregation.
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