Dr. V. John Massari ©
History:
A. Finklemann in 1930 stimulated the sympathetic input to rabbit intestine and found a decrease in spontaneous movements. Perfusate did the same thing to a 2nd piece of intestine. Effects mimicked by "adrenaline".
B. Von Euler 1946 demonstrated that NE, not EPI is the main endogenous catecholamine in sympathetically innervated tissue.
C. The study of the sympathetic nervous system is important from a clinical perspective. The SNS is involved in controlling heart rate, contractility, blood pressure, vasomotor tone, carbohydrate and fatty acid metabolism etc. Stimulation of the SNS occurs in response to physical activity, psychological stress, allergies etc. Drugs influencing the SNS are used in treatment of hypertension, shock, cardiac failure and arrhythmias, asthma and emphysema, allergies and anaphylaxis.
D. There are three major catecholamines: NE, EPI, and DA naturally found in the body.
EPI and NE mediate the response of the sympathoadrenal system to activation, and are also
found in the CNS. DA is primarily a CNS neurotransmitter.
I. Sympathomimetic amines have 7 major classes of action
A. A peripheral excitatory action: ie on smooth muscles of blood vessels supplying skin.
B. A peripheral inhibitory action: ie on smooth muscles of gut, bronchioles, and blood vessels supplying skeletal muscle.
C. A cardiac excitatory action: ie positive chronotropic, dromotropic, and inotropic effects.
D. Metabolic actions: ie enhanced glycogenolysis and lipolysis.
E. Endocrine actions: ie modulation of secretion of insulin
F. CNS actions: ie increased wakefulness and inhibition of appetite.
G. Presynaptic actions: ie inhibition of release of NE, NPY, and ACh at autonomic
nerve terminals by activation of alpha 2 receptors. Enhanced release of ACh by activation
of presynaptic alpha 2 receptors on somatic motor neurons. Enhanced release of NE,
and NPY by activation of Beta 2 receptors.
II. Pharmacology of Epinephrine
A. Epinephrine is a potent stimulator of both alpha and beta receptors, therefore, its
effects on target organs is complex.
B. Effects of EPI on blood pressure are dose dependent.
1. When given in large doses intravenously, EPI gives a rapid increase in blood pressure. As the response wanes, the mean pressure falls below normal before returning to control levels. The pressor effects are due to A) the positive inotropic effect of EPI, B) the positive chronotropic effect, and C) vasoconstriction in many vascular beds. The depressor effect is due to the activation of vasodilator beta 2 receptors in the vasculature perfusing skeletal muscle. This effect is not seen initially because it is overwhelmed by the vasoconstrictive effect of alpha 1 receptors on vascular smooth muscle at other sites, however vasoconstriction is lost as the concentration of EPI goes down, but the beta 2 mediated vasodilatory effect is retained. If you pretreat a person with an alpha adrenergic receptor blocker, one sees the so-called epinephrine reversal effect ie the unopposed effect of the beta 2 receptors causes a pronounced decrease in total peripheral resistance, and mean blood pressure falls in response to EPI.
2. When given in small doses, there is little or no effect on the mean blood pressure because the increase in blood pressure resulting from increased heart rate and contractility is counteracted by the decrease in total peripheral resistance due to vasodilation in blood vessels perfusing skeletal muscle. You will recall that these beta 2 receptors have a lower threshold to activation than alpha 1 receptors, therefore the net effect of low doses of EPI is vasodilation.
3. When EPI causes an increase in mean arterial pressure (High doses), it activates a compensatory vagal baroreceptor mediated bradycardia which also helps to return blood pressure toward normal.
C. Effects of EPI on vascular smooth muscle is variable, resulting in a substantial redistribution of blood flow. That is, EPI causes a marked reduction of blood flow through the skin by activating its alpha 1 receptors, while simultaneously redistributing flow through the muscles by causing vasodilation there through the activation of Beta 2 receptors. This has obvious utility in survival of the organism by preparing it for fight or flight. EPI can reduce renal blood flow by 40% in doses that do not effect mean blood pressure. Effects of EPI on Cerebral Circulation. No significant constrictor action on cerebral blood vessels. If you think about it, it is a lucky thing that the blood flow to the brain is not restricted during responses to stressors.
D. Effects of EPI on Cardiac Muscle are mediated primarily by beta 1 receptors, although some Beta 2 and alpha receptors are also present in the heart. As indicated before, EPI has a powerful chronotropic and inotropic effect. The chronotropic action of EPI is due to its ability to accelerate the slow depolarization of pacemaker cells of the SA node that takes place during diastole. Large doses may provoke cardiac arrhythmias.
E. Effects of EPI on Other Smooth Muscles. In general GI muscle
is relaxed, and resting tone and peristaltic movements are reduced. This is due to the
inhibitory effect of beta 2 receptors, and possibly also due to inhibition of release of
ACh by activation of inhibitory presynaptic alpha 2 receptors on cholinergic nerve
terminals. The response of the uterus is variable depending on phase of the sexual
cycle, state of gestation, and dose of the drug. During the last month of pregnancy, EPI
inhibits uterine tone and contractions, by activating beta 2 receptors. As a result,
selective beta 2 agonists are used to delay the onset of premature labor. Bronchial
smooth muscle is powerfully relaxed by EPI via activation of Beta 2 receptors.
Selective beta 2 agonists are used in the treatment of asthma. Epi relaxes the detrusor
muscle of the bladder by activating beta receptors, and contracts the sphincter
muscles due to alpha agonist effects. the result is urinary retention.
F. Metabolic effects of EPI:
1. Glycogenolysis via activation of beta 2 receptors, results in an increase in blood glucose.
2. Lipolysis via activation of beta 3 receptors, results in an increase in the concentration of free fatty acids in blood.
3. Insulin secretion is inhibited by alpha 2 receptors, and increased by beta 2 receptors, but inhibition predominates in man.
G. Absorption of EPI
1. Absorption from GI tract is negligible due to rapid conjugation and oxidation in GI tract and liver. Subcutaneous absorption slow due to vasoconstriction. Inhaled effects largely restricted to the respiratory tract in low doses. Larger doses can give systemic effects, including arrhythmias.
H. Toxicity and contraindications
1. EPI causes disturbing reactions such as fear, anxiety, tenseness, restlessness, headache, tremor , weakness, dizziness, etc. Hyperthyroid, and hypertensive patients are particularly susceptible.
2. More serious reactions include cardiac arrhythmias, including fatal ventricular arrhythmias when EPI is given to a patient anesthetized with halogenated hydrocarbon anesthetics such as halothane. Also cerebral hemmorhage due to severe hypertension has occurred. Use of EPI in patients receiving nonselective Beta blockers is contraindicated because the unopposed actions of EPI on vascular alpha 1 receptors can lead to severe hypertension and cerebral hemmorhage.
I. Therapeutic uses of EPI
1. Relief of bronchospasm
2. Relief of hypersensitivity reactions and anaphylaxis
3. To prolong the duration of action of local anesthetics.
4. As a topical hemostatic to control superficial bleeding from skin and mucosae
5. To restore cardiac rhythm in patients with cardiac arrest.
III. Pharmacology of Norepinephrine
A. Cardiovascular effects of NE
1. NE is a potent agonist at alpha and Beta 1 receptors, and has little action on beta 2 receptors, therefore when given by intravenous infusion of low doses, NE causes a pronounced increase in total peripheral resistance. This is combined with its direct inotropic effect on the heart to cause a substantial increase in mean blood pressure, and a reflexly mediated bradycardia. In contrast to EPI, pretreatment with an alpha 1 antagonist will block the pressor effects of NE, but will not cause reversal to a depressor effect.
B. Other responses to NE are not prominent in Man.
C. Toxicity
1. The toxic effects of NE are like those of EPI, except they ar less pronounced and less frequently seen ie anxiety, headache, palpitations, etc. In toxic doses, can get severe hypertension. NE, like EPI is contraindicated in anesthesia with drugs that sensitize the heart to the arrhythmic effects of catecholamines such as halothane. Accidental extravasation of NE during attempted intravenous infusion can cause local anoxic necrosis and impaired circulation through the limb. In pregnant females, NE should not be used because it stimulates alpha 1 receptors in the uterus that cause contraction.
D. Therapeutic uses
1. Currently very little therapeutic use. Sometimes used as a cardiac stimulant in
cardiogenic or septicemic shock.
IV. Pharmacology of Dopamine
A. Cardiovascular effects
1. At low doses DA activate D 1 receptors in renal, mesenteric, and coronary vascular beds. This leads to vasodilation. Increased flow through renal blood vessels is useful in cardiogenic and septicemic shock when perfusion of vital organs is compromised. DA activates Beta 1 receptors at higher concentrations leading to a positive inotropic effect. Total peripheral resistance is usually unchanged, although at higher concentrations DA can cause activation of alpha 1 receptors mediating vasoconstriction.
B. Toxicity
1. Toxicity of high doses of DA is similar to that noted above for NE. Since the drug has an extremely short half life in plasma, DA toxicity usually disappear quickly if the administration is terminated.
C. Therapeutic uses
1. Useful in treatment of shock in patients with reduced renal function.
V. Pharmacology of Isoproterenol
A. Cardiovascular effects
1. ISO is primarily a beta receptor agonist, therefore intravenous infusion of ISO leads to a substantial reduction of total peripheral resistance. Simultaneously, ISO causes a direct inotropic and chronotropic effect on the heart. The net result is a reduction in mean pressure.
B. Actions on other smooth muscles.
1. ISO relaxes almost all varieties of smooth muscle, but particularly bronchial and GI smooth muscle. Its effectiveness in asthma may also be due to inhibition of the release of histamine by activation of Beta 2 receptors.
C. Metabolic effects
1. ISO is a potent lipolytic (Beta 3) and glycogenolytic (beta 2) drug. It also strongly releases insulin by activating Beta 2 receptors.
D. Metabolism
1. Primarily by COMT, not MAO. Mainly in the liver.
E. Toxicity
1. Like EPI, but much less pronounced. Cardiac arrhythmias can occur readily.
F. Therapeutic uses
1. Used in emergencies to stimulate heart rate in patients with bradycardia or heart
block. Its use in asthma and shock has been discontinued due to development of more
selective sympathomimetics.
VI. Pharmacology of Dobutamine
A. The mechanism of action of dobutamine are complex. It is given as the racemic mixture. The l-isomer is a potent agonist at alpha 1 receptors, while the d-isomer is a potent alpha 1 antagonist. Both isomers are beta receptor agonists with greater selectivity for Beta 1 than beta 2 receptors. The net result of administration of the racemic mixture is more or less selective Beta agonist effects.
B. Cardiovascular effects
1. Total peripheral resistance is not much effected, presumably by the counterbalancing effects of beta 2 agonist mediated vasodilation, and alpha 1 agonist mediated vasoconstriction. Dobutamine has a prominent inotropic effect on the heart, without much of a chronotropic effect. The explanation for this is unclear.
C. Toxicity is like isoproterenol, esp. arrhythmias
D. Not effective orally. Given by I.V. route, however its half life in plasma is two minutes, therefore it must be given by a continuous infusion. After a few days, tolerance develops to its effects. This has led to short term use repeated intermittently.
E. Therapeutic Uses
2. Used in the short term treatment of congestive heart failure or acute myocardial
infarctions, because of its inotropic effect, and because it does not increase heart rate
and has minimal effects on blood pressure. These effects minimize the increased oxygen
demands on the failing heart muscle.
VII Pharmacology of Selective Beta 2 Agonists
A. These compounds are mainly utilized for treatment of asthma. Their advantage over non-selective beta agonists, is that they do not cause undesired cardiovascular effects by stimulating beta 1 receptors of the heart.
B. Metaproterenol, Terbutaline, Albuterol, Pirbuterol are structural analogues of the catecholamines which have been modified so that they are not substrates of COMT and are poor substrates for MAO. This results in a longer duration of action compared to catecholamines and varies from 3 to 6 hours when administered by inhalation.
C. Ritodrine is a selective Beta 2 agonist which was developed as a uterine relaxant. It is used to delay the onset of premature labor. Other beta 2 agonists have been used for the same purpose in Europe. While these drugs can delay the onset of birth, they may not have any significant effect in reducing perinatal mortality and may increase maternal morbidity.
D. Adverse effects of Beta 2 agonists
1. Skeletal muscle tremor is the most common adverse side effect. This may be due to the presence of Beta 2 receptors in skeletal muscle, which when activated, cause twitches and tremor. Tolerance generally develops to this side effect.
2. Restlessness, apprehension, anxiety
3. Tachycardia may occur possibly secondary to beta 2 receptor mediated vasodilation. In patients with heart disease particularly, can see arrhythmias.
4. Increased glycogenolysis
5. Some recent epidemiological studies suggest that regular use of Beta 2 agonists may
actually cause increased bronchial hyperreactivity and deterioration in the
control of asthma. In patients requiring regular use of these drugs, strong
consideration should be given to the use of additional or alternative therapies, such as
use of inhaled corticosteroids.
VIII. Pharmacology of Alpha 1 Agonists
A. Phenylephrine and Methoxamine
1. Primarily directly acting vasoconstrictors by activating alpha 1 receptors. The resulting hypertension results in a prominent reflex bradycardia. They are used in the treatment of atrial tachycardia to terminate the arrhythmia by causing a reflex bradycardia. Phenylephrine is also used as a nasal decongestant and mydriatic. They are not metabolized by COMT, therefore they also have a longer duration of action than the catecholamines.
B. Mephentermine and Metaraminol
1. These drugs have two effects: a) They are directly acting alpha 1 agonists, and b)
they are indirectly acting sympathomimetics ie they cause the release of endogenous
norepinephrine. The direct effect on alpha 1 receptors mediates vasoconstriction and an
increased blood pressure. The indirect effect of released NE on the heart is a positive
inotropic and chronotropic action that also increases blood pressure. This results in a
reflex bradycardia. Both drugs are administered intravenously. Adverse effects are due to
CNS stimulation, excessive increases in blood pressure, and arrhythmias. They are used in
the treatment of the hypotension which is frequently associated with spinal anesthesia.
Metaraminol is also used in the termination of paroxysmal atrial tachycardia, particularly
in patients with existing hypotension.
IX. Pharmacology of Alpha 2 Agonists
A. Introduction
1. Selective alpha 2 agonists are used primarily for the treatment of hypertension.
Their efficacy is somewhat surprising since many blood vessels, especially those of the
skin and mucosa, contain post-synaptic alpha 2 receptors that mediate vasoconstriction.
Indeed clonidine, the prototype alpha 2 agonist drug which we will consider was originally
developed as a nasal decongestant because of its ability to cause vasoconstriction of
blood vessels in the nasal mucosa. The capacity of alpha 2 agonists to lower blood
pressure results from their CNS effect, possibly from the activation of alpha 2
receptors in the medulla that diminish centrally mediated sympathetic outflow.
B. Pharmacology of Clonidine
1. Pharmacological effects
a. Intravenous clonidine can cause a transient rise in blood pressure due to its ability to cause vasoconstriction via an alpha 2 agonist effect on vascular smooth muscle of skin and mucosa. This is followed by a decreased blood pressure due presumably to activation of CNS alpha 2 receptors, resulting in a decreased central outflow of impulses in the sympathetic nervous system, although this is an area of intense current research interest, and some evidence suggests that different mechanisms may be more important. Some of the antihypertensive effect of clonidine may also be due to diminished release of NE at sympathetic postganglionic nerve terminals due to activation of presynaptic alpha 2 receptors.
2. Pharmacokinetics
a. Clonidine is well absorbed orally, and is nearly 100% bioavailable. The mean half life of the drug in plasma is about 12 hours. It is excreted in an unchanged form by the kidney, and its half life can increase dramatically in the presence of impaired renal function. A transdermal delivery system is available in which the drug is released at a constant rate for about a week. Three or four days are required to achieve steady state concentrations.
3. Adverse effects
a. The major adverse effects of clonidine are dry mouth, and sedation. Other effects include bradycardia, and sexual disfunction. About 20% of patients develop a contact dermatitis to the transdermal delivery system. In patients with long term therapy with clonidine, abrupt discontinuation is associated with development of a withdrawal syndrome and potentially life threatening hypertension.
4. Therapeutic uses
a. The major use of clonidine is in the treatment of hypertension.
b. Clonidine is useful in the management of withdrawal symptoms seen in addicts after withdrawal from opiates, alcohol, and tobacco. This may be due to its ability to suppress sympathomimetic symptoms of withdrawal.
c. Clonidine is useful in the diagnosis of hypertension due to pheochromocytoma. In
primary hypertension, clonidine causes a marked reduction in circulating levels of
norepinephrine. This is not seen if the cause of hypertension is pheochromocytoma.
C. Pharmacology of Guanfacine and Guanabenz
1. Guanfacine and guanabenz are alpha 2 receptor agonists which are also believed to
lower blood pressure by activation of central sites. Their pharmacological effects and
side effects are quite similar to clonidine. Guanfacine has a longer mean half life in
plasma than clonidine (12-24 hrs).
X. Miscellaneous Adrenergic Agonist Drugs
A. Amphetamine
1. Amphetamine is an indirectly acting sympathomimetic which causes release of NE from adrenergic nerve endings, and also blocks its reuptake into the cytoplasm of the nerve terminal.
2. Cardiovascular effects of amphetamine include increased blood pressure, and reflex bradycardia. In larger doses see cardiac arrhythmias.
3. Other smooth muscles respond to amphetamine as they do to previously described sympathomimetics. The contractile effect on the sphincter of the urinary bladder is particularly pronounced and has been used for the treatment of incontinence.
4. Amphetamine is one of the most potent sympathomimetic amines in stimulating the CNS. The d-isomer is 3 to 4 times more potent than the l-isomer. CNS effects include increased wakefulness and alertness; decreased sense of fatigue; elevation of mood, with increased initiative, self-confidence, and ability to concentrate; elation and euphoria; depressed appetite; physical performance in athletes is improved; performance of simple mental tasks is improved, however although more work is accomplished, the number of errors increases. The most striking improvement with amphetamine occurs when performance is reduced by fatigue and lack of sleep. Amphetamine stimulates the respiratory center. When respiration is depressed by centrally acting drugs, amphetamine can stimulate respiration.
5. Toxicity includes: restlessness, dizziness, tremor, irritability, insomnia, confusion, assaultiveness, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies. The psychotic effects of amphetamine can be elicited in any individual taking sufficient quantities of amphetamine for a long period of time. Cardiovascular effects are common and include cardiac arrhythmias, hypertension or hypotension, and circulatory collapse. GI symptoms include dry mouth, nausea, vomiting, and diarrhea. Fatal poisoning usually terminates in convulsions, stroke, and coma. Repeated use leads to the development of tolerance and psychological dependence.
6. Therapeutic uses include treatment of narcolepsy, obesity, and attention-deficit hyperactivity disorder.
7. Methamphetamine, in low doses, has prominent CNS effects like
amphetamine, without significant peripheral actions. Methylphenidate is a
mild CNS stimulant whose pharmacological properties is essentially the same as amphetamine
but which may not lead to as much motor activation. Pemoline is another
CNS stimulant which has minimal cardiovascular effects. It is used in the treatment of
attention-deficit hyperactivity disorder and is given once daily due to its long
half-life.
B. Ephedrine
1. Ephedrine is an alkaloid isolated from the plant Ephedra sinica. Extracts of this plant have been used in Chinese herbal medicine for atleast 2000 years. Ephedrine has both directly- and indirectly- mediated sympathomimetic effects. That is, it stimulates both alpha and beta receptors, and it causes release of NE. Ephedrine was the first sympathomimetic drug which was effective orally. Its spectrum of effects is similar to EPI, another sympathomimetic with both alpha and beta agonist effects, however it has a longer duration of effect. In addition it has CNS effects similar to amphetamine, but less intense. In the past it was used as a CNS stimulant for treatment of narcolepsy, and as a bronchodilator in asthma. More selective agents have replaced ephedrine.
C. Ethylnorepinephrine
1. It is primarily a beta agonist with some alpha agonist effects. It is administered IM or SC to cause bronchiolar dilation as well as vasoconstriction in the bronchioles, which reduces bronchial congestion.
D. Oral sympathomimetics used primarily for relief of nasal congestion include phenylephrine, pseudoephedrine, and phenylpropanolamine.
E. Topical sympathomimetics used primarily as nasal decongestants or mydriatics
include naphazoline, tetrahydrozoline, oxymetazoline.,and
xylometazoline
XI. A Summary of Therapeutic Uses of Sympathomimetics
A. Uses that relate to vascular effects of sympathomimetics
1. Control of superficial hemmorhage, ie in facial, oropharyngeal, and nasopharyngeal surgery. EPI
2. Decongestion of mucous membranes.
a. Usually get temporary relief, but it is often followed by a rebound swelling.
3. To prolong the duration of action of local anesthetics: EPI
4. In the treatment of hypotension and shock.
a. Use controversial because autoregulatory phenomena usually cause intense sympathetic activation, and sympathomimetics may compromise perfusion of vital organs. DA!
B. Uses that relate to CNS effects of sympathomimetics
1. Narcolepsy (amphetamines)
2. Weight Reduction (amphetamines)
3. Attention deficit-hyperactivity disorder (amphetamines, methylphenidate)
C. Uses for conversion of cardiac arrhythmias
1. Phenylephrine and methoxamine used in PAT by causing a reflex bradycardia.
2. Epinephrine used in emergency treatment of cardiac arrest.
D. Uses in allergic reactions
1. Epinephrine is the drug of choice to reverse the manifestations of serious acute hypersensitivity reactions due both to its cardiovascular effects and its ability to suppress release of histamine.
2. Asthma is preferentially treated with selective beta 2 agonists (Metaproterenol, terbutaline, albuterol).
E. Uses in ophthalmology
1. Sympathomimetics cause mydriasis ie phenylephrine and epi. These two drugs also cause a reduction in intraocular pressure in wide angle glaucoma.
F. Uses in obstetrics
1. Beta 2 agonist (Ritodrine) blocks onset of premature labor by inhibiting contractility of uterus