AGENTS ACTING N-CHOLINERGIC RECEPTORS. NICOTINE TOXICOLOGY (Benzohexonium, Pirilenum, Hygronium, Pentaminum, Tubocurarini chloridum, Pipecuronii bromide (Arduanum, Mellictinum, Dithylinum)
ADRENERGIC RECEPTOR-ACTIVATING DRUGS. ADRENERGIC RECEPTOR-BLOCKING DRUGS. SYMPATHOLYTIC AGENTS (Adrenalini hydrochloridum, Noradrenalini hydrotartras, Ephedrini hydrochloridum, Mesatonum, Naphthyzinum, Xylometasolinum, Isarinum,Salbutamolum, Fenoterolum, Fentolaminum, Prasosinum, Anaprilinum, Atenololum, Metoprololum, Talinololum, Reserpinum, Octadinum)
Agents acting N-cholinergic receptors. Nicotine toxicology
Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), predominantly in tobacco, and in lower quantities in tomato, potato, eggplant (aubergine), and green pepper.
Nicotiana tabacum
Nicotine alkaloids are also found in the leaves of the coca plant. Nicotine constitutes 0.3 to 5% of the tobacco plant by dry weight, with biosynthesis taking place in the roots, and accumulating in the leaves. It is a potent neurotoxin with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine derivatives such as imidacloprid continue to be widely used. In lower concentrations (an average cigarette yields about 1mg of absorbed nicotine), the substance acts as a stimulant in mammals and is one of the main factors responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, “Nicotine addiction has historically been one of the hardest addictions to break. Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot, a French ambassador, who sent tobacco and seeds from Portugal to Paris in 1550 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists, Posselt & Reimann. Its chemical empirical formula was described by Melsens in 1843, and it was first synthesized by A. Pictet and Crepieux in 1893.
Pharmacokinetics
As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two hours[2]. The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves (most of the substance is destroyed by the heat). The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, often called dip, snuff, or snus, which is held in the mouth between the lip and gum, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.
Pharmacodynamics
Nicotine acts on the nicotinic acetylcholine receptors. In small concentrations it increases the activity of these receptors, among other things leading to an increased flow of adrenaline (epinephrine), a stimulating hormone. The release of adrenaline causes an increase in heart rate, blood pressure and respiration, as well as higher glucose levels in the blood.
The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts oicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream.
Cotinine is a byproduct of the metabolism of nicotine which remains in the blood for up to 48 hours and can be used as an indicator of a person’s exposure to smoke. In high doses, nicotine will cause a blocking of the nicotinic acetylcholine receptor, which is the reason for its toxicity and its effectiveness as an insecticide.
In addition, nicotine increases dopamine levels in the reward circuits of the brain. Studies have shown that smoking tobacco inhibits monoamine oxidase (MAO), an enzyme responsible for breaking down monoaminergic neurotransmitters such as dopamine, in the brain. It is currently believed that nicotine by itself does not inhibit the production of monoamine oxidase (MAO), but that other ingredients in inhaled tobacco smoke are believed to be responsible for this activity. In this way, it generates feelings of pleasure, similar to that caused by cocaine and heroin, thus causing the addiction associated with the need to sustain high dopamine levels.
Dependence
Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, its addictive nature has been found to show that nicotine activates reward pathways—the circuitry within the brain that regulates feelings of pleasure and euphoria.
Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than cocaine, and even heroin, though chronic treatment has an opposite effect on reward thresholds. Like other physically addictive drugs, nicotine causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. In addition, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain inturn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. The net effect, is an increase in reward pathway sensitivity, opposite of other drugs of abuse (namely cocaine and heroin, which reduces reward pathway sensitivity). This neuronal brain alteration persists for months after administration ceases. Due to an increase in reward pathway sensitivity, nicotine withdrawal is relatively mild compared to ethanol or heroin withdrawal. Also like other highly addictive drugs, nicotine is addictive to many animals besides humans. Mice will self-administer nicotine and experience behavioral unpleasantries when its administration is stopped. Gorillas have learned to smoke cigarettes by watching humans, and have similar difficulty quitting.
Nicotinic receptors are pentamers of these subunits; i.e., each receptor contains five subunits. Thus, there is an immense potential of variation of the aforementioned subunits. However, some of them are more notable than others, to be specific, (α1)2β1δε (muscle-type), (α3)2(β4)3 (ganglion-type), (α4)2(β2)3 (CNS-type) and (α7)5 (another CNS-type).[23] A comparison follows:
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Receptor-type |
Location |
Effect |
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Muscle-type: |
· α-bungarotoxin · atracurium* |
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Ganglion-type: |
· nicotine |
· ibogaine |
||
|
Heteromeric CNS-type: |
Post- and presynaptic excitation |
· nicotine · cytisine |
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|
Further CNS-type: |
· nicotine · cytisine |
|||
|
Post- and presynaptic excitation, mainly by increased Ca2+ permeability |
|
Arterioles |
Vasoconstriction, hypertension |
|
|
Veins |
Sympathetic |
Vasoconstriction, increased venous return |
|
Heart |
Parasympathetic |
Tachycardia |
|
Parasympathetic |
Increased motility and secretions |
Effects of Nicotine on the CNS
Post-synaptic nAchR neurons are rare in CNS (left) while pre-synaptic nAchR neurons are common (right). Main CNS effect of nicotine is to cause release of other neurotransmitters which act on their post-synaptic receptors. Presynaptic release of acetylcholine is mimicked by nicotine. Nicotine activates pre-synaptic nAchR; Calcium influx depolarizes cell and causes release of glutamate which acts on post-synaptic gluamate receptors.
A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adulthood [5].
There is only anecdotal evidence about abuse or addiction with nicotine gum or nicotine patches.
Toxicology
The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 40–60 mg can be a lethal dosage for adult human beings.[6] This makes it an extremely deadly poison. It is more toxic than many other alkaloids such as cocaine, which has a lethal dose of 1000 mg.
The carcinogenic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated by the IARC, and it has not been assigned to an official carcinogen group. The currently available literature indicates that nicotine, on its own, does not promote the development of cancer in healthy tissue and has no mutagenic properties.
Its teratogen properties have not yet been adequately researched, and while the likelihood of birth defects caused by nicotine is believed to be very small or nonexistent, nicotine replacement product manufacturers recommend consultation with a physician before using a nicotine patch or nicotine gum while pregnant or nursing. However, nicotine and the increased cholinergic activity it causes have been shown to impede apoptosis, which is one of the methods by which the body destroys unwanted cells (programmed cell death). Since apoptosis helps to remove mutated or damaged cells that may eventually become cancerous, the inhibitory actions of nicotine creates a more favourable environment for cancer to develop. Thus nicotine plays an indirect role in carcinogenesis. It is also important to note that its addictive properties are often the primary motivating factor for tobacco smoking, contributing to the proliferation of cancer.
At least one study has concluded that exposure to nicotine alone, not simply as a component of cigarette smoke, could be responsible for some of the neuropathological changes observed in infants dying from Sudden Infant Death Syndrome (SIDS).[7]
It has beeoted that the majority of people diagnosed with schizophrenia smoke tobacco. Estimates for the number of schizophrenics that smoke range from 75% to 90%. It was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine. [8] [9] More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects. [10]However, research oicotine as administered through a patch or gum is ongoing.
Lobeline is a natural alkaloid found in “Indian tobacco” (Lobelia inflata), “Devil’s tobacco” (Lobelia tupa), “cardinal flower” (Lobelia cardinalis), “great lobelia” (Lobelia siphilitica), and Hippobroma longiflora. In its pure form it is a white amorphous powder which is freely soluble in water.
Lobeline has been used as a smoking cessation aid,[1][2][3] and may have application in the treatment of other drug addictions such as addiction to amphetamines,[4][5] cocaine[6] or alcohol.[7]
Lobeline has multiple mechanisms of action, acting as a VMAT2 ligand,[8][9][10] which stimulates dopamine release to a moderate extent when administered alone, but reduces the dopamine release caused by methamphetamine.[11][12] It also inhibits the reuptake of dopamine and serotonin,[13] and acts as a mixed agonist–antagonist at nicotinic acetylcholine receptors [14][15] to which it binds at the subunit interfaces of the extracellular domain. [16] and an antagonist at μ-opioid receptors.[17]
Cholinergic antagonists
The majority of the drugs used to reduce the effects of acetylcholine inhibit specifically certain types of acetylcholine receptors and can be named cholinolytic or cholinergic antagonists. Others inhibit acetylcholine release at the synaptic level.
Cholinergic Antagonists
The most common side effects of cholinergic antagonists
PHARMACOLOGY OF NEUROMUSCULAR TRANSMISSION
I. Introduction and History
A. There are two general classes of neuromuscular blocking drugs. They are the competitive, and the depolarizing blockers. The prototype of the competitive blockers is curare.
B. Although the South American arrow poisons have fascinated scientists since the 1500s, the modern clinical use of curare dates to 1932 when it was first used in patients with tetanus. Its first trial for muscular relaxation in general anesthesia occurred in 1942.
II. Pharmacology of Competitive Neuromuscular blockers
A. Examples
1. d-tubocurarine, metocurine, pancuronium
a. Long lasting duration of blockade
2. Vecuronium, atracurium, rocuronium
a. Intermediate duration
3. Mivacurium
a. Short acting
B. Actions on skeletal muscles:
1. After I.V. injection, the onset of effects is rapid. Motor weakness rapidly progresses to flaccid paralysis. Small muscles such as those of the fingers and extraocular muscles of the eyes are effected before those of the limbs, neck, and trunk. Subsequently, the intercostal muscles and finally the diaphragm is paralyzed. Recovery of function occurs in the reverse order, with the diaphragm recovering first. Death is due to paralysis of the muscles of respiration.
C. CNS effects
1. Almost all contain a quaternary nitrogen therefore they do not cross the blood brain barrier.
D. Effects on Autonomic Ganglia
1. Although tubocurarine is more potent at Nm receptors than at Nn receptors of ganglia, some degree of nicotinic receptor blockade is probably produced at autonomic ganglia and the adrenal medulla by usual clinical doses. The net result is hypotension and tachycardia. One also sees a decrease in the tone and motility of the GI tract. Vecuronium, Atracurium, Rocuronium cause considerably less ganglionic blockade.
E. Effects on Histamine release
1. Tubocurarine, Atracurium, and Metocurine cause the release of histamine with resulting hypotension, bronchospasm, and excessive bronchial and salivary secretions. Vecuronium causes less release of histamine, while Pancuronium causes essentially no release of histamine.
F. Drug Interactions with Competitive Neuromuscular Blockers
1. Synergistic potentiation occurs with a variety of inhalation anesthetic agents such as halothane, enflurane, isoflurane. Aminoglycoside antibiotics (…mycins) inhibit release of ACh and thereby potentiate the Nm blockers. Tetracyclines also produce some neuromuscular blockade, possibly by chelating Ca++.
2. Anticholinesterases such as neostigmine, pyridostigmine, and edrophonium will antagonize the effects of the competitive neuromuscular blockers.
G. Pharmacokinetics
1. Tubocurarine and metocurine, pancuronium are excreted primarily by the kidneys.
2. Atracurium and Mivacurium are metabolized by plasma esterases (accounting for briefer duration of action).
3. Vecuronium and Rocuronium are metabolized by the liver.
4. Because of their ionized structures, they are poorly absorbed orally, and are given i.v.
H. Toxicity
1. Prolonged apnea:
2. Hypotension (ganglionic blockade, inhibition of release of catecholamines from medulla, release of histamine):
3. Bronchospasm and increased secretions due to histamine release.
III. Pharmacology of Depolarizing Neuromuscular Blockers
A. Mechanisms of action and effects on skeletal muscle
1. The depolarizing blockers succinylcholine and decamethonium (C-10 no longer available in the USA) block transmission by causing prolonged depolarization of the end plate at the neuromuscular junction. This is manifested as an initial series of twitches (fasciculations), followed by flaccid paralysis. This is referred to as phase one blockade.
a. Phase 1 blockade is potentiated by anticholinesterases and antagonized by competitive blockers.
2. If the duration of blockade is prolonged however, or if the concentration of the blocker is excessive, then phase two blockade occurs in which the pharmacological characteristic is that of a competitive inhibition.
a. Phase 2 blockade is antagonized by anticholinesterases, and potentiated by competitive blockers.
B. Effects on the CNS
1. Both compounds contain quaternary nitrogens and therefore do not cross the BBB.
C. Effects on autonomic ganglia are relatively rare.
D. Histamine is released by succinylcholine, but not by decamethonium.
E. Drug interactions
1. Potentiation of the neuromuscular blockade caused by the aminoglycoside antibiotics (mycins), and tetracyclines.
2. Do not potentiate the effects of the halogenated hydrocarbon anesthetics (halothane et al).(Mechanism unclear).
3. Phase 1 block potentiated by anticholinesterases and antagonized by competitive blockers.
4. Phase 2 block antagonized by anticholinesterases and potentiated by competitive blockers.
5. Lithium in therapeutic concentrations used in the treatment of manic disorders can slow the onset and increase the duration of action of succinylcholine.
Neuromuscular Physiology
The neuromuscular junction consists of:
1. a motor nerve ending with mitochondria and acetylcholine vesicles(prejunctional)
2. a synaptic cleft of 20-30nm in width containing extracellular fluid .
3. a highly folded skeletal muscle membrane(post junctional)
4 .nicotinic cholinergic receptors located on both the presynaptis and postsynaptic membranes.
F. Pharmacokinetics
1. Succinylcholine is a structural analogue of ACh which is metabolized rapidly by plasma esterases. Thus it has an ultrashort duration of action. Some patients who have a prolonged response to the action of succinylcholine have a genetic deficiency in plasma cholinesterase. Procaine type local anesthetics are also metabolized by plasma cholinesterases, and will competitively inhibit the metabolism of succinylcholine, resulting in a prolonged duration of action.
2. Decamethonium is excreted directly by the kidney.
3. Because of their ionized structure, they are poorly absorbed orally, and are given i.v.
Mechanism of action of competitive neuromuscular blocking drugs.
At high doses: Nondepolarizing blockers can block the ion channels of the end plate. This leads to further weakening of neuromuscular transmission, and it reduces the ability of acetylcholinesterase inhibitors to reverse the actions of nondepolarizing muscle relaxants.
Actions: Not all muscles are equally sensitive to blockade by competitive blockers. Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers. Thereafter, the limbs, neck, and trunk muscles are paralyzed. Then the intercostal muscles are affected, and lastly, the diaphragm muscles are paralyzed. Those agents (for example, tubocurarine, mivacurium, and atracurium), which release histamine, can produce a fall in blood pressure, flushing, and bronchoconstriction.
Therapeutic uses: These blockers are used therapeutically as adjuvant drugs in anesthesia during surgery to relax skeletal muscle. These agents are also used to facilitate intubation as well as during orthopedic surgery.
Pharmacokinetics: All neuromuscular blocking agents are injected intravenously, because their uptake via oral absorption is minimal.
G. Toxicity
1. Prolonged apnea
2. Malignant hyperthermia can occur when patients are receiving halothane and succinylcholine. It is one of the main causes of death due to anesthesia.
a. In vitro tests are available to evaluate susceptibility to malignant hyperthermia and results in a prediction of susceptible, normal, or equivocal. Malignant hyperthermia is treated by rapid cooling, inhalation of O2, and treatment with Dantrolene. This drug blocks release of Ca++ from the sarcoplasmic reticulum and reduces muscle tone and heat production.
3. During prolonged depolarization, muscle cells may lose significant quantities of K+. In patients in whom there has been extensive injury to soft tissues the efflus of K+ following continued administration of succinylcholine can be life threatening due to hyperkalemia.
a. Administration of succinylcholine is contraindicated or very dangerous because of life threatening hyperkalemia in such conditions as burns, trauma, spinal cord injuries with paraplegia or quadriplegia, and muscular dystrophies. In these cases, competitive neuromuscular blockers should be used.
IV. Therapeutic Uses of Neuromuscular Blockers
A. Mainly as adjuvants to surgical anesthesia to cause muscle relaxation.
B. In orthopedics to facilitate correction of dislocations and alignment of fractures.
C. To facilitate endotracheal intubation
D. To prevent trauma in electroconvulsive shock therapy
E. In treatment of severe cases of tetanus
I. Ganglionic Neurotransmission
A. The primary event at autonomic ganglia is the rapid depolarization of postsynaptic Nn receptors by ACh. The duration of this event is on the order of milliseconds. This effect is blocked by hexamethonium.
B. The next event seen is the development of an IPSP which also lasts only milliseconds. The IPSP is blocked by both atropine, and by alpha adrenergic blockers. This evidence suggests that a preganglionic cholinergic nerve terminal in the ganglion acts on M2 receptors to activate a catecholaminergic interneuron (probably containing dopamine) which then synapses on the postganglionic neuron.
C. The next event is the development of the late EPSP. This event lasts on the order of 30-60 seconds. It is blocked by atropine and appears to be due to the activation of M1 receptors.
D. Finally one sees the late slow EPSP, which persists for several minutes. This appears to be due to the action of multiple peptides including VIP, SP, NPY, Enkephalin, etc.
E. It should be emphasized that the secondary events of ganglionic transmission modulate the primary depolarization, by making it more or less likely to occur. This is so because these secondary events either facilitate or inhibit the processes of spatial and temporal summation of subthreshold depolarizing stimuli. The relative importance of secondary pathways and receptors also appear to differ between different parasympathetic and sympathetic ganglia. Remember that conventional Nn receptor antagonists can inhibit ganglionic transmission completely, but muscarinic antagonists, alpha adrenergic antagonists, and peptidergic antagonists caot do so.
II. Ganglionic Stimulating Drugs
A. Nicotine is an alkaloid isolated from the leaves of tobacco, Nicotiana tabacum in 1828. Its pharmacological actions are complex and often unpredictable because 1) its effects are on both sympathetic and parasympathetic ganglia, and 2) because stimulation is frequently followed by depolarization blockade. The drug also can stimulate and desensitize receptors. The ultimate response of any one system thus represents the summation of several different and opposing effects of nicotine. For example, heart rate can be increased by excitation of sympathetic or inhibition of parasympathetic ganglia. Conversely, heart rate can be decreased by excitation of parasympathetic or inhibition of sympathetic ganglia. Nicotine also 1) stimulates release of Epi from the adrenal medulla, 2) excites cardiorespiratory reflexes by a direct effect on the chemoreceptors of the carotid and aortic bodies, 3) excites cardiovascular responses secondary to evoked blood pressure changes mediated by baroreceptors, and 4) stimulates and blocks CNS cholinergic pathways in the medulla influencing heart rate.
2. Nicotine also stimulates the nicotinic receptors of muscle (Nm), and this is followed rapidly by depolarization blockade.
3. Nicotine stimulates sensory receptors including mechanoreceptors, thermoreceptors, and pain receptors.
5. Nicotine is readily absorbed from the respiratory tract, oral membranes, and skin. Since nicotine is a strong base it is highly ionized in the stomach and hence poorly absorbed from the stomach. It is metabolized primarily in the liver, but also in the lung and kidney. Both nicotine and its metabolites are rapidly excreted by the kidney. Nicotine is excreted in the milk of lactating mothers who smoke.
6. Poisoning occurs from exposure to insecticides containing nicotine, or in children by accidental ingestion of tobacco products. Death may result within a few minutes from respiratory failure. For therapy, vomiting should be induced with syrup of ipecac, or gastric lavage performed. Activated charcoal is then passed into the stomach to bind free nicotine.
B. Other ganglionic stimulants
1. Tetramethyl ammonium (TMA) and dimethylphenyl piperazinium (DMPP) are also ganglionic stimulants. They differ from nicotine primarily in the fact that stimulation is not followed by ganglionic depolarization blockade.
III. Ganglionic blocking drugs
Ganglionic Blockers
Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some also block the ion channels of the autonomic ganglia. These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic receptor. Except for nicotine, the other drugs mentioned in this category are nondepolarizing, competitive antagonists. The responses observed are complex and unpredictable, making it impossible to achieve selective actions. Therefore, ganglionic blockade is rarely used therapeutically. However, ganglionic blockers often serve as tools in experimental pharmacology.
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A. The available ganglionic blockers in the U.S.A. are trimethaphan and mecamylamine. They are competitive antagonists. Trimethaphan has a positive charge, while mecamylamine does not, therefore trimethaphan is given intravenously and acts peripherally, while mecamylamine can be given orally, but crosses the blood-brain barrier. Trimethaphan is rapidly excreted in unchanged form by the kidney. Mecamylamine is excreted by kidney much more slowly. Other ganglionic blockers that you may hear about include hexamethonium and pentolinium, but they are no longer in clinical use in the U.S.
B. Pharmacological properties of ganglionic blockers can often be predicted by knowing which division of the ANS exerts dominant control of various organs ie
SITE PREDOMINANT TONE EFFECT OF GANGLIONIC BLOCKADE
|
Blood vessels |
Sympathetic |
Vasodilation, hypotension |
|
Sweat glands |
Sympathetic |
Anhidrosis |
|
Heart |
Parasympathetic |
Tachycardia |
|
Iris |
Parasympathetic |
Mydriasis |
|
GI tract |
Parasympathetic |
Reduced tone and motility |
|
Bladder |
Parasympathetic |
Urinary retention |
|
Salivary Gland |
Parasympathetic |
Xerostomia (reduced secretions) |
1. The importance of existing sympathetic tone in determining the extent to which blood pressure is reduced by ganglionic blockers is illustrated by the fact that they may have little or no effect when the patient is recumbent, but cause orthostatic hypotension when shifting to the standing state, because standing activates sympathetic reflexes to prevent pooling of blood in the feet. Since these reflexes are blocked postural hypotension is a major problem in ambulatory patients. In the old days, these compounds were in fact used for the treatment of hypertension, but they were abandoned as more selective treatment became available, which did not cause so many side effects. Some of the more severe side effects include marked hypotension, constipation, fainting, paralytic ileus, and urinary retention. For mecamylamine, which crosses the blood-brain barrier, large doses can cause tremors, mental confusion, seizures, mania or depression. The only remaining use of ganglionic blockers in hypertension is for the initial control of blood pressure in patients with acute dissecting aortic aneurysm. An additional use of these compounds is in the production of controlled hypotension during surgery in order to minimize hemmorhage in the operative field, and to facilitate surgery on blood vessels. Trimethaphan can be used in the treatment of autonomic hyperreflexia. This syndrome is commonly seen in patients with injuries of the spinal cord in whom minimal provocation (ie distended bladder) can elicit profound sympathoadrenal discharge.
Adrenergic receptor-activating drugs. Adrenergic receptor-blocking drugs. Sympatholytic agents
The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic. Others block the action of the neurotransmitters at the receptors (sympatholytics), whereas still other drugs affect adrenergic function by interrupting the release of norepinephrine from adrenergic neurons.
The Adrenergic Neuron
Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and also in the sympathetic nervous system, where they serve as links between ganglia and the effector organs. The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs.
A. Neurotransmission at adrenergic neurons
Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons, except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission takes place at numerous bead-like enlargements called varicosities. The process involves five steps:synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap.
Synthesis and release of norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.)
- Synthesis of norepinephrine: Tyrosine is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.1 This is the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron.
- Storage of norepinephrine in vesicles: Dopamine is then trans-ported into synaptic vesicles by an amine transporter system that is also involved in the reuptake of preformed norepinephrine. This carrier system is blocked by reserpine. Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase. [Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate (ATP), and β-hydroxylase, as well as other cotransmitters.] In the adrenal medulla, norepinephrine is methylated to yield epinephrine, both of which are stored in chromaffin cells. On stimulation, the adrenal medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation.
- Release of norepinephrine: An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse.
- Binding to a receptor: Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system,2 and the phosphatidylinositol cycle,3 to transduce the signal into an effect.
- Removal of norepinephrine: Norepinephrine may 1) diffuse out of the synaptic space and enter the general circulation, 2) be metabolized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-methyltransferase (COMT) in the synaptic space, or 3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium/potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (see Figure 6.3). Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine’s effects.
Potential fates of recaptured norepinephrine: Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present ieuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine.
B. Adrenergic receptors (adrenoceptors)
In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, designated α and β, were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. The use of specific blocking drugs and the cloning of genes have revealed the molecular identities of a number of receptor subtypes. These proteins belong to a multigene family. Alterations in the primary structure of the receptors influence their affinity for various agents.
α1 and α2 Receptors: The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine (Figure 6.4). For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol. The α-adrenoceptors are subdivided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs. For example, the α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. Conversely, the drug clonidine selectively binds to α2 receptors and has less effect on α1 receptors.
α1 Receptors: These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects—originally designated as α-adrenergic—involving constriction of smooth muscle. Activation of α1 receptors initiates a series of reactions through a G protein activation of phospholipase C, resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell.
α2 Receptors: These receptors, located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released norepinephrine traverses the synaptic cleft and interacts with the α1 receptors. A portion of the released norepinephrine “circles back” and reacts with α2 receptors on the neuronal membrane (see Figure 6.5). The stimulation of the α2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron. This inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity. [Note: In this instance these receptors are acting as inhibitory autoreceptors.] α2 Receptors are also found on presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting acetylcholine release [Note: In these instances these receptors are behaving as inhibitory heteroreceptors.] This is another local modulating mechanism to control autonomic activity in a given area. In contrast to α1 receptors, the effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP.
Further subdivisions: The α1 and α2 receptors are further divided into α1A, α1B, α1C, and α1D and into α2A, α2B, α2C, and α2D. This extended classification is necessary for understanding the selectivity of some drugs. For example, tamsulosin is a selective α1A antagonist that is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland.
Summary of adrenergic agonists. Agents marked with an asterisk (*) are catecholamines.
ALPHA AND BETA ADRENERGIC RECEPTOR AGONISTS
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.
Classification of adrenergic receptor agonists:
II. Pharmacology of Epinephrine A. Epinephrine is a potent stimulator of both alpha (1 & 2) and beta (1,2, & 3) 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 Beta 2 and alpha receptors are also present in the heart. As indicated before, EPI has a powerful chronotropic and inotropic effect. EPI reduces the time for systole and makes it more powerful without decreasing the duration of diastole. The latter effect occurs because EPI also increases the rate of relaxation of ventricular muscle. Cardiac output is enhanced and the work of the heart and its oxygen consumption are markedly increased. Cardiac efficiency (work done relative to oxygen consumption) is lessened! 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. Large doses of EPI, or long term elevation of plasma catecholamines damages the myocardium. This may in part explain the beneficial effects of beta blockers in heart failure.
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 trigone and 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.
4. EPI promotes a fall in plasma K due to enhanced uptake of K into skeletal muscle via an action on Beta 2 receptors. This action has been exploited in the management of hyperkalemia.
G. Absorption and fate of EPI
1. Absorption of EPI as well as other catecholamines from GI tract is negligible due to rapid conjugation and oxidation in the intestinal mucosa of the 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. The liver which is rich in both COMT and MAO destroys most circulating EPI.
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 (i.e. because there is no opposing Beta 2 mediated vasodilation). 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. Since the effects of NE are mainly on alpha and Beta 1 receptors, indirectly acting sympathomimetics which act by releasing NE have predominantly alpha mediated and cardiac effects.
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 severe congestive heart failure, particularly in patients with oliguria or impaired renal function. DA is also useful in the treatment of cardiogenic and septic shock in patients with reduced renal function.
C. DA Agonists
1. Fenoldopam is a rapidly acting vasodilator which is used for acute control of severe hypertension. It is a D1 receptor agonist as well as an alpha 2 agonist. It does not effect alpha 1 or beta receptors. The half life of fenoldopam is 10 minutes.
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 mechanisms 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. Like other inotropic agents, dobutamine may potentially increase the size of a myocardial infarct by increasing oxygen demand.
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. Formoterol is a selective Beta 2 agonist with similarities to the above agents, however it has the advantages a rapid onset of action (minutes) and a long duration (12 hours).
D. Salmeterol is another long acting Beta 2 agonist however it has a slow onset of action, therefore it is not useful for acute asthmatic attacks. It may also have anti-inflammatory activity.
D. 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. Nifedepine ( a calcium channel blocker: NOT a beta 2 blocker) caused longer postponement of delivery, fewer maternal side effects, and fewer admissions to the neonatal intensive care unit.
E. 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 glucocorticoids.
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.
C. Midodrine1. It is an orally effective alpha 1 agonist which is a prodrug. Its activity is due to metabolism to desglymidodrine. Sometimes used in patients with autonomic insufficiency and postural 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. Clonidine also stimulates parasympathetic outflow and causes slowing of the heart.
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.
d. Apraclonidine and Brimonidine are structural analogues of clonidine (ie alpha 2 agonists) which are used topically in the treatment of glaucoma by decreasing the rate of synthesis of aqueous humor. Brimonidine also acts by enhancing the outflow of aqueous humor. Its efficacy in reducing intraocular pressure is equivalent to timolol.
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. As such it has potent peripheral effects on alpha 1 & 2 receptors, and Beta 1, but not beta 2 receptors. It is also a potent CNS stimulant which is orally effective.
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. The behavioral effects of amphetamine depend both on the dose and the mental state or personality of the individual. Prolonged use or high doses are nearly always followed by depression and fatigue. Tolerance develops to the appetite suppressant effects rapidly. 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, including vivid hallucination and paranoid delusions, which are often mistaken for schizophrenia is the most common serious effect, and 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. It has a high potential for abuse. It is used principally for its central effects which are more pronounced than amphetamine. 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
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 cardiac effects
1. Phenylephrine and methoxamine used in PAT by causing a reflex bradycardia.
2. Epinephrine used in emergency treatment of cardiac arrest.
3. DA is useful in the treatment of cardiogenic or septicemic shock especially in patients with compromised renal function.
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
G. Nasal decongestion
Adrenoblockers, Sympatholytics agents
All beta-blockers (BBs) except esmolol and sotalol are approved for treatment of hypertension and one or more of following indications: angina pectoris, myocardial Infarction, ventricular arrhythmia, migraine prophylaxis, heart failure and perioperative hypertension.
Only sotalol delays ventricular repolarization and is effective for maintenance of sinus rhythm in patients with chronic atrial fibrilation. Esmolol has short half-life and is given for hypertensive (perioperative) urgency and for atrial arrhythmias after cardiac surgery.
Beta-blockers act by blocking the action of catecholamines at adrenergic receptors throughout the circulatory system and other organs. BBs major effect is to slow the heart rate and reduce force of contraction. BBs via inhibition of receptors at justaglomerular cells inhibit renin release.
Beta-blockers may be classified based on their ancillary pharmacological properties. Cardioselective agents have high affinity for cardiac β 1 and less affinity for bronchial and vascular β2 receptors compared with non-selective agents and this reduces (but does not abolish) β 2 receptor-mediated side effects. However, with increasing doses cardiac selectivity disappears. Lipid-soluble agents cross the blood-brain barrier more readily and are associated with a higher incidence of central side effects.
Some beta-blockers have intrinsic sympathomimetic activity – ISA (i.e., they stimulate β receptors when background sympathetic nervous activity is low and block them when background sympathetic nervous activity is high). Therefore, theoretically BBs with ISA are less likely to cause bradycardia, bronchospasm, peripheral vasoconstriction, to reduce cardiac output, and to increase lipids. BBs with ISA are less frequently used in the treatment of hypertension.
|
Beta Blocker |
Relative Cardiac Selectivity |
Intrinsic Sympathomimetic Activity |
Daily Dosing Frequency |
Lipid Solubility |
b1 + a1 |
|
Acebutolol SECTRAL |
++ |
+ |
2 |
Moderate |
– |
|
Atenolol TENORMIN |
++ |
– |
1 |
Low |
– |
|
Betaxolol KERIONE |
++ |
– |
1 |
Low |
– |
|
Bisoprolol ZEBETA |
++ |
– |
1 |
Low |
– |
|
Carteolol CARTROL |
– |
++ |
1 |
Low |
– |
|
Carvedilol COREG |
– |
– |
2 |
High |
+ |
|
Esmolol BREVIBLOC |
+ |
– |
i.v. |
Moderate |
– |
|
Labetalol TRANDATE NORMODYNE |
– |
– |
2 |
Moderate |
+ |
|
Metoprolol LOPRESSOR |
+ |
– |
1 or 2 |
Mod. / High |
– |
|
Nadolol CORGARD |
– |
– |
1 |
Low |
– |
|
Penbutol LEVATOL |
– |
+ |
1 |
High |
– |
|
Pindolol VISKEN |
|
+++ |
2 |
Moderate |
– |
|
Propranolol INDERAL |
– |
– |
2 |
High |
– |
|
Timolol BLOCADREN |
– |
– |
2 |
Low / Mod. |
– |
Lipophilic beta blockers may enter CNS more extensively and readily which may lead to increased CNS side effects. Labetalol and carvedilol have both β1– and α1-blocking properties, and decrease heart rate and peripheral vascular resistance. Both agents possess the side effects common for both classes of drug. Beta-blockers tend to be less effective in the elderly and in black hypertensives. To reduce side effects in hypertensive patients it is recommended to use a beta-blocker with high cardioselectivity, low lipid solubility and long half-life that allows once daily dosing.
Adverse effects: BBs slow the rate of conduction at the atrio-ventricular node and are contraindicated in patients with second- and third-degree heart block. Sinus bradycardia is common and treatment should be stopped if patient is symptomatic or heart rate falls below 40 b/min. Because of blockade of pulmonary ß2 receptors, even small doses of BBs can cause bronchospasm (less common with cardioselective agents), and all beta-blockers are contraindicated in asthma. Blockade of ß receptors in the peripheral circulation causes vasoconstriction and may induce particularly in patients with peripheral circulatory insufficiency adverse affects such as cold extremities, Raynaud’s phenomenon, and intermittent claudication. Nevertheless, they are reasonably tolerated in patient with mild peripheral vascular disease. Lipid-soluble agents can cause central nervous system side effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced by BBs and patients may experience tiredness and fatigue. BBs can worsen glucose intolerance and hyperlipidemia and in diabetic patients mask signs of hypoglycemia. However, diabetic hypertensive patients with previous MI should not be denied BB because of concerns about metabolic side effects.
Alpha-1 adrenergic receptor blockers ( …. OSIN )
Prazosin [MINIPRESS] Terazosin [HYTRIN] Doxazosin [CARDURA]
Alfuzosin [UROXATRAL] Tamsulosin [FLOMAX]
The β1-adrenoceptor blockers produce vasodilatation by blocking the action of norepinephrine at post-synaptic β1 receptors in arteries and veins. This results in a fall in peripheral resistance, without a compensatory rise in cardiac output. Doxazosin, terazosin, and, less commonly, prazosin are used as oral agents in the treatment of hypertension. They are relatively more selective for a1b – and a1d-receptors which are involved in vascular smooth muscle contraction. Alfuzosin and tamsulosin are used for symptomatic treatment of begin prostatic hyperplasia (BPH), since compared to other oral α1-blockers, they have less antihypertensive effects and are relatively more selective as antagonists at the α1a subtype, the primary subtype located in the prostate.
Based on ALLHAT study data, alpha blockers are not longer considered first-line drug for treatment of hypertension. They are drugs of choice for treatment of hypertensive patient with BPH. Adverse effects include first dose hypotension, dizziness, lethargy, fatigue, palpitation, syncope, peripheral edema and incontinence.
Adverse Reactions: The adverse effects of beta-blockers are generally mild and temporary; they usually occur at the onset of therapy and diminish over time. Most adverse reactions of beta-blockers are extensions of their therapeutic effects. Bradycardia and hypotension are rarely serious and can be reversed with IV atropine, if necessary. AV block, secondary to depressed conduction at the AV node, might necessitate sympathomimetic and/or pressor therapy or the use of a temporary pacemaker. Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of beta-blocker therapy.
Adverse CNS effects include dizziness, fatigue, and depression. Although much less common with hydrophilic beta-blockers, CNS depression can occur, resulting in mental disorders, fatigue, and, in some cases, vivid dreams. Diarrhea and nausea/vomiting are the most common GI adverse effects during therapy with beta-blockers. Bronchospasm and dyspnea are more likely to occur with nonselective beta-blockers or with high doses of cardioselective agents because the beta selectivity of the drug is lost. Patients with preexisting bronchospastic disease are at greater risk.
Both hypoglycemia and hyperglycemia can occur during beta-blocker therapy. Beta-blockers can interfere with glycogenolysis to cause hyperglycemia and can also mask signs of hypoglycemia. Beta-blockers should be used cautiously in brittle diabetics.
beta-blockers have little effect on total cholesterol and plasma LDLs, but have been shown to increase triglycerides and decrease plasma HDLs. The role that the characteristics of cardioselectivity and intrinsic sympathomimetic activity of beta-blockers play in these effects are more controversial. In a recent meta-analysis, it was shown that agents with intrinsic sympathomimetic activity or cardioselectivity tend to have less effect on triglycerides and HDLs. Agents with both characteristics tended to reduce total cholesterol and LDLs.
Adverse reactions from ophthalmic beta-blockers are usually limited to their ocular effects, such as transient burning, stinging, and blurred vision however, these preparations can be absorbed causing systemic adverse reactions, similar to oral or parenteral beta-blockers. Ophthalmic betaxolol appears to cause less systemic effects compared to ophthalmic timolol and levobunolol.
Comparison of agonists, antagonists, and partial agonists of β adrenoceptors.
Despite the current knowledge of the diversity and function of beta-receptors within the human body, much remains to be learned about some of their regulatory roles in physiologic homeostasis. Although the variety of beta-receptor antagonists that are currently available is plentiful, the pharmacologic uses for beta-receptor antagonists is likely to continue to grow.
1. http://www.youtube.com/watch?v=797WAV3kZhQ&playnext=1&list=PL83879046C561EB07&index=5
2. http://www.youtube.com/watch?v=fPzjU6YRsf4&feature=related
3. http://www.youtube.com/watch?v=TaAvhG2SInM&playnext=1&list=PLE304A951086EE624&index=50
4. http://www.apchute.com/moa.htm
5. http://www.youtube.com/watch?v=ejq99wLEMTw&playnext=1&list=PL4DE83C6B1D56C4E4&index=5
