Cholinergic Drugs. Anticholinergic Agents
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. 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. [3]
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. [4]
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.[citatioeeded]
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 teratogenic 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 been noted 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.
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.
Muscarinic receptor antagonists
Muscarinic receptor antagonists, called previously parasympatholytic and now muscarinic, cholinolytic, antimuscarinic, atropinic drugs, inhibit the muscarinic effects of acetylcholine. The drugs of this group are atropine, scopolamine and their derivatives.
Atropine
Atropine is an alkaloid extracted of the leaves of a shrub called Atropa belladonna, which acts primarily at the peripheral level.
Action on the autonomic nervous system
Atropine is a competitive inhibitor of acetylcholine muscarinic receptors. Its action results in a decrease of the parasympathetic tonus, so that the influence of the sympathetic nerve becomes dominating.
Cardiovascular action
1. Cardiac action: atropine effect results primarily in modifications of the heart rate:
o in very low dose, it can give a slight cardiac slowing attributed to a central vagal stimulation and to peripheral parasympathetic effect leading to a transient increase of acetylcholine release.
o in therapeutic dose there is generally cardiac acceleration by reduction of vagal tone, and suppression of reflex bradycardia during arterial hypertension.
2. Vascular action:, atropine does not have vascular effects since there is no parasympathetic tonus on the vessels but it inhibits vasodilation caused by an intravenous injection of acetylcholine.
3. Action on the arterial pressure:
o in therapeutic dose, atropine does not induce modifications of arterial pressure in spite of incresed cardiac rate.
o in very high or toxic dose, it induces a fall of the arterial pressure by depression of the vasomotor centers and cutaneous vasodilation, perhaps secondary to an histamine release.
Eye Action
Atropine inhibits parasympathetic influence on the eye, which results in:
- passive pupil dilation or mydriasis and increase of the diameter of the iris.
- tendency to elevation of intraocular pressure by increase in the diameter of the iris which, in patients predisposed to narrow-angle glaucoma, obstructs evacuation of aqueous humor by the Schlemm channel . Atropine is thus contraindicated in these patients.
- Accommodation paralysis or cycloplegia, disturbing vision .
After local administration in the form of ophthalmic solution, atropine effects last very long: dilation of the pupil can persist several days.
Action on smooth muscles
Acetylcholine contracts smooth muscles except vascular muscles and atropine has an antispasmodic action by inhibiting this acetylcholine effect.
On the digestive tract, atropine decreases tone, amplitude and frequency of the peristaltic contractions; it decreases hypertonicity produced by morphine, which justifies its combination to morphine in the treatment of colic pain.
On isolated intestine, atropine gives a reduction of tonus and peristalsis, prevents and inhibits contracture elicited by acetylcholine.
Antispasmodic action of atropine is also exerted on biliary tract, bronchi, urinary routes: ureters and bladder. Urographies showed that atropine dilates ureters.
The bladder receives sympathetic and parasympathetic innervation. The sympathetic nerve tends to dilat the bladder and constrict its internal sphincter. The parasympathetic, on the contrary, constricts bladder and relaxes the internal sphincter. The suppression of the influence of the parasympathetic by atropine gives an increase in the tone of the internal sphincter and a dilation of the bladder, which can induce urinary retention, especially in case of prostate hypertrophy.
Atropine practically has no action on uterus.
Action on secretions
Atropine reduces the majority of secretions:
- Digestive: inhibition of salivary secretion results in a feeling of thirst, of dryness of the mouth. The reduction of gastric secretion explains why atropine was used in therapeuticsas a gastric antisecretory. It hardly modifies pancreatic secretioor biliary.
- Bronchial: bronchial secretion is reduced.
- Cutaneous: it inhibits sudation, which gives a dry and hot skin. It is necessary to be wary about its use when ambient temperature is high or in patients with fever, because the inhibition of sudation increases temperature, particularly in infants, with the risk of provoking hyperthermia.
- Lacrimal secretion is reduced, lacteous secretion during lactation is little or not modified.
Action on central nervous system
In therapeutic doses, in human beings, atropine has only little or no action on the central nervous system, sometimes a respiratory stimulation.
Atropine was for a long time the only drug to have some efficacy in Parkinson’s disease. In animals, it inhibits tremors elicited by cholinomimetic agents such as oxotremorine.
Atropine and scopolamine, lower the cerebral acetylcholine concentration in animal experiments: the inhibition of acetylcholine receptors elicited causes an exaggerated release of acetylcholine, which is hydrolysed by cholinesterases.
In high dose, the stimulant action of atropine appears with restlessness, ataxia, and +++++ , hyperthermia, dizziness, visual and memory disturbances, hallucinations, delusion. This picture can evoke an acute schizophrenic episode or an alcoholic delirium. However, in severe intoxication, a CNS depression and a respiratory arrest can occur.
Metabolism
Atropine is quickly absorbed by digestive route and one resorts to its administration by parenteral route only when one wants to obtain a very fast effect, for example in the treatment of colic pain. Its plasma half-life is of approximately four hours.
Part of atropine administered in the form of ophthalmic solution is likely to diffuse into the general circulation.
It crosses the placental barrier and traces can be found in various secretions, of which breast milk.
The duration of action of atropine administered by general route would be of approximately six hours.
Therapeutic use
Atropine has several therapeutic uses:
In administration by general route
1. Treatment of painful syndromes with spasmodic component, i.e. involving an exaggerated contraction of smooth muscles, such as biliary and renal colic pain.
2. In anesthesiology: prevention of respiratory tract secretion, bronchospasm, laryngospasm and reflexe reactions such as bradycardia, before surgical operations.
3. Treatment of poisonings:
by cardiac glycosides, to increase lowered cardiac rate
o by anticholinesterase agents and mushrooms of Amanita muscarina type, to reduce muscarinic symptoms. In poisonings by anticholinesterase agents such as organophosphorus compounds, atropine is administered in large doses in combination with pralidoxime.
Atropine is not used any more as a gastric antisecretory. After being used as a gastric antisecretory in the treatment of ulcer, atropine was replaced by a more specific muscarinic receptor antagonist of gastric secretion, pirenzepine which, itself, was withdrawn from the market because much more active products, acting by different mechanisms, were marketed.
Atropine and scopolamine were the first drugs used in the treatment of Parkinson’s disease but they have been replaced by other muscarinic receptor antagonists such as trihexyphenidyl and, benztropine, and especially by L-dopa which has a different mechanism of action.
In local administration: ophthalmic solution
Atropine is a powerful mydriatic with a very long duration of action, now generally replaced by tropicamide
Adverse effects and contraindications
The principal adverse effects of atropine are a dry mouth, constipation, dryness of skin, tachycardia, mydriasis.
The contraindications are primarily glaucoma, because atropine raises intraocular pressure in patients with narrow angle, and prostate hypertrophy (difficulty in micturition and risk of urine retention ).
Scopolamine, also called hyoscine, has a chemical structure very close to that of atropine. Its peripheral effects are similar to those of atropine, but its central effects differ: it has a sedative and tranquillizing action, it induces sleep, reinforces the action of hypnotics and tranquilizers and has an amnestic effect. However in patients who experience strong pains, it can have an exciting effect and elicit hallucinations.
Scopolamine is used by injectable route as an antispasmodic in certain acute pains with spasmogenic component of digestive or gynaecological localization and in the treatment of agonic rails by obstruction of the higher air routes by excess of salivary secretion.
By percutaneous route it is primarily used as an antiemetic agent in the prevention of motion sickness. It should be noted that scopolamine was marketed a long time in France under the name of Buscopan , proprietary name always used in many countries. It is exceptional that all properties of atropine are simultaneously useful in the same patient and effort has been made to obtain compounds having a greater specificity of action and particular pharmacokinetic features. Their adverse effects and their contraindications are however quite similar to those of atropine.
Mydriatic agents
Tropicamide is a muscarinic receptor antagonist used as a mydriatic.
Tropicamide is different from atropine by its shorter duration of action which is approximately 1 hour and half. The effect appears in 10 minutes, is maximum in 15 or 20 minutes. The pupil finds its normal diameter in approximately 6 hours.
Cyclopentolate is presented in the form of an ophthalmic solution with mydriatic effect of shorter duration than atropine.
Gastric acid secretion inhibitors
Numerous muscarinic receptor antagonists, including pirenzepine which has a quite specific action on the stomach, have been used in the management of peptic ulcer disease. Pirenzepine was withdrawn from the market after the introduction in therapeutics of H2antihistamines and proton pump inhibitors which are more effective and better tolerated.
Bronchodilatators
The two muscarinic receptor antagonists used as bronchodilatators are oxitropium and ipratropium.
They are given by pulmonary route, in the form of aerosol, in the preventive and curative treatment of asthma. Their efficacy is however lower than that of beta-mimetics.
The advantage of these products compared to atropine result from a pharmacokinetic particularity: as they involve a quaternary ammonium in their chemical formula, they are only little or not absorbed by bronchi and thus have a predominantly local effect.
There is also a preparation for nasal use for rhinorrhea treatment.
Tiotropium, anticholinergic of long duration of action, used in inhalation, is released on the market in Switzerland and Belgium but not in France.
With vesical indications
Tolterodine is a cholinergic antagonist whose effect on the bladder prevails. It is used in the treatment of vesical instability with symptoms of pressing micturition or incontinence.
Oxybutynine, which is a muscarinic receptor antagonist and has direct effects on smooth muscles, is proposed for the treatment of urinary incontinence of adults and could be used in the treatment of infantile enuresis.
Trospium, an anticholinergic known for a long time, involving a quaternary ammonium group in its structure, was the subject of recent studies in urinary disorders.
Used as antispasmodics
Muscarinic receptor antagonists have antispasmodic properties, but all the antispasmodic agents are not necessarily muscarinic receptor antagonists. The antispasmodic effect of some of them results from a direct effect on smooth muscle, often by calcium-channel antagonism.
Muscarinic receptor antagonists used as antispasmodics are, in addition to atropine itself, dihexyverine, prifinium and propantheline.
Among antispasmodic drugs having at the same time a muscarinic receptor antagonist effect and a direct effect on smooth muscles one can quote tiemonium., although its effect on smooth muscle activity predominates over its muscarinic receptor antagonist activity
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.
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.
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
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 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.
Ganglionic blocking drugs
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
