04Anatomical and physiological peculiarities of autonomic nervous system. indirect acting cholinergic stimulants. cholinesterase reactivators

CHOLINERGIC DRUGS. ANTICHOLINERGIC AGENTS

 

Anatomical and physiological peculiarities of autonomic nervous system

Langley originally defined the autonomic nervous system (s/a ANS) as consisting as nerve cells and fibers by which efferent impulses pass to tissues other than skeletal muscle. So ANS is motor system controlling visceral organs for homeostasis. There is a sensory component of ANS. Sensory nerves innervating viscera are part of ANS. Sensory components establish reflex loops for smooth control of ANS (ex. baro and chemoreceptor reflexes).

Baroreceptor Reflex In bifurcation of common carotid artery, there is a region of thinning of common carotid (this region pulses when you squeeze it) that is richly innervated by autonomic fibers from petrosal ganglion at neck. When blood pressure goes up, these sensory nerves activate. This is a bipolar neuron: one pole -> in carotid sinus and other pole in dorsal medulla. Brain processes information and send efferent impulse to heart slowing heart and reducing contractility letting blood pressure go down. If heart go down too much, sympathetic reflex speeds it up. Chemoreceptor Of Carotid Body They sense O2 levels in blood. CO2 levels go up. CO2 go to dorsal medial medulla. Brain tells lung to breathe fast.

 

Baroreceptor And Chemoreceptor Reflexes

Baroreceptor reflex maintains blood pressure iarrow range. Chemoreceptor reflex maintain O2 levels.

ANS – Afferent and efferent components that mediate reflex loops.

ANS Functions

1. Secretion of gland.

2. Actions of many smooth muscles.

3. Extrinsic control of heart.

4. Variety of metabolic processes including release of catecholamines, glucagon, insulin, and others.

Two Divisions Of ANS

1. Sympathetic

2. Parasympathetic

Anatomic Distinction Of Sympathetic And Parasympathetic

Depends on position of ganglia.

Parasympathetic neurons are in brain (medulla) and sacral spinal cord.

Sympathetic neurons are in the thoracolumbar spinal cord.

ANS – All autonomic preganglionic neurons make synapses with clusters of neurons called ganglia. Spinal Cord And The Sympathetic System – The spinal cord has grey matter and white matter. The spinal cord has the intermedial lateral cell column which has the origin of sympathetic preganglionic neurons which send axons through ventral root where they synapse on a ganglion. The ganglionic neurons send out postganglionic neuron to target cell (i.e. a visceral organ like the heart). The ganglion are found in a chain of ganglion that is close to spinal cord in paravertebral ganglionic chain. Sympathetic system has short preganglionics and long post ganglionic axons.

Diffusion Effect Of The Sympathetic System

The nervous system

When this axon comes out spinal cord, it goes up and down the chain to synapse on adjacent ganglion so have diffusion effect so one preganglionic neuron can stimulate neuron in multiple ganglion. Have collateralization of terminals in ganglion so one can stimulate many ganglia giving global discharge of sympathetic system -> this is useful for fight or flight.

Brain And The Parasympathetic Nervous System

Long presynaptic acetylcholine fiber comes off of brain. Short postsynaptic with nicotinic receptor goes to target organ. So the preganglionic neuron is long and the postganglionic neuron is short. The postganglionic neuron is usually on surface of innervated organ.

Discrete Effect Of The Parasympathetic Nervous System

Activity of parasympathetic nervous system give discrete activation of specific organ (not a global effect). Ganglia not only relay stations, but serve as integrated areas. Have multiple ganglia on heart (not just one). Different ganglia control aspects of cardiac function through different pathways: one controls cardiac rate, one controls AV conduction, and one controls myocardial contractility. Efferent ANS This includes the sympathetic and parasympathetic systems. Sensory Component Of ANS Major sensory neurons are found in the dorsal root ganglia. They are not as well understood as efferent component. They utilize different neurotransmitter.

Neurotransmitter Of ANS

With respect to preganglionic neuron (be it parasympathetic or sympathetic), it will release acetylcholine (s/a Ach) and the receptor effected is nicotinic. In sympathetic nervous system, postganglionic neuron has norepinephrine and receptor that is activated depends on target system ( and receptors). In heart, have receptor. In parasympathetic nervous system, parasympathetic postganglionic releases acetylcholine as does its preganglionics. This acetylcholine of the postganglionic influences a muscarinic receptor.

ANS

It regulates activities not considered under voluntary control and function below the level of consciousness. Examples of these activities are respiration, circulation, digestion, body temperature, metabolism, sweating, and secretion of certain endocrine glands.

Sympathetics And Parasympathetics Acting As Physiological Antagonists

ANS maintain constant internal environment to maintain homeostasis. In most cases, sympathetics and parasympathetics act as physiological antagonist. (Heart: Sympathetic accelerate cardiac rate. Parasympathetic diminishes cardiac rate). (Eye: Sympathetics open pupil. Parasympathetics close pupil). Most viscera innervated by both divisions of ANS. Level of activity in any given organ represent effect of activation of parasympathetics and sympathetics effects on organ. Physiological antagonist effect may occur by action on same cell. In heart and intestine, sympathetics and parasympathetics act on same effector cell for antagonist response. In eye, sympathetics act by controlling radial muscle of eye. If contract radial muscle pupil get larger.

Parasympathetics affect different muscle (sphincter muscle). If contract sphincter muscles pupil get smaller. Sympathetics And Parasympathetics Acting In Tandem Parasympathetics gives copious watery salivary secretion. Sympathetic activation gives thick viscous secretion.

Cases Where Parasympathetics And Sympathetics Don’t Innervate An Organ

Both parasympathetic and sympathetic don’t innervate an organ (i.e. blood vessels just get sympathetic activation -> no antagonism is possible).

 

Physiological Characteristics Of Sympathetic Nervous System

Sympathetic nervous system is on continuously (i.e. basal tone). It varies minute to minute and from organ to organ. Sympathoadrenal system often acts as a unit to facilitate fight or flight. Activation of sympathetic nervous system increases blood pressure, increases heart rate, blood goes to skeletal muscle, blood vessel dilate, pupils dilate, and bronchioles dilate. In a controlled environment and in the absence of stress, sympathetics not needed for life. In chemosympathonectomy (using drugs to destroy sympathetic system), animals do just fine.

 

Parasympathetic

It is organized for discrete activation of localized target organ. Its main function is conservation of energy and maintenance of organ function during periods of normal activity. See decrease in heart rate, blood pressure, enhanced GI mobility and secretion, emptying of bladder, and constriction of pupils.

 

Video-1

  Synaptic Сleft

The neurotransmitter diffuse down synaptic cleft where they interact with post or pre synaptic receptors.

      

 

Ways Of Stopping Neurotransmitter

When transmitter released, to stop process, neurotransmitter can diffuse away in blood stream (get lower concentration of neurotransmitter) or can have metabolic enzyme process (i.e. acetylcholinesterase metabolize Ach).

In case of NorEp, there is an active transport system that brings NorEp back into the cytoplasm of the nerve terminal and there is an active transport system that takes NorEp back into synaptic vesicle.

 

 

Neuropeptides

These peptides are degraded by peptidases. No reuptake. Demonstrated they are found in vesicles.

Mechanism Of Action Of Drugs That Influence ANS

1. Drug can interfere with synthesis of the neurotransmitter. (hemicholinium, methyl paratyrosine)

For example, on cholinergic side, hemicholinium interferes with synthesis of Ach. Precursor for biosynthesis of catecholamines is tyrosine (later on it is dopamine). Use structural analog of tyrosine -> methyl para tyrosine -> inhibit biosynthesis of catecholamines on adrenergic side.

2. Metabolic transformation by same pathway of precursor of the neurotransmitter.

(methyl DOPA)

The biosynthetic enzyme of catecholamine aren’t substrate specific. So on adrenergic side, methyl DOPA (not DOPA) can be metabolized to methyl dopamine and methyl norepinephrine. Methyl norepinephrine gets released due to action potential, but don’t have same activity of endogenous neurotransmitter. So false transmitter blocked effect of sympathetic nervous system.

3. Blockade of neurouptake  (cocaine, tricyclic antidepressants, reserpine)

NorEp gets reuptaken -> drugs can block reuptake. Cocaine blocks NorEp uptake. Tricyclic antidepressant drugs block reuptake of the neurotransmitter.

Active transport process take NorEp from synaptic cleft to cytoplasm. Active transport take NorEp from cytoplasm to synaptic vesicle -> reserpine blocks that active transport process.

4. Other drugs cause release of content at nerve terminal.

(black widow toxin, amphetamine)   Black widow toxin has cholinergicomimetic effect via release of Ach. Amphetamine is sympathomimetic -> effect by release of catecholamines.

5. Other drugs block release of neurotransmitter. (botulinum toxin, bretylium) Botulinum toxin prevents release of Ach. Drug called bretylium blocks release of NorEp.

6. Lots of drugs mimic effect of endogenous neurotransmitter postsynaptically.

(muscarine, nicotine, phenylepinephrine, clonidine, isoproterenol) On cholinergic side, muscarine mimics muscarinic effects of Ach. Nicotine mimics nicotinic effects of Ach.

On adrenergic side, variety of receptor types: and . 1 receptor activation is mimicked by drug called phenylepinephrine. 2 receptor activation is mimicked by clonidine. Isoproterenol mimics either receptor.

7. You can also block effect of neurotransmitter postsynaptically. (atropine, curare, trimethaphan, phenoxybenzamine, propranolol) Muscarinic effects of Ach blocked by atropine. Nicotinic effects of Ach on skeletal muscle blocked by curare. Nicotinic effects at ganglia blocked by trimethaphan. On adrenergic side, receptor blocked by phenoxybenzamine. receptors blocked by propranolol (a nonspecific blocker).

8. Inhibition of enzymatic degradation  (anticholinesterase drugs, monamine oxidase inhibitors)  On cholinergic side, have anticholinesterase drugs.  On adrenergic side, monoamine oxidase inhibitors. 

Responses of Effector Organs to Autonomic Nerve Impulses

ORGAN SYSTEM SYMPATHETIC EFFECTa   ADRENERGIC RECEPTOR TYPEb   PARASYMPATHETIC EFFECTa   CHOLINERGIC RECEPTOR TYPEb   Eye            Radial muscle, iris Contraction (mydriasis)++ 1         Sphincter muscle, iris     Contraction (miosis)+++ M3, M2     Ciliary muscle Relaxation for far vision+   2   Contraction for near vision+++ M3, M2     Lacrimal glands Secretion+ Secretion+++ M3, M2   Heartc            Sinoatrial node Increase in heart rate++ 1 > 2   Decrease in heart rate+++ M2 >> M3     Atria Increase in contractility and conduction velocity++ 1 > 2   Decrease in contractility++ and shortened AP duration M2 >> M3     Atrioventricular node Increase in automaticity and conduction velocity++ 1 > 2   Decrease in conduction velocity; AV block+++ M2 >> M3     His–Purkinje system Increase in automaticity and conduction velocity 1 > 2   Little effect M2 >> M3     Ventricle Increase in contractility, conduction velocity, automaticity and rate of idioventricular pacemakers+++ 1 > 2   Slight decrease in contractility M2 >> M3   Blood vessels            (Arteries and arterioles)d            Coronary Constriction+; dilatione++  1, 2; 2   No innervationh  —   Skin and mucosa Constriction+++ 1, 2   No innervationh  —   Skeletal muscle Constriction; dilatione,f++  1; 2   Dilationh (?)  —   Cerebral Constriction (slight) 1   No innervationh  —   Pulmonary Constriction+; dilation 1; 2   No innervationh  —   Abdominal viscera Constriction +++; dilation + 1; 2   No innervationh  —   Salivary glands Constriction+++ 1, 2   Dilationh++  M3     Renal Constriction++; dilation++ 1, 2; 1, 2   No innervationh      (Veins)d  Constriction; dilation 1, 2; 2       Endothelium      Activation of NO synthaseh  M3   Lung            Tracheal and bronchial smooth muscle Relaxation 2   Contraction M2 = M3     Bronchial glands Decreased secretion, increased secretion 1   Stimulation M3, M2   2   Stomach            Motility and tone Decrease (usually)i+  1, 2, 1, 2   Increasei+++  M2 = M3     Sphincters Contraction (usually)+ 1   Relaxation (usually)+ M3, M2     Secretion Inhibition 2   Stimulation++ M3, M2   Intestine            Motility and tone Decreaseh+  1, 2, 1, 2   Increasei+++  M3, M2     Sphincters Contraction+ 1   Relaxation (usually)+ M3, M2     Secretion Inhibition 2   Stimulation++ M3, M2   Gallbladder and ducts  Relaxation+ 2   Contraction+ M Kidney            Renin secretion Decrease+; increase++ 1; 1   No innervation — Urinary bladder            Detrusor Relaxation+ 2   Contraction+++ M3 > M2     Trigone and sphincter Contraction++ 1   Relaxation++ M3 > M2   Ureter            Motility and tone Increase 1   Increase (?) M Uterus  Pregnant contraction; 1       Relaxation 2   Variablej  M Nonpregnant relaxation 2       Sex organs, male  Ejaculation+++ 1   Erection+++ M3   Skin            Pilomotor muscles Contraction++ 1         Sweat glands Localized secretionk++  1       Generalized secretion+++     M3, M2   Spleen capsule  Contraction+++ 1   — — Relaxation+ 2   —   Adrenal medulla  —       Secretion of epinephrine and norepinephrine     N (3)2(4)3; M (secondarily)   Skeletal muscle  Increased contractility; glycogenolysis; K+ uptake   2   — — Liver  Glycogenolysis and gluconeogenesis+++ 1, 2   — — Pancreas          Acini Decreased secretion+   Secretion++   M3, M2     Islets ( cells) Decreased secretion+++   2   —   Increased secretion+   2       Fat cellsl  Lipolysis+++; (thermogenesis) 1, 1, 2, 3   — — Inhibition of lipolysis 2   Salivary glands  K+ and water secretion+   1   K+ and water secretion+++   M3, M2   Nasopharyngeal glands  —   Secretion++ M3, M2   Pineal glands  Melanton synthesis —   Posterior pituitary   Antidiuretic secretion 1   —   Autonomic nerve endings            Sympathetic terminals             Autoreceptor Inhibition of NE release 2A > 2C (2B)           Heteroreceptor —   Inhibition of NE release M2, M4     Parasympathetic terminal —           Autoreceptor     Inhibition of ACh release M2, M4       Heteroreceptor Inhibition ACh release 2A > 2C

 

 

Indirect acting cholinergic stimulants. Cholinesterase reactivators

Since acetylcholine is inactivated by cholinesterases, inhibition of cholinesrerases leads to a rise in acetylcholine concentration. If this rise remains moderate, it can have beneficial effects but if is too high it causes toxic effects. Cholinesterase inhibitors, also called anticholinesterase agents, are schematically classified, according to their intensity and duration of action and consequently of their toxicity, into reversible and irreversible inhibitors. In human beings, inhibition of cholinesterases induces, by accumulation of acetylcholine, muscarinic and nicotinic effects. These effects are predominately central or peripheral according to whether the inhibitor penetrates or not into the brain. Inhibition of cholinesterases of insects is a way to obtain their destruction.

Reversible inhibitors

The reversible inhibtors, which inhibit enzyme in a transitory way, as long as their concentration is sufficient, are used in therapeutics and, for the majority of them, are known for a long time.

Physostigmine or eserine

 

Calabar Bean (Physostigma venenosum)

Physostigmine, also callad eserine, alkaloid obtained from calabar bean, gives primarily muscarinic effects and crosses the blood-brain barrier. It increases the gastric and intestinal peristalsis and induces bronchoconstriction and contraction of ureters. It increases bronchial and digestive secretions (gastric, intestinal, salivary), as well as lacrimal secretion. Its cardiovascular action is complex but, in general, it has a muscarinic action: bradycardia and decrease of the force of cardiac contractions. Eserine elicits miosis, spasm of accommodation, fall of intraocular pressure, hyperemia of conjunctiva and lacrymation.  Generally, it stimulates neuromuscular transmission, what results in muscle fasciculations. In addition to its indirect action by inhibition of cholinesterases, it could directly stimulate neuromuscular nicotinic receptors. It does not have an action on the uterus.  Eserine is indicated in treatment of paralytic ileus, intestinal atonicity, glaucoma, myasthenia, post-anesthetic long-lasting curarization. It was tested in the treatment of Alzheimer’s disease using transdermal preparations which make possible to obtain relatively stable plasma concentrations.  The multiplicity of effects of eserine is often a disadvantage in therapeutics where only an effect is generally sought.

Neostigmine

Pharmacology

By interfering with the breakdown of acetylcholine, neostigmine indirectly stimulates both nicotinic and muscarinic receptors. Unlike physostigmine, neostigmine has a quaternary nitrogen; hence, it is more polar and does not enter the CNS. Its effect on skeletal muscle is greater than that of physostigmine. Neostigmine has moderate duration of action, usually two to four hours.^[3] Neostigmine binds to the anionic site of cholinesterase. The drug blocks the active site of acetylcholinesterase so the enzyme cao longer break down the acetylcholine molecules before they reach the postsynaptic membrane receptors. This allows for the threshold to be reached so a new impulse can be triggered in the next neuron. In myasthenia gravis there are too few acetylcholine receptors so with the acetylcholinesterase blocked, acetylcholine can bind to the few receptors and trigger a muscular contraction.

Clinical uses

It is used to improve muscle tone in people with myasthenia gravis and routinely in anesthesia to reverse the effects of non-depolarizing muscle relaxants such as rocuronium and vecuronium at the end of an operation, usually in a dose of 25 to 50 mcg per kilogram.It can also be used for urinary retention resulting from general anesthesia and to treat curariform drug toxicity.Another indication for use is the Ogilvie syndrome which is a pseudoobstruction of the colon in critically ill patients.Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration of neostigmine can provoke menstrual bleeding. Modern tests which rely on detecting hCG in urine have rendered this application obsolete.Though one of only two treatments available for myasthenia gravis, this drug is no longer available to anyone using the Medicare Part D program.

Side effects

Neostigmine can induce generic ocular side effects including: headache, brow pain, blurred vision, phacodonesis, pericorneal injection, congestive iritis, various allergic reactions, and rarely, retinal detachment.^[4]Neostigmine will cause slowing of the heart rate (bradycardia); for this reason it is usually given along with a parasympatholytic drug such as atropine or glycopyrrolate. Gastrointestial symptoms occur earliest after ingestion and include anorexia, nausea, vomiting, abdominal cramps, and diarrhea.^[Neostigmine, better tolerated than eserine, acts less on eye, cardiovascular system and central nervous system, but it is more active on digestive tract and bladder.  Neostigmine is used in the treatment of the postoperative atonicity (intestine, bladder), and of myasthenia in high dose combined or not with atropine. It accelerates decurarization as an indirect antidote of competitive neuromuscular inhibitors.

Pyridostigmine

Pyridostigmine has pharmacological properties close to those of neostigmine, with perhaps a more progressive and more durable action. It is used in the treatment of intestinal atonicity and myasthenia.

Clinical uses

Pyridostigmine is used to treat muscle weakness in people with myasthenia gravis and to combat the effects of curariform drug toxicity. Pyridostigmine bromide has been FDA approved for military use during combat situations as an agent to be given prior to exposure to the nerve agent Soman in order to increase survival. Used in particular during the first Gulf War, pyridostigmine bromide has been implicated as a causal factor in Gulf War syndrome.^[2]Pyridostigmine sometimes is used to treat orthostatic hypotension.^[3] It may also be of benefit in chronic axonal polyneuropathy. ^[4]It is also being prescribed ‘off-label’ for the postural tachycardia syndrome^[5][6]Pyridostigmine bromide is available under the trade names Mestinon (Valeant Pharmaceuticals) and Regonol.Pyrostigmine bromide is contraindicated in cases of mechanical intestinal or urinary obstruction and should be used with caution in patients with bronchial asthma

Clinical use

Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer’s disease. Studies found that it may have a small beneficial effect on cognition and other clinical measures, though study data was limited and the clinical relevance of these findings was unclear.^[1][2]Newer cholinesterase inhibitors, such as donepezil, are now preferred over tacrine.^{[citation needed]}

Overdosage/toxicity

As stated above, overdosage of tacrine may give rise to severe side effects such as nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Tertiary anticholinergics, such as atropine, may be antidotes for overdose.Major form of metabolism is in the liver via hydroxylation of benzylic carbon by Cytochrome P450 (CYP450). This forms the major metabolite 1-hydroxy-tacrine (velnacrine) which is still active.^{[citation needed]}

Galantamine

Galantamine, also written galanthamine, is a product known for about fifty years. Recent studies showed that it could have an interest in the treatment of Alzheimer’s disease. It is metabolized by cytochromes CYP 2d6 and CYP3A4 and interactions with drugs inhibiting these cytochromes were described.

 

Notice

Huperzine is an alkaloid of vegetable origin, known for many years, which inhibits cholinesterases reversibly and penetrates into the brain. It was proposed as a dietary supplement of vegetable origin intended to reduce memory disorders.

 

Galantamine (Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine) is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of vascular origin. It is an alkaloid that is obtained synthetically or from the bulbs and flowers of Galanthus caucasicus (Caucasian snowdrop, Voronov’s snowdrop), Galanthus woronowii (Amaryllidaceae) and related genera like Narcissus (daffodil)),^[1] Leucojum (snowflake), and Lycoris including Lycoris radiata (Red Spider Lily).

Studies of usage in modern medicine began in the Soviet Union in the 1950s. The active ingredient was extracted, identified, and studied, in particular in relation to its acetylcholinesterase (AChE)-inhibiting properties. The bulk of the work was carried out by Soviet pharmacologists Mashkovsky and Kruglikova-Lvova, beginning in 1951.^[2] The work of Mashkovsky and Kruglikova-Lvova was the first published work that demonstrated the AChE-inhibiting properties of galantamine.^[3]

The first industrial process was developed in Bulgaria by prof. Paskov in 1959 (Nivalin, Sopharma) from a species traditionally used as a popular medicine in Eastern Europe, and, thus, the idea for developing a medicine from these species seems to be based on the local use (i.e., an ethnobotany-driven drug discovery).^[4][5] Galantamine has been used for decades in Eastern Europe and Russia for various indications such as treatment of myasthenia, myopathy, and sensory and motor dysfunction associated with disorders of the central nervous system. In the US, it is FDA approved for the treatment of Alzheimer’s disease.It is available in both a prescription form and as an over the counter supplement.Galantamine in its pure form is a white powder. Galantamine is a competitive and reversible cholinesterase inhibitor. It reduces the action of AChE and therefore tends to increase the concentration of acetylcholine in the brain. It is hypothesized that this action might relieve some of the symptoms of Alzheimer’s. It is also an allosteric ligand at nicotinic acetylcholine receptors.The atomic resolution 3D structure of the complex of galantamine and its target, acetylcholinesterase, was determined by X-ray crystallography in 1999 (PDB code: 1DX6; see complex).^[6] There is no evidence that galantamine alters the course of the underlying dementing process.^[7] Galantamine has also shown activity in modulating the nicotinic cholinergic receptors on cholinergic neurons to increase acetylcholine release.^[8]

Pharmacokinetics

Absorption of galantamine is rapid and complete and shows linear pharmacokinetics. It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a half-life of seven hours. Peak effect of inhibiting acetylcholinesterase was achieved about one hour after a single oral dose of 8 mg in some healthy volunteers.

Plasma protein binding of galantamine is about 18%, which is relatively low.

 Metabolism

Approximately 75% of a dose of galantamine is metabolised in the liver. In vitro studies have shown that Hepatic CYP2D6 and CYP3A4 are involved in galantamine metabolism.For Razadyne ER (the once-a-day formulation), CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers. About 7% of the population has this genetic mutation; however, because the drug is individually titrated to tolerability, no specific dosage adjustment is necessary for this population.

Indications

Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimer’s.^[9][10]

Available forms

The product is supplied in both a prescription form as well as an over the counter supplement. in twice-a-day tablets, in once-a-day extended-release capsules, and in oral solution. The tablets come in 4 mg, 8 mg, and 12 mg forms. The capsules come in 8 mg, 16 mg, and 24 mg forms.

Adverse events

In clinical trials, galantamine’s side effect profile was very similar to that of other cholinesterase inhibitors, with gastrointestinal symptoms being the most notable and most commonly observed. In practice, some other cholinesterase inhibitors might be better tolerated; however, a careful and gradual titration over more than three months may lead to equivalent long-term tolerability.^[11]

Irreversible inhibitors

Irreversible inhibitors of cholinesterases, while being fixed at enzymes by covalent bonds, inhibit them irreversibly. In fact they are mainly organophosphorus compounds which, because of their toxicity, are only exceptionally used in therapeutics. One of the least toxic among more than 50 000 derivatives which were prepared, diisopropyle fluorophosphate or D.F.P., was tested in treatment of myasthenia, paralytic ileus and of glaucoma as an ophthalmic solution. It was at the origin of poisonings and is not released on the market any more. The sulfur organophosphorus compound ecothiopate, was used in therapeutics in the form of an ophthalmic solution, in the treatment of glaucoma. It has very long action and its use has to be very spaced (once-daily to twice a week). Malathion is the active product of certain preparations intended for the treatment of lice of the scalp (lice). When it is applied strictly to the hair, the scalp being intact, one does not observe general effects.

Metrifonate and dichlorvos are organophosphorus compound inhibitors of cholinesterases, having antihelminthic activity against Schistosoma mansoni and haematobium. In the body metrifonate is partly converted to dichlorvos which is considered as the active product. Irreversible inhibitors of cholinesterases are largely used in agriculture as insecticides and some of them, because of their very great toxicity, were retained as chemical warfare agents, also called nerve gases. Other derivatives such as formathion, diethion, malathion and diazinon are very much used as insecticides. Generally, the substitution of the phosphorus atom by a fluorine atom or a cyanide group increases toxicity and one obtains compounds such as tabun, sarin and soman classified as nerve gas.

Anticholinesterase poisoning

The symptoms of poisoning by organophosphorus compounds depend on the conditions of poisoning and more particularly on its severity.

Between latent forms, detected by cholinesterases determination, and forms quickly fatal, there are many intermediate forms. The following symptomatology is generally observed:

• muscarinic signs: miosis, nausea, salivation, vomiting, diarrhea, sweats, bradycardia, bronchial obstruction.

• nicotinic signs, neuromuscular (twitchings, fasciculations, cramps, paralysis in the case of severe poisoning) and cardiac (tachycardia, rise in arterial pressure).

• central signs :headache, drowsiness, disorientation, coma or generalized convulsions.

In severe forms where the disorders appear very quickly, death, preceded by a loss of consciousness and seizures, comes from a respiratory arrest by central inhibition and paralysis of the neuromuscular transmission phrenic nerve/diaphragm. The bronchial hypersecretion worsens moreover the respiratory failure. Persistence of various neuropsychiatric disorders a long time after an acute poisoning or following a chronic poisoning by irreversible anticholinesterases is possible. Treatment of poisoning by anticholinesterases consists of discontinuation of the poison, administration of atropine and possibly of pralidoxime, a cholinesterase reactivator.

• Atropine which inhibits muscarinic effects is administered by parenteral route in doses higher than in its usual indications (1 mg possibly renewed)

• Pralidoxime, which reactivates inhibited cholinesterases, is administered by parenteral route, generally intravenous, at renewable dose of 0,5 g in adult. It acts by detaching the phosphate group of the inhibitors from the esterasic site. It should be noticed that in animal experiments, pralidoxime in large dose can partially inhibit cholinesterases and may cause transient neuromuscular blockade. Thus, it should not be administered as an antidote in too high doses. Obidoxime is another reactivator of cholinesterases

• Recent data show that, during severe poisonings by organophosphorus compounds, the stimulation of acetylcholine receptors by acetylcholine which accumulates induces glutamate release which makes sodium and calcium enter the cell inducing cellular damage. The use of antagonists of glutamate can thus be considered.

Agents acting M-cholinoreceptors

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 a naturally occurring tropane alkaloid extracted from deadly nightshade (Atropa belladonna), Jimson weed (Datura stramonium), mandrake (Mandragora officinarum) and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects.In general, atropine counters the “rest and digest” activity of all muscles and glands regulated by the parasympathetic nervous system.

This occurs because atropine is a competitive antagonist of the muscarinic acetylcholine receptors (acetylcholine being the main neurotransmitter used by the parasympathetic nervous system). Atropine dilates the pupils, increases heart rate, and reduces salivation and other secretions.Atropine is a core medicine in the World Health Organization‘s “Essential Drugs List“, which is a list of minimum medical needs for a basic health care system. The species name “belladonna” (“beautiful woman” in Italian) comes from the original use of deadly nightshade to dilate the pupils of the eyes for cosmetic effect. Both atropine and the genus name for deadly nightshade derive from Atropos, one of the three Fates who, according to Greek mythology, chose how a person was to die.

Physiological effects and uses

It is a competitive antagonist for the muscarinic acetylcholine receptor types M1, M2, M3, M4 and M5.^[2] It is classified as an anticholinergic drug (parasympatholytic).

Working as a nonselective muscarinic acetylcholinergic antagonist, atropine increases firing of the sinoatrial node (SA) and conduction through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions.

Ophthalmic use

Topical atropine is used as a cycloplegic, to temporarily paralyze the accommodation reflex, and as a mydriatic, to dilate the pupils. Atropine degrades slowly, typically wearing off in 7 to 14 days, so it is generally used as a therapeutic mydriatic, whereas tropicamide (a shorter-acting cholinergic antagonist) or phenylephrine (an α-adrenergic agonist) is preferred as an aid to ophthalmic examination. Atropine induces mydriasis by blocking contraction of the circular pupillary sphincter muscle, which is normally stimulated by acetylcholine release, thereby allowing the radial pupillary dilator muscle to contract and dilate the pupil. Atropine induces cycloplegia by paralyzing the ciliary muscles, whose action inhibits accommodation to allow accurate refraction in children, helps to relieve pain associated with iridocyclitis, and treats ciliary block (malignant) glaucoma. Atropine is contraindicated in patients pre-disposed to narrow angle glaucoma. Atropine can be given to patients who have direct globe trauma.

Resuscitation

Injections of atropine are used in the treatment of bradycardia (an extremely low heart rate). Atropine blocks the action of the vagus nerve, a part of the parasympathetic system of the heart whose main action is to decrease heart rate. Therefore, its primary function in this circumstance is to increase the heart rate. Atropine was previously included in international resuscitation guidelines for use in cardiac arrest associated with asystole and PEA, but was removed from these guidelines in 2010 due to a lack of evidence.^[3] For symptomatic bradycardia, the usual dosage is 0.5 to 1 mg IV push, may repeat every 3 to 5 minutes up to a total dose of 3 mg (maximum 0.04 mg/kg).^[4]

Atropine is also useful in treating second-degree heart block Mobitz Type 1 (Wenckebach block), and also third-degree heart block with a high Purkinje or AV-nodal escape rhythm. It is usually not effective in second-degree heart block Mobitz type 2, and in third-degree heart block with a low Purkinje or ventricular escape rhythm.One of the main actions of the parasympathetic nervous system is to stimulate the M₂ muscarinic receptor in the heart, but atropine inhibits this action.

Secretions and bronchoconstriction

Atropine’s actions on the parasympathetic nervous system inhibit salivary and mucus glands. The drug may also inhibit sweating via the sympathetic nervous system. This can be useful in treating hyperhidrosis, and can prevent the death rattle of dying patients. Even though atropine has not been officially indicated for either of these purposes by the FDA, it has been used by physicians for these purposes.^[5]

Treatment for organophosphate poisoning

Atropine is not an actual antidote for organophosphate poisoning. However, by blocking the action of acetylcholine at muscarinic receptors, atropine also serves as a treatment for poisoning by organophosphate insecticides and nerve gases, such as tabun (GA), sarin (GB), soman (GD) and VX. Troops who are likely to be attacked with chemical weapons often carry autoinjectors with atropine and obidoxime, for rapid injection into the muscles of the thigh. Atropine is often used in conjunction with pralidoxime chloride.

Atropine is given as a treatment for SLUDGE syndrome (salivation, lacrimation, urination, diaphoresis, gastrointestinal motility, emesis) symptoms caused by organophosphate poisoning. Another mnemonic is DUMBBELSS, which stands for diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (as of muscle in the form of fasciculations and CNS), lacrimation, salivation, and sweating (only sympathetic innervation using Musc receptors).

Some of the nerve agents attack and destroy acetylcholinesterase by phosphorylation, so the action of acetylcholine becomes prolonged, pralidoxime (2-PAM) is the cure for organophosphate poisoning because it can cleave this phosphorylation. Atropine can be used to reduce the effect of the poisoning by blocking muscarinic acetylcholine receptors, which would otherwise be overstimulated by excessive acetylcholine accumulation.

Optical penalization

In refractive and accommodative amblyopia, when occlusion is not appropriate sometimes atropine is given to induce blur in the good eye.^[6]

Side-effects and overdose

Adverse reactions to atropine include ventricular fibrillation, supraventricular or ventricular tachycardia, dizziness, nausea, blurred vision, loss of balance, dilated pupils, photophobia, dry mouth and potentially extreme confusion, dissociative hallucinations and excitation especially amongst the elderly. These latter effects are because atropine is able to cross the blood–brain barrier. Because of the hallucinogenic properties, some have used the drug recreationally, though this is potentially dangerous and often unpleasant.In overdoses, atropine is poisonous. Atropine is sometimes added to potentially addictive drugs, particularly anti-diarrhea opioid drugs such as diphenoxylate or difenoxin, wherein the secretion-reducing effects of the atropine can also aid the anti-diarrhea effects.Although atropine treats bradycardia (slow heart rate) in emergency settings, it can cause paradoxical heart rate slowing when given at very low doses, presumably as a result of central action in the CNS.^[7]Atropine is incapacitating at doses of 10 to 20 mg per person. Its LD₅₀ is estimated to be 453 mg per person (per oral) with a probit slope of 1.8.^[8] The antidote to atropine is physostigmine or pilocarpine. A common mnemonic used to describe the physiologic manifestations of atropine overdose is: “hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter”.^[9] These associations reflect the specific changes of warm, dry skin from decreased sweating, blurry vision, decreased sweating/lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type 4 and 5. This set of symptoms is known as anticholinergic toxidrome, and may also be caused by other drugs with anticholinergic effects, such as scopolamine, diphenhydramine, phenothiazine antipsychotics and benztropine.^[10]

Chemistry and pharmacology

Atropine is a racemic mixture of d–hyoscyamine and l-hyoscyamine, with most of its physiological effects due to l-hyoscyamine. Its pharmacological effects are due to binding to muscarinic acetylcholine receptors. It is an antimuscarinic agent. Significant levels are achieved in the CNS within 30 minutes to 1 hour and disappears rapidly from the blood with a half-life of 2 hours. About 60% is excreted unchanged in the urine, most of the rest appears in urine as hydrolysis and conjugation products. Effects on the iris and ciliary muscle may persist for longer than 72 hours.The most common atropine compound used in medicine is atropine sulfate (monohydrate) (C₁₇H₂₃NO₃)₂·H₂SO₄·H₂O, the full chemical name is 1α H, 5α H-Tropan-3-α ol (±)-tropate(ester), sulfate monohydrate.The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells comprising the sinoatrial (SA) and atrioventricular (AV) nodes. Muscarinic receptors are coupled to the Gi-protein; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells.

Increases in vagal activity to the SA node decreases the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential (phase 4 of the action potential); this decreases heart rate (negative chronotropy). The change in phase 4 slope results from alterations in potassium and calcium currents, as well as the slow-inward sodium current that is thought to be responsible for the pacemaker current (If). By hyperpolarizing the cells, vagal activation increases the cell’s threshold for firing, which contributes to the reduction in the firing rate. Similar electrophysiological effects also occur at the AV node; however, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node (negative dromotropy). In the resting state, there is a large degree of vagal tone on the heart, which is responsible for low resting heart rates.There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and even smaller decreases in ventricular contractility.Muscarinic receptor antagonists bind to muscarinic receptors thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate and conduction velocity.

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.

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.

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:

o    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.

Scopolamine, also known as levo-duboisine and hyoscine, sold as Scopoderm, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from solanaceae (nightshade) family of plants, such as henbane, jimson weed (datura), Angel’s Trumpets (brugmansia), and corkwood (duboisia).^[2][3] Scopolamine exerts its effects by acting as a competitive antagonist at muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic, anti-muscarinic drug. (See the article on the parasympathetic nervous system for details of this physiology). Although scopolamine is a dangerous drug, its anticholinergic properties give it some legitimate medical applications in very minute doses. As an example, in the treatment of motion sickness, the dose, gradually released from a transdermal patch, is only 330 micrograms (µg) per day. In rare cases, unusual reactions to ordinary doses of scopolamine have occurred including confusion, agitation, rambling speech, hallucinations, paranoid behaviors, and delusions.Scopolamine is named after the plant genus Scopolia.^[3] The name “hyoscine” is from the scientific name for henbane, Hyoscyamus niger.^[4]

Methods of administration

Scopolamine can be administered orally, subcutaneously, ophthalmically and intravenously, as well as via a transdermal patch.^[7] The transdermal patch (e.g., Transderm Scōp) for prevention of nausea and motion sickness employs scopolamine base, and is effective for up to 3 days.^[8] The oral, ophthalmic and intravenous forms have shorter half-lives and are usually found in the form scopolamine hydrobromide (for example in Scopace, soluble 0.4 mg tablets or Donnatal). NASA is currently developing a nasal administration method. With a precise dosage, the NASA spray formulation has been shown to work faster and more reliably than the oral form.^[9]

Medical use

Scopolamine has a number of uses in medicine:

• Primary Uses:

• Its primary use is for the treatment of post-operative nausea and vomiting, sea-sickness, leading to use by scuba divers.^[10][11]

• Treatment of intestinal cramping.

• For ophthalmic purposes.

• As a general depressant and adjunct to narcotic painkillers.

• Secondary Uses:

• As a preanesthetic agent.

• As a drying agent for sinuses, lungs, and related areas. In otolaryngology it is used to dry the upper airway (anti-sialogogue action) prior to instrumentation of the airway.

• To reduce motility and secretions in the GI tract—most frequently in tinctures or other belladonna or stramonium preparations, often used in conjunction with other drugs as in Donnagel original forumulation, Donnagel-PG (with paregoric), Donnabarb/Barbadonna/Donnatal (with phenobarbital), and a number of others.

• Uncommonly, for some forms of Parkinsonism.

• As an adjunct to opioid analgesia, such as the proprietary fixed-ratio product Twilight Sleep and the technique after which it was named which contained morphine and scopolamine, Scophedal (oxycodone, ephedrine & scopolamine), some of the original formulations of Percodan and some European brands of methadone injection.^{[citation needed]}

• As an over-the-counter sedative, (Up until November 1990 scopolamine in minute doses could be purchased OTC in the United States). It can be used as a depressant of the central nervous system, and was formerly used as a bedtime sedative.

Scopolamine is an ingredient of Schlesinger’s Analgesic Solution, invented in the first decade of the previous century for use as a general-purpose analgesic as well as drops for painful eye conditions and an antitussive. The combination, as given in the 1913 US Pharmacopoeia and other national formularies, is 15 mg dionine hydrochloride, 10 mg morphine sulphate, and 125 µg scopolamine hydrobromide per cc. Some sources give the recipe as ¹/₄ grain dionine, ¹/₆ grain morphine, and ~²⁹/₈₁₀ grain of scopolamine; in some cases the salts of morphine and dionine may differ.

Nausea

Its use as an antiemetic in the form of an transdermal patch (applied behind the external ear).

Ophthalmic

The drug is used in eye drops to induce mydriasis (pupillary dilation) and cycloplegia (paralysis of the eye focusing muscle), primarily in the treatment of eye disorders that benefit from its prolonged effect, e.g. uveitis, iritis, iridocyclitis, etc.

Memory research

Because of its anticholinergic effects, scopolamine has been shown to prevent the activation of medial temporal lobe structures for novel stimuli during spatial memory tasks. It has also been shown to impair memory in humans to mimic the cognitive deficits found in Alzheimer’s Dementia.

Other medical uses

• Scopolamine is used as an adjunct anesthetic in trauma surgery. Light anesthesia is required to keep the patient hemodynamically stable, and this increases risk of awareness. Scopolamine decreases awareness and recall.

• Scopolamine has been tested as a topical treatment for Aquagenic pruritus and was shown in several cases to be effective.^[12]

• The drug has been reported as used by astronauts including those on Skylab for the treatment of motion sickness ^[13][14]

• Transdermal scopolamine patches are sometimes used to help control excessive saliva and drooling in patients with ALS ^[15]

• Scopolamine is also used for mild sedation and saliva management in end-of-life care as an adjunct to other comfort medications.^[16]

• In October 2006, researchers at the US National Institute of Mental Health found that scopolamine reduced symptoms of depression within a few days, and the improvement lasted for at least a week after switching to a placebo.^[17]

• Intravenously administered scopolamine has been found to be effective^[18] against major depressive disorder. A phase II clinical trial^[19] of its efficacy against both major depressive disorder and depression due to bipolar disorder when administered via transdermal patches was scheduled to finish in September 2013, until it was terminated.

Addiction

Scopolamine has historically been used in the past to treat addiction to drugs such as heroin and cocaine. The patient was given frequent doses of scopolamine until they were delirious. This treatment was maintained for 2 to 3 days after which they were treated with pilocarpine. After recovering from this they were said to have lost the acute craving for the drug to which they were addicted.^[20]

Currently, scopolamine is being investigated for its possible usefulness alone or in conjunction with other drugs in treating nicotine addiction.^{[citatioeeded]} The mechanism by which it mitigates withdrawal symptoms is different from that of clonidine meaning that the two drugs can be used together without duplicating or canceling out the effects of each other.^{[citatioeeded]}

Adverse effects

The common side effects are related to the anticholinergic effect on parasympathetic postsynaptic receptors: dry mouth, throat and nasal passages in overdose cases progressing to impaired speech, thirst, blurred vision and sensitivity to light, constipation, difficulty urinating and tachycardia. Other effects of overdose include flushing and fever, as well as excitement, restlessness, hallucinations, or delirium. These side effects are commonly observed with oral or parenteral uses of the drug and generally not with topical ophthalmic use.

Use in scuba diving to prevent sea sickness has led to the discovery of another side effect. In deep water, below 50–60 feet, some divers have reported pain in the eyes that subsides quickly if the diver ascends to a depth of 40 feet or less.^{[citatioeeded]} Mydriatics can precipitate an attack of glaucoma in susceptible patients, so the medication should be used with extra caution among divers who intend to go below 50 feet.^{[citatioeeded]}

Drug interactions

When combined with morphine, scopolamine is useful for pre-medication for surgery or diagnostic procedures and was widely used in obstetrics in the past; the mixture also produces amnesia and a tranquillised state known as Twilight Sleep, also the name of a proprietary drug available in the past in ampoules of injectable fluid containing morphine sulfate and scopolamine hydrobromide (and in some cases the phenothiazine anti-nauseants prochlorperazine or promethazine as a third ingredient). Although originally used in obstetrics, it is now considered dangerous for that purpose for both mother and baby.^{[citatioeeded]}

Recreational use

While it is occasionally used recreationally for its hallucinogenic properties, the experiences are often extremely mentally and physically unpleasant, and frequently physically dangerous, so repeated use is rare.

Another separate group of users prefer dangerously high doses, especially in the form of datura preparations, for the deliriant and hallucinogenic effects. The hallucinations produced by scopolamine, in common with other potent anticholinergics, are especially real-seeming, with many users reporting hallucinations such as spiders crawling on walls and ceilings, especially in the dark. While some users find this pleasant, often the experience is not one that the user would want to repeat. An overdose of scopolamine is also exceedingly unpleasant physically, and can be fatal, unlike the effect of other more commonly used hallucinogens. For these reasons, naturally occurring anticholinergics are rarely used for recreational purposes.

Scopolamine in transdermal, oral, sublingual, and injectable formulations can produce a cholinergic rebound effect when high doses are stopped. This is the opposite of scopolamine’s therapeutic effects: sweating, runny nose, abdominal cramps, nausea, vomiting, vertigo, dizziness, irritability, and diarrhea. Psychological dependence is also possible when the drug is taken for its tranquilizing effects.^]

    

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

 

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). A comparison follows:

Receptor-type	Location	Effect	Nicotinic agonists	Nicotinic antagonists
Muscle-type: (α1)2β1δε or (α1)2β1δγ	Neuromuscular junction	EPSP, mainly by increased Na+ and K+ permeability	·         acetylcholine ·         carbachol ·         suxamethonium	·         α-bungarotoxin ·         α-conotoxin ·         tubocurarine ·         pancuronium ·         atracurium*
Ganglion-type: (α3)2(β4)3	autonomic ganglia	EPSP, mainly by increased Na+ and K+ permeability	·         acetylcholine ·         carbachol ·         nicotine ·         epibatidine ·         dimethylphenylpiperazinium	·         mecamylamine ·         trimetaphan ·         hexamethonium ·         bupropion ·         ibogaine ·         18-methoxycoronaridine ·         Dextromethorphan
Heteromeric CNS-type: (α4)2(β2)3	Brain	Post- and presynaptic excitation , mainly by increased Na+ and K+ permeability	·         nicotine ·         epibatidine ·         acetylcholine ·         cytisine ·         varenicline	·         mecamylamine ·         methylcaconitine ·         α-conotoxin ·         Dextromethorphan
Further CNS-type: (α3)2(β4)3	Brain	Post- and presynaptic excitation	·         nicotine ·         epibatidine ·         acetylcholine ·         cytisine	·         hexamethonium ·         mecamylamine ·         tubocurarine ·         Dextromethorphan
Homomeric CNS-type: (α7)5	Brain	Post- and presynaptic excitation, mainly by increased Ca2+ permeability	·         epibatidine ·         dimethylphenylpiperazinium ·         varenicline	·         mecamylamine ·         memantine ·         amantadine ·         α-bungarotoxin ·         Dextromethorphan

Nicotine increases both sympathetic and parasympathetic tone, and its effects change with duration of exposure. This makes the ultimate effect of nicotine on each organ system rather difficult to predict. Through the autonomic ganglia, both parasympathetic and sympathetic pathways are stimulated by nicotine. Parasympathtic effects include decreased heart rate, bronchoconstriction, and increased GI motility while sympathetic stimulation leads to vasoconstriction, increased heart rate, bronchodilation, and decreased GI motility. The adrenal gland also has nicotinic cholinergic innervation, functioning like a post-ganglionic sympathetic nerve to release epinephrine and norepinephrine. Nicotine thus stimulates release of these sympathetic neurotransmitters. Prolonged exposure to nicotine results initially in stimulation of transmission, followed by a form of depolarization blockade that can result in inhibition of transmission, and is similar to cholinergic blockers such as succylcholine. In depolarizing block, the receptors are unable to faciliate ion flow and are inactivated. The predominant effects of nicotine also depend on the dominant autonomic tone, reflexes to the CNS to oppose primary stimulation, and on the frequency and time interval of nicotine absorption.

Site	Predominant Tone	Most Common Effect of Nicotine
Arterioles	Sympathetic	Vasoconstriction, hypertension
Veins	Sympathetic	Vasoconstriction, increased venous return
Heart	Parasympathetic	Tachycardia
GI Tract	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. 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, and may have application in the treatment of other drug addictions such as addiction to amphetamines, cocaine^[ or alcohol.^[

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. and an antagonist at μ-opioid receptors.

Lobelin (lobelinum)

 

LOBELIN (Lobelinum).

Alkaloid contained in the plant Lobelia inflata, herewith. kolokolchikovyh (Campanulaceae). Optically active. Rasemat lobelina receive synthetic means. In clinical practice using lobelina hydrochloride (Lobelini hydrochloridum). l-1- benzoilmetil-6- Methyl 2 – (2-hydroxy yl) – piperidine hydrochloride. Synonyms : Lobesil, Antisol, Atmulatin, Bantron, Lobatox, Lobeline, Lobelinum hydrochloricum, Lobesilum, Lobeton, Lobidan and others. The white crystalline powder bitter taste, and odourless. It is soluble in water (1:100), is soluble in alcohol (1:10). Provides specific stimulation of the nerve of the vegetative nervous system and karotidnye klubochki (see also Ganglioblokiruyuschie drugs), accompanied by the excitation of respiratory and other centres suffering brain. Stirring while wandering psyche, lobelin is slowing heartbeat and lowering blood pressure. Later, blood pressure may rise slightly from narrowing vessels due to the drug to excite sympathetic nerve, and adrenal glands. In high doses lobelin brings emetic center, is deeply respiratory depression, convulsions toniko- klonicheskie, stopping the heart. With the ability to bring a breath lobelin was suggested as a means for analepticheskogo with reflex stops breathing (mainly by inhalation of irritating substances, carbon monoxide poisoning, etc.). Recently, a respiratory stimulant is rarely used. In reducing or stopping breathing, developing as a result of progressive depletion of the respiratory center, a lobelina not shown. Applied intravenously, intramuscularly less. Adults enter for 0,003-0,005 grams (0,3-0,5 ml 1% solution), children depending on the age of 0,001-0,003 grams (0,1-0,3 ml 1% solution). Intravenous introduction of a more efficient manner. Intravenous lobelin enter slowly (1 ml for 1-2 min). Rapid introduction is sometimes temporary stops breathing (patients), and develop side effects of the cardiovascular system (aetiology, violation conductivity). The maximum dose for adults : in the non-off 0,005 g, 0.01 g daily; In muscle-off 0.01 grams daily 0.02 g. The drug is not suitable for organic expressed Cardiovascular diseases. Lobelin and others similar to it on the substance of gangliostimuliruyuschie (tsitizin, Anabasine) found in recent years as aids to smoking cessation. Tablets containing at 0,002 g (2 mg) lobelina hydrochloride, produced for this purpose entitled “Lobesil (Tabulettae” Lobesilum “). They covered shell (atsetilftaliltsellyulozoy) that the flow of drugs through the stomach intact and rapid release in the gut. After taking into smoking cessation pill to 1 4-5 times a day for 7-10 days. Subsequent to receiving tablets continue 2-4 weeks with a gradual decrease its frequency. When relapse rate can be repeated. Application pills lobelinom, tsitizinom and anabizinom contraindicated in acute gastric ulcer and duodenal ulcer, organic diseases, cardiovascular system.

Treatment must be carried out under the supervision of a doctor. In overdose possible side effects : weakness, irritability, dizziness, nausea, vomiting.

Method of issuance : 1% solution in capsules and liquid pumps for 1 ml; Pill (lobesil) to 0,002 grams (2 mg).

Storage : List A.

 

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 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.

The most common side effects of cholinergic antagonists

 

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.^{[citatioeeded]}

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.

Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae). It acts as a nicotinic acetylcholine receptor agonist. It is made in the roots and accumulates in the leaves of the plants. It constitutes approximately 0.6–3.0% of the dry weight of tobacco^[1] and is present in the range of 2–7 µg/kg of various edible plants.^[2] It functions as an antiherbivore chemical; therefore, nicotine was widely used as an insecticide in the past^[3][4][5] and nicotine analogs such as imidacloprid are currently widely used.

In smaller doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (30–60 mg^[6]) can be fatal.^[7] This stimulant effect is likely a major contributing factor to 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, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those determining addiction to heroin and cocaine. The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.^[8]

Research in 2011 has found that nicotine inhibits chromatin-modifying enzymes (class I and II histone deacetylases) which increases the ability of cocaine to cause an addiction.^[9]

History and name

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, and who promoted their medicinal use. The tobacco and seeds were brought to ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo. Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison. Its chemical empirical formula was described by Melsens in 1843, its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893, and it was first synthesized by Amé Pictet and A. Rotschy in 1904.

Historical use of nicotine as an insecticide

Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide (waste from the tobacco industry) were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.^[4]

Currently, nicotine is a permitted pesticide for organic farming because it is derived from a botanical source. Nicotine sulfate sold for use as a pesticide is labeled “DANGER,” indicating that it is highly toxic.^[5] However, in 2008, the EPA received a request to cancel the registration of the last nicotine pesticide registered in the United States.^[15] This request was granted, and after 1 January 2014, this pesticide will not be available for sale.^[16]

Chemistry

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble, for example nicotine sulfate which, being a solid, is easier to handle in its use as an insecticide. (For retail use it is sold as solution in water ready for spraying.)^[5] Its flash point is 95°C and its auto-ignition temperature is 244°C.^[17]

Optical activity

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]_D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.^[18] The salts of (+)-nicotine are usually dextrorotatory.

Biosynthesis

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ¹-pyrrollidium cation.^[19][20] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ¹-pyrrollidium cation.

The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reactioow proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.

The N-methyl-Δ¹-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ¹-pyrrollidium cation.

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ¹-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ¹-pyrrollidium cation to form enantiomerically pure (–)-nicotine.^[21]

Pharmacokinetics

As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.^[23] The elimination half-life of nicotine in the body is around two hours.^[24]

The amount of nicotine absorbed by the body from smoking depends on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco, snus and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco.^{[clarificatioeeded]} Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

Side effects of nicotine.^[22]

Other primary metabolites include nicotine N’-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.^[25] Under some conditions, other substances may be formed such as myosmine.^[26]

Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.^[27]

Detection of use

Medical detection

Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.^[28][29] Nicotine use is not regulated in competitive sports programs, yet the drug has been shown to have a significant beneficial effect on athletic endurance in subjects who have not used nicotine before.^[30]

Pharmacodynamics

Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.

In the central nervous system

Effect of nicotine on dopaminergic neurons.

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of “volume control”. It is thought that increased levels of dopamine in the reward circuits of the brain are responsible for the apparent euphoria and relaxation, and addiction caused by nicotine consumption. Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle

, though at toxic doses it can induce contractions and respiratory paralysis.^[31] Nicotine’s selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.^[32]

Tobacco smoke contains anabasine, anatabine, and nornicotine. It also contains the monoamine oxidase inhibitors harman and norharman. These beta-carboline compounds significantly decrease MAO activity in smokers. MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOIs and the nicotine is responsible for most of the addictive properties of tobacco smoking.^[35] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions^[37][38] but not habenulopeduncular structures. Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.

In the sympathetic nervous system

Nicotine also activates the sympathetic nervous system,^[41] 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 the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred. By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes 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. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.

 

In adrenal medulla

Effect of nicotine on chromaffin cells.

Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.^[44]

Psychoactive effects

Further information: Psychoactive drug

Nicotine’s mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.^[45] First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.^[46] Like any stimulant, it may very rarely cause the often uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence. When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, vasopressin, histamine, arginine, serotonin, dopamine, autocrine agents, and beta-endorphin. This release of neurotransmitters and hormones is responsible for most of nicotine’s effects. Nicotine appears to enhance concentration and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems. Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine. This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use. Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties. However, after coadministration with an MAOI, such as those found in tobacco, nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to amphetamine.

A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that NRT increases a quitter’s chance of success by 50 to 70%.^[56] But in 1990, researchers found that 93% of users returned to smoking within six months. Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco, nicotine lozenges and electronic cigarettes.

 

Side effects

Nicotine increases blood pressure and heart rate in humans. Nicotine can stimulate abnormal proliferation of vascular endothelial cells, similar to that seen in atherosclerosis. Nicotine induces potentially atherogenic genes in human coronary artery endothelial cells. Nicotine could cause microvascular injury through its action oicotinic acetylcholine receptors (nAChRs), but other mechanisms are also likely at play. A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus, an estrogen-sensitive region of the brain involved in memory formation and retention.

Dependence and withdrawal

See also: Smoking cessation

Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, research examining its addictive nature has been found to show that nicotine activates the mesolimbic pathway (“reward system”) – 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 heroin.^[64][65][66] Like other physically addictive drugs, nicotine withdrawal causes downregulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine regulates the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors, in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity. This neuronal brain alteration can persist for months after administration ceases. A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence. Some have been able to restart their natural dopamine production and bypass months or years of depression caused by nicotine withdrawal by using a combination of two over-the-counter supplements: 5-HTP (5-Hydroxytryptophan also known as oxitriptan) and L-Tyrosine (para-hydroxyphenylalanine). Studies of the combination have been conducted only on general depression and no one has yet measured the effects specifically oicotine withdrawal-related depression. However, anecdotal evidence suggests that the combination can be effective. In addition to being a natural and low-cost alternative to prescription anti-depressants, this protocol also has the benefit of being short-term in that the treatment is only necessary for a few months after nicotine abatement. Certain side effects, especially negative drug interactions, have been found with 5-HTP, so this treatment should not be undertaken in combination with any prescription medication or without specific approval from a doctor.

Immunology prevention

A model of a nicotine molecule

Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle operates under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.

These include attaching the nicotine molecule as a hapten to a protein carrier such as Keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.

Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.^[70]

Toxicology

The LD₅₀ of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.^[6][71] Nicotine therefore has a high toxicity in comparison to many other alkaloids such as cocaine, which has an LD₅₀ of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose oicotine through smoking alone, although overdose can occur through combined use of nicotine patches or nicotine gum and cigarettes at the same time.^[7] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.^[72]

Historically, nicotine has not been regarded as a carcinogen and the IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer (on the contrary, a mechanism of urinary excretion of nicotine metabolites was identified as the link between smoking and bladder cancer ^[73]), research over the last decade has identified nicotine’s carcinogenic potential in animal models and cell culture.^[74][75] Nicotine has beeoted to directly cause cancer through a number of different mechanisms such as the activation of MAP Kinases.^[76] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer^[77]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.^[78][79] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).

The teratogenic properties of nicotine has been investigated. According to a study of ca. 77,000 pregnant women in Denmark^{[citatioeeded]}, women who used nicotine gum and patches during the early stages of pregnancy were found to face an increased risk of having babies with birth defects. The study showed that women who used nicotine-replacement therapy in the first 12 weeks of pregnancy had a 60% greater risk of having babies with birth defects compared to women who were non-smokers.

Tobacco use among pregnant women has also been correlated to increased frequency of ADHD. Children born to mothers who used tobacco were two and a half times more likely to be diagnosed with ADHD. Froelich estimated that “exposure to higher levels of lead and prenatal tobacco each accounted for 500,000 additional cases of ADHD in U.S. children”.

Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.

Therapeutic uses

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.

However, in a few situations, smoking has been observed to be of therapeutic value. These are often referred to as “Smoker’s Paradoxes“. Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other ingredients found in tobacco.

For instance, studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention (PCI).^[84] Risk of ulcerative colitis has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.^[85][86] Smoking also appears to interfere with development of Kaposi’s sarcoma in patients with HIV.^[87][88]

Nicotine reduces the chance of preeclampsia, and atopic disorders such as allergic asthma. A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.

Tobacco smoke has been shown to contain compounds capable of inhibiting monoamine oxidase, which is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson’s and Alzheimers disease.

Many such papers regarding Alzheimer’s disease and Parkinson’s Disease have been published. While tobacco smoking is associated with an increased risk of Alzheimer’s disease, there is evidence that nicotine itself has the potential to prevent and treat Alzheimer’s disease. Nicotine has been shown to delay the onset of Parkinson’s disease in studies involving monkeys and humans. A study has shown a protective effect of nicotine itself oeurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.

Studies have indicated that nicotine can be used to help adults suffering from autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are responsible for processing nicotine in the brain.

Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.^[102][103] Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.

Mechanisms of Nicotine Action

Nicotine stimulates all nicotinic acetylcholine receptors. These are found in the central nervous system, the ganglia of the peripheral nervous system, at the neuromuscular junction, and in the adrenal gland. NAchR have also been reported in many epithelial tissues such as bladder and lung.

Nicotine increases both sympathetic and parasympathetic tone, and its effects change with duration of exposure. This makes the ultimate effect of nicotine on each organ system rather difficult to predict. Through the autonomic ganglia, both parasympathetic and sympathetic pathways are stimulated by nicotine. Parasympathtic effects include decreased heart rate, bronchoconstriction, and increased GI motility while sympathetic stimulation leads to vasoconstriction, increased heart rate, bronchodilation, and decreased GI motility. The adrenal gland also has nicotinic cholinergic innervation, functioning like a post-ganglionic sympathetic nerve to release epinephrine and norepinephrine. Nicotine thus stimulates release of these sympathetic neurotransmitters.

Prolonged exposure to nicotine results initially in stimulation of transmission, followed by a form of depolarization blockade that can result in inhibition of transmission, and is similar to cholinergic blockers such as succylcholine. In depolarizing block, the receptors are unable to faciliate ion flow and are inactivated. The predominant effects of nicotine also depend on the dominant autonomic tone, reflexes to the CNS to oppose primary stimulation, and on the frequency and time interval of nicotine absorption.

          Site                  Predominant Tone   Most Common Effect of Nicotine

                Arterioles  Sympathetic              Vasoconstriction, hypertension

                Veins         Sympathetic              Vasoconstriction, increased venous return

                Heart         Parasympathetic      Tachycardia

GI Tract 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. Example (right): 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.

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 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.

Cellular Events following Cholinergic Receptor Activation

• Nicotinic Muscle Receptor

• Response:

• Membrane Depolarization leading to muscle contraction

• Molecular Aspects:

• Nicotinic (muscle) receptor’s cation ion channel opening

• Nicotinic Neuronal Receptor

• Responses:

• Depolarization: postsynaptic cell activation

• Catecholamine secretion

• Molecular Aspects

• Nicotinic (muscle) receptor’s cation ion channel opening

Ganglion Blocking Drugs

Ganglionic blockers act mainly at the primary nicotinic-type cholinergic receptor at sympathetic and parasympathetic autonomic ganglia.

Agents which are classified as ganglionic blockers are not included among those drugs which block neuromuscular junctions.

One class of blocker produces a depolarization block: Nicotine could produce this effect.

The second class of agents include hexamethonium & trimethaphan These agents either competitively block the receptor or block the open channel configuration.

For essential hypertension, ganglionic blockers have been replaced by better drugs.

Ganglionic blockers may be used for initial blood pressure control in patients with dissecting aortic aneurysm because, in addition to reducing blood pressure, blunting of sympathetic responses reduce sheer forces at the tear.

 

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.

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.

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.

1. In autonomic ganglia,the major action of nicotine consists initially in transient stimulation and subsequently in a more persistent depression. In larger doses, stimulation is followed very rapidly by blockade of transmission.

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.

4. In the CNS, nicotine can cause tremors which proceed to convulsions as the dose is increased. Excitation of respiration which is a prominent effect seen after nicotine is due to both activation of medullary sites, and activation of chemoreceptors of carotid body. Stimulation is followed by depression and death occurs from respiratory paralysis of both central origin and due to paralysis of muscles of respiration. Another CNS effect of nicotine is stimulation of the area postrema ie the chemoreceptor trigger zone to induce vomiting.

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.

 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.

 

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=7_frccgVAWQ&feature=related

6.     http://www.youtube.com/watch?v=CGNpELKAqQw&feature=player_detailpage

7.     http://www.youtube.com/watch?v=SCasruJT-DU&feature=related

8.     http://www.youtube.com/watch?v=7tBWl4GE8rk&feature=related

9.     http://www.youtube.com/watch?v=g_H5PWlr3lk&feature=related

10.    http://www.youtube.com/watch?v=RUhn2rvt9eA&feature=related

11.    http://www.youtube.com/watch?v=HXx9qlJetSU&feature=related

12.    http://www.youtube.com/watch?v=LT3VKAr4roo&feature=related

13.    http://www.youtube.com/watch?v=HXx9qlJetSU&feature=related

14.    http://www.youtube.com/watch?v=LT3VKAr4roo&NR=1

15.    http://www./watch?v=9nUY6o–LCWY&feature=related

List of literature

1.      Pharmacology at your palms: reference book / Drogovoz S.M., Kutsenko T.A. – Kharkiv: NPhaU, 2008. – 80 p.

2.      Pharmacology secrets / edited by Patricia K. Anthony. – Hanley Belfus, INC/ – Philadelphia, 2002. – 305 p. www.hanleyandbelfus.com

3.      Rang and Dale’s Pharmacology / H.P. Rang, M.M. Dale, J.M. Ritter, R.J. Flower // Churchill Livingstone, 2007. – 829 p. www.studentconsult.com

4.      Tripathi K.D. Essentials of medical pharmacology 6 th Edition. – Jaypee Brothers Medical Publishers (P) LTD New Delhi, 2008. – 875 p.

5.      Stefanov O., Kucher V. Pharmacology with general prescription. – Kiev, 2004. – 150 p.

6.      Multimedia lectures from pharmacology for 3^d course students

7.      http://intranet.tdmu.edu.ua/education.php