04 Anatomical and physiological peculiarities of autonomic nervous system

Anatomical and physiological peculiarities of autonomic nervous system. Indirect acting cholinergic stimulants. Cholinesterase reactivators (Proserinum, Pyridostigmini bromidum, Galanthamini hydrobromidum, Dipiroximum, Alloximum,Amizysilum, Cyclodolum).

Agents acting M-cholinergic receptors (Pilocarpini hydrochloridum, Aceclidinum, Atropini sulfas, Platyphyllini hydrotartras, Scopolamini hydrobromidum, Extractum Belladonnae siccum, Ipratropii bromidum (Atrovent), Pirensepinum (Gastrocepinum), Methacinum)

 

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.

Sensory Neurons And Neuropeptides

The sensory neurons have variety of neuropeptides (a dozen have been identified). An example is substance P. Substance P is probably a neurotransmitter contained in sensory neurons that mediate sensation of pain. Pain is carried by unmyelinated sensory neurons that release substance P to dorsal root of spinal cord.

 

ANS And CNS

((In ANS and CNS -> they contain NorEp and Ach, they are cholinergic, adrenergic)).

 

Multiple Neurotransmitters

It is found neurons have multiple neurotransmitters (NT).

In sympathetic system, norepinephrine (NorEp) is commonly cofound with neuropeptide y (NPY). Stimulation of sympathetic nerves causes vasoconstriction. NPY is a more potent vasoconstrictor than NorEp.

Cholinergic neurons have VIP (vasoactive intestinal polypeptide).

These multiple transmitters -> one transmitter modulate action of other compound released.

 

Terminology

Adrenergic -> to release adrenalin. Neuron with catecholamine (NorEP) is adrenergic (or noradrenergic).

On parasympathetic side, nerve with Ach and releases Ach would be cholinergic.

Tissue responsive to neurotransmitter is called adrenoreceptive or cholinoreceptive (they are activated or inhibited by NorEp or Ach).

Sympathomimetic drugs -> drugs where action mimic turning on sympathetic nervous system.

Parasympathomimetic drugs (s/a cholinomimetic) -> drugs that mimic effect of turning on parasympathetic nervous system.

Opposite of mimicry is block effect.

Sympatholytic -> they inhibit action of sympathetic nervous system.

Parasympatholytic -> inhibits action of parasympathetic nervous system.

 

Receptor Nomenclature

All autonomic preganglionic neurons activate nicotinic receptors. Nicotinic receptors on autonomic ganglion is oeuron. Nn is nicotinic receptor oeuron. Nm is nicotinic receptor is on voluntary muscle cell.

Postganglionic parasympathetic activate muscarinic receptors.

Postganglionic sympathetic neuron activate adrenergic receptors.

 

Lists receptor on organ and what happens when you turn it on. Pay attention to receptor of eye, heart, blood vessels, lungs, intestines, bladders, sex organs, adrenal medulla, liver, pancreas, fat cells, and everything else).  

Blocker

blocker -> receptor on vascular smooth muscle. Turn it on gives vasoconstriction. Block it gives vasodilation.  

 

 

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.

 

Neurophysiology

Action potential (AP). Axonal conduction. Membrane potential. – 70 mV in interior of axon with respect to exterior. High [K+] intracellularly and low Na+ and Cl– intracellularly. Energy requiring ionic pumps maintain concentration. Depolarization -> get permeability of membrane to sodium. See delayed opening of potassium channels and repolarization process propagated down axons. When axon terminal invaded by action potential, Ca++ flows in.

 

Axon Terminal

Synaptic vesicles (sacs with neurotransmitter). These sacs go to terminal membrane where they fuse with membrane and contents get ejected. We would predict the membrane would get longer, but some membrane gets pinched off to form new synaptic vesicle.

Video-1

 

Neurons

For ANS neurotransmitters, neurotransmitter synthesized in nerve terminal.

By contrast, the neuropeptide must be synthesized at the perikaryon (cell body) by protein synthesis machinery. These compounds are transmitted down axon to terminal.

 

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.

 

Ways Of Stopping Neurotransmitter

Diffusion

Degradation

Reuptake

 

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

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.

In a synapse, action potentials are conducted along motor nerves to their terminals where they initiate a Ca2+ influx and the release of acetylcholine (ACh). The ACh diffuses across the synaptic cleft and binds to receptors on the post synaptic membrane, causing an influx of Na+ and K+ ions, resulting in depolarization. If large enough, this depolarization results in an action potential. To prevent constant stimulation once the ACh is released, an enzyme called acetylcholinesterase is present in the endplate membrane close to the receptors on the post synaptic membrane, and quickly hydrolizes ACh.

Pyridostigmine inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the hydrolysis of acetylcholine. It is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood–brain barrier which carbamylates about 30% of peripheral cholinesterase enzyme. The carbamylated enzyme eventually regenerates by natural hydrolysis and excess ACh levels revert to normal.

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

Ambenonium

Ambenonium is a long-acting inhibitor of cholinesterase, about five to six hours after oral intake, used in the treatment of myasthenia gravis.

Tacrine

Tacrine or 9 amino-1,2,3,4-tétrahydroacridine is an anticholinesterase agent which penetrates into the brain and has been used in the treatment of Alzheimer’s disease. It was successively proposed as a disinfectant, as antagonist of morphine respiratory depression and finally used in the treatment of Alzheimer’s disease for which it attenuates certain symptoms.

Tacrine has various adverse effects of muscarinic type but its major disadvantage is its hepatic toxicity which usually results in a rise of transaminases. A metabolite of tacrine could be responsible for this hepatic toxicity. It is not used now.

Tacrine is a centrally acting anticholinesterase and indirect cholinergic agonist (parasympathomimetic

). It was the first centrally-acting cholinesterase inhibitor approved for the treatment of Alzheimer’s disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney. See William_K._Summers He is listed as inventor of Tacrine. It also acts as a histamine N-methyltransferase inhibitor.

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.^{[citatioeeded]}

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.^{[citatioeeded]}

Donepezil

Donepezil is a selective and reversible inhibitor of acetylcholinesterase, having little effect on butyril-cholinesterase and penetrating well iton brain. Its half-life of plasma elimination is about 70 hours and just a once-daily intake is enough. Donepezil is indicated in the supportive care of Alzheimer’s disease.

The most frequent adverse effects of the donepezil are digestive disorders (diarrhea, nausea, vomiting, abdominal pains). It can also induce dizziness and bradycardia but without hepatic toxicity, the major undesirable effect of tacrine.

Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor.^[1] Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer’s disease.^[2] Common side effects include gastrointestinal upset. It has an oral bioavailability of 100% and easily crosses the blood–brain barrier. Because it has a half-life of about 70 hours, it can be taken once a day.

Currently, no definitive proof shows the use of donepezil or other similar agents alters the course or progression of Alzheimer’s disease (AD). However, 6 to 12-month controlled studies have shown modest benefits in cognition and/or behavior.^[3] Pilot studies have reported donepezil therapy may potentially have effects on markers of disease progression, such as hippocampal volume. Therefore, many neurologists, psychiatrists, and primary-care physicians use donepezil in patients with Alzheimer’s disease. In 2005, the UK National Institute for Clinical Excellence (NICE) withdrew its recommendation for use of the drug for mild-to-moderate AD, on the basis of no significant improvement in functional outcome, quality of life, or behavioral symptoms. However, NICE revised its guidelines to suggest donepezil be used in moderate-stage patients for whom the evidence is strongest.

While the drug is currently indicated for mild to moderate Alzheimer’s, evidence from two clinical trials also indicates it may be effective for moderate to severe disease. An example of this is a Karolinska Institute paper published in The Lancet in early 2006, which states donepezil improves cognitive function even in patients with severe AD symptoms.^[4]

In mild to moderate Alzheimer’s Disease, a starting dose of 5 mg given once daily should be used. In a minimum of four to six weeks, an increase to 10 mg is recommended. The usual dose is 5 to 10 mg once daily. Moderate to severe AD indicates the same regimen, but in a minimum of three months, a patient may receive a dose of 23 mg once daily. Dementia patients should receive 5–10 mg once daily. The maximum daily dose is 23 mg once daily.^[5] Clinicians should use caution in prescribing the maximum daily dose as the risk of severe side effects may outweigh the unclear clinical benefits.^[6] In the UK, the maximum licensed dose is 10 mg.

Contraindications

Donepezil (Aricept) should be used with caution in patient with cardiac disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmias and sick sinus syndrome. Patients with gastrointestinal disorders should use caution because nausea or vomiting may occur. These symptoms may appear more frequent when initiating treatment or increasing the donepezil dose. Although occurrence of seizures is rare, patients who have a predisposition to seizures should be treated with caution.^[5] The British Medical Journal (BMJ) cautioned that the largest dosage, 23 mg, was crafted to extend patent protection rather than for medical reasons,^[7] and was not shown to be more effective compared to the 10 mg dose.

Donepezil has been tested (off label) in other cognitive disorders, including Lewy body dementia,^[8] and vascular dementia,^[9] but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in Alzheimer’s patients.^[10]

Donepezil has also been studied in patients with mild cognitive impairment, schizophrenia, attention deficit disorder, postcoronary bypass

 cognitive impairment, cognitive impairment associated with multiple sclerosis, CADASIL syndrome, and Down syndrome. A three-year National Institutes of Health trial in patients with mild cognitive impairment reported donepezil was superior to placebo in delaying rate of progression to dementia during the initial 18 months of the study, but this was not sustained at 36 months. In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study (Petersen 2005). At this time, though, donepezil is not indicated for prevention of dementia.

Recent studies suggest donepezil can improve speech in children with autism. The studies found the speech of autistic children who were mildly to moderately affected appeared to improve from the use of donepezil.^[11][12]

Adverse effects

Common side effects include bradycardia, nausea, diarrhea, anorexia, abdominal pain, and vivid dreams. In 2006 Eisai, the manufacturer, issued a statement that a single vascular dementia study found a difference in the percentage of study participants who died in the donepezil group (1.7%) versus the placebo group (0%), and this could be due to an unusually low death rate on the placebo group. An analysis of all three vascular dementia trials, according to Eisai, “shows no statistically significant differences in observed mortality rates between the donepezil and placebo groups.” A physician has reported several cases of mania.^[13]

Rivastigmine

Rivastigmine is a new anticholinesterase, quite well absorbed by oral route and crossing well the blood-brain barrier. It is used twice daily in the supportive care of Alzheimer’s disease. It does not present hepatic toxicity.

Rivastigmine (sold under the trade name Exelon) is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson’s disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects,^[1] which typically include nausea and vomiting.^[2] The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.^[2]

History

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology, at the Hebrew University of Jerusalem^[3] and sold to Novartis for commercial development.(It is a semi-synthetic derivative of physostigmine)^[4] It has been available in capsule and liquid formulations since 1997.^[5] In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson’s disease;^[6] and in 2007 the rivastigmine transdermal patch became the first patch treatment for dementia.

Administration

Rivastigmine tartrate is a white to off-white, fine crystalline powder that is both lipophilic (soluble in fats) and hydrophilic (soluble in water). Like other cholinesterase inhibitors, it requires doses to be increased gradually over several weeks; this is usually referred to as the titration phase.^[2] Oral doses of rivastigmine should be titrated with a 3 mg per day increment every 2 to 4 weeks.

Rivastigmine is classified as pregnancy category B, with insufficient data on risks associated with breastfeeding. In cases of overdose, atropine is used to reverse bradycardia. Dialysis is ineffective due to the drug’s half-life.

Pharmacodynamics

Rivastigmine, an acetylcholinesterase inhibitor, inhibits both butyrylcholinesterase and acetylcholinesterase (unlike donepezil, which selectively inhibits acetylcholinesterase). It is thought to work by inhibiting these cholinesterase enzymes, which would otherwise break down the brain neurotransmitter acetylcholine.^[7]

Indication

The U.S. Food and Drug Administration has approved rivastigmine capsules and patches for the treatment of mild to moderate dementia of the Alzheimer’s type and for mild to moderate dementia related to Parkinson’s disease. It has been used in more than 6 million patients worldwide.^{[citatioeeded]}

Rivastigmine has demonstrated significant treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems commonly associated with Alzheimer’s^{[8][9][10][11]} and Parkinson’s disease dementias.^[12]

Efficacy

In patients with either type of dementia, rivastigmine has been shown to provide meaningful symptomatic effects that may allow patients to remain independent and ‘be themselves’ for longer. In particular, it appears to show marked treatment effects in patients showing a more aggressive course of disease, such as those with younger onset ages, poor nutritional status, or those experiencing symptoms such as delusions or hallucinations.^[13] For example, the presence of hallucinations appears to be a predictor of especially strong responses to rivastigmine, both in Alzheimer’s and Parkinson’s patients.^[14][15] These effects might reflect the additional inhibition of butyrylcholinesterase, which is implicated in symptom progression and might provide added benefits over acetylcholinesterase-selective drugs in some patients.^[13][14] Multiple-infarct dementia patients may show slight improvement in executive functions and behaviour. No firm evidence supports usage in schizophrenia patients.

Its efficacy is similar to donepezil and tacrine. Doses below 6 mg/d may be ineffective. The effects of this kind of drug in different kinds of dementia (including Alzheimer’s dementia) are modest, and it is still unclear which AcCh(ButCh) esterase inhibitor is better in Parkinson’s dementia, though rivastigmine is well-studied.

Side effects

Side effects may include nausea and vomiting.^[2]

The strong potency of rivastigmine, provided by its dual inhibitory mechanism, has been postulated to lead to more nausea and vomiting during the titration phase of oral rivastigmine treatment.^[2] This enforces the importance of taking oral forms of these drugs with food as prescribed.^[5] However, rates of nausea and vomiting are markedly reduced with the once-daily rivastigmine patch (which can be applied at any time of the day, with or without food).

In a large clinical trial of the rivastigmine patch in 1,195 patients with Alzheimer’s disease, the target dose of 9.5 mg/24-hour patch provided similar clinical effects (e.g. memory and thinking, activities of daily living, concentration) as the highest doses of rivastigmine capsules, but with one-third fewer reports of nausea and vomiting.^[1]

Pharmacokinetics

When given orally, rivastigmine is well absorbed, with a bioavailability of about 40% in the 3-mg dose. Pharmacokinetics are linear up to 3 mg BID, but nonlinear at higher doses. Elimination is through the urine. Peak plasma concentrations are seen in about one hour, with peak cerebrospinal fluid concentrations at 1.4–3.8 hours. When given by once-daily transdermal patch, the pharmacokinetic profile of rivastigmine is much smoother, compared with capsules, with lower peak plasma concentrations and reduced fluctuations.^[16] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose).^[16]

The compound does cross the blood–brain barrier. Plasma protein binding is 40%.^[17] The major route of metabolism is by its target enzymes via cholinesterase-mediated hydrolysis. Elimination bypasses the hepatic system, so hepatic cytochrome P450 (CYP) isoenzymes are not involved.^[18] The low potential for drug-drug interactions (which could lead to adverse effects) has been suggested as due to this pathway compared to the many common drugs that use the cytochrome P450 metabolic pathway.^[2]

Galantamine

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.

Clinical use

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.

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 an alkaloid extracted of the leaves of a shrub called Atropa belladonna, which acts primarily at the peripheral level.

Action on the autonomic nervous system

Atropine is a competitive inhibitor of acetylcholine muscarinic receptors. Its action results in a decrease of the parasympathetic tonus, so that the influence of the sympathetic nerve becomes dominating.

Cardiovascular action

1.    Cardiac action: atropine effect results primarily in modifications of the heart rate:

o   in very low dose, it can give a slight cardiac slowing attributed to a central vagal stimulation and to peripheral parasympathetic effect leading to a transient increase of acetylcholine release.

o   in therapeutic dose there is generally cardiac acceleration by reduction of vagal tone, and suppression of reflex bradycardia during arterial hypertension.

2.    Vascular action:, atropine does not have vascular effects since there is no parasympathetic tonus on the vessels but it inhibits vasodilation caused by an intravenous injection of acetylcholine.

3.    Action on the arterial pressure:

o   in therapeutic dose, atropine does not induce modifications of arterial pressure in spite of incresed cardiac rate.

o   in very high or toxic dose, it induces a fall of the arterial pressure by depression of the vasomotor centers and cutaneous vasodilation, perhaps secondary to an histamine release.

Eye Action

Atropine inhibits parasympathetic influence on the eye, which results in:

• passive pupil dilation or mydriasis and increase of the diameter of the iris.

• tendency to elevation of intraocular pressure by increase in the diameter of the iris which, in patients predisposed to narrow-angle glaucoma, obstructs evacuation of aqueous humor by the Schlemm channel . Atropine is thus contraindicated in these patients.

• Accommodation paralysis or cycloplegia, disturbing vision .

After local administration in the form of ophthalmic solution, atropine effects last very long: dilation of the pupil can persist several days.

Action on smooth muscles

Acetylcholine contracts smooth muscles except vascular muscles and atropine has an antispasmodic action by inhibiting this acetylcholine effect.

On the digestive tract, atropine decreases tone, amplitude and frequency of the peristaltic contractions; it decreases hypertonicity produced by morphine, which justifies its combination to morphine in the treatment of colic pain.

On isolated intestine, atropine gives a reduction of tonus and peristalsis, prevents and inhibits contracture elicited by acetylcholine.

Antispasmodic action of atropine is also exerted on biliary tract, bronchi, urinary routes: ureters and bladder. Urographies showed that atropine dilates ureters.

The bladder receives sympathetic and parasympathetic innervation. The sympathetic nerve tends to dilat the bladder and constrict its internal sphincter. The parasympathetic, on the contrary, constricts bladder and relaxes the internal sphincter. The suppression of the influence of the parasympathetic by atropine gives an increase in the tone of the internal sphincter and a dilation of the bladder, which can induce urinary retention, especially in case of prostate hypertrophy.

Atropine practically has no action on uterus.

Action on secretions

Atropine reduces the majority of secretions:

• Digestive: inhibition of salivary secretion results in a feeling of thirst, of dryness of the mouth. The reduction of gastric secretion explains why atropine was used in therapeuticsas a gastric antisecretory. It hardly modifies pancreatic secretioor biliary.

• Bronchial: bronchial secretion is reduced.

• Cutaneous: it inhibits sudation, which gives a dry and hot skin. It is necessary to be wary about its use when ambient temperature is high or in patients with fever, because the inhibition of sudation increases temperature, particularly in infants, with the risk of provoking hyperthermia.

• Lacrimal secretion is reduced, lacteous secretion during lactation is little or not modified.

Action on central nervous system

In therapeutic doses, in human beings, atropine has only little or no action on the central nervous system, sometimes a respiratory stimulation.

Atropine was for a long time the only drug to have some efficacy in Parkinson’s disease. In animals, it inhibits tremors elicited by cholinomimetic agents such as oxotremorine.

Atropine and scopolamine, lower the cerebral acetylcholine concentration in animal experiments: the inhibition of acetylcholine receptors elicited causes an exaggerated release of acetylcholine, which is hydrolysed by cholinesterases.

In high dose, the stimulant action of atropine appears with restlessness, ataxia, and +++++ , hyperthermia, dizziness, visual and memory disturbances, hallucinations, delusion. This picture can evoke an acute schizophrenic episode or an alcoholic delirium. However, in severe intoxication, a CNS depression and a respiratory arrest can occur.

Metabolism

Atropine is quickly absorbed by digestive route and one resorts to its administration by parenteral route only when one wants to obtain a very fast effect, for example in the treatment of colic pain. Its plasma half-life is of approximately four hours.

Part of atropine administered in the form of ophthalmic solution is likely to diffuse into the general circulation.

It crosses the placental barrier and traces can be found in various secretions, of which breast milk.

The duration of action of atropine administered by general route would be of approximately six hours.

Therapeutic use

Atropine has several therapeutic uses:

In administration by general route

1.    Treatment of painful syndromes with spasmodic component, i.e. involving an exaggerated contraction of smooth muscles, such as biliary and renal colic pain.

2.    In anesthesiology: prevention of respiratory tract secretion, bronchospasm, laryngospasm and reflexe reactions such as bradycardia, before surgical operations.

3.    Treatment of poisonings:

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.

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.

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]

Biosynthesis in plants

The biosynthesis of scopolamine begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase (EC 4.1.1.17). Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase (EC 2.1.1.53).^[5]

A putrescine oxidase (EC 1.4.3.10) that specifically recognizes methylated putrescine catalyzes the deamination of this compound to 4-methylaminobutanal which then undergoes a spontaneous ring formation to N-Methyl–pyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated that catalyzes this reaction. Hygrine further rearranges to tropinone.^[5]

Subsequently, tropinone reductase I (EC 1.1.1.206) converts tropinone to tropine which condenses with phenylalanine-derived phenyllactate to littorine. A cytochrome P450 classified as Cyp80F1^[6] oxidizes and rearranges littorine to hyoscyamine aldehyde. In the final step, hyoscyamine undergoes epoxidation which is catalyzed by 6beta-hydroxyhyoscyamine epoxidase (EC 1.14.11.14) yielding scopolamine.^[5]

History

One of the earlier alkaloids isolated from plant sources scopolamine has been in use in its purified forms (such as various salts including hydrochloride, hydrobromide, hydroiodide and sulfate), since its isolation by the German scientist Albert Ladenburg in 1880, and as various preparations from its plant-based form since antiquity and perhaps pre-historic times. Following the description of the structure and activity of scopolamine by Ladenburg, the search for synthetic analogues of and methods for total synthesis of scopolamine and/or atropine in the 1930s and 1940s resulted in the discovery of diphenhydramine, an early antihistamine and the prototype of its chemical subclass of these drugs, and pethidine, the first fully synthetic opioid analgesic, known as Dolatin and Demerol amongst many other trade names.

Scopolamine was used in conjunction with morphine, oxycodone, or other opioids from before 1900 up into the 1960s to put mothers in labor into a kind of “twilight sleep“. The analgesia from scopolamine plus a strong opioid is deep enough to allow higher doses to be used as a form of anaesthesia.

Scopolamine mixed with oxycodone (Eukodal), and ephedrine was marketed by Merck as SEE (from the German initials of the ingredients) and Scophedal starting in 1928, and the mixture is sometimes mixed up on site on rare occasions in the area of its greatest historical usage, namely Germany and Central Europe.

Scopolamine was also one of the active ingredients in Asthmador, an over-the-counter smoking preparation marketed in the 1950s and ’60s claiming to combat asthma and bronchitis. In November 1990 the U.S. Food and Drug Administration forced OTC products with scopolamine and several hundred other ingredients that had allegedly not been proved effective off the market. Scopolamine shared a small segment of the OTC sleeping pill market with diphenhydramine, phenyltoloxamine, pyrilamine, doxylamine and other first generation antihistamines, many of which are still used for this purpose in drugs like Sominex, Tylenol PM, NyQuil, etc.

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.^{[citatioeeded]}

• 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.^[21]

The use of medical scopolamine/opioid combination preparations for euphoria is uncommon but does exist and can be seen in conjunction with opioid use. Doses of scopolamine by itself near the therapeutic range can create euphoria and anxiolysis of anticholinergic origin, similar to that of some first-generation antihistamines and similar drugs.^{[citatioeeded]}

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.^{[citatioeeded]}

Used as antispasmodics

Muscarinic receptor antagonists have antispasmodic properties, but all the antispasmodic agents are not necessarily muscarinic receptor antagonists. The antispasmodic effect of some of them results from a direct effect on smooth muscle, often by calcium-channel antagonism.

Muscarinic receptor antagonists used as antispasmodics are, in addition to atropine itself, dihexyverine, prifinium and propantheline.

Among antispasmodic drugs having at the same time a muscarinic receptor antagonist effect and a direct effect on smooth muscles one can quote tiemonium., although its effect on smooth muscle activity predominates over its muscarinic receptor antagonist activity PHARMACOLOGY OF  NEUROMUSCULAR TRANSMISSION

I. Introduction and History

A. There are two general classes of neuromuscular blocking drugs. They are the competitive, and the depolarizing blockers. The prototype of the competitive blockers is curare.

B. Although the South American arrow poisons have fascinated scientists since the 1500s, the modern clinical use of curare dates to 1932 when it was first used in patients with tetanus. Its first trial for muscular relaxation in general anesthesia occurred in 1942.

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.

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.

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

1.    http://www.youtube.com/watch?v=7_frccgVAWQ&feature=related

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

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

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

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

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

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

8.    http://www.youtube.com/watch?v=LT3VKAr4roo&feature=related
9. http://www.youtube.com/watch?v=PhD6CEOcuno

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

10.http://www.apchute.com/moa.htm

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

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

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