Patrick

An Introduction to Medicinal
Chemistry 3/e
Chapter 19

CHOLINERGICS,
ANTICHOLINERGICS
& ANTICHOLINESTERASES
Part 3: Cholinergics & anticholinesterases

 

©1

Contents
Part 3: Cholinergics & anticholinesterases
14. Acetylcholinesterase
14.1.
Role
14.2.
Hydrolysis reaction catalysed
14.3.
Effect of inhibition
14.4.
Structure of enzyme complex
14.5.
Active site - binding interactions
14.6.
Active site - Mechanism of catalysis (3 slides)
15. Anticholinesterases
15.1.
Physostigmine
15.2.
Mechanism of action (3 slides)
15.3.
Physostigmine analogues
15.4.
Organophosphates (9 slides)
15.5.
Anticholinesterases as ‘Smart Drugs’ (2 slides)
[30 slides]

 

©1

14. Acetylcholinesterase
14.1 Role  
• Hydrolysis and deactivation of acetylcholine
• Prevents acetylcholine reactivating receptor

...

Nerve 1
Signal

...

 

Nerve 2

...

Acetylcholinesterase enzyme

©1

14. Acetylcholinesterase
14.2 Hydrolysis reaction catalysed

O

O

C
CH3

O

HO

C

NMe3

CH3

Acetylcholine

OH

+
Choline

Acetic acid

active

NMe3

inactive

 

©1

14. Acetylcholinesterase
Enzyme inhibitor
(Anticholinesterase)

14.3 Effect of inhibition

2o Message

Ach




Inhibitor blocks acetylcholinesterase
Ach is unable to bind
Ach returns to receptor and reactivates 
it
Enzyme inhibitor has the same effect as 
a cholinergic agonist
 

Nerve 2
©1

Acetylcholinesterase 14.14.4 Structure of enzyme complex S S Enzyme S S S S Enzyme S   S S S S S S S S S S S Enzyme ©1 .

Acetylcholinesterase 14.5 Active site ­ binding interactions Ester binding region Anionic binding region Serine OH Aspartate Histidine N hydrophobic  pockets vdw Me :O:: Ionic N C N O CH2 CH2 O O H­bond H CH3 O vdwMe Me Tyrosine • • • Anionic binding region similar to cholinergic receptor site Binding and induced fit strains Ach and weakens bonds   ©1 Molecule positioned for reaction with His and Ser .14.

14.6 Active site ­ Mechanism of catalysis O CH3 C : :O O :N H : :O : CH2CH2 NMe3 NH CH3 C O O R :N H Serine                                Histidine (Nucleophile)                    (Base) : : O: CH3 C O O R H N NH Histidine Acid catalyst   NH Histidine (Base catalyst) CH3 C O : :O : OR H :N NH Histidine ©1 . Acetylcholinesterase 14.

Acetylcholinesterase 14.14.6 Active site ­ Mechanism of catalysis H2O CH3 C : :O : O OR :N H NH CH3 C ROH O N O Histidine Histidine CH3 C O NH : _ : O: O : :O H :N NH CH3 C O OH H :N NH H Histidine   Histidine Basic catalyst ©1 .

Acetylcholinesterase 14.6 Active site ­ Mechanism of catalysis : _ :O : : :O : CH3 C OH O H NH :N CH3 C OH H :O : N Histidine Basic catalyst : Histidine (Acid catalyst) _ :O : CH3 NH C O OH NH :N O CH3 C OH H   Histidine OH :N NH ©1 .14.

Acetylcholinesterase • Serine and water are poor nucleophiles • Mechanism is aided by histidine acting as a basic catalyst • Choline and serine are poor leaving groups • Leaving groups are aided by histidine acting as an acid catalyst • Very efficient ­ 100 x 106 faster than uncatalysed hydrolysis • Acetylcholine hydrolysed within 100  secs of reaching active  site • An aspartate residue is also involved in the mechanism   ©1 .14.

Acetylcholinesterase The catalytic triad • An aspartate residue interacts with the imidazole ring of  histidine to orientate and activate it : :O H :N N H     Serine                              Histidine (Nucleophile)                     (Base)   :O: O Aspartate ©1 .14.

Anticholinesterases • Inhibitors of acetylcholinesterase enzyme • Block hydrolysis of acetylcholine • Acetylcholine is able to reactivate cholinergic receptor • Same effect as a cholinergic agonist   ©1 .15.

1  Physostigmine O C O Me N H Urethane      or Carbamate • • • • • Me N N Me Me Pyrrolidine N Natural product from the African calabar bean Carbamate is essential (equivalent to ester of Ach) Aromatic ring is important  Pyrrolidine N is important (ionised at blood pH) Pyrrolidine N is equivalent to the quaternary nitrogen of Ach   ©1 . Anticholinesterases 15.15.

15.2  Mechanism of action : O H : MeNH C O :N NH MeNH O Ar H C O :N Ar NH :O : : O Physostigmine O MeNH : C O: Ar H O N NH MeNH C :O : : :O : :   O Ar :N NH H ©1 .

15.2  Mechanism of action ­ArOH O MeNH C :O : : O Ar O NH MeNH H C :N O Stable carbamoyl intermediate O Hydrolysis very slow :N H :N NH 6 Rate of hydrolysis slower by 40 x 10   ©1 NH .

2  Mechanism of action O N C H O N C O :: H : O : Me Me Carbonyl group 'deactivated'   ©1 .15.

15.3  Physostigmine analogues Me O C Me O O CH NMe2 N H • • • • Me C O N Me (ionised at blood pH) Miotine Neostigmine Simplified analogue Susceptible to hydrolysis Crosses BBB as free base CNS side effects • • • • •   NMe3 Fully ionised Cannot cross BBB No CNS side effects More stable to  hydrolysis Extra N­methyl group  increases stability ©1 .

Hydrolysis mechanisms Possible mechanism 1 Me N  ­O +C : N OAr H H Water O Me : O: Me C N OH H   C OAr OH MeNH2 + CO2 ©1 .

Hydrolysis mechanisms Possible mechanism 2 O Me N C H2O Me ­H N OAr C O Me O N C MeNH2 + CO2 OH H H Too reactive Compare: O Me N C ­Me No hydrolysis OAr Me   ©1 .

S. from the Greek myastheneia. it is one of the lesser known autoimmune disorders.).healcentral. At about 14 cases per 100. in selected cases. http://www. Myasthenia is treated with immunosuppressants.000 (in the U. Weakness is typically caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction. inhibiting the stimulative effect of the neurotransmitter acetylcholine. 'serious') is a neuromuscular disease leading to fluctuating muscle weakness and fatiguability. 'muscle disease'.Myasthenia gravis Myasthenia gravis (sometimes abbreviated MG. and Latin gravis. lit. cholinesterase inhibitors and. org/healapp/showMetadata? metadataId=3621   ©1 . thymectomy.

eg 3x20mg pyridostigmine.Me 2 N Me2N O NMe3 O O O N Me Neostigmine Pyridostigmine Treatment Myasthenia gravis can usually be controlled with medication. symptoms will be mild during eating. and increase until the desired result is achieved. Medication is used for two  different endpoints: Direct improvement of the weakness Reduction of the autoimmune process Muscle function is improved by cholinesterase inhibitors. These slow the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate. If taken 30 minutes before a meal. like perspiration and diarrhea can be countered by adding atropine. Usually doctors will start with a low dose. Side effects. the neurotransmitter is therefore around longer to stimulate its receptor. Pyridostigmine is a short-lived drug with a half-life of about 4 hours. such as neostigmine and pyridostigmine.   ©1 .

healthtouch.com/bin/EContent_HT/dnoteShowLfts.asp? fname=04867&title=NEOSTIGMINE+(Injection)+(Injectable )+&cid=HTDRUG http://www.healthtouch.http://www.com/bin/EContent_HT/dnoteShowLfts.asp? fname=04944&title=PYRIDOSTIGMINE+(Injection)+(Injectable )+&cid=HTDRUG   ©1 .

cognitive (intellectual) impairment extends to the domains of language (aphasia). principally in the temporoparietal cortex. which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression. also known simply as Alzheimer's. together with an inflammatory response to the deposition of amyloid plaques and neurofibrillary tangles.Alzheimer's disease (AD) Alzheimer's disease (AD). This pathological process consists principally of neuronal loss or atrophy. The most striking early symptom is loss of short term memory (amnesia). and those functions (such as decision-making and planning) closely related to the frontal and temporal lobes of the brain as they become disconnected from the limbic system. recognition (agnosia).   ©1 . It is the most common type of dementia. These changes make up the essential human qualities. with relative preservation of older memories. skilled movements (apraxia). reflecting extension of the underlying pathological process. is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. but also in the frontal cortex. and thus AD is sometimes described as a disease where the victims suffer the loss of qualities that define human existence. As the disorder progresses.

html   ©1 .http://www.healthcentral.com/alzheimers/introduction­7­115.

Marketed as Reminyl or Nivalin in the rest of the world) rivastigmine .   ©1 . are costly. but also some independent clinicians.(marketed as Exelon) There is significant doubt as to the effectiveness of cholinesterase inhibitors.(marketed as Aricept) galantamine .no longer clinically used donepezil .[70][71] The pharmaceutical companies. AChE-inhibitors reduce the rate at which acetylcholine (ACh) is broken down and hence increase the concentration of ACh in the brain (combatting the loss of ACh caused by the death of the cholinergin neurons). Novartis) N Acetylcholinesterase inhibitors Acetylcholinesterase (AChE) inhibition was thought to be important because there is a reduction in activity of the cholinergic neurons. and confer many side effects. A transdermal patch is under development that may ease administration of rivastigmine. A number of recent articles have criticized the design of studies reporting benefit from these drugs.(marketed as Razadyne in the U.Et O MeO Me N O Me O MeO Donepezil (Aricept) NMe 2 Rivastigmine  (Exelon.S. concluding that they have doubtful clinical utility. Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms but do not alter the course of the underlying dementing process.A.[67][68][69] Examples include: tacrine . dispute the conclusions of these articles.[72]ivastigmine.

15.4 Organophosphates a) Nerve gases i PrO O i PrO P iPrO P F Dyflos (Diisopropyl fluorophosphonate) • • • • O Me F Sarin Agents developed in World War 2 Agents irreversibly inhibit acetylcholinesterase Permanent activation of cholinergic receptors by Ach Results in death   ©1 .

O N P O S VX Nerve Agent The VX nerve agent is the most well-known of the V-series of nerve agents. through evaporation. It is odorless and tasteless. Normally. Sustained contraction of the diaphragm muscle causes death by asphyxiation.   ©1 . The only countries known to possess VX are the United States and Russia. Its chemical name is O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothiolate and its molecular formula is C11H26NO2PS. VX agent is considered an area denial weapon due to its physical properties. into small amounts of vapor. The acetylcholine is then broken down to non-reactive substances (acetic acid and choline) by the acetylcholinesterase enzyme. With its high viscosity and low volatility VX has the texture and feel of high-grade motor oil. and can be distributed as a liquid or. an electric nerve pulse would cause the release of acetylcholine over a synapse that would stimulate muscle contraction. as it has a high persistence in the environment. thus resulting in sustained contractions of all the muscles in the body. VX blocks the action of acetylcholinesterase. It works as a nerve agent by blocking the function of the enzyme acetylcholinesterase. If more muscle tension is needed the nerve must release more acetylcholine. This makes it especially dangerous.

so that the build up of acetylcholine produced by loss of the acetylcholinesterase function can no longer affect their target. which is issued for military personnel in the form of an autoinjector. as little as 200 micrograms is enough to kill an average person. depending on method of absorption. Death can be avoided if the appropriate antidote is injected immediately after exposure. The most commonly used antidote is atropine and pralidoxime.O N P O S VX Nerve Agent Often regarded as the deadliest nerve agent created to date. Standard chemical agent resistance pills are also effective. Atropine works by binding and blocking a subset of acetylcholine receptors (known as muscarinic acetylcholine receptor.   ©1 . The injection of pralidoxime regenerates bound acetylcholinesterase. mAchR). This prevents involuntary muscle actions so that muscles like the diaphragm are not in constant contraction.

New Jersey. pre-treaty disposal included the US Army's CHASE (Cut Holes And Sink 'Em) program. in which the S. Cpl. in which old ships were filled with chemical weapons stockpiles and then scuttled. In 1958 the British government traded their research on VX technology with the United States of America in exchange for information on thermonuclear weapons.200 feet of water. but are ultimately unknown. Eric G. Gibson was filled with 7. England in 1952. The United Kingdom unilaterally renounced chemical and biological weapons in 1956.380 VX rockets and scuttled in 7. CHASE 8 was conducted on June 15. off the coast of Atlantic City. VX was passed over in favour of continuing with sarin as their chemical weapon of choice. The long-term environmental ramifications of exposing large quantities of VX to seawater and marine life could pose a grave danger. The US then went into production of large amounts of VX in 1961.S.   ©1 .The chemist Ranajit Ghosh discovered the V-series nerve agents at the government research establishment at Porton Down. Earlier. 1967. as mandated by the US accession to the Chemical Weapons Convention. The US later destroyed all of its stockpiles of the deadly nerve agent (by incineration at Johnston Island in the South Pacific).

[2]   ©1 . and New York have opposed this plan and the New Jersey Governor Codey instructed the New Jersey Department of Transportation to deny entry to any trucks carrying the hydrolysate to the Deepwater facility.000 US gallons (950 m³) of the chemical weapon are stored at the Newport Chemical Depot in Newport.[2] The governors of Delaware. On June 12. a tributary of the Ohio River. one of which is in Russia. but authorities said no agent was released and no one was injured in the spill. The VX hydrolysate produced will contain mainly a phosphonate ester and a thiolamine. NJ where it was to be further treated to destroy the phosphonate ester and the thiolamine. it had been proposed that the hydrolysate be dumped into the Great Miami River. 20 ppb is the level of VX in water that is considered permissible for drinking by US combat troops. about 30 miles (50 km) north of Terre Haute. near Dayton. with 20 parts per billion or less of residual VX. New Jersey. Iraq under Saddam Hussein admitted to UNSCOM that it had researched VX. it was reported that more than 250.The US is also destroying chemical weapons stockpiles containing VX in nine other locations. The VX is in the process of being hydrolyzed to much less toxic byproducts using concentrated caustic solution. Indiana.) A plan was developed to truck the hydrolysate from Indiana to the DuPont Chambers Works Secure Environmental Facility at Deepwater.894 US gallons (11 m³) of VX. (Interestingly. Pennsylvania. [1] Subsequent investigation after the 2003 Invasion of Iraq indicates that Iraq had indeed weaponized VX in 1988 and had dropped three VX-filled bombs on Iran. A contained spill of 30 US gallons (100 L) drew attention to the disposal process. and dumped into the Delaware River. Indiana. 2005. Prior to the current plan. VX hydrolysis began on May 5 2005 and as of June 12 the facility had destroyed 2. but denied weaponizing the agent due to production failure. Ohio but the community there successfully defeated the proposal.

4 Organophosphates b) Mechanism of action ­H Serine O Serine H O i iPrO iPrO • • PrO O P O iPrO P F STABLE Irreversible phosphorylation P­O bond very stable   ©1 .15.

15.4 Organophosphates c)  Medicinal organophosphate O Me 3N CH2 CH2 S P OEt Ecothiopate OEt • • • • Used to treat glaucoma Topical application Quaternary N is added to improve binding interactions Results in better selectivity and lower. safer doses O N P S VX Nerve Agent   O ©1 .

4 Organophosphates d) Organophosphates as insecticides EtO S MeO P P EtO S O NO 2 MeO S CO 2Et CH CH2 CO2Et Parathion • • • Malathion Relatively harmless to mammals Agents act as prodrugs in insects Metabolised by insects to produce a toxic metabolite   ©1 .15.

15.4 Organophosphates d) Organophosphates as insecticides MAMMALS EtO S EtO P EtO INSECTS O NO 2 PARATHION (Inactive Prodrug) Insect Oxidative desulphurisation O P EtO O NO 2 Active drug Mammalian  Metabolism EtO Phosphorylates enzyme S P EtO OH INACTIVE & excreted DEATH   ©1 .

S N N OEt P O OEt Diazinon   ©1 .

http://www.html N N N Me N Cl Nicotine NO2 NH N Imidacloprid   ©1 .com/movies/neurotoxic_insecticides/index.physioviva.

4 Organophosphates e) Design of Organophosphate Antidotes Strategy • Strong nucleophile required to cleave strong P­O bond • Find suitable nucleophile capable of cleaving phosphate esters • Water is too weak as a nucleophile • Hydoxylamine is a stronger nucleophile O O NH 2 OH + RO P OR Hydroxylamine • • OR H2 N O P OR + ROH OR Hydroxylamine is too toxic for clinical use Increase selectivity by increasing binding interactions with active site   ©1 .15.

4 Organophosphates e) Design of Organophosphate Antidotes N CH N CH3 • • • • Pralidoxime OH Quaternary N is added to bind to the anionic region Side chain is designed to place the hydroxylamine moiety in  the correct position relative to phosphorylated serine Pralidoxime 1 million times more effective than  hydroxylamine Cannot act in CNS due to charge ­ cannot cross bbb   ©1 .15.

4 Organophosphates e) Design of Organophosphate Antidotes O N Me CH N N H O O P CO2 O H Me CH N O P OR OR OR OR CO2 OH SER Active Site  (Blocked)   SER Active Site (Free) ©1 .15.

4 Organophosphates e) Design of Organophosphate Antidotes H H ProPAM NOH N CH3 • • • Prodrug for pralidoxime Passes through BBB as free base Oxidised in CNS to pralidoxime   ©1 .15.

com/ImagePreview/1245­W477   ©1 .http://www.superstock.

15.5 Anticholinesterases as ‘Smart Drugs’ • Act in CNS  • Must cross blood brain barrier • Used to treat memory loss in Alzheimers disease • Alzheimers causes deterioration of cholinergic receptors in  brain • Smart drugs inhibit Ach hydrolysis to increase activity at  remaining receptors   ©1 .

5 Anticholinesterases as ‘Smart MeDrugs’ O N C Me O Cl O MeO NH2 CH 2 Rivastigmine (Exelon) (analogue of physostigmine) N H MeO Donepezil N Tacrine (Cognex) Toxic side effects H N O P MeO MeO HO Anabaseine (ants and marine worms) CCl3 OH Metrifonate (organophosphate) O MeO N S N N N Me O Me Galanthamine (daffodil and snowdrop bulbs   N Me Xanomeline ©1 .NMe2 Et CH 15.

While scientific studies support some of the claimed benefits.   ©1 . used to treat people with cognitive learning difficulties. and are used as nutritional supplements. 'acting on the mind'). These drugs have a variety of human enhancement applications as well. and obvious. roots. The word nootropic is derived from the Greek words noos or "mind" and tropein meaning "to ward. available over the counter at health food and grocery stores. beans. bark. by improving the brain's oxygen supply. and hormones). At the other end of the spectrum are nootropics which have effects that are immediate. are substances which boost human cognitive abilities (the functions and capacities of the brain). profound. popularly referred to as "smart drugs". or by stimulating nerve growth. and may take weeks or even months before any cognitive improvement is noticed. such as with most nerve growth inducers." Typically. are marketed heavily on the World Wide Web.). neural degradation (Alzheimer's and Parkinson's). enzymes. Most alleged nootropic substances are nutrients or plant components (herbs. nootropics are alleged to work by increasing the brain's supply of neurochemicals (neurotransmitters. Some nootropics are drugs. it is worth noting that many of the claims attributed to a variety of nootropics have not been formally tested. With some nootropics the effects are subtle and gradual. etc. and are used by many people in personal cognitive enhancement regimens. and for cases of oxygen deficit to prevent hypoxia.Nootropics Nootropics (from Greek.

They include changes due to diseases (Alzheimer's and Creutzfeld-Jakob diseases). Description The absent-mindedness and confusion about familiar settings and tasks that are hallmarks of dementia used to be considered as part of a typical aging pattern in the elderly. Mental retardation is a condition that usually dates from childhood and is characterized by impaired intellectual ability. mentally retarded individuals typically have IQ (intelligence quotient) scores below 70 or 75. Dementia is now recognized not to be a normal part of aging. This operating definition encompasses 70–80 different typesentia.   © 1 . dementia historically has been called senility.Dementia Definition The term dementia refers to symptoms. Delirium is typically a brief state of mental confusion often associated with hallucinations. Some of the changes to the brain that cause dementia are treatable and can be reversed. The symptoms of dementia can result from different causes. personality. that result from a change in the functioning of the brain. including changes in memory. and behavior. Dementia is not the same thing as delirium or mental retardation. These declining changes are severe enough to impair the ability of a person to perform a function or to interact socially. while other changes are irreversible. Indeed. and damage due to long-term alcohol abuse. changes due to a heart attack or repeated blows to the head (as suffered by boxers).

Dementia is especially prominent in older people. However. and multi-infarct dementia (also called vascular dementia). The historical tendency of women to live longer than men has produced a higher prevalence of dementia in older women.The elderly are most prone to dementia.   ©1 . Over age 80. particularly those at risk for a stroke. women and men are equally prone to dementia. more than 20% of people have at least a mild form of dementia. dementia with Lewy bodies. The three main irreversible causes are Alzheimer's disease.

dopamine. The four main neurotransmitters are acetylcholine. Keeping the brain's neurotransmitters at high levels improves concentration. Exercise is highly synergistic with nutritional supplementation. mental focus. creativity. by increasing the body's capacity to supply brain cells with oxygen. recall. norepinephrine and serotonin. and a health regimen is incomplete without it. and cures and prevents most depressions. memory encoding.supplying the body with the precursors and cofactors it needs to produce neurotransmitters.What type of drugs will enhance cognition? Neurotransmitter support .   ©1 . calculation ability. Note that cardiovascular exercise performed on a regular basis also has nootropic effects. mood.

and high-order thought processes (abstract thought. Acetylcholine facilitates memory. concentration. innovation. Increasing the availability of this neurotransmitter in the brain may improve these functions and increase the duration in which they may be engaged without slowing down or stopping. temporarily reducing rather than improving mental performance. focus.   ©1 .Cholinergics are substances which affect the neurotransmitter acetylcholine or the components of the nervous system which utilize acetylcholine. calculation. Oversupplying the brain with acetylcholine may have the opposite effect. etc.).

 enhances  color perception. . anti­depressant. readily crosses the  blood­brain barrier. Alpha­GPC (L­alpha glycerylphosphorylcholine.  anti­depressant. CDP­Choline (Cytidine Diphosphate Choline) ­ choline precursor. Choline ­ precursor to acetylcholine (an essential component of the  acetylcholine molecule). Choline  alfoscerate) ­ most effective choline precursor. It is synergistic with lipoic acid. Choline citrate ­ precursor of the neurotransmitter acetylcholine.Examples of Cholinergic Nootropic Drugs Acetyl­L­carnitine (ALCAR) ­ Amino acid. Centrophenoxine (Lucidril) ­ Drug. Choline bitartrate ­ precursor of acetylcholine.  tends to be less expensive and similar in effect to Alpha GPC. Precursor of  acetylcholine (donating the acetyl portion to the acetylcholine  molecule).    ©1 general nootropic. cholinergic agent. general nootropic.

[4] [5]and some believe that understanding the mechanism through which it works can teach us about the role of inter-hemispheric communication in the brain. It is one of the racetams. is a cerebral function regulating drug which is claimed to be able to enhance cognition as well as slow down brain aging. Several meta-reviews of literature on piracetam indicate that piracetam increases performance on a variety of cognitive tasks among dyslexic children. and has shown positive results in the treatment of post-stroke aphasia. Piracetam also seems to inhibit brain damage caused by a variety of factors including hypoxia and excessive alcohol consumption. though this may reflect its enhancement of cross-hemispheric communication and of cognitive function in general.[1] [2] Piracetam has been studied in an extensive number of clinical experiments. rather than a specific improvement in whatever causes dyslexia. dementia[3]. and myoclonus. Myocalm®) Piracetam (brand name: Nootropil®. Though rare in the United States. piracetam is commonly prescribed in Europe for a variety of conditions. Piracetam is a cyclic derivative of GABA. cognitive decline following heart and brain surgery. epilepsy. and is similar to the amino acid pyroglutamate. Myocalm®).O NH2 O N Piracetam (brand name: Nootropil®. Piracetam's chemical name is 2-oxo-pyrrolidone.   ©1 . or 2-oxo-1pyrrolidine acetamide.

a disruption of blood flow to the brain. Not simply a speech disorder. its most common cause is stroke. as well as the ability to read and write. aphasia can affect the ability to comprehend the speech of others. However.   ©1 . Description Aphasia has been known since the time of the ancient Greeks. Although aphasia can be caused by a head injury and neurologic conditions. usually in adulthood. it has been the focus of scientific study only since the mid-nineteenth century. In most instances.Aphasia Definition Aphasia is a communication disorder that occurs after language has been developed. which affects brain metabolism in localized areas of the brain. intelligence per se is not affected.

stroke. involving much of the brain. or poisoning. in which case it is termed "essential myoclonus." Myoclonus may occur in epilepsy. or can be the only or primary neurological finding. shock-like jerking movement. Description Myoclonus can be a symptom of a separate disorder. or may be generalized.Myoclonus Definition Myoclonus is a brief.   ©1 . trauma. rapid. such as lack of oxygen. Myoclonus can occur in one or more limbs. or following many different types of brain injury.

  ©1 . The usual cause is occlusion of an artery by a thrombus or embolus and sometimes by severe atherosclerosis.Infarction The process of anoxic tissue death.