今天又考了一科，惨不忍睹，惨不忍睹啊。上帝啊，保佑我吧！

今天早上考完试后我的心情很差。算了一下这个学期的GPA, 因为我今天的失误，预计将会下降很多。而因此可能会影响到我的实习，心里更加难过。 回家来写了一篇博客之后，午饭也没吃，就爬到床上去了。我蜷缩在床上，室内温度20多度吧，盖了3层被子，还是觉得冷。全身哪里都疼，头疼，脊柱疼，眼睛疼，心疼。沮丧，颓废，愤怒，失望，担心，很多种感情充斥着我的心。迷迷糊糊的，我睡着了。

 

醒来以后，看了一下表，睡了一个小时。我振作了一些。

 

说实话，我有些不敢相信今天的自己，会变成这个样子。曾经那个开朗乐观的我，跑到哪里去了？ 曾经那个镇定从容、不轻易言败的我，又跑到哪里去了? 我何时变得如此功利狭隘? 或许真的是因为这几年压力太大、吃的苦太多，我才变得如此患得患失，不堪一击？

 

我仔细的想了想。Dr. Schmitz 提到的 “底线法”，还真是有几分道理。

 

如果我这次考试考得很差，低于74分，导致整门课得不了B得C，最坏的结果会是什么？OK, GPA slump, classmates would look down on me, wouldn't be able to get my dream internship, but I still will be able to move onto next semester, and will be able to graduate with a doctorate degree on time.

 

再退一步，如果我真的今天这次考试发神经，得了低于34分(I hope not)，导致整门课过不了，最坏的结果是什么？ GPA slump, classmates would look down on me, extremely embarassed of myself, graduation would be push back a year, lose $150000.   

 

分析完最坏的结果，心里有一点小小释然。我还会活着，或许会很失望很伤心，或许会给父母更多的负担，可是我还会活着，我还有机会按时顺利毕业。然后我又想到了我的同班同学，他跟我的父亲年龄差不多，还在辛苦的读书。相比之下，我还算年轻。

 

想完以后，我心里好受了一些。人啊，有的时候，期望越大，失望也就越大。平常心！平常心啊！

 

我问自己，为什么不快乐？因为我允许了自己不快乐，自找的。 开心一点，往远看，战略上藐视，战术上重视。

 

明天我就23岁了，前23年过得太快，我还没来得及好好观赏沿路风景。23年间，我长大了，我的父母老了。我的心愿，就是顺利完成学业，全家人能健康幸福的生活在一起，多点时间来享受生活的美好。

 

上帝，感谢您赐给我这个机会，让我能停下脚步来自省。我要改了，还是好汉一条吧？ 不过，您还是保佑一下我吧!

刚考完试，neuro, 心情很差。因为感觉考得一团糟。这门课学期初两次大考都还OK, 然后第三次大考彻底失败只考了64分，今天的考试必须要考到74分以上，可是，我觉得我考不了74分了。已经错了n道题了。short term management for pheochromocytoma??  大前天、前天、昨天，看书看得快要疯了，早知何必那么辛苦？其实我都有复习到的！可是不知为什么考试时坐在那里就是没心机去慢慢推理。妈的人人都考得比我好，志得意满的样子. 我恨我自己！！！！！！！！！！！！！！！！！！杀了我吧！！！！！！！！！！！！！！

 

然后再说说mangement， group project 和presentation的分数终于出来了，我们组很神奇的得了倒数第五。我好伤心！差点心脏病发。加上几次考试，这门课的总分是88.8%, 妈的又没有A了。这种烂课都能弄成这样... 为什么今年要增加这门课？往届的人都不用的。 我恨这门课，我恨这几个老师，我恨之入骨！！！

 

上帝啊，保佑我吧！！！My birthday wish is to do well in the rest of my finals and please let me get a B in orouke's class! Please!

没有提纲，没有板书，只有一张嘴在说... 整理的笔记的一部分,两节课的内容。I hate my life. Oh that's right, I have NO life. 保佑我吧上帝，我真的需要考好这一次试！呜呜呜！

 

cholinergic receptors (nicotinic, muscarinic receptors):

nicotinic receptors represent a family of receptors referred to as ligand gated ion channels.  The nicotinic receptor is an ion channel.  The nicotinic receptor was the first receptor that was isolated and purified.  The nicotinic receptor was the first one that was cloned.

 

Nicotinic receptors are pentamers.  They are comprised of 4 different types of subunits alpha, beta, gamma, delta.  2 alpha, 1 beta, 1 gamma, 1 delta.  While there are 4 different types of subunits can make up a nicotinic receptors are still 5 subunits (pentamer structure) These subunits projected into the extracellular space as well as the intracellular space.  They traverse the cell membrane and project into the intracellular compartment, the cytoplasm.  Most of the receptor is on the external surface, which is extracellular location. 

 

It takes two acetylcholine molecules to bind to the receptor in order for it to open.  The binding sites are right on the channel.  When compared to the G. protein coupled receptor.  Everything is sort of spatially distinct.  You have a receptor that is linked to a G. protein which is linked to activation of an enzyme and then intracellular events, usually phosphorylation events that ultimately lead to a response.  The binding site for the ligand, for the neurotransmitter is right on the channel itself. 

 

Acetylcholine binds to its binding sites.  This binding causes a change in the configuration of the subunits such that the channel opens, and ions rush down their concentration gradient through the channel.  In the case of nicotine the major ion is positively charged sodium ion.  Calcium can get through this channel well but most of the ions are positively charged sodium ions.  When this channel opens the membrane depolarizes and that is an excitatory event. 

 

These channel open and close in milliseconds.  When a single channel is open about 50 million ions can pass through this channel in one second. 

 

Alpha 1, alpha 2 represents typical skeletal muscle nicotinic receptors.  There are nicotinic receptors in lots of different places, and each of those receptors has a different composition to it.  They all have 2 alpha subunits, 1 beta, 1 gamma, 1 delta.  The subtype of the alpha subunit and subtype of the beta subunit vary depending on where these receptors are.  There are nicotinic receptors in the ganglia.  The structural makeup of those channels are a little bit different configuration.  Nicotine, nicotinic receptor drugs can have a affect at skeletal muscle.

 

Nicotine binds to the receptor and the channel opens, increasing current.  Even though the nicotine remains in bond to the channel it goes back very slowly to the baseline, it is in a desensitized state.  Once the nicotine is removed the channel closes.  Nicotinic receptors desensitized very rapidly in the presence of agonists.  When the receptor is desensitized, there is no conductance of ions through channel anymore, or it is significantly impaired.  You can't get the normal current going through the membrane that you would expect. 

 

Desensitization of the channel is determined by several factors:

First the drug has to be an agonist.  You don't see desensitization with an antagonist because they don't open the channel.

Second it depends on the concentration of the agonist

Third what the duration of the binding is to the receptor.  How tightly does the drug bind to the receptor and how long does it take to dissociate from the receptor.

 

If you try to use nicotine as a drug or in some sort of experiment the receptors are going to desensitized very quickly.  Particularly as the concentration of nicotine increases.  The more nicotine you have the more desensitization you'll get.  Desensitization means the channels can't work properly (channels are blocked).  They are not blocked in this sense of an antagonist their blocked in this sense that they can't open properly in response to an agonist. 

 

If we didn't have desensitization, what you would see you to presence of continuous exposure to nicotine the channel would open and it would stay open.  And all that time current would be conducted through those channels.

 

Some of the antagonist are referred to as depolarizing antagonist.  i.e. : Succinylcholine

 

Channel is closed.  The drug (ligand) binds to the receptor.  Channel is opened.  Current increases.  If there is too much drug or if the duration of exposure is too long the channel becomes desensitized and they don't work, they can't respond.  Once the drug is taking away the channels go back to the closed configuration.

 

Nicotine is currently used as a drug.  It is used in cigarettes as a delivery device for nicotine.  There are several other ways in which nicotine can be delivered, transdermal patches, nicotine gum, nicotine nasal spray.  Nicotine is used for one purpose only as a drug, which is smoking cessation otherwise there is no clinical indication for the use of nicotine.  Nicotine will have effects on autonomic ganglia, neuromuscular junction (skeletal muscle), adrenal medulla, nicotinic receptors on the adrenal medulla, the sensory nerves also contain nicotinic receptors.  When they are activated they have effects on the sensory nervous system.

 

People using nicotine have the potential for the nicotine to interact with the sites in the periphery.

 

Autonomic standpoint adverse effects are somewhat dependent on the state of the autonomic nervous system in any given individual.  Most of the effects sympathetic, parasympathetic, are due the sites where the nicotinic receptors are eliciting these responses.  The adrenal medulla (sympathetic nervous system).  The ganglia nicotine is going to activate both parasympathetic and sympathetic ganglia and this is going to happen simultaneously.

 

The sympathetic side In most people what you'll see is an increase in heart rate and increase in blood pressure due to the sympathetic activation of the adrenal medulla, and sympathetic ganglia to the heart and blood vessels.

 

The parasympathetic side of the in most people you'll see, nausea, vomiting, and diarrhea.  The GI symptoms and diarrhea due to activation of parasympathetic nerves going to the GI tract, some of this could be attributed to sensory nerves.  Increasing salivation, increasing sweating due to activation of parasympathetic nerves and sympathetic nerves.

 

You won't see this in everybody.  You may see complex effects.  Example: decrease in heart rate, blood pressure followed by an increase.  Or, you may see salivation followed by dry mouth.

 

Depolarizing vs. non-depolarizing blockers:

non depolarizing blockers are the true competitive receptor antagonist, just like atropine is for muscarinic receptors.  That is everything covered except succinylcholine.

 

Onset and duration of action:

some are shorter acting than others.  Some are quicker acting than others.  Example rocuronium has the most rapid onset of any of the non depolarizing blockers.  Mivacurium is a very short acting drug, it is the shortest acting drug of the non depolarizing blockers.  Pancuronium is very long acting.

 

Metabolized and excreted:

some are metabolized in the liver, some are excreted to the kidney, some are substrates for plasma cholinesterase (butryrylcholine esterase).  Atracurium spontaneously breaks down at physiological pH.  Kidney disease or liver disease will impact the way these drugs are metabolized or excreted

 

Selectivity:

these drugs are not entirely selected for nicotinic receptors in the neuromuscular junction which is our prime target.  These drugs can interact with other receptors example d-tubocurarine is a weak ganglionic blocker, blocks nicotinic receptors in the ganglia as well as the neuromuscular junction.  Pancuronium is a muscarinic receptor antagonist.  Pancuronium is a good blocker of M 2 receptors in the heart.  We have some potential for some non specific effects at the sites.

 

Histamine release:

Isoquinilines like d-tubocurarine is noted for causing histamine release.  The others do as well.  Drugs like atracurium, mivacurium.  The main concern here is effects on blood pressure and cardiovascular system.

 

Succinylcholine:

Has a very rapid onset and a very short duration of action that is the major benefit of succinylcholine. 

 

Succinylcholine drawbacks; metabolized by butryrylcholine esterase not AChE.

Because of its structure it can also bind to nicotinic receptors in the ganglia and the heart activating these receptors.  Succinylcholine has some weak effects on histamine release. 

 

Other problems:

Bradycardia most likely due to the fact that succinylcholine binds directly to muscarinic receptors in the heart and decreases heart rate. 

 

Increased intraocular pressure; succinylcholine can cause contraction of the muscles that surround the eyeball.  Extra ocular muscle it causes contraction of that.  Succinylcholine looks like acetylcholine, it binds to the receptors just like acetylcholine causing muscle contraction just like acetylcholine and increases intra ocular pressure.  For many people this is not an issue but if somebody has trauma to their eye and they are having surgery on their eye this could be an important consideration.  We have to put them under want them to stop breathing and we will also cause muscle contraction. For somebody that has glaucoma this is an important consideration.

 

Muscle pain:  succinylcholine causes contraction of skeletal muscle initially, but this drug causes paralysis of skeletal muscle. Succinylcholine is an agonist.  The initial response to succinylcholine isn't muscle contraction, it is transient and it dissipates very quickly, but it does occur.  This is referred to as fasiculation, skeletal muscle twitching.  We get some transient muscle contraction to begin with.  How do we get from muscle activity to paralysis?  Constant stimulation of the receptor, succinylcholine is not a substrate for AChE it is going to hang around in the neuromuscular junction continuously stimulating those receptors leading to desensitizion, and in addition to that when the channels are held open succinylcholine molecules can physically block the channels as well.  Initially get an agonist effect causing muscle contraction, but quickly that wears off and you get paralysis.

 

Why doesn't this happen with atracurium, pancuronium?  They are pure antagonist.  Antagonists and binding to the receptor does not to activate any signaling pathway, does not activate the cell.

 

Hyperkalemia:   Potassium concentrations is normally high inside the cell and low outside of the cell.  This influences cell membrane polarization which in turn influences cell processes such as conduction of nerve impulses.  If the concentration of potassium  is too high outside the cell the concentration ingredient is reversed and potassium can't run down its normal concentration gradient.  If you have high extracellular potassium levels, ion conductance, action potentials will be impacted.  The heart is driven by continuous action potentials and the generation of these action potentials.  The cardiac action potential, the repolarization phase of the cardiac action potential is primarily driven by the movement of potassium ions.  Hyperkalemia or hypokalemia can have significant effects on cardiac rhythm.  Potassium levels in the blood or held within a very narrow window.  If you start to get outside the normal range this can lead to cardiac arrhythmias.  In normal healthy people the small increase in intracellular potassium isn't going to do anything significant for most people because they can adapt to these changes in potassium levels.  For people that have experienced some sort of trauma particularly burn patients that cause denervation of the skeletal muscle, something that causes paralysis.  In these types of patients changes in potassium levels can be extremely important.

 

Paralyzed vs. non paralyzed and the presence of succinylcholine:

the blood collected from the veins of patients with a paralyzed limb and a non paralyzed limb.  They infused succinylcholine.  Blood in the normal limb potassium went up, but not enough to cause any concern.  In the paralyzed denervated limb potassium levels spiked considerably when compared to the normal limb.  When the succinylcholine was removed levels returned to normal.  In the presence of succinylcholine there is a efflux of potassium out of the cell.  Intracellular levels of potassium are higher than extracellular levels.  In the presence of succinylcholine potassium moves from inside the cell to outside the cell, and increasing potassium levels in the blood.  If this level of potassium reaches the heart this can have serious adverse effects on cardiac action potential. 

 

Malignant Hyperthermia:

Can be triggered by different drugs.  Succinylcholine is well noted for causing malignant hyperthermia.  It is believed this is due to a genetic disorder.  Hyperthermia is characterized by intense muscle contraction.  In people with a genetic disorder succinylcholine causes intense muscle contractions, rigidity of the muscles, they become stiff and very hard in an intense prolonged contraction.  This muscle contraction produces heat because you are burning ATP.  Actin, myosin, contration of muscle is driven by ATP.  ATP is being burned driving body heat, temperature up.

 

Normally what happens in the skeletal muscle acetylcholine is released it binds to nicotinic receptors opens up to sodium channels causing depolarization which in turn causes calcium to be released from storage sites inside the skeletal muscle.  It is this calcium that triggers muscle contraction.

 

In people with malignant hyperthermia the same events take place, this time in the presence of succinylcholine.  What happens you get a massive release of intracellular calcium from these intracellular storage sites in skeletal muscle.  Abnormally high levels of calcium are being released.  This is driving the contraction of skeletal muscle to an extreme, causing intense, prolonged contraction, rigidity, and heat.  There are channels on the storage sites inside the skeletal muscle.  The channels determine how much calcium is released.  In people with malignant hyperthermia they give them Dantrolene.  Dantrolene is an antidote to people who experience malignant hyperthermia.  Dantrolene binds to specific sites on these calcium storage sites within the skeletal muscle and blocks calcium release.  It doesn't interfere with succinylcholine binding to the receptor.  It blocks the massive efflux of calcium out of the storage sites, and by doing so it relaxes the skeletal muscle.  Other drugs cause this as well not only succinylcholine. 

 

Reversing the effects of the Drugs:

The main thing we are concerned about is getting the patient to breathe on their own.  Some of these drugs are pretty short-acting their effects may wear off quickly, others are relatively long acting.  We have a way to reverse this.  Give a drug like neostigmine for example that block AChE. 

 

You've given pancuronium it binds to nicotinic receptors in a competitive manner blocking the effects of acetylcholine paralyzing skeletal muscle.  To overcome the effects of pancuronium you could increase the concentration of acetylcholine.  We have a competitive receptor antagonist the way to overcome that is to increase the concentration of the agonist.  Why don't we just give acetylcholine?  Acetylcholine is not selective we are mainly concerned with effects at the neuromuscular junction.  Acetylcholine will act in the ganglia parasympathetic and sympathetic ganglia were there are nicotinic receptors and parasympathetic neuroeffector junction.

 

Why don't we give pilocarpine?  Pilocarpine is muscarinic receptor agonist.  We are talking about nicotinic receptors in the skeletal muscle.  We want to block AChE.  Any of the reversible AChE inhibitors will block AChE enzyme and increase the concentration of acetylcholine at the level of the nicotinic receptors in the skeletal muscle.  This will increase the number of acetylcholine molecules that can compete with the antagonist and overcome their effects.

 

Will this work for the non depolarizing nicotinic receptor antagonist?  Do you predict that blocking AChE will benefit those people are in terms of overcoming the effects?  Yes.  Blocking AChE is beneficial in overcoming the effects in the non depolarizing blockers.  What about succinylcholine?  Do you give an AChE inhibitor?  Succinylcholine is not a substrate for AChE.  Succinylcholine is not a competitive antagonist.  It is more like an agonist.  It is binding to the receptors and turning them on and it is desensitizing these receptors.  If the receptors are already desensitized and we give AChE inhibitor increasing the amount of acetylcholine that won't help.  It might make things worse because these receptors are already desensitized, leading to further desensitization.  Blocking AChE only makes sense to reverse the effects of the non depolarizing nicotinic receptor antagonist.

 

Now, when we do this example we have given neostigmine.  You have given neostigmine to reverse the effects of the nicotinic receptor antagonist.  This will happen at the level of the skeletal muscle.  Neostigmine is given intravenously.  Neostigmine will work wherever there is AChE.  It will have effects in the ganglia, parasympathetic and sympathetic, and will have effects in the parasympathetic neuroeffector junction.  Any of the cholinesterase inhibitors effects, increased salivation, increased tearing, cardiovascular effects, GI effects, bladder effects, etc..

 

You have given an antagonist to block transmission in the skeletal muscle.  You want the effects to wear off so you block AChE.  Maybe you gave too much neostigmine.  You would be okay in terms of overcoming the paralyzing effects, but you probably wouldn't be okay in terms of the ganglia, parasympathetic and sympathetic and the parasympathetic neuroeffector junction you would start to see a bunch of adverse effects.  You could give a muscarinic receptor antagonist to in essence block the effects of the overstimulation that's occuring through the parasympathetic nerves.  The classic example is atropine.  Atropine is useful as an antidote here, if too much of the AChE inhibitor is given and you start to see effects at the parasympathetic level you can block those effects with atropine. 

 

First block the nicotinic receptors, then overcoming the effects with AChE inhibitor, then overcoming the effects of the AChE inhibitor.

 

The rise of acetylcholine in the ganglia and the ultimate integrated response that is manifested vary quite significantly from one person to the next.  Depending on the relative activity of the parasympathetic vs. sympathetic nervous system in that individual.  Under surgery it is likely that the sympathetic nervous system is going to be dampened considerably.  In general the parasympathetic nervous system activity is the dominant respondents manifested.  If you block AChE you will augment the effects at the neuro muscular junction but the transmission through the ganglia as well. 

 

There isn't anything to give to reverse the effects of succinylcholine.  Theoretically you could give d-tubocurarine or pancuronium or any of the non depolarizing blockers.  They would inhibit the effect of succinylcholine, but what would the outcome be of doing that?  They will still be paralyzed just by a different mechanism.  You just have to wait until it wears off. 

 

The drugs on the handout are more selective for the skeletal muscle nicotinic receptors.  You can't minimize the possibility that these drugs can block nicotinic receptors in the ganglia.

 

When we are talking about AChE inhibitors those drugs will work wherever AChE is found.

 

Botox-botulinum toxin type A.  Botox inhibits the release of acetylcholine from cholinergic nerve terminals.  It is specific for cholinergic nerves.  Botox is a molecule composed of two subunits it has a heavy chain and a light chain.  Botox binds to proteins along the cell membrane.  Botox is taken up into the vesicles as they are releasing their acetylcholine.  The vesicles are recycled after they release the contents of acetylcholine and other transmitters.  These vesicles get a signal and migrate to the membrane before opening up and expelling their contents.  Botox gets into the nerve ending on by being bound to the nerve terminal.  When the vesicles migrate to the surface and expelling their contents they reform.  In that reformation the vesicles integrate some of the surface membrane into their membrane.  Once it is inside the cell because of the pH inside the reformed vesicles the heavy chain light chain are split apart.  The light chain gets into the cytosol where it binds to proteins.  There are proteins on storage vesicles and there are proteins on the nerve terminal membrane.  These proteins are required for the vesicles to attach to the inner surface.  It is this step that botox blocks.  The toxin clips these inner surface membrane proteins that are necessary for the vesicles to attach to the nerve terminal membrane.  We have perfectly formed storage vesicles but they can't bind and release acetylcholine into the neuro muscular junction.  No acetylcholine is being released.

 

Cholinergic nerves:

They are in the ganglia, parasympathetic and sympathetic ganglia, parasympathetic neuro effector junction, skeletal muscle neuro effector junction.

Botox is delivered locally.  Most of the applications of botox are applications that deal with neuromuscular junction, skeletal muscle, not all but most.  Botox when it enters systemically people stop breathing.

 

Some other uses of botox:

Strabismus - a disorder of vision due to a deviation from normal orientation of one or both eyes so that both cannot be directed at the same object at the same time.

Blepharospasm - spasmodic winking, blinking of the eyelids rapidly uncontrollably. 

Facial spasms - abnormal movement of skeltal muscles in the face. 

Wrinkles - cosmetic

Sweating - inject directly into or very near to the sweat glands. 

 

Go to hell bitch! F**k YOU!!!!!!!!! If I could kill you I'd do it in a heartbeat!

十四周年祭。

第n次看这篇文章:

http://blog.163.com/leaf_luo/blog/static/2400532008118104554251/?fromTodayFocus

 

大家都别动,让领导先走!这句话在大火中葬送了288名学生的命

你是否也对这些事情见怪不怪了？ 这种适应、麻木本身就让人感到悲哀。

11名官员“北美考察团”的35万元之旅: http://news.163.com/08/1201/08/4S2KOAAJ00011SM9.html ~~~ 怎么才花35万？这些领导真不愧是公仆，一切替人民着想，去赌城考察也没忘了纳税人的辛苦，太节省了！

代课老师24年未转正 讨要工资卡猝死校长室 http://news.163.com/08/1202/04/4S4MI6Q600011229.html   ~~~ 400元一个月的代课工资！ 谁还愿意当代课老师？ 当乞丐一个月都一万多呢！

9岁男孩发烧没钱看病 用红领巾上吊自杀 http://news.163.com/08/1201/04/4S262HD700011229.html  ~~~ 没有10元钱看病的可怜孩子。10元钱！红领巾的新作用--上吊！

深圳官方称"亿元资产副局长"受贿仅6万 http://news.163.com/08/1127/04/4RNRC0EH0001124J.html ~~~ 6万？ 你当打发俺们村村长啊? 妈的，太小瞧我们局长了！

十教授联名上书国务院:扩大内需应先救股市 http://news.163.com/08/1202/02/4S4G3S170001124J.html ~~~ 看清楚了，扩大内需！！！政府救市！

中国富人在巴黎狂烧钱 只买贵的不买对的 http://lady.163.com/08/1128/14/4RRGFA5M00262416.html ~~~ 除了恶俗，我想不到另外一个词来形容这些同胞。 这里面，应该也有不少人是公款消费吧。怎么老跑去扩大外需？现在见到LV包包就觉得恶心。 

结论：难怪大家都削尖了脑袋要做“人上人”！难怪大家都想着钻空子赚钱！难怪几十万人去考公务员！没钱没权根本没人鸟你；有钱，可以买官；有权，可以卖爵。平民老百姓，给人当孙子；有钱有权，咱就是爷。那你说你想当哪个？