Fundamentals II: 11:00 - 12:00Scribe: Matthew Davis

Monday, November 30, 2009Proof: Melissa Precise

Dr. PillionAdrenergic DrugsPage1 of 4

  1. Andrenergic Drugs [S28]:
  2. Now we are going to turn our attention to the adrenergic system. As we do so we will see the parallel with the cholinergic system
  3. Picture [S29]
  4. This slide is back up again to remind us that for the adrenergic system we will be looking at norepinephrine being released from neurons at sympathetic terminals, cardiac and smooth muscles, gland cells, nerve terminals and it will encounter alpha and beta adrenergic receptors. We have alpha 1 and 2, and beta 1,2,3.
  1. Figure 6-4 [S30]
  2. This again is a cartoon we saw before again just to reiterate, tyrosine comes up and gets transformed to DOPA and then to dopamine, gets stored as norepinephrine in a vesicle, the vesicle is released when the neural cell is depolarized. The NE comes out into the synaptic cleft, binds to a receptor over here, or diffuses over here, or binds to a receptor on the presynaptic neuron. Diffusion is one way NE leaves the synaptic cleft. From what we know about diffusion its not the fastest process in the world. You have NE out here looking for something to bind to and these receptors as they are available will be the first ones they get to. This cartoon is not drawn to scale, you have millions of these and so the actual place where NE is released is adjacent to the receptors on this side as well as the receptors on this side. You also have NE transporter which takes it back up into the neuron in tact. This is the site of action of cocaine and tricyclic anti-depressants. You have to make NE, you have to transport, store, release NE and the whole thing is cyclic and if you interfere with some of those steps you diminish the NE response and you get less of an adrenergic action. There are some cases where you want to do that. If someone is hypertensive you might want to get in there and block some of that affect. We will talk about uses of adrenergic blocking drugs. Some drugs block by competitively binding to the receptors and blocking NE binding while other drugs interfere by diminishing the reuptake of NE back into the cell or by diminishing the amount of NE stored in the vesicle like recerpine does.
  1. Sites where NE action might be affected [S31]
  2. This is the same slide you saw before for ACh we just morphed it to be the same thing with NE
  1. Subtypes of Adrenergic Receptors [S32]
  2. Alpha 1, Alpha 2, beta 1, beta 2. Alpha 1 formation of IP3, alpha 2 inhibits adenyl cyclase. Beta 1, 2, and 3 stimulate adenyl cyclase. The enzymes like caffeine and theophilline inhibit the enzyme that breaks down cyclic AMP so they are cAMP phosphodiesterase inhibitors. If I told you that caffeine or theophilline had the affect of inhibiting cAMP breakdown how do you think they would interact with the adrenergic system? If a drug inhibits the breakdown of cAMP it is just like stimulating the activity adenylate cyclase, it is the same net affect. So caffeine and theophilline are like beta 1 or beta 2 agonists in the sense that they increase the level of cAMP in a target cell. When I drink 5 cups of coffee my heart rate is going to go up and not down. To increase adrenergic stimulation is what I am seeing because I am inhibiting the breakdown of cAMP. It also causes broncho dilation and that is where the drug is used most successfully, in people with asthma or COPD the drug causes broncho-dilation which is an adrenergic affect.
  1. Subtypes of Adrenergic Receptors [S33]
  2. I’m going to walk through the four subtypes of adrenergic receptors and as I walk through I am going to give you the drug list so pay attention to the drugs. I know that is going to help you study for the next test
  3. Alpha 1 receptors, they work by formation of IP-3. Their function, usually NE effect is to cause contraction of vascular smooth muscle and mydriasis because it contracts the papillary dilator muscle and increase contraction of the heart. So what drugs bind successfully to alpha 1 receptors. Epinephrine binds to all four of the receptor subtypes so you can never go wrong if you say epinephrine. NE binds to 3 of the 4 receptors.
  4. Epinephrine binds to alpha 1’s, NE binds to alpha 1’s, phenylephrine binds to alpha 1. What is phenylephrine used for in optometry? We use it to dilate the eyes, it causes mydriasis. So you take phenylephrine drops and it makes the eyes dilate. So for you dentists, phenylephrine is a drug we typically put in eye drops to cuase mydriasis. If you took a lot of these drugs it would increase heart rate as well.
  5. What drugs block it? These are relatives of epinephrine of NE that prevent the binding of these drugs to the alpha 1 receptor. Prazosin, and Phentolamine. Prazosin is specific for alpha 1. Phentolamine is not, it also binds to alpha 2. So always get a test question on that. You are going to get a test question on where does Prazosin work, at what receptor, is it an agonist or antagonist? So remember that Prazosin is an alpha 1 antagonist and is used to lower blood pressure.
  1. Subtypes of Adrenergic Receptors [S34]
  2. Alpha 2’s. Remember these are the ones that are on the presynaptic membrane and they are the brake pedal that slows down adrenergic function. When the alpha 2 receptor is able to bind NE it slows down the release of NE so it is an auto-inhibitory receptor. Its function is to inhibit NE release and it inhibits lipolysis in fat cells as well, we are not sure why that is but it has been observed.
  3. Agonist: Again NE and epinephrine and now there is a specific one called clonidine. Clonidine has the effect of lowering blood pressure. Does that make sense? Remember Prazosin was the alpha 1 antagonist that lowered blood pressure because it got right to the heart cells and slowed them down. Here you have an opposite kind of drug. You have an agonist at the alpha 2 receptor but it causes the release of NE to be diminished. NE wants to speed up the heart rate, but by blocking its action or slowing down its action you lower heart rate and blood pressure. So could you give clonidine and prazosine together as a double drug to lower blood pressure a lot? You could, the clonidine would diminish the amount of NE released and prazosine would block the binding of NE to its receptor. They don’t usually get given together because the timing of the two drugs isn’t the same and there is a fear of a severe hypotensive response so you normally only take one or the other. Lots of people that have high blood pressure aren’t controlled by one drug anyway. Your body usually compensates when you take 1 drug by some reflex pathways to get heart rate back up again. Often times you take 2-3 drugs to control blood pressure.
  4. The antagonists: Yohimbine is specific and Phentolamine is not specific. Another test question is which receptor does Yohimbine bind to and what kind of drug is it? It is an alpha 2 antagonist and Phentolamine is an antagonist at both alpha 1 and alpha 2 receptors. So if you think about that, if it blocks both alpha 1 and alpha 2 it is going to, because of alpha 1 blocking effect, have an anti-adrenergic action and because of its anti-alpha 2 effect by blocking the break it will accelerate the adrenergic system. This is kind of a stupid drug because it blocks NE action but increases NE release. The net effect is you have a huge beta effect and dampen the alpha effect so it is not used very much because of this reason.
  5. This part of the system is easy once you have gone through the overall theme. A bunch of memorization but not conceptually hard.
  1. Subtypes of Adrenergic Receptors [S35]
  2. The beta 1 you have stimulation of adenylyl cyclase that increases cAMP, it increases heart rate, increases force of heart contractions.
  3. Agonists: NE also binds to beta 1’s so it will increase your heart rate. NE binds to alpha 1, alpha 2, and beta 1 but not to beta 2. When someone has an asthma attack do we take a Nor-epi pen or do we take an Epi pen and inject them with Epi? An Epi pen. You wouldn’t keep a nor-epi pen because the beta 2 receptor is predominantly found in the lung and causes bronco-dilation, epinephrine binds to it causing broncho-dilation while NE does not therefore it would be of no benefit to give an asthmatic having an attack to give them a shot of NE. The adrenal gland, when it gets stimulated, it dumps out a lot of epinephrine and NE that act as hormones. It dumps Epi in high amounts. Your nerve cells release NE so NE is the neurotransmitter but Epi is the predominate hormone that is found in the blood stream that causes bronco-dilation. The lungs do have some beta 1 and NE will bind to beta 2 with very low affinity so if you gave someone massive amounts of NE you might get some bronco-dilation but much more with Epi. Dobutamine is a beta 1 specific agonist, so if you had a failing heart that wasn’t going fast enough and you wanted to speed it up you could give them dobutamine
  4. What about a beta blocker? These are the beta blockers we have used for years and years. On the beta 1 list you see propanalol that is also included on the next list. Betaxolol is the one that is specific for beta 1. If you have someone who has a rapid heart rate what drug would you want to give them? You can give them propanolol or betaxolol. Betaxolol is more expensive but it is more specific.
  1. Subtypes of Adrenergic Receptors [S36]
  2. The beta 2 receptors cause stimulation of adenylyl cyclase. The agonist here is epi but we do not see NE. Isoproterenol is one we saw on the previous slide because it is one that stimulates both beta 1 and beta 2 receptors. And then albuterol and a couple of other drugs are specific to beta 2’s and are used in the treatment of asthma. The other drug that is used in the treatment of asthma is cheap and is a derivative of caffeine. It is an inhibitor of cAMP phosphodiesterase so it will have the same effect as these drugs have.
  3. So how about a beta 2 blocker? Propanolol and Butoxamine. There aren’t too many cases where we would want to actually block a beta 2 receptor.
  1. Alpha-Adrenergic Agonists [S37]
  2. Here is a list of uses of these different classes of drug. So for the alpha adrenergic agonists, they are used for nasal decongestion and to cause mydriasis. It will also promote vasoconstriction locally and in addition to a local anesthetic it will increase the action of that anesthetic. So the anesthetic will have a longer effect if taken with an alpha agonist then if it was taken by itself. Phenylephrine has the alpha 1 selectivity. Clonidine is an alpha 2 selective agonist that is mainly used for high blood pressure. Sedation and constipation are the main side effects along with xerostomia.
  3. The beta agonists. Dobutamine is a beta 1 selective drug that isn’t used a lot unless you have severe cardiac decompensation. And then the beta 2 specifics, Albuterol and terbutaline are used for the treatment of asthma. They can both be given by aerosols. What is the benefit of an aerosol drug? It can go straight to the lungs without much if any getting to the heart and therefore minimize side effects. The side effects however, are nervousness, headaches, tachycardia, palpitations and skeletal muscle tremors.
  1. Beta-Antagonists [S38]
  2. The beta antagonists do get used a lot clinically. Propanolol has the greatest lipophilicity and can therefore get to the brain, so there are certain considerations in people with anxiety attacks. Atenolol and metoprolol both have beta 1 selectivity, usually if a drug is a beta 1 selective antagonist it is translated in the literature as cardio-selective. When you think of beta 1 you think of the heart. That’s not to say beta 1 can’t be found in other places but in the heart beta 1 is the main receptor. So these drugs are sometimes called cardio-selective because they prefer beta 1 receptors.
  3. Labetolol in particular, has alpha and beta selectivities. And abrupt withdrawal of the beta blocker can lead to super sensitivity. Does that make since to you? If you put the drug into someone that has lots of beta 1 receptors and you put them on beta blockers for lets say 6 months when you take them off that drug now the normal NE is there but the number of receptors on the cell surface is very high and is therefore more responsive to the normal amount of NE. Therefore when someone comes off of beta blockers they get a heart rate that is way out of line and that can be due to a change in receptor number and they are therefore hypersensitive because of the effect of long duration of beta blockers. The normal amount of NE will cause a supersensitive response.
  4. And I found out today that Tamsulosin is actually used quite a bit for the treatment of glaucoma. It is selective to the alpha 1 receptor.
  1. Figure 18-4 [S39]
  2. Here is a cartoon meant to help you put a blocker with a receptor type. In a normal situation a nerve cell has millions of NE released and it will bind to receptors on post synaptic membrane, it might bind alpha 1, it might bind beta 1, and it might bind alpha 2 on its own membrane. So it would have an effect over here and over here it would bind to its own receptor and slow down the release of NE. If to put in phentolamine it will block both alpha 1 and alpha 2 receptors. NE can’t have any effect on alpha 1 because it is blocked and it can’t bind to alpha 2 to slow the release of NE. So if NE is released here it will have to bind to the beta 1 receptor because the other receptors are blocked, and since it can’t bind to alpha 2 there is no self-regulation and more and more NE will be released. This is what they were trying to show by NE being in bold here. So if phentolamine was given to a patient you would see a significant increase in heart rate because of the amount of NE being released and beta 1 being the only receptor for NE to bind to. So down here if you add prazosin it will bind to the alpha 1 receptor because it is alpha 1 specific. Because it is blocking the binding of the alpha 1 receptor, NE can be released to bind to the beta 1 receptor or it can bind to the alpha 2 receptor and slow the release of more NE. Less NE would be available in the synaptic cleft and therefore less can bind to beta 1. So a guy on prazosin won’t have as high of a heart rate as someone on phentolamine.
  1. Clinical Uses of Beta-Receptor Antagonist Agents [S40]
  2. The clinical uses of beta receptor blockers is to reduce blood pressure and in the long term it decreases the release of rennin.
  3. It can be used as an antiarrhythmatic, with beta blockers the arrhythmia that it will block is that of a tachycardia (where the heart rate is very rapid). So beta blockers can decrease heart rate. It also can be used to combat angina. This is where the heart is not getting enough blood and causing a pain response. Basically beta blockers decrease the load on the heart and decreases its oxygen demand. So you slow down its beating rate and you diminish its need for oxygen and the pain goes away. Does it necessarily fix the problem? Probably not, angina is normally an indication something else is wrong but beta blockers do usually get rid of the heart pain.
  4. Hyperthyroidism, when you have a massive amount of thyroid hormone in your blood you become hyper everything, hyperthermic, high blood pressure, and hyper everything. A beta blocker will slow that down. If someone is hyperthyroidic then a beta blocker is something good to give them.
  5. Glaucoma, high intra-ocular pressure. Timilol is a beta blocker not specific to beta 1 or beta 2. It causes a decrease in intraocular pressure. It decreases aqueous humor production.
  6. Anxiety, beta blockers can be helpful and with people with migraines, nothing has seemed to be extremely effective but beta blockers have been tried and some people have gotten some improvement from that.
  1. Major Adverse Effects of Beta-Receptor Antagonists[S41]
  2. Major adverse side effects. You can imagine bradycardia, if you slow down the heart rate too much you can get heart failure and the heart can stop beating.
  3. Controversy has come from people who use beta blockers prophalactically. Currently anyone who has had a heart attack is put on beta-blockers. Some people think that people on beta-blockers live longer.
  4. If you are a diabetic one of the things that can happen is that as the diabetes progresses you begin to lose the ability to sense low blood sugar. If you are put on beta-blockers it dampens your ability to detect low blood sugar. This is bad because diabetics often have heart attacks and you want to put them on beta-blockers. Asthmatics are at risk for heart attacks also but you don’t want to give them beta blockers because of the affect it would have on broncho-constriction.
  1. Other Drugs that Affect Norepinephrine Synthesis and Release [S42]
  2. Other drugs that affect NE synthesis and release. Amphetamines compete with NE for reuptakes. They do two things. They get put into the vesicles along side NE so that means less NE is put in the vesicles and therefore less NE is released. They also compete for uptake which causes enhanced NE effects on the cell because more NE is left in the synaptic cleft.
  3. Cocaine works in a different scenario by actually blocking the re-uptake of NE into the cell. Cocaine doesn’t get into the presynaptic cell but stays in the synaptic cleft and continually blocks the entry of NE back into the cell. So two people, ones on cocaine and one isn’t, they release NE but the guy on cocaine can’t take NE back into the cell and therefore it stays in the cleft much longer and therefore increases its adrenergic effects. Therefore his heart rate will go up tremendously. The cardiovascular effects can really be damaging.

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