Pharm: glucocorticoids

Wednesday, November 12, 2008

Glut corticoids - best we have
-control the inflammation process. Inhaled glucocorticoids have very mild adverse effects. Very well tolerated. Sometimes there’s some hoarseness but that resolves over time. Kids may have stunted growth but they catch up.
For pts with severe asthma, oral prednisone may be used for less than two weeks. But over extended period of time, we worry aobut systemic issues. We can review the side effects. The systemic side effects are the stress response primarily. That’s pretty much it. So glucocorticoids are a drug of first choice for control of asthma. There are some combinatino products, that purple discuss Advair. Two drugs. One is a long acting albuterol and the other is a glucocorticoid. Other drugs like Pulmicort is an inhaled glucocorticoid and can be used for long periods of time.

Mast Cell Stabalizers.
-Chromalin Sodium.
Mast cells are filled with granules, leukotryines and stabilizes the mast cell membrane so they don’t burst so easily in response to allergens. Used in peds and pts with exercise induced asthma. Virtually no side effects, a really nice controller. This is inhaled as well.

Leukotryine antagonists.
-also increasingly used for pts with allergy. Ltos of pts with allergy who are on leukotryine antagonists who have no asthma coupon? Growing use of this type of drug. Antileukotryines. Anti inflammatory mediators. If we block the receptors we block the leukotryines. Helps reduce the Eosinophils which infiltrate into the bronchi and cause swelling. Leukotryine inhibitors block all of that. All of these cells that come in and fix the situation actually make it worse. Fairly new in the late 1990s. One issue we should be aware of is the potential for liver injury. Pretty rare, but the risk is there.

Questions about rescuers, controllers, asthma, or respiratory drugs at all?


The next several lectures will seem to be disorganized, but it is for a reason. The book is arranged in a funky way. What She’s trying to do is separate the drugs that act on blood vessels as vasocontrisctors or vasodialators. Catagories of new drugs work on the heart as separate mechanisms and separate things. Some thigns will be repeating. Work both on blood vessels and the heart. Is a pretty complicated process managing blood fialure? And all that. Bear with me, by the Monday Dec 1st, we’ll have put the whole big picture together.

A couple of things on the blood vessels worksheet. Components of the vascular system are arteries, arterioles capillaries, veins and venules. Muscular, contract and dilate. So there is the center of where resistance will change. On the other hand, the veins and venules will not constrict so much they have a great stretch capacity. Where blood is pooled. Majority of blood is in the venous system. If I have a very wide tube, is fluid going to flow though it nicely or is it going to be kind of stuck? Great big vein, blood will go through very nicely. Nice good blood flow.
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Homework
1. What are the major components of the vascular system?
The vascular system is made up of the vessels that carry our blood. Arteries carry oxygen-rich blood away from the heart. Veins carry oxygen-poor blood back to your heart. There is one exception to that statement; when the blood starts its vascular system trip at the right side of the heart,
How do the following variables affect blood flow
a. diameter of the vessel
Vaso dilation: decreases resistance. So many of the vaso dialtors we talk about are used for HTN.
b. pressure gradient
c. vessel resistance
d. distrubution of pressure in the blood vessel:
Tissue necrosis is something you need to keep an eye out ofor. Epi, if IV comes out of vein and gets into the tissue you can get tissue necrosis. So another adverse effect of Epinephrine is crisis, constiction of arteries and we want to incrase BP we can increase it allot, way over what we want. This hypertensive state can actually cause cerebral hemmorhage. Pts who get this drug need continous CV monitoring. Its not to be given nonchalantly without monitoring BP, hear rate.
e. venous return.
3. Formula for regulation of blood pressur eis AP
What role the autonomic nervous system play in the blood pressure regulation
4. Review the nervous sytem worksheet and descrie what happens when each of the folliwng receptor types are stimulated
a. Alpha 1 If alpha one binds to the beta 1 receptors they constrict. So you will see epinephrine used in dental procedures in combination with a local anesthetic. They dilver the anesthetic to a certain spot and constrict the vessels around that spot to keep it right there. It constricts those vessels and prevents movement of tipopcal anesthesia.
Alpha one effect: Controls superficial bleeding. Put epinephrine to stop bleeding wounds.
Alpha one effect: helps treat anaphalyxis: a huge drop in BP, so by constircing the blood vessels, you push more blood to heart and increase the bp
Alpha one effect: nasal congestion. They are vaso constrictors in the nose and if they constrict, they use congestion. Not used as nasal decongestant. Epinephrine can be given in a viariaty of forms. Given topically, IV, IM, Sub Q, down the ET tube in codes in the delivery room. Can be inhaled. IN the nicu when we extibate babies and they have lots of stridor and constriciton, we give inhaled epi nebulized and it helps to constrict and reduces the constriction in their bronchi. But that’s actually a beta 2 effect.
Dopamine High doses: And then at high concentraitons: 18 to 20ish, dilation of renal vasculator in repsonse ot dopamine sitmulation, Beta 1 stimulation, and Alpha 1 stimulation. Peripheral vasoconstriction. High doses used in pts with shock and dramatically critical pts with awful cardiac output. Sick pts.
One common vaso constictor for all of them is Alpha 1, so blocking the alpha 1 receptors would cause vasodilation, and so it does. So our first vasodilator is an alpha blocker called Minpress or Vasowon?
b. Aphla 2
c. Beta 1Giving EPI can jump starrt the heart. A beta 1 affect. Hyperstimulation causes increased HR, dysrhythmias, and if there is narrowing of the coronary artery, then the increased work of the heart can cause aingina.
Dopamine High doses: And then at high concentraitons: 18 to 20ish, dilation of renal vasculator in repsonse ot dopamine sitmulation, Beta 1 stimulation, and Alpha 1 stimulation. Peripheral vasoconstriction. High doses used in pts with shock and dramatically critical pts with awful cardiac output. Sick pts.
d. Beta 2. Can be inhaled. IN the nicu when we extibate babies and they have lots of stridor and constriciton, we give inhaled epi nebulized and it helps to constrict and reduces the constriction in their bronchi. But that’s actually a beta 2 effect.
Hypoglycemia: beta 2 receptors in the liver. Breaking glygogen down, glycogenolysis, so we can creat glucose. So pts with DM, we want to monitor very carefully their glucose levels if they are on this drug. Everyone is thinking about arteries, hearts and lungs, but often we forget aobut monitoring the liver. Important for pts who are getting a lot of Epi. A while algo a baby was coded, and teacher was the nurse. She teasted the glucose and the baby’s glucose was 350, so lots of epi with ltos of stress caused huge glucose. Least of baby’s problems, but it had to be dealt with.

5. What is the result of domaine receptor activation?
Increase peripheral resistance which means I can constrict a tube or I could increase my cardiac output. How do I increase my cardiac output? I increase my heart rate, or the strength of the stroke of my heart. Increase contractility and squeeze more out with each contraction.
Changes in peripheral resistance: constriction and changes in diameter of the blood vessels.

Vaso constrictors and a couple of vasodialators.
Epinephrine and Domapmine: Ones you should HIGHLIGHT.
Remember the receptors times 2, are all of them. Alpha one alpha two beta one and beta two.

Drug interactions:
MAO inhibitors
Breaks down catecholamines to their inactive metabolites. So epinephrine, nor epinephrine, Dopamine. Monoaminone oxidase breaks down their catecoholamines. If you do this, the level of Epi goes UP. SO if MAO is given, much higher risk of seeing those adverse affects of Hypertension, tissue necrosisi, angina, dysrhytmias.
Need for FINAL
Trycyclic reactors Promote uptake of seratonin and catecolamines. This reuptake is a way to get rid of it in the synaptic cleft. So it’s the same effect as an Mao inhibitor. You have too much. And suppose you have a pt taking a beta blocker used for hypertension. What if a pt is on a beta blocker to reduce his BP but then you give epinephrine which is a beta agonist. You just cancel out the effect. So if she wants to give epinephrine to increase HR or BP because its low, she will override the beta blocker effect. Cancels it out. Same is true with Alpha Blockers.
MAO inhibitors
TCAs
Alpha inhibitors
Beta blockers.

Administeration:
Monitor IV sites
Very diluted 1 in 10,000. Make sure it’s the right dilution. Higher concentration given for other things. Always always.
Norepinephrine is similar to epi in almost all respect
Trigers Alpha 1, Alpha 2, Beta 1 and Beta 2.
Use epinephrine instead. Not one you need to highlight.

Dopamine:
-has a serious of effects that are dose related. Dopamine infusion seen in the ICU.
-Low doses: binds to dopamine receptors in the kidneys and increases renal perfusion by dilating renal vasculature.
-moderate doses: binds to the dopamine receptors in the kidneys AND to beta 1 recptors. So you get the dilation of renal vasculator AND increased HR. Moderate to high dose, you can measure HR to see if its working as well as urine output. What you really want if pt is in shock and has horrible cardiac output: BP.
Dopamine High doses: And then at high concentraitons: 18 to 20ish, dilation of renal vasculator in repsonse ot dopamine sitmulation, Beta 1 stimulation, and Alpha 1 stimulation. Peripheral vasoconstriction. High doses used in pts with shock and dramatically critical pts with awful cardiac output. Sick pts.
Measure urine output to see if renal is working

In some pts who have dopamine infusing through peripheral line, you can see a white streaking gioing through arm or leg. Reduced blood flow right around the vein in which its flowing. So if that extravagates, you have a problem.
So if moderate dose is given, stimulating Beta 1 recptors, HR ggoes up and you have a risk of Tachycardia and dysrhythmias. Then heart cant feed as well, asthrosclerosis, narrowing of artiers, you can get angina. A mismatch between work of heart and how well heart can feed itself with blood. Tlak more about it later. Don’t worry aobut it too much.

Contraindications: pts with dysrhytmias, or ventricular fibrilation should not receive dopamine or very carefully. Same with Epi or MAO inhibitors since its metabolized by same enzyme. Also TCAs, trycyclics.
Q: Why would dopamine have a complimentary effect with diuretics?
A. They both increase the urine out put. One uses dilation of renal vasculator, vs. soemting else. Work nicely together for pulmonary edema. Given by continous infusion sinc eits reapidly metabolized. Micrograms per kilo per minute. Weight based, minute to minute, in micrograms. Math of that is fun when pt is dying and you’re calculating micrograms per kilo per minute.

Vaso constirction in nose and that reduces congestion. Technically vaso constrictors.

Reduce the preload to the heart: more blood in this pool here, you have less returning to the heart. Less returning to heart is less out of the heart. Decreased cardiac output, decreased BP. This is an indirect effect of the veins. BP is direct.
So presosin
-is used for Pts with HTN primarily.
Adverse effects:
-orthostatic hypotension. Happens with first dose. Also start with low doses titrating up slowly to what pt can tolerate and what controls their BP. So don’t give targeted theraputic dose. So one issue with vasodilators is reflex tachycardia. And that is because right here in the aortic arch is a bar receptor. A pressure receptor. If you vasodialate and decrease the BP, then receptor says not enough pressure. One way to increase pressure is to increase the HR. So, for presosin this is very ture: drop in BP causes reflex tachycardia in order to bump pressure back up. So an effective drug, but it has this compensation effect by the body so higher HR is pretty normal.
- Constict Alpha 1 by stimulation, dilating in the nose vessels will cause congestion: the opoosite. Pseudoephedrine reduces congestion, the opposite would b etrue if we dilate. Nasal congestion is pretty common.
Administration: Drug is administered PO: start low doses, increase slowly. First dose don’t let pt stand up too quickly.
Indirect Vasodilators
Resurpine
Direct effect of dilation and oncstriction of these vessels. Also indirectly and how we do that is presynaptic neuron and post synaptic neuron. Precursors get taken into the presynaptic neuron, converted to Dopamine and then converted to nor epinephrine and converted to little vessicles. Under normal circumastances. Preoduce nor epinephrine and package in little vessicles. Sitmulus cause vessicles to go into surface where they pur contects into the cleft and transmission goes downstream.
Resurpine blocks production of dopamine in the production pathway. IT pokes holes in vessicles and nor epinephrine leaks out and then gets metabolized by MAO.
-prevents production of norpeinephrine
-pokes holes so norepinprine leaks out if its already. There.
So body doesn’t produce dopamine or nor epinephrine. So lower levels of nor epinephrine indirectly cause vaso dilation of the sympathetic nervous sytem. Indirect vasodilatory effect. Unfortonately respurpine goes directly int o the CNS because its very lipid soluble. So,. Which disease process did we talk about that we need to treat low levels of norepinpehrine and seratonin and dopamine? Which disease process do we need to boost concentrations in the synaptic cleft? Depression. Giving resurpine causes depression. Depleting suplly in synaptic cleft. Common, dramatic side effect of resupine. Not sued often for that reason.
-works in whole body, not just vasculator. A dramatic side effect is stimulation of intestinal motility. The Parasympathetic system gets a boost, and it seems that that increases gastric motlity and diarrhea is a horrible consequence.
-Depressed rats with diarrhea. Haha.
Guinethidine
-does not get through BBB blood brain barriar
-still horrendous diarrhea issue.
-Reduces sympathetic nervous system in body. Reduces Alpha 1 and auses vaso dilation.
-Used for: HTN,
-neither drug is popular.

Alpha 2 receptors:
A bit confusing and we don’t worry aobu them in the periphery, but we think about htem in the CNS. We are here with our neuron. Alpha 2 receptors are presynaptic receptors. So, there you can think of them as being part of a feedback mechanism. If a neuron receives allot of imput and puts allot of neurostramitter in a synaptic cleft, rush of activity, running from a bear tons of nor epinephrine in body. Tons of epinephrine in the body, escaped form bear and you need to settle. Down. High concentratin of norpehinephine and epi will bind ot alpha 2 receptor when concetration is high enough. And that signals to neuron that enough is enough and you can stop pouring so much out. Enough is enough.
-So, in the CNS there are signal from brainstem to cardiovascular system so that when you turn on the neurons in the brainstem you turn on the vascular system constict the blood vessels andc ause effects in the periphery. If you block the CNS stimulation you reduce the HR and constgriction and you get vasodilation. Alpha 2 receptors in the CNS and brainstem, turning those on will stop transmissoin in the CNS. So an alpha2 algonist that wokrs in the brain will turn this on which turns this off. This stops transmission and activaiton of the cardiovascular system and causes vasodialtion. AN that drug is called Claunadine.
Claunadine:

First mechanism: presynaptic neuron when it receives all ot of stimulation it pours a lot so fneurotramitter in cleft.
High neurotramitte rin cleft it duffises to alpha2 recptor
Pre synaptic neuron realizes enough is in cleft and turns it off.
So by turning on alpha2 you turn off the presynpatic neuron.~!
Now if you have a brainstem and utrni on the sympathetic system in the brain you turn signal in the heart and vessels to increae the HR and turn on the cardiovascular system. By turning one thing on you turn on another. Bu ti fyou turn on alpha2 recptorsi nthe brain you turn off the stimulation there. If you turn this one, that goes off in the brain. Vasodilation then occurs. Clear as mud.
AP=PR x CO
HR x SV
!!Claunadine: KNOW FOR EXAM of alpha 2? Agonists?
-used for HTN. Not sure of mechanism but used for pts with severe cancer pain.
-vasodilatory effect
-lipid soluble in CNS
-works rapidly
-Since it getes into CNS it has CNS effects like: sedation, dry mouth, does not have reliance on body position like raisoin does so you do Not have orthostatic hypotension. Acting in CNS not directly in the periphery so moving body do es not cause changes in bp. But if a pt has been on claunadine for a while and stop taking it suddenly, there is rebound hypertension that can be pretty significant that last for many days. So they are treated well, they should taper it over time, not abruptly stop it.
Guanamens and Guamycine
Similar effects to claunadine.
Methyldopa?
Similar to claunadine in mechanism
Use is an antihypertensive drug causing vasodilation works centrally, side effects of dry mouth, sexual dysfunction, and two side effects tahtare unique
-hemolytic anemia and hepatotoxicity: only drug with tehse side effects.




Renin angiogenesis system.
Lets talk about the system now. On Monday, we will cover the drugs associated with it.
So angiotensinogen:
-is converted to angiogenesis 1 by the enzyme renin.
Renin is a rate limiting step. So without renin, this reaction is very slow. Or doesn’t occur at all. Angiotesin 1 is inactive, but angiostenin 2 is highly active, and converted by angiostensin1-ase. Extremely rapid process. Renin is the rate limiting step. As soon as renin is there you have repid conversion to angiotensin 2. Renin
-released in kidney
-release triggered by:
* decreased BP and
* decreased sodium
*decreased blood volume
*decreaed kidney perfusion.
Low BP is going to be a pump in renin release to convert ot angiogenesis 1 and then rapidly to angiotesnin 2. So angiotensin’ job is to increase BP by vasoconstriction.
Aldosterone:
Renains water. Wherever sodium goes, water follows. Change in water and sodium and blood balance. Vasoconstriction happens very quickly.
Angiotensin 2 and aldosterone:
-cause cardiac remodeling which is not a good thing for pts who have these in consistently high levels. Vasculator changes as well as in thicking of the wall like athrosclerosis. Not a good thing.