Memorizing Pharmacology Podcast: Prefixes, Suffixes, and Side Effects for Pharmacy and Nursing Pharmacology by Body System

Classroom Lecture Endocrine Pharmacology Part 1 of 1

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The Classroom Endocrine Lecture Part 1 of 1, you can complete the quizzes here https://residency.teachable.com/p/mobile

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Auto Generated Transcript:

Okay, welcome to Endocrine Pharmacology: Diabetes, Thyroid Disorders, Bladder Disorders, and Erectile Dysfunction. So what I want to do is I’ll go over some of the hormonal issues first so Diabetes and Thyroid and Sex Hormones then we’ll talk about the Bladder Disorders and ED. So we’ll start with Diabetes Mellitus or the pathology.

There’s Type 1 which the pancreas doesn’t produce insulin it’s usually diagnosed in childhood and treatment requires insulin. Type 2 insulin is produced but not utilized very efficiently and traditionally diagnosed in adulthood and we’re seeing it in children now obviously with the American diet. And then treatment starts with oral medications.

Gestational Diabetes insulin is produced but not utilized very efficiently and occurs during pregnancy and continues shortly after delivery it’s treated like Type 2 Diabetes with some caveats. All forms of Diabetes result in excess glucose in the blood and the medications all focus on moving glucose out of the blood and into cells or out of the body.

The pathology of Diabetes Mellitus so multiple organs are involved in regulating insulin and glucose levels the liver the pancreas the small intestine and the circulatory system glucose is ingested with food it comes through the stomach into the small intestine where it’s absorbed from the small intestine it goes into the bloodstream that’s a donut the organs become targets.

And one we can stop the intestinal absorption of glucose two we can stop the liver from making glucose three we can increase insulin sensitivity for we can increase pancreatic insulin production and five we can just provide insulin.

So in the pancreatic beta cells uh the red cells are in the isolate and it’s called an isolate of longer hans because it looks a little bit like an island those are the beta cells they’re responsible for insulin production and release and eventually stop producing insulin this is problematic in diabetic patients.

One of the oral medications we can use for diabetes is are the biguanides or Metformin which is brand Glucophage it works on three of the targets one stops intestinal absorption of glucose two stops the liver from making glucose and three increases insulin sensitivity indications are Type 2 Diabetes Gestational Diabetes.

And adverse drug reactions include nausea and vomiting diarrhea and loose stools and lactic acidosis which is pretty rare. The diarrhea in loose stools can depend on how quickly someone has started someone on Metformin and it’s unfortunate because a lot of times this is a very good medication but when started too quickly, the patient will say I don’t want to take that stuff give me something else when if they had started at a lower dose it might have been okay.

The most common reason patients stop taking it is diarrhea 53 percent of patients experience it and it must be taken with meals so start with a low dose and gradually increase. Two oral medications for Diabetes Mellitus, The Sulfonylureas we don’t use them as much anymore because of hypoglycemia which I’ll talk about in a minute but Glyburide brand Diabeta and Glipizide brand Glucatrol these work on one of targets so one increased pancreatic insulin production a beta cells create insulin.

So indications again Type 2 Diabetes and really for Gestational Diabetes this would be last line adverse drug reactions this is real concern that we don’t really have with Glucophage that’s that we can have hypoglycemia nausea vomiting. The hypoglycemia is serious problem must be taken with meal to be prevented use it for limited time for years beta cells can only produce insulin for so long before they’re done.

Another oral medication for diabetes are DPP-4 inhibitors Cytoglyptin brand Januvia so Dipeptidyl Peptidase 4 inhibitors they work on one of targets that target is increased pancreatic insulin production so again increase indication will be Type 2 Diabetes adverse drug reactions we don’t really see too many but pancreatitis is rare.

Injectable meds for diabetes, The Insulins so Insulin is hormone that causes glucose to be taken up by cells there’s several different types of insulins difference is how long they work for so when we’re talking about um when we’re talking about um [Music] The Injectable Meds For Diabetes include Insulins so Insulin is hormone that causes glucose to be taken up by cells."

"There are several different types of insulin and differences in how long they work for. Two types are available over the counter, the others are prescription only. The indications are Type 1 Diabetes, Type 2 Diabetes, and Gestational Diabetes. The adverse drug reactions of course include hypoglycemia, that we reduce the glucose too much. Any form of insulin produces the highest risk of hypoglycemia. So even the highest dose of Sulfonylurea doesn’t come close to the risk of insulin, so this is a real concern.

One image that you want to kind of put in your brain is this one of how high the spike goes over time. So something’s very rapid acting, you see that it has a very high spike and then something short acting like regular its spike is a little lower, intermediate even lower than that and then long acting Glargine works over about a day and we’ll go through each of these but again this is something you want to kind of get in your brain that as I go and go longer I’m gonna have much lower effects overall.

So the insulin Lice Pro or brand Humalog it works within like 15 minutes with meals we use it 30 minutes before eating and it lasts for about two hours. Regular insulin works with 30 minutes within 30 minutes we use about an hour before eating and it lasts for about four hours. Now I say it’s over the counter but that doesn’t mean that you’re going to find it in the refrigerator next to the soda, it’s simply that you don’t need a prescription you can go to the pharmacy and just say hey I’d like to buy insulin and it’s possible to buy it although the cost is so prohibitive most use their insurance for it.

The other over-the-counter one is NPH Insulin or Humilin N. The P in NPH is for Protamine, it comes from trout and it works within four hours and it covers between meals and overnight so it lasts eight to twelve hours.

Finally there’s the long acting uh Insulin Glargine Lantis Baciglar and Toujeo Atlantis one way to remember it is it lasts all night. It’s very long acting and is used nightly to provide 24-hour insulin delivery.

So that’s a very very abbreviated review of insulin oral and injectables thyroid disorder agents so we begin with the thyroid it’s a butterfly shaped organ on the trachea and a healthy thyroid has a perfect balance of hormone levels not too low not too high.

If we get Hypothyroidism we go too low then we have fatigue weight gain cold all the time very shaky if on the other hand we’re way too high it’s the opposite where we can’t sleep rather than fatigue we have weight loss rather than weight gain we have sweating rather than being cold all the time and very jittery very bouncy so that’s what happens when it goes too high.

So Hypothyroidism is the most straightforward we replace it with hormone Levothyroxin and Synthroid which is literally squishing the word synthetic and thyroid together. The dose is modified based on the symptoms and the hormone levels and it takes about six to eight weeks to see the full effects.

The indication of course Hypothyroidism and adverse drug reactions kind of related to thyroid levels so we kind of look at symptoms but what we’re really worried about is going too far where we take some Hypothyroid and make them Hyperthyroid.

When we look at dosing a small dose makes a big change so it’s dosed in micrograms rather than milligrams and just conversion just remember that we have a thousand-fold difference between a microgram and a milligram so we take with water first thing in morning with nothing else is best way to do it.

And we want all dose to be absorbed consistently due to potency of hormone an anti-thyroid agent could be something like Propylthiouracil. It stops production of new thyroid hormones and dose is modified based on symptoms hormone levels so takes six to eight weeks see full effects indication is Hyperthyroidism average."

"Drug reactions are related to thyroid levels again see the Hypo Hyperthyroidism symptoms. Sex hormones and contraceptives so Testosterone it comes as Androgel or a transdermal gel it’s synthetically made but it’s identical to endogenous Testosterone. The application area should be covered to prevent transfer to children so we want to be very careful when the children around. Indications low Testosterone levels obviously and then the adverse drug reactions those things that you might expect acne prostate enlargement and Gynecomastia which is relatively rare.

Testosterone is available in a variety of dosage forms creams gels patches injections and implants and the hormone alone can be used for low Testosterone levels in men and women female to male gender conversion many different uses. Hormonal contraceptives the cycle overview looking at Estrogen and Progestin levels and how it goes from the Follicular phase the Ovulatory phase to the Ludial phase and then the egg releases from the ovary on day 14.

So as we look at the mechanism of action and kind of put this picture in our heads all the hormonal contraceptives they prevent ovulation the egg never gets released they thicken the cervical mucus so sperm can’t reach the egg all forms contain Progestins and some contain Estrogens but we don’t see Estrogen only contraceptives now. The pregnancy rates and oral contraceptives should be around half a percent but where humans, the way that we actually take it, it’s closer to eight percent but the theoretical number would require perfect adherence taking it every day exact same time.

One of the drugs this combination is Norethendron which is a Progestin with Ethanol Estradiol which is an Estrogen with Ferrous Fumarate which is iron replacement and this is Luestrin 24FE same hormone amounts in active pills for 24 to 28 days to reduce the length of menstruation but we also have these iron pills at the end. We have a combined oral contraceptive so Nordgestamate which is Progestin and again that just stem and then Ethanol Estradiol for Estrogen it’s all in Trisprintec.

And there are three different hormone amounts over 21 days each seven days days long so more Estrogen at the beginning more Progesterone at the end last week is placebo so why do we do this we’re just really mirroring the normal cycle. Another more recent not relatively recent combination is Nor Algostromine with Ethanol Estradiol in a transdermal patch so it’s applied to the torso the back or the buttock once per week for three weeks then a week off so very similar to dosing for tablets except only need one patch so it stays on all week long even when showering or bathing in actual failure rate closer to around 8 percent.

Same thing with vaginal ring so Edina Gestural Ethanol Estrodial vaginal ring or Nuvaring Progestin is Edina Gestural Estrogen is Ethanol Estrodiol it’s this flexible polymer ring that releases hormones slowly and it’s inserted vaginally for 21 days removed for seven then a new one’s inserted actual failure rate again around uh eight percent uh remote emergency hormonal contraception so we’re talking about Levonorgestrel oral tablet or Plan B One Step uh it’s a Progestin.

And it’s a Progestin only contraceptive and it’s effective up to 72 hours after unprotected sex but you really, the closer you get to uh when it happened, the better off you are. It doesn’t terminate a pregnancy, it simply is meant to prevent it. The odds of pregnancy with no contraception are normally eight percent uh Plan B is 89 percent effective so odds of pregnancy with Plan B go down to one percent but it comes at cost of extreme cramping and discomfort.

One thing that can be done is to take some soda let it go flat and sip on it, it can help with nausea. Contraceptives IUDs so Copper Intrauterine Devices Copper T380A is Paraguard so no hormones Copper is spermicidal in itself lots of cramping it’s uncomfortable at first actual failure rate is around 0.8 percent and it’s inserted once every 10 years.

There’s a hormonal Intrauterine Device IDU IUD and this releases very small amount of Progestin there’s less cramping with Copper IUD and then actual failure rate at 0.2 percent so inserted once every 5 years going on to some of bladder disorders so Overactive Bladder pathology there’s disconnect between nerves bladder muscle brain about urine quantity there’s sudden urge empty bladder even when not full.

And it’s most commonly seen in older adults but can occur anytime with male female medications focus on drying things up so Anti-Muscarinics or Anticholinergics."

However, you want to call them Oxybutynin brand Oxytroll and Ditropan Solophenosine which is Vesicare Dolterodine which is Detroit they relax the smooth muscle of the bladder the Detrusor muscle allowing more urine to fill in the bladder before needing to be emptied. Indications obviously OEB which is Overactive Bladder and then adverse drug reactions come from the Anticholinergic effects drowsiness confusion dry mouth and urinary retention.

The next issue we’ll talk about is that urinary retention which is inability to avoid the bladder content it’s caused by poor Detrusor muscle contractility so the contraction is voiding in the bladder inappropriate bladder relaxation and the medications focus on re-wetting so Cholinergic Muscarinic are the opposite of Anticholinergic so these would be ones that take care of that retention.

The one example we could use is Bethennicol or Urocholine it increases the muscle tone and contractility of the Trusor muscle allowing for bladder voiding. The indications are urinary retention adverse drug reactions so you can have excessive tear production loose stools diarrhea cramping urge to urinate all of these things are Cholinergic effects.

BPH a little bit different so the growth of the prostate that squeezes onto the urethra inhibits urine flow. The urge to urinate still there but the flow is blocked so there’s two treatment pathways we can one increase the diameter of the urethra or two shrink the prostate.

So a normal prostate is a bit larger and then benign prostatic hyperplasia we see that we have an expansion of the prostate and it puts this pressure on the urethra. The first group that we could use are Alpha One Blockers so Tamsulosin which brandon Flomax Alfuzosin which is Uroxytrol it causes relaxation of prostate increasing urine flow increases urethral diameter indications obviously BPH benign prostatic hyperplasia adverse drug reactions they’re all uncommon dizziness headache or static hypertension.

The Five Alpha Reductase Inhibitors Dutasteride Finasteride they decrease hormone production and prostate uses to grow eventually this leads to prostate shrinkage and indications BPH again and average drug reactions decreased libido and erectile dysfunction talking about that next topic ED.

So this is inability to attain or maintain an erection most men with ED have some underlying microvascular disorder whether it be hypertension coronary artery disease peripheral artery disease or diabetes mellitus type one or two treatment involves increasing blood flow to penis and we use Phosphodiesterase 5 PDE5 inhibitors Sociodenophil brain Viagra taken one hour before needed to Dalaphyl Cialis taken one hours before needed last 72 hours.

So it increases penile blood flow through Nitric Oxide induced vasodilation and indications of course ED adverse drug reactions you would expect with something that is like a nitrate so headache flushing hypotension. We do want to be careful though we don’t want to use these PDE5 inhibitors with nitrates so they must not be used with them Nitric Glycerin tablets patches gels Isosorbide minor nitrate Dinitrate okay.

The combination can cause extreme vasodilation and hypotension.

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Classroom Lecture Cardio Pharmacology Part 3 of 3 

The Classroom Cardio Lecture Part 3 of 3, you can complete the quizzes here https://residency.teachable.com/p/mobile

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Auto Generated Transcript:

Welcome to Cardiology Pharmacy Part Three. The topics we’re going to cover include Angina Pectoris agents, Anticoagulating and Anti-Platelet agents, and then MI or Myocardial Infarction agents. So let’s start with Angina Pectoris or pain in the chest.

So the pathology behind Angina or Angina begins with this pain behind the sternum and it starts pretty rapidly. Usually it’s caused by some kind of atherosclerosis from coronary artery disease but at rest the heart receives as much oxygen as needed for the contraction and so there’s an oxygen demand that meets oxygen supply and so we can represent this by a scale and this scale is even there’s no tipping of demand or no tipping of supply when exerted the heart needs to have more oxygen to be able to contract more and a healthy heart increases the supply as needed so the demand goes up the supply goes up no problem the scales are still where they need to be.

So this isn’t a problem where we do have a problem is when the heart doesn’t get the oxygen it wants it causes a pain beneath the sternum sometimes this pain will radiate to the left shoulder and arm and it will eventually reach the jaw so when oxygen demand exceeds oxygen supply and we have coronary artery disease in this exertion then we have an imbalance.

So we’re going to look at the cardiac output factors, the preload, the afterload, the myocardial contraction and the heart rate. So let’s start with the preload again that’s how much blood in the left ventricle is there before contraction, the afterload is the squeeze required to push the blood into the aorta so what’s going on afterwards, the myocardial contraction is how powerful the squeeze is and the heart rate is how fast the squeeze is.

So, the more the heart works, the more oxygen it needs and treatment involves decreasing how much the heart needs to work or getting it more oxygen. So again less demand it needs less oxygen or getting more oxygen more supply all Angina types are caused by a lack of oxygen and the treatments entail decreasing myocardial oxygen requirements so if we’re decreasing cardiac output we can decrease oxygen demand.

But let’s first take a look at classifications or the three types of Angina there’s Chronic Stable Angina which is Exertional Angina and the cause is usually Coronary Artery Disease or CAD there’s Variant Angina or Vasospastic literally a vessel and the cause is Coronary Artery Spasm and then there’s Unstable Angina where we have severe Coronary Artery Disease with clots or blockage that’s unpredictable and that’s a medical emergency so again Chronic Stable Variant or Unstable.

One medication we can use are Nitrates so with Chronic Stable or Variant Nitroglycerin brand Nitrostat causes vasodilation of the veins by directly acting on the vascular smooth muscle. The vasodilation decreases the preload so if there’s less preload there’s going to be less oxygen demand or the vasodilation can decrease spasms but it doesn’t decrease oxygen demand what it does is it increases oxygen supply.

And you can imagine this that when you have a vessel and it’s spasming it’s obviously not a nice smooth flow of blood and oxygen but when that spasm goes away we get that smooth flow again as we’re looking at beta blockers we see that with Chronic Stable Angina we can use Propranolol brand Enderol Metoprolol Tartrate Metoprolol Succinate Toprol XL and we can decrease heart rate and contractility so slower heart rate weaker pumping less work for heart causes decreased oxygen demand again sometimes compensatory reaction of heart is to increase heart rate to point that it’s difficult to fill.

And if we can slow that heart rate then we can create this lesser demand with Variant we don’t use beta blockers they don’t help at all with vasospasm so when you’re thinking about Variant we’re thinking okay well maybe I can use Nitrate or maybe I can use Calcium Channel Blocker which is next one we’ll talk about.

So Diltiazem brand Cartazam or Verapamil brand Kalin both dilate arterioles decrease heart rate contractility so this results in decreased afterload so less afterload decreased oxygen demand.

"If we want to think back to just basic physiology where calcium is so important in muscle contraction and by blocking that calcium we’re in a way decreasing the heart rate, decreasing that contractility because we affect it. We can also with variant angina induce relaxation of the spasms and cause an increased oxygen supply. So again, the two that work for variant are calcium channel blockers and nitro and for chronic stable we have calcium channel blockers, beta blockers and nitro.

Nitroglycerin can be given via different routes: sublingual tablets which is the most common and fastest outside of IV works in about three minutes and it’s an oral spray, transdermal patches as well. And then the adverse drug reactions as you would expect if you’re going to rapidly vasodilate something you can get orthostatic hypotension and orthostatic quite literally means ortho standing straight static and standing so straight standing hypotension is a rapid loss of blood pressure and then headache again from that vasodilation.

The way that we deal with someone who’s having a painful chest or having this angina and has to take a nitro pill is that if it doesn’t go away after five minutes take another tablet and call 9-1-1. The chest pain that doesn’t respond to a nitrate may be an MI or heart attack. Male patients cannot take nitrates with the PDE5 inhibitors those are the Viagra Cialis or Sildenafil as it were due to the hypotension interaction.

Okay so now we move on to anticoagulants, antiplatelets, Anoxiparon, Heparin, Warfarin, Dabigatran and Clopidogrel. The coagulation cascade is something we’re going to overview but because it all kind of meets in one place we’re going to see how it’s relatively straightforward as what we want to affect. The interaction between the different proteins or factors cause fibrin to be deposited at the end a tissue injury site and the proteins have been named long time ago and they were named as Roman numerals so factor VI is factor six and so forth.

And they were numbered based on the discovery not their function so the cascade doesn’t follow a numerical order if you’re wondering why it doesn’t go one two three or something like that. And what we’re doing is we’re going from an inactive protein to an active protein and we represent this by VII so the inactive protein 7 becomes active protein 7A.

So as we look at the pathways there’s extrinsic and intrinsic and the way that we measure them is by the prothrombin time for the extrinsic pathway or the PTT or the for the intrinsic pathway. So what we’re looking at is two different ways to get to this thrombin and fibrin and what we want to look at is where do the medications that we use what factors do they affect? So all these factors become targets for medications when we try to stop coagulation PTT and PT become important when we want to monitor how well the anticoagulation is working.

So Warfarin, we see is going to work on 9A10A 7A and then eventually Thrombin2A. The bigotran goes right to 2A and Heparin low molecular weight Heparin 10A and Thrombin2A. So when we’re looking at these, we’re going to start linking all the pathways together and we see the common middle where factor 10A or XA in the Roman numerals links both pathways together and becomes an efficient way to stop coagulation.

So anticoagulation, the Vitamin K antagonists Warfarin brand Coumadin it was developed as a rodenticide by Wisconsin Alumni Research Foundation and you see WHARF W-A-R-F which is beginning of name in 1950s. And rodenticide is something that kills rats and it prevented regeneration of Vitamin K epoxide Vitamin K used to create factors further down cascade it’s used by factors 7A 9A 10A and Thrombin which is 2A.

It’s a bit of a delayed onset five to seven days and it’s inappropriate for emergencies so dose changes take seven to fourteen days to take effect monitoring INR or International Normalized Ratio that’s marketer of time to coagulation so most patients have INR of two to three if lower than two to three increase dose or higher than two to three decrease dose.

And obviously it depends on patient depends on condition that trying prevent adverse drug reactions."

"If we have high drug levels we could have hemorrhage or bleeding, bruising, bloody stools all of these different things. There are many interactions with Warfarin and we’ll go over just a few with this pop-up. So green leafy vegetables have Vitamin K and this interacts with Warfarin and then several of the SIP 450 enzymes work on Warfarin as well so a lot of drugs change the metabolism.

So Coumarin was discovered in cattle that died of hemorrhagic disease after eating spoiled sweet clover and it was refined and developed into Warfarin is how we put this all together. Okay well that’s Warfarin in a nutshell this is an oral anticoagulant let’s look at something that’s an IV anticoagulant the Heparins both inhibit factors 10A and Thrombin 2A and are equally effective.

There’s Unfractionated Heparin which is given by injection only given in the hospital and requires extensive monitoring it’s relatively cheap but being in the hospital is not. Then there’s Low Molecular Weight Heparin LMWH or An Oxaparin which is brand Lovenox it’s injection only and it’s given in the hospital and at home there’s no monitoring required it’s quite expensive but not as expensive as being in the hospital so the choice is to take someone from Heparin in the hospital they both start with H and then go on to An Oxiparin.

Now as we look at the anticoagulants and one of the newer ones Debigatran brand Pradaxa it’s an oral direct Thrombin inhibitor it’s quite expensive but it doesn’t require monitoring. We do have adverse drug reactions like hemorrhaging, bleeding, bruising, bloody stools and while it doesn’t require monitoring not having monitoring also says that we may not know how the patient is doing as well as if we did when we had Warfarin.

So the anticoagulants work on the coagulation cascade usually we’re talking about the larger vessels but if you’re talking about a high speed vessel like an artery arteriole then we’re talking about platelets and the first antiplatelet we’ll talk about is Clopidogrel brand Plavix. So Glycoproteins 2B and 3A act as hands on the platelets grabbing more and sticking them together Clopidogrel prevents the hands from opening up grabbing more platelets to form a clot.

So what indications do we have Myocardial Infarction or MI Cerebrovascular Cerebrovascular Incident Percutaneous Coronary Intervention and then the ADR is just like with Warfarin just like with Heparin and Oxaparin and Bigatran hemorrhage or bleeding are always possible.

So looking at MI or Myocardial Infarction we’re going to talk a little bit about this and just just a heart attack so an infarct is tissue death due to the lack of oxygen coronary artery supply the oxygen to the myocardial tissues blood flow stopped usually by some kind of narrowing or blockage and then the myocardial tissue stops receiving oxygen.

So if the heart stops receiving oxygen that’s obviously a very bad thing for the patient what we can see is that when we have this blockage it’s going to stop what’s going distal to it or what’s going after the blockage and that’s going to be really really difficult for the patient because these vessels are very tiny and we don’t necessarily think of we think of the heart giving blood to the body but we forget the blood still has to give blood to itself so if it can’t do that then how does it pump the blood there that’s why a heart attack is so such a concern.

So, the two types ST Elevated Myocardial Infarction are STEMI it’s the more common uh myocardial tissue death and it releases cardiac Troponins One and T these are the best markers to see if someone had a heart attack and then the treatment we’ll discuss next. The Non-ST Elevated Myocardial Infarction NSTEMI is less common, The Troponins are also released but The ECG is going to show different rhythms. The treatment’s not covered in this lecture but let’s look at what The Elevated S STEMI rhythm looks like next to a normal heart rhythm.

So The Elevated rhythm you’re going to see here and that’s contrasted to The Normal ST Segment that we see here so The ST Segment is after The Ventricles contract and are recharging electrically for The Next Contraction. So what do we do to treat an MI? Well uh we used to have this acronym called MONA where you have Morphine for pain relief Oxygen to reduce The Infarct size Nitroglycerin to decrease preload and afterload into vasodilate and then Aspirin to be chewed to prevent platelet aggregation but The Guidelines are currently under review they’re going to be updated soon but often Beta Blockers are used instead of Nitroglycerin slow down The Heart allow it to fill because one of The Responses of The Heart is to start beating very fast because it’s noticing that it’s not getting oxygen to itself.

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Classroom Lecture Cardio Pharmacology Part 2 of 3

The Classroom Cardio Lecture Part 2 of 3, you can complete the quizzes here https://residency.teachable.com/p/mobile

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Auto Generated Transcript:

"Okay, welcome to Cardiovascular Pharmacology 2. We’ll go over hypertension agents, then heart failure agents and thirdly dyslipidemia agents. So with the hypertension agents, we’re first going to go over a little bit about what’s normal and what’s abnormal. So normal, we expect to see a systolic somewhere below 120, diastolic below 80. And again, hypertension, hyper meaning high, tension is the pressure within a blood vessel so high pressure within the blood vessel and what we want to do is we want to clarify or classify what those numbers mean. So if the blood pressure is elevated a little bit, we just say literally it’s elevated or then we have stage one hypertension, stage two or if it’s really high we’re in hypertensive crisis.

So how common or how prevalent is hypertension in the United States? 85 million Americans have hypertension and it’s associated with many other issues including heart disease like heart failure, heart attack or myocardial infarction, antenna pectoris, kidney disease and stroke. So that leaves the question, how do we treat hypertension? So what we want to do is look on the left-hand side you can see elevated versus stage one versus stage two and we start with non-drug therapy lifestyle changes throughout. Can the patient lose weight? Can they improve their aerobic activity? Can they change their diet? Can they reduce their sodium intake? Can they moderate alcohol?

On the right side, we have drug therapy which gets more aggressive as we go through starting with maybe a calcium channel blocker or thiazide diuretic or an ACE inhibitor or ARB. Once we get to stage two we start thinking two drugs combination from them and then maybe thinking loop diuretic potassium sparing diuretic beta blockers alpha one blocker alpha two ant alpha two agonist all of these trying to reduce that blood pressure.

So we’ll start by talking about some of the drugs themselves. The beta receptor antagonists or the beta blockers there’s two different kinds of beta receptor beta one and beta two because you have one heart and two lungs that’s often a mnemonic to remember okay well beta one is with the heart and beta two is of the lungs. So when you activate a beta-1 receptor in the heart you increase heart rate rhenium production is likely and so we’re going to get this increase in blood pressure if you activate beta 2 you’re bronchodilating or opening up the smooth muscle.

So this is what happens when we activate them so what happens when we block them? Well if we were to block beta 1 in the heart we would actually decrease heart rate and if we were to block beta 2 then we actually vasoconstrict.

So when we see in the next slide about the drugs that also affect beta 2 then we want to be careful with asthmatics. So let’s look at these three generations first generation propranolol which is brand enderol it’s non-selective for beta 1 and beta2 that means that while it does lower the heart rate unfortunately it can in asthmatics cause a bit of bronchoconstriction.

Second generation was an improvement on that where atenolol metoprolol tartrate metoprolol succinate are selective for beta-1 so they just reduce the heart rate and you think well that solves it but it doesn’t because what happens is the body will vasodilate or vasoconstrict and vasoconstrict to increase blood pressure against this decreased heart rate.

So the third generation was supposed to solve that so something like carvedilol or co-reg is a selective beta-1 blocker and alpha-1 blockage as well and what we have with this means that not only are we affecting the heart and reducing the heart rate but we’re also taking care of that response or that vasoconstriction that the body would normally do and hopefully maintaining blood pressure reduction.

A common adverse drug reaction for all of them is of course bradycardia. We can reduce the heart rate too much so bradycardic is a heart rate under 60."

"So, the beta blockade is thought to stop region production in the RAS system or the Renin-Angiotensin Aldosterone System. It creates limited vasodilation, they decrease the heart rate to lower the blood pressure and again the body vasoconstricts to keep the blood pressure up and then the alpha one blockage prevents the vasoconstriction to create the best BP outcomes with that third generation. But we still want to be careful, we don’t want to use those non-selective beta blockers in COPD or asthmatic patients because of the smooth muscle constriction causing exacerbations.

Let’s talk a little bit about heart failure and the pathology to start. So cardiac output can’t provide enough oxygen needed by the tissues and something we maybe forget is that the heart pumping in the heart sending blood to the tissues, it’s also sending blood to itself. So if the body can’t get enough oxygen, it might also not get enough oxygen. So we are going to classify it based on the overall effect of failure on the left hand side we have systolic heart failure, a reduced ejection fraction HFREF and the heart cannot pump well enough. On the right hand side we have diastolic heart failure so you’ve got preserved ejection fraction and the heart can’t fill enough with enough blood. So a little bit different but what’s going on with systolic is the heart can’t pump enough and then the diastolic his heart can’t fill with enough blood and the systolic is more common and this is the heart failure we’ll talk about in these slides where the ejection fraction is the percentage of blood left in the ventricle after contraction.

So, the five-year mortality rate is 50 percent and the most common cause is coronary artery disease then hypertension. So let’s look at the cardiac output factors where we have the coupling factors preload how much blood is left in the left ventricle before contraction then afterload what kind of squeeze is required to push blood into the aorta and then the cardiac factors myocardial contraction how powerful that squeeze is and then heart rate how fast the squeeze is.

So when we talk about endogenous compensatory factors for heart failure we’re talking about an increase in preload more blood in the ventricle increase in after load, the peripheral vascular constricts to keep pressure up myocardial contraction decreases and heart rate increases to try to keep blood moving through the tissues.

So, heart failure medication increases the cardiac output. So let’s look at some of the medicines. The RAZ inhibitors are RAAS, The ACE inhibitors are the first line treatment for heart failure they decrease preload and afterload through vasodilation these include Enalapril and Lysinopril. ARBs there’s not as much clinical trial data as an ACEI and should be reserved for patients who can’t tolerate them but really, one caveat is that if you get that ACE inhibitor-induced cough then we would switch someone to an ARB or a Sartan taking the last letters of Losartan Homosartan or Valsartan so ACE inhibitors are Prils ARBs are Sartans.

Another thing with heart failure is getting some of the salt water and blood volume off so Furosemide is brand Lasiks Spironolactone is Aldactone and what we do is we can decrease venous pressure and preload it allows the heart to pump more efficiently because we’re just taking off some of that fluid that would be going into the heart and it just couldn’t handle as much so any diuretic can really be used but loop and aldosterone antagonists are most common big drug reaction that would be electrolyte imbalance that comes from especially Furosemide which is hypokalemia or too little potassium and then Spironolactone too much potassium.

And then also with Spironolactone, we have gynecomastia. In heart failure with beta blockers only a few have shown benefit but it’s valuable to kind of think about why would something that slows heart rate be helpful for someone that has a heart that’s not doing its job well Metoprolol succinate and Carvedilol both will reduce heart rate until decreased heart rate interferes with daily activities what we’re saying is that you decrease heart rate a little bit so that heart can better fill.

So if a heart’s beating so fast that it can’t fill then it’s being inefficient but if it’s so slow that it doesn’t get its job done then it’s also not good so we want to be somewhere in middle adverse drug reactions of course within beta blocker we worry about bradycardia and then beta blockers are notorious for causing fatigue.

Another drug for heart failure is cardiac glycoside Digoxin or Linoxin in 90s this was drug to use but since it’s fallen out of favor it has electrical and mechanical effects to increase cardiac output and we’ll see those in next slide but it has very narrow therapeutic index which means that if you go too low it’s not effective and if you go too high it’s toxic so we want to be very careful about being between that 0.5 nanograms per milliliter to 0.9 nanograms per milliliter it’s indicated for heart failure and atrial fibrillation and adverse drug reactions dysrhythmias at very high levels nausea and vomiting can happen as well it isn’t used first line anymore it only helps with symptoms.

"There’s no mortality benefit plus there’s a lot of monitoring involved. So again, I’m going to show you how this works mechanically in just a second but heart failure and Digoxin are not the best friends that they were before. So we begin and we look at the Sodium Potassium ATPase pump and the Sodium Calcium exchanger and what we’re really trying to do is get calcium to help with the force of contraction. So we exchange sodium for potassium then Digoxin comes in have more sodium.

And then that sodium exchanges for calcium and then we see that the muscle cell will work. So this is it in words but Digoxin binds to Sodium Potassium ATPase, increases the sodium levels, sodium leaves the cell by the Sodium Sodium Calcium exchange increasing calcium levels. Calcium is used by the myocardial cell to increase the contraction strength. So how does it work electrically? So it slows down conduction velocity from the SA node to the AV node and there’s more time in between contractions allowing more time to fill.

And the heart rate decreases a bit so we can see this in the slide where we have heart failure with no Digoxin and this happens very quickly and then we have it with the jocks and it slows down a little bit allowing the heart to fill. Once we have medication effects on cardiac output we decrease preload and with ACEs and ARBs and diuretics afterloads with the ACEs and ARBs myocardial contraction can increase with Digoxin and then heart rate can go down a bit with Digoxin and Beta Blockers to help make the filling more efficient and cardiac output better.

So again preload decreased less blood fills the heart each time after load decreased it’s easier to get pump that blood out of the heart because we’re not pushing into as much pressure. The contraction is increased, we get more squeeze to pump the blood and the heart rate’s decreased more efficient blood pumping.

So dyslipidemia is dis meaning bad and then lipid so we’re in some way the lipids are just not working the way that they should so VLD or the levels aren’t so VLDL is a very low density lipoprotein it’s all about transporting triglycerides from the liver to the tissues. LDL is low density low lipoprotein so this is where the liver goes to the tissues this is the bad cholesterol.

And then the HDL is the high density lipoprotein that transports cholesterol from the tissues back to the liver this is the good cholesterol. So what’s the big deal? Well high triglyceride levels for example are associated with coronary artery disease and plaques. The treatment for lipid disorders usually it’s not dictated by blood levels anymore but hypertriglyce hypertriglyceridemia is an exception.

And we begin when triglycerides are greater than 500 milligrams per deciliter. So one example is Phenofibrate or Tricor it causes creation of more Lipoprotein Lipase breaks down triglycerides in liver so VLDL levels decrease less triglycerides for them to transport. So when do we use this? Hypercholesterolemia, Hypertriglyceridemia, and then mixed Dyslipidemia as well.

Now we might see some abdominal pain, back ache, abnormal liver function tests but when you think Phenofibrate think triglycerides. But what’s it look like when you’ve got too much cholesterol? Well you start with a normal artery but then you get this damage maybe it’s from smoking maybe it’s harding out arteries and then you get this fatty streak.

And then this fibrous cap comes on top and then cap ruptures and we see a thrombus and that occludes or blocks area. So again a normal artery everything moves smoothly number two excessive lipids accumulate form a fatty deposit called a fatty streak. The streak is covered by fibrous tissue in body and then cap ruptures and clotter thrombus forms.

And if it breaks off it can end up in smaller vessels cause thromboembolisms and so forth. So how do we treat it on left side? We have non-drug therapy so we decrease fat fatty acids cholesterol in diet try to get weight loss of 10 smoking cessation controlled hypertension on right side we have drug therapy.

And statins are definitely mainstay so HMG Koi Reductase inhibitors and we dose it based on cardiovascular risk other disease states rather than saying okay your LDL is this or your LDL is that two examples are Atorvastatin Rosuvastatin Lipitor Crestor HMG CoA is enzyme responsible for creating cholesterol in hepatocytes statins inhibit HMG CoA decrease cholesterol production.

So indications Hypercholesterolemia Hypertriglyc Ceridemia mixed Dyslipidemia famous reactions are muscle pain or Rhabdomyolysis tender tendon rupture so Rhabdo is where you kind of dissolve muscle muscle pain or Myopathy will usually precede it but that’s very serious condition uh maximum LDL lowering in four to six weeks but some results uh you can in two uh grapefruit juice any SIP three A4 inhibitors cause levels of statins to build up so we want to be careful about that.

And then it’s dosed in evening generally as most cholesterol is made overnight though Atorvastatin is one of those that doesn’t necessarily have to follow that rule. And if you were wondering what HMG Co-A stands for it stands for three Hydroxy III Methyl Glutaral Coenzyme A but most important thing to know is it’s involved in cholesterol it’s enzyme responsible for creating cholesterol in liver.

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Classroom Lecture Cardio Pharmacology Part 1

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Auto Generated Transcript:

Okay, welcome to cardiovascular pharmacology. We're going to do a hemodynamics review or an overview first, and then we'll talk about diuretics, the RAS system (Renin-Angiotensin-Aldosterone System), and then calcium channel blocking agents. So, let's start off with the cardiovascular system and just an overview of what we have going on.

So, the first thing is, what is the responsibility of the cardiovascular system? We want to distribute and transport these nutrients and oxygen to the tissues, but we also want to get rid of wastes and get them out of the body. And then there's homeostasis. Homeostasis is really just keeping things normal. Stasis means to stay in one place. So, thermoregulation, immune system distribution, hormone communication, all of these things are the responsibility of the cardiovascular system.

What are the components of this system? So, the first is the pump or the heart, and then obviously it circulates blood through the system, and then it has these three levels of vessels. So we have the distribution vessels with the arteries, the exchange vessels with the capillaries, and we'll see how depending on what area of the body we're in, those are more or less important, and then collection vessels, which are the veins.

It's important to know where the blood is distributed in what quantities. So when we're talking about the pulmonary system, only a very small amount of the blood is in the pulmonary system, and it's not as much of a pressure system either because it's just not that far from the heart; the lungs and the heart are right next to each other. Seven percent of the time or seven percent of that blood distribution is in the heart, and then 84 percent is throughout the body. In a 70-kilo male, you're talking about 5.6 liters, something like that, of circulating blood.

What is the blood made of? So there are three large components or our main components: the white blood cells and platelets (white blood cells usually help with immune function, platelets help if there's some kind of injury or bleed), and the red blood cells oxygenate, and then the plasma as well.

There's not a ton of math that we go over, but this is one important equation, and it's more important really to understand it rather than numerically, but understand what's going on. So, the cardiac output or the rate of blood flow out of the heart is equal to the heart rate times the stroke volume. Let's take each of those in turn.

So, cardiac output, how much blood flow is getting out of the heart. If there's just a little bit of blood flow, then we don't oxygenate enough, and if there's too much, then we might be trying to make up for some issues other places where the body's just not getting enough oxygen.

The heart rate: there are a couple of ways to control that, and we'll talk about those a little bit later. But just think about it this way: if you increase the heart rate, you're going to get more oxygenation as you go, and then if you decrease the heart rate, you're going to get a little bit less. So, there are some times when you're running or doing something active, you want to have a higher heart rate, and then there are times when you want it lower.

Stroke volume is another component, which is each time the heart pumps, how much volume is actually getting out in each heartbeat. And sometimes when the heart rate is too high, it just doesn't have time to fill, and if it doesn't have time to fill, then it's very inefficient. So sometimes we'll use medications that will actually slow down the heart, allow it to fill properly, and that will actually create a better cardiac output.

There are a number of factors that we talk about, and we start with coupling factors and cardiac factors. The coupling factors, we begin with preload (how much blood is in the left ventricle before the contraction), and then afterload (the squeeze required to push the blood into the aorta, and it has to be a lot of pressure to get it all the way through the body).

The cardiac factors include myocardial contraction (how powerful does it contract), and heart rate (how fast that squeeze is), and all of this adds up to the cardiac output. So, when we're talking again about preload, we're filling the ventricles before the contraction, and then with the afterload, we're seeing how much pressure does it take to get into the systemic circulation. Some factors that can affect this, for example, if someone is fluid overloaded, then it's going to take a lot more pressure to get into that space than if there isn't.

When we think of blood pressure, arterial blood pressure, we again divide it into systolic pressure versus diastolic pressure, and that's really what is going to cause this blood pressure cuff to take the measurement. Systolic on the top, diastolic on the bottom. So you see as you pump through, the blood goes out, and we go systolic, diastolic, and then we get the blood flow.

Diuretic agents: So, let's first talk about the processes involved, then we'll make a map of the nephron that hopefully will help you learn this spatially.

The kidney function is divided into three different processes. There's filtration where you clean things out, filter the fluids. You reabsorb it, so maintaining the balance, don't keep from losing those electrolytes, and then secreting or removing metabolic waste. And a lot of times when we think of kidneys, we're just thinking of getting rid of the urine, getting rid of the waste, but really there are three major processes, the nephron, and that's what this is. It's a picture of the nephron going from the glomerulus on, and we're going to call the glomerulus in the top left. You have millions of nephrons in your kidney, so again, this is huge blown up out of scale, but you start with the glomerulus.

What's important is that you have the afferent arteriole and then the efferent arteriole and capillaries in between. And that's really unusual because generally you say artery, capillary, vein. In this case, by having a high-pressure system, that means that if something is a bit closer to the glomerulus, then there's going to be more diuresis, and if it's further, there's going to be less.

Let's first get the map of the tubule transport system, starting with the proximal convoluted tubule or the PCT. Just as if someone is in close proximity to you, that means it's close to you or proximal. We go down the loop of Henle, then up the thick ascending limb, and that's where one of our most common diuretics, furosemide, works. We get to the distal convoluted tubule, just again the word distant means far, so it's far from the glomerulus, and then the collecting tubule and collecting duct.

But let's overlay this with some pressures, watch water permeability to better understand how this works. So we have very high water permeability or a diuretic effect starting with the glomerulus and going into the proximal convoluted tubule. Then when we go into the loop of Henle, we're still pretty high. As we get to the distal convoluted tubule, not as much, and then it's a bit variable when you get to the collecting tubule.

What we want to do is we want to replace these very high, high, low, and variable with drug names. So, mannitol, which is here at the proximal convoluted tubule or the PCT, is the one that's going to have the most diuresis, and we use this when we're talking about something like intracranial pressure.

Furosemide as the loop of Henle, and that's something we're talking about like CHF (congestive heart failure). HCTZ, maybe some blood pressure issues. Triamterene, spironolactone, really more valuable for maintaining potassium than they are for anything else.

When we look at mannitol, we're expanding the systemic plasma volume, forcing the kidneys to filter a lot faster, and then sodium and water are not reabsorbed in the PCT. The urine volume increases, really reducing intracranial pressure. That's one of the issues but also reducing intraocular pressure. On the adverse drug reaction side, we have headache, nausea, vomiting, electrolyte imbalances, dehydration, but usually, this is some kind of medical emergency that you'd have to use something like osmitrol.

Talking about furosemide or Lasix, we're preventing sodium from being reabsorbed in the loop of Henle. The water follows the sodium and causes increased urine formation. We're really talking about maybe pulmonary edema or other edemas that we would have throughout the body, sometimes congestive heart failure is a cause. Adverse drug reaction, so hypokalemia, we lose potassium, electrolyte imbalances, so mention the potassium but also magnesium, and then ototoxicity where we might have some issues with hearing.

The thiazide diuretics, hydrochlorothiazide (brand Microzide), they prevent sodium from being reabsorbed into the distal convoluted tubule. Water follows sodium and causes this increased urine formation. Some of the indications we'd have would be hypertension. Someone just becomes hypertensive; they might use hydrochlorothiazide or heart failure. Adverse drug reactions just like furosemide, we lose potassium, so hypokalemia, potassium, magnesium, and then in some cases, increased cholesterol levels.

The next one are the potassium-sparing diuretics, so spironolactone, brand Aldactone, this aldosterone antagonist. If you think a little bit about what aldosterone does, it helps you better know what spironolactone does. So aldosterone normally causes sodium and water to be retained, and the body holds onto it. If you hold onto sodium and water, you increase blood pressure, and that's what the body wants to do if the blood pressure is too low. But if spironolactone is blocking aldosterone, now we release this sodium and water, and now we decrease blood pressure. But again, while the indications are hypertension, heart failure, hyperaldosteronism, what we're really trying to do is often hold onto potassium to counteract either furosemide or hydrochlorothiazide's hypokalemic effect. Adverse drug reactions, so hyperkalemia, gynecomastia, metabolic acidosis, those are some of the adverse drug reactions.

Okay, the potassium-sparing diuretics move on to triamterene, which is often paired with hydrochlorothiazide as a combination. So triamterene blocks sodium resorption in the collecting duct and the distal convoluted tubule. Water, again, follows sodium into the urine, so we would see this with hypertension and edema, but again, compared to furosemide, hydrochlorothiazide, it is certainly nowhere near the amount of diuresis. Adverse drug reactions include hyperkalemia and then certainly electrolyte imbalances, but now we're going the other way, just as with spironolactone, we're holding on to the potassium rather than getting rid of it.

Next slide is the renin-angiotensin-aldosterone system or the RAAS system, taking the R, the A, the A, and the S, and we'll talk about a few medications here. So the RAAS system is meant to maintain fluid and salt in the body, regulate blood pressure, and there are two main enzymes that are involved, and it'll be critical in understanding how the medications work and knowing how this very straightforward RAAS system works.

So, angiotensinogen goes through renin, and when we think of an enzyme, we usually think we're going to see an ace, and a lot of times you can have an in at the end instead of the ase, and that's what renin is. It's an enzyme that gets angiotensinogen to angiotensin one, and it's a response to low arterial pressure, low sodium, where the body's saying, "Hey, our blood pressure is a bit too low. We need to raise it. Please release renin, the enzyme." And once that enzyme goes out, then angiotensin 1 forms.

We have to go through one more step, and that next step is the angiotensin-converting enzyme, which we call ACE. So once ACE gets in there, we get the angiotensin II. So we've gone from angiotensin one, from the liver to angiotensinogen to angiotensin one to angiotensin II. Angiotensin II does two important things: it promotes sodium and water reabsorption, but it also maintains constriction of the arteries. Both things are going to increase blood pressure, which is what we want. But if you have someone who's hypertensive and you want to lower their blood pressure, well, we're going to want to block some of these pathways or some of these steps.

ACE inhibitors or ACEIs are going to block at the angiotensin-converting enzyme step, and the angiotensin II receptor blockers are going to block at the receptor, bypassing the enzyme. And these two ways of doing it are really helpful.

Let's talk about the ACE inhibitors versus the ARBs. So the ACE inhibitors like enalapril and lisinopril, enalapril's brand Vasotec, lisinopril's brand Zestril. Both of these end with "pril," that's a common suffix, and they stop the angiotensin-converting enzyme. It prevents the conversion of angiotensin I to angiotensin II, so we don't get that salt and sodium and water retention, we don't get that vasoconstriction, hopefully lowering blood pressure.

So the indications include hypertension and heart failure. Adverse drug reactions we can see hypotension, dry cough, hyperkalemia. So again, we want to be mindful. For example, if we're giving a diuretic, and that diuretic causes hyperkalemia, we could make the condition even worse. This dry cough is not something that you treat, rather you discontinue the ACE inhibitor, and you would go to the ARB, which is in the next slide.

"So, an ARB or Angiotensin II Receptor Blocker. We’re going to first go over the three examples: Losartan which is Kosar, Omasartan Benicar, and Valsartan which is Diovan. So we see the Sartan ending and that again our suffix and that again helps us know that these are ARBs. We prevent Angiotensin II from binding to sites on kidneys and arteries that causes vasodilation and prevents sodium reabsorption. Indications again are hypertension and heart failure and adverse drug reactions can include hypotension where we take their blood pressure too low and hyperkalemia again just like the ACEI. Here’s a caveat: there’s no dry cough adverse drug reaction so we may need to switch a patient from an ACE to an ARB if this presents. They should not be used together because the outcomes are no better and we can cause renal impairment as well.

Calcium blockers or calcium channel blockers, we’ll go over the two major classes. So the first class is, well let’s start with what calcium does. Calcium, we need it for smooth muscle contraction and the vasculature, the blood vessels use calcium for vasoconstriction. So if we block the calcium from entering the smooth muscles it causes vasodilation or opening up the vessels. The heart uses calcium for regulating the timing of the contraction so if we block calcium in the heart we can help reduce arrhythmias.

But let’s look at the two different categories and we use a very formal chemical class it’s either a non-dihydropyridine or a dihydropyridine. So the non-dihydropyridine is what we’ll start with: Dotism brand Cartism Verapamil brand Kalin. These block the calcium channels in the heart and blood vessels. They’re used most commonly for dysrhythmias and indications include hypertension, antonopectorus, cardiac dysrhythmias and we’ll see that that’s going to be missing from the next group of calcium channel blockers, those cardiac dysrhythmias.

Adverse drug reactions: constipation, bradycardia and why are those? So the first constipation because again just like with the muscles your body when it’s trying to use the GI system also uses calcium and if you take block that calcium it makes it harder for the GI system to do its job and get things out of the body. Bradycardia is on the other end where instead of just lowering heart rate a little bit maybe we reduce heart rate a bit too much and we make the patient bradycardic.

The other group of calcium channel blockers are the dihydropyridine so Amlodipine which is brand Norvasc, Nifedipine which is brand Procardia. You notice that the peen ending a lot of people say oh that’s a dip in blood pressure is a way to remember it. So we block the calcium channels in the blood vessels there’s no heart activity so there’s no using these for dysrhythmias and it’s most commonly for hypertension but again we see the hypertension angina pectoris as two of the indications but we don’t see, and I’ll go back to that slide, uh, the cardiac dysrhythmias that we did with the non-dihydropyridines.

Adverse drug reactions: we could get some peripheral edema again we’re vasodilating and we could get some headache again from that vasodilation.

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The Classroom Neuro/Psych Lecture Part 4 of 4, you can complete the quizzes here https://residency.teachable.com/p/mobile

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Auto Generated Transcript:

Okay, welcome to Neuropsych 4. We're going to go over three topics: local anesthetics in a little more detail than when we first talked about axonal conduction versus synaptic transmission, substances of abuse, including alcohol and nicotine.

So, the two different steps to neuron signal transmission are the targets for medications. The axonal conduction, like the local anesthetics, the drugs aren't selective. All axons work basically the same. There are many adverse effects relative to synaptic transmission. Although they can certainly have some, there are very few medications that inhibit this transmission in this way. On the other side, the synaptic transmission drugs, like the selective serotonin reuptake inhibitors that affect serotonin, or the serotonin-norepinephrine reuptake inhibitors that affect serotonin and norepinephrine, they can be really selective, working on different synapses, specific neurotransmitters, and most medications work this way because we want something selective rather than something that is not selective.

Again, the mechanism of action for a local anesthetic is to inhibit sodium channels. It stops the action potential and the neurotransmitter release. Benzocaine is one example. You can use it over the counter to take care of a toothache, and it's an ester type, so it would be more allergenic and a little bit more of a concern if you were going to inject it. Whereas lidocaine, which you can find over the counter as well, like Solarcaine, is an amide-type that causes fewer allergic reactions. This is one we prefer. We'll talk about lidocaine in a very different use - an injectable use - in a minute. But in this case, when everything's topical, there's not really much of a difference. It's just that you wouldn't really want to inject something like benzocaine. There's less of a risk of CNS depression with something like this than an inhaled systemic anesthetic, just as a caveat. Local anesthetics work on the fast-firing neurons, and the sensory neurons are the ones that fire most frequently. It eventually inhibits the motor neurons but on a graph of time to loss sensation, we begin with getting rid of the pain, then cold, then warmth, touch, pressure, then the motor function. A local anesthetic like an epidural, we would inject into the epidural space that surrounds the spinal cord. Lidocaine, bupivacaine, these are often used for this, and the spinal injections go even closer to the spinal cord. You can get severe hypotension - that's "hypo" meaning less tension in blood pressure, so a severe reduction in blood pressure. Headaches can occur, and then the headaches can be resolved by lying down.

So another use for local anesthetics is going to be when we're talking about Lidocaine and you're going to the dentist. The local anesthetic can cause a bit of vasodilation where the vessels open up, and that creates really fast absorption in a short duration of action. When you're going to have a procedure, you don't want a short duration of action. You want the dentist to have all the time they need to work on whatever's going on with your teeth in as long a time as they need. So what they can do is add a vasoconstrictor to counter these effects. It slows absorption, lengthens the duration of action up to 100 percent, and also reduces some risk of toxicities. Epinephrine is commonly added with local anesthetics.

The first substance of abuse we'll look at is alcohol. It's been consumed for thousands and thousands of years. It used to be there's a book that talks about this great kind of water really caused a real problem back in the day in that getting clean drinking water was really tough, and one well was affected by a diaper.

I think it was that it was in someone's basement, and I know this sounds gross, but what happened was the water went through the feces into the well, and then there was this great cholera epidemic. But one of the area businesses had no problem with cholera, and that business was a brewery, and the workers there would drink during their lunch break. It wasn't the beer that you're thinking of now; it was more like food back then. That was a way to keep drinking water safe because the alcohol would kill the bacteria.

Alcohol we're talking about now is one of the most commonly abused substances in the US and the world. Seventy-five percent of US adults consume it regularly; eight percent have an alcohol abuse disorder, and three percent of children or adolescents have an alcohol abuse disorder. So it's very widespread. What happens with alcohol? Well, if we're doing it in moderation, the effects on the body are a discrete decreased risk of ischemic stroke, coronary artery disease, myocardial infarction, and heart failure. You may have heard this: that a couple of drinks is protective for your cardiovascular system. However, it's very tough because alcohol can be addicting. So, the misuse effects on the brain generalize CNS depression, activates the reward pathway, and kind of feeds into it that you want it over and over again.

So what happens with certain blood alcohol levels? I'm not sure anymore, but I know that some states have even lowered the 0.08 to even a little bit lower than that, but legal intoxication is where you've got a slowed reaction, and the idea is that if you're drinking alcohol, you're more likely to hurt someone else while you're driving a car. As we go up, and we usually hear like 0.08 is the legal limit in most states, but as you go up, you not only impair motor function, but you can go into a coma and you can actually go into respiratory depression and death. So very dangerous in quantities that exceed that moderation.

We can have acute renal effects, so anti-diuretic hormone causes the kidneys to reabsorb water and decreases urinary formation, and alcohol inhibits ADH in the pituitary gland. It acts as a diuretic and increases urine formation. So when someone's drinking alcohol, sure, they're drinking 12 ounces or 24 ounces of liquid, but the alcohol itself is a diuretic and acts as a diuretic. That's why they're urinating. It's not necessarily that they're just drinking all of this water.

What are the chronic issues that are going to happen to the liver? First of all, we get fatty liver swollen because of fat accumulation. This is reversible. Hepatitis or fibrosis, where scar tissue forms, it's possible to recover, but the scar tissue remains. Cirrhosis is where the connective tissue destroys the liver cells or the hepatic cells, and this is irreversible.

There are a couple of different issues that come along with this. First of all, there's Wernicke's encephalopathy, where you have these involuntary eye movements, mental changes, and ataxia. This is an issue of thiamin deficiency. Korsakoff psychosis is a chronic memory disorder, brain lesions formed because of the lack of thiamine. Wernicke's encephalopathy usually goes away with thiamin administration. Korsakoff psychosis occurs in 85 percent of Wernicke patients that survive, and that unfortunately is permanent.

Another issue is pregnancy. So fetal alcohol syndrome, alcohol is teratogenic, it's a leading cause of mental retardation and congenital malformation in the United States. It can cause certain abnormalities, including craniofacial malformations, growth restrictions, neurodevelopmental irregularities, and withdrawal symptoms can be pretty severe as well.

So the days since last drink on the bottom, have it at 2, 4, 6, 8, and then this very long 30 to 90 days. But if you don't treat it, it can cause ultimately death. If you have tachycardia, hypertension, fever, tremor, delirium, agitation, seizures, those things can be deadly. Hallucinations are possible around the second to sixth day. Anxiety, insomnia, tremors, nausea, and anorexia. And you can see that if someone doesn't get alcohol, these are the things that are in the future for them. Why they would just continue to drink, continue to drink, not only for the pleasure of it but to avoid this withdrawal syndrome.

There are three primary medications that you'll see with someone that has a diagnosis of alcoholism. Naltrexone (Vivitrol), it inhibits the mu-opioid receptor and the euphoria. Disulfiram (Antabuse), literally anti-abuse, creates incomplete alcohol breakdown, building up acetaldehyde, and it causes flushing, headache, and severe nausea and vomiting. But the thing with this is that a patient can just say, "Well, I'm not going to take these pills, and then I won't feel this bad effect." And then the last one is acamprosate (Campral). This binds to the same sites as alcohol in the CNS and prevents the uncomfortable feelings from abstinence. So three different ways now that we can attack this alcoholism. But again, it's a very, very, very difficult thing to get away from.

The second substance of abuse we'll talk about is nicotine. And as with alcohol, it's prevalent. It's a substance with the most people addicted to it around the world. It's the greatest cause of premature deaths and preventable illness in the US. And it's delivered via cigarettes, electronic cigarettes, cigars, chewing tobaccos. Many different ways that someone can get nicotine, and it only takes eight seconds for 90 to 98 percent of nicotine to be absorbed by the lungs and bind to receptors in the CNS. If you're watching rather than listening, I'm going to show you an animation that is in real time, that is eight seconds worth. So that's it, and then you could do the "one one thousand, two one thousand, three one thousand," and so forth, and see just how quickly it goes into the lungs and then into the brain.

Nicotine is actually a mixed agonist-antagonist. If you have a very low dose, it's very activating to the nicotine receptor, and there are cardiovascular, GI, and central nervous system effects. If you have a very high dose, it actually blocks the nicotinic receptor action, and that's acute poisoning. Nicotine is more complex than just something that makes you feel good. Depending on the dose, it can have very different effects. The GI effects begin by activating the nicotinic receptors in the parasympathetic "rest and digest" system. This activation causes increased acid secretion and GI motility and can promote vomiting. So when you see someone has an ulcer and you see that the person's not supposed to smoke, this is why. The second part is it activates nicotinic receptors in the sympathetic system, the "fight-or-flight" response. So norepinephrine and epinephrine are released, and we see this increased heart rate, constricted blood vessels, and increased ventricular contraction force.

So what do we do to stop smoking? What are the options, and there are a lot of them?

So there are five FDA approved OTC dosage forms (over the counter dosage forms) to help stop smoking:

1. Chewing gum

2. Lozenge

3. Inhaler

4. Nasal spray

5. Transdermal patch

For the gum, the gum must be chewed for nicotine release. You chew and park it between the gum and cheeks for 30 minutes, then repeat. Some of the drug reactions are throat and mouth soreness, kind of aching jaw muscles, get hiccups, get belching, a little bit of an uncomfortable situation with those. But I've heard success stories from all five different forms. It really is personal to the person and deciding what is the best way and what would do the best job of replacing not only the nicotine itself but the action of smoking. I used to have a teacher who would hold their chalk as if they had a cigarette in their hand, and you could just see that the first thing that they were going to do after they got out of class was replace that chalk with a cigarette. So there are mental components as well as physical components that go along with the actual activation of nicotine cessation.

So there are two FDA approved medications for smoking cessation. The story behind the first one, which is bupropion SR (Sustained-Release), has another name called Wellbutrin. It first came out as an atypical antidepressant, and what people found was that while they were getting treated for depression, they just really didn't have much of an urge to smoke. The manufacturer said, "That's great, let's change the brand name from Wellbutrin, which was for depression, let's repackage it as something that's going to help someone with smoking," and they called it Zyban to ban smoking. Now, the issue with bupropion, which we'll talk about in a second, is that there can be some risks with seizures. On the other end, there's varenicline, which is branded as Chantix and has great results, but there can certainly be some side effects with that, which I'll talk about in a second. So these are the two choices that we have.

Bupropion sustained-release, brand Zyban, is the only SR formulation approved for smoking cessation. It's again an atypical antidepressant. We're not exactly sure how it works, so it doesn't fit neatly into SSRI or SNRI and things like that. It decreases the urge to smoke as these depressants were taking the medication, and it reduces withdrawal symptoms. The anxiety, the irritability, all those things that people have as they try to stop smoking. Adverse drug reactions that can come along with it include insomnia, which seems counterintuitive, but some agitation as well, dry mouth, and headache. Here's the big caveat, though: it lowers seizure threshold. Don't use it with a history of seizures. What that means is there's a certain threshold that something has to happen in the brain for someone to have a seizure. This drug would make it easier for that seizure to happen in those with a history of seizures.

The other drug is varenicline or Chantix, and this is a partial nicotinic receptor agonist. It prevents withdrawal symptoms and blocks that nicotine reward pathway. It's the most effective medication for smoking cessation. I personally have heard people that have stopped in a few days, and the issue that they had were some of the side effects: nausea, insomnia, very abnormal dreams, very vivid dreams, headache, and skin rash. The adverse drug reaction for nausea is dose-dependent, so maybe almost a third, maybe a little more, two-fifths can experience that nausea, but the more that someone has to take, the more prevalent the nausea would be.

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Classroom Lecture Neuro/Psych Pharmacology Part 3 of 4

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Auto Generated Transcript:

Okay, welcome to Neuropsych Pharmacology Three. We have three topics in this section: Parkinson's disease agents, Alzheimer's disease agents, and anti-epileptic agents. The first Parkinson's disease agent we'll talk about is levodopa-carbidopa and selegiline. So, how these work is, we have to kind of go back to the Parkinson's disease pathology. In the substantia nigra, we have an accelerator and brake pedal for the motor cortex of the brain. So, dopamine is the accelerator, and GABA, a neurotransmitter, is the brake. So the normal...

Dopaminergic neuron releases dopamine, and then the GABAergic neuron releases GABA. Okay, and when that happens that way, then we get smooth movement, green light, everything's working fine. With the pathology that comes along with Parkinson's disease, we get low dopamine and elevated acetylcholine. If that's the case, then we're going to see that the movement is not smooth, that the body is very jerky, and we're going to see some very specific movements that go along...

...with Parkinson's. So Parkinson's disease presents as postural impairment, it's difficult to maintain a straight posture, tremors, rigidity of the limbs in the body. Just like bradycardia is a slow heartbeat, brady is low. Bradycardia is less than 60 beats per minute. Bradykinesia, just like kinesiology is a kinesiology major, majors in the study of movement. Bradykinesia is a very slow movement. There's feet shuffling, but it's very distinctive, the Parkinson's presentation.

The treatment goal is to restore dopamine levels in the brain. But it's not as simple as just saying, "Okay, we'll just put some dopamine in their brain." The problem is that dopamine does not cross the blood-brain barrier (BBB). As we grow or as we're born, our blood-brain barrier protects us from many different toxic substances, but unfortunately, with many neuro drugs, it actually prevents something that could really help us from getting there. So the solution is to give a dopamine precursor that does cross the blood-brain barrier, and that precursor is called levodopa; it's also known as L-DOPA. All Parkinson's disease patients eventually require levodopa. It crosses the blood-brain barrier, no problem, and it's converted to dopamine in the brain. We have a second problem, though, in that it converts the dopamine in the peripheral tissues before it even gets to the brain by an enzyme called dopa decarboxylase. This is kind of a deal-breaker.

Until we add dopa decarboxylase inhibitor to stop the conversion. That's called carbidopa. So carbidopa is the dopa inhibitor blocking the enzyme. In a little bit of a different way, it's structurally very similar to levodopa. Because of that, it kind of distracts the enzyme to target carbidopa instead of levodopa. So it's over here, and then levodopa makes it to the finish line, makes it to the brain. So what we have is this combination of levodopa-carbidopa (Sinemet). We adjust the dose based on the symptom response, and then over time, patients will report on and off as the response diminishes. On is the medication working, we've got good movement; off the medication is not working, we've got tremors, rigidity, slowness returns. It should not be given to those with psychosis of any kind because what we're doing is we're adding dopamine and this could be a really bad thing if someone has psychosis. It takes months to see full effects and then there could be a hypertensive crisis if given with non-selective...

...MAOIs, so those are the three caveats to watch out for with carbidopa or levodopa. Carbidopa, another drug that we can use, is selegiline and in the brand name you can see Eldepryl and they were going for elderly that many elderly find this Parkinson's disease is something that they have. Monoamine oxidase B, it's a monoamine B inhibitor and the a isomer of the enzyme breaks down norepinephrine, serotonin or 5th and dopamine. The b isomer breaks down dopamine selectively so it slows the breakdown of this dopamine in the brain and it allows for lower doses of levodopa so two different ways of approaching Parkinson's disease. In both cases, we want to make sure we can get more dopamine in the brain. It should not be given alone and levodopa-carbidopa must also be given to be effective in Parkinson's disease.

"Alzheimer's disease agents, so we're just going to talk about two of them: donepezil and memantine. The thing about Alzheimer's disease is you can never really know until after someone has passed if the person had Alzheimer's disease.

You have to actually look at their brain and see, you know, okay, well, this is what we're seeing, and we'll see what the pathology looks like in the next slide. But the exact cause we still don't know. There are some anomalies or things wrong within the hippocampus. The current treatments can slow disease progression, but there's no cure yet. Diagnosis to death can occur in four to eight years or it could be a bit longer; it depends on who you're reading.

Symptoms: A lot of times, we think just about the memory loss in Alzheimer's, and that is certainly one of the things that happen with it, but there's also impaired thinking, cognitive decline, and the inability to perform activities of daily living. So it's extremely hard on the patient, certainly, but it's also extremely hard on the partner or caregiver as well.

The pathology: So we have this neuron, and we're going to have these amyloid plaques, which are a hallmark in the anatomy of Alzheimer's. Decreased acetylcholine levels, these deformed microtubules, and the neurons are just kind of a mess.

So, what can we do with it? Well, two classes of medications we'll talk about are cholinesterase inhibitors and NMDA receptor antagonists. The first thing we'll talk about is how a cholinesterase inhibitor works. Much like Parkinson's, where we can't just give dopamine, we can't just give acetylcholine. So instead of giving acetylcholine with donepezil (brand Aricept), which is for mild to moderate symptoms, it prevents the breakdown of acetylcholine, which is a common neurotransmitter. By preventing the breakdown what we do is allow more acetylcholine to be around. The thing is, if you allow more acetylcholine to be around, you're going to see that we're going to have cholinergic adverse drug reactions. We're going to see maybe nausea, vomiting, diarrhea, some dyspepsia as some of the side effects. As you can see in the graphic, it's only effective for 1 in 12 patients. So not the best prognosis for a medication.

Another drug, memantine or Namenda, is an NMDA receptor antagonist. You can see the brand name Namenda, and it regulates calcium levels in the neurons by binding to these NMDA receptors. So high calcium in the neurons is implicit for Alzheimer's disease. We have decreased learning and memory ability, neuron degradation. Regulated calcium in the neurons increased or normalized learning memorability, increased neuron lifespan. But those are the two Alzheimer's disease medications.

Anti-epileptic agents: We're going to first talk a little bit about epilepsy itself, kind of just a very big view of some of the conditions that someone can have. Epilepsy is a chronic seizure condition. We have hyperexcitability of the neurons in the brain. And 70 percent of the time, it's primary; it's idiopathic. We have no idea what's going on, maybe genetic CNS abnormalities. But we need chronic treatment with medications. So these are for partial focal simple and complex generalized tonic-clonic absence myoclonic febrile or fever seizures and status epilepticus. Secondary or symptomatic seizures are caused by illnesses, and so a temporary anti-epileptic treatment is needed until the underlying cause is corrected.

So these seizures can happen, and it's really about figuring out whether it's the illness that's causing it or if it's something that we're just not sure about. But really, the anti-epileptic treatment for each type is pretty much the same. A term that I want you to know, though, is that the seizure focus, that's where the beginning of the seizure is. So in terms of the anti-epileptic agents, they decrease neuronal activity during the seizure focus, they slow or stop the spread of the seizure from the focus to other areas of the brain. But there are these two terms that we want to make sure we're clear about: a seizure is any type of epileptic event, whereas a convulsion is just an abnormal motor phenomenon. So these are just a little bit different. But let's look at some of the medications that we can use.

So as far as the older medications, carbamazepine is one of them, and it inhibits sodium channels on hyperactive neurons and prevents sodium from entering the neuron, stopping the action potential. But we have serious adverse drug reactions, including bone marrow suppression. Grapefruit juice can increase levels. Divalproex or Depakote works in three ways: it inhibits sodium channels on the hyperactive neurons, just like carbamazepine. It inhibits calcium influx into the neurons and promotes GABA activity and release. But there are some serious adverse drug reactions in hepatic and pancreatic toxicities, teratogenicity, and interactions with phenytoin.

The third of the traditional anti-epileptics we'll talk about is phenytoin or Dilantin. It inhibits sodium channels on the hyperactive neurons, prevents sodium from entering the neuron, stopping the action potential, the same as carbamazepine. But it requires lots of monitoring. Small dose increases can cause toxicities, and small dose decreases can cause therapy failure. So what we want to do is make sure we're monitoring appropriately and keeping phenytoin at the right levels.

And then two of the newer medications, just to give you some examples. There are many newer anti-epileptics. Gabapentin, which is Neurontin, and pregabalin, which is Lyrica. Pregabalin happens to be the metabolite of gabapentin, and both work as adjunct therapy for epilepsies. Common adverse drug reactions include drowsiness, blurry vision, and peripheral edema. But that's really how you want to divide them. The older drugs, which we know quite a bit about, have a lot more history, and the newer drugs may have a little bit fewer adverse drug reactions, but we're not necessarily as confident sometimes with the newer ones in terms of what we know about what seizures they work for.

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Classroom Lecture Neuro/Psych Pharmacology Part 2 of 4 

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Auto Generated Transcript:

Okay, welcome to Neuro and Psych Pharmacology 2. We're going over sedative-hypnotics, anti-anxiety, and ADHD medications. We're going to start with sedative-hypnotic agents first and then ADHD agents second. So let's get started with an overview of the difference between a sedative and a hypnotic.

A sedative is often referred to as an anxiolytic, which means it's meant to reduce anxiety and calm the patient. On the other hand, a hypnotic helps the patient fall asleep and may also help them stay asleep. Some medications work to help the patient fall asleep, while others may help them stay asleep. The choice depends on the patient's needs.

Now, let's dive into a specific class of sedative-hypnotics, the benzodiazepines. In a normal neuron, we have gamma-aminobutyric acid (GABA) receptors and normal action potential firing. Benzodiazepines bind and activate GABA receptors on neurons, allowing chloride ions to enter. This makes it more difficult for the neuron to fire action potentials, helping to calm the patient.

There are several benzodiazepines, and you can remember a few of them using the "CALM" mnemonic: C for clonazepam (Klonopin), A for alprazolam (Xanax), L for lorazepam (Ativan), and M for midazolam (Versed).

Benzodiazepines have various indications, including treating anxiety, panic disorders, sedation, anesthesia premedication, and seizures. However, in this section, we are focusing on their use for insomnia. Some common adverse reactions include drowsiness, dizziness, confusion, and central nervous system (CNS) depression.

It's important to note that benzodiazepines should not be combined with opioids, as it increases the risk of CNS or respiratory depression. Prolonged use is not recommended due to the potential for abuse.

The onset time of benzodiazepines when taken orally can vary. Alprazolam and clonazepam may take an hour to start working, while lorazepam may take up to two hours. In emergency situations, intravenous midazolam can be used, which works within minutes.

In the context of treating insomnia, it's essential to consider how the medication may affect the person's daytime activities and ensure it's the right fit for their needs. Some people may feel fine with just five hours of sleep, while others require seven or more hours.

But the benchmark is, is it affecting your day? How are you feeling throughout the day? And if you can’t do the things you normally need to do, go to work and those types of things, then that’s insomnia. So the patient’s symptoms are going to drive the individual treatment. If you’re just anxious about things, and I don’t want to say just, but if there’s an anxiety component, we would treat that. And if it’s a sleep component, then we would treat that. But individual treatment based on the condition.

Benzodiazepine-like is actually not a benzodiazepine. They’re structurally different but have the same mechanism of action. They produce only hypnotic effects, so they’re only going to be used for sleep. But how do we decide between two like Eszopiclone, which is Lunesta, or Zolpidem, which is Ambien?

With Eszopiclone, there’s no real limit on the duration of use. If someone needs it for six months, nine months, something like that, this is what we would probably turn to. Whereas Zolpidem we can only use for three to six months. There is a metallic aftertaste and while uncomfortable, it’s something that most patients can tolerate. But certainly, if we don’t have to have something like that, it would be nice to use Zolpidem where we wouldn’t have to deal with that.

And then the adverse drug reactions are similar to benzodiazepines but the advantage of these is that these are specifically for that sleep state and the hypnotic effects.

Another form of a sedative hypnotic is a melatonin agonist. So again, an agonist activates and melatonin in the brain is a hormone that produces sleep. Ramelteon or Rozerem and you can see the REM like REM cycle at the very end of that or rose rhymes with dose that’s another easy way to remember what it’s for.

Instead of giving the patient melatonin we’re just going to activate the melatonin receptors as if there was melatonin in there and that will cause drowsiness. There’s no abuse potential like the benzodiazepine and benzodiazepine likes this isn’t scheduled like the other one so that wouldn’t be as big a deal and then there’s no limit on the length of use and the adverse drug reaction is very similar to placebo so if a patient can use Ramelteon certainly a good choice.

Patients may try to self-treat and go over the counter before they ever go to a prescriber and the first-generation antihistamine Diphenhydramine does produce drowsiness. We usually find it in Acetaminophen with Diphenhydramine or Tylenol PM. The Tylenol is there for pain because a lot of times pain will keep someone up at night but the combination takes care of the pain takes care of the insomnia or tries to at least so with these though we’re going to see adverse drug reactions that are cholinergic or anticholinergic effects like dry mouth blurry vision constipation which can be quite troubling for the patient and it only works for a week or two because the body will become tolerant to the drowsiness and you’ll still get the side effects so this is a very short-term solution not a long-term solution.

Next, we’ll do the anti-anxiety agents and talk first about what anxiety is. It’s an emotional state from a real or perceived danger so if someone is worried about something it’s still going to activate that same fear center that a real danger would even if it’s not going to happen.

What are some of the characteristics? Apprehension and dread and fear and unease deep discomfort deep worry about what’s going to happen in the future is a concern it impairs normal daily functioning so if anxiety is discomfort like you don’t want to go up and speak but you do and it’s fine then it’s very different than you’re not being able to make presentations to keep your job or something like that possibly cause is serotonin and norepinephrine dysfunction so when we’re talking about how these drugs work if we see that there’s serotonin norepinephrine dysfunction then we know that maybe we could use something like SSRIs or SNRIs to treat because if that’s the underlying cause.

And we can talk about it as acute or chronic so an anxiety where certain instances or certain issues cause anxiety is acute versus something chronic where we have something that’s a long-standing issue they’re continuously dealing with anxiety issues, maybe obsessive-compulsive disorder, things like that.

So there are five classifications: Generalized Anxiety Disorder, Panic Disorder, Obsessive Compulsive Disorder, Social Anxiety Disorder, and then PTSD or Post Traumatic Stress Disorder.

Something like Generalized Anxiety Disorder, we might start with an SSRI or SNRI. It’ll take two to three months to see the full benefits but we don’t wait that long. If in four to six weeks we really see no response or maybe just a small response, we might add a Benzodiazepine or we might add Buspirone. But this is how we would deal with Generalized Anxiety Disorder.

A bit about Buspirone or brand Buspar, we don’t really know how it works. It might affect serotonin. It can take up to two weeks to be effective but certainly much quicker than that two to three months. It has to be taken a number of times a day which is somewhat difficult for some patients and we want to be consistent. If you take it with food continue to take it with food. If you take it without, take it without. But that will affect its ability to do its job.

Panic Disorder versus Panic Attack, so a Panic Attack is an episode of intense unprovoked fear so something is just terrifying a person and it’s very quick in its onset and it just kind of comes on the person. When we call it a Panic Disorder, it’s going to be multiple Panic Attacks that continue to happen.

And how do these Panic Attacks present? Certainly palpitations or that pounding heartbeat, chest pain, shortness of breath, sweating, chills, fear of losing control or fear of death all of these things can precipitate a Panic Attack and really disable the patient.

To treat something like that we would use an SSRI with a Benzodiazepine. We would use the Benzo for maybe two to four weeks. SSRI should have kicked in by then or we can use an SNRI Serotonin Norepinephrine Reuptake Inhibitor like Venlafaxine XR and that might take about 12 weeks to be effective. We’ll continue to treat for at least six months and we’ll hopefully have fewer relapse rates.

Obsessive-Compulsive Disorder, we want to watch out for obsession versus compulsion. So an obsession is a recurring thought that reason cannot remove and so although logically you’re saying I shouldn’t be thinking these things you continue to think about them. When you have an action like washing hands or something like that where you can’t control that repetitive act that would be a compulsion.

So drug treatment, we would keep the patient on a Selective Serotonin Reuptake Inhibitor for at least a year.

Social Anxiety Disorder, this is just a fear of an intense recurrent fear of other scrutiny and a couple treatments we can use if it’s something chronic we could certainly use the SSRIs Paroxetine or Sertraline but if it’s something for a performance like I’m going to get up on stage in front of someone to speak a Benzodiazepine which might start working after an hour or two or a Beta-Blocker which can reduce the heart rate now that can be used for performance only Social Anxiety Disorder.

PTSD the patients are continuing to re-experience a traumatic event in their past and we want to actively avoid reminders of those I remember a student asking if I could remove all mentions of firearms or guns from my exams because of that PTSD and it was very easy to do for that student so again trying to avoid reminders and then it’s a persistent hyper arousal state always in that fight or flight-ready to attack mode or ready to defend mode treatments that we have Fluoxetine Paroxetine and Sertraline as SSRIs or maybe Venlafaxine as an SNRI.

The ADHD agents, we’ll first talk a little bit about what ADHD really gets in the way of and then we’ll talk about some treatments so in the prefrontal cortex we have centers for planning and problem-solving and short-term memory and behavior there’s more activity in the non-ADHD brain than there is in the ADHD brain and what we want to do is in some way see if we can’t help improve focus and allow them to plan problem solve remember and improve their behavior.

So the animation is just basically saying this is a lot more activity in the non-ADHD brain regarding these four big caveats with this decreased prefrontal cortex neuronal activity and I know that’s a mouthful but we’re just saying that there’s less activity with increased dopamine and norepinephrine reuptake."

So what we’re saying is that the drugs are there in the synapse, but we are finishing up with them too quickly. So the medications will release or prevent the reuptake of that dopamine and norepinephrine, but the mechanism is a bit different than SSRIs and SNRIs, just to be clear.

A couple of examples: Methylphenidate, which you may know as Ritalin or Concerta, it’s a 50-50 mix of Levo and Dextro isomers. And then there’s Dexmethylphenidate which is Focalin. You can see the word ‘concentrate’ in Concerta for Methylphenidate and ‘focus’ in Focalin. Focalin is really just the Dextro isomer or the right-handed isomer of the Levo and Dextro mix. And so, is it necessarily that much better? Maybe, maybe not, but that was the idea.

We have availability as immediate release and extended release versions because depending on when you are in the year for example if someone’s using something like Ritalin for school we wouldn’t really want it to last too long if they just need help during school or for their school work which they do right after school. So we might move to an immediate release if we find that they’re having some of these adverse drug reactions. One that’s not on here is insomnia that can happen if we give it too late in the day and we’ll talk about the next slide.

But adverse drug reactions we can expect weight loss, maybe gross suppression, increased heart rate and blood pressure, psychosis which looks very much like schizophrenia, and then if stopped abruptly possibly withdrawal.

So the four that I’ll just put on this chart are Methylphenidate which is Ritalin, Dexmethylphenidate which is Focalin XR, Methylphenidate is Concerta or Methylphenidate immediate released three times a day. And we see that these peaks happen somewhere around maybe 4 or 5 pm and then it gradually tapers off.

But imagine if instead of taking at 7 am the patient took it at 11 am. In that case, they would be wide awake for quite a long time and we would want to take something like the immediate release and only maybe give two doses instead of three so that we avoid that insomnia at the end of the night.

There is a non-stimulant Atomoxetine which is Stratera. It’s a selective Norepinephrine Reuptake Inhibitor with no Dopamine activity and it takes a couple of weeks to see the effects and almost up to three months for full benefits. And it is less effective than the stimulants like Ritalin but it doesn’t have abuse potential so it’s kind of one or the other. Are you going to choose something that’s a little more effective with a stimulant or is there an issue with the abuse potential that we have to use this? And then adverse drug reactions similar to the stimulants.

Note there is an increased risk of suicidal thinking in children very rarely and it appears during the first several months of use so certainly something to watch out for.

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Classroom Lecture Neuro/Psych Pharmacology Part 1 of 4 

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Auto Generated Transcript:

Okay, welcome to chapter five neuro and psych pharmacology one. What I want to go over are four topics. First, it's going to be a little introduction to neuro-psych. Then we'll get right into the antipsychotic agents, then the antidepressant agents, and finally, for just this part, the bipolar disorder agents. So, we begin with an introduction, just kind of what is going on in terms of this whole chapter, I guess you could call it, but neurology plus pharmacology becomes neuropharmacology or studying drugs that affect the nervous system.

And the drugs either work on the peripheral nervous system (PNS) or the central nervous system (CNS), and we'll see how this is important. So, in the PNS and CNS, the neurons will transmit information through these electrical impulses, and they'll message one of three cells. Either they will message another neuron, or to a muscle cell, or some kind of secretory gland cell. When we're talking about the actual transmission, what happens is that we get a signal, and this is step one. That signal travels from the soma on the left, moving down, moving the action potential.

Developing the synaptic transmission is step two, and I set it up as step 2A, step 2B, step 2C. So, step 2A first, the action potential reaches the nerve terminal. Step 2B, the neurotransmitter releases. And then step 2C, the transmitter binds to the receptor on the postsynaptic cell, and "post" just means after, and then neuron, muscle cell, or secretory gland cell.

So when we're talking about medications and their targets, medications are either going to cause some kind of axonal conduction, and the drugs aren't really selective. All axons are like the same, so you've got lots of adverse effects with something like that, generally, and very few medications inhibit the transmission this way. We're really talking about benzocaine, lidocaine, those local anesthetics. On the other side, you've got synaptic transmission, which can be very selective. It works on different synapses.

Very specific for neurotransmitters, most of the medications are going to work on this target. But let's see what the five synaptic transmission steps are. So the first thing that has to happen is you have to synthesize the transmitter. So although this is simplified here, we've got an A and a B, and they come together as the transmitter. This is what happens. The body takes pieces and puts it together to make these neurotransmitters like serotonin, norepinephrine, dopamine, and so forth.

But the parts combine to form the whole. The second step is to store this transmitter, and so we've got a little package here. We package this neurotransmitter into vesicles. When we need the transmitter, there's a release of the transmitter, step three, and the action potential reaches the presynaptic terminal and causes the neurotransmitter to enter the synapse. Step four is the binding of that transmitter. So it's going to reversibly bind, goes over, does its thing, then comes back, so it reversibly binds to the receptors on the postsynaptic cell.

Again, "post" just means after the synapse or after that gap, and this creates a new action potential. So we get to step five, which is terminating the transmitter, and it breaks from the receptor. But there are really three ways it can go. It can either come back to the terminal that it was at in the first place, it can get degraded by some enzyme, or it can kind of just diffuse into another synapse. Two of the common local anesthetics that we would use, so this would be that axonal conduction, and again, it's non-selective, and it'll stop the action potential and block the neurotransmitter release.

So when you're feeling pain from a toothache, you might use benzocaine, brand Anbesol, and this is an ester-type. But when you're using something topically, we don't really worry about its allergenicity or its ability to cause an allergic reaction or something like that. We really worry about them when you have an injectable. So that's why we really reserve benzocaine for something topical. On the other side, you have lidocaine. One example is brand Solarcaine, so when you get a sunburn, you can put this on. This is an amide-type, and it's less allergenic.

So, in addition to its topical use, like Solarcaine, we would see this with something like your dentist giving you an injection so you won't feel the pain as they're working on your tooth or something like that. This is the preferred, especially when we're talking about those kinds of procedures where you're going to need to inject a local anesthetic. Our next group are the antipsychotic agents, and what we do is we divide them into generations.

So when you have a first and a second generation, the second generation, in some way, is supposed to be better. We first name them as first-generation / conventional or second-generation / atypical. The big change as we go from first to second are the movement disorders, which we'll see in just another slide. But the first thing to kind of get down is that we divide this into three parts. You've got the first generation which goes into low potency, medium potency, and high potency. I'll just talk about the extremes. Chlorpromazine, you would need a hundred milligrams of that to do the same thing that haloperidol does with two milligrams.

Now, I want to be careful because potency is just a required dose. Low potency doesn't mean it's less effective; it just means it takes more milligrams to do the same thing. We'll see why this is really important when it comes to side effects in a second or in another slide. The second generation, which is the atypicals, we have risperidone and quetiapine, so two different drugs in the second generation that are going to probably cause a little bit less in terms of movement disorders, but there is going to be a trade-off, and we'll see that next.

So first thing, the first-generation antipsychotics, they can block the CNS acetylcholine, dopamine, histamine, and norepinephrine, and what we really worry about is this blocking of dopamine, which can lead to extrapyramidal effects or EPS, which can be permanent. Examples include:

1. Acute dystonia: Breaks down into "dys-" plus "-tonia," so literally bad in muscles. We're going to see spasms in the back, the face, the neck, and the tongue.

2. Parkinsonism: It looks like Parkinson's disease but just shares the symptoms. It isn't really Parkinson's disease.

3. Akathesia: Literally means dance if you take it from the Greek, and it's restlessness. It's like you've had a lot of energy drinks and can't sit still. Not to be confused with akinesia, which is a complete lack of movement.

4. Tardive Dyskinesia: "Tardive" means late, so it comes much later than acute dystonia or parkinsonism, but it also stays around quite a bit longer and can be lifelong. It can involve choreoathetoid movements, which are uncontrollable.

So, which antipsychotics are going to cause these EPS? Something like chlorpromazine, which is a low-potency first-generation antipsychotic, is usually going to cause much more sedation, but the extrapyramidal symptom potential is somewhat moderate. Haloperidol, which is brand Haldol, is high potency. The sedation is not going to be bad, but the EPS potential is very high, which is a real concern because then we're going to see these movement disorders that we just talked about.

The second-generation antipsychotics were an improvement. They block dopamine 2 receptors and strongly block 5-hydroxytryptamine (serotonin) receptors but with less dopamine affinity and a lower EPS risk result. That's good because we're not going to have the movement disorders as much, and that was a big improvement. However, this generation is known for metabolic symptoms like diabetes, dyslipidemia, and weight gain.

Diabetes, obviously, is a hyperglycemic state with too much sugar in the blood. Dyslipidemia means you have too many lipids in the blood, including high LDL. Weight gain can also contribute to these problems. When we look at risperidone (brand Risperdal) and quetiapine (Seroquel), we see that their blockade is moderate or low to moderate, and their EPS or extrapyramidal symptoms are moderate or very low. That's the real advantage of the second-generation antipsychotics.

As we move on to the antidepressant agents, we first want to talk about how we think about neurotransmitters and what we're trying to do. A very academic way of saying it is a monoamine deficiency hypothesis of depression.

Two neurotransmitters are low. So, deficiency means low. Hypothesis means we're not exactly sure, but we think this is how it works, and this is our current model. If someone isn't depressed, we expect that they have higher levels of norepinephrine and serotonin. If they're depressed, we expect that there's less norepinephrine and serotonin in the central nervous system. When we get treatment, we expect these levels to go up. So what we're trying to do is replace these lower levels that aren't necessarily where we'd like them to be. How do we do that?

And as we look at these antidepressants in the next slide, that they affect norepinephrine and serotonin is a bit hidden, and I'll show you what I mean. All antidepressants work to increase the levels of monoamines in some regard or another. The SSRIs quite literally are trying to stop the reuptake of that neurotransmitter serotonin, keep it in the synapse, and hopefully, the patient's mood improves. Serotonin-norepinephrine reuptake inhibitors (SNRIs) do the same thing, except they affect both serotonin and norepinephrine. Tricyclic antidepressants are named after the shape, so it's three rings, tri and then cycle. That's what it's trying to talk about because this was named by chemists a while back. It hides that the real effect is on serotonin and norepinephrine, just like the SNRIs. But there are some issues with those kinds of drugs. And then the monoamine oxidase inhibitors, again, kind of hiding that this enzyme monoamine oxidase affects serotonin and norepinephrine. Again, the monoamine is just a fancy way of saying serotonin-norepinephrine. So if we block one of the enzymes that breaks them down, there's more of it around. And then we've excluded the atypical antidepressant. We'll talk about that when we get to the smoking cessation or anti-smoking section. These are the main four classes, so we want to take these categories and translate them into some drugs. So the SSRIs, citalopram, escitalopram, sertraline, fluoxetine, and paroxetine. And we notice that that -oxetine ending is common to both fluoxetine and paroxetine. That's a little bit tricky because if we look at the SNRI, we see duloxetine. You can think of duo for two neurotransmitters, norepinephrine and serotonin. And that ending is still there. So why are endings in two different therapeutic classes the same? Those endings actually come from chemists, and those endings really say that they're chemically the same, which means that sometimes they're not going to necessarily be therapeutically the same. They're not going to do the same thing for the patient exactly. So be careful with the -oxetine ending. It can mean SSRI or SNRI or, as we'll see later, something for ADHD. Then venlafaxine is also an SNRI affecting serotonin and norepinephrine. On the bottom left, we have amitriptyline, which is a tricyclic antidepressant. The nice thing is that it has tri literally in the middle of the drug name to help you remember. And isocarboxazid is an MAOI monoamine oxidase inhibitor. So those are the four main classes, translating them into drugs. But let's go over each of the drugs with the PowerPoints so that we have a good idea of how they work. SSRIs are selective serotonin reuptake inhibitors. They bind to the presynaptic terminal to prevent serotonin 5-HT reuptake, which was step 5 in that list. If serotonin stays in the synapse, it's hopefully going to improve the patient's mood because you have more serotonin around. So again, depression is supposed to be not having enough serotonin. So if we just keep it around, then hopefully it'll improve their mood. We've gone over citalopram, brand Celexa, escitalopram, brand Lexapro, sertraline, which is Zoloft, fluoxetine, which is Prozac, and paroxetine, which is Paxil.

They're all equally effective in treating depression, but we're going to see where, based on the timing and side effects, we might want to use one over the other.

An SNRI (serotonin-norepinephrine reuptake inhibitor) binds to the presynaptic terminal. It prevents serotonin and norepinephrine reuptake to hopefully improve mood. So there are some caveats with it. Duloxetine (or Cymbalta) is especially useful with chronic pain. It just happens to work that way. And then venlafaxine (brand Effexor) has to be taken with food daily. You can't skip doses, and you would think, "Certainly, if the patient is depressed, they want to make sure that they get their medicine every day." But a depressed patient often does things that are self-defeating, might skip doses, and things like that. So if you have a patient that doesn't take their medicine as well as they should, something like fluoxetine, which tends to last a bit longer, might be a better choice.

The tricyclic antidepressants, something like amitriptyline, are much less safe than the SSRIs and SNRIs. They work just the same, blocking serotonin and norepinephrine reuptake, so we have more of it around to help improve the patient's mood. That's why it's effective. But it also blocks histamine, alpha-adrenergic blockers, and shows anticholinergic effects. These are really difficult for the patient, especially the anticholinergic effects, where you get this dry mouth, some dizziness, and a lot of different other effects that we really don't want to see.

The last group, the monoamine oxidase inhibitors (isocarboxazid, brand Marplan), these were the first antidepressants developed but are not safe relative to the newer agents. There's a serious interaction with tyramine that can elevate blood pressure. You can find tyramine in aged cheese, certain craft beers, certain red wines like Chianti, things like that. And that excess norepinephrine can be really dangerous for the patient. These monoamine oxidases on the left normally break down serotonin-norepinephrine. So if we stop the breakdown with an inhibitor, there's more of it around, and that really helps the patient. But again, because of drug interactions and the possibility of having this hypertensive crisis, we really only see these when most of the other antidepressants have failed.

A big thing with these agents is timing. Certain drugs you want to give in the morning, certain it doesn't really matter, others are going to make a patient drowsy, and we want to reserve those for nighttime. So those that would really give someone energy would be sertraline, fluoxetine, venlafaxine, duloxetine. Those that are neutral are citalopram and escitalopram, and those that cause drowsiness are paroxetine and amitriptyline. Those are the ones that we really want to give closer to bedtime.

Now, something you can do, especially with a patient who has many medications, is as you're looking at the chart to see if there are drugs for insomnia. Is a patient maybe getting sertraline or fluoxetine at bedtime, and it's causing them to stay up? Then we have this medication cascade where we give a medicine to combat the side effect of another medicine.

Isocarboxazid is given twice daily, so it doesn't necessarily fall into this group. The bipolar disorder agents, I just wanted to talk briefly about that. It was formerly called manic-depressive disorder, and it's been changed a little bit.

Patients will experience periods of elevated and depressed mood, but those periods can last for months or even years before switching to the other. So someone might receive a depressed diagnosis because it's just been months of depression. But later, this mania comes on where they don't feel like they need medications, and it's somewhat difficult to assess and treat. We're not exactly sure why this happens, and right now, there's a hypothesis that says genetics might play a role, and there might be an issue with the synapses, but we're not exactly sure.

One drug that we use, and that's extremely inexpensive, is lithium. We're not even sure how it works necessarily, but it might affect cell energy metabolism and might protect the neurons. It requires monitoring because high levels can cause serious toxicity, and low levels will be sub-therapeutic. So we've got a sweet spot in the middle. The issue we have is its relationship to sodium. If you look at the periodic table and you can see hydrogen, lithium, sodium, and potassium, this is the very far left of the periodic table, and they all have plus one charges. So the body has trouble telling the difference between lithium, which is a monovalent cation (mono meaning one valence meaning one electron), and sodium. They are like sodium, so the body can't always tell them apart. So when the sodium is low, the body is going to hold onto sodium, trying to keep water. But then lithium can be toxic because it can't necessarily tell the difference. So it holds onto sodium, holds onto lithium, and the patient's taking their regular dose, and now they're actually becoming toxic.

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Classroom Lecture Immune Pharmacology Part 2

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Auto Generated Transcript:

Okay, welcome to immune pharmacology 2. We're going to go over antifungals and antivirals and be a little more specific about that, but we'll first cover antifungal medications. Next, anti-mycobacterial agents, which is a fancy way of saying Tb or tuberculosis. Three is the non-HIV antivirals, and then four is going to be the HIV antivirals. So for fungi, not bacteria or viruses, the two major categories are the systemic mycoses and the superficial mycoses. So the systemic mycoses are those that are in the bloodstream, and then the superficial mycoses are those that are either dermatologic or outside the body. Nystatin for thrush, fluconazole for vaginal yeast infections, butenafine maybe for athlete's foot, and things like that. Amphotericin B, which is Fungizone, or nystatin, which is Mycostatin. These bind to sterols; they're polyene antifungals. They bind to sterols in some cell membranes and increase permeability. So cations like potassium and sodium, especially. They can be fungostatic or fungicidal based on the concentration. Just like we had bacteriostatic and bactericidal, the fungostatic is going to stop the growth, and then fungicidal will kill the fungi. They're really toxic because they also bind to human cell membranes, and they bind to cholesterol and cause the same effects. So fungal cell membranes have ergosterol, while we have cholesterol. And because those look alike, that's where the danger comes in. But again, some of these systemic fungal infections are life-threatening. So it's really benefit versus risk, and the benefit outweighs the risk of death.

Antifungals are azoles like fluconazole or Diflucan. This inhibits ergosterol synthesis, preventing cell membrane formation, and causes increased membrane permeation. A fancy way of just saying that it weakens the fungi. And you can use them for both systemic and superficial fungal infections. The big difference between the two, the polyenes that we just saw, as they work on the outside of the membrane to bind to sterols and increase permeation, and they're really toxic because they bind to mammal sterol cholesterol. Azoles work on the inside of the cell to prevent sterol formation and increase permeation. They're minimally toxic because only the fungi uptake them. An over-the-counter option is something like butenafine, which is Lotrimin. It's a topical antifungal, so you could treat superficial mycoses, mycosis, which is a fancy way of saying fungal infection. It causes the fungus to create excessive squalene, which is normally converted to ergosterol, and then large amounts of that squalene are toxic to the fungi.

Antimicrobial agents. So we're really talking about tuberculosis and the pathology. So there are bacteria, and they're covered in this kind of waxy mycolic acid shell, and that's what gives them the name mycobacteria. They need oxygen-rich environments, so they want to be in the lungs, and they are respiratory infectors. And both versions of TB must be treated, so the one that's controlled by the immune system, the latent tuberculosis, can't be spread. There are no symptoms. But then there's that which is uncontrolled by the immune system, active tuberculosis, easily spread and causes mortality. There are a number of options that we have, and multiple medications are used at the same time, usually three to four, to prevent inadequate drug therapy. So TB can become resistant to a single med very easily, but it leads to multi-drug resistance. TB grows very slowly, and most antibiotics target fast-replicating cells. So the four biggies are rifampin, Rifadin, isoniazid, INH, pyrazinamide, PZA, ethambutol, Myambutol. Use them for six to eighteen months continuously, depending on the combination.

HIV antivirals. We really want to look at how this all happens, and that's how we can know where they work. So the HIV replication cycle is to attach, to fuse, reverse transcription, replication, integration, transcription, translation, assembly, budding off, and HIV protease processing. What we want to first look at is what step are they stopping things at? And if you look at the cellular, and this is why we call them CCR5s, but cellular chemokine receptor 5 antagonists like Maraviroc, which is cell entry, some HIV strains require the CCR5 to gain entry to the cell. Wherever it binds to the CCR5, preventing the virus from entering the cell.

The next one, step five, is the integrase strand transfer inhibitor. So raltegravir. Integrase is an enzyme used by the HIV virus to insert its viral DNA into host DNA and take over host production machinery. So the integrase strand transfer inhibitors halt this process. And then there are the HIV antivirals, protease inhibitors. So darunavir. This is the last step in the HIV replication processing by HIV protease. Without protease, the virus is inert and unable to infect other host cells. Protease inhibitors prevent viral maturation, and they're very effective. So again, when looking at HIV, we really look at where it happens, and then how we match those drugs to that area.

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Classroom Lecture Immune Pharmacology Part 1

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Auto Generated Transcript:

All right, here we go with immune pharmacology one, and we're going to cover an introduction, penicillins, cephalosporins, but more specifically, we'll start with an antimicrobial introduction. Then antibiotics affecting cell walls like the penicillins, cephalosporins, vancomycin. Then go on to bacteriostatic protein synthesis inhibitors and bactericidal protein synthesis inhibitors. So let's get started with the antimicrobial introduction. One big separation between the bacteria are gram-positive versus the gram-negative, and Gram was a person, and he had a stain.

If it's gram-positive, then we expect there's a cell wall on the exterior. But if it's positive, that means the stain got through, and it doesn't have a second layer, or really, it's a third layer. Gram-negative means that it didn't take the stain. So it's really stained negative. We just shorten it to gram-negative, and the cell wall is covered by a peptidoglycan layer that's in orange. So I hate to say that gram-negative is harder to kill than gram-positive, but let's just say that gram-negative is more protected.

There are a number of targets that you would have with antimicrobials. You can target the cell wall, damage or disrupt the cell wall structure because humans don't have cell walls; they have cell membranes but not cell walls. You can use a DNA RNA synthesis inhibitor to prevent the creation of new DNA or RNA. You can use an anti-metabolite that prevents the usage of certain vitamins and minerals that we can take in through our food, but that bacteria have to make. You've got the protein synthesis inhibitor.

Protein synthesis, building proteins can be bacteriostatic, and static means that it keeps it from replicating but doesn't kill the bacteria. So it stops the proteins from being produced. It only slows the growth; it doesn't kill them. On the other hand, you can have a protein synthesis inhibitor that's bactericidal, and that stops the proteins from being produced, and it does kill the bacteria. But there are some issues with that as well. So the first thing you want to be able to do is match.

The target or the mechanism of action to actual antibiotics, and this is where it gets a little bit crazy. You can see how many drugs are on this slide. But let's go through the cell wall inhibitors. Amoxicillin and then amoxicillin with clavulanate to protect itself against beta-lactamase, and we'll talk about that later. But that's an enzyme bacteria produce to destroy the amoxicillin. Three cephalosporins, first generation cephalexin, third generation ceftriaxone, fourth-generation cefepime.

Vancomycin, which is not able to work against MRSA, doesn't have that beta-lactamase issue. DNA RNA synthesis inhibitors like ciprofloxacin and levofloxacin, these are the fluoroquinolones. An anti-metabolite like sulfamethoxazole with trimethoprim that affects folate, something we can take in through our food, the bacteria can't. Protein synthesis inhibitors, so these are bacteriostatic. Doxycycline, minocycline are both tetracyclines. Azithromycin, erythromycin, clarithromycin are all macrolides. Then clindamycin and linezolid in their own classes.

But the idea is that these drugs don't kill the bacteria, but they keep them from replicating. The immune system can come in and have a fighting chance. The protein synthesis inhibitor bactericidal, amino amikacin and gentamicin are both aminoglycosides, and we'll talk about those a little bit later. You would say, "Why don't you just use something that kills the bacteria instead of just affecting its growth?" But we also know that not only are the bad bacteria hurt but some of the good bacteria. So there are reasons to use either in different situations.

The other thing we want to look at is the spectrum. So the antimicrobial spectrum, when you have a broad-spectrum antimicrobial, it covers a lot of different microbes. It's the jack of all trades, master of none. A lot of times when they're not sure exactly what it is, you might get a broad spectrum. But then they should be doing testing to get a narrow spectrum, know exactly what it is. A narrow-spectrum antimicrobial would cover very specific types of microbes. They're very hard hitters, and it's preferred once the microbe type is known.

You can show up in hiking boots, but they may not be appropriate for the situation. And then you would change into heels if the situation calls for it. The same thing, the boot covers a lot, but it doesn't hurt a lot when someone is stepped on by it. But the heel covers very little, but it really hurts when someone steps on your toe with a heel because of the pounds per square inch. So hopefully, that's an analogy that's helpful to explain broad spectrum versus narrow-spectrum antibiotics.

Antimicrobial resistant mechanisms: There are four major mechanisms that you have. You reduce the drug concentrations at the site. You can alter the drug molecules. You can create an antagonist. Or you can inactivate the drug. So bacteria are able to make changes because while a human generation might be 20 or 30 years, a bacterial generation can be hours. So millions and millions of bacteria can form, and all these changes happen, giving some resistance and some of these abilities or resistance mechanisms.

A superinfection is a new infection that starts when you're treating a current one. Anyone that's taken an antibiotic and had gotten a yeast infection knows, okay, that's a superinfection. So "super" comes from Latin, which means "over and above." So just like a supervisor is above a subordinate, a superior is above someone that you're. So you would go to your superiors if you're going to your manager or something like that. The same thing is true here; it's over and above the original infection. So most commonly occurs after a broad spectrum antibiotic. So, for example, you're treating an ear infection with a broad-spectrum antibiotic, and one of the following develops: maybe a vaginal yeast infection, oral thrush, or Clostridium difficile, which can cause terrible diarrhea. Oral thrush and vaginal yeast infections are both candida infections.

MRSA or methicillin-resistant Staphylococcus aureus. This is resistant to penicillins and most cephalosporins because it can create altered PBPs or penicillin-binding proteins. So the antibiotics have a low affinity to these altered proteins, and it's a serious infection. I hate to use the word "strong" antibiotics, but maybe antibiotics that we reserve for these particular cases. And because fewer antibiotics work against MRSA, we try not to use them for other things as best as we can.

Antibiotics affecting the cell walls. So amoxicillin is our first example. It binds to the penicillin-binding protein on the bacterial cytoplasmic membrane. What does that mean in plain English? There's a protein on the bacteria that this binds to, and it keeps it from creating a new cell wall. So the cells, if they can't create these cell walls, then weaken, or they lyse or burst just like balloons. And these are most effective against gram-positive bacteria. So again, if it's gram-positive, that means that it doesn't have that extra layer. But bacteria have mutated to become resistant. One specific resistance that we'll talk about is the beta-lactamase enzyme that bacteria produce. So all penicillins and cephalosporins have what's called a beta-lactam ring. If you've had organic chemistry, you know exactly what this is. But it's just a chemical structure, and it's an important one because this is the target for resistance. So bacteria can create beta-lactamase. When you see "-ase" at the end, it might be an enzyme, which is, in this case, it is, and that changes the ring structure. It renders the medication useless. And what we do is we kind of add a bodyguard to amoxicillin. That bodyguard is clavulanate, and Augmentin just like it sounds, it augments amoxicillin by itself. And a beta-lactamase inhibitor is a compound to distract beta-lactamases, so the antibiotic is still effective. Clavulanic acid does basically a way to have the bacteria go after the clavulanate instead of the amoxicillin, and because of that, the amoxicillin can still be effective. You can see that in clavulanate; we have a beta-lactam ring very similar to the amoxicillin.

The next group of antibiotics is the cephalosporins, and they all have beta-lactam rings just like penicillins. They work the same as penicillins; they still inhibit cell wall synthesis, and there are five generations. So four of them that I'll go over are cephalexin, brand Keflex, ceftriaxone, Rocephin, cefepime, Maxipime, and ceftaroline, which is Teflaro. As we go up, and again this is in general, as we go to the fourth to the fifth things get a little weird. But three good things happen: we increase the coverage for gram-negative and anaerobic bacteria, we increase the resistance to beta-lactamases, and we increase the penetration into the CSF or the cerebrospinal fluid. As we go on, we can see that what kind of coverage do we have, and when we look at Keflex, we see we definitely have gram-positive coverage, but the gram-negative coverage is not that good, and we have no activity against MRSA. We go to the next; we see the gram coverage is a little bit weaker, and then no MRSA. But then as we get to the third generation, that was really the big change when we said, "Oh wow, we've got some better gram-negative coverage." We still don't have MRSA coverage, but it's getting better. Cefepime, Maxipime, we have very good gram-positive and gram-negative coverage, but not really with MRSA. And then ceftaroline, we don't have the greatest gram-negative coverage, but we do have MRSA coverage, and that's a big deal.

But that's the cephalosporins. Something we should talk about, though, are allergies. They're over-reported and poorly documented, but because we are a very litigious nation, that is, we have a lot of lawyers, there are a lot of issues in terms of as soon as somebody says penicillin allergy, put it in the chart. All of a sudden, they can never get a penicillin or a beta-lactam, even though more than 80 percent of "allergies" can be ruled out with objective measures like skin testing. So 95 percent of the patients with the allergy tolerate the penicillin, and 10 percent of all patients report a penicillin allergy. So what we see is that very few have this true allergy, and what's the big deal? Penicillin allergies are associated with worse health outcomes and increased costs. You have to use stronger and more toxic antibiotics instead of the penicillins. So we want to clarify the type of reaction that they have. Was it an intolerance?

So, like an adverse drug event, or was it a true allergy? If an intolerance, didn't remove it from the patient's profile. If an allergy, consider testing to confirm. So intolerance means, "Oh, my stomach kind of hurt a little bit." True allergies are usually forgotten by the body after 10 years. But again, it's a litigious nation we're in, and the concern is that someone's going to get sued. In terms of numbers, when we're looking at this, it becomes kind of a muddled mess. But really, if you're looking at penicillins and cephalosporins, the penicillin-cephalosporin cross-reactivity is a common concern because they're the most used. But if you want to break it down, a patient has a true penicillin allergy, they have less than a five percent chance of being allergic to cephalosporins. If they have a true allergy, they have a one to five percent chance of being allergic to penicillins. So again, caveat emptor. You just have to be careful with this. But the truth is that for most patients, it would be better for them to use a penicillin, and unfortunately, the allergy is misreported.

So antibiotics glycopeptide, vancomycin or Vancocin. This is a huge molecule relative to the other antibiotics. It doesn't have a beta-lactam ring, so beta-lactamases don't do anything to it. And it doesn't bind to the penicillin-binding proteins. Rather, it works by binding to these kinds of bricks that are used to make the cell walls. It's the drug of choice for MRSA or methicillin-resistant Staph aureus and C-diff or Clostridium difficile. But we want to save it for severe infections. There's usually probably a vancomycin protocol that says this is when you can use it, this is when you don't. We don't want to get resistance at this hospital or wherever we are. As far as drug monitoring, we want to be very careful because if we go too high, then the patient can become nephrotoxic, damage to their kidneys, or ototoxic, damage to their ears. But go too low, then it's not effective, and the infection is still active. So we dose it based on levels at the highest and lowest points. It can also cause red man syndrome where the skin turns red all over, so we use a very slow infusion time of 60 minutes to prevent that particular issue.

In the next group, we want to go over the bacteriostatic protein synthesis inhibitors, and let's make clear the difference between bacteriostatic and bactericidal. So bacteriostatic means that we're suppressing bacterial growth and replication, and the body's immune system is required to fully eliminate the infecting bacteria. We didn't kill the bacteria, but in some way, we've stopped its growth or slowed its growth. Bactericidal, on the other hand, just like homicidal is killing a person, suicidal is one who kills themselves, bacteriocidal is killing a bacterium. So killing the bacteria outright, the body's immune system is not required for bacterial elimination. But these are often a bit more toxic.

We'll refer back to this train analogy with bacteriostatic inhibitors and bacterial ribosomes. There are two subunits, the 50s, which we can think of as the train station, and the 30s, which we can think of like the parking lot, and then the peptide chain, which is the train. So macrolides and lincosamides would work on the train station, oxazolidinones would work on the train, and then the tetracyclines would work on the parking lot. And we'll see how this is as we go through these.

So let's start with the first bacteriostatic class, the tetracyclines. Minocycline, brand Minocin, and doxycycline, brand Doryx. They bind to that 30s ribosomal subunit, and they prevent the binding of transfer RNA to messenger RNA. So people can't get out of the parking lot; the peptide chain's production is halted, and the train can't leave the station without the passengers. Is there MRSA coverage? Yes, it's not the best, but again, it does have some coverage. The issue with the tetracyclines is binding and forming these insoluble complexes or chelating with aluminum, calcium, iron, magnesium, or zinc. Where we find these are dairy and calcium supplements, calcium, for example, iron supplements, obviously, iron, and then antacids, which can contain aluminum, calcium, or magnesium. So take one hour before or two hours after meals. Of course, antacids are always used after a meal, so that would be after meals only. Adverse drug reactions, you could get a yellow-brown tooth discoloration that's lifelong, so we avoid it in pregnancies, avoiding children under eight. The only way to really fix that discoloration is to cover it up with veneers.

Bacteriostatic macrolides. So we've got azithromycin, brand Zithromax, clarithromycin, brand Biaxin, erythromycin, brand E-mycin. So you bind to the 50s ribosomal subunit, which is the train station in this case. We prevent the amino acids from adding to the peptide, and passengers can't get on the train. So erythromycin, though, is a SIP 450 inhibitor, which leads to lots of drug interactions, whereas azithromycin and clarithromycin are a bit safer. The other issue is that really erythromycin, you have to take four times a day. Clarithromycin even twice a day, that's where the Biaxin name comes from. And then azithromycin is nice because you only take it once a day.

So we see that compliance, or how often the patient takes their medicine as they should, is much better with Z-pak than the others. And again, QT prolongation isn't also an issue.

Clindamycin or Cleocin is a lincosamide. This binds to the 50s subunit, prevents protein synthesis. Again, passengers can't get onto the train. It's more associated with toxicity than it is therapeutically. So C diff or Clostridium difficile-associated diarrhea. You can get a superinfection of the bowel. So we want to use it for the least amount of time. But a lot of times, you'll see this dermatologically for acne and things like that. So much safer dermatologically than it is orally.

Linezolid or Zyvox. This binds to the 50s subunit, prevents the formation of the initiation complex. So it prevents the train from coming into the station. It's a unique mechanism. It prevents that initiation complex and it leads to little resistance. So it interacts with SSRIs and SNRIs, those antidepressant classes, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors, potentially causing serotonin syndrome. But it does have MRSA coverage. Not only does it have MRSA coverage, but also VRE coverage, which is vancomycin-resistant enterococcus due to a lack of resistance.

Bactericidal protein synthesis inhibitors. So now we're moving from bacteriostatic to bactericidal. We're going to kill the bacteria rather than prevent their or delay their growth. And so, again, we're working in that parking lot, the 30s subunit.

The two bactericidal aminoglycoside drugs that I'll go over are amikacin, brand Amikin, and gentamicin, brand Garamycin. So bacteriocidal drugs work against gram-negative aerobes. It binds to the 30s subunits and causes three different things: either it inhibits protein synthesis (the train can't leave the station), it prematurely terminates the protein synthesis (train departure is canceled), or the production of abnormal proteins where the wrong train leaves the station. So those are the three ways that it can work against these gram-negative aerobes. However, we have to really, really monitor these because of the two main toxicities. You've got nephrotoxicity and permanent kidney damage, and ototoxicity.

Kind of said two things at once there. On the left side is nephrotoxicity. It can increase kidney damage. And then on the right is ototoxicity with the hearing damage and potential balance issues. Both are produced by high trough levels over time. So thinking of the peak where the top of the concentration and the trough is the bottom. If the bottom is too high, then we haven't let it wash out enough, and that's where the toxicity comes from. It's just too high a concentration for too long.

The DNA RNA synthesis inhibitors. So the examples we'll use are the fluoroquinolones, and we'll get to the actual drugs in a sec. But enzymes coil and uncoil bacterial DNA for replication. So fluoroquinolones inhibit that process with DNA gyrase and topoisomerase IV. So you've got relaxed DNA, which is ready for replication, and supercoiled DNA, which is ready for storage. Remember S for storage.

So the two examples we have are ciprofloxacin, which is brand Cipro, and levofloxacin, which is Levaquin. They're broad-spectrum antibiotics, and the ADRs include phototoxicity, which is burning in the sun much quicker or even in a tanning bed, confusion, superinfections like a fungal infection, and then rare but serious is the concern about tendon rupture. So if any time you have somebody that their tendon is getting warm or they're just feeling it's not right, definitely watch out there. The administration, just like those tetracyclines, we've got to watch the dairy, calcium, plus vitamins like zinc and iron, and then the antacids like aluminum, calcium, and magnesium. We saw that chelation interaction just like the tetracyclines.

And then some of the miscellaneous antibiotics, they just didn't really fit neatly into the other class, but one are those that are anti-metabolites. And metabolites are just a fancy way of saying what comes out at the end. So cells require folate for DNA, RNA, and protein production. And mammals can eat food with folate, but bacteria cannot. So we can target this folate production as our prime target, and we make sure that it doesn't happen.

So PABA is used to make folate. It's the building block. And sulfamethoxazole, you can see, looks an awful lot like PABA. So sulfamethoxazole gets used instead of the PABA by the bacteria because it is similar in structure. And the result is that it stops production of folate. You've got to watch out though for sun sensitivity with sulfamethoxazole and trimethoprim, or brand Bactrim. You'll notice that Bactrim is just a shortening of bacterium. They both work to prevent folate from being used to create more DNA and RNA and proteins.

Serious adverse drug reactions include Stevens-Johnson syndrome, hemolytic anemia, kernicterus, bilirubin in the brain, crystalluria, and renal damage. But it does have some MRSA coverage.

The last one are the nitroimidazoles, brand Flagyl, or metronidazole, brand Flagyl. It's a unique antibiotic. It's only effective for obligate anaerobic bacteria. It has to be activated, so there's a structural change to be effective. It's only done by obligate anaerobes and causes DNA strand breaks, microbe death. So it causes extreme vomiting if mixed with alcohol. So we want to make sure to let patients know 24 hours before, 24 hours after, don't take this with any kind of alcohol. And that doesn't have to be a beverage like a beer or wine. It can also be the alcohol that's in certain mouthwashes and things like that. So I need to be careful with alcohol and metronidazole.

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