Pharm Endocrine Review

Oral Hypoglycemic Medications

α‐Glucosidase Insulin Secretagouges Insulin Sensitizer Inihibitors

Sulfonylureas Meglitinides Phenylalanine Biguanides Thiazolidinediones Acarbose Miglitol Tolbutamide (1) Repaglinide Nateglinide Metformin Rosiglitazone Chloropramide (1) Pioglitazone Glyburide (2) Glipizide (2) Glimepiride (2)

INSULIN SECRETAGOUGES

The goal of these medications is simply to increase secretion of insulin from the pancreas. Each has its own nuances and proper usage, but essentially, they all regulate potassium efflux in the pancreatic β‐ islets causing an increased release of insulin in a still‐functioning pancreas

Sulfonylureas. There are two generations of Sulfonylureas. The first generation (Tolbutamide and Chloropramide) are generally not used anymore because they have a risk of sulfur allergies. The second generation (Glyburide, Glipizide, Glimepiride) have no risk of sulfur allergies and are used much more frequently. Regardless of the generation, these function by blocking potassium efflux leading to depolarization of the pancreatic cells, calcium influx, and the release of insulin. Sulfonylureas can be taken just one time a day and are generally well tolerated. However, they run the risk of hypoglycemia, especially in those with hepatic failure.

Meglitanides (Repaglinide). This functions just like a sulfonylurea: blocking potassium channels Æ increased insulin release. This differs from the sulfonylureas in that it has a rapid onset and short duration so is used as a supplement when eating. These are taken just prior to meals. When taken appropriately (i.e. you eat right after you take this) there is a lower risk of hypoglycemia. Of course, these drugs are new, which means expensive, and you must have a diligent diabetic who remembers to take his pill every time he eats. Generally not used as monotherapy.

Phenylalanine (Nateglinide). This might as well be a Meglitinide. It has all the same properties, it just happens to be a naturally occurring amino acid.

INSULIN SENSITIZERS

While the distinction is small, these drugs are antihyperglycemic as opposed to hypoglycemic. That is, these do not drop your sugar, they just prevent your sugar from becoming elevated.

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Biguanides (Metformin). This is a classic Type 2 diabetes pill, commonly seen on exams. It functions to decrease the liver’s production of glucose. While it has no risk of hypoglycemia, it must be used with caution in patients who have congestive heart failure or kidney/liver disease. These are good because of their safety and their effects on weight and lipids: there is no weight change (unique in oral hypoglycemics) and the lipid profile decreases. It also benefits the LDL HDL ratio. However, it has been known to cause lactic acidosis in some patients (thus its contraindications in conditions that promotes the formation of acidosis such as CHF or Renal Failure).

Thiazolidinediones (“‐glitazones”). A problem with type 2 diabetes is phosphorylation and gene modification of the insulin pathway that leads to insulin resistance. A long life of hyperglycemia and obesity lead to the downregulation of the insulin receptor pathways. These bad boys rev that pathway back up. They do this by activating the PPAR‐y part of the steroid receptor in the thyroid superfamily. These basically make insulin work better, getting the glucose into muscle and fat cells. That is good, since it will decrease glucose without risk of hypoglycemia, it can be used once a day, and it well tolerated. Unfortunately, they cause increased weight gain and increased LDL levels. The biggest problem is that at least one (Rosiglitazone) has been shown to cause increased risk of myocardial infarction and heart failure. That is a recent black box warning on a new medication, and sounds like a prime exam question to me.

α‐GLUCOSIDASE INHIBITORS

α‐Glucosidase Inhibitors (Acarbose, Miglitol). All the drugs above dealt with making insulin work on the sugar that got into the blood. Well, what if we could prevent the absorption altogether? These are drugs that work in the gut, inhibiting the enzymes required to metabolize carbohydrates such as sucrase. These have been found not to work very well. While they do limit the amount of sugar absorbed, they do not alter the HgbA1c significantly, and therefore are not used as monotherapy. What is worse, is that preventing absorption of anything in the GI tract leads to an osmotic diarrhea with gas and bloating (decreasing compliance).

COMAPRING BENEFITS AND RISKS OF ORAL DIABETES MEDICATION Sulfonylurea Meglitanides Biguanides Glitazones Glucaronidase Weight ↑ ↑ No Gain ↑ ‐ Lipids ‐ ‐ ↓ ↓↓ ‐ HDL ‐ ‐ ↑ ↓ ‐ LDL ‐ ‐ ↓ ↑ ‐ HbA1c ↓↓ ↓ ↓↓ ↓ ‐ Dosing 1/day Per Meal 1/day 1/day Per meal Onset Long Short Long Really Long Rapid Duration Long Short Long Really Long Rapid Mechanism ↑Insulin ↑Insulin ↓ Glucose ↑ Glucose ↓ Glucose Release Release Production Uptake Absorption Organ Pancreas Pancreas Liver Skeletal Gut Muscle / Fat Side Effect Hypoglycemia Hypoglycemia Lactic acidosis “None” Flatulence

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Insulin

Rapid Acting Insulin Intermediate Insulin Long‐Acting Insulin

Lispro Regular Detemir

Aspart Inhaled Glargine Glulisine Lente UltraLente

There are many ways to do the right thing, and no one regimen is the best. It is important to know how the pancreas works. The pancreas secretes a small amount of insulin all day (basal insulin) in addition to the spikes of insulin every time you eat. In order to get good diabetic control, we have to replace the basal insulin with long‐acting insulin (one a day) and the spikes with short‐acting insulin (postprandial). You have to choose cost, ease of use, number of injections, etc. You do not really have to know which long acting insulin is right for a given patient. Rather, you need to know that you need both long‐acting and short‐acting. Some patients may require only basal insulin if their pancreatic function is maintained enough to give the postprandial burst. The way you determine if someone needs a long‐acting glucose is by looking at their fasting glucose (if its high, you need long‐acting). If your fasting glucose is low, but their postprandial glucose is high, then that patient needs extra prandial help (you need a short‐acting insulin). Knowing the names of the insulins and when they act is the most important thing to do.

“LAG, LIRN, DUG.” I had no good mnemonic for this, and it seems to be important only for this exam. So, I remembered (lAg, leern, duhg) said out loud, remembering that Lente means slow in Spanish (so it’s the second L) and Glargine is the really long acting one on the graph above. Crappy, I know, but, much like in biochem, just learn this for the exam and forget it for the shelf.

HbA1c is usually 4‐6, target for diabetics is 7

Normal Insulin is a special kind of immediate acting that is given in the hospital

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Pituitary And Estrogens

Estrogens Synthetic Estrogens Anti‐Estrogens

Estradiol, Estrone, Estriol Diethylstilbestrol Clomiphene Ethinyl Estradiol Tamoxifen Mestranol Raloxifen Leuprolide

ESTROGENS IN GENERAL

Most of this lecture was not about the drugs themselves, but rather the general concepts therein. The guy who gives this lecture has an excellent handout to go along with it.

Functions and Uses. Estrogen receptors are everywhere in the body. We generally think of estrogens (physiologically 17‐β‐Estradiol) as activating growth, stimulation of secondary sex characteristics, bone growth and involvement in the LH surge/ovulation. They do this by binding nuclear receptors which then bind to estrogen‐response elements on genes that regulate transcription. There are a heap of uses of estrogens that include (take a look at the drug list).

Problems. Estrogen replacement therapy in postmenopausal osteoporotic women seemed like a great idea. They had no estrogen, that caused their bone loss, so we might as well give them estrogen. Unfortunately, estrogen is also a growth signal. This is particularly true in the breast and endometrium of the uterus. Administration of exogenous estrogen can and will cause carcinoma in either of these locations. Likewise, while estrogens can be used in abortive preparations, they cannot offer their beneficial side while a woman is pregnant without causing the abortion. You have to realize that estrogen is a steroid hormone and cannot be stored; it simply floats into and through all cell membranes. That means, even if estrogens are in the drinking water, their effects will be seen (such as in gynecomastia in males).

SYNTHETIC ESTROGENS

Diethylstilbestrol. This is used in the treatment of prostatic carcinoma (estrogens feedback to the pituitary and hypothalamus to decrease the GnRH signal which ultimately produces the growth signal for prostatic growth, DHT) and postcoital contraceptive.

Ethinyl Estradiol. This is the most common form of estrogen found in oral contraceptives and is used as one of the morning after pills. This is not THE morning after pill (Mifepristone), but works to prevent blastocyst implantation. It must be taken as a regimen for 5 days. I suppose it is more of the “week after pill.” It must be started within 72 hrs

Mestranol. This is a prodrug that gets converted to estrogen that is found in oral contraceptives. Few modern pills contain mestranol.

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ANTI ESTROGENS

Clomiphene. This is a competitive inhibitor of estrogen nuclear receptor. It is designed to block the estrogen receptor in the hypothalamus, acting as a selective estrogen receptor modulator (SERM). The net effect is to activate the ↓the feedback from the periphery to ↑the estrogen “go” signal (↑GnRH, ↑FSH/LH) used to treat infertility. It induces ovulation.

Tamoxifen. This is another SERM that targets the breast. In ER+ breast carcinoma, tamoxifen antagonizes the effect of estrogen at the breast to limit the growth of the tumor. It doesn’t cure it, it just slows the growth of breast cancer. Unfortunately, while it is anti‐estrogen in the breast, it is pro‐ estrogen in the uterus, leading to endometrial cancer with prolonged use.

Raloxifen. The “Jean Luc Picard” to Tamoxifen (the Next Generation®), it also antagonizes estrogen in breast carcinoma but has the added benefit of non inducing endometrial cancer. Again, it requires a breast carcinoma be ER+, but it comes with the added benefit of being breast specific.

Leuprolide. This did not make it to the drug list, but is essentially important. Leuprolide is a drug used to treat prostatic carcinoma and in fertility preparations. How can one drug treat a male GU problem and treat infertility? Well, it has to do with its use. This is a SERM that effects the pituitary and hypothalamus. When bound, it inhibits the signal of GnRH. At first, it dumps GnRH (whatever is already made gets released) but then depletes the stores. This means that there wont be any FSH/LH release, which means no testosterone, which means no DHT, which means no growth for the prostate. It must be given in continual dosage to treat prostatic carcinoma. If it were given in a Pulsatile fashion, as the drug wore off, the pituitary would sense “no estrogen” and it would ↑↑↑ the production of GnRH, FSH/LH. If this were in a man, the prostate would balloon. If this were in a woman, it would lead to ovulation. Therefore, Pulsatile dosage is required to treat infertility.

Progestin and Androgens

Progestins Anti‐androgen Androgen Mifepristone Progesterone Testosterone Cypionate Finesteride Medroxyprogesterone Danazol Norethindrone Stanozolol Levonorgestrel Fluoxymesterone

PPROGESTINS IN GENERAL

Progestins, like estrogens, are steroid hormones that bind to nuclear receptors. However, progestin receptors must first be primed by estrogen for binding. Like estrogen, progestins can be used to induce negative feedback on the anterior pituitary and hypothalamus to limit the secretion of GnRH and FSH/LH. Generally, progestins are used in conjunction with estrogens for contraception, prevention of uterine bleeding and the management of endometriosis.

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Medroxyprogesterone. Better known as Depo‐Provera, this is a contraceptive administered as an injection that has a prolonged effect. Essentially, the woman is guaranteed to be pregnancy‐free for 3 months, and thus the shot must be repeated every 3 months.

Norethindrone with mestranol. This is the most common form of progestin used in oral contraceptives.

Levonorgestrel. L‐Neorgestel is the progestin component in the triphasic combination contraceptive tablets (these also contain ethinyl estradiol). It is found in Mirena (“Finish a book, Finish a Sentence!”) which has gained popularity on TV. The progestin component not only lessens menstrual bleeding, but also contributes to the contraception.

ANTIANDROGENES

Mifepristone. This is RU426, THE quintessential abortive drug. It is used in the termination of pregnancy by inhibiting the progesterone receptor, effective for the first 50 days. In addition, it can also be used to treat tamoxifen‐resistant breast cancer. Since this is a progesterone antagonist, the breast cancer would have to be Progesterone Receptor Positive. Followed by Misoprostol (PGE1), it is an effective abortive drug.

Finesteride. Leuprolide was useful in controlling the hypothalamic‐pituitary axis for the management of prostatic carcinoma. Finesteride is used for treating a similar disease, Benign Prostatic Hyperplasia (BPH). Finesteride is an inhibitor of 5‐α‐reductase, the enzyme that converts testosterone to DHT. Without DHT as a growth signal, BPH will in fact shrink. Of course, guys like myself would like to get our hands on it in order to regrow some hair. Finesteride is also known as propecia. Women shouldn’t use it, for risk of becoming pregnant and screwing up the hormone levels.

ANDROGENS

Testosterone Cypionate. These are “roids,” the testosterone dudes take to “GET HUGE!” Testosterone is converted to DHT, where it binds to nuclear receptors and upregulates the growth and development of muscles and bones. While this does have legitimate uses (such as hypogonadism in males), it is far more commonly abused by body builders. Given as an injected depot formulation, it causes an increase in LDL, decrease in HDL, premature closure of epiphysis, along with an increased aggression (roid rage), decreased sperm count, and hypogonadism. How can the treatment for hypogonadism lead to hypogonadism? Well, if you inject the compound the gonads make, the thing you injected will feedback onto everything, and shut them off. We treat hypogonadism with testosterone replacement, it isn’t really a cure. Testosterone must be injected, the first pass effect is too great.

Danazol, Stanozolol, and Fluoxymesterone are simply “other synthetic testosterones.” Stanozolol is the most commonly abused steroid by athletes, Fluoxymesterone is stronger, and Danazol is used to treat fibrocystic breast disease and endometriosis by feeding back on and inhibiting the hypothalamic‐ pituitary‐axis.

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Thyroid Drugs

Prothyroid Antithyroid

Triodothyronine (T3) Potassium Iodide Levothyroxine (T4) Radioactive I‐131 Propylthiouracil Methimazole Review of physiology. The organification of iodine is very challenging and cumbersome. Iodine is taken up from the blood, it is converted into iodide by Peroxidase, then expelled into the colloid. When stimulated by TSH, Mono‐Iodine‐Thyroxine (MIT) and Di‐Iodine‐Thyroxine (DIT) start forming together to make T3 and T4. The colloid is resorbed into the cell, the proteins are chopped up, and T3/T4 is released into the blood while MIT and DIT are recycled to the colloid. T4 is the T3 prodrug. T3 is 10 times more potent than T4, though both can form Ligand‐Receptor Complexes in the nucleus of target cells. Along the way, many things, particularly iodides, can inhibit the organification of iodine and slow or stop the production of T3/T4.

PROTHYROID

Triodothyronine (T3). This is T4, but with a shorter half‐life and a more expensive price tag.

Levothyroxine Sodium (T4). This is the preferred drug for hypothyroidism (over T3). T4 is cheaper, has a longer half life, and is the T3 prodrug. T4 is going to be converted to T3 and then it will enact its desired response. This is mandatory after thyroid resection for a thyroid carcinoma. Keep in mind that these drugs are metabolized by P450 (Phenytoin, Rifampin, Carbamazepine are P450 inducers , for example), and are deiodinated in the periphery.

ANTITHYROID

Potassium Iodide. Look back at that picture. Iodides inhibit both peroxidation and proteolysis. This prevents the creation of new T3/T4 and it prevents the release of T3/T4 already made. It is used to treat hyperparathyroidism (most commonly caused by Graves disease). In this version of iodide, we immediately, temporarily and transiently eliminate thyroid function. This is reversible (thyroid gland will “escape” within 2‐8 weeks) and so causes no permanent defect. Note that an acne‐like rash or a metallic taste may be included in a vignette (it was underlined in drug list, but not in lecture).

Radioactive I‐131. Its radioactive. It kills things. It emits Beta‐rays that kills tissue nearby. The only place where iodide is concentration is the thyroid, so the administration of radioactive iodide will all go straight to the thyroid. This is used to kill functioning/toxic goiters or adenomas. Since you are killing the thyroid, you will end up with hypothyroidism. People near babies (moms and moms‐to‐be) should avoid it. This is generally the first attempt at curing a thyroid cancer before resection.

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Iopanoic Acid and Ipodate Sodium. Given right now for treatment right now, this is a rapidly acting drug that prevents the deiodination of T4 to T3, limiting the effects of T3. Useful for preventing thyroid storm.

Propylthiouracil. This is a slow‐acting Thioamide that basically blocks every step in T3 synthesis. It inhibits the thyroid Peroxidase (blocking iodine organification), it blocks coupling of iodotyrosines (preventing formation of T3 and T4), and it inhibits the deiodination of T4 to T3. However, because it reflects synthesis rather than release of thyroid hormone, its effects are not seen until much later. It is used over Methimazole in pregnant females because it does not accumulate in breast milk. It is used to treat hyperthyroidism.

Methimazole. This is a powerful version of Propylthiouracil. It is 10 times more potent but does not affect the deiodination (so it takes even longer to see effects). Despite being more potent, it accumulates in breast milk, so cannot be used to pregnant or nursing mothers.

Drugs and Kids

Fluid Volume Clearance Albumin Growth Placenta Milk

Any drug Chloramphenicol Sulfonamides Quinolones Aminoptrerin Metrondiazole Gentamicin Ceftriaxone Tetracycline Sulfonamides Sulfonamides Tetracycline Nitrfurantoin DRUGS AND KIDS Teratogens Children are not tiny people. You cannot assume that because you give an adult 5mg/kg of drug X, you can give a baby 5mg/kg of drug X. Their hepatic clearance, renal clearance, and blood albumin levels vary from what is considered “normal.” Once again, the handout is really stellar, and the drug list concise, for this, but I will highlight some key points, sort of, “Review of the Red” for this lecture.

Extracellular Fluid Volume and Loading Dose. Babies have more water per body weight. Therefore, baby’s extracellular fluid volume is proportionately larger than an adult. This means that drugs that distribute in the extracellular fluid will require a larger loading dose to reach therapeutic effect. You should use the surface area instead of mg/kg.

Clearance Rates and Maintenance Dose. Babies have a reduced clearance of most drugs, owing to an incomplete liver (immaturity of hepatic enzymes) and a decreased glomerular filtration rate. Remember, the nephrons continue to develop into the second year of life while hepatic enzymes become operational in year 1. This means that even though you needed a larger loading dose, the maintenance dose must be smaller or fewer between. You will reach toxic levels too quickly in kids. Examples of this are Chloramphenicol (where the decreased hepatic metabolism leads to aplastic anemia more frequently in babies than in adults) and Gentamicin (where the decreased renal clearance increases the risk for hearing loss in babies, especially since they cannot tell you something is wrong).

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Bilirubin. Because the hepatic enzymes are insufficient, any increase in the free bilirubin will cause problems for a baby. Without the ability to conjugate the bilirubin, the fat‐soluble unconjugated bilirubin can get into the baby’s brain and cause kernicterus. Many drugs ride in the blood stream attached to albumin. Bilirubin rides in the blood stream attached to albumin. There are only so many seats on the bus, so if medication competes with bilirubin on albumin, there may be an increased concentration of free bilirubin. This is a combination of the bilirubin‐displacement and the infant’s inability to regulate bilirubin because of the immature liver. Drugs that displace bilirubin are sulfonamides and ceftriaxone.

Growth. Tricyclics cause the staining of teeth while Quinolones (cipro) screw up cartilaginous bone growth.

Placenta. Drugs can get into the embryo through the placenta, especially those that are lipid soluble (like hormones). The first trimester is of most concern. This is where we get into thinks like teratogenicity, virilization, and any other abnormal growth. Drugs like aminoptrerin can cause fetal death. Sulfonamides we already talked about causing kernicterus. Tetracycline we know can cause inhibition of bone growth and staining of the teeth. Streptomycin can cause ototoxicity. The big ones you should always remember are the teratogens (thalidomide, cocaine, ethanol, Phenytoin, lithium, valproic acid, warfarin), which are generally CNS depressants. Of course, transplacental passage of medications can be useful. Penicillin and AZT can cross the placenta and prevent vertical transmission of, and even treat, syphilis or HIV.

Breast Milk. After the pregnancy is over, baby needs to eat. Those who are breast fed are put at risk by lipid soluble medications. While complications are generally rare, we still want to be aware of them so we do not accidentally put the baby at risk. Antibiotics may alter the gut flora of the baby. Mutagens like Metrondiazole or those that can produce hemolytic anemia (nitrfurantoin, sulfonamides) should be avoided.

Drug Problem Risk Comments Chloramphenicol Hepatic Clearance Neonate, Infant Aplastic Anemia Gentamicin Renal Clearance Neonate, infant Ototocixity Sulfonamides Displaced Bilirubin – Albumin Any Route Kernicterus Ceftriaxone Displaced Bilirubin – Albumin Neonate, Infant Kernicterus Quinolones Bone Development Kids Abnormal Epiphysis Tetracycline Bone Development Any Route Stained Teeth Aminopterin Placental Crossing Placenta Fetal Death Metronidazole Mutagenic Breast Milk Cancer Nitrofurantioin G‐6‐PD Deficiency Breast Milk Hemolytic Anemia Teratogens After first Trimester Phenytoin, ethanol, lithium, Valproic Heparin osteoporosis in mothers acid, warfarin, thalidomide, cocaine, Warfarin fetal brain bleeds Carbamazepine, Sex Hormones, ACE Inhibitors fetal renal failure, switch to α‐methyldopa Retinoic Acids Bolded items were red in lecture

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DRUGS AND WOMEN

The same concerns for pregnancy, breast feeding, and teratogenicity hold for women as well. Those details were included above, in the tables on the preceding page.

Pregnancy and Dosing. Amongst other changes, there is generally an increase in body water and an increase in body fat as the woman becomes pregnant. In addition, there is an increased renal blood flow. These effects essentially tell us that there is a larger volume of distribution and a faster clearance. The conclusion, then, is that doses must be larger and more frequent to achieve the targeted therapy. Just make sure they are not teratogens! As the slide said, by far the most clinically relevant change to occur during pregnancy involve the clearance of anticonvulsants. Carbamazepine, Valproate, and Phenytoin have increased clearances, decreased plasma levels, which result in increased seizures. Again, it is important to increase the dose and dosing frequency. Of course, those drugs he had listed are teratogens anyway, and would screw up the baby pretty good.

Aspirin. In men, the risk of myocardial infarction was significantly decreased when their medication regimen involved aspirin. In women, there was no significance in the improvement of myocardial infarction, but there was in stroke.

Digoxin. Digoxin may increase mortality in women. Since dig does not alter mortality (only hospitalization), should we be giving women dig? Along the same lines, women are more predisposed to suffer from drug‐induced cardiac arrhythmias (Torsades De Pointes) , irrespective of digoxin, pregnancy, or aspirin. Elderly

Renal Body Composition Hepatic Polypharmacy Clearance Clearance

Polypharmacy. Since old people have lots of things that go wrong with them, there are, on average, 6‐8 medications per patient. With so many drugs and so many subtleties, it is almost guaranteed to have adverse drug reactions. Whether or not they become clinically significant is another story. Yet we must be cautious with our dosing and the risk of noncompliance.

Body Composition. Be careful with body composition. The elderly are different than women and kids. There is increased body fat and decreased body water. This causes a decrease in the volume of distribution of water soluble drugs (old people get drunk faster) and an increase in the volume of distribution in fat‐soluble drugs (like seizure medications or sedative such as diazepam).

Renal Clearance. There is an age‐related decrease in GFR, thus the drugs that undergo renal clearance are going to have longer half‐lives and increased risk of overdose or drug interaction (Aminoglycosides and digoxin). Unfortunately, serum creatinine levels rise as muscle breakdown starts (common in the elderly) making creatinine an unreliable measure of clearance

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Hepatic Clearance. As people age, the heart generally begins to fail. The decreased cardiac output means a decreased hepatic blood flow. This means that hepatic drug metabolism may be impaired and it may be less inducible. Well, if renal clearance is down and hepatic clearance is down, that in general means there is an increased half‐life of all drugs.

Sensitivity. So, there is not a whole lot of evidence, but the elderly are just more susceptible to some drugs as they age, separate from the decrease in clearance or body composition. Drugs like the sedative‐hypnotics (benzos) and opiod analgesics which includes the respiratory depression and CNS suppressive effects.

Drug Interactions

P450 Inducers P450 Inhibitors P450 Metabolized Chronic EtOH Acute EtOH Warfarin Rifampin Amiodarone Amiodarone St John’s Wart Cimetidine Cyclosporine Phenobartbital Fluxoetine Statins Barbiturates Grape Fruit Juice HIV Drugs Carbamazepine Ca Channel Blockers Ca Channel Blockers Induction of P450 P450 Inhibition slows clears drugs faster clearing of drugs There are of course, many others, these are included in lecture

PGP Inducers PGP Inhibitors PGP Excreted Rifampin Amiodarone Amiodarone St John’s Wart Grape Fruit Juice Cyclosporine Digoxin Simvastatin PGP induction PGP inhibition slows Verapamil clears drugs faster clearing of drugs There are many examples in the handout, this is going to review only the “red Stuff” from lecture.

Presystemic Clearance = PGP and P450. PGP is a protein that is the drug extruder found in the intestinal cells. Drugs must first get passed PGP, then get past P450 enzymes in the intestinal cells, then again passed the first‐pass metabolism of the liver, again with P450 enzymes. Certain drugs can induce PGP (making it so that less drug can get in, requiring a larger oral dose), or inhibit PGP (either by competing for the protein requiring dose adjustment / timing of medications, or by downregulating its formation requiring decreased dosage). Grapefruit Juice inhibits PGP. Hepatic P450 is covered next.

Cytochrome P450 Interactions (Hepatic). There can be two possible results. Induction of P450 takes a long time (about a week) to increase the amount of enzyme present. Rifampin and chronic alcohol does this really well. Inducing P450 in the liver will allow the liver to clear hepatically metabolized drugs faster, requiring an increased dose or more frequent dosing. Inhibiting P450 is almost immediate. Either

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Pharm Endocrine Review the drug you have added competes for the enzyme (competitive inhibitor) or it noncompetitively inhibits it. Generally, this does not cause alteration in gene transcription. So long as that drug is there, smaller doses are required. Cimetidine is a prime example of a P450 inhibitor, as is acute alcohol.

Altered Distribution. This is where one drug displaces another from the plasma proteins. This is usually not clinically significant, causing a transient blip that dissipates rapidly because a rise in free drug also increases drug clearance. However, given certain conditions, such as being a neonate, can produce severe complications (sulfonamides and something else displaces bilirubin resulting in kernicterus). There are also problems with displacing drugs from tissue binding sites (generally doesn’t occur, especially now, and is not in bold/red). Finally, interactions with PGP is being investigated because it might be involved in the blood brain barrier, keeping out drugs like antibiotics from the brain.

Grape Fruit Juice. Grape fruit juice is an interesting phenomena. It is a naturally occurring compound found in fruit. It has the ability to degrade/inhibit intestinal p450 and inhibit intestinal PGP. The effective net result is to decrease the protection conferred by the gut. This means that drugs will have a greater‐than‐intended effect. This is particularly important with the statins (Lovastatin and Simvastatin), where Rhabdomyolysis and renal failure can result from overdose.

Amiodarone and Digoxin. Amiodarone inhibits renal excretion of digoxin. Reduce dig levels and titrate back up.

Amiodarone and Warfarin. Amiodarone inhibits cP450, which metabolizes warfarin. Reduce warfarin doses.

There are many specific examples. In this block, look for birth control failures, rhabdomyolysis with Statins, Bradycardia/Arrhythmia with digoxin, renal failure, and bleeding from warfarin. Those seemed to be really reinforced over the year and again in this block. Taking a look at the drug profile where it has about 75 drug combinations you should know might be worth a look over, but for me, at this time, it was just too much to care about.

Environmental Toxicology

Vocabulary Antidotes Toxidromes Environmental Tox

LD50 True Antidotes Sympathomimetics BTEX

TD50 Complexers Sedative Hypnotics Hydrogen Sulfide Therapeutic Index Metabolic Enhancers Opiates Carbon Monoxide

Acute Toxicity Metabolic Inhibition Anticholinergic Natural Gas/Mercaptans Chronic Toxicity Excretion Enhancers Cholinergics Mercury TLV, NOEL, ADU Absorption Inhibitors Tricyclics Lead STEL, ALD Receptor Antagonists Salicylates Arsenic Toxicon Cadmium

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TOXICOLOGY VOCABULARY

‐ LD50 ‐ Dose at which 50% die, measure of harmfulness

‐ TD50 – Dose at which therapeutic effect is achieved in 50% of patients

‐ T.I. – Therapeutic index, TD50/LD50 Æ the bigger the better, measure of safety ‐ Acute Toxicity – single dose within 24 hrs (short period), defining intrinsic toxicity ‐ Chronic Toxicity – daily exposure, lower levels over many years has the same effect ‐ TLV – Threshold limit value, the concentration below which there is no expected untowards effect over a period of 8hrs/day 5 days/week. This is a safety standard o NOEL‐ no observable effect level o ADU – allowed daily intake ‐ STEL ‐ short term exposure level ‐ ALD – average lethal dose, an estimate of how bad a drug is based on accidental exposure ‐ Toxicon – toxic principle of the given chemical, what is so bad of it? ‐ Dose is the most significant determinant of toxicity

ANTIDOTAL TREATMENTS

‐ True Antidotes o Naloxone – used to treat opioid/opiate overdose, may induce vomiting o Insulin – treats hyperglycemia, Diabetic Ketoacidosis, Nonketotic Hyperosmolar Coma o Glucose – treats hypoglycemia, which may cause coma and death ‐ Absorption Limiters o Emesis = syrup of ipecac induces emesis to remove unabsorbed drug (acute toxicity) ƒ Emesis is contraindicated in Petroleum, Caustic Acid/Alkali, Seizures, Comatose o Gastric Lavage = “washing the stomach” flow in fluid, then suck it out (acute) o Activated Charcoal = adsorbent, binding chemicals preventing their absorption o Cathartics = prevent absorption by speeding gastric motility, so they poop it out ‐ Complexers We give Amyl Nitrite and o Heavy Metals Æ use Chelators such as BAL and EDTA that bind to metals Thiosulfate to both complex o Heparin Æ Protamine binds to acidic heparin to terminate its action the CN and convert it to something harmless. This is o Toxins Æ ABCs, lavage, emesis, charcoal done in Europe, not really o Organophosphates Æ Pralidoxime (2‐PAM‐Cl) tying up organophosphates done here. o Cyanide Æ Methemoglobin is made by adding Nitrites that ties up CN ‐ Metabolic Enhancers o Cyanide Æ Rhodanese converts CN to benign compound, but it needs a sulfur source, so we give it some, called Thiosulfate ‐ Metabolic Inhibitors o Ethylene Glycol Æ not as bad as when it is metabolized. If we give ethanol to tie up the enzymes that would make the bad metabolite, we can excrete the toxin before it gets made into its toxic metabolite

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‐ Rate of Excretion (NOTHING WAS BOLDED) o We can give things that compete for reabsorption in the Renal Tubules o Give Calcium or Chloride for certain ion poisonings ‐ Competition for receptors o Carbon Monoxide ƒ Binds to hemoglobin and ties it up so it cannot carry oxygen (200x affinity) ƒ Presents with a classic cherry red appearance along with confusion and coma ƒ Treatment is artificial respiration with oxygen, competing for receptors on Hgb o Turbocurare/Pancuronium ƒ Cause a competition between the poison and Ach ƒ Give Cholinesterase Inhibitors and some Acetyl Choline to fight back o Coumarin ƒ Inhibits the synthesis of coagulation, inhibiting vitamin K ƒ If their INR goes too high, we can just give Vitamin K to counteract o Opiates ƒ Really driving this one home, use Naloxone ‐ Bypass or Repair Poison o Digitalis ƒ Digibind ‐ Blockage of receptors o Atropine blocks muscarinic receptors to block the effects of anticholinesterases, for example, organophosphates (how this is different than competition, im not sure)

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TOXIDROMES

SYMPATHOMIMETICS SEDATIVE HYPNOTIC CNS Agitation, Hallucinations, Paranoia CNS Coma Respiration No Change Respiration Decreased Pupils Mydriasis (Dilated Pupils) Pupils Mydriasis (Dilated Pupils) Other Seizure, HTN, tremor, hyperrflexia, Other Hypothermia, Decreased Reflexes, hyperthermia Hypotension Drugs Cocaine, Amphetamines, PCP Drugs Alcohol, Barbiturates, Benzos Antidote None, control symptoms Antidote Flumazenil for Benzos

OPIOD/OPIATE ANTICHOLINERGIC CNS Coma CNS Agitation Respiration Decreased Respiration No Change Pupils Miosis (pinpoint) Pupils Mydriasis (Dilated Pupils) Other Hypothermia, Hypotension, Other Fever, Dry Skin, Flushing, Urinary Hypotension Retention, ACS = “Hot as hell, Dry Drugs Morphine, Heroin, Hydrocodone, as Bone, Mad as a hatter, Red as a Methadone, Codeine beat, blind as a bat” Antidote Naloxone reverses CNS effects and Drugs Atropine, Other’s Not Listed may induce vomitting Antidote Symptom control

CHOLINERGIC TCAs CNS Coma CNS Coma Æ Agitation Respiration ‐‐‐ Respiration ‐‐‐ Pupils Mydriasis (Dilated Pupils) Pupils Mydriasis (Dilated Pupils) Other SLUDE = Salivation, Lacrimation, Other Arrhythmias, Convulsions, Urination, Defecation, Emesis Hypotension, Hyperthermia Drugs Organophosphates, carbamates, Drugs TCA’s: Amitriptyline, Imipramine Nicotine Antidote None Antidote Anticholinergics

SALICYLATES Dr. George told us that the questions will be CNS ‐‐‐ “here are a bunch of symptoms, what caused Respiration ‐‐‐ it?” If possible, there might be “how do you fix Pupils ‐‐‐ it?” Specific poisons are coming up, and last Other Diaphoresis, Tinnitus, Agitation, about 2 lectures, so there is a crap load to Alkalosis (early), Acidosis (Late) remember. We try to tone is down for you. Drugs Aspirin Antidote None

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SPECIFIC POISONS – this is a review of the entire course, with selected drug classes

ACIDS BASE Source Cleaners, Bleaches, Food, Batteries Source Lye, Liquid Plumber, Oven Cleaner Signs Burns, Black Bloody Diarrhea, Signs Swallowing is painful and difficult, epigastric pain, 50% mortality vomitus thick and slimy and may Treatment ABCs, Analgesia, tons of water contain blood, shock esophageal (dilute on skin and in GI tract), strictures, 25% mortality using bases to neutralize causes Treatment Same as for Acids, no lavage or heat, and exacerbates injuries emetics!

OPIATES MEPERIDINE Source Heroin, Morphine, Oxycodone, Source Demerol Hydrocodone, Fentanyl Signs Dilate Pupils, Increase in Heart Rate Signs Bilateral Miosis (pinpoint pupils) (it is an opioid with anticholinergic respiratory depression / arrest properties), and seizures (nor‐ and CNS depression Meperidine metabolite) Treatment Naloxone (fixes them if Opioids are Treatment Same as Opiates, but give benzos for the cause, benign if they aren’t) seizures

BARBITURATES ATROPINE Source Suicide, automatism Source Atropine, Deadly Nightshade Plant Signs Sedative Hypnotic Toxidrome Signs Hot, Dry, Mad, Red, Blind Treatment ABCs, Lavage/Charcoal if ingestion (anticholinergic toxidrome) is recent, hemodialysis if it’s a long Treatment ABCs, lavage with slightly acidic time since they took it. There is no content and cholinergics like antidote for barbiturates Pilocarpine or physostigmine

BENZOS Source ‐pams and –lams ETHANOL

Signs Sedative Hypnotic Toxidrome, Source Liqour Beer rarely fatal (unless mixed) Signs Odor, CNS depression, etc. Treatment ABCs, emesesis, lavage, Flumazenil Treatment ABCs, Gastric Lavag, fatal if above is antidote (dangerous) 0.500, 500mg/dL

KEROSENE NEUROLEPTICS Source Illuminating effect, paint thinners Source Tranquilizers, Haldol, Signs Euphoria and Vfib, Headache, Phenothiazides weakness, drowsiness, convulsions Signs Extrapyramidal Signs, tardive Treatment ABCs, water, saline, steroids to dyskinesia, and poikilothermia

avoid kerosene pneumonitis, do (approach that of environment)

NOT induce emesis Treatment ABCS, Lavage, treat symptoms

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PCP ACETAMINOPHEN Source Angel Dust, PCP Source Tylenol, Vicodin, Percocet Signs Hepatic Failure (once glutathione Signs Rotary Nystagmus, uncontrollable

depleted), nausea, vomiting, liver rage, psychosis

enzyme markers (ALT, AST, Bili) Treatment Haldol/Benzos for Sedation, Treatment ABCS, Emesis, Lavage, Charcoal, N‐ Acidify urine (cranberry) to acetyl‐cysteine to restore ↑excretion glutathione SALICYLATES Source Aspirin (requires a lot or chronic) COCAINE Signs Deep Breathing, Tinnitis, Source Crack, Coke, Coca Plant Alkalosis, Acidosis Signs CNS stimulation, “Cocaine Bugs," Treatment ABCs. Emetics, Lavage, Treat hallucinations, seizures symptoms (like seizures) Treatment ABCs, Charcoal, Emesis, nonspecific treatment DIGOXIN PHENYTOIN Source Dig Source Signs Headache, Nausae, Vomitting, Signs Blured Vision Bradycardia, Treatment ABCs, emesis, lavage, charcoal, Arrythmias cathartics. Once it’s in, it’s in, and Treatment ABCs, Dose Adjustment, lavage,

you just have to wait it out charcoal, emesis, Digibind, Potassium Supplements THEOPHYLLINE DIOXIN Source Aminophylline Source Herbacides, Cigarette Smoke Signs CNS Stimulation, cardiac Signs Cloracne (small yellow arrhythmias, death from resp comedones) on the face and failure limited systemic effects Treatment ABCs, emesis, lavage, charcoal, Treatment ABC, Alkaline Diuresis. If its acute, cathartics, fluids, and induce emesis/lavage, but its anticonvulsants if they start seizing usually a chronic exposure thing

ENVIRONMENTAL TOXICOLOGY

BTEX (Benzene, Toluene, Ethylbenzene, and Xylene). Gasoline is a refined product of petroleum. The four molecules that make up the bulk of the gas is BTEX. They are also found in other products, but let’s talk about them in relation to gas. These are mainly CNS depressants though they may also cause nausea, vomiting, mucous membrane irritation, skin irritation and convulsions at high doses. Benzene is also a known carcinogen, and may be found in many cleaning agents. The treatment, as always, is ABCs, removal of exposure, and to add anticonvulsants for seizures. There is no antidote, just manage the patient and hope they make it out alive. This can be kind of fun, like when you sniff markers and get light headed. That’s toluene. Bad idea to snuff.

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Hydrogen Sulfide is found in petroleum production, processing and use as well as brewery work, mining, and natural gas production. It is a toxic gas that smells awful (“rotten egg stink bomb smell”) that is one of the leading causes of death in the workplace. At high concentrations, the rotten egg smell is not detected leading to insidious exposure. Most likely, it acts similar to cyanide, where there is an inhibition of cytochrome oxidase resulting in increased anaerobic activity (blunts the use of oxygen). Acutely, there is CNS depression, Coma, or Respiratory Arrest. There are other neurologic symptoms such as eye pain, headache, and abnormal nystagmus. Chronically, you get headache, nausea, and vomiting. This one we can actually TREAT. Of course we do ABCs and supportive care (often summed up as “IV, O2, Monitor.”) We can give nitrites, which create methemoglobin that binds to the sulfur, creating sulfmethemoglobin, preventing the binding of sulfur to cytochrome oxidase. Luckily, sulfmethemoglobin is rapidly renally eliminated from the body.

Natural Gas/Mercaptans. Natural Gas is a mixture of aliphatic hydrocarbons, mostly methane, propane, and ethane. Natural gas is a simple asphyxiant and has little to no irritant or systemic effects that has no odor. Say that again: it prevents your ability to breathe but is nearly undetectable through other symptoms. By law, we make unburned gas with essentially no risk because we add mercaptans which cause the rotten egg odor that is used as an indicator for the presence of gas. Methane is “not a toxic product.” The only way it can kill you is by displacing oxygen in your lungs, causing asphyxia. It does NOT have systemic effects. Of course, if you are in a room full of natural gas and light a match, the mushroom cloud might have a small impact on your death.

Carbon Monoxide. This comes from cigarette smoke, automobile exhaust, faulty heating equipment. This is a colorless, odorless gas present in the atmosphere normal. The TLV is 35ppm; you can be exposed to a lot of CO without symptoms. However, when they get to really high levels, carboxyhemoglobin levels rise (CO binds to hemoglobin 10‐100 times greater than oxygen does). As they do, there is slight headache and exertional dyspnea. As levels rise further, you get a headache, fatigue, and dizziness. The classic finding (especially for exams) is the cherry red appearance of your cheek. The treatment is ABCs and supportive care.

Metals begin on the next page in an outline format. These metal slides come at the end of Toxicology II on blackboard. The rest of the above lecture came from Toxicology III on blackboard.

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Mercury

‐ Source o Batteries, Thermometers, Fungicide, Amalgam Fillings ‐ Path o Blocks –SH Containing Enzymes o Can be Ingested or inhaled, with presentations differing based on intensity (acute Mercury is a liquid at amount versus accumulation) or the form of exposure (elemental, organic, inorganic) room temperature Clinical Take a look at the highlighted effects. The pneumonitis and acute renal tubular necrosis are the most important. The tremors and anxiety leads us back to the “Mad Hatter” who suffered mercury poisoning. He really breezed through this slide, so I am not so certain as to how important it was.

Do watch out for mercury in tuna and fish. There may be concern for young adults, but you have to eat A LOT of tuna. ‐ Treatment o Toxic levels are defined as 40ng/mL – “don’t remember the numbers” o Remove the patient from exposure, ensure ABC’s and supportive care o Ipecac, Gastric Lavage, and activated charcoal if mercury is ingested Use the chelator BAL or N‐Acetyl Penicillamine Mercury Pneumonitis o Every metal has a chelator, mercury uses BAL = Dimercaprol or Penicillamine

Lead

‐ Source o Paint, batteries, old pipes, bullets (wash your hands after shooting!), newsprint o Usually it is ingested, though it could be inhaled, but it is NOT dermally absorbed ‐ Path o Mechanism = binds to sulfhydryl groups on proteins Lead is a solid, it looks like o Targets include the Brain, PNS, kidney, bone marrow squished poop ƒ Half life is 1‐2 months in soft tissue, 30 years in the bone ‐ Clinical o Inorganic Lead ƒ Absorption must be through the oral route, which is very slow, or inhalation ƒ There are blue‐black lines along the gums, abdominal pain, and metallic taste ƒ Neuro symptoms such as wrist and foot drop and convulsions are late stage o Organic Lead Hyperdensity at the ends of the ƒ Requires weeks of exposure, a lot longer than inorganic lead bone (the really white areas) ƒ Predominated by tremors, convulsions, weakness, mania, liver/kidney failure ‐ Treatment o Toxic Levels are >60ug% in blood, X‐rays = densities at the end of bones (image) o Free Erythrocyte Protoporphrin (FEP) level is > 250ug/100mg RBCs o Supportive care (ABCs, Benzos for seizures), increase urine flow with 10% Dextrose IV o Use chelators such as BAL and EDTA

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Arsenic

‐ Source o Pesticides, Herbicides, Paints, Ceramics, Wood Preseravatives o Has been used as a homicidal agent in the past for assassination attempts (Middle Ages)

Arsenic Powder ‐ Path o Forms As5+ and As3+ which are toxic o It affects the skin, lungs, kidney, and liver o There was no real mention of what it does in terms of mechanism ‐ Clinical o Oral irritation and metallic taste are caused by ingestion o Eventually, there will be liver damage as well as kidney damage Salt/Pepper Skin o Diarrhea is common, especially after acute ingestion o Classic findings are Salt/Pepper skin lesions, Mees Lines (chronic), Hemolytic Anemia ƒ Mees Lines = little lines on the finger nails occurring under chronic exposure o Coma and death results (1‐4 days after ingestion) from shock and organ failure ‐ Treatment Mees Lines, white stripes o Toxic levels are a blood level >7ug/dL in the middle of the nails o As always, protect the ABCs and give supportive care (Fluids and Electrolytes) o Induce emesis, do a gastric lavage, and give them charcoal if acutely ingested o Blood transfusions may be required for hemolytic anemia o Give a chelator such as BAL or penicillamine; BAL is the drug of choice

Cadmium

‐ Source o Batteries, Solder, Coated Metals, Jewelry, Cigarettes and Paint ‐ Path o Damage is primarily to the kidneys and liver Cadmium Metal o May be inhaled (10‐40%) or ingested (2‐6%), Half‐life is 7‐10 years o Cadmium binds to metallothionein which is filtered and resorbed from renal tubules; eventually, metallothionein is depleted, and cadmium is directly toxic to renal cells ‐ Clinical

Acute‐Inhalation Chronic Inhalation Beware delayed chemical pneumonitis Emphysema, Anemia, Liver Dysfunction, Insomnia Noncardiac pulmonary edema Proteinuria, general Liver/Renal/Liver Problems Acute Ingestion Chronic Ingestion Nausea, Vomiting, Diarrhea Renal Failure = altered tubular function, vit D Acute Liver and renal failure deficiency, Osteomalacia, demineralization of bones, proteinuria ‐ Treatment = You’re Screwed o ABC’s, Ipecac/Lavage for ingestion, Supportive Pulmonary Care for Inhalation There is no specific antidote and BAL is contraindicated

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