Chapter 70: Cox Inhibitors, NSAIDS, and Acetaminophen

Cyclooxygenase (COX)o General Info

Enzyme that converts arachidonic acid into prostoglandins and related compounds Prostaglandins

Sensitize pain receptors Promote uterine contraction Promote normal renal function Stimulate secretion of gastric mucous (to protect the stomach from all the acid

in there) Lower set-point for temp in the hypothalamus

COX’s are bad for people with renal failure. Cox 2 causes renal vasodilation and renal perfusion

Cox 1’s are usually good, Cox 2’s are usually bado Classifications of Cox Inhibitors

Anti-inflammatory properties NSAIDs – (Non-Steroidal Anti Inflammatory) Cox’s fall in this group

o First generation – Nonselective Aspirin (Cardio-protective)

o Second generation “coxibs” – selective Selective to COX 2. Celebrex is an example

Non- anti-inflammatory properties Acetaminophen (Tylenol) COX inhibitor, but no anti-inflammatory, so it’s not as

good as the others Aspirin is the only one that is Cardio-protective, the others are not. Most first

generations are cardio-toxic. They wanted to get away from using COX 1’s inhibitors because they (Cox 1’s) are protective of the stomach. If I take a first generation what I’ve done is taken away from the protection in my stomach. This leads to ulcers and bleeding, one of the main problems for this drug.

o 1st Generation Non-Selective COX Inhibitors Protoype: acetylsalicylic acid (Aspirin) ASA

MOA / TE / Useso Non-selective COX Inh- inhibits both cox 1 and 2 o Analgesic, antipyretic, anti-inflammatoryo Suppression of platelet aggregation

Irreversible for 8 d – life of the platelet Treat / prevent Ischemic stroke, TIA, MIs (acute & old),

anginas, adjunct to angioplasty & revascularization ADME

o Rapidly absorbed orally, slower rectallyo Half-life (2 h to 20 h)o Distributes to all body tissues – pregnant? Don’t give to preggers, can

make the baby bleed. o Excretion pH dependent (increases pH, Increases excretion 4x)

Side Effectso Gastric distress, heartburn (related to the acidity of aspirin, because

it’s actually an acid), and nausea Adverse Effects

o Gastrointestinal – (occult (hidden) and overt) Occult blood in the stool. You have to look for it by collecting

a sample. o Bleedingo Renal impairment – Signs?

acute/reversible – Na+/H2O Pre-existing condition dependent

o Salicylism (overdose of aspirin) – acid/base – tinnitus (ringing in the ears, first sign).

o Reye’s syndrome A children’s disease. Basically children liver failure. Aspirin

can give rise to this, so it’s contraindicated in children. They watch them very closely.

o Hypersensitivity – asthma – rhinorrhea (runny nose) to shock 1st generation is broad spectrum. They aren’t good for

kidneys. The damage can be irreversible. When you’re kidneys quit working your serum sodium goes up. Where sodium goes, water follows. This causes hypertension.

Contraindicationso PUD & Bleeding disorders (cause it can give you ulcers and thins your

blood, if they already have these, don’t give them aspirin that will only make it worse!)

o Hypersensitivityo Extreme caution in pregnancy

D-D Interactionso Anticoagulants & other NSAIDs o Glucocorticoids (gastric ulcertion)o Ibuprofen – impairs cardioprotective properties

Acute Poisoning (LD=Lethal Dose)o LD adult = 20-25 g - LD children = 4 g

LD 50 is the dose that will be lethal to 50 percent of the population. Aspirin is an acid, so if you overdose on it your body becomes acidic. That acidity results in exitation. They come in hyperventilating and ultimately (cause they’ve been breathing like that for so long), it will depress respiration, they become stuporous and coma, and die. You also get a fever from the acid.

o Sxms Resp excitation ® depression ® Hyperthermia, stupor, coma, death

o Treatment

Supportive, charcoal, alkalinization of urine Supportive treatment= trying to bring the fever

down. Use tepid water or icepacks to the armpits and groin. Try to get their core temperature down. You can also have acute renal failure, which would mean they need dialysis. You give them an alkaline shot in the blood it will alkaline the urine.

Dialysis Additional Info on 1st Generation Non-Selective COX Inhibitors

o People take baby aspirin to suppress platelet aggregation, to keep them from having a heart attack. It actually binds to the platelets (once it’s stuck to it it’s stuck to it until the platelet dies). Makes the blood flow more smoothly thru the vessels. Not used to treat hemmorhagic stroke (because a bleed caused the stroke, not a clot).

o If you have a stent, if you have a valve, if you have a graft in a vessel, they’re going to put you on something that will minimize the stickiness of the platelets. The platelets see these things as foreign objects and want to stick to them. That’s a bad thing!

o If someone is having an MI (heart attack) the best thing you can do is give them an aspirin. Have them chew it and hold it under their tongue for fast absorption. It could save their friggin life!

o Non-ASA 1st Generation COX Inhibitors Not caridoprotective –CONVERSE – hold in CABG (a kind of heart surgery, Coronary

Artery Bypass Graft) procedures and at least 14 days afterward Indicated in RA and OA – shortest time, lowest effective dose Reversible inhibition DON’T impair platelets, they cause water retention

Exampleso Ibuprofen, Fenoprofen, other “profens”o Ketorolac (Toradol) – 5 d – renal (lowers renal excretion, don’t give for

more than 5 days) o Naproxen (Naprosyn) – better tolerated

o 2nd Generation Selective Cox Inhibitors Prototype: Celecoxib (Celebrex) Benefits: Lower GI bleeding risk than the others! Uses:

OA, RA, Acute pain, dysmenorrheal Familial adenomatous polyposis- if you have these and you take this, you can

develop cancer in those. They can become cancerous, as it were NOT Cardio Protective Doesn’t cause the mental cloudiness that the narcotic pain pills do!

Adverse Effects Dyspepsia (basically indigestion), abdominal pain Renal toxicity GI ulceration/bleeding Sulfonamide allergy

Contraindicated (Or used with extreme caution) with blood thinners because celebrex can cause

bleeding.o Another 2nd Generation Selective Cox Inhibitor

Tylenol (Acetaminophen) MOA: Inhibits prostaglandin synthesis in CNS

o Remember, prostaglandins help amplify the pain in your body! Uses: Pain, fever, NOT anti-inflammatory Benefits: 0% GI Bleeding, renal impairment Adverse Effects

o Hepatotoxicity- short term, if they are on long term therapy with Tylenol it can be hepatotoxic in only 2g/d

o ETOH connection- alcohol impairs the conversion of toxic metabolites to non toxic metabolites.

Acute Toxicity- Sxms 24-72 hours post Overdose (you can overdose and it may take a while for you to notice)

o N/V/D, sweating, abd pain, liver failure, and comao Mucomyst- the antidote for Tylenol (if given w/i 24 hours)! Because

you don’t see symptoms for 24-72 hours, you have a high risk for liver damage. The quicker you get help the less your chances of liver damage, duh!

Chapter 71: Glucocorticoids in Non-Endocrine Diseases

Physiology of Glucocorticoids in Non-Endocrine Diseaseso Artificial ones are nearly identical to natural oneso Metabolic Effects

Breakdown of fats, proteins, carbs - glucose (part of the stress response. They want sugar and they want it now! Fight/Flight. From the adrenals. So we can go fast and fight hard.

Rob proteins for glucose production (actually steals proteins to make glucose) Fats redistributed long-term to “moon” face (they get chipmunk cheeks, their face gets

very round) o Cardiovascular Effects

Low levels Like 5 mg – permeable vessels, dilated vessels (can get hypotension) Increase RBCs and PMN (polymorphonuclear) Leukocytes (going to have an elevated

hemoglobin and their white cell count can go up) Decrease Lymphs, Eosins, basophils, and monosites

o Effects During Stress Large quantity glucocorts / epi secreted If inadequate = circulatory failure

You have to have steroids in your body or you will dieo Effects on water and electrolytes

Aldosterone effect: increases Na, increases H20, lowers K

When you are on steroid therapy you retain water and you get puffy High doses- impair intestinal Ca absorption (hypocalcemia, cause you aren’t absorbing it,

but excreting it out)o Respiratory System in neonates- RSD (? I don’t know what this means)o Fun Facts

They make you feel absolutely wonderful while they are doing all these bad things to your body. Hilton called it Sweet Poison. They used to think the effects were short term and only while you were on it. But now they know the effects are longer than that.

o Even More Actions of Glucocorticoids! Inhibit synthesis of prostaglandins, leukotriens, and histamines Impedes the function of phagocytes and lymphocytes in inflammatory response Used for anaphylaxis Tells the body that everything is absolutely great! But they are liars! Everything is not

absolutely great! Glucocorticoids kick ass but suck for you and your body

Glucocorticoidso TE / Uses

Anti-inflammatory and immunosuppressant effects (high doses) Rheumatoid arthritis Systemic lupus erythematosus Inflammatory bowel disease Miscellaneous inflammatory disorders Allergic conditions Asthma Dermatologic disorders Neoplasms – toxic to malignant lymphocytes (in some of your blood cancers) Can also stimulate your appetite Suppression of allograft rejection Prevention of respiratory distress syndrome

o Adverse Effects Adrenal insufficiency Osteoporosis (resorption, rebuilding & calcium) (limits absorption of calcium. They tell

the body that the bone isn’t broken, so new bone isn’t made) Infection – esp. Pneumocystis Carinii Pneumonia (PCP) Glucose intolerance (raises you’re blood sugar, long term use can cause you to become

diabetic) Myopathy Fluid and electrolyte disturbance Growth retardation (in children esp, because of the bone remodeling stuff). Psychologic disturbances Cataracts (from deposits in the lids) and glaucoma Peptic ulcer disease Iatrogenic Cushing’s syndrome (related to the adrenals) Use in pregnancy and lactation

o D-D Interactions Interactions related to potassium loss

Nonsteroidal anti-inflammatory drugs Insulin and oral hypoglycemics Vaccines (because you won’t get the immune or inflammatory response you are looking

for from the vaccine because, remember, they stop your body from having an inflammatory response!)

o Adrenal Suppression Atrophy Stress & “flat” response (Alt. day Tx – so they might give you a dose today, skip a day,

another dose, skip a day. Trying to prevent loss of function in your adrenalso Glucocorticoid Withdrawal

Taper over 7 days Switch from multiple doses to single doses Taper the dosage to 50% of physiologic values Monitor for signs of insufficiency

Hypo Tension, hypoglycemia, mylagia, arthralgia and fatigue

Chapter 73: Drugs Affecting Calcium Levels and Bone Mineralization

Calcium Physiologyo Critical to skeletal, nervous, muscular, and cardiovascular systemso Body stores – review (99% of your calcium is in bone, other 1% is in blood) o Absorption – occurs in the gut

with PTH (parathyroid hormone?) & Vit D Glucocorticoids – effect? They impair absorption in your gut in high doses

o Excretion Calcitonin augments calcium elimination

Hypercalcemia: Drug Therapyo Usually asymptomatic (you usually don’t know it) o Causes: PTH, Vit D toxicity, thiazides o Drug Therapy (try to make the urine excrete it)

Promote urinary excretion – furosemide (lasix) & IV saline Decrease mobilization from bone

calcitonin, bisphosphonates, inorganic phosphates, gallium nitrate Decrease intestinal absorption

Glucocorticoids Increases Neuromuscular excitability Causes: ¯PTH, ¯Vit D & Absence of Ca++

Clinical presentation Tetany, convulsions, and spasm of the pharynx Treatment

Treatment IV Calcium (calcium gluconate) Vitamin D

Fun Facts: The body lets the bones waste away to keep the serum calcium levels the same. Ca plays a role in muscle contraction and all that shit, so you need it no matter

what happens to your bones. You can survive with crappy bones, but you can’t survive with a heart that can’t beat!

Drugs for Ca Disorders: Calcium Saltso Prototype: Calcium Citrate (Citracal)

MOA / TE / Uses – Keeps levels up, prevents reabsorption to treat mild hypocalcemia in children, adolescents, elderly, post-menopause, & preggers

Adverse effects – hypercalcemia DDD, DDF

Glucocorticoids (may have to take higher doses of citrical or whatever) Spinach, beets, bran, cereals – impair absorption of calcium

Adverse Effects of IV administration ONLY IV (can cause necrosis elsewhere) IM or extravascular can cause necrosis May cause severe bradycardia of also on digoxin You have to keep a close eye on their heart when they are taking this crap!

o Vitamin D Stuff (Not Calcium Salts)o Prototype: cholecalciferol (Vitamin D3)

MOA – TE – Uses – increases serum Ca++ and phosphorus levels to prevent osteomalacia / osteoporosis

ADME Daily exposure to sun (D2)/vs oral supplement Dosage – 800-1000 IntUnits/d or more

o They say you need up to 8000 units a day! We are deficient because people go out and play.

Children – 200 or more IN FOODS onlyo Don’t supplement children with tablets or pills because they are more

susceptible to toxicity. Make them go outside and play for at least an hour a day.

Adverse effects: hypercalcemia o Drugs For Ca Disorders: Calcitonin-Salmon (not calcium salts of Vit D)o Prototype: calcitonin-salmon (Calcimar)

MOA – Uses: is similar to natural calcitonin 1) inhibits osteoclasts decreasing bone resoprtion to tx established

osteoporosis 2) inhibits tubular resorption of Ca++ increasing its excretion to treat

hypercalcemia (kidneys will let the calcium go out your pee) Nursing considerations: Intranasal & long-term Rx

o Drugs for Ca Disorders: Biphosphonates (not calcium salts, Vit D, etc.)o Prototype: Alendronate (Fosamax)

MOA – TE – Uses Structural analogs of pyrophosphate of bone incorporated into bone and inhibit

resorption by decreasing osteoclast activity and used to treat osteoporosis, glucocorticoid induced osteopororis, Paget’s, and hypercalcemia of malignancy.

Half life may be 180 years? WTF? Weeks? They don’t fucking know. A long freakin time

They incorporate into the bone. The osteoclasts eat them, and it turns the clasts off. It’s like rat poison for the osteoclasts. They eat it and stop working. Fosamax = rat poison for clasts

ADME – CRITICAL!! Bioavailability drops if taken with food (0.7%) or drinks other than water (60%)!

NEVER TAKE WITH FOOD, COFFEE, TEA, ORANGE JUICE, OR WHATEVER!! ONLY WATER BITCHES!!!

Remains for decades once incorporated Adverse Effects

Esophagitis – implications (sit upright for a while or whatever. From contact of the drug in your espophagus, or people with reflux the drug drops into your stomach and gets absorbed, then the reflux goes back into your esophagus and hurts you.

Ocular inflammation Osteonecrosis of the jaw (ONJ) – mostly IV administration. (there isn’t really a

treatment for this) Treating Osteoporosis In Women

o Other drugs that prevent bone reapbsorption Estrogen [Premarin] Raloxifene [Evista]

Selective estrogen receptor modulator (SERM) Reduces spinal fx (55%) Cardioprotective in high risk women (40%) Reduces estrogen-receptor breast cancer Can cause blood clots / not as bad as estrogen

o Hold dose 72 hr before prolonged immobilization (impending surgery or whatever).

Table 73-5o Drugs that promote bone formation

Teriparatide [Forteo] – recombinant PTH and increases activity of osteoblasts to build bone (instead of suppressing osteoclasts like the other ones)

Expensive SubQ May promote bone cancer