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114 Cards in this Set

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  • Back
What is Folate essential for?
DNA synthesis and mitosis of proliferating cells
What is the function of Folate?
Coenzyme for 1-carbon transfer involved in the biosynthesis of Purines and Pyrimidines
What are the sources of Folic Acid?
Plants and Animals:
Green Vegetables
Folate Absorption:
-readily and completely absorbed from the __1__ by __2__
-__3__ folate is absorbed daily
-absorption is increased in __4__, but so is __5__
1. Small Intestine
2. Active transport system
3. 50-200 micro-grams (=10-25% of folate)
4. pregnancy
5. demand
Describe the process of Folate absorption
1. Polyglutamate form is ingested
2. Glutamyl transferase in GI tract clips glutamate residues
3. Monoglutamate form is absorbed via active and passive transport in the PROXIMAL JEJUNUM
Folate Distribution:
-__1__ and other tissues store __2__ of folate
-Major dietary and storage form of folate is __3__
-Because the body stores relatively little folate (relative to high demand), __4__ anemia can develop in __5__ (timespan) following folate deficiency
1. Liver
2. 5-20 milligram
3. 5-methyl-THF
4. Megaloblastic
5. 1-6 months (relatively fast)
How are Folates excreted?
Metabolized and excreted in Urine and Feces
When is Folate deficiency due to inadequate dietary intake common?
Give four examples of when Folate is needed in increased requirements?
1. Pregnancy
2. Renal dialysis
-blood folates are removed
-EPO is also removed
3. Proliferative disorders (CA, leukemia, etc)
4. Hemolytic anemia
What drugs interfere with the utilization of Folate and can lead to deficiency?
1. Anticonvulsants
2. Oral Contraceptives
3. Isoniazid
What is maternal Folate deficiency associated with?
Neural Tube Defects = Spina bifida
Why is Folate sometimes used to treat Coronary Heart Disease?
Hyper-homocysteinemia is a possible risk factor for CHD
-Folate and B12 are BOTH needed to convert Homocysteine -> Methionine
-Methionine is a major Antioxidant in the body
What can cause low Methionine levels?
Both Folate and B12 can cause Methionine levels to be low, either together or independently
What are the 3 functions of Vitamin B12?
1. DNA synthesis: converts 5-methyl-THF -> THF

2. Lipid synthesis: converts Methylmalonyl-CoA -> Succinyl-CoA

3. Amino acid synthesis: B12 + Folate convert Homocysteine -> Methionine
Which defiency can cause neurological symptoms: Folate or B12? Why?
- converts Methylmalonyl-CoA -> Succinyl-CoA
-Succinyl-CoA helps to produce Myelin
Why does B12 have to be present for Folate's effects?
B12 converts dietary Folate (5-methyl-THF) to its active form (THF)
-In Vitamin B12 deficiency, levels of __1__ increase with a decrease in the other forms of folate required for __2__ synthesis
-This defect can be circumvented by administration of __3__ which can be reduced to __4__ by __5__
-Thus the defects in Nucleotide synthesis caused by B12 deficiency can be corrected by __6__ treatment
1. 5-methyl-THF
2. nucleotide
3. Folic acid
4. THF
5. Dihydrofolate reductase
6. Folic acid
Vitamin B12 structure:

__1__-like ring system complexed with __2__
1. Porphyrin

2. Cobalt
Cobalamin (B12) forms:
-Active form: R = 1
-Drugs: R = 2
-Food: R = various ligands
1. 5-deoxyadenosyl or Methyl group

2. Cyano (CN-) or Hydroxy (OH-)

**drugs are converted to active forms in the body
What are the sources of Vitamin B12?
Meat (liver)
Dairy products
Absorption of Vitamin B12 requires what?
Intrinsic Factor (glycoprotein) synthesized by Parietal Cells in the Stomach
Where is the B12/IF complex absorbed?
Vitamin B12 Distribution:
-transported via __1__, a plasma glycoprotein
-excess is stored in the __2__
-it takes __3__ to deplete stores from the body
1. Transcobalamin II
2. Liver
3. 3-6 years = deficiency occurs ver very slow compared to Folate (1-6 months)
Describe the excretion of Vitamin B12
-occurs in Bile but undergoes Enterohepatic circulation and most is reabsorbed from the Small Intestine
-When Transcobalamin is saturated excess B12 is excreted in Urine
Lack of Intrinsic Factor = ?

How is this treated?
Pernicious Anemia

treat with B12
What causes Pernicious Anemia?
Autoantibodies to Parietal Cells or Intrinsic Factor
Aside from Pernicious Anemia, what are 3 other causes of Vitamin B12 deficiency?
1. Lack of receptors for IF/B12 complex in the Ileum -> genetic or surgical resection
2. Fish tapeworm infections
3. Patient with Gastrectomy -> no Parietal Cells = no IF
Therapeutic uses of B12:
-only approved use is treatment of __1__
-usually given by __2__
1. B12 deficiency
2. Intramuscular injection
T or F: Vitamin B12 can be toxic if given in large amounts
False: it is nontoxic even in large amounts
What are the 2 therapeutic preparations of Vitamin B12?

List the properties of Cyanocobalamin (3)
1. available nasally, orally, parenterally

2. does not cause Ab response

3. preferred agent for Long-term use
List one advantage and one disadvantage of Hydroxycobalamin
Ad: highly protein bound and remains in circulation longer

Disad: some patients produce ANTIBODIES against Hydroxycobalamin-Transcobalamin II complex
Why is it important to distinguish between Folate and B12 deficiency?
If it is B12 deficiency and you give Folate:
-the anemia can be corrected
-BUT Neurological symptoms can still occur
What are the 2 clinical tests to determine Folate and B12 deficiency?
Folate -> red cell levels

B12 -> serum levels
How is a Schilling Test performed?
Oral administration of radioactive Vitamin B12 with and without pig IF, after which the presence of radioactivity in the urine is determined
A negative Schilling Test of BOTH free B12 and B12/IF indicates what?
Malabsorption in the distal ileum
-inflammatory bowel disease
-small bowel resection
A negative Schilling Test of JUST B12 indicates what?
Malabsorption due to the lack of Intrinsic Factor
-Pernicious Anemia
What would comprise a positive Schilling Test?
Both free B12 and B12/IF in the urine
Pernicious Anemia:
-__1__ anemia due to __2__ deficiency resulting from lack of production of __3__ by the __4__ cells of the gastric mucosa
-Accompanied by __5__, which is often seen first
1. Megaloblastic
2. B12 (need it to make THF)
3. Intrinsic Factor
4. Parietal Cells
5. Achlorhydria (no HCl) = gastric infections
What group of people is Pernicious Anemia generally observed?
Older men and women of Northern European decent (Scandinavians)
How much time may it take between the loss of Intrinsic Factor and the development of Megaloblastic Anemia?

5 years

Thats how long it takes to deplete the stores of B12 from the Liver
Treatment with __1__ should not be delayed after gastrectomy, and should be continued for __2__
1. parenteral B12

2. life
List 3 things that could cause Bone Marrow failure, causing decreased RBC production and anemia
1. Myelofibrosis and Multiple Myeloma

2. Myelosuppressive Chemotherapy
-Antitumor agents
-drugs used to treat AIDS
-Immunosuppressive agents

3. Deficiency of hematopoietic growth factors
-chronic renal failure -> EPO deficiency
This is a glycoprotein that stimulates red cell production and is derived from genetically modified cells of Chinese Hamster Ovary
Epoetin Alpha (Erythropoietin)
Under what 2 conditions is Epoetin alpha used?
1. Anemia patients with Chronic Renal Failure (kidney produces EPO)

2. Cancer patients receiving chemotherapy
Recombinant granulocytic-macrophage colony stimulating factor (GM-CSF)
When is Sargramostim used?
1. promotes myeloid recovery in patients with non-Hodgkin's Lymphoma, Acute Lymphoblastic Leukemia, and Hodgkin's disease who are undergoing Bone Marrow transplantation
2. promotes Myeloid Recovery after standard-dose chemotherapy
3. treats drug-induced bone marrow toxicity or neutropenia associated with AIDS
Recombinant G-CSF used to prevent and treat chemotherapy-related febrile neutropenia, for promotion of myeloid recovery in patients undergoing bone marrow transplantation

**Granulocytes = Neutrophils, Eosinophils, Basophils
Promotes megakaryopoiesis and therefore platelet production
Oprelvekin (IL-11)

** vs. Anagrelide which inhibits Megakaryocyte development
NSAID that is only analgesic and antipyretic, but not anti-inflammatory
-effects are due to inhibition of __1__ synthesis from __2__
1. Eicosanoid

2. Arachidonic acid
What 4 things are Prostaglandins involved in?
1. Pain (analgesic)
2. Fever (antipyretic)
3. Inflammation
4. Platelet aggregation
Draw the Arachidonic Acid pathway
Aspirin and most other NSAIDs are weak bases or acids?
Weak Acids
Aspirin and other NSAIDs inhibit __1__ and __2__ biosynthesis but generally not __3__ synthesis
1. Prostaglandin
2. Thromboxane
3. Leukotriene
What is the target of Aspirin?
Where is Cox-1 found and what does Aspirin inhibit the production of?
Most cells and Platelets --/ TXA2 production = vasodilation and anti-platelet aggregation
Where is COX-2 present and what does Aspirin inhibit the production of?
Inflammation cells and Endothelial Cells --/ PGI2 production
What are the new NSAIDs that selectively inhibit COX-2? (3)
1. Celecoxib (Celebrex)
2. Rofecoxib (Vioxx)
3. Valdecoxib

***all end in -ecoxib
What is unique about Aspirin's mechanism of action
IRREVERSIBLY inhibits COX by Acetylating the enzyme
How is Aspirin different from Salicylic acid?
it is acetylated
Low doses of NSAIDs are given for __1__ and __2__ effects

High doses of NSAIDs are given for __3__ effects
1. Analgesia (pain)
2. Antipyresis (fever)
3. Anti-inflammatory
Most NSAIDs inhibit COX, but what 2 inhibit both COX and Lipoxygenase?

Why does Acetaminophen not inhibit Inflammation?
Inhibition of COX by Acetaminophen is blocked by Peroxides, which are formed during inflammation
What is the 1/2 life of Aspirin? Why?
15 min -> rapidly metabolized to Salicylic Acid = reversible inhibitor of COX
Salicylic acid is extensively conjugated with these 2 things
1. Glucuronic Acid

2. Glycine
Explain the "dose-dependent pharmacokinetics" of Aspirin
When conjugation pathway become saturated, small increases in the dose of aspirin can produce large increases in plasma Salicylate levels
-low dose = first-order kinetics = Analgesic, Antipyretic
-High dose = zero-order kinetics = Anti-inflammatory
What dose of Aspirin gives Zero-order kinetics?

What is the Half-life?
> 4000 mg = anti-inflammatory

> 12 hours
What dose of Aspirin gives first-order kinetics?

What is the Half-life?
600 mg = analgesic, antipyretic

3-5 hours
How is Aspirin excreted?
In urine as Salicylic acid, Salicyluric acid, glucuronic acid conjugates
Aspirin Anti-inflammatory effects:
-due to inhibition of __1__
-__2__ synthesis is inhibited
-Inhibits __3__ and __4__ migration to the site of inflammation
1. COX-2
2. Prostaglandin
3. macrophage
4. lymphocyte
Antipyretic effects of Aspirin:
-lowers body temp when __1__ is present
-blocks production of __2__ in the CNS to "reset" temp control at the hypothalamus facilitating heat dissipation by __3__
1. fever
2. prostaglandins
3. vasodilation
Antiplatelet effects of Aspirin:
-aspirin prolongs __1__
-Antithrombotic effect due to inhibition of __2__ synthesis via irreversible inhibition of platelet __3__
1. bleeding time
2. Thromboxane
3. COX-1
Effects of Aspirin on Uric Acid:
-Large doses of aspirin are __1__
-Lower doses __2__ uric acid levels
1. uricosuric = decrease uric acid levels
2. increase

**Large doses inhibit both secretion and reabsorption in the Kidney
**Low doses inhibit only Secretion
Why is Aspirin contraindicated in Gout?
b/c low doses increase uric acid levels
What is the main adverse effect of Aspirin when using usual dosages?
Gastric upset
What can minimize the gastric discomfort when taking aspirin?
taking with food or milk
Why does Aspirin cause GI effects?
Aspirin inhibits synthesis of prostaglandins, which are required for normal mucosal cell proliferation
Patients taking of any NSAID for prolonged periods may be given a PGE1 analog __1__, or proton pump inhibitors =__2__, to prevent peptic ulcers
1. Misoprostol

2. Omeprazole
Why can Aspirin cause Renal Toxicity?
inhibits PGE2 and PGI2, which normally increase renal blood flow

When they are deficient = decreased renal blood flow -> HTN
Large doses of Aspirin should be administered with caution in these types of patients? Why?

Can have an effect on Glucose tolerance
Under what 3 conditions is Aspirin contraindicated?
1. Hemophiliacs = b/c aspirin has an antiplatelet effect

2. Patients with Aspirin-induced Nasal polyps or with allergic rxns (urticaria)

3. Children with viral infections due to associated risk of Reye's syndrome
If you give Aspirin to a patient with Aspirin-induced Nasal Polyps or with Allergic rxns, what are they at risk of developing?

Aspirin overdose toxicity is a common cause of poisoning in ________
young children
What are the symptoms of Aspirin Overdose Toxicity?
1. Salicylism (tinnitus, vertigo, deafness)
2. Hyperthermia (aspirin uncouples oxidative phosphorylation)
3. Hyperpnea = rapid breathing
4. initially, respiratory alkalosis
5. Later, respirator and metabolic acidosis
What is the treatment for Aspirin Overdose Toxicity?
1. if seen early, gastric lavage
2. maintain their temp (cool them down)
3. IV fluids
4. Bicarb + Potassium
5. Hemodialysis or Hemoperfusion, in severe cases
What are the 3 uses of Aspirin?
1. Antipyretic = fever reducer
2. Acute Rheumatic Fever
3. Mild pain associated with inflammation
-myalgia = muscle pain
-Dysmenorrhea = painful period
What 4 things can Aspirin be prophylatically be used for?
1. Platelet hyperaggregation
2. Coronary Artery disease
3. MI
4. Postoperative deep-vein thrombosis

***All Prophylaxes are for Anti-platelet effects
What 5 drugs or group of drugs does Aspirin displace from Albumin and cause increased free concentration?
1. Oral Hypoglycemic drugs
2. Other NSAIDs
3. Methotrexate -> important b/c 50% is protein bound w/o aspirin and is intrinsically toxic
4. Phenytoin
5. ORAL ANTICOAGULANTS (WARFARIN) -> both anti-coagulant/anti-platelet = potential for bleeding

*all exacerbated more with anti-inflammatory doses
Other Nonselective NSAIDs:
-Antipyretic, analgesic, and anti-inflammatory effects similar to __1__
-All agents alter __2__ fxn and prolong __3__
-Treats mild to moderate pain, fever, and Rheumatoid Arthritis when patients cannot __4__
-Major differences are __5__ of action and potency
1. Aspirin
2. platelet
3. bleeding time
4. tolerate aspirin
5. duration
List other 6 NSAID drugs

1. Ibuprofen
2. Sulindac
3. Piroxicam
4. Aspirin
5. Indomethacin
6. Naproxen
Half-life and RA dosage:
1. Ibuprofen
2. Naproxen
3. Piroxicam
1. 2 hours / 4 X 600mg

2. 14 hours / 2 x 375 mg

3. 45 hours / 1 x 20 mg
What are 3 newer NSAIDs that are selective COX-2 inhibitors?
1. Celecoxib
2. Rofecoxib
3. Valdecocoxib

What is the major difference between Aspirin and the other NSAIDs?
Aspirin binds IRREVERSIBLY

the others bind reversibly
These 2 NSAIDs were removed from the market b/c of increased CARDIAC events

What were the events likely due to?
1. Rofecoxib & Valdecoxib

2. inhibition of PGI2 formation
What NSAIDs inhibit both Cyclooxygenase and Lipoxygenase?


All NSAIDs except __1__ have a Black Box Warning of increased __2__ risks; likely due to inhibition of __3__
1. Aspirin
2. Cardiovascular
3. Renal Prostaglandins
-One of the few NSAIDs that can be given parentally (IV, IM, PO) for moderate pain.
-Systemic use should not be more than 5 days.
-Eye preparation is available for ocular pain.

*use dramatically cuts down the amount of narcotics needed post-surgically
-not suggested as a general use __1__, but particularly effective for __2__
-Produces numerous __3__ effects and several severe __4__ reactions
1. Analgesic
2. pain at night
3. GI
4. Hematopoietic
What 4 things can Indomethacin be used to treat?
1. Acute GOUT
2. Ankylosing spondylitis
3. Osteoarthritis of the hip
4. PDA closure in premature infants
What are some side effects of Indomethacin?
1. Headache
2. Indigestion
3. CNS
- vertigo
- Dizziness
- confusion
With the exception of newborns with __1__, Indomethacin is not given to children. Nor is it given to __2__
1. Patent Ductus Arteriosus
2. Pregnant women = don't want the PDA to close in utero
-selective antagonist of __1__
-does not inhibit __2__ and does not cause __3__
1. COX-2 (found in Inflammatory cells and mediates inflammation and pain)
2. platelet function
3. gastropathy
When is Celecoxib contraindicated?
patients with known Celecoxib hypersensitivity or SULFONAMIDE hypersensitivity
- Celecoxib contains a Sulfonamide side chain
What is Celecoxib's approved uses? (2)

What things is it being studied to treat? (4)
1. Rheumatoid Arthritis
2. Osteoarthritis

1. sporadic adenomatous polyps of the colon
2. Barrett's esophagus
3. Actinic keratosis
4. superficial bladder cancer
Trade name for Rofecoxib
Why was Rofecoxib removed from the market?
Selective COX-2 inhibitor
-inhibits PGI2 formation but causes a higher amount of TXA2 production from COX-1 pathway
-TXA2 = vasoconstriction and platelet aggregation
What does Rofecoxib use have an increased risk of causing?
Cardiovascular events with prolonged use and high doses
Before being removed from the market,what was Rofecoxib indicated for?
1. to relieve the signs and symptoms of Osteoarthritis
2. treatment of Dysmenorrhea or acute pain
-compared to __1__, it lacks a __2__ and thus is not contraindicated in patients allergic to __3__
1. Celecoxib
2. Sulfonamide
3. Sulfonamides
What were 2 advantages of Rofecoxib?
1. no sulfonamide hypersensitivities

2. not primarily dependent on CYP450 enzymes = no drug-drug interactions
-Selective COX-2 inhibitor that was withdrawn from the market
-was contraindicated in patients with Sulfonamide hypersensitivity
What was Valdecoxib indicated for before being taken off the market? (3)
1. Dysmenorrhea
2. Osteoarthritis
3. Rheumatoid arthritis

*Dysmenorrhea is caused by excessive prostaglandin synthesis
Why was Valdecoxib taken off the market?
Shifts the TXA2/PGI2 balance to an unfavorable ratio = increased risk for CV events