Pharm - S2B1 - Hemato/immunopharamacology 3

Front 1

What is Folate essential for?

Back 1

DNA synthesis and mitosis of proliferating cells

Front 2

What is the function of Folate?

Back 2

Coenzyme for 1-carbon transfer involved in the biosynthesis of Purines and Pyrimidines

Front 3

What are the sources of Folic Acid?

Back 3

Plants and Animals:
Yeast
Liver
Kidney
Green Vegetables

Front 4

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__

Back 4

1. Small Intestine
2. Active transport system
3. 50-200 micro-grams (=10-25% of folate)
4. pregnancy
5. demand

Front 5

Describe the process of Folate absorption

Back 5

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

Front 6

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

Back 6

1. Liver
2. 5-20 milligram
3. 5-methyl-THF
4. Megaloblastic
5. 1-6 months (relatively fast)

Front 7

How are Folates excreted?

Back 7

Metabolized and excreted in Urine and Feces

Front 8

When is Folate deficiency due to inadequate dietary intake common?

Back 8

Alcoholics

Front 9

Give four examples of when Folate is needed in increased requirements?

Back 9

1. Pregnancy
2. Renal dialysis
-blood folates are removed
-EPO is also removed
3. Proliferative disorders (CA, leukemia, etc)
4. Hemolytic anemia

Front 10

What drugs interfere with the utilization of Folate and can lead to deficiency?

Back 10

1. Anticonvulsants
-Phenytoin
-Primidone
-Mephobarbital
2. Oral Contraceptives
3. Isoniazid

Front 11

What is maternal Folate deficiency associated with?

Back 11

Neural Tube Defects = Spina bifida

Front 12

Why is Folate sometimes used to treat Coronary Heart Disease?

Back 12

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

Front 13

What can cause low Methionine levels?

Back 13

Both Folate and B12 can cause Methionine levels to be low, either together or independently

Front 14

What are the 3 functions of Vitamin B12?

Back 14

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

Front 15

Which defiency can cause neurological symptoms: Folate or B12? Why?

Back 15

B12
- converts Methylmalonyl-CoA -> Succinyl-CoA
-Succinyl-CoA helps to produce Myelin

Front 16

Why does B12 have to be present for Folate's effects?

Back 16

B12 converts dietary Folate (5-methyl-THF) to its active form (THF)

Front 17

-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

Back 17

1. 5-methyl-THF
2. nucleotide
3. Folic acid
4. THF
5. Dihydrofolate reductase
6. Folic acid

Front 18

Vitamin B12 structure:

__1__-like ring system complexed with __2__

Back 18

1. Porphyrin

2. Cobalt

Front 19

Cobalamin (B12) forms:
-Active form: R = 1
-Drugs: R = 2
-Food: R = various ligands

Back 19

1. 5-deoxyadenosyl or Methyl group

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

**drugs are converted to active forms in the body

Front 20

What are the sources of Vitamin B12?

Back 20

Meat (liver)
Eggs
Dairy products

Front 21

Absorption of Vitamin B12 requires what?

Back 21

Intrinsic Factor (glycoprotein) synthesized by Parietal Cells in the Stomach

Front 22

Where is the B12/IF complex absorbed?

Back 22

Ileum

Front 23

Vitamin B12 Distribution:
-transported via __1__, a plasma glycoprotein
-excess is stored in the __2__
-it takes __3__ to deplete stores from the body

Back 23

1. Transcobalamin II
2. Liver
3. 3-6 years = deficiency occurs ver very slow compared to Folate (1-6 months)

Front 24

Describe the excretion of Vitamin B12

Back 24

-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

Front 25

Lack of Intrinsic Factor = ?

How is this treated?

Back 25

Pernicious Anemia

treat with B12

Front 26

What causes Pernicious Anemia?

Back 26

Autoantibodies to Parietal Cells or Intrinsic Factor

Front 27

Aside from Pernicious Anemia, what are 3 other causes of Vitamin B12 deficiency?

Back 27

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

Front 28

Therapeutic uses of B12:
-only approved use is treatment of __1__
-usually given by __2__

Back 28

1. B12 deficiency
2. Intramuscular injection

Front 29

T or F: Vitamin B12 can be toxic if given in large amounts

Back 29

False: it is nontoxic even in large amounts

Front 30

What are the 2 therapeutic preparations of Vitamin B12?

Back 30

Cyanocobalamin

Hydroxycobalamin

Front 31

List the properties of Cyanocobalamin (3)

Back 31

1. available nasally, orally, parenterally

2. does not cause Ab response

3. preferred agent for Long-term use

Front 32

List one advantage and one disadvantage of Hydroxycobalamin

Back 32

Ad: highly protein bound and remains in circulation longer

Disad: some patients produce ANTIBODIES against Hydroxycobalamin-Transcobalamin II complex

Front 33

Why is it important to distinguish between Folate and B12 deficiency?

Back 33

If it is B12 deficiency and you give Folate:
-the anemia can be corrected
-BUT Neurological symptoms can still occur

Front 34

What are the 2 clinical tests to determine Folate and B12 deficiency?

Back 34

Folate -> red cell levels

B12 -> serum levels

Front 35

How is a Schilling Test performed?

Back 35

Oral administration of radioactive Vitamin B12 with and without pig IF, after which the presence of radioactivity in the urine is determined

Front 36

A negative Schilling Test of BOTH free B12 and B12/IF indicates what?

Back 36

Malabsorption in the distal ileum
-inflammatory bowel disease
-small bowel resection

Front 37

A negative Schilling Test of JUST B12 indicates what?

Back 37

Malabsorption due to the lack of Intrinsic Factor
-Gastrectomy
-Pernicious Anemia

Front 38

What would comprise a positive Schilling Test?

Back 38

Both free B12 and B12/IF in the urine

Front 39

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

Back 39

1. Megaloblastic
2. B12 (need it to make THF)
3. Intrinsic Factor
4. Parietal Cells
5. Achlorhydria (no HCl) = gastric infections

Front 40

What group of people is Pernicious Anemia generally observed?

Back 40

Older men and women of Northern European decent (Scandinavians)

Front 41

How much time may it take between the loss of Intrinsic Factor and the development of Megaloblastic Anemia?

Why?

Back 41

5 years

Thats how long it takes to deplete the stores of B12 from the Liver

Front 42

Treatment with __1__ should not be delayed after gastrectomy, and should be continued for __2__

Back 42

1. parenteral B12

2. life

Front 43

List 3 things that could cause Bone Marrow failure, causing decreased RBC production and anemia

Back 43

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

Front 44

This is a glycoprotein that stimulates red cell production and is derived from genetically modified cells of Chinese Hamster Ovary

Back 44

Epoetin Alpha (Erythropoietin)

Front 45

Under what 2 conditions is Epoetin alpha used?

Back 45

1. Anemia patients with Chronic Renal Failure (kidney produces EPO)

2. Cancer patients receiving chemotherapy

Front 46

Recombinant granulocytic-macrophage colony stimulating factor (GM-CSF)

Back 46

Sargramostim

Front 47

When is Sargramostim used?

Back 47

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

Front 48

Recombinant G-CSF used to prevent and treat chemotherapy-related febrile neutropenia, for promotion of myeloid recovery in patients undergoing bone marrow transplantation

Back 48

Filgrastim

**Granulocytes = Neutrophils, Eosinophils, Basophils

Front 49

Promotes megakaryopoiesis and therefore platelet production

Back 49

Oprelvekin (IL-11)

** vs. Anagrelide which inhibits Megakaryocyte development

Front 50

NSAID that is only analgesic and antipyretic, but not anti-inflammatory

Back 50

Acetaminophen

Front 51

NSAIDs:
-effects are due to inhibition of __1__ synthesis from __2__

Back 51

1. Eicosanoid

2. Arachidonic acid

Front 52

What 4 things are Prostaglandins involved in?

Back 52

1. Pain (analgesic)
2. Fever (antipyretic)
3. Inflammation
4. Platelet aggregation

Front 53

Draw the Arachidonic Acid pathway

Back 53

-

Front 54

Aspirin and most other NSAIDs are weak bases or acids?

Back 54

Weak Acids

Front 55

Aspirin and other NSAIDs inhibit __1__ and __2__ biosynthesis but generally not __3__ synthesis

Back 55

1. Prostaglandin
2. Thromboxane
3. Leukotriene

Front 56

What is the target of Aspirin?

Back 56

Cyclooxygenase

Front 57

Where is Cox-1 found and what does Aspirin inhibit the production of?

Back 57

Most cells and Platelets --/ TXA2 production = vasodilation and anti-platelet aggregation

Front 58

Where is COX-2 present and what does Aspirin inhibit the production of?

Back 58

Inflammation cells and Endothelial Cells --/ PGI2 production

Front 59

What are the new NSAIDs that selectively inhibit COX-2? (3)

Back 59

1. Celecoxib (Celebrex)
2. Rofecoxib (Vioxx)
3. Valdecoxib

***all end in -ecoxib

Front 60

What is unique about Aspirin's mechanism of action

Back 60

IRREVERSIBLY inhibits COX by Acetylating the enzyme

Front 61

How is Aspirin different from Salicylic acid?

Back 61

it is acetylated

Front 62

Low doses of NSAIDs are given for __1__ and __2__ effects

High doses of NSAIDs are given for __3__ effects

Back 62

1. Analgesia (pain)
2. Antipyresis (fever)
3. Anti-inflammatory

Front 63

Most NSAIDs inhibit COX, but what 2 inhibit both COX and Lipoxygenase?

Back 63

Ketoprofen

Indomethacin

Front 64

Why does Acetaminophen not inhibit Inflammation?

Back 64

Inhibition of COX by Acetaminophen is blocked by Peroxides, which are formed during inflammation

Front 65

What is the 1/2 life of Aspirin? Why?

Back 65

15 min -> rapidly metabolized to Salicylic Acid = reversible inhibitor of COX

Front 66

Salicylic acid is extensively conjugated with these 2 things

Back 66

1. Glucuronic Acid

2. Glycine

Front 67

Explain the "dose-dependent pharmacokinetics" of Aspirin

Back 67

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

Front 68

What dose of Aspirin gives Zero-order kinetics?

What is the Half-life?

Back 68

> 4000 mg = anti-inflammatory

> 12 hours

Front 69

What dose of Aspirin gives first-order kinetics?

What is the Half-life?

Back 69

600 mg = analgesic, antipyretic

3-5 hours

Front 70

How is Aspirin excreted?

Back 70

In urine as Salicylic acid, Salicyluric acid, glucuronic acid conjugates

Front 71

Aspirin Anti-inflammatory effects:
-due to inhibition of __1__
-__2__ synthesis is inhibited
-Inhibits __3__ and __4__ migration to the site of inflammation

Back 71

1. COX-2
2. Prostaglandin
3. macrophage
4. lymphocyte

Front 72

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__

Back 72

1. fever
2. prostaglandins
3. vasodilation

Front 73

Antiplatelet effects of Aspirin:
-aspirin prolongs __1__
-Antithrombotic effect due to inhibition of __2__ synthesis via irreversible inhibition of platelet __3__

Back 73

1. bleeding time
2. Thromboxane
3. COX-1

Front 74

Effects of Aspirin on Uric Acid:
-Large doses of aspirin are __1__
-Lower doses __2__ uric acid levels

Back 74

1. uricosuric = decrease uric acid levels
2. increase

**Large doses inhibit both secretion and reabsorption in the Kidney
**Low doses inhibit only Secretion

Front 75

Why is Aspirin contraindicated in Gout?

Back 75

b/c low doses increase uric acid levels

Front 76

What is the main adverse effect of Aspirin when using usual dosages?

Back 76

Gastric upset

Front 77

What can minimize the gastric discomfort when taking aspirin?

Back 77

taking with food or milk

Front 78

Why does Aspirin cause GI effects?

Back 78

Aspirin inhibits synthesis of prostaglandins, which are required for normal mucosal cell proliferation

Front 79

Patients taking of any NSAID for prolonged periods may be given a PGE1 analog __1__, or proton pump inhibitors =__2__, to prevent peptic ulcers

Back 79

1. Misoprostol

2. Omeprazole

Front 80

Why can Aspirin cause Renal Toxicity?

Back 80

inhibits PGE2 and PGI2, which normally increase renal blood flow

When they are deficient = decreased renal blood flow -> HTN

Front 81

Large doses of Aspirin should be administered with caution in these types of patients? Why?

Back 81

Diabetics

Can have an effect on Glucose tolerance

Front 82

Under what 3 conditions is Aspirin contraindicated?

Back 82

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

Front 83

If you give Aspirin to a patient with Aspirin-induced Nasal Polyps or with Allergic rxns, what are they at risk of developing?

Back 83

Bronchoconstriction

Anaphylaxis

Front 84

Aspirin overdose toxicity is a common cause of poisoning in ________

Back 84

young children

Front 85

What are the symptoms of Aspirin Overdose Toxicity?

Back 85

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

Front 86

What is the treatment for Aspirin Overdose Toxicity?

Back 86

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

Front 87

What are the 3 uses of Aspirin?

Back 87

1. Antipyretic = fever reducer
2. Acute Rheumatic Fever
3. Mild pain associated with inflammation
-headache
-myalgia = muscle pain
-arthritis
-Dysmenorrhea = painful period

Front 88

What 4 things can Aspirin be prophylatically be used for?

Back 88

1. Platelet hyperaggregation
2. Coronary Artery disease
3. MI
4. Postoperative deep-vein thrombosis

***All Prophylaxes are for Anti-platelet effects

Front 89

What 5 drugs or group of drugs does Aspirin displace from Albumin and cause increased free concentration?

Back 89

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

Front 90

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

Back 90

1. Aspirin
2. platelet
3. bleeding time
4. tolerate aspirin
5. duration

Front 91

List other 6 NSAID drugs

Back 91

NSAID "IS PAIN"

1. Ibuprofen
2. Sulindac
3. Piroxicam
4. Aspirin
5. Indomethacin
6. Naproxen

Front 92

Half-life and RA dosage:
1. Ibuprofen
2. Naproxen
3. Piroxicam

Back 92

1. 2 hours / 4 X 600mg

2. 14 hours / 2 x 375 mg

3. 45 hours / 1 x 20 mg

Front 93

What are 3 newer NSAIDs that are selective COX-2 inhibitors?

Back 93

1. Celecoxib
2. Rofecoxib
3. Valdecocoxib

**-ecoxib

Front 94

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

Back 94

Aspirin binds IRREVERSIBLY

the others bind reversibly

Front 95

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

What were the events likely due to?

Back 95

1. Rofecoxib & Valdecoxib

2. inhibition of PGI2 formation

Front 96

What NSAIDs inhibit both Cyclooxygenase and Lipoxygenase?

Back 96

Ketoprofen

Diclofenac

Indomethacin

Front 97

All NSAIDs except __1__ have a Black Box Warning of increased __2__ risks; likely due to inhibition of __3__

Back 97

1. Aspirin
2. Cardiovascular
3. Renal Prostaglandins

Front 98

-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.

Back 98

Ketorolac

*use dramatically cuts down the amount of narcotics needed post-surgically

Front 99

Indomethacin:
-not suggested as a general use __1__, but particularly effective for __2__
-Produces numerous __3__ effects and several severe __4__ reactions

Back 99

1. Analgesic
2. pain at night
3. GI
4. Hematopoietic

Front 100

What 4 things can Indomethacin be used to treat?

Back 100

1. Acute GOUT
2. Ankylosing spondylitis
3. Osteoarthritis of the hip
4. PDA closure in premature infants

Front 101

What are some side effects of Indomethacin?

Back 101

1. Headache
2. Indigestion
3. CNS
- vertigo
- Dizziness
- confusion

Front 102

With the exception of newborns with __1__, Indomethacin is not given to children. Nor is it given to __2__

Back 102

1. Patent Ductus Arteriosus
2. Pregnant women = don't want the PDA to close in utero

Front 103

Celecoxib:
-selective antagonist of __1__
-does not inhibit __2__ and does not cause __3__

Back 103

1. COX-2 (found in Inflammatory cells and mediates inflammation and pain)
2. platelet function
3. gastropathy

Front 104

When is Celecoxib contraindicated?

Back 104

patients with known Celecoxib hypersensitivity or SULFONAMIDE hypersensitivity
- Celecoxib contains a Sulfonamide side chain

Front 105

What is Celecoxib's approved uses? (2)

What things is it being studied to treat? (4)

Back 105

Approved:
1. Rheumatoid Arthritis
2. Osteoarthritis

Studies:
1. sporadic adenomatous polyps of the colon
2. Barrett's esophagus
3. Actinic keratosis
4. superficial bladder cancer

Front 106

Trade name for Rofecoxib

Back 106

Vioxx

Front 107

Why was Rofecoxib removed from the market?

Back 107

Selective COX-2 inhibitor
-inhibits PGI2 formation but causes a higher amount of TXA2 production from COX-1 pathway
-TXA2 = vasoconstriction and platelet aggregation

Front 108

What does Rofecoxib use have an increased risk of causing?

Back 108

Cardiovascular events with prolonged use and high doses

Front 109

Before being removed from the market,what was Rofecoxib indicated for?

Back 109

1. to relieve the signs and symptoms of Osteoarthritis
2. treatment of Dysmenorrhea or acute pain

Front 110

Rofecoxib:
-compared to __1__, it lacks a __2__ and thus is not contraindicated in patients allergic to __3__

Back 110

1. Celecoxib
2. Sulfonamide
3. Sulfonamides

Front 111

What were 2 advantages of Rofecoxib?

Back 111

1. no sulfonamide hypersensitivities

2. not primarily dependent on CYP450 enzymes = no drug-drug interactions

Front 112

-Selective COX-2 inhibitor that was withdrawn from the market
-was contraindicated in patients with Sulfonamide hypersensitivity

Back 112

Valdecoxib

Front 113

What was Valdecoxib indicated for before being taken off the market? (3)

Back 113

1. Dysmenorrhea
2. Osteoarthritis
3. Rheumatoid arthritis

*Dysmenorrhea is caused by excessive prostaglandin synthesis

Front 114

Why was Valdecoxib taken off the market?

Back 114

Shifts the TXA2/PGI2 balance to an unfavorable ratio = increased risk for CV events