Medications for EXAM #3 COPY

Question 1

1. ) Give an example of cofactor/coenzyme supplementation in manipulation of metabolism and what it’s for.
2. ) It’s efficacy is conditional of what?

Answer 1

1.) Sapropterin dihydrochloride (KUVAN) – BH4 cofactor effective in some PKU patients.
2.) Requires at least 12.5% residual enzyme activity.
L26 #10

Question 2

Name three medications that treat OTC deficiency through the mechanism of metabolic diversion.

Answer 2

1.) Glycerol phenylbutyrate (Ravicti)
2.) Sodium phenylbutyrate (Buphenyl)
1 and 2 are metabolized to phenylacetate, which conjugates with glutamine, which then mobilizes nitrogen excretion
3.) Sodium benzoate, Sodium phenylacetate (Ammonul) –Benzoate combines with glycine to form HIPPURATE, which is excreted in the urine.
L26 #11

Question 3

What medication is an example of enzyme inhibition in the context of metabolic manipulation? Describe (what does it do, what is it for).

Answer 3

Allopurinol: A xanthine oxidase inhibitor used to decrease uric acid production.
-Used in Lesch-Nyhan syndrome, which is an HGPRT deficiency in which the body is unable to salvage hypoxanthine or guanine, which results in excessive production of uric acid.
L26 #12, p.40 njp

Question 4

1. ) What class of medications are an example of enzyme inhibition (metabolic inhibitors) in the context of metabolic manipulation.
2. ) What are they used for?
3. ) How do they work?

Answer 4

1.) Statins –Structural analogs of HMG-CoA.
2.) Used for patients with familial hypercholesterolemia (heterozygous) —> Deficiency in functioning LDL receptors, which results in elevated LDL-cholesterol.
3.) Statins are competitive inhibitors of HMG-CoA reductase.
L26 #13

Question 5

What type of drug is often used with statins in order to reduce circulating LDL and increase LDL receptors? Give two examples.

Answer 5

Bile acid sequestrants —> Cholestyramine, Colestipol.

L26 #14

Question 6

1. ) What drug utilizes the receptor antagonism mode of metabolism manipulation to exert its effect?
2. ) What is it used for?
3. ) How does it work?

Answer 6

1.) Losartan, an AT II receptor antagonist.
2.) Used to prevent dilatation of the ascending aorta in Marfan syndrome.
3.) Losartan inhibits AT II signaling, which decreases TGF-β (transforming growth factor) activity. Decreased TGF-β activity decreases rate of dilatation of the aorta in individuals with Marfan syndrome.
L26 #15, p.41 njp

Question 7

1. ) What is the drug Ataluren most effective at?

2. ) What two disorders is this drug used for (describe the nature of these disorders)?

Answer 7

1.) Most effective in allowing UGA read-through (i.e. allows skipping over nonsense codons).
2.) (i) Cystic fibrosis: Nonsense mutation of the ∆F508 in the CFTR protein (Arg553). Shows significant improvement in lung function with Ataluren.
(ii) Duchenne Muscular Dystrophy (DMD): Helps patients walk an average of 47 meters farther.
L26 #20

Question 8

1. ) What is the most common mutation that causes CF and how?
2. ) Besides Ataluren, which other small molecular therapy drug treats Cystic Fibrosis and how? What else does it need?

Answer 8

1.) ∆F508 mutation in CFTR protein (most common of all CF mutations).
-Mutant protein trapped in ER and degraded by proteasome (trafficking defect).
2.) Lumacaftor: Drug serves as a pharmaceutical chaperone; it interacts directly with the mutant CFTR and stabilizes the 3D structure.
Not sufficient on its own —> needs to be combined with another drug —> Ivacaftor (serves as a potentiator for Lumacaftor)
L26 #21, p.42 njp

Question 9

A drug is of clinical benefit to cystic fibrosis if it increases ________________ of the cell by 20-25%.

Answer 9

Increases CFTR channels in the apical surface of the cell by 20-25%.
L26 #21

Question 10

What is the role of Ivacaftor?

Answer 10

Drug serves as a potentiator for Lumacaftor —> Improves Cl- transport of some mutant CFTR proteins.
FDA approved for 9 CFTR missense mutations
L26 #23

Question 11

Concerning protein/amino acid replacement, what treats hemophilia A and B (2)?

Answer 11

Hemophilia A: Clotting factor VIII.
Hemophilia B: Clotting factor IX.
L26 #23

Question 12

Concerning enzyme replacement therapy, how do you treat the following:

1. ) Gaucher disease
2. ) Pompe disease
3. ) Fabry disease
4. ) ADA deficient SCID
5. ) Hurler syndrome, MPS I
6. ) Hunter syndrome, MPS II

Answer 12

1.) Beta glucocerebrosidase
2.) Alpha glucosidase
3.) Alpha galactosidase
4.) Adenosine deaminase
5.) Alpha-L-iduronidase (Laronidase; aldurazyme)
6.) Iduronate-2-sulfatase (Idursulfase; elaprase)
L26 #23, p.43 njp