Kinetics/genomics lecture

Question 1

5 aminoglycoside antibiotics

Answer 1

gentamicin

tobramycin

amikacin

neomycin

streptomycin

(poor GI absorption so must be admin via parenteral route. water soluble. renal clearance)

Question 2

Vancomycin

Answer 2

used to treat C. difficile. administred PO route (otherwise poorly absorbed orally).

• systemic infections require parenteral dosing
• Vd is wide= goes to all tissues except CSF —(exception: in meningitis patients, drug can cross blood-brain-barrier)

Question 3

Phenytoin

Answer 3

Anti-epileptic.

–p450 INDUCER

–highly protein bound (so when dosing, consider patients albumin and renal function)

–tricky dosing (capacity-limited metabolism)–changes from 1st order to 0-order kinetics quickly.

Question 4

Valproic acid

Answer 4

anti-epileptic

ONLY P450 INHIBITOR (in anti-epileptic class)

Metabolism: extensively hepatic via glucuronidation (mostly phase II conjugation)

–kinetics of unbound drug are linear BUT relationship between doses and total valproate concentration is non-linear. doesn’t increase with dose proportionatly but increases to lesser extent due to saturable plasma protein binding.

Question 5

Carbamazepine

Answer 5

anti-epileptic

–metabolized by CYP3A4, slow absorption

–highly protein bound to plasma alb and alpha-acid glycoprotein.

–co treatment w/ valproate sodium increases free fraction (since both bind protein)

–reach steady state 2-5 days

–narrow range before you reach toxic levels

Question 6

Warfarin

Answer 6

Anticoagulant

Metabolized by CYP2C9. Highly protein bound–creates dosing issues.

Genomic variant in CYP2C9 metabolism: if homozygous or heterozygous, cant meabolize Warfarin well so you end up with bleeding problems

Question 7

Digoxin

Answer 7

Cardiac medication. Absorption by passive non-saturable difusion in small intestine.

Large Vd–extensive diffusion. After 6-8 hrs, heart/serum ration is 70:1= very good since heart is target organ.

Has very narrow therapeutic index. monitor to avoid toxicity.

Question 8

BChE (butyrylchoinesterase)

Answer 8

Hydrolysis of Succinylcholine (a short acting muscle relaxer).

Patients with BChE variations have lower rates of metabolism of succinylcholine= results in prolonged paralysis after exposure.

Question 9

NAT2 (N-Acetyltransferase 2)

Answer 9

catalyzes acetylation of: Isoniazid, Hydralazine, Procainamide.

If it catalyzes too slow: builds up= toxic. Too fast= wont work

Question 10

CYP2D6

Answer 10

metabolizes: 1)metropolol (a beta blocker), 2)Haloperidol (an antipsychotic), 3)codeine, 4) fluoxetine (SSRI)

Several variations in metabolism amongst people. 1)poor metabolizers: standard doses result in toxicity. Codeine is inefective b/c it requires CYP2D6 to metabolize and form morphine. 2)extensive metabolisers 3)ultra rapid metabolizers: normal codeine doses= overdose

Question 11

TPMT (thiopurine S-Metyltransferase) and TMPT*3A

Answer 11

Catalyzes S-methylation of thiopurine drugs: (Azothiopurine, 6-mercaptopurine=immunosuppresents used in chemo)

TPMT*3A- decreases tissue levels of TPMT. Homozygous patients at great risk for myelosyppression when treated with standard toses of thiopurine drugs (life-threatening)

Question 12

5-lipoxygenase

Answer 12

target for Zileuton (asthma drug)–decreases airway inflammation by inhibiting 5-lipoxygenase.

Enzyme encoded by gene ALOX5. People w/ 5-repeat allele express more enzyme. Only people w/ at least 1 copy of 5-repeat allele respond to zileuton (~6% of population doesn’t respond at all to therapy)