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Pharmacology > Drugs to Recognize Exam I (August 15) > Flashcards

Drugs to Recognize Exam I (August 15) Flashcards

1
Q

Carbamazepine

A

3A4 inducer
induces 2C9 and 2C19

-induces enzyme responsible for its own metabolism, reducing levels of active drug over time

Prodrug (Prodrugs are inactive compounds that are metabolized in the body to their active forms)

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2
Q

Rifampin

A

induce 3A4
induce 2C9 and 2C19

induces P-gp/MDR1 transporters (gut kidney liver efflux) increase drug efflux and decrease drug plasma conc

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3
Q

Phenytoin

A

induce 3A4
zero-order kinetics of eliminations

restrictive hepatic clearance/low hepatic extraction (Q greater than f x CLint)

Little “first pass metabolism” when given orally. A change in binding or drug metabolism/excretion activity will have a greater effect on hepatic clearance than changes in liver blood flow. Capacity-limited clearance.

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4
Q

Phenobarbital

A

induce 3A4

induce 2C9 and 2C19

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5
Q

St. John’s wort

A

induces 3A4

induces P-gp/MDR1 transporters (gut kidney liver efflux) increase drug efflux and decrease drug plasma conc

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6
Q

grapefruit juice

will bioavailability or half life be affected?

A

inhibits 3A4 in enterocytes (intestinal)
not hepatic 3A4

affects bioavailability NOT half life

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7
Q

Clarithromycin

A

strong inhibitor of 3A4

3A4 catalyzes both hydroxylation and N-demethylation of Clarithromycin

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8
Q

Ritonavir

A

strong 3A4 inhibitor
anti-HIV protease inhibitor
significant GI adverse effects limit its critical use; low dose has no GI effects but potently inhibits 3A4

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9
Q

chemicals in cigarette smoke, charboiled food, cruciferous vegetables

A

induce 1A2 3 fold

smokers sometimes need higher doses of certain drugs metabolized by CYP1A2

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10
Q

A patient presents with severe broken leg and is in extreme pain; you prescribe x amount of codeine but thirty minutes later is still writhing in pain; you double check the dose and that it was administered but there were no errors. What might explain this?

A

drug isn’t working
-codeine is a Prodrug

-patient has variant allele of 2D6 - could lead to poor metabolize and consequently decreased efficacy and lack of sedative effect

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11
Q

N-acetyl benzoquinoneimine

A

this is a highly reactive metabolite generated from acetaminophen when phase II enzymes are saturated; usually is conjugated by glutathione; if glutathione is depleted then hepatotoxicity ensues

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12
Q

sulfonamides

A

Sulfonamides may compete for protein binding and increase the unbound fraction of other drugs.

adding sulfonamide will increase distribution of other drug

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13
Q

Warfarin

A

zero order kinetics of elimination

restrictive hepatic clearance/low hepatic extraction (Q greater than f x CLint)

Little “first pass metabolism” when given orally. A change in binding or drug metabolism/excretion activity will have a greater effect on hepatic clearance than changes in liver blood flow. Capacity-limited clearance.

patients with 2C9*2 or *3 have decreased metabolic inactivation of S warfarin (most potent form); increased conc. of active warfarin with standard dose; prone to experiencing bleeding events; patients require lower warfarin dosing

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14
Q

lidocaine

A

exhibits NON-RESTRICTIVE HEPATIC CLEARANCE (Q is less than f x CLint)

Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance. Flow-dependent clearance: conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.

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15
Q

propranolol

A

exhibits NON-RESTRICTIVE HEPATIC CLEARANCE (Q is less than f x CLint)

Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance. Flow-dependent clearance: conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.

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16
Q

morphine

A

Phase II reactions will activate drug

(exceptions bc for most drugs Phase II inactivates)

ex of a parental drug that contains –OH, -COOH or –NH2 functional groups and can directly undergo Phase II metabolism without prior phase I metabolism

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17
Q

minoxidil

A

Phase II reactions will activate drug

exceptions bc for most drugs Phase II inactivates

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18
Q

Isoniazid

A

ex of a parental drug that contains –OH, -COOH or –NH2 functional groups and can directly undergo Phase II metabolism without prior phase I metabolism

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19
Q

Irinotecan

A

Prodrug

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20
Q

Codeine

A

Prodrug

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21
Q

Prednisone

A

Prodrug

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22
Q

Glucocorticoids

A

induce 3A4

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23
Q

Fluconazole
Ketoconazole
Itranaconazole

A

inhibits 3A4

24
Q

Ritonavir

A

inhibits 3A4

25
Q

Erthyromycin

A

inhibits 3A4

26
Q

Cyclosporin

A

3A4 substrate
(immunosuppressant drug to prevent organ rejection)

potent inhibitor of OATP1B1 and blocks statin uptake

INHIBITS P-gp/MDR1 transporters in gut kidney and liver (decreased drug elimination and increased drug plasma conc)

27
Q

elderly

A

decreased renal function

decreased activity of Phase I metabolism

28
Q

chloramphenicol

A

given to babies (who have conjugating enzyme deficiency) will lead to build up of chloramphenicol oxidation metabolite which will result in gray baby syndrome and circulatory collapse and cyanosis

29
Q

pregnancy

A

some enzymes (2C9 2D6 and 3A4 increase) with others decrease (1A2, C219)

30
Q

alcohol

A

induces expression of 2E1

31
Q

pollutants and xenobiotics

A

induce specific p450 enzymes

32
Q

Disease

A

effect liver or blood flow to liver (cardiac disease)

33
Q

inflammatory cytokines

A

decrease expression of many CYP450 isoforms

34
Q

Probenecid

A

potent inhibitor of OAT1

Probenecid prevents
Nephrotoxicity by blocking OAT1-dependent
Cidefovir uptake
into the proximal tubules

great for preventing renal toxcitiy w Cidefovir… but now all OAT1 transporters inhibited… (can have effects on other drugs that utilize OAT1 elsewhere)

35
Q

Cidefovir

A
  • anti-viral used to treat CMV retinitis
  • transported into proximal tubules by OAT1
  • treatment limited by severe renal toxicity
  • Cidefovir always co-administered with probenecid bc it blocks uptake into the renal epithelium
  • will still be cleared eventually but this time through Glomerular filtration not through transport across renal epithelium
36
Q

Statins

A

OATP1B1 transport
(BCRP efflux)

SNP in OATP1BI influence STATIN efficacy and systemic exposure

OATP1B1*5 and 15 have decreased transporter activity; decreased STATIN uptake and efficacy; increased systemic statin exposure and increased statin toxicity
(15 most commonly reduced in Caucasians, Asians, then African Americans)

(Cyclosporin is potent inhibitor of OATP1B1 and blocks statin uptake)

Statin in muscle causes myopathy and rhabdomyolysis

37
Q

metformin

A

very basic anti-diabetic drug that acts in the liver and is eliminated unchanged by renal tubular excretion

(OCT/MATE SNPs result in loss of transporter activity and decreased kidney uptake/excretion so increased systemic drug availability)

38
Q

cimetidine

A

histamine H2 receptor antagonist used to treat acid peptic disorder (eliminated extensively via kidney)

mediates lots of OCT/MATE interactions

prevents renal elimination of other OCT dependent drugs

-administered w Cisplatin and prevents Cisplatin-induced nephrotoxicity

(non-selective inhibitor of several p450 isoforms)

39
Q

Cisplatin

A

chemotherapeutic agent to treat certain cancers
-use limited by nephrotoxicity

Co-administration of CIMETIDINE blocks Cisplatin uptake into the kidney and prevents Cisplatin-induced nephrotoxicity

(primarily eliminated via renal tubular excretion)

40
Q

BBB

A
  • tight junctions prevent ions and large molecules passing between endothelial cells
  • ABC transporters expressed on endothelial cells of BBB (P-gp/MDR1 BCRP MRP family efflux pumps)
  • prevent access of xenobiotic compounds (drugs) to the CNS
  • will exclude most drugs other than those small (less than 400Da and lipophilic)
41
Q

P-gp1/MDR1 (cancer connection)

A
  • tumor cells often “upregulate” expression of P-gp/MDR1
  • increased expression of P-gp/MDR1 in tumor cells is associated with a more aggressive phenotype, poorer prognosis and decreased sensitivity to chemotherapeutic drugs
  • increased expression of P-gp/MDR1 in tumor cells promotes efflux of anti-cancer drugs
42
Q

Through what transporter will glutathione, glucuronide and sulfate conjugates be excreted?

A

MRP

43
Q

Loperamide

A

opiod receptor agonist used to treat diarrhea

substrate for P-gp and does not cross BBB

Co administration w cyclosporin (P-gp inhibitor) allows Loperamide to cross BBB and can cause respiratory depression

44
Q

CYP2D6, 2C9 and 2C19

A

polymorphic

together they metabolize approx 50% of the 200 most commonly used drugs

  • significant variation in enzyme activity between individuals
  • polymorphisms are clinically significant

(2D6) Significant polymorphisms and levels of enzyme activity between ethnic groups

45
Q

2C191
2C192 and 3
2C1917

A
  • 1 normal
  • 2 and *3 non functional
  • 17 increased expression/increased activity
46
Q

2C9*2 and *3

2C9*15 and *25

A
  • 2 and *3 reduced function variants
  • 15 and *25 null variants

2C9*2 or *3 have decreased metabolic inactivation of S warfarin (most potent form); increased conc. of active warfarin with standard dose; prone to experiencing bleeding events; patients require lower warfarin dosing

47
Q

VKORC1

A

direct target of warfarin
common polymorphism is 1639 G to A

G is associated with higher VKORC1 expression and a higher warfarin dose

A is associated with lower VKORC1 expression and a lower warfarin dose needed

(90% Asians carry A allele, 37% whites, 14% Africans)

Rare mutations in the VKORC1 coding region are associated with warfarin resistance (reduced affinity) that require v. high doses of warfarin to achieve anticoagulation

48
Q

OATP1B1*15

A

polymorphisms in drug transporters causing elevated drug levels

OATP1B1*15 results in increased statins and increased risk of myopathy

49
Q

HLA-B*1502

A

Carbamazepine-induced Steven Johnson Syndrome in Han Chinese

FDA recommends Pharmacogenetic testing to be used to screen Asian patients requiring carbamazepine in order to avoid SJS

Drug-induced hypersensitivity reactions
(Allergic-like reactions, often life threatening)

50
Q

Trastuzumab (Herceptin)

A

an anti-Her2/ErbB2 monoclonal antibody used to treat breast cancer in patients whose tumor overexpresses the Her2/ErbB2 receptor

51
Q

Imatinib (Gleevac)

A

a tyrosine kinase inhibitor specific for the BCR-ABL Chr breakpoint oncoprotein found in patients with Chronic Myeloid Leukemia

52
Q

Gefitnib (Iressa)

A

an EGFR tyrosine kinase inhibitor used to treat a subset (10-20%) of Non-Small cell lung cancers patients that harbor the L858R activating mutation in their EGFR

53
Q

Ritonavir

A

potent 3A4 inhibitor

anti-HIV protease inhibitor
-significant GI adverse effects limit its use clinically

(low doses of Ritonavir has no GI effects but potentially inhibits 3A4 so will decrease first pass metabolism of Lopinavir “boosting” its levels -enhanced anti-HIV effect

54
Q

Ethanol/chronic alcohol

A

induce p450 enzymes

  • chronic alcohol induces expression of CYP2E1

can result in N-acetyl benzoquinoneimine metabolite from acetaminophen

higher first pass metabolism in men than women

55
Q

What is tachyphylaxis?

A

rapid development of tolerance to drug’s effects

describes the rapid development of diminished responsiveness to a drug.

Pharmacology (13 decks)

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