FDN2_SM_WK2_DrugMetabolism Flashcards

Question

Describe the metabolism of Midazolam

Answer 1

Phase I: oxidation (N-dealkylation) mediated by **CYP3A4** Phase II: **Glucuronidation** mediated by UGT (They typical drug metabolism pathway; this applies to all \_\_\_\_\_-azolam benzodiazepine drugs)

Answer 2

Cimetidine inhibits all CYPs except CYP2E1; This creates the potential for adverse drug interatctions - Inability to activate a pro-drug, resulting in a reduced effect - Inability to excrete a standard drug, resulting in an increased effect or toxicity

Answer 3

Caffeine and theophylline (treats respiratory diseases) are both methylxanthines They are **competitive inhibitors** of adenosine (adenosine ususally inhibits cell function)

Answer 4

SAGGMeth Sulfation Acetylation Glucuronidation Glutathione conjugation Methylation

Answer 5

Glutathione conjugation (mediated by GST) can "rescue" hepatocytes from the toxic intermediate NAPQI. NAPQI is created by CYP3A4 and CYP2E1. If it is conjugated to glutathione, it can be safely excreted. If instead it interacts with a nucleophilic macromolecule, it can lead to toxicity and hepatocyte death

Answer 6

CYP2C19 slow metabolizer

Answer 7

CYP2D6 ultrarapid metabolizer

Answer 8

CYP3A4 has a large active site cavity volume. It can bind to substrates of a wide variety of shapes and sizes

Answer 9

CYP3A4 and CYP2E1

Answer 10

CYP1A2: Phase I metabolism of methylxanthines (caffeine and theophyline) CYP1A?: Causes environmental pollutants containing benzo[a]pyrene to become toxic

Answer 11

Glomerular filtration, tubular secretion, passive tubular reabsorption

Answer 12

As blood rushes through the glomerulus, **filtrate** enters the kidney through the glomerulus The three layers that make up the glomerular filtration barrier determine what enters the filtrate, and what stays in the blood. **Small particles that are not bound to blasma proteins can easily enter the firltrate.**

Answer 13

The three membrane layers that achieve a size- and charge-sensitive filtration of drugs and solutes in the glomerulus. - Glomerular capilary endothelum - Porous glomerular basement membrane - Podocytes These membranes contain fenestrae and negatively charged glycoproteins. The result is that **negatively charged plasma proteins cannot enter** (among other things)

Answer 14

In tubular secretion, ionized drugs are secreted **into the filtrate** from the bloodstream. This process is driven by transporters - SLC22 transporters uptake molecules from the capilaries into the tubular endothelium - SLC and ABC transporters promote the efflux of molecules from the endothelium to the limunal spacs

Answer 15

SLC: Organic Anion Transporters and Organic Cation Transporters ABC: P-glycoprotein and MRP1

Answer 16

SLC transporters. This is the side that faces the capilaries - OATs and OCTs uptake anions and cations into the tubular endothelium

Answer 17

SLC: OATs and OCTs ABC: P-glycoprotein, MRP1 Together, these transporters move substances **from the tubular endothelium into the lumen** of the proximal tubule

Answer 18

Basic drugs are charged in their **protonated** form. If the pH of urine **To promote the excretion of a basic drug, make the urine more acidic**

Answer 19

Drugs and solutes are reabsorbed into the systemic circulation from the renal tubule. Nonionized, lipid soluble forms of the drug are able to pass back into the interstitium Changing the pH of the urine can promote the retention or excrection of acidic or basic drugs

Answer 20

Acidic drugs are charged in their **de****protonated** form If pH of urine \> pKa of the drug, the ionized form will dominate, and the drug will not be reabsorbed **To promote the excretion of an acidic drug, make the urine more basic**

Answer 21

Overdose or toxicity due to high drug concentration

Answer 22

Proximal tubular secretion Both involve ABC and SLC transporters

Answer 23

SLC: OAT and OCT transporters ABCs These transporters exist in canalicular membranes of hepatocyctes to secrete drugs into the bile

Answer 24

SLCO1B1; Defects in this transporter result in imparied secretion of the drug into the bile This results decreased excretion and increased plasma concentrations of the drug, which can lead to myotoxicity

Answer 25

Heavy drugs; molecular weight \>300

Answer 26

A recycling system! Drugs that are glucuronidated in the liver are secreted into the bile and then dumped into the gut Bacteria in the colon may cleave the glucuronide off of the drug, increasing its lipophilicity The drug is now more likely to be reabsorbed into the hepatic circulation

Answer 27

Antibiotics may disrupt the bacteria in the colon The bacteria normally cleave glucuronide off of the drug, allowing the drug to be reabsorbed into the circulation. **If the bacteria are dead, more of the drug will be excreted, lowering the expected plasma concentration of the drug and reducing its efficacy**

Answer 28

You would want to **lower the dosage** of the drug; less will be filtered into the kidney, which means that more will remain in the plasma. Lowering the dosage can reduce the risk of toxicity

Answer 29

Clearance depends on blood flow to the liver Metabolism is not rate-limiting, and plasma-protein binding doesn't really matter Note: These drugs tend to have high first-pass metabolism

Answer 30

CL = (Rate of elimination) /[plasma concentration]

Answer 31

Hepatic metabolism and plasma protein binding Blood flow to the liver is not rate limiting, because metabolism in the liver is slower, and dependent on the fraction of free drug in the blood (which is impacted by binding to plasma proteins)

Answer 32

Morphine, propanolol, lidocaine

Answer 33

Digoxin, diazepam, phenytoin, valproic acid, cimetidine (DDPVC)

Answer 34

More binding to proteins = less excretion Bound proteins cannot enter glomerular filtrate

Answer 35

Both are related to the study of genes Pharmacogenetics looks at individuals or families, and how their SNPs may affect drug response Pharmacogenomics looks at genes that are associated with differential drug responses among groups of unrelated indivdiuals, on a population-wide level

Answer 36

Malignant hyperthermia susceptibility G-6-P dehydrogenase deficiency Pseudocholinesterase deficiency

Answer 37

Codeine is a **prodrug** that requires converstion to morphine by **CYP2D6** **CYP2D6 ultrarapid metabolizers** end up making a lot of morphine. This can lead to a dangerous functional morphine oversdose (increased sedation, respiratory depression) **CYP2D6 poor metabolizers** have lower than expected analgesic effects from codeine

Answer 38

Clopidogrel is a pro-drug that is prescribed as an anti-platelet agent. **CYP2C19** is required to activate the drug. **CYP2C19 ultrarapid metabolizeers** are at an increased risk for bleeding **CYP2C19 poor metabolizers** do not have adequate antiplatelet effects; they are at an increased risk for blood clots

Answer 39

CYP2D6 activates codine to morphine

Answer 40

CYP2C19 activates clopidogrel

Answer 41

CYP2C19 and CYP3A4 facilitate excretion of omeprazole

Answer 42

Thiopurine S-Methyltransferase; required for excretion of the drug

Answer 43

CYP2C9 facilitates excretion of warfarin

Answer 44

\_\_\_\_-**pr**azole drugs are **pr**oton pump inhibitors. CYP2C19 and CYP3A4 are required for metabilism and **CYP2C19 ultrarapid metabolizers** clear the drug too quickly, resulting in poor treatment of gastric acidity **CYP2C19 poor metabolizers** experience a higher efficacy of PPI drugs, but in children this may be associated with upper respiratory infections and strep

Answer 45

Thiopurine drugs like Azathioprine are pro-drugs that are used to treat leukemia, rehumatic disease, IBD, and organ transplantation. They are activated by a metabolic pathway to **glutathione nucleotides** Thiopurine S-Methyltransferase (TPMT) facilitates the excretion of an intermediate of the pathway, 6-mercaptopurine. If there is a loss of function/reduced function mutation in the TPMT gene, **more glutathione nucleotides will be made**. This results in increased drug efficacy, but also risk for toxic effects

Answer 46

Thiopurine drugs are used to treat leukemia, IBD, rheumatic disease, and organ transplant (Think Autoimmune disorders)

Answer 47

Azathioprine, 6-mercaptopurine, and 6-thioguanin

Answer 48

Warfarin is an anticoagulent that is metabolized by **CYP2C9.** **CYP2C9** **ultrarapid metabolizers** will clear the drug quickly, putting the patient at **risk for clotting** **CYP2C9 poor metabolizers** will clear the drug slowly, resulting in higher plasma concentration and **risk for bleeding** Warfarin exerts its effects by inhibiting VKORC1, an endogenous enzyme required for sythesis of clotting factors **LOF mutations in VKORCI** result in **increased baseline INR** (it takes longer for the patient to clot, putting them at increased risk for bleeding)

Answer 49

Tumors may contain genetic variants that make them more or less responsive to anti-cancer drugs **Hyperactive EGF Receptors**: This drug will respond really well to anti-cancer drugs that target the EGF receptor **Nonresponsive EGF Receptors**: If anti-cancer drugs work to eradicate 99% of tumor cells, the ones that remain are likely resistant to the drugs due to a mutation that gives them resistance to the drug. Relapse due to growth of these resistant cells is hard to treat, because they are **unresponsive to the anti-cancer drug.**

Answer 50

**Good:** Glutathione conjugation via GST can **protect against toxic metabolites** and therefore prevent cancers from developing **Bad:** If cancer does develop, high levels of GST in tumors can cause **cancer cell proliferation** and **resistance** **to chemotherapy**

Answer 51

Grapefruit juice **inhibits** CYP3A4, resulting in **slower metabolism** of the drug. The effects of the statin will be **potentiated**.

Answer 52

N-Acetylcysteine (NAC) NAC conjugates directly with NAPQI, replaces glutathione stores, and can protect against extrahepatic injury Giving extra glutathione may seem like it could work, but it would be ineffective because it can't cross cell membranes.

Answer 53

The individual has an extra functional copy of the reference CYP2D6 gene; they may have increased CYP2D6 activity

Answer 54

Vd = (dose)/(plasma concentration) Unit = L

Answer 55

The amount of the administered drug that is in tissues, organs, or otherwise sequestered out of the systemic circulation. This measurement is only meaningful *right* after the drug has been distributed (before it is metabolized or excreted)

Answer 56

**Patient factors:** age, gender, body muscle/fat proportion, level of hydration, water distribution (pregnancy, edema) **Drug Factors:** High lipid solubility, low ionization = higher Vd Vd is unaffected by half-life or clearance

Answer 57

For first order drugs **t_1/2= 0.693\*Vd/Cl** For zero-order drugs, half life cannot be calculated by a simple equation; the time it takes for 50% of the drug to be eliminated will depend on how much drug is in the system

Answer 58

CL = (rate of elimination)/(plasma concentration of the drug) Unit: L/hr or mL/min CL is constant for first order drugs; the rate of elimination increases or decreases with the [drug] CL is not constant for zero order drugs

Answer 59

The **volume of plasma** cleared of the drug per unit time.

Answer 60

Rate of Elimination = **CL \* [drug in plasma]**

Answer 61

**First order drugs:** Rate of Elimination is a fixed fraction of the [drug]; this is not a saturated system, and can change based on the [drug] **Zero order drugs:** Rate of Elimination is a fixed amount of drug. It doesn't depend on the [drug]; think of it like a saturated system that is going as fast as it can

Answer 62

For IV drugs: (infusion rate)/(CL) For oral drugs: (Oral dose)/(dosing interval \* CL)

Answer 63

~3.3 half-lives to reach 90% C_ss (which is pretty much the goal)

Answer 64

LD = C_ss \* Vd

Answer 65

A high Vd means that a large amount of the drug gets sequestered in tissues or other spaces outside of the systemic circulation

Answer 66

It isn't; C_ss doesn't depend on Vd C_ss = Infusion rate/CL The goal for C_ss is to have a steady [drug] in the systemic circulation. After a drug has been distributed to tissues and other spaces outside of the systemic circulation, it kind of just stays there and doesn't affect [drug}

Answer 67

IV drug: I = C_ss \* CL

Answer 68

ATP Binding Cassette (Directly energy dependent = Involved in active transport)

Answer 69

More than 2 copies of \*1 or \*2

Answer 70

Two copies of anything that isn't \*1 or \*2 \*1 or \*2 plus any other allele = within normal range (\*4 and \*5 are most common)

Answer 71

\*1/\*17 or \*17/\*17 (17 is ultrarapid)

Answer 72

Any genotype that doesn't contain \*1 or \*17 (\*2 and \*3 are common)

Answer 73

Caucasians (8-10%) African Americans (1-3%)

Answer 74

Ethiopians and Saudi Arabians (30%)

Answer 75

Asians (15-20%) Caucasians (3-5%) African Americans (3-5%)

Answer 76

Caucasians (10-35%)

FDN2_SM_WK2_DrugMetabolism Flashcards

Drug Metabolism