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Flashcards in Drug Metabolism & Elimination Deck (20)
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1

Describe the general principles and consequences of drug metabolism.

Drug metabolism is also known as biotransformation. Drug metabolizing enzymes have endogenous substrates and play a role in normal metabolism (duh). The liver is the primary metabolism organ but the intestines [6%], lungs [30%], kidneys [8%], skin [1%], placenta [5%], and bacteria in the lumen of the intestines all play a role in metabolism. Oxidation is the most frequent metabolism pathway. Oxidation and other transformations are catalyzed by membrane bound proteins in the SER and soluble enzymes in the cytosol. Finally, lipid soluble compounds are converted to more water soluble compounds for easy excretion.

2

What are the general characteristics of  Phase I reactions?

Phase I reactions usually insert or unmask a functional group on the drug [OH-, -NH2, -SH] that renders the molecule more water-soluble and the molecule can then undergo conjugation in a Phase II reaction. Phase I reactions include: Oxidation, reduction, hydrolysis.

3

What are the general characteristics of Phase II reactions? 

Phase II metabolism involves attaching larger endogenous biochemical units (not just oxygen) to the drug by way of cofactor enzymes. Makes a highly water soluble conjugate that is readily excreted in the urine. This process is referred to as conjugation. Reactions include glucouronidation, acetylation, and some glucothione and sulfate conjugation. Sometimes Phase 2 reactions can preceed Phase 1 reactions.

4

Describe how Phase 1 and Phase 2 reactions relate to qualitative and quantitative role in drug metabolism.

CYP3A4 is responsible for 50% of drug metabolism, and CYP1, 2, 3 are also of primary importance in drug metabolism. Therefore, Phase I reactions are responsible for more drug metabolism than Phase II.

5

Which enzymes are involved in Phase I and Phase II reactions?

Phase 1 uses: oxidizers (microsomal CYP450 and non-microsomal CYP450), reducers, and hydrolyzers (esterases, amidases)Phase 2 uses: transferases

6

How are genetic polymorphisms important in Phase I and Phase II reactions?

There's extensive genetic variability of CYP enzymes (phase I). There's extensive genetic variability of N-acetylation enzymes (phase II). This can be important in terms of analgesic response (CYP2D6 for codeine to morphine) and blood clotting with regard to Warfarin. 

7

What reactions are CYP450 dependent?

Aromatic hydroxylations, aliphatic hydroxylations, epoxidation, oxidative dealkylation, o- and s-dealkylation, n-oxidation, secondary and tertiary amines, s-oxidation, deamination, desulfuration, dechlorination.  

8

How is age related to the effects of Phase I and phase II reactions?

Perinatal: some enzymes may not be fully developedNeonatal:can usually metabolize at lower rates than adultsOld age: 1/3 decrease in CYP activityNot much change in Phase II activity with aging. 

9

Please discuss Phase I and Phase II reactions in regard to inducibility.

Phase I reactions can be induced or inhibited with relative ease. Phase 2 are not usually inducible. Phase 2 glucourinidations are inducible but not to the extent that Phase I reactions are, especially CYP450).

10

Please discuss Phase I and Phase II reactions in regard to developmental patterns of activity. 

Some Phase II enzymes only show up at a certain age-- infants often lack the metabolizing enzymes that adults have (eg. glucuronidation enzymes). Also, depending on in what state your liver is in, it can be better or worse at both phases of metabolism. Some phase 1 enzymes occur at higher rates in pediatric patients, so it is important to be aware of theses types of situations.

11

Please discuss Phase I and Phase II reactions with regards to relative ease of saturability at high drug substrate levels. 

Phase II reactions usually saturate faster than Phase I reactions.

12

What is induction?Explain the therapeutic consequences of induction. 

Increased drug metabolism activity in response to certain compounds including drugs. Maximal effects of enzyme induction usually seen in 7-10 days and require similar time to dissipate.Production of pharmacokinetic tolerance: induction by a drug of its own metabolism, e.g., phenobarbital, meprobamate, carbamazepine.Induction by one agent may increase the clearance of other drugs. The resulting drug interactions may have clinical implications such as reduced therapeutic effect of drug whose elimination is accelerated or increased toxicity via a toxic metabolite.One drug may induce the metabolism of another to toxic metabolites; e.g., ethanol induces CYP2E1 that metabolizes acetaminophen to a hepatotoxic metabolite.Very important for CYP450, not very important in Phase II reactions. 

13

What is inhibition? Explain the therapeutic consequences of inhibition?

Inhibition is decrease in drug metabolizing activity by certain compounds.Inhibition of metabolism can occur as soon as sufficient hepatic concentration is reached (generally within hours), although time to effect on steady state plasma concentration dependent on the inhibited drug’’s half-life.Inhibition by one agent of the metabolism of another can result in decreased clearance of the inhibited drug, higher circulating plasma levels, and increased toxicity.Very important for CYP450, not very important in Phase II reactions. 

14

Describe the therapeutic implications of enterohepatic recirculation of drugs.

Drugs and drug metabolites with molecular weights higher than 300 may be excreted via the bile, stored in the gallbladder, delivered to the intestines by the bile duct, and then reabsorbed into the circulation where it can return to the liver by way of the superior mesenteric and portal veins. This process reduces the elimination of drug and prolongs its half-life and duration of action in the body. For some drugs (e.g., morphine and ethinyl estradiol), this effect creates a ““reservoir”” of recirculating drug that can amount to about 20% of total drug present in the body.

15

Describe the factors influencing drug passage from plasma to breast milk.

Select drug(s) with clinically insignificant amounts of passage into breast milk. The milk concentrations of ethanol and lithium can approximate maternal plasma levels.Drugs with rapid clearance (> 0.3 L/hr/kg) and no active metabolites are generally cleared too rapidly by the mother to affect the nursing infant.Milk is more acidic than plasma (pH 6.5 vs pH 7.4) therefore tendency to accumulate basic compounds (e.g., opiate analgesics) by ion-trapping.Lipid soluble compounds → generally increased milk concentration.High protein binding → decreased milk concentration.Drugs contraindicated by American Academy of Pediatrics: amphetamines, cocaine, bromocriptine, ergotamine, lithium, nicotine, most antineoplastic agents, drugs of abuse.Drugs that can affect milk synthesis, secretion, and / or ejection through effects on prolactin (PRL) and / or oxytocin release include: dopamine receptor agonists (↓ PRL release) and antagonists (↑ PRL release) and ethanol (↓ oxytocin release).

16

Describe the general characteristics of drug excretion by the kidney (filtration, secretion, reabsoption, influence of pH and protein-binding).

Water soluble drugs and drug metabolites excreted via the urine. Ability to excrete drugs through kidney doesn’t vary much among healthy individuals in relation to variability in hepatic capability. Kidney is most important organ for excretion.First, drug goes through glomerular filtration, then tubular secretion, and then tubular reabsorbtion.GFR: Cannot filter protein bound drugs. Can filter ionized drugs. Filtration is primarily affected by renal blood flow and function. Extensive protein binding can prolong half life.Secretion: The kidney secretes drugs that are stronger acids and bases. However, reversible protein binding does not affect secretion because equilibrium is always being manipulated.Reabsorbtion: is passive. Diffusion of weak acids and bases is dependent upon urine pH by altering deionized form amounts, occurs in proximal and distal tubules for lipid soluble drugs. Can use ion trapping by altering urinary pH (acidic urine traps basic drugs and vice versa).

17

Please tell me the basics about clearance. 

The volume of plasma (Vd) which is completely cleared of drug in a given period of time by the combined processes of tissues such as kidney (excretion) and liver (drug metabolism) with some contribution from other tissues such as lung, muscle, etc.The value for clearance is given by the formula: CL=Vd x ke

18

Please tell me about Half-life (t1/2)with regards to Time to steady state or removal from body, selecting dosage intervals, relation to fluctuations in plasma drug levels between drug doses (difference between Cp max and Cp min).

Knowing the half life will help you figure out: The time it takes a drug to be essentially eliminated (4-5 half-lives), The time it takes to reach steady state when drugs are administered continuously (4-5 half-lives), The degree of fluctuations in plasma levels between doses (related to number of half-lives in dosing interval). However, the t1/2 cannot be used to accurately calculate the amount of drug that will remain at times in between the half-life times. For that type of calculation the more general equation derived below must be used.

19

Please tell me about the elimination rate constant (Ke).

Ke is the fraction of drug leaving body per unit time via all elimination processes. ke is best thought of simply as a number or constant that allows us to calculate the amount of drug remaining at any time during the elimination process.

20

Please describe first-order and zero-order kinetics and implications for chronic dosing regimens.

Most drugs are first order kinetics. That means, double the dose and the clearance will double, or half it and elimination will be halved, etc. Only 1st order have ½ lives. Rate of clearance is proportional to amount. A constant percent or fraction is eliminated.Zero order kinetics describes the process in which the rate of elimination of drug from the body is independent of the amount of drug in the body (NOT first order). The AMOUNT of drug removed per unit time is constant, i.e., is independent of drug concentration.Drugs eliminated by zero order kinetics do not have half-lives and can present dose adjustment challenges, especially at the upper end of the therapeutic range of narrow therapeutic index drugs, where a small change in dose can produce large changes in plasma concentrations and subsequent toxicity.