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BIO200 > Test 2 Prep > Flashcards

Test 2 Prep Flashcards

1
Q

What does ADME stand for?

A

Absorption, Distribution, Metabolism, Elimination

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2
Q

If the drug pKA > pH, the drug will be ___. If the drug pKA < pH, the drug will be ___

A

pKA > pH, drug will be protonated (basic)

pKA < pH, drug will be deprotonated (acidic)

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3
Q

How is renal control of pH related to drug elimination?

A
  • increasing the acidity of urine enhances excretion and decreases reabsorption
  • drug gets protonated (ionized)
  • prevents overdose and minimizes side effects
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4
Q

volume of distribution

A
  • the amount of drug found in the body compared to its concentration in the blood
  • to what extent is the drug distributed from the blood to tissues
  • V = (dose of drug)/([drug] in blood in mg/ml)
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5
Q

What does a high/low volume of distribution indicate?

A
  • high volume of distribution = higher [drug] in extravascular than in blood
  • low volume of distribution = drug doesn’t leave vasculature
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6
Q

What complications arise due to a high volume of distribution?

A
  • widespread distribution = more side effects possible, decreased efficacy, requires more drug = more off target effects
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7
Q

clearance

A
  • the factor predicting rate of elimination
  • related to [drug]
  • CL = (rate of elimination)/([drug])
  • additive: CLsystemic = CLliver + CLlungs + CLkidney + CLother
  • CL per organ is rate of elimination based on [drug] that reaches the organ
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8
Q

renal clearance

A

clearance of unchanged drug in the urine

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9
Q

half-life

A
  • time needed to decrease amount of drug in plasma by 50%

- t1/2 = 0.7V/CL

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10
Q

What do higher half lives indicate?

A
  • less elimination
  • less drug required
  • low volume of distribution (stays in vasculature longer)
  • less rate of decay
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11
Q

accumulation

A

build up of [drug] in the body when drug doses repeated, due to the previous dose not being cleared completely

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12
Q

accumulation factor

A

= 1 / (fraction of drug lost in 1 interval)

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13
Q

bioavailability

A

the fraction of unchanged drug that reaches the blood/systemic circulation after administration

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14
Q

Cmax

A

max concentration of drug absorbed

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15
Q

tmax

A

time at which max concentration of drug is absorbed (Cmax)

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16
Q

AUC

A
  • area under the curve

- represents total drug exposure over time

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17
Q

system bioavailability (F) equation

A

F = f x (1–ER)

where f is extent of drug absorption and (1-ER) is oral bioavailability (ER is extraction ratio)

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18
Q

first-pass effect

A

initial metabolism of drug by the liver

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19
Q

extraction ratio (ER)

A

ER = (CLliver)/(Q)

where CLliver is clearance rate from liver and Q is hepatic blood flow (rate of blood flow through liver)

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20
Q

If a drug is highly extracted by the liver, will it have a large or small “f” value?

A

small “f” value

- low absorption due to higher loss of drug

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21
Q

Which of the following routes of administration do NOT incur the first-pass effect: oral, IV, IP (intraperitoneal), topical, sublingual, transdermal, rectal?

A
  • IV
  • topical
  • sublingual (directly into systemic circulation)
  • transdermal
  • rectal (if lower since lower rectum drains into systemic circulation, 50% if upper)
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22
Q

What does the time course of a drug depend on?

A
  • dose of drug administered and absorbed
  • EC50/ED50: drug needed to inhibit target
  • half-life: plasma drug concentration over time
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23
Q

immediate/fast effects

A
  • drug target is within cardiovascular system or easily accessible from blood stream
  • travel time minimized
  • drug effect is directly related to drug concentration
  • max effect almost immediately seen after administration
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24
Q

delayed effects

A
  • changes in [drug] in plasma result in changes drug effects
  • time taken to distribute to tissues
  • time taken for dissociation of drug from target/receptor
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25
Q

cumulative effects

A
  • high potency; drug binds to target fast after absorption
  • drug effect occurs after enough drug is bound to the target to induce some change (amount, location, function) in the target to induce clinical benefit
  • cumulative exposure
26
Q

xenobiotics

A

foreign molecules that enter the body

27
Q

What is the main goal of drug metabolism?

A
  • to enhance drug elimination
  • decrease half life
  • prevent toxic accumulation of drug in the body
28
Q

How is metabolism related to the half life of a drug?

A
  • slow metabolism = longer half life

- fast metabolism = shorter half life

29
Q

How do enzymes catalyze reactions?

A

increase the liklihood of reaction occurring by holding 2 molecules in close proximity to each other

30
Q

catalysis

A

increases the rate of reaction by lowering the activation energy

31
Q

phase I reactions

A
  • enzymes add small polar groups
  • makes drugs more polar and hydrophilic
  • removes lipophilic groups
  • example: oxidation
32
Q

phase II reactions

A
  • add big bulky groups to original drug or to the phase I product
  • forms inactivated drug conjugates that can be easily excreted
  • example: addition of glucose makes drug more hydrophilic
33
Q

microsomes

A
  • mini metabolic machines

- isolated from smooth ER in cells to study phase I rxns

34
Q

mixed function oxidases (MFOs)/monooxygenases

A
  • a P450-mediated substrate oxidation mechanism
    Step 1: Fe3+ state, P450 oxidized
    Step 2: NADPH reducing agent donates electron to CYP450 with the help of P450 reductase, reducing Fe3+ to Fe2+
    Step 3: second time NADPH donates electron, does not change Fe2+ but allows binding of O2 to CYP450
    Step 4: drug is oxidized (attachment of -OH), CYP450 back to Fe3+ state
35
Q

induction of P450 activity

A
  • increase in drug metabolism over time
  • increase rate of elimination
  • increased risk of toxicity if drug metabolite is reactive
  • example: cirrhosis due to ethanol-mediation induction of CYP2E1
36
Q

inhibition of P450 activity

A
  • decrease in drug metabolism over time
  • binding to the heme iron (competitive inhibition/suicide inhibition)
  • inability to metabolize leads to accumulation of other drugs
37
Q

examples of P450-catalyzed oxidation reactions

A
  • aromatic hydroxylations

- aliphatic hydroxylations

38
Q

other phase I transformations (not P450-catalyzed)

A
  • amine oxidation
  • dehydrogenations (increase polarity; RCH2OH –> RCHO)
  • hydrolysis (of esters and amides)
39
Q

metabolic enzymes other than P450

A
  • esterase/lipase: ester bond hydrolysis into alcohol and acid
  • peptidase/protease: peptide bond hydrolysis
  • amylase: breakdown of sugar into glucose monomers
40
Q

glucuronidation

A
  • UGT enzyme transfers glucuronosyl onto nucleophilic atom
  • donor: UDP-G
  • substrates: alcohols, carboxylic acids, amines, amine oxides (N-OH)
  • metabolites: glucuronides
41
Q

sulfation

A
  • sulfotransferase enzyme transfers sulfate group to nucleophilic atom
  • donor: PAPS
  • transfers sulfate onto hydroxyl (-OH) or amine (-NH2) of the substrate
  • metabolite: sulfamates
42
Q

GSH conjugation

A
  • glutathione transferase transfers glutathione (GSH) group onto electrophile
  • donor: GSH itself (a nucleophile)
  • metabolite: GSH attached to electrophilic centre of drug
43
Q

N-acetylation

A
  • N-acetyltransferase (NAT) enzyme transfers acetyl group onto the N of an aromatic amine group
  • deactivates drug activity
  • donor: acetyl-CoA
  • metabolite: acetylated aromatic amine
44
Q

methylation

A
  • methyltransferase (MT) enzyme transfers methyl group onto nucleophile
  • donor: SAM
  • transferred to alcohol, amine, etc.
  • metabolite: + charged methylated nucleophile
45
Q

Are phase II or phase I reactions faster?

A
  • phase II rxns are faster
  • reactive donor groups
  • neutralizing rxns occur faster than oxidation/reduction
46
Q

P-glycoproteins

A

associated with drug efflux

47
Q

metabolism in the lungs

A
  • very fast absorption and high bioavailability

- lower levels of metabolism (less amount of enzymes)

48
Q

metabolism in the gut

A
  • gut wall epithelium with P-glycoproteins and CYP450 enzymes
  • part of the first pass effect
  • gut flora can also metabolize drugs
49
Q

metabolism in the skin

A
  • intercellular route: between cells
  • transcellular route: passes through cell membranes and cytosol (*face higher metabolism through this route due to enzymes in cytosol)
50
Q

metabolism in the brain

A
  • CYP450 and some phase II enzymes

- can create active metabolites (increase half life in CNS) or deactivate them

51
Q

Explain how acetaminophen illustrates the idea that drugs can be transformed into reactive intermediates that are toxic to many organs.

A
  • acetaminophen can undergo phase I oxidation, glucuronidation, sulfation, ultimate goal is GSH conjugation but intermediate is reactive and toxic
  • if acetaminophen is taken in excess, the body doesn’t have enough GSH + glucuronidation and sulfation pathways are already saturated
  • reactive intermediate will begin to bind to proteins in the liver, covalently modifying them = liver cell death
  • antidote: acetylcysteine binds to the intermediate, competing with proteins
52
Q

prodrug

A

compound that is metabolized after administration into an active drug

53
Q

promoiety

A
  • a group originally attached to a drug to mask it
  • removed by enzymes/chemical transformation
  • should be safe and rapidly cleared, not active
  • enhances solubility and delivery to site of action
54
Q

2 goals of the prodrug approach

A

enhance absorption and active transport

55
Q

Levodopa (L-DOPA) prodrug

A
  • prodrug for morphine: treatment of parkinson’s disease
  • L-DOPA is a substrate of the LAT1 transporter in BBB endothelial cells but dopamine is not
  • converted to dopamine in neurons
  • enhanced active transport
  • bioavailability improved if co-administered with carbidopa (decarboxylase inhibitor), as parcopa
56
Q

Bacampacillin prodrug

A
  • prodrug for ampicillin, an antibiotic that inhibits cell wall production
  • increases absorption bc it is more hydrophobic and less prone to first-pass effect and metabolism
  • slowly converted to ampicillin by esterases in gut intestinal wall and increases its absorption into blood
57
Q

pharmacogenomics

A

the role of our genome in drug response

58
Q

epigenetic modifications

A

covalent modifications to the genome due to environmental or biological changes

59
Q

genetic polymorphisms

A
  • changes in nucleotide or number of nucleotide repeats (SNPs and CNVs)
60
Q

single nucleotide polymorphisms (SNPs)

A
  • single nucleotide substitution, insertion or deletion
61
Q

copy number variations (CNVs)

A

sections of the genome are repeated

62
Q

organic anion transporter (OATPs)

A
  • membrane molecule influx or efflux transporters

BIO200 (2 decks)

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