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Pharmacology Unit 1 > Basic Principles IV > Flashcards

Basic Principles IV Flashcards

1
Q

biotransformation of toxicants

A
  • can have a widespread influence on drug use
  • route of admin
  • dose
  • effectiveness
  • tox, safety
  • duration of effect
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2
Q

purposes of biotransformation

A
  • one method of clearing drug from the plasma
  • rate will depend on endogenous enzyme systems
    1. drug detox- change structure and thus activity
    2. prepare for drug excretion- reduce drug characteristics to make it easy to absorb
  • make it larger, add charges, make it more water soluble- esp important
  • can make drugs active or inactive
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3
Q

sites of biotransformation

A

A. liver
1. on cellular structural components, SER- lipid enviro- enhances equil with lipid soluble drugs
2. cytoplasm
3. mitochondria
B. anywhere else in the body- plasma, RBC, synaptic cleft, bone

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4
Q

phase I

A
  • xenobiotic to primary product
  • exposes or adds functional groups
  • oxidation, reduction, hydrolysis
  • primary product can be excreted
  • takes substance from lipophilic to hydrophilic
  • activities of drug vs activities of metabolites
  • may have variable results on activity
  • both in the target tissue and on secondary receptors in the other tissues- tox
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5
Q

phase II

A
  • primary product to secondary product
  • biosynthetic conjugation
  • conjugation-synthesize a new molecule by combining the drug or metabolic product of phase I with a molecule provided by the cell
  • metabolic energy is used and a covalent bond is formed
  • resulting molecule is larger, charged, water soluble, and inactive
  • liver has to be healthy
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6
Q

hepatic microsomal drug metabolizing systems

A
  • system in liver we use to measure the metabolism
  • microsomal is SER
  • both phase I and phase II processes
  • induction- increase metabolism of primary drug or other drugs, can manifest as an increase in first pass metabolism
  • inhibition- use a drug to block the metabolism of another drug or endogenous compound
  • if phenobarb given, dicumerol decreases, and therefore so does PT (faster clotting)
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7
Q

non-microsomal systems

A
  • other organs, plasma, red cells
  • usually phase I- acetyl cholinesterase, alcohol dehydrogenase
  • inhibition but no induction- enzymes are not near the nucleus they were made by and therefore not autoregulated or getting feedback
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8
Q

enzyme system

A
  • can be relatively specific for certain drugs or endogenous compounds, or more likely nonspecific and have a broad range of activity for classes or types of molecules
  • mass action
  • products of phase I become substrates of phase II
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9
Q

drug oxidation

A
  • add oxygen or change proportion of oxygen in molecule
  • most common metabolic transformation
  • hepatic mixed function oxidase system
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10
Q

hepatic mixed function oxidase

A
  • NADPH, cytochrome p450 reductase (flavoprotein), cytochrome p450 (hemoproteins) Mg++, phospholipid, O2
  • usually metabolize lipid soluble drugs- concentrates in SER
  • reductase changes iron from Fe +++ to fe ++ and becomes oxidized in the process
  • O2 then binds, and drug becomes oxidized
  • fe gains electrons (is reduced while reductase is oxidized) so O2 can come in and take them
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11
Q

p450

A
  • 12 groups in humans
  • some for toxins and others for endogenous compounds
  • low specificity
  • very large genetic variations in populations of people
  • catalyzes reductions and oxidations
  • 10:1 ratio of p450 to a reductase- constant cycling (reductase is faster, can do one p450 after another)
  • number of variations- CYP1a2, 2e1, 2c, 3a, 2d6
  • most by 3a, but 2d6 is most trouble
  • system also influenced by disease factors- liver disease/ perfusion
  • age and sex- fetal-geriatric
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12
Q

CYP2D6

A
  • largest degree of identified genetic variations
  • about 70 nucleotide variations exist
  • resulting in an inactive enzyme or reduced catalytic activity
  • 4 phenotypes-
    1. poor- toxicity possible
    2. intermediate
    3. extensive
    4. ultrarapid- potential no effect- high first pass
  • variation by race- caucasians 5-10% poor
  • SE asian 1-2% poor
  • 65 commonly used drugs metabolized by it
  • potential drug interactions when metabolized by same p450 enzymes
  • competition with inhibition- potential tox
  • induction- decrease effectiveness for a given dose
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13
Q

oxidation

A
  • adds oxygen to molecule to make it less active

- lose oxygen

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14
Q

drug reduction

A
  • add hydrogen or change the proportion of hydrogen in the molecule
  • gain electrons
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15
Q

drug hydrolysis

A

-cleave a molecule by the addition of a water molecule

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16
Q

first order

A
  • if concentration of D is much less than km, the enzyme is efficient
  • V= vmax X D/ Km = constant x [D]
  • 98% of drugs
17
Q

biotransformation summary

A
  • the enzyme systems may be a rate limiting step in the clearance of a drug from plasma when:
  • metabolism is more important than renal elimination
  • when enzyme is relatively slow
  • biotransformation determines how fast clearance is from plasma
18
Q

zero order

A
  • if [D]&raquo_space; km, inefficient enzyme
  • V= Vmax x [d] / d, which equals Vmax- constant
  • maximum velocity but constant rate
  • few drugs
19
Q

renal excretion

A

-most important route of elimination of drugs or metabolites

20
Q

excretion is equal to

A

-equal to amt entering tubule - amt reabsorbed

21
Q

drug enters nephron by

A
  • by glomerular filtration- only free drug molecules are filtered
  • amount filtered depends on glomerular blood flow and free drug concentration
  • also enter by secretion
  • active transport, one system for acids and one for bases
  • exists for endogenous compounds like uric acid or choline
  • inhibition- usually competitive- to make another drug work better and still let system work on endogenous compounds
  • saturation- can occur at therapeutic doses or with overdoses
  • changes primary process to zero order process
22
Q

drugs are reabsorbed by

A
  • passive reabsorption- especially for lipid soluble drugs
  • after free water absorption these are concentrated in the loop of henle- reverse concentration gradient
  • active reabsorption- active transport for endogenous compounds, works for some drugs
23
Q

amount of drug excreted

A

(glomerular filtration +active tubular secretion)-(passive reabsorption +active reabsorption)

24
Q

enhancing renal excretion

A
  • forced diuresis
  • manipulate pH of the urine, trapping of ionized drug
  • add bicarb to pull pH up and make acidic to pull HA out and bring it into urine
  • alkalinization changes the urinary excretion by 4 fold to 6 fold
25
Q

biliary excretion

A

-amount of drug excreted= (amount of drug entering bile)- (amount of drug reabsorbed)

26
Q

enter bile by

A
  • secretion- active transport system- acids or bases

- passive diffusion

27
Q

reabsorbed from bile by

A
  • passive diffusion and the original absorption mechanism

- enterohepatic cycling can occur

28
Q

other routes of elimination

A
  • lungs
  • sweat
  • saliva
  • tears
  • breastmilk
29
Q

elimination of drugs from site of action

A
  • decrease concentration in the plasma
  • redistribution
  • biotransformation
  • excrtion
30
Q

redistribution

A

-changes the location of the drug

31
Q

biotransformation

A

-primarily hepatic, metabolically changes the drug to metabolites and causes a clearance of the drug from the plasma

32
Q

excretion

A

-primarily renal, produces a clearance of the drug from the plasma and from the body

33
Q

clearance

A
  • a combination of biotransformation and excretion
  • contribution of each process with vary for different drugs
  • a volume of plasma that is cleared of drug per unit time
  • clearance total=clearance metabolic + clearance renal
  • in hepatic disease, metabolic is reduced
  • in renal disease, renal is reduced
34
Q

factors influencing clearance

A
  1. body surface area
  2. protein binding
  3. cardiac output
  4. renal function
  5. hepatic function
  6. blood flow to systemic organs
35
Q

inulin

A
  • filtered
  • 130 ml/min
  • GFR
  • all excreted that is filtered
36
Q

glucose

A
  • reabsorbed
  • 0 ml/min excreted
  • all reabsorbed
37
Q

PAH

A
  • secreted
  • up to 650 ml/min
  • renal blood flow

Pharmacology Unit 1 (10 decks)

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