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MLSCI 466 > Pharmacokinetics & Pharmacodynamics > Flashcards

Pharmacokinetics & Pharmacodynamics Flashcards

1
Q

pharmacology definition

A

studies interactions between living organisms and chemicals that affect function

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2
Q

toxicology definition

A

examines undesirable effects of chemicals on living systems

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3
Q

pharmacodynamics

A

therapeutic and/or toxic actions of the drug on the body, receptor interactions (agonist, antagonist) concentration-effect component

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4
Q

pharmacokinetics

A

effect of the body on the drug, dose-concentration component
LADME

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5
Q

pharmacogenetics

A

effect of genetic makeup on how the drug is handled by the body and affects the body, sequence DNA and predict individual response to drugs ([harmacogenomics)

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6
Q

mathematically describes fate of a drug with a specific dosing schedule, dosage form and route of administration

A

pharmacokinetics

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7
Q

how is pharmacokinetics useful?

A
  • Predict the effectiveness of different drugs/different dosage strategies
  • Predict blood levels in an individual under various conditions
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8
Q

main application of pharmacokinetics

A

to predict, monitor, and adjust drug regimens to optimize efficacy and safety

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9
Q

LADME

A

determines how rapid, in what concentration, and how long the drug takes to reach the target organ
liberation, absorption, distribution, metabolism, elimination

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10
Q

_______________ is a function of liberation and absorption

A

availability

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11
Q

the rate at which drug is absorbed into the body

A

availability
slope

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12
Q

rate of drug liberation depends on:

A
  • formulation (polymer layers, distribution in formulation)
  • dose (more is typically faster)
  • ionization state
  • environment pH
    ** last two helps w dissolving
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13
Q

factors influencing absorption

A
  • gastrointestinal factors = food, pH, perfusion, motility, SA, enzymes, microflora, permeability
  • physicochemical drug properties = solubility, charge, size, structure
  • transporters
  • route of administration
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14
Q

these molecules need help getting across lipid bilayers

A

large, charged molecules

  • small, neutral molecules freely diffuse!
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15
Q

slope =

A

availability

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16
Q

H-H equation

A

pH = pKa + log10 {[A-]/[HA]}

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17
Q

what does the H-H equation describe?

A

the propensity for a functional group to carry a proton at a specific environmental pH

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18
Q

H-H example: weak acid

A

aspirin (pKa = 3.5)

pH < pKa = not ionized
pH > pKa = ionized

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19
Q

H-H example: weak base

A

morphine (pKa = 7.9)

pH < pKa = ionized

pH > pKa = not ionized

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20
Q

T or F. In general, charged molecules are less readily absorbed than uncharged molecules, which can freely pass through lipid bilayers

A

T!

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21
Q

T or F. pH = pKa + log (proton donor/ proton acceptor)

A

F!
proton acceptor / proton donor*

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22
Q

this is the best indicator of total exposure to a dose of a pharmacological compound

A

AUC = area under the curve
bioavail

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23
Q

what is the bioavailability?

A

amount of drug dose that reaches circulation

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24
Q

how to calculate bioavailability if given oral dose and intravenous dose AUC

A

AUC alt route / AUC intravenous route

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25
Q

suppository pros

A
  • rapid absorption
  • bypasses first-pass metabolism = reduced side effects
  • local effects
  • improved compliance = ease of consumption
  • relatively safe (pediatric and geriatric use)
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26
Q

what is first pass metabolism

A

intestinal and liver metabolism reduce bioavailability of an orally administered drug prior to the drug reaching systemic circulation

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27
Q

when we want to calculate the amount of drug absorbed OR the amount of drug making it to circulation, these are considered:

A
  • bioavailability (F) factor: fraction of active dose that makes it to circulation
  • chemical (S) factor: fraction of formulation that is active form of the drug
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28
Q

effective dose formula

A

ED = F (bioavail factor) x dose admin (mg)

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29
Q

what does F=1 mean?

A

100% availability (intravenous!) therefore, extravascular or incomplete absorption is F<1

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30
Q

bioavailability vs availability

A

bioavail = only estimates extent and not the rate of absorption

avail = includes rate of absorption

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31
Q

what is the chemical factor

A

S
considers form of drug (salt or ester) and active ingredient

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32
Q

what is distribution?

A

the delivery of drug via circulation to extravascular fluids and tissues in the body (target receptor sites, eliminating organs)
- drug is equilibrating and partitioning into tissues

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33
Q

what is drug distribution influenced by?

A

size of organ
tissue perfusion (blood flow)
drug binding to plasma proteins/tissues
ability of drug to cross cell membrane (solubility)

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34
Q

what is Vd?

A

volume of distribution (L/kg)
- reflects extent of drug distribution
- size of compartment required to contain total mt of drug in body IF it were present throughout body in same conctn fund in plasma

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35
Q

Vd formula

A

Vd = total dose (A)/drug conctn (C) x weight (kg)

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36
Q

large Vd

A

extensive distribution to peripheral tissues
[tissue] > [plasma]

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37
Q

T or F. gentamicin is very water soluble

A

T! low Vd

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38
Q

warfarin Vd

A

binds to plasma albumin = small Vd

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39
Q

tricyclic antidepressants Vd

A

large
- lipid soluble and distribute to brain and fat

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40
Q

factors influencing Vd

A

drug solubility
- more water soluble = increased plasma conctn = decreased Vd

plasma protrein binding
- if patient had liver cirrhosis and produced less albumin - how would the Vd change for an albumin bound drug?
- decreased PPB = decreased plasma conctn = increased Vd

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41
Q

why is Vd important?

A
  1. determines whether dialysis of a drug is likely to be beneficial
  2. estimates body burden (amt) of drug
  3. calculates loading dose if drug
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42
Q

total body clearance

A
  • vol of plasma cleared of drug per unit time by processes of metabolism and excretion
    > does not indicate how much drug removed - merely the vol of plasma from which the drug removed
  • organism’s ability to eliminate drug
  • total body clearance = metabolic + non-metabolic clearance
  • influenced by blood flow and organ function
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43
Q

total body clearance formula

A

Vd x Kel

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44
Q

what is Kel?

A

derived experimentally
- plot of concentration vs time of elimination phase of AUC = slope is negative elimination constant

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45
Q

t1/2 =?

A

0.693/k

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46
Q

what is the drug elimination half life?

A

time required for the mt of drug in the body or its concentration to fall by 50%

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47
Q

t1/2 formula

A

[0.693 x Vd] / Cl

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48
Q

elimination half-life: what does it tell you?

A
  • time to steady state: how long do I need to take drug before I can perform TDM?
  • rate at which blod conctn falls after drug admin stops: how long do I have to wait to get rid of the drug/xenobiotic from by body?
  • estimate appropriate dosing interval: how frequently do I need to take the drug to keep my plasma conctns within the therapeutic range?
49
Q

rate in = rate out

A

steady state

50
Q

in practice, steady state is assumed to be reached in ___ half lives

A

5

51
Q

what is steady state influenced by?

A

drug half life
and
dose

** time to achieve steady state influenced by half-life and syteady state conctn determined by dose and frequency of dose **

52
Q

maintenance dose

A

amt of drug administered to maintain a desired steady state drug conctn in the body

53
Q

TDM candidates

A
  • narrow therapeutic range
  • clinically dangerous or difficult to interpret for over or underdoing
  • high biological variation
  • conctn proportional to clinical effect
  • avail of a standardized, reliable assay
  • conc changes with polypharmacy, inhibition, induction, diet
54
Q

how to properly perform TDM

A
  • drug should be at steady state
  • should be collected at a trough or peak for consistent eval
  • if drug too low/high = dose adjustments necessary = can use PK to approximate an appropriate initial dose or adjusted dose
55
Q

FIRST ORDER ELIMINATION

A
  • rate of drug clearance is proportional to drug conctn
  • fraction or % of total drug removed at any instant in time is constant
  • slope = -kel
56
Q

zero-order elimination

A
  • rate of drug clearance or amount of drug eliminated per unit time is CONSTANT regardless of drug conctn
    > constant amount of drug, instead of proportion is eliminated per unit time
  • drugs that saturate elimination mechanism (enzyme/transporter)
  • ex: alcohol, phenytoin, aspirin, etc.
57
Q

hepatic elimination of drugs

A
  1. cell dissocisyion (free drugu)
  2. protein dissociation
  3. hepatocyte uptake
  4. metabolism (into detergents or salts or conjugare to make more water-sol)
  5. biliary excretion
  6. bacteria hydrolysis
  7. enterohepatic re-circulation
58
Q

renal elimination of drugs

A
  1. passive glom filtration
  2. active proximal tubular secretion (OAT = weak acids; OCT = weak bases)
  3. passive distal tubular reabsorption (non-ionized)

non-volatile, water sol, low MW drugs

59
Q

factors affecting renal excretion

A

drug properties
plasma protein binding
fluid intake (flow)
urine pH
other drugs
kidney function

60
Q

T or F. Charged molecules are easier t clear

A

T!

61
Q

what alters pharmacokinetics?

A

lots!

body fat
intestinal permeability
renal funtion
organ perfusion, etc.

62
Q

how does bioavailability change between peds and geriatrics?

A

peds
- decreased gastric acidity
- prolonged gastric residence time
- slower intestinal motility
- decreased bile salts
- good absorption of pen, amp and digoxin
- poor absorption of phenobarbital, phenytoin, gabapentin
- poor transporter function
- increased skin permeability

gers
- delayed gastric emptying
- decreased absorption surface
- decreased GI motility

63
Q

how does distribution change between peds and geriatrics?

A

peds
- increased total bod water to body fat ratio = increased Vd for hydrophilic drugs
- decreased binding capacity of albumin
- decreased alb and alpha1 acid glycoprotein
- high bili displaces drugs

gers
- dec total body water to body fat ratio = decreased Vd for hydrophilic drugs
- decreased plasma protein binding increases free drug conctn in plasma

64
Q

how does clearance change between peds and geriatrics?

A

peds
- immature renal function
- unique metabolic pathways (theophylline => caffeine)
- immature liver function (CYP P450 and UT activity)

gers
- slight decline in renal function
- slight decline in hepatic function
- phase I metabolism (reduced or no change)
- no change in phase II

65
Q

these are often not considered by practitioners but may contribute significantly to therapeutic or adverse side effects

A

metabolites (of active drug)

66
Q

what are xenobiotics?

A

organic compounds that are foreign to the body such as drugs, industrial chemicals, pesticides, pollutants, alkaloids, and toxins produced by mold, plants, and animals

67
Q

most pharmacologically active molecules are ______________ and remain ___-________ or only partially at physiological pHH

A

lipophilic and non-ionized
> means that even after filtration in kidneys, can still be reabsorbed in the body

68
Q

a means of converting molecules into substances that are easily more excreted

A

drug metabolism

69
Q

biotransformation

A

the enzymatic transformation of molecules by fuctionalization (Phase I) and/or conjugation (II) rxns into molecules that are polar and water soluble

70
Q

phase I rxn

A

introduction, exposure or modification of specific chemical functional group
- ex: redox rxns

71
Q

phase II rxn

A

conjugation of small endogenous molecules (ex: glucuronic acid)
- makes something more water sol

72
Q

T or F. Water sol compounds of phase I rxns still require conjugation to be efficiently eliminated

A

T!

73
Q

T or F. Decreased polarity reduces tubular reabsorption in kidney = excretion of compounds

A

F! It is increasing polarity that results in reduced reabsorption ; decreased polarity = increased reabsorption

74
Q

what is the main goal of metabolism?

A

increase the hydrophilicity to dissolve xenobiotics in urine for efficient elimination

75
Q

acetaminophen toxicity

A
  • effect of metabolism = toxic components are the metabolites
  • CYP2E1 converts APAP to toxic free radical, NAPQI
  • NAPQI destroys liver cells unless conjugated with glutathione
  • depleted glutathione = damage
76
Q

the major organ responsible for biotransformation of xenobiotics

A

LIVER
but every tissue has ability to metabolize compounds

77
Q

major enzymes for biotransformation

A
  • cytosolic like acetyltransferase

OR

  • membrane-bound to ER like CYP enzymes and glucuronosyltransferase
78
Q

examples of phase I rxns

A

oxidation
- cytochrome P450 or CYP enzyme system
- alc dehydrogenase and aldehyde oxidase
- N- and S-oxidation

reduction (aldehydes to primary alcohols)

  • hydrolysis (esterases, amidases)
79
Q

examples of phase II rxns

A

glucuronidation
sulphation
acetylation
methylation
glycine conjugation
glutamine “
glutathione “

most increase water sol of xenobiotic

80
Q

effects of benzodiazepines

A

anxiolytic, sedative, and anticonvulsant properties
“-ams”

81
Q

compared to tertiary amine, 2ry amines more potent inhibitors of ____________ reuptake and less potent inhibitors of reuptake of __________ into nerve terminals

A

noradrenaline; serotonin

82
Q

the 2ry and 3ry amine tricyclics also differ markedly in their ability to block ___________, ____________, and _-___________ receptors

A

histaminergic, muscarinis, alpha-adrenergic

> so side effects associated w blockade of these receptors differ

83
Q

hydroxy metabolites important with respect to ________________

A

cardiotoxicity

84
Q

2ry amines examples

A

desipramine
nortriptyline

85
Q

3ry amines

A

imipramine
amitriptyline

86
Q

T or F. SSRIs are safer than Tricyclic antidepressants

A

T! don’t matter if been metabolized into other forms

87
Q

SSRIs (PK/PD)

A
  • fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil)
  • inhibit reuptake of serotonin from nerve terminals
    unlike metabolites of tertiary amine tricyclics, metabolites of SSRIs also selectively inhibit the reuptake of serotonin (and/or are very weak noradrenaline reuptake inhibitors)
88
Q

CYP enzyme system components

A

hemoprotein
flavoprotein
heat stable, lipid component

89
Q

CYP Enzyme system: hemoprotein

A
  • iron protoporphyrin IX = heme group
  • serves as substrate and O2 binding site of enzyme system in which heme iron underoes cyclic REDOX that is mandatory for catalytic function
    > terminal oxidase component of electron transfer system present in ER
90
Q

CYP Enzyme system:flavoprotein

A

NADPH-cytochrome P450 reductase; NADPH-cytochrome c reductase
- acts as electron carrier shuttling electrons from NADPH to CYP substrate complex
- binds to cofactor NADPH

91
Q

CYP Enzyme System: heat-stable, lipid component

A
  • may be needed for substrate binding, facilitation of electron transfer or providing a template for the interaction of CYP and NADPH-cytochrome P450 reductase molecules
  • HOLDS everything where it’s supposed to be positioned in space
92
Q

CYP 450 (11)

A

steroid 11 B-hydroxylase

93
Q

CYP 450 (17)

A

steroid 17 a-hydroxylase

94
Q

CYP 450 (21)

A

steroid 21-hydroxylase

95
Q

nomenclature of CYP genes

A

CYP with arabic number = family

letter after is the subfamily

arabic number after = individual gene

corresponding gene products - mRNA, cDNA and enzyme are not italicized

96
Q

variations in drug metabolism can be divided into 4 categories

A
  1. host factors: diet and disease states
  2. genetics
  3. enzyme induction by exposure of CYP enzymes to drugs, endogenous compounds o environmental agents
  4. inhibition of CYP enzymes by drugs, endougeous compounds or environmental agents
97
Q

T or F. Host factors may inihibit or induce CYP mediated metabolism depending on dietary items and diseases processes in question.

A

T

98
Q

Brassica veg

A

increases CYP 1A2
- brocolli, cauliflower, etc.

99
Q

Apiaceous vegs

A

decrease CYP1A2 activity
- carrots, celery, etc.

100
Q

grapefruit juice

A

inhibits CYP3A4 activity

101
Q

what does aging do to CYP enzymes?

A

slight decrease in some oxidation rxns catalyzed by them

102
Q

grapefruit juice can inhibit ________, mustards can induce _________.

A

CYP3A4 and CYP1A2

103
Q

the study of genetically determined variation in drug metabolism

A

pharmacogenetics

104
Q

what is pharmacogenomics?

A

customization of dosing to match a patient’s specific genetic profile

105
Q

mutations that occur in at least 1% of population

A

polymorphisms

106
Q

many polymorphisms are functionally significant, often resulting in:

A

decreased activity
increased activity
no activity
no change in activity

107
Q

extensive metabolizer

A
  • wild type
  • person who metabolizes a probe drug at a rate similar to that of most of the popln
108
Q

poor metabolizer

A

person who metabolizes a probe drug at a rate slower than most of the population

consequence: lack of response due to inability to convert prodrug to its active form (codeine to morphine) or it may result in excessively high levels of the parent drug such that toxic side effects develop

109
Q

ultra-rapid metabolizer

A

person who metabolizes a drug more rapidly than most of the popln due to presence of multiple copies of CYP2D6 genes

consequence: these people fail to respond to conventional doses of drugs; they may be suspected of non-compliance when in fact they require very high doses to achieve therapeutic effects

110
Q

how do we determine whether patients are PMs, EMs, and URMs

A

genotyping (predict the optimal dose using genetic info) and phenotyping (predict dose using metabolite/parent drug ratio in urine)

111
Q

where is CYP2D6 expressed?

A

liver, intestine, kidney, brain

112
Q

this metabolizes ~30% of drugs currently in clinical use

A

CYP2D6

113
Q

substrates of CYP2D6

A

codeine
amitriptyline
Fluoxetine (Prozac)
Paroxetine (Paxil)

114
Q

T or F. CYP2C92 and CYP2C93 show reduced rates of metabolism toward substrates compared to CYP2C9*1

A

T

115
Q

how is warfarin administered?

A

as a recemate (S-isomer = 5X more potent than R as anticoag)

116
Q

R-warfarin is metabolized by….

A

CYP1A2, 2C19, and 3A4

117
Q

S-warfarin metabolized by…

A

CYP2C9

118
Q

what is enzyme induction?

A
  • occurs through action of drugsm endogenous compounds or environmental agents
  • can increase CYP enzyme expression by increasing synthesis, decreasing degradation, activating pre-existing components of metabolic system
  • lowers blood levels of parent drug (parent is metabolized more quickly than usual)
  • lowers blood levels of parent drug (parent metabolized more quickly than usual)
119
Q
A

MLSCI 466 (19 decks)

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