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Pharma midterm 1 > Lecture 3 - ADME > Flashcards

Lecture 3 - ADME Flashcards

Pharmacokinetics

1
Q

What does pharmacon mean?

A

drug

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2
Q

what does kinetikos mean?

A

putting in motion

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3
Q

what is pharmacokinetics?

A

it is a branch of pharmacology that is dedicated to the determination of the fate of substances administered externally to a living organism

we talk about how the drug is deposited in the body but the term concenerns all compounds digested or delivered externally to an organism - nutrients, metabolites, hormones, toxins

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4
Q

What areas are pharmacokinetic divided into?

A

ADME

absorption

distribution

metabolism

excretion

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5
Q

What are the classifications of drug passages?

A
  1. transcellular transport
  2. intercellular transport
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6
Q

Explain the way transcellular transport works

A

it is the most significant

it means the drug goes across cell-membranes, layers or pores

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7
Q

what are the different ways a drug can move transcellularly?

A

Diffusion

  • passive - majority
  • free

filtration

facilitated diffusion

active transport

pinocytosis

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8
Q

Explain how the intercellular transport is functioning

A

across the gaps or intracellular channels

between the endothelial and epithelial cells

  • filtration
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9
Q

What is meant by semipermeable membrane?

A

membrane that allows certain molecules or ions to pass through it by diffusion or occasionally specialized facilitated diffusion

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10
Q

Give an example of an semi-permeable membrane

A

lipid bilayer

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11
Q

what is the rate of passage through a semipermeable membrane dependent upon?

A
  • pressure
  • concentration
  • temperature of the molecules or solutes on either side
  • permeability of the membrane to each solute
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12
Q

what features concerning the membrane or the solute will determine the passage of a solute by affecting the permeability?

A
  • solute size
  • solubility properties
  • chemistry
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13
Q

what is an example of a natural material that is thicker than a membrane but still is semipermeable?

A

thin film on the inside of an egg

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14
Q

Describe the arrangement of the semipermeable membrane:

phospholipid bilayer

A

a group of phospholipids - phospahte head + 2 fatty acid-tails

double layer

outside: hydrophilic phosphate head exposed to water
inside: hydrophobic fatty-acid tails

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15
Q

what solutes can most easily pass a phospolipid bilayer?

A

small, uncharged solutes

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16
Q

what is the fluid mosaic model?

A

the combination of the phospholipid bilayer and protein channels that float through the phospholipids

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17
Q

What way of semipermeable transport is the most common?

A

diffusion

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18
Q

What may influence the diffusion?

A

the lipid-water partition coefficient of the drug

concentration gradient of the drug across the cell membrane

the thickness of cell membrane

surface area of cell membrane

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19
Q

what is the lipid-water partition coefficient of a drug?

A

the ratio of solubility in an organic solvent to solubility in an aqueous solution

absorption increases as lipid solubility increases

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20
Q

In what state can drugs diffuse across biological membranes?

A

un-ionized

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21
Q

what is the degree of ionization of a weak acid or base determined by?

A

the pK of the drug and pH of its environment according to the Henderson-hasselbach equation

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22
Q

How is the henderson-hasselbch equation for a weak base?

A
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23
Q

When do we have equal numbers of ionized and un-ionized species (drugs)

A

when the pK of a drug equals the pH of the surroundings

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24
Q

what does a low pK indicate?

A

stronger acid

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25
Q

What does a low pK indicate?

A

a strong base

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26
Q

How will drugs with different pK values move?

A

they will diffuse across membranes at different rates

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27
Q

How does the pH of the biological fluid influence the drug?

A

the degree of ionization and therefor the rate of the drug transport

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28
Q

What is filtration?

A

the bulk flow of solvent and solute throough protein channels in the membranes

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29
Q

what molecules are usually filtrated?

A

smaller ones, molecular weight less than 100

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30
Q

what affects the rate of filtration?

A

the concentration gradients

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31
Q

what is facilitated diffusion? and what are the properties of it

A

the movement of a substance down a concentration gradient

it is carrier mediadet, specific and saturable

does not require energy

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32
Q

What is active transport? its properties

A

energy dependent process that can move drugs against a concentration gradient

protein mediated transport systems

occurs only in one direction

saturable

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33
Q

what drugs are usually activly transported?

A

drugs that resemble actively transported endogenous substances

sugars, amino acids and nucleosides

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34
Q

what is meant by absorption in pharmacology?

A

the movement of a drug into the blood stream (not IV)

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35
Q

What must happen before the drug can be absorbed

A

it needs to be administered: oral, skin, in a spesific dosage form

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36
Q

What happens with absoprtion in case if intraperitoneal, intramuscular injections, parenteral nutririon and others?

A

the absorption is straight forward, less variability in absorption, bioavailability is often near 100%

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37
Q

How is the drug, most oftenly, getting into the bloodstream?

A

through the mucous surface of the digestive tract

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38
Q

when the drug gets into the blood stream, it should also be able for the target organ or cell to take it up, what factors may influence this and cause the reduce of the extent to which a drug is absorbed after administration?

A

some natural barriers causes problems: BBB, placenta

poor compound solubility

chemical instability in the stomach

inability to permeate the intestinal wall

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39
Q

what determines the compunds bioavailability?

A

absorption

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40
Q

what is the bioavailability of a drug?

A

the fraction of the drug that reaches the bloodstream unaltered

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41
Q

what administration method of drugs have highest bioavialbility?

A

intravenously administration

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42
Q

what does the absolute bioavailability measure?

A

the availability of the active drug in the systemic circulation after non-intravenous administration

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43
Q

How is the bioavailability determined?

A

pharmacokinetic study

plasma drug concentration vs time plot under the curve for the drug after both intravenous and non-intravenous administration

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44
Q

how do we calculate the bioavailability?

A

it is the dose-corrected area under the curve non-intravenous divided by AUC intravenous

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45
Q

what is the relative bioavailability?

A

the bioavailability of a certain drug when it is compared with another formulation of the same drug

usually the have an established standars, but administered via a different route

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46
Q

How do we classify the routes of administration?

A

topical/external

internal

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47
Q

Where are drugs applied when they are applied topically or externally?

A

on the skin

mucous membranes, eye, nose, mouth, rectum

the blood should not absorb too much - defects - antiparasitic

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48
Q

how are drugs applied when theya re applied internal?

A
  • enteral :oral. rectal
  • oro-naso-gastric
  • intra-ruminal
  • intra-abomasal
    parenteral: injectable drugs, IV, SC, IM = most frequent
  • intradermal, peritoneal, arterial,pleural.medullar. cerebral, epidural, retrobulbbar, lingual = less frequent
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49
Q

what are some special routes for veterinary applications?

A

intramammary application

intrauterin infusion

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50
Q

which administration is the most convenient, economical and common route of administration?

A

oral

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51
Q

what are the sites of absorption for orally administered drugs?

A

stomach

small intestine

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52
Q

what drugs are absorbed directly from the stomach?

A

lipid-soluble drugs and weak acids

un-ionized at low pH of gastric content

53
Q

why are not weak bases and strong acids absorbed from the stomach?

A

they are usually protonated at the pH of the gastric content - iontrapping

54
Q

why is the small intestines the primary site of absorption of most drugs?

A

very large surface area where the drugs, including the partially ionized weak acids and bases may diffuse

55
Q

is acids mostly absorbed from the stomach or the small intestines?

A

even though the intestines have a higher pH they are nromally absorbed here

56
Q

what is the key target for controlling the duration of the drugs effect?

A

the rate of dissolution

57
Q

How can a drug be released more gradually over time with a longer duration of action?

A

when it is supplied in a form that is nor readily dissolved

58
Q

what are the advantages of slow release dosage forms?

A
59
Q

What equation describes the rate of dissolution?

A

Noyes-Whitney equation

60
Q

What are some factors that may alter the time and passage of drug to the intestines?

A
  • gastric content
  • intestinal motility
  • decreased emptying time
61
Q

How is the gastrointestinal blood flow playing a role in the drug absorption?

A

it will continously maintain the concentration gradient across the epithelial membrnaes

small very lipid soluble molecules: blood flow limited absorption

highly polar molecules are: blood flow independent

62
Q

Why is enteric coating useful?

A

it will prevent the stomach acid and inactivating enzymes to destru certian drugs, prevent the breakdown by the acid pH

63
Q

what is the first-pass effect and how does it influence the affect by the drug?

A
  • it is the metabolism of the liver or the bilary secretion which will alter the absorption of the drug.
  • The drug needs to pass through the liver before reaching the general circulation and its target size
64
Q

The pH, membrane, blood supply, surface area, transient time and liver-bypass

Buccal

A

The pH: 7
membrane: thin

blood supply: good, fast absorption w/low dose

surface area:small

transient time: short unless controlled

liver-bypass:yes

65
Q

The pH, membrane, blood supply, surface area, transient time and liver-bypass

esophagus

A

The pH: 5-6

membrane:very thick

blood supply: good, fast absorption w/low dose

surface area:small

transient time: short

liver-bypass: yes

66
Q

The pH, membrane, blood supply, surface area, transient time and liver-bypass

stomach

A

The pH: 1-3

membrane: normal

blood supply: good

surface area: small

transient time: 30-40min

liver-bypass: no

67
Q

The pH, membrane, blood supply, surface area and liver-bypass

duodenum

A

The pH: decompositing weak acid,

membrane: normal

blood supply: good

surface area: very large

liver-bypass: no

68
Q

The pH, membrane, blood supply, surface area, transient time and liver-bypass

small intestine

A

The pH: 6-6,5

membrane: normal

blood supply:good

surface area: very large

transient time: 80 cm

liver-bypass: no

69
Q

The pH, membrane, blood supply, surface area, transient time and liver-bypass

large intestine

A

The pH:surfacant

membrane: normal

blood supply: good

surface area: not very large, 4-5ft

liver-bypass: no

70
Q

What are the three major routes for parenteral administration?

A

intravenous

intramuscular

subcutaneous

71
Q

What are the general considerations for parenteral administration?

A
  • more predictable bioavailability than oral administration
  • Iv - directly into blood stream - no absorption - 100% bioavailability
  • usefull in emergencies
  • IM and SC administrated drugs, can ften enter the capillaries directly through pores between endothelial cells
  • depot preparations for sustained release may be administered by IM or SC routes, but some preparations may cause irritation and pain
72
Q

What is the advantages of inhalation route and what drugs are used?

A

rapid absorption becuase of the large surface area and rich blood supply of the alveoli

gaseous anasthetics

epinephrine, glucocorticoids

73
Q

when is intrathecal administration used?

A

for drugs that not readily crosses the BBB

injection into the spinal canal

74
Q

when is sublingual injections used?

A

useful for drugs with high first pass metabolism -nitroglycerin

bypasses the hepatic metabolism

75
Q

when is rectal administration used?

A

used to prevent nausea and vomiting that is common with oral administration

minimizes first-pass metabolism

76
Q

When is topical administration used?

A

ehn local effect is desired

minimize the systemic effect - dermatology, opthalmology

non-irritating preparations is essential

may cause systemic effects

77
Q

What does distribution describe?

A

the reversible transfer of drug from one location to another within the body

the process by which a drug leaves the bloodstream and enter the extracellular fluids and tissues

movement of a drug from the bloodstream to the various tissues of the body

78
Q

what is the distribution of a drug between tissues dependent on?

A
  • permeability between tissues (blood and tissues oftenly)
  • blood flow and perfusion rate of the tissue
  • the ability of the drug to bind plasma proteins and tissue
79
Q

what is the volume of distribution describing?

A

it is a property that quantifies the extent of distribution

80
Q

What is the ratio of body fluids?

A

ICF: 40% (24liter)

IF: 16% (9,6l)

plasma: 4% (2,4l)

81
Q

What is an important quality for the drug to diffuse effectivly acrosscellular membranes?

A

the lipid solubility

82
Q

what tissues have the fastes initial rate of distribution and the lowest?

A

brain, liver, kidney > muscle, skin > fat, bone

83
Q

what is the amount of drug in an organ related to ?

A

the mass of the organ and its porperties

properties of the specific drug

84
Q

what is meant by drug redistribution?

A

it describes when the relative distribution of a drug in the body changes with time

85
Q

When is drug redistribution sually seen?

A

highly lipophilic drugs - thiopental

they initially enter the tissues with high blood flow and quickly redistribute to tissues with lower blood flow

86
Q

How can you find the drug in the plasma?

A

either in free form or bound to plasma proteins or bound to other blood somponents (RBC)

87
Q

How is the extent of plasma protein binding drug?

A

highly variable

ranges from 0%-99% bound

depends on the drug

88
Q

is the bond between the plasma proteins reversible?

A

yes

89
Q

can protein bound drugs pass through capillary walls?

A

no

90
Q

what is the consequences of drugs binding to proteins in terms of duration?

A

extensive binding retards the rate at which the drug reaches its site of action and may prolong duration of action

91
Q

What proteins binds acidic drugs?

A

serum albumins

92
Q

Which proteins binds basic drugs?

A

alpha-acid - glycoprotein and globulins

93
Q

Give some examples of drugs that binds to albumins

A

bilirubin

bile acids

fatty acids

vitamin c

salicylates

sulfonamides

barbiturates

phenylbutazone

penicillins

tetracyclines

probenecid

94
Q

Give some examples of drugs that would bind to globulins

A

adenisine

quinacrine

quinine

streptomycin

chloramphenicol

digitoxin

ouabain

coumarin

95
Q

name two special transporters

A

corticosteroid-binding globulin - CBG, transcortin

thyroxine-binding globulin - TBG

96
Q

What are two important barriers to drug distribution

A

BBB and the placental barrier

97
Q

what types of drugs passes the BBB poorly?

A

ionized or polar drugs

98
Q

How will inflammation effect the to the passage of drugs through BBB?

A

menginits may increase the ability of ionized, poorly soluble drugs to cross

99
Q

when is the BBB not working properly, physiologcaly?

A

at time of birth

100
Q

which drugs can cross the placental barrier more easily?

A

lipid-soluble drugs, and with a molecular weigh with less than 600Da

101
Q

what drug transporters transfers drugs out of the foetus?

A

P-glycoprotein transporters

102
Q

what is meant by volume of distribution?

A

The volume of distribution is useful in estimating the dose required to achieve a given plasma concentration

103
Q

how is volume of distribution determined?

A

by administering a known dose of drug intravenously and then measuring the initial plasma concentration

104
Q

what are the standard values of volumes of fluid compartments in average (plasma, ECF, Total body water)

in an adult 70kg

A

plasma - 3l

ECF - 12l

TBW - 41l

105
Q

what are the standard values of volumes of fluid compartments in average (plasma, ECF, Total body water)

ina 20kg dog

A

plasma - 0,085l

ECF - 3,5l

TBW - 11,7l

106
Q

What can a very low Vd value indicate?

A

extensive plasma protein binding of the drug

107
Q

what can a very high Vd value indicate?

A

that the drug is extensivly bound to tissue sites

108
Q

How are compounds and their metabolites excreted from the body?

A

through the kidneys or in the faeces

109
Q

List allt he diffrent routes of excretion

A

urine

faeces

saliva

sweat

tears

milk

lungs - alcholos and anasthetics

110
Q

What can happen if the drugs are excreted by the liver into the bile?

A

they might get eliminated through the faeces or reabsorbed from the intestine - prolonged persistence

111
Q

What is the net renal excretion?

A

the result of three separate processes

  • amount of drugs filtrated at the glomerulus
  • amount of drug secreted by active transport mechanisms in the kidney
  • amount of drug passively reabsorbed throughout the tubule
112
Q

What drugs are filtrated at det glomerulus?

A

most drugs of low molecular weight are freely filtrated

serum protein binding drugs will not be filtrated

113
Q

how is the glomerular filtration rate in newborns first year of life?

A

30-40% lower

114
Q

in the kidney, there are two transport systems in the proximal tubule that can secrete drugs into the ultrafiltrate. What are these transporting?

A

one is for organic acids

second for organic bases

115
Q

why are these transport systems in the prox.tubule a site for potential drug-drug interactions?

A

becuase drugs may compete with eachother for binding to the transporters

116
Q

Where does reabsorption occur?

A

throughout the tubule

117
Q

How is un-ionized drugs that are weak acids and bases reabsorbed?

A
  • simple passive diffusion
  • the rate is dependent upon the lipid solubility and pK of drug
  • concnetration gradient of the drug between urine and plasma
118
Q

what can affect the reabsorption?

A

the urinary pH

also effects the elimination of weak acids or bases

119
Q

What does renal clearance measure?

A

the volume of plasma that is cleared of drug per unit time

120
Q

what will the glomerular filtration rate be if a drug is excreted by filtration alone?

A

an equal clearance

121
Q

What will a drug that is excreted by filtration and complete secretion have clearance equal to?

A

renal plasma clearance

122
Q

what clearance values shows us that a drug has been

filtrated, secreted and partially reabsorbed

A

130 and 650 ml/min

123
Q

What factors influence the renal clearance?

A

age

other drugs

disease

124
Q

what happens in case of renal failure, excretion

A

clearance is reduced significantly - higher plasma levels

125
Q

What is the excretion ratio in the liver?

A

amount of drug removed in the liver divided by the amount of drug entering the organ

126
Q

What will the hepatic clearance be if a drug is highly extracted?

A

1500ml/min

127
Q

What is the first-pass effect?

A

drugs taken orally pass across the membranes of the GI tract into the protal vein and through the liver before entering the general circulation

128
Q

What is important to think of when administering a drug into an animal with hepatic diseases?

A

if they have a high first pass extraction, it might reach te cystemic circulation in higher than normal amounts - dose adjustment is needed

129
Q
A

Pharma midterm 1 (14 decks)

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