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CH 456 Medicinal Chemistry > Chapter 11: Pharmacokinetics and Related Topics > Flashcards

Chapter 11: Pharmacokinetics and Related Topics Flashcards

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1
Q

What are the three phases involved in drug action?

A

pharmaceutical phase
pharmacokinetic phase
pharmacodynamic phase

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2
Q

_____ phase for an orally administered drug, this includes the disintegration of a pill or capsule in the gastrointestinal tract (GIT), the release of the drug and its dissolution

A

pharmaceutical

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3
Q

_____ phase includes absorption from the GIT into the blood supply and the various factors that affect a drug’s survival and progress as it travels to its molecular target

A

pharmacokinetic

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4
Q

______ phase involves the mechanism by which a drug interacts with its molecular target and the resulting pharmacological effect

A

pharmacodynamic

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5
Q

What are the four main topics of pharmacokinetics?

A

absorption, distribution, metabolism and excretion

often abbreviated to ADME

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6
Q

_____ are the basic unit of a biological system

A

Cells

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7
Q

____ are collections of cells with a common function

A

Tissues

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8
Q

____ are multiple tissue types that have a common role

A

Organs

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9
Q

_____ are the highest level of organization

A

Organ systems

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10
Q

What are the 5 systems?

A

Circulatory, digestive, nervous, skeletal, urinary

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11
Q

True or False: All drugs must be introduced into the body by some method

A

True

called route of administration (ROA) or route of delivery

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12
Q

What are the 3 different drug delivery methods?

A

enteral, parenteral, topical

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13
Q

_____ delivery method is entry into bloodstream by a route other than the digestive system

A

parenteral

-includes intravenous (IV), intramuscular (IM) and subcutaneous (SC)

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14
Q

_____ delivery method is absorption through the digestive system

A

enteral

includes oral (PO) and rectal delivery

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15
Q

_____ delivery method is applied directly to site of action

A

Topical

includes auricular (ear), conjunctival (eye) and cutaneous (skin)

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16
Q

What is the route of orally administered drugs (5 steps)?

A

mouth, throat, stomach and upper and lower intestines (could be absorbed by mucosal membrane in mouth)

most enters stomach containing digestive juices and HCl (pH 1-3)

if drug survives, it enters upper intestine containing digestive enzymes

has to pass through cells lining the intestines

relatively easy for drug to enter capillaries

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17
Q

When is drug is passed through the intestines, it crosses the ____ membrane from intestinal lumen to cell interior then the cross ______ membrane from cell interior to capillary bed.

A

Apical, Basal

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18
Q

The ______ contains enzymes that are ready and waiting to intercept foreign chemicals and modify them such that they are more easily excreted. This process is called ______.

A

Liver, drug metabolism

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19
Q

______ is preferred method of drug delivery

A

Oral

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20
Q

Why can asprin, ASA be absorbed in the stomach?

A

has pKa of about 3.5

therefore mostly neutral in stomach and can be absorbed

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21
Q

What are the 3 reasons why the presence of food greatly influences rate of drug absorption?

A

increases the volume of the stomach

raises pH in stomach

slows drug passage into small intestine

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22
Q

What type of digestion occurs in the small intestine?

A

primarily with enzymatic digestion of proteins and fats

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23
Q

True or False: PH and length decreases as you go down the small intestine.

A

False, both increase

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24
Q

_____ have a large surface area they present allows for rapid absorption of digestion products.

A

Villi

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25
Q

What are the 4 advantages of small intestine absorption over stomach absorption

A

food is more digested, retains less drug

drug spends much greater time in small intestine

higher pH of small intestine more favourable for drug absorption

has a large surface area due to folds, villi and microvilli

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26
Q

What is the effect of grapefruit juice on certain drugs?

A

can increase amount of drug that reached the circulation

effect due to bergamottin, a coumarin derivative, in the juice
potent inhibitor of cytochrome P-450 3A4 (CYP3A4)
reduces metabolism of the drug before it enters circulation (first pass

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27
Q

drugs absorbed from stomach and small intestine enter the ______ system. It collects blood from the stomach, small intestine, large intestine, spleen and pancreas and delivers it to the liver, from there can enter the general circulatory system.

A

Hepatic portal

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28
Q

_____ acts as a protective system against xenobiotics

A

Liver

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29
Q

first pass metabolism leads to ______ bioavailability.

A

Low

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30
Q

True or False: Drugs can still be absorbed through the large intestine.

A

False, drugs are usually absorbed before they reach large intestine, if drug is found in feces it can indicate poor absorption

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31
Q

What is the simplified 4 step pathway of oral drugs.

A

Tablet disintegrates and is released in stomach

Drug absorbed through SI and transported via portal vein to liver

Liver breaks down active ingredient before it reaches the heart

Heart pumps blood with remainder of active ingredient

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32
Q

For efficient absorption in the GIT you need the correct balance of _______.

A

of hydrophobicity (i.e., fat vs. water solubility)

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33
Q

too polar (_______) will not pass through membrane and too fatty (______) – poorly soluble in gut (fat globules)

A

hydrophilic, hydrophobic

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34
Q

What is the pharmacokinetic advantage of drugs having amine functional groups?

A

They are weak bases and are in equilibrium between the ionized and free base forms

Slightly acidic in upper intestine and slightly alkaline in blood

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35
Q

______ was used to determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans

A

Lipinski’s rule of five

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36
Q

What is the criteria for Lipinski’s rule?

A

an orally active drug has no more than one violation of the following criteria:

a molecular weight less than 500 Daltons

not more than 5 hydrogen bond donors (HBD) (nitrogen or oxygen atoms with one or more hydrogen atoms)

not more than 10 hydrogen bond acceptors (HBA)
(nitrogen or oxygen atoms)

an octanol-water partition coefficient log P of less than +5

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37
Q

True or False: compounds with good oral bioavailability tend to have more molecular flexibility, as measured by the number of freely rotatable bonds

A

False, compounds with good oral bioavailability tend to have reduced molecular flexibility

65% of fairly rigid compounds in the collection (those with seven or fewer rotatable bonds) exhibited good-to-excellent oral bioavailability, independent of molecular weight

more than 75% of floppy compounds (those with more than 10 rotatable bonds) had poor oral bioavailability

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38
Q

True or False: Drugs entering the blood supply are evenly distributed round the blood supply within one minute, but are unevenly distributed to different organs.

A

True

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39
Q

True or False: Drugs have to leave blood supply to reach target organs and tissues

A

True

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40
Q

body has an estimated 10^10 capillaries with surface area of ____ m^2

no cell is more than ______ μm away from a capillary

capillaries have pores that are ______ nm in diameter that allow most drugs to escape but retains plasma proteins

A

200, 20-30, 9 – 15

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41
Q

Drugs such as local anaesthetics, enzyme inhibitors and drugs which act on nucleic acids or intracellular receptors need to enter the individual cells of tissues. Therefore, drugs must be ______ enough to pass through the cell membrane unless they are smuggled through by carrier proteins or taken in by pinocytosis

A

Hydrophobic

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42
Q

What are 3 other distribution factors involved with drug distribution to cells?

A

excessively hydrophobic drugs absorbed by fatty tissues

ionized drugs may be bound to macromolecules

may be bound to blood 
plasma proteins (e.g., serum albumin)
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43
Q

Why is it hard for drugs to cross the blood brain barrier (2 reasons)

A

the blood capillaries feeding the brain are lined with tight-fitting cells that do not contain pores

the capillaries are also coated with a fatty layer formed from nearby cells, providing an extra fatty barrier through which drugs have to cross

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44
Q

True or False: In order to cross the blood brain barrier, drugs must have a minimum number of polar groups or have these groups masked temporarily (prodrug)

A

True

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45
Q

What drug crosses the blood brain barrier with the aid of a carrier protein?

A

Insulin

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46
Q

What is lipinski’s rule of 5 for CNS drugs?

A

Molecular weight (Da) less than 400

Hydrophobicity (logP)
not greater then 5

Hydrogen bond donors (HBD)
not more than 3

Hydrogen bond acceptors (HBA)
not more than 7

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47
Q

_____ drugs will cross the placental barrier most easily

A

Fat soluble

drugs such as barbiturates will reach the same levels in fetal blood as in maternal blood

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48
Q

True or False: Orally taken drugs must be sufficiently polar to dissolve in the GIT and blood supply, but sufficiently fatty to pass through cell membranes.

A

True

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49
Q

Most orally taken drugs obey Lipinski’s rule of five and have no more than _____ rotatable bonds.

A

7

50
Q

True or False: Highly polar drugs can be orally active if they are small enough to pass between the cells of the gut wall, are recognized by carrier proteins or are taken across the gut wall by pinocytosis.

A

True

51
Q

Distribution to the interstitial fluid surrounding tissues and organs is rapid if what?

A

if the drug is not bound to plasma proteins

52
Q

Most drugs undergo some form of metabolic reaction, resulting in structures known as _______.

A

Metabolites

53
Q

True or False: Metabolites may have no effect, more active affect, or a different effect from the parent drug

A

True

54
Q

True or False: A single drug is usually metabolized by multiple enzymes

A

True, some reactions faster than others, some reactions are reversible or can be reversed by another enzyme

55
Q

The metabolite most important for elimination of a drug depends on?

A

the rate and reversibility of each step

56
Q

Phase I reactions include _____ and phase II reactions include ______.

A

oxidation, reduction and hydrolysis

conjugation

57
Q

Phase ______ add fragments to the original drug in a process called including acetylation, sulfonylation, glucuronidation, conjugation with amino acids and conjugation with glutathione

A

II

58
Q

Phase _____ usually fragment the drug into smaller molecules that are eliminated more easily.

A

I

59
Q

True or False: newly appended fragments form a metabolite with increased polarity for improved clearance

A

True

60
Q

How can phase I and phase II reactions work together?

A

products of phase I reactions contain functional groups such as carboxylic acids, alcohols and amines

these functional groups may serve as handles for attachment of polar fragments during phase II metabolism

61
Q

True or False: many drugs are metabolized by only phase I or only phase II processes

A

True

62
Q

What type of reactions are catalyzed by cytochrome P450 enzymes?

A

Oxidation (therefore phase I)

63
Q

reactions catalyzed by cytochrome P450 enzymes can involve the oxidation of ______, ______, ______, ______ and other atoms

A

carbon, nitrogen, phosphorus, sulphur

64
Q

_______enzymes are chiefly responsible for metabolic reactions involving oxidation at nucleophilic nitrogen, sulphur and phosphorus atoms, rather than at carbon atoms

A

Flavin-containing monooxygenases

65
Q

True or False: monoamine oxidases are involved in the deamination of catecholamines

A

True

66
Q

other important oxidative enzymes include ______ and ______.

A

alcohol dehydrogenases and aldehyde dehydrogenases

67
Q

reductive phase I reactions are less common than oxidative reactions, but reductions of ______, ______, ______, and ______ functional groups have been observed in specific drugs.

A

aldehyde, ketone, azo and nitro

68
Q

hydrolysis of _____and _____ is a common metabolic reaction, catalyzed by esterases and peptidases, respectively

A

Esters and amides

69
Q

Most phase II reactions are conjugation reactions catalyzed by ______ enzymes

A

Transferase

usually results are inactive, but there are exceptions

70
Q

True or False: Glucuronic acid conjugation is excreted in the urine, but may also be excreted in the bile if the molecular weight is over 300

A

True

71
Q

_____-glucuronides by reaction with UDFP‑glucuronate such that a highly polar glucuronic acid molecule is attached to the drug

sulphonamides, amides, amines and thiols can react to form ____‑ or _____‑glucuronides

_____-glucuronides are also possible in situations where there is an activated carbon centre next to carbonyl groups

A

O

N or S

C

72
Q

Sulphate conjugation is less common than glucuronation and is restricted mainly to ______, ______, _______, and _______.

A

phenols, alcohols, arylamines and N-hydroxy compounds

73
Q

primary and secondary amines, secondary alcohols and phenols form ______ conjugates, whereas primary alcohols form ______ sulphates, which can act as toxic alkylating agents

A

stable, unstable

74
Q

aromatic _______ and ______ also form unstable sulphate conjugates that can be toxic

A

hydroxylamines and hydroxylamides

75
Q

In amino acid conjugation, drugs bearing a ______ group can become conjugated to amino acids by the formation of a peptide bond

A

carboxylic acid

76
Q

in most animals, ______ conjugates are generally formed, but _______ is the most common amino acid used for conjugation in primates

A

glycine, glutamine

77
Q

electrophilic functional groups, such as epoxides, alkyl halides, sulphonates, disulphides and radical species, can react with the nucleophilic thiol group of the tripeptide glutathione (Glu-Cys-Gly) to give _______, which can be subsequently transformed to mercapturic acids

A

glutathione conjugates

78
Q

the glutathione conjugation reaction can take place in most cells, especially those in the ____ and _____, and is catalyzed by _______.

A

Liver, kidney, glutathione transferase

79
Q

______ is important in detoxifying potentially dangerous environmental toxins or electrophilic alkylating agents formed by phase I reactions

A

Glutathione conjugation

80
Q

glutathione conjugates are often excreted in the _____, but are more usually converted to _______ conjugates before excretion

A

bile, mercapturic acid

81
Q

Methylation and acetylation are important phase II reactions that ______ drug polarity

A

decrease

82
Q

True or False: An ideal drug should be resistant to drug metabolism

A

True

83
Q

acetaminophen metabolism produces toxic ______

A

NAPQI

84
Q

What is an example of metabolites that bind the same target as the unchanged drug and do not necessarily have the same activity

A

morphine (and heroin) are metabolized by glucuronidation

morphine-3-glucuronide (M3G) is considered largely inactive (90%)

morphine-6-glucuronide (M6G) is thought to be responsible for pain relief (10%)

85
Q

Why do significant numbers of women might not receive optimal benefit from tamoxifen treatment?

A

4-hydroxytamoxifen and endoxifen are 30-100x more potent than tamoxifen and are generated by cytochrome P450 isozymes in the liver

due to genetic polymorphism of CYP2D6, there are large variations among patients in both therapeutic efficacy and side effects

86
Q

True or False: CYP2D6 interacts with specific selective serotonin reuptake inhibitors (SSRIs), frequently used to prevent the hot flushes experienced by up to 45% of patients taking TAM.

A

True

87
Q

In 1966, _____ synthesized tamoxifen

A

Dora Richardson

88
Q

What is the metabolic resistance of tamoxifen? (2)

A

mutation of CYP2D6 to reduce activation of prodrug

administration of SSRIs and other drugs that inhibit CYP2D6

89
Q

What is the intrinsic resistance of tamoxifen?

A

much less effective in controlling the growth of tumours that are progesterone-receptor negative and have high levels of membrane growth factor receptors (GFRs) that can activate phosphorylation cascades via Src, Akt and PAK

90
Q

What is the acquired resistance of tamoxifen?

A

tumours that initially respond to tamoxifen can acquire resistance to tamoxifen by increasing the level of GFRs that phosphorylate Src and Akt

91
Q

_____ is any process, typically irreversible, that diminishes the amount of a drug that is distributed throughout the body

A

Elimination

92
Q

What are the 5 ways drugs can be eliminated from the body?

A

Gas through lungs

Blood supply back through intestines in bile produced by liver

10-15% can be lost through sweat

Saliva and breast milk

Kidneys

93
Q

What is the principal route where drugs are excreted?

A

Kidneys

94
Q

_______ increases drug concentration in lumen

_______ decreases drug concentration in lumen

_______ increases drug concentration in lumen

A

Glomerular filtration

Tubular reabsorption

Tubular secretion

95
Q

Renal Excretion =

A

Filtration – Reabsorption + Secretion

96
Q

What are the 6 routes of drug administration?

A

oral

sublingual

rectal

epithelial

inhalation

injection

97
Q

True or False: The oral route places the greatest demands on the chemical and physical properties of the drug

A

True

98
Q

drugs taken as pills or capsules are mostly absorbed in the ______.

A

Upper intesitne

99
Q

_______ binds strongly to calcium ions, which inhibits absorption, so foods such as milk should be avoided

A

Tetracycline

100
Q

Why could there be complications when taking cholestyramine?

A

binds to warfarin (anticoagulant) and also to levothyroxine sodium (thyroid drug)

101
Q

What is an advantage of drugs absorbed through mucous membranes?

A

avoids the digestive and metabolic enzymes encountered during oral administration

102
Q

What are two examples of drugs absorbed through the mucous membranes?

A

heart patients take glyceryl trinitrate (nitroglycerin) by placing it under the tongue (sublingual administration)

the opiate analgesic fentanyl has been given to children in the form of a lollipop

103
Q

Why may a patient receive rectal admission medicine?

A

unconscious, vomiting or unable to swallow

104
Q

What are 3 problems associated with rectal admission?

A

the patient may suffer membrane irritation

interruption of absorption by defecation

lack of patient acceptability

105
Q

it is also possible for some of the drug to be absorbed through the skin (transdermal absorption ) and to enter the blood supply, especially if the drug is _______.

A

Lipophilic

ie, nicotine patches, hormone replacement therapies for estrogen

106
Q

____ are applied topically to treat local skin irritations

A

Steroids

107
Q

Advantages of drug inhalation?

A

drugs administered by inhalation avoid the digestive and metabolic enzymes of the GIT or liver

108
Q

True or False: assuming the drug is able to pass through the hydrophobic cell membranes, absorption is rapid and efficient because the blood supply is in close contact with the cell membranes of the lungs

A

True

ie, general anaesthetic gases

109
Q

anti-asthmatic drugs are administered as ______ allows it to be delivered to the lungs in far greater quantities than if they were given orally or by injection

A

Aerosols

110
Q

Why is injection faster than oral administration ?

A

reaches the blood supply more quickly

111
Q

What type of drug administration has more accurate absorption

A

injection, oral route has a level of unpredictability owing to the first pass effect

112
Q

Why is injection more hazardous

A

unexpected reaction to a drug and there is little that can be done to reduce the levels once the drug has been injected

113
Q

What are the two disadvantages of injection?

A

include potential pain or discomfort for the patient and the requirement of trained staff using aseptic techniques for administration

114
Q

What are the 4 types of injection?

A

Intramuscular, subcutaneous, intravenous, intradermal

115
Q

What are 3 examples of drug implants?

A

continuous osmotically driven minipumps for insulin

Gliadel is a carmustine wafer that has been implanted into the brain to administer anticancer drugs directly to brain tumours

polymer-coated, drug-releasing stents have been used to keep blood vessels open after angioplasty

116
Q

______ drugs that are unable to cross cell membranes are given by injection

A

Polar

117
Q

What is the range within maximum and minimum concentrations known as?

A

Therapeutic window

118
Q

What are the factors that can alter dosage ?

A

differences of age, sex and race

diet, environment and altitude

obesity – it can be very difficult to estimate how much of a drug will be stored in fat tissue and how much will remain free in the blood supply

the precise time when drugs are taken may be important because metabolic reaction rates can vary throughout the day

119
Q

True or False: if a drug has a half-life of 1 h it takes 7 h for the level to fall below 1%

A

True, not linear with time

120
Q

Why is it important to know the half life of a drug?

A

to calculate the frequency of dosing required to reach and maintain these levels

121
Q

In general, the time taken to reach a steady state concentration is _______ the drug’s half-life

A

6 times

122
Q

What are the four factors that effect bioavailability?

A

absorption –bioavailability is directly related to absorbance

first-pass metabolism – first-pass metabolism lowers bioavailability

chemical instability – may be destroyed by the HCl or enzymes in the GIT

manufacturing methods – particle size, excipients, compression pressure, moisture content, drug polymorphism all affect bioavailability

CH 456 Medicinal Chemistry (7 decks)

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