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PHAR 300 > Pharmacokinetics 2 > Flashcards

Pharmacokinetics 2 Flashcards

1
Q

what does magnitude of drug effect equal

A

pharmacodynamics and pharmacokinetics x individual biological properties (variations)

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2
Q

what does elimination involve

A

Biotransformation = Converted to a form that is easier to eliminate or handle
Metabolized then excretion

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3
Q

define metabolism

A

Conversion of drug to less active or inactive (more common) metabolite = more water soluble
Loses biological effect

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4
Q

does metabolism always inactivate a drug

A

Sometimes converts inactive prodrug to active form
Sometimes will not completely eliminate biological action of drug

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5
Q

describe concentration of parent drug vs metabolite

A

Concentration of parent drug rises quick then decreases
Concentration of metabolite starts to rise
= Convert parent drug to metabolite

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6
Q

where does conversion of drug happen in body

A

Mostly = liver (major)
Some in Intestines = reasonable amount of metabolism here - As being absorbed through intestine = some of drug may be broken down, As getting to liver
Bit in kidneys, lungs, skin, brain (tiniest amount)

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7
Q

where are drugs mainly absorbed

A

mainly absorbed in small intestine
Then goes through liver - portal venous circulation
Venous drainage from intestines

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8
Q

where are drugs mainly metabolized

A

Liver metabolizes
Main site
Lose fair amount of drug in first pass through liver
Inactivates certain fraction

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9
Q

how are drugs eliminated

A

Some may be inactivated by kidney or excreted
Some put out in sweat
Or exhaled in breath
Ex = garlic breath, released in saliva

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10
Q

describe liver

A

First pass metabolism occurs because have all the blood draining both small and large intestines goes through liver first
Second largest organ
Vital for life

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11
Q

describe regenerative abilities of liver

A

Greatest regenerative ability
Exposed to many toxic compounds - anything you swallow will pass through liver
Can inactivate certain amount of toxins
Can be injured by exposure to different compounds
Can lose certain amount of cells and will regenerate

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12
Q

describe functional reserve of liver

A

Large functional reserve
Can survive on small fraction of liver

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13
Q

what organ is Primary site of metabolism of exogenous compounds

A

liver

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14
Q

describe liver disorders

A

Disorders are common and symptoms are diverse
Because liver does many things
Example = cirrhosis - alcohol liver disease

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15
Q

describe structure of liver - gen

A

Blood flow comes from portal vein - drains intestines
Mingled with blood from hepatic artery

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16
Q

describe structure of liver - blood flow

A

Blood flows through sinusoids in liver
Small channels
Close contact between sinusoids and hepatocytes
Hepatocytes line sinusoids
Wall of sinusoids very thin
Exchange between liver and blood flowing through it

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17
Q

what can hepatocytes do

A

Hepatocytes can inactive many compounds flowing through sinusoids and then sinusoidal blood drains out

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18
Q

name and describe phases of drug metabolism

A

Phase 1 = oxidation/reduction/hydrolysis
Drug altered
Phase 2 = conjugation
Something attached and then eliminated

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19
Q

describe property of drug metabolism

A

Start off with drug that is lipid soluble = lipophilic
Readily absorbed and able to transfer through plasma membranes

Then made water soluble by metabolism
Kidneys have easier time to get rid of it
More readily eliminated

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20
Q

describe phase 1 drug metabolism

A

drug usually inactivated
Done by liver enzymes = cytochrome p450 enzymes

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21
Q

describe nomenclature of p450s

A

Cyp = cytochrome p450
3= family
A= subfamily
4 = gene

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22
Q

where are p450s synthesized

A

Synthesized in smooth endoplasmic reticulum of hepatocyte
Also in GI tract, lungs, skin, kidneys

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23
Q

true or false each p450 can metabolize only one drug

A

FALSE
Most p450’s can metabolize more than one type of drug

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24
Q

describe phase 1 reactions

A

oxidation
Inactivate its biological activity
Other reactions too
Hydroxylation
Demaination
Dealkylation
Reduction
Hydrolysis (aspirin → salicylic acid = metabolite that retains some biological activity)

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25
Q

describe p450 cycle

A

Drug comes in and is acted on by p450 enzymes
Oxidized and comes out other side with oxygen incorporated into structure of drug
Then p450 liberated to deal with other molecules
Sequence of reactions

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26
Q

describe p450s in diff creatures

A

P450’s present in many creatures
Plants, sea creatures, butterflies - find families of p450
20 p450 families in humans

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27
Q

describe p450s through evolution

A

number and variation of p450s have increased
Reason = continually exposed to more types of chemicals and need more sophisticated mechanisms to inactivate them

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28
Q

name the 3 p450s mainly involved in drug metabolism

A

CYP 1, 2 and 3=Drugs and xenobiotics

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29
Q

do only cyp 1,2,3 metabolize drugs

A

Other families still metabolise some drugs and also involved in metabolism endogenous compounds we create

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30
Q

what does cyp 4,5,8 deal with

A

fatty acids, prostaglandins, thromboxanes

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31
Q

what does Cyp 7,11,17,21,24,27 deal with

A

= steroid hormones

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32
Q

describe p450s more heavily involved in drug metabolism

A

1A =
2D6= second most common
3A4= most common in drug metabolism

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33
Q

what influences enzyme function between individuals

A

olymorphisms
Variants = can break down drugs slower or faster
Many of the enzymes can be induced
If take drug repeatedly =causes enzyme induction and get more and more of enzyme, Break drug down faster
Liver inflammation
Diseases
Age - in babies and elders

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34
Q

are metabolizing enzymes only in liver

A

no Some enzymes in intestinal epithelium Reasonable amount of drug metabolism

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35
Q

describe metabolizing enzymes of intestines

A

Significant activity of CYP3A
DRUG must go through intestinal wall
Also have p glycoprotein - Can dump back into intestine and inhibit absorption

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36
Q

describe first pass - removes

A

First pass removed 75%
Absorb 120mg out of 150mg
Liver extracts 90mg (90/120=75%)
30mg goes to systemic circulation
30/150mg = 20% = bioavailability
If bioavailability too small = not a good drug orally

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37
Q

describe p450s in other organs

A

Smallest amount in brain
Drug metabolizing enzymes in brain very different in frequency and type compared to liver

38
Q

describe variations in individuals of enzymes - variation

A

Impacted by many things
Polymorphisms
Gender
Age
Pregnant
Inflammation
Liver diseases
Other diseases
Kidney diseases - because has some metabolizing enzymes and involved in excretion

39
Q

describe variations in individuals of enzymes - environment

A

Environmental exposure =
Pollutants
Water
Stressful circumstances
Occupational exposure
Starvation

40
Q

enzymes can be what

A

Enzymes can be induced and inhibited

41
Q

describe study looking at variability of p450s

A

Study = variability in levels of individual p450s in 18 human liver samples
Looked at p450s = 1A2, 2E1, 3A4
Incredible variation
Everybody is different

42
Q

describe enzyme induction

A

can be rapid
Powerful and quickly

43
Q

describe enzyme induction - example

A

Previous exposure to 2 different drugs that induce p450s
Phenobarbital induction
Dramatic enzyme induction
Benzo[a]pyrene
Even more dramatic
Within 1 hour drug is gone
= get more p450 = drug now broken down more rapidly
The first drug no longer effective
interactions like this can be dangerous
Must be careful with interactions between drugs

44
Q

describe drug inhibition

A

do not break down well
So drug can become toxic and end up with very high levels of the drug

45
Q

what can many drugs do

A

Many drug interactions alter metabolism
Drug interactions common
Many drugs are inducers or inhibitors of p450s
Troublesome for hospitalised people

46
Q

who has different metabolizing effects

A

Must be concerned about very young people = Drug metabolising enzymes not fully developed
And in very old = Effect of age is highly variable

47
Q

describe metabolizing enzymes in elders - half life

A

Plasma half life of drug
People in late 80s plasma half life goes up
But biological variation so older person could have liver which is breakdown drugs as younger person
Cannot jump to conclusions on age

48
Q

describe Influence of Age on dose of warfarin

A

Warfarin = anticoagulant, can prevent heart attack for certain people
Has narrow margin of safety
Need to monitor people taking it
With age = decrease in handling of warfarin
But its variable
Must consider individual person

49
Q

describe pharmacokinetics of p450s

A

Individual variation in p450s
Genetic and environmental
Someone can have genetic variation which greatly affects metabolism of drug

50
Q

describe what happens if drug has 2 major ways of being metabolized

A

Drug can have 2 major variants
2 peaks - 2 main types of ways people metabolise it
Must figure out which one person is

51
Q

describe genetic variability in drug metabolism

A

One major peak = regular
But also have

Ultrarapid metabolizers = have a greater concentration of the enzyme
Intermediate = able to metabolize but slightly longer
Poor metabolizers = different variation of p450 enzymes = hinder ability to break it down, Low amount of metabolite & Higher concentration of active drug

52
Q

describe ex= p4502D6 polymorphisms

A

Catalyzes primary metabolism of some common drugs
can be =

Absent ~7%
Can make big difference, Drug that is predominantly metabolized by this enzyme will be along for a long time, Slower breakdown
If take codeine -dentist, Will not work because codeine metabolized to morphine by 2D6
Hyperactive ~30%
Break down more rapidly = drug more ineffective

53
Q

describe Notable biological variation in enzymes - 2D6 - TYPES

A

normal = wild/wild
Heterozygote = wild/variant
variant/variant

54
Q

describe Notable biological variation in enzymes - 2D6 - normal

A

Drug given at dose that will allow you to have absorption take place
Level will be effective for a given period of time and it will stay within therapeutic range for desired amount of time

55
Q

describe Notable biological variation in enzymes - 2D6 - wild/variant

A

Moderate problem
End up with slight level of toxicity and drug will be around for long time

56
Q

describe Notable biological variation in enzymes - 2D6 - variant/variant

A

Pretty sick = drug will be toxic

57
Q

describe extensive vs poor metabolizer

A

Can have extensive metabolizer= Break down rapidly,Get rid of almost all of it before next dose, Does not stay at effective level for long
Or poor metabolizer= Hardly break down anything and level gets higher with each dose

58
Q

describe pharmacogenomics

A

Field of study where people investigate genetic variations between people in terms of their ability to metabolise drugs
As we learn = able to treat people in better ways
Can check for variants ahead of time
Can be bad for uncommon variants = Cannot test - May see a serious reaction in this person

59
Q

describe other drug metabolizing enzymes

A

Other drug metabolising enzymes
Enzymes in liver that can breakdown alcohol
Alcohol dehydrogenase= in cytosol
Acetaldehyde dehydrogenase = mitochondrial

60
Q

describe phase 2- general

A

conjugation
Facilitates elimination
Usually by kidneys
Portal blood = have p450s and conjugation enzymes in hepatocyte

61
Q

what is used for conjugation

A

Transfers something onto parent molecule
Glutathione transferase = transfers glutathione onto parent molecule
Most common ones
= transferring glutathione or glucuronic acid onto the compound produced from phase 1

62
Q

give ex of phase 2 - aspirin

A

Initial metabolite = salicylic acid is active but then acted on by transferases and have inactive products then exerted by kidney

63
Q

what can some drugs do in process of being metabolized

A

can cause liver damage
Can cause toxic consequences
Oxidative stress, protein oxidation, apoptosis, necrosis, steatosis
Can end up with accumulating theses drugs if liver injured and cannot metabolise them properly
Liver injury will alter drug metabolism - toxicity

64
Q

describe respiratory viruses effect on liver

A

can cause liver damage
Can cause toxic consequences
Oxidative stress, protein oxidation, apoptosis, necrosis, steatosis
Can end up with accumulating theses drugs if liver injured and cannot metabolise them properly
Liver injury will alter drug metabolism - toxicity

65
Q

Describe drug excretion - gen

A

Removal of drug from body

66
Q

Describe drug excretion - major site

A

kidney
Filters blood
Secrete things into urine
Reabsorb things from urine
Very effective at getting rid of foreign compounds in circulation

67
Q

describe how phase 2 helps eliminate drugs

A

Phase 2 made it water soluble so now kidney can get rid

68
Q

describe structure of kidney

A

Free drug can go through glomerulus and get to proximal convoluted tubule
If drug bound to albumin = too big so drug that is still protein bound will not be filtered in kidney
Blood flows in and out of glomerulus

69
Q

describe glomerulus - kidney

A

Certain fraction of drug will be filtered in glomerulus and will enter proximal tubule
Goes through different regions of kidney
Some active drug secretion and some active drug reabsorption
Can have secretion from capillary network
Can have some reabsorption if drug back into circulation in distal tubule

70
Q

what happens if main drug gets filtered

A

If main drug gets filtered = will be reabsorbed because its lipid soluble
BUT Kidney can excrete both drug and metabolites

71
Q

describe how much of drug is eliminated - initially vs after metabolized

A

2/3rds changed in liver - Some of it excreted by kidney
1/3rd = initially excreted unchanged in urine
(Aspirin = break down most into metabolite but some of it will be excreted as aspirin- Small molecule so kidney can get rid of it )

72
Q

where else can drugs be secreted

A

Some drugs exhaled through lungs = Breathalyzer (Measures amount of alcohol they are breathing out)
Some drugs secreted by salivary glands (Garlic breath Onion breath)
Now testing saliva for cannabis (Not being used yet but in the works)
Secrete and metabolise some drug in skin (Not a lot)

73
Q

describe drug clearance

A

Ability to get rid of one drug versus another in body
Clearance quantifies elimination
Is the volume of body fluid cleared per time unit (L/hr, mL/min)
Usually constant

74
Q

describe renal drug clearance

A

How much of blood cleared of certain drug per minute by kidneys
Renal clearance = filtration + secretion - reabsorption
Can compare between drugs

75
Q

describe heptapic drug clearance

A

How much you metabolize and bioabvailablity

76
Q

describe total body drug clearance

A

total body clearance
CLtotal=CLhepatic+CLrenal+CLpulmonary + CLother
Sum of individual organ clearances
Useful thing to know

77
Q

describe time course of drug elimination

A

Drug in drug out
distribution= concentration in blood falls quickly as being distributed
Elimination= drug concentration will fall slowly as drug being metabolised by enzymes and removed by kidney

78
Q

what is half life

A

Half life =time it takes to get rid of 50% of drug

79
Q

describe half life

A

tart with 100% - after 8 hours = down to 50 after 8 hours down to 25…
Half life = 8 hours
Lose constant fraction of drug in unit time
Takes 4 half lives to eliminate drug
When down to 6% of original amount = no longer clinically active

80
Q

how many half lives to eliminate drug

A

4 x t ½ to eliminate drug
Drug eliminated or steady state achieved
By 4 half lives = 94% of drug eliminated = down to 6% active = no longer effective

81
Q

does half life depend on dose of drug

A

Half life does not depend on dose of drug
Enzymes can deal with usually therapeutic amount
Can handle effectively

82
Q

describe first order kinetics

A

First order kinetics -
Constant fraction per unit of time
MOST but not all drugs
No matter the dose - as long as within therapeutic range

83
Q

describe zero order kinetics

A

Few drugs = zero order kinetics
Breaking down constant amount of drug
Do not have excess of drug metabolising enzymes
At saturation point for the enzyme so can only break down certain amount

84
Q

when can first order kinetics become zero order

A

if high dose of drug can saturate enzyme
Ex = aspirin

Normal therapeutic dose
= Breakdown with first order kinetics
Half life is 3 hours

If swallow most of bottle
= Can saturate enzyme = zero order kinetics
Half life now = 15 hours

85
Q

describe dosing schedules

A

Want to stay within therapeutic window
Dropping below minimum effective concentration not ideal so want to give drug at doses and intervals that will stay above minimum, But not toxic

86
Q

describe how describe dosing schedules work

A

If give drugs at multiple of half life = will reach plateau in 4 half lives
Plateau in 4 x t ½
Works for all methods of administering
Do not want to be toxic or ineffective
More often at smaller doses = standard strategy

87
Q

what is an issue with dosing schedules

A

Can discover outlier
Slow or rapid metabolism
Have to watch and see and adjust

88
Q

what to do in emergencies - dosing schedule

A

For emergencies = give loading dose
Higher dose right away intravenously
Then give maintenance dose to stay within therapeutic range

89
Q

what happens if infuse drug - dosing schedules

A

If infuse drug = will get steady state at 4 half lives
All doses have same plateau

90
Q

describe pharmacodynamics - summary

A

Drug action on receptors
Mechanism of drug action
Concentration versus effect

91
Q

describe pharmacokinetics - summary

A

How body handles drugs
Concentration versus time

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