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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
describe p450 cycle
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
26
describe p450s in diff creatures
P450’s present in many creatures Plants, sea creatures, butterflies - find families of p450 20 p450 families in humans
27
describe p450s through evolution
number and variation of p450s have increased Reason = continually exposed to more types of chemicals and need more sophisticated mechanisms to inactivate them
28
name the 3 p450s mainly involved in drug metabolism
CYP 1, 2 and 3=Drugs and xenobiotics
29
do only cyp 1,2,3 metabolize drugs
Other families still metabolise some drugs and also involved in metabolism endogenous compounds we create
30
what does cyp 4,5,8 deal with
fatty acids, prostaglandins, thromboxanes
31
what does Cyp 7,11,17,21,24,27 deal with
= steroid hormones
32
describe p450s more heavily involved in drug metabolism
1A = 2D6= second most common 3A4= most common in drug metabolism
33
what influences enzyme function between individuals
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
34
are metabolizing enzymes only in liver
no Some enzymes in intestinal epithelium Reasonable amount of drug metabolism
35
describe metabolizing enzymes of intestines
Significant activity of CYP3A DRUG must go through intestinal wall Also have p glycoprotein - Can dump back into intestine and inhibit absorption
36
describe first pass - removes
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
37
describe p450s in other organs
Smallest amount in brain Drug metabolizing enzymes in brain very different in frequency and type compared to liver
38
describe variations in individuals of enzymes - variation
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
describe variations in individuals of enzymes - environment
Environmental exposure = Pollutants Water Stressful circumstances Occupational exposure Starvation
40
enzymes can be what
Enzymes can be induced and inhibited
41
describe study looking at variability of p450s
Study = variability in levels of individual p450s in 18 human liver samples Looked at p450s = 1A2, 2E1, 3A4 Incredible variation Everybody is different
42
describe enzyme induction
can be rapid Powerful and quickly
43
describe enzyme induction - example
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
describe drug inhibition
do not break down well So drug can become toxic and end up with very high levels of the drug
45
what can many drugs do
Many drug interactions alter metabolism Drug interactions common Many drugs are inducers or inhibitors of p450s Troublesome for hospitalised people
46
who has different metabolizing effects
Must be concerned about very young people = Drug metabolising enzymes not fully developed And in very old = Effect of age is highly variable
47
describe metabolizing enzymes in elders - half life
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
describe Influence of Age on dose of warfarin
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
describe pharmacokinetics of p450s
Individual variation in p450s Genetic and environmental Someone can have genetic variation which greatly affects metabolism of drug
50
describe what happens if drug has 2 major ways of being metabolized
Drug can have 2 major variants 2 peaks - 2 main types of ways people metabolise it Must figure out which one person is
51
describe genetic variability in drug metabolism
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
describe ex= p4502D6 polymorphisms
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
describe Notable biological variation in enzymes - 2D6 - TYPES
normal = wild/wild Heterozygote = wild/variant variant/variant
54
describe Notable biological variation in enzymes - 2D6 - normal
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
describe Notable biological variation in enzymes - 2D6 - wild/variant
Moderate problem End up with slight level of toxicity and drug will be around for long time
56
describe Notable biological variation in enzymes - 2D6 - variant/variant
Pretty sick = drug will be toxic
57
describe extensive vs poor metabolizer
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
describe pharmacogenomics
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
describe other drug metabolizing enzymes
Other drug metabolising enzymes Enzymes in liver that can breakdown alcohol Alcohol dehydrogenase= in cytosol Acetaldehyde dehydrogenase = mitochondrial
60
describe phase 2- general
conjugation Facilitates elimination Usually by kidneys Portal blood = have p450s and conjugation enzymes in hepatocyte
61
what is used for conjugation
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
give ex of phase 2 - aspirin
Initial metabolite = salicylic acid is active but then acted on by transferases and have inactive products then exerted by kidney
63
what can some drugs do in process of being metabolized
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
describe respiratory viruses effect on liver
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
Describe drug excretion - gen
Removal of drug from body
66
Describe drug excretion - major site
kidney Filters blood Secrete things into urine Reabsorb things from urine Very effective at getting rid of foreign compounds in circulation
67
describe how phase 2 helps eliminate drugs
Phase 2 made it water soluble so now kidney can get rid
68
describe structure of kidney
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
describe glomerulus - kidney
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
what happens if main drug gets filtered
If main drug gets filtered = will be reabsorbed because its lipid soluble BUT Kidney can excrete both drug and metabolites
71
describe how much of drug is eliminated - initially vs after metabolized
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
where else can drugs be secreted
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
describe drug clearance
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
describe renal drug clearance
How much of blood cleared of certain drug per minute by kidneys Renal clearance = filtration + secretion - reabsorption Can compare between drugs
75
describe heptapic drug clearance
How much you metabolize and bioabvailablity
76
describe total body drug clearance
total body clearance CLtotal=CLhepatic+CLrenal+CLpulmonary + CLother Sum of individual organ clearances Useful thing to know
77
describe time course of drug elimination
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
what is half life
Half life =time it takes to get rid of 50% of drug
79
describe half life
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
how many half lives to eliminate drug
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
does half life depend on dose of drug
Half life does not depend on dose of drug Enzymes can deal with usually therapeutic amount Can handle effectively
82
describe first order kinetics
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
describe zero order kinetics
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
when can first order kinetics become zero order
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
describe dosing schedules
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
describe how describe dosing schedules work
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
what is an issue with dosing schedules
Can discover outlier Slow or rapid metabolism Have to watch and see and adjust
88
what to do in emergencies - dosing schedule
For emergencies = give loading dose Higher dose right away intravenously Then give maintenance dose to stay within therapeutic range
89
what happens if infuse drug - dosing schedules
If infuse drug = will get steady state at 4 half lives All doses have same plateau
90
describe pharmacodynamics - summary
Drug action on receptors Mechanism of drug action Concentration versus effect
91
describe pharmacokinetics - summary
How body handles drugs Concentration versus time

PHAR 300 (22 decks)

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