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EXAM 5 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Pharmacokinetics

A

effect of the body on the drug

AMDE

Absorption

Distribution

Metabolism

Elimination

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2
Q

Pharmacodynamics

A

effect of the drug on the body

  1. receptor binding
  2. signal transduction
  3. physiological effect
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3
Q

Phase 1

A

is it safe

what are kinetics

20-100 normals

all healthy - give to small group to see how it behaves in the body

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4
Q

Phase 2

A

Does it work

20-100 patients with disease

compare to placebo

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5
Q

Phase 3

A

How well does it work

randomized trial - compared to something that works or placebo

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6
Q

Phase 4

A

post marketing suveillance

drug with rare side effect - won’t find in first 3 phases

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7
Q

Bioavailibility

A

F

amount of drug that reaches systemic circulation

IV = 1

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8
Q

Factors that affect bioavailability

A

gastric emptying time/food

dissolution/disintegration

dosage form - elixer v tablets

first pass metabolism - drug interactions

chemical formulation

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9
Q

disintegration

A

fall apart - big bolus

starts to dissolve

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10
Q

dissolution

A

after disinitegration

makes it in solution

slowed by: acidity, large particle size, water insolubility

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11
Q

toxicokinetics

A

what happens if you take too much

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12
Q

drug distribution

A

where does a drug reside in body

what properties alter where drugs reside

what properties allow drugs to move through bio membranes

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13
Q

Apparent V(d)

A

1 compartment model

put a known amt of drug into the body (mg)

measure blood concentration (mg/L)

can find the size of the theoretical space the drug resides in

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14
Q

small Vd

A

more drug in the blood

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15
Q

large Vd

A

most drug is outside of the blood (in fatty compartments)

can be bigger than body

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16
Q

old faithful

A

drug mg/L = s x F x dose (mg)/Vd

risk assessment

diff for diff things

f = percent bioavailibility

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17
Q

1 compartment model

A

instantaneous distribution

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18
Q

2 compartment model

A

slow distribution into a certain region

i.e. water to fat, how drug moves from one to the next

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19
Q

alpha distribution

A

alope of absorption rate?

2 compartment model

can’t calculate elimination until equilibrium and distrbution evens out

i.e. digoxin - doesn’t work until it gets into your heart

when concentration is blood and heart is the same (equilibrium) can discuss elimination

may be high in blood (if IV) but not in heart because distribution is low

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20
Q

beta elimination

A

slope of elimination rate constant

need to wait until distribution and elimination even out

refers to beta elimination of first order process - elimination from the blood does not mean elimination from body

some drugs result in long lasting effects (suicide inhibition, irreversible changes)

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21
Q

lipophilicity

A

fat soluble drugs live in fat soluble compartments

don’t always work where you live

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22
Q

Log P

A

actanol/water partition coefficient

how much fat, how much water

Log D - adjusts for physio pH

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23
Q

protein binding

A

some drugs are highly bound to plasma proteins

acidic - albumin

basic - alpha 1 acid glycoprotein

only unbound drug can cross bio membranes

change in protein –> dramatic change in bio effect bc alter distribution

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24
Q

phenytoin

A

only biologically active when free

binds to albumin

if decreased albumin (sick) - drug level doesn’t change but goes out in tissues and body and you think you ahve a higher level than you do

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25
Q

pH and charge

A

charged molecules DO NOT cross bio membranes well

membrane are lipid, charges increase water solubility

important for weak acids and bases - shift amout charged as a function of pH

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26
Q

aspirin and membrane permability

A

weak acid

only passes in HA form, not in charged form

at low PH (sick, acidemic) - in HA form, more passes over membrane

Pka = 3

at higher pH (physio) - most is chargd form and doesn’t move across membrane, most is in blood

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27
Q

weak acid/base rules

A

pH

pH > pKa - deprotonated forms mostly A-, B (acids stay in blood, bases cross)

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28
Q

Lipid emulsion

A

couldn’t revive after overdose

gave a bolus of fat - cause drug to diffuse from tissue into blood because it became fatty - took all drug away from the heart

increase BP

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29
Q

Aspirin poisoning and alkinization

A

normally, acid in eq between tissues, plasma, urine

if make uring really basic, make aspirin become uncharged and drag it out of tissues

urine [ASA} increases as a function of pH

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30
Q

redistribution

A

drugs that move slowly into compartments move slowly out of compartments

extravascular compartment can serve as a reservoir to maintain high blood concentrations following chronic administration

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31
Q

Digoxin redistribution

A

digoxin overdose - lives in heart

give Fab - big and can’t leave blood but binds free digoxin and drags all of the drug into blood from heart

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32
Q

Biotransformation

A

phase I - redox - reactive species made

phase II - conjugation - reactive conjugates made

phase II - elimination

phase II can happen before phase I, can skip a phase or 2

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33
Q

Phase I

A

prepare lipophilic drugs for the addition of functional groups or add the groups - convert to active/inactive/less active/prodrug to drug

oxidation

hydrolysis

reduction

dehydrogenation

dealkylation

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34
Q

Oxidation

A

primarily CYP450

Phase I

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35
Q

hydrolysis

A

phase 1

i.e. aspirin

ASA + H2O –> Salicylic acid (effect) + acetic acid (inactive)

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36
Q

alcohol metabolism

A

3 phase I reactions, no phase II

ethanol –> acetylaldehyde –> acetic acid (easily eliminated, not active)

ethanol –> acetyl aldehyde: CYP2E1, ADH (alcohol dehydrogenase, CATALASE

acetylaldehyde –> acetic acid : ALDH (aldehyde dehydrogenase)

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37
Q

Phase II

A

Conjugation

after Phase I or parent drug itself

enhance solubility allowing increased renal and other pways to elimination

detoxification - reduce toxic effects of parent/metabolized drug

38
Q

Glucuronidation

A

most common phase II

addition of glucuronic acid

helps drug get out - doesn’t always make it inactive

morpine: add in diff spots, metabolites still a little active, some pain relief but not a lot

39
Q

CYP450

A

cytochromes - class of hemoproteins that transfers electrons between oxidized Fe3+ and reduced Fe2+ forms of iron

predominatly responsible for Phase I drug metabolism

40
Q

CYP450 location

A

on smooth ER

most in liver

some in kidney

some in intestine (in enterocytes of SI - contribute to “first pass” metabolism)

41
Q

First pass metabolism

A

the concentration of a drug is greatly reduced before it reaches the systemic circulation

After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus greatly reduces the bioavailability of the drug.

42
Q

CYP450 Substates

A

drugs, chemicals, hormones that undergo biotransfrmation via CYP450

depends on Km - if small, enzyme requires only a small amount to become saturated

43
Q

CYP450 Inhibitors

A

alters enzyme activity resulting in decreased metabolism of substrate

most common cause of drug-drug interactions

can result in increased or decreased bioavailaiblity of a drug

i.e. grapefruit

44
Q

CYP450 Inducers

A

alters enzyme activity causing increased metabolism of substrate

nuclear receptor mediated! gene transcription - more enzymes, more activity

enhance druge effect beceuase increasted activity of prodrug to active druge

decrease effect by enhanced elimination

45
Q
A
46
Q

Km

A

concetration of substrate at which 50% max activity of the enzyme

small Km - substrate only needs a small amt of substrate to be saturated

large Km - need a lot to reach max V

for substrate of CYP450 enzyme

47
Q

alcohol metabolism and enzymes

A

low Km - ADH - at low amount, use ADH

high Km - CYP2E1 - in alocholics, use mostly, metabilize better at high concentrations

48
Q

substrate selectivity

A

depends on many properties

i.e. S-warfarin and R-warfarin - work in diff CYP450

49
Q

Simvastatin and Grapefruit

A

lowers cholesterol but can cause liver and muscle damage

grapefruit juice in small intestine - inhibits CYP34A mediated first-pass metabolism - cause serious liver and muscle problems because severe statin toxicity

50
Q

Extensive metabolizers

A

considered normal

normal amt of enzyme and ddrug response

51
Q

Intermediate Metabolizers

A

at least one gene isn’t working normally

less enzyme than normal

may be less response OR more side effects

52
Q

Poor metabolizers

A

variants in both genes

much less enzyme/not at all

high risk for side effects, or may need higher drug if it needs to be broken down before it works

53
Q

Ultrarapid metabolizers

A

extra copies of CYP genes –> more enzymes than normal

may break some drugs down so quickly that don’t work at usual doses

may neeed a lower dose if it has to be metabolized before it works

54
Q

pharmacogenomics

A

enzyme activity is different in different regions

i.e. codeine, needs to be broken down into morphine to work, no effect for poor metabilizers, toxic effect for ultrarapid metabolizers

55
Q

P-glycoproteins

A

sit on cell surface and actively pump drug out of cell

ATP

can move drugs against concentration gradient

has inducers and inhibitorsactivel extrudes drugs back into intestinal lumen, also BBB, kidneys, liver bile ducts

if inhibit - more intracellular = toxicity

56
Q

Acetaminophen Metabolism

A

PHASE II - sulfation/glucuronidation –> detox and elim

PHASE I - oxidation via CYP450 to NAPQI –> phase II to detox and elim

at therapeutic concentrations - Phase II reactions

if overdose - make too much NAPQI, can’t detox - toxicity to hepatocytes, poisn liver - centrally located holes in cells

57
Q

Mu opioid receptor

A

GPCR

hyperpolarizes post-synaptic neurons

inhibits presynaptic nt release

58
Q

affinity

A

abilinty of drug to bind its biological compartment

how it gets on its receptor

Kd = [L][R]/{LR]

Ka = 1/[Kd}

59
Q

low Kd

A

high affinity!

it will bind a greater number of a particular receptor at a lower concentration than a low affinity drug

60
Q

high Kd

A

low affinity

61
Q

Potency

A

all will ultimately have the same effect but which has ED50 at the lowest dose

62
Q

Efficacy

A

effect is notbinding

once binding occurs what is the effect

63
Q

EC50

A

median effective concentration

how much is needed for 50% max effect - find where effect is 50% and drop down

64
Q

full agonist

A

provides max effect at given receptor

65
Q

partial agonist

A

same efficacy but can never get 100%

66
Q

neutral antagonist

A

drug that sits on R and does nothing

if have agonist, can occupy and prevent agonist from working

67
Q

inverse agonist

A

if constituitively active - does opposite - gives decreased signaling up to 100%

68
Q

reversible inhibition

A

noncovalent binding

i.e. ibuprofen

69
Q

irreversible

A

permanent alteration

i.e. aspirin at COX1

70
Q

competitive inhibition

A

A and I acting at same site

as increase antagonist - act at same site + reversible

mass action - inhibits less - shift EC curve to the right! have to give more agonist

71
Q

noncompetitive inhibition

A

allosteric - binds and takes it out - doesn’t mater if increase [agonist]

pseudo-irreversible also

72
Q

pseudo-irreversible inhibition

A

competitive (bind at same site) but noncompetitive! binds so tightly that it looks like non comp

73
Q

Varenicline

A

smoking cessation drug

partial agonist!

withdrawl attenuation: stronger potency but partial agonist - relieves craving and withdrawl

blocks nicotine induced domaminergic activation: partial agonist - if take nicotine with it, block reward

74
Q

tolerance

A

adaptation such that exposure to a drug induces changes that result in a decrease of one or more effects over time, or the nee for a higher dose to maintain an effect

many mechanisms: desensitistation, internalization, downregulation

75
Q

Therapeutic Index

A

LD50/ED50

average!

76
Q

therapeutic window

A

window between efficacy and no toxicity

ED50-LD1 (where 1 person dies)

77
Q

Warfarin TW

A

very small TW - experiemental! keep between 2-3 need to test

between benefit and hemorrhage

78
Q

chirality implications

A

in a chiral environment, stereoisomers may have steroselective protein binding, transport, receptor, enzyme interactions —-> diff effects

i.e. Methodone is chiral

79
Q

spare receptors

A

when EC50 < Kd

between the biologican resoinse you want and all of the receptors that are avaiable

if EC50 = Kd - if you remove one receptor you will decrease efficacy

80
Q

major centers of elimination

A

Kidney and liver

81
Q

diffusion

A

break in membrane bilayer - passive

how big, soluble

82
Q

kidney elimination

A

FIRST ORDER

filtration process

how much drug is in concentration, in the system - into kidneys!

more in blood –> more scooped out - certain PERCENTAGE of total drug (dilution of remaining drug passes through the kidney again)

percent/time concentration dependent

83
Q

first order kinetics

A

percent/unit time

concentration dependent

84
Q

first order k(e)

A

slope of the line when drawn in natural logs

how much you are removing - percent/time

85
Q

half life equation

A

.693/k(e)

elimination constant!

how much it takes for 1/2 of drug to be gone

helps to dose medication correctly

86
Q

liver enzymes

A

ZERO ORDER

limited number of enzymes - a certain amount of a drug can be broken down by unit time

doesn’t matter how much there is - concentration independent

87
Q

Michaelis Mentin

A

enzymes - when concentration of drug is low - function based on blood flow and metabolize a certain percent per time (FIRST ORDER) and then when get overwhelmed (massive overdose) they switch to ZERO ORDER and are at capacity - metabolize a certain amount

88
Q

Clearance

A

analogous to the Vd - amount of blood that is totally removed of a drug in a unit of time

Cl = rate of elimination/Cp (plasma concentration)

vol/time

total body clearance is sum total of all routes of elimination

89
Q

Steady State

A

when drug concentration remains relatively constant over time

absorbtion and elimiation rates are equal!

SS = absorption/elimination = rate in/rate out

usually - 5 half lives to get steady state

90
Q

Tau

A

dosing interval!

how often you have to give a drug over a period time

91
Q

heodialysis

A

first order process (like kidneys!)

blood in, drug out

remove certain amt in 4 hours

factors favoring elim: small Vd, low protein binding, water soluble, molecular weight is small

calculate how long patient needs to stay on HD to bring drug concentration down to an acceptible amount

92
Q

charcoal

A

decrease amount of drug absorbed

enters enterohepatic ciruclation

if IV drug - can still leave through feces

EXAM 5 (11 decks)

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