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Flashcards in Pharmacokinetics- Week 2 Deck (88):
1

What are the routes of administration for medications

Mouth-oral
eyes-occular
parenteral
inhalation
oral
sublingual/buccal
transdermal
epidural
rectal
topical
bone

2

What is ADME?

absorption
distribution
metabolism
excretion

3

Pharmaceutic phase - 3 parts (pharmaceutical)

1. formulation of drug into dosage form
2. administration of drug
3. disintegration and dissolution

4

Pharmacokinetics phase - 4 parts
Definition of

When a drug enters the body, the body immediately begins to work on the drug.
1. absorption
2. distribution
3. metabolism (biotransformation)
4. excretion

5

What is the Pharmacodynamic phase?

drug-receptor interaction

6

What is the pharmacotherapeutic phase?

1. therapeutic effects
2. adverse reactions

7

define absorption
Site
Main concept
Factors effecting absorption

Absorption: transfer of the drug from the administration site to circulation

Site: Gut to plasma

Concept: bioavailability

Factors: environment where drug is absorbed,
chemical drug characteristics - influence movement
Route of administration

blood flow
cell membrane

8

define distribution of drug
Site



Main concept
Factors

distribution -reversibly leaves the bloodstream and enters the extracellular fluid and tissues (interstitium)

Site: Plasma to tissue
from from circulation to site of:
action (tissue and organ)
storage (bone and fat)
uptake
elimination

Concepts: volume of distribution

Phase 1: blood flow from site of administration
Phase 2: delivery of drug into tissues at site of drug action

9

Metabolism (biotransformation)
Site?

Site
Main concept
Factors

circulation
tissue
organ of action

Site: liver

Concept: enzyme inhibition/induction
first phase effect

phase 1 oxidation cytochrome P450
Phase 2 Glucuronidation

10

Elimination
Site
Main concept

Kidney

Concepts: clearance, half-life, steady state, linear and non-linear kinetics

11

In systemic circulation where can drug be found?

receptors: free and bound
Tissue reservoirs: free and bound
plasma: protein-bound
Metabolism: active and nonactive metabolites

12

Routes of administration - enteral/oral
Key point regarding oral medications
Why is rate of absorption variable?

Routes of administration - enteral/oral
safest, most common and convenient

physical properties of drug may lead to poor absorption
destruction of some drugs by pH of stomach
GI motility diferences
drug-food interactions

13

What are two ways to combat problems with enteral administration of medications?

Rates of absorption in oral preperations

Enteric coated (EC) protection from stomach acid
ER/XR special coating that controls release for a steadier concentration

liquids, elixirs, syrups, suspensions, solutions, powders, capsules, tablets, coated tablets, enteric coated, slow release formulas.

14

Enteric administration
Define sublingual and buccal admin
benefit of sublingual/buccal admin of med

under tongue/between cheek and gum
enters the systemic circulation directly by diffusing into capillary network.
rapid absoprtion
avoidance of harsh GI environment
Avoid first -pass metabolism -venous from mouth goes to superior vena cava and avoids the liver

15

Transdermal admin
absorption?
liver?
most common use?

dependant on?

absorption varies markedly
bypass the liver and
sustained delivery of drug

affected by lipid solubility of drug and skin characteristics

16

Rectal admin of drugs
Liver?
problems?

useful for?

partial bypass of first pass metabolism (50%)
absorption irregular and/or incomplete
possible rectal irritation

vomiting, unconscious, poor swallow,

17

Inhalation - administration
Liver?
compare to IV absorption

use?

Avoids first pass metabolism
rapid delivery almost as rapid as an IV

ideal for respiratory conditions - right to site of action and limits adverse side effects
cumbersome - think inhaled insulin

18

Parenteral administration of meds
Absorption?
use?
liver?
routes?

Directly into circulation
HIGHEST BIOAVAILABILITY

best if drug is poorly absorbed or unstable in GI tract

avoid first pass metabolism
IV, IM, SubQ

19

IV administration of meds
advantages?

Disadvantages?


Rapid effect of maximum control of dose
IV bolus gives full amount almost immediately
IV infusions given over time results in lower peak concentration

can not be recalled
risk for infection at IV site
adverse reaction if given too fast or too high of concentration - toxcicity

20

IM positives and negatives

Not as rapid as IV more rapid than Subq
variable absorption r/t blood flow at site (heat, exercise and massage increase absorption

21

what is a depot injection?

use?

Example?

IM injection or subQ that is absorbed slowly over time
suspension in a nonaqueous vehicle
provides sustained release over time

good for self-administration

Example is lantus or heparin

22

SubQ drug administation
Positives and negatives

Absorption via passive diffusion into plasma

rate of absorption is constant and slow

small volumes only - 1.5-2 mL

23

Movement of a drug across a cell membrane is influenced by its:

size
shape
degree of ionization (pos or neg charge)
lipid solubility (increase lipid solubility, increase movement into cell)
binding to serum and tissue proteins.

MUST pass through many membranes to reach target

24

Cell membranes are impermeable to molecules that are:

highly polar
ionized
large (glucose, sucrose)

25

Cell membranes are permeable to molecules that are:

small, nonionized and less polar
examples - gases (oxygen, nitrogen), water, alcohol
small uncharged - water, urea, glycerol

26

what are 3 functions of membrane proteins?
Relationship to drugs?

receptors, ion channels and transporters (transduce chemical or electrical signal)
target for drugs - integral proteins (channels), peripheral proteins (surface),
P-glycoprotein transporters

27

What are the 6 functions of cell membrane proteins

transport channel - integral
enzyme
cell surface receptors
cell surface markers
cell adhesion
attachment site of cytoskeleton

28

4 ways of drug movement in GI tract
saturable?

passive diffusion - water soluble through pore
Passive diffusion - lipid soluble through membrane.
concentration gradient NOT SATURABLE - most common

facilitated diffusion -transmembrane carrier protien that has a conformation change SATURABLE

active transport - ( Carrier protein transports and ATP dependent so can go against a concentration gradient SATURABLE

endocytosis and exocytosis (not frequent) large size molecules

29

Factors influencing drug absorption

pH - alters the drug and the ratio of uncharged to charged

Blood flow - intestines more blood flow than stomach = better absorption

Surface area - intestine microvilli = greater surface area (x1000) vs stomach = better absorption

Contact time at absorption sites fast transit = lower absorption rate

Delaying gastric emptying = lower absorption rate
(food slows gastric emptying = lower absorption rate

30

What is P-glycoprotein transporter?
Where is it?

It is a DRUG PUMPER - pumps out of cell and reduces absoprtion

Located throughout the body (intestine, astrocytes in bloodbrain barrier, liver and kidney

31

Bioavailability definition

Calculation

rate and extent to which administered drug reaches systemic circulation. How much drug gets from GI tract into the blood?

Bioavailability = AUC oral/AUC IV x 100

32

First pass metabolism and effect on bioavailability

Drugs administered orally are first exposed to the loved and may be extensively metabolized be reaching the site of action in the body.

limits efficacy

need higher doses to ensure drug reaches site of access compared other routes of administration.

33

Factors effecting bioavailability

Solubility of drug -
very hydrophilic - cannot cross cell membrane.
very lipophilic - insoluble in body fluids

ideal - soluble in gastric fluids but have enough lipid solubility to cross GI cell membranes

chemical instability example - pen G unstable in GI pH
insulin is destroyed.

drug formulation - particle size, enteric coating, binders

34

Define bioequivalent drug

drugs have comparable bioavailability (rate and extent of drug to which drug reaches systemic circulation) and similar times to achieve peak blood concentrations

35

Define therapeutically equivalent drug

comparable efficacy and safety profile

36

Define pharmaceutically equivalent drug

same concentrations, dosage and route of administration
HOWEVEr
pharmaceutically equivalent drugs are not neccesarily bioequivalent.

37

bioequivalence vs therapeutic equivalence
what is the legal requirement for generic drugs

pharmaceutically equivalent are not always bioequivalent. fillers and binders and alter rate, absorption etc. and clinical effectiveness.
legally most drugs must demonstrate bioequivalence within +/- 20% of plasma concentration to be generic

38

Distribution - first sites?

second distribution?

Drug storage?

well perfused organs - liver, kidney, brain, heart >

muscle, adipose, viscera and skin is slower (second distribution) from minutes to hours before concentration of drug in tissue is in equilibrium with the blood.

muscle, adipose tissue, bones and teeth

39

Distribution from plasma to interstitium depends on?

in CNS?

-blood flow
(rate varies by tissue)
Vessel rich organs (brain, liver, kidney > muscle, fat

-capillary permeability
variable fraction of slit junctions
Liver, spleen have LARGE slit junctions
Brain has no slit junctions
IN CNS transport by lipid solubility or active transport
ionized or polar will not cross.

-Binding of drugs to plasma proteins and tissues
reversible binding to plasma proteins sequesters
drugs and slows transfer from vascular compartment
Albumin is major drug binding protein.
Tissue binding can be a source to prolong drug
actions or cause toxicity.

-Lipophilicity - readily moves across cell membranes

40

Define Volume of distribution (Vd)

how is Vd calculated?

fluid volume that is required to contain the entire drug in the body at same concentration measured in the plasma

Vd = dose in systemic /concentration in blood at time zero.

41

Distribution into water compartments - plasma

high molecular weight drugs
extensively protein bound drugs (can't pass through slit junctions) are trapped in plasma compartment.
low Vd that approximates plasma volume

42

Distribution into water compartments - EC fluid

low molecular weight drugs
hydrophilic so can pass through slit junctions but cannot cross the lipid membrane to enter IC fluid
Vd = plasma volume PLUS interstitial fluid =EC fluid

43

Distribution into water compartments - TBW

total body water
Low molecular weight
lipophilic can move through interstitium and pass through cell membrane into INTRACELLULAR fluid
LARGE Vd

44

Calculating Vd Vd = Dose / Measured Conc
dose = 10 mg IV
concentration at time 0 = 1 mg/L
Vd = 10mg Vd = 10L

10 mg/ 1 mg/L Vd = 10L

45


What does drug elimination depends on?
How does Vd effect half-life of a drug?

the amount of drug delivered to the liver, kidney or other organ where metabolism occurs per unit of time.
the delivery of drug depends on blood flow
Fraction of the drug in plasma

Large Vd = most in extraplasmic space
unavailable for excretion.

46

Large Vd implies?

Exceptionally large Vd implies?

Small Vd implies

wide distribution throughout the body
low serum concentration compared to the total amount of drug in body

Considerable sequestration of drug in tissues or compartments

Narrow distribution in body

47

Vd of lipophilic drugs?
Vd of hydrophilic drugs?

Large Vd
Small Vd

48

Drug distribution by compartment
TBW

small molecules such as ethanol very wide distribution

49

Drug distribution by compartment
Extracellular

larger water soluble molecules such as mannitol

50

Drug distribution by compartment
Blood Plasma

narrow distribution
Highly protein bound molecules
large molecules
highly charged molecules
example heparin

51

Drug distribution by compartment
Adipose tissue

highly lipid soluble molecules
ex diazepam

52

Drug distribution by compartment
Bone and teeth

ions such as fluoride and strontium

53

Vd clinical pearls
albumin

drug stays in the plasma
Small Vd
low albumin levels lead to more free drug in plasma which creates increased activity of drug

54

Vd clinical pearls
Obesity

Lipophilic drugs accumulate in adipose tissue
large Vd
slowly released into circulation
Prolongs duration in the body

55

Vd clinical pearls
Edema

increased distribution of hydrophilic drugs
normally small Vd becomes a large Vd

56

Vd clinical pearls
Dehydration

hydrophilic drugs have a small Vd. concentration of drug increases in plasma

57

Vd clinical pearls
Gender

Women have more fat = large Vd of lipophilic drugs

58

Vd clinical pearls
age

Elderly have more fat content therefore large Vd

59

Drugs clear by metabolism and elimination and begin as soon as drug enters the body
3 major parts of elimination

hepatic metabolism
biliary elimination
urinary elimination

60

What does it mean to decrease plasma concentration exponentially?

What is first order elimination kinetics?

Linear kinetics?

constant fraction per unit of time.

eliminates as a percentages, no saturable


rate is proportional to drug concentration?

61

Drug clearance (CL) is an estimate of?

What is total clearance?

CL = 0.693 x Vd/T1/2

Why is T 1/2 (half-life) often used as a measure of CL?

the amount of drug cleared per unit of time

is an estimate reflecting all mechanisms of clearance such as liver, kidney

For many drugs Vd is a constant

62

calculating Drug Clearance CL

CL = .693 x Vd/T1/2
for many drugs half-life T 1/2 = CL because Vd is constant

63

Most drugs clear by first order kinetics. describe
Michaelis-Menton kinetics

aka Linear kinetics
Steady state kinetics
Constant fraction of drug is metabolized per unit of time
with each 1/2 life concentration decreases by 50%

64

Zero order kinetics or non-linear kinetics

rate of elimination of the drug is constant and independent of the drug concentration

Constant amount of drug is metabolized per unit of time
examples are: aspirin, ethanol, phenytoin

65

Metabolism of drug

What are the usual metabolic changes?

physiochemical reactions that alter structure and function
increase polarity, more hydrophilic (less lipid soluble)
some metabolites are still active

66

Why is the kidney unable to eliminate lipophilic drugs?

kidney can not eliminate lipophilic drugs because they cross the cell membrane and reabsorb in distal convoluted tubules of kidney

67

Where and how are lipophilic drugs metabolized?

metabolized in the liver into more hydrophilic molecules in the liver by phase 1 and phase 2
Phase 1-oxidation, reduction and hydrolysis usu inactive
Phase 2 - conjugated (water soluble) usu inactive

68

Describe the phase I p450 system

makes a drug more polar by adding or unmasking a more polar functional group such as OH or NH2

69

What is the P450 system?
Nomenclature? CYP3A4
Genetics?

Cytochrome P450 system is a superfamily of isozymes in the liver and the GI tract.
CYP3A4 = subfamily 3A, 4 isozyme
many different p450 isoforms
examples are variability/polymorphisms for codeine and plavix metabolism

70

define substrate


Define inducer drug



inhibitor drug

a drug that is affected by a change in its enzyme metabolism.

inducer causes acceleration of P450 enzyme system therefore causes increases in metabolism of another drug-decrease plasma concentration & reduce activity

Inhibits the P450 enzyme system which decreases metabolism of another drug and therefore increases drug concentration & activity

71

Describe the Phase II system in metabolism

Phase II metabolites are still too lipophilic to be excreted
addition of chemical group to increase hydrophilicity
most common is glucoronidation. molecule is usually inactive and is more easily excreted.

72

pearls of drug Elimination -

elimination = removal of drug from body
must be polar enough
most important route is renal
renal dysfunction is risk for accumulation and adverse effects

73

Define drug clearance

Organs of drug clearance

What determines drug clearance

What alters clearance?

The ability of body organs to remove a drug from blood.

kidney and liver

the blood flow to organ and efficiency of the organ

alterations to blood flow such as shock or CHF

binding changes in blood (highly protein bound are displaced)

intrinsic clearance is altered by metabolizing enzymes are induced or inhibited.

74

process of renal elimination
How does blood flow?
What does glomerular filtration do?

drugs enter the kidney from renal artery & flow through capillary slits as part of glomerular filtrate.
filtration moves drug from blood to urine - but not if protein binding to albumin decreases filtration
reduced GRF reduces filtration

lipid soluble drugs move back into blood polar and ionized drugs remain in urine (passive reabsorption)

75

What is Proximal tubular secretion?

drugs not removed by GF can be removed by proximal tubular secretion.
Energy requirement for active transport tubular pumps to move organic acids and bases from blood to urine.
competition for carriers

76

Describe Tubular reabsorption


What does manipulating urine pH do for ionized drugs?

Is drug enters distal tubule, drug concentration increases. reabsorption of filtered drug if lipid soluble and non-ionized.

For ionized drugs, urine pH can be altered to minimize the back diffusion. (tubular reabsorption)De

77

describe Fecal elimination

drugs that are NOT absorbed by GI tract or are secreted into intestine or bile

78

Importance of lungs for drug elimination

route for anesthetic gases

79

Clinical significance of breast milk, tears, saliva or
sweat

not except for breast milk in nursing mothers.

80

Define clearance

What is the total body clearance?

3 things that change drug clearance

how to calculate clearance
rate of removal of drug (mg/mL)/
plasma concentration of a drug (mg/mL)

ability of the body to remove a drug from the blood

sum of the clearances from the various metabolizing and eliminating organs.

1. blood flow to clearance organ
2. binding in the blood changes (protein-bound drugs
are displaced)
3, metabolizing enzymes are induced or inhibited.

81

Cockcroft-gault equation use. Why?

CrCl = (140-age) x Ideal body wt (kg)
/ 72 x SCr (mg/dL)
women equation above x 0.85


Ideal body weight
2.3 kg x inches > 5' + 50 kg men
2.3 kg x in inches > 5' + 45 kg women
Adjusted body weight (adjBW) = IBW + .4 (actual - IBW)
used if weight is > 20% more IBW

drugs cleared renally will need adjustment for changes in renal function.

equations is used to estimate creatinine clearance (CrCl)

renal drugs have dose and frequency recommendations based on this equation.

82

normal creatinine clearance for men?
women?

110-120 mL/min
100-110 mL/min

83

Understanding the Plasma concentration -time curve

What is peak plasma level?

Therapeutic range ?

What is duration of action?


highest level if drug reaches

the area between effective concentration and toxicity

time curve reaches minimum effective concentration

84

Steady State (Css) Definition
When repeated doses of a drug are administered, the drug accumulates in the body. Define Css:

How long does it take to reach steady state?

How do you achieve therapeutic serum levels if half-life is long?

How does infusion rate effect steady state?


when the amount of drug administered with each equal dose equals the amount cleared

Css is a function of the half-life of the drug.

4-5 half-lives to reach steady state

provide a loading dose - fills up the tank

Increase the rate of infusion causes a higher steady state concentration. (Assumption of continuous infusion) does not change the time needed to achieve steady state.

85

Define Half-life

What is half-life is effected by?

the time required for amount of a drug in the body to decrease by 1/2 after absorption and distribution is complete.

Effected by Vd and clearance
Example: 1/2 life of diazepam is increased with age because the Vd increases r/t fat stores.


86

What information can half-life provide?

When is 90% steady state achieved?

How many half-lives to steady state?

What happens to steady state when dosages are changed such in double, 1/2 or stopped.

T1/2 gives indication of
1. time to reach steady state,
2. for elimination estimation
3. means to estimate the dosing schedule

3.3 T1/2 is 90% of steady state

4-5 half-lives is steady state or 93.75-100%
reverse or elimination has same percentages

time is the same to reach and route makes no difference.

87

If half life of a drug is 3 hours and you give 50 mg,
what is amount left

0 = 50 mg
3 hrs = 1 T1/2 = 25 mg = 50%
6 hours 2 T1/2 = 12.5 mg =75%
9 hours 3 T1/2 = 6.25 mg = 87.5 %
12 hours 4 T 1/2 = 3.125 mg = 93.75 %
15 hours 5 T1/2 = 1.5625 = .56%

88

Pharmacokinetics pearls

use oral when available
understand bioavailability of oral vs IV
think of Vd as a tank of water with multiple compartments
CYP450 - learn common inhibitors and inducers
always check renal function
once in steady state, T1/2 determines time for drug elimination.