Pharmacokinetics- Week 2

Question 1

What are the routes of administration for medications

Answer 1

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

Question 2

What is ADME?

Answer 2

absorption
distribution
metabolism
excretion

Question 3

Pharmaceutic phase - 3 parts (pharmaceutical)

Answer 3

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

Question 4

Pharmacokinetics phase - 4 parts

Definition of

Answer 4

When a drug enters the body, the body immediately begins to work on the drug.

1. absorption
2. distribution
3. metabolism (biotransformation)
4. excretion

Question 5

What is the Pharmacodynamic phase?

Answer 5

drug-receptor interaction

Question 6

What is the pharmacotherapeutic phase?

Answer 6

1. therapeutic effects

2. adverse reactions

Question 7

define absorption
Site
Main concept
Factors effecting absorption

Answer 7

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

Question 8

define distribution of drug
Site

Main concept
Factors

Answer 8

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

Question 9

Metabolism (biotransformation)
Site?

Site
Main concept
Factors

Answer 9

circulation
tissue
organ of action

Site: liver

Concept: enzyme inhibition/induction
first phase effect

phase 1 oxidation cytochrome P450
Phase 2 Glucuronidation

Question 10

Elimination
Site
Main concept

Answer 10

Kidney

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

Question 11

In systemic circulation where can drug be found?

Answer 11

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

Question 12

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

Answer 12

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

Question 13

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

Rates of absorption in oral preperations

Answer 13

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.

Question 14

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

Answer 14

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

Question 15

Transdermal admin
absorption?
liver?
most common use?

dependant on?

Answer 15

absorption varies markedly
bypass the liver and
sustained delivery of drug

affected by lipid solubility of drug and skin characteristics

Question 16

Rectal admin of drugs
Liver?
problems?

useful for?

Answer 16

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

vomiting, unconscious, poor swallow,

Question 17

Inhalation - administration
Liver?
compare to IV absorption

use?

Answer 17

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

Question 18

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

Answer 18

Directly into circulation
HIGHEST BIOAVAILABILITY

best if drug is poorly absorbed or unstable in GI tract

avoid first pass metabolism
IV, IM, SubQ

Question 19

IV administration of meds
advantages?

Disadvantages?

Answer 19

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

Question 20

IM positives and negatives

Answer 20

Not as rapid as IV more rapid than Subq

variable absorption r/t blood flow at site (heat, exercise and massage increase absorption

Question 21

what is a depot injection?

use?

Example?

Answer 21

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

Question 22

SubQ drug administation

Positives and negatives

Answer 22

Absorption via passive diffusion into plasma

rate of absorption is constant and slow

small volumes only - 1.5-2 mL

Question 23

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

Answer 23

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

Question 24

Cell membranes are impermeable to molecules that are:

Answer 24

highly polar
ionized
large (glucose, sucrose)

Question 25

Cell membranes are permeable to molecules that are:

Answer 25

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

Question 26

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

Answer 26

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

Question 27

What are the 6 functions of cell membrane proteins

Answer 27

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

Question 28

4 ways of drug movement in GI tract | saturable?

Answer 28

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

Question 29

Factors influencing drug absorption

Answer 29

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

Question 30

What is P-glycoprotein transporter? | Where is it?

Answer 30

It is a DRUG PUMPER - pumps out of cell and reduces absoprtion Located throughout the body (intestine, astrocytes in bloodbrain barrier, liver and kidney

Question 31

Bioavailability definition Calculation

Answer 31

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

Question 32

First pass metabolism and effect on bioavailability

Answer 32

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.

Question 33

Factors effecting bioavailability

Answer 33

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

Question 34

Define bioequivalent drug

Answer 34

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

Question 35

Define therapeutically equivalent drug

Answer 35

comparable efficacy and safety profile

Question 36

Define pharmaceutically equivalent drug

Answer 36

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

Question 37

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

Answer 37

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

Question 38

Distribution - first sites? second distribution? Drug storage?

Answer 38

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

Question 39

Distribution from plasma to interstitium depends on? in CNS?

Answer 39

-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

Question 40

# Define Volume of distribution (Vd) how is Vd calculated?

Answer 40

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.

Question 41

Distribution into water compartments - plasma

Answer 41

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

Question 42

Distribution into water compartments - EC fluid

Answer 42

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

Question 43

Distribution into water compartments - TBW

Answer 43

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

Question 44

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

Answer 44

10 mg/ 1 mg/L Vd = 10L

Question 45

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

Answer 45

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.

Question 46

Large Vd implies? Exceptionally large Vd implies? Small Vd implies

Answer 46

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

Question 47

Vd of lipophilic drugs? | Vd of hydrophilic drugs?

Answer 47

Large Vd | Small Vd

Question 48

Drug distribution by compartment | TBW

Answer 48

small molecules such as ethanol very wide distribution

Question 49

Drug distribution by compartment | Extracellular

Answer 49

larger water soluble molecules such as mannitol

Question 50

Drug distribution by compartment | Blood Plasma

Answer 50

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

Question 51

Drug distribution by compartment | Adipose tissue

Answer 51

highly lipid soluble molecules | ex diazepam

Question 52

Drug distribution by compartment | Bone and teeth

Answer 52

ions such as fluoride and strontium

Question 53

Vd clinical pearls | albumin

Answer 53

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

Question 54

Vd clinical pearls | Obesity

Answer 54

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

Question 55

Vd clinical pearls | Edema

Answer 55

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

Question 56

Vd clinical pearls | Dehydration

Answer 56

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

Question 57

Vd clinical pearls | Gender

Answer 57

Women have more fat = large Vd of lipophilic drugs

Question 58

Vd clinical pearls | age

Answer 58

Elderly have more fat content therefore large Vd

Question 59

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

Answer 59

hepatic metabolism biliary elimination urinary elimination

Question 60

What does it mean to decrease plasma concentration exponentially? What is first order elimination kinetics? Linear kinetics?

Answer 60

constant fraction per unit of time. eliminates as a percentages, no saturable rate is proportional to drug concentration?

Question 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?

Answer 61

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

Question 62

calculating Drug Clearance CL

Answer 62

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

Question 63

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

Answer 63

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%

Question 64

Zero order kinetics or non-linear kinetics

Answer 64

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

Question 65

Metabolism of drug What are the usual metabolic changes?

Answer 65

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

Question 66

Why is the kidney unable to eliminate lipophilic drugs?

Answer 66

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

Question 67

Where and how are lipophilic drugs metabolized?

Answer 67

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

Question 68

Describe the phase I p450 system

Answer 68

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

Question 69

What is the P450 system? Nomenclature? CYP3A4 Genetics?

Answer 69

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

Question 70

# define substrate Define inducer drug inhibitor drug

Answer 70

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

Question 71

Describe the Phase II system in metabolism

Answer 71

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.

Question 72

pearls of drug Elimination -

Answer 72

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

Question 73

# Define drug clearance Organs of drug clearance What determines drug clearance What alters clearance?

Answer 73

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.

Question 74

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

Answer 74

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)

Question 75

What is Proximal tubular secretion?

Answer 75

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

Question 76

Describe Tubular reabsorption What does manipulating urine pH do for ionized drugs?

Answer 76

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

Question 77

describe Fecal elimination

Answer 77

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

Question 78

Importance of lungs for drug elimination

Answer 78

route for anesthetic gases

Question 79

Clinical significance of breast milk, tears, saliva or | sweat

Answer 79

not except for breast milk in nursing mothers.

Question 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)

Answer 80

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.

Question 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 ```

Answer 81

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.

Question 82

normal creatinine clearance for men? | women?

Answer 82

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

Question 83

Understanding the Plasma concentration -time curve What is peak plasma level? Therapeutic range ? What is duration of action?

Answer 83

highest level if drug reaches the area between effective concentration and toxicity time curve reaches minimum effective concentration

Question 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?

Answer 84

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.

Question 85

# Define Half-life What is half-life is effected by?

Answer 85

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.

Question 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.

Answer 86

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.

Question 87

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

Answer 87

``` 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% ```

Question 88

Pharmacokinetics pearls

Answer 88

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.