Pharmacokinetics Ch.

4
1.Pharmacokinetics: The study of drug movement within the body, the effect
the body has the drug.
2. Four Pharmacokinetic Processes:
1. Absorption
2. Distribution
3. Metabolism
4. Excretion
*Cell membrane Structure: Drugs usually pass through the cells, instead of
between them to cross the membrane. Page 28
Transport System: Important in drug transport, only way certain oral drugs are
absorbed are when the drug reaches the site of action and speed up renal
excretion.
3. How do drugs cross membrane?
1. Channels and pores: Very small, specific for certain protein, sodium
and potassium
2. Transport Systems: Move molecules on one side of the membrane to
the other.
E.g.: P-Glycoprotein: Transmembrane protein that transport a wide variety
of drugs out of cell.
--P-Glycoprotein transports drugs to:
1. Kidney: excreted into urine
2. Liver: excreted into the bile
3. Placenta: excreted into mothers circulation
4. Intestine: excreted into intestinal lumen
5. Capillaries of the CNS: P-glycoprotein pumps drugs back into
the blood; again limiting drug access to the brain.
-Most movement of drugs throughout the body is by direct penetration of
membranes.
-Channels are too small and most drugs lack a transport system.
-In order to directly penetrate, the drug must be lipophilic, because
membranes are composed mostly of lipids.

3. Direct Penetration of the membrane: Drug must be Lipid-soluble:

Since the cell membrane is composed of phospholipids, therefore lipid
soluble drugs can pass directly through the membrane.
4. Polar Molecules and Ions: Polar: Are not lipid soluble, therefore
cannot pass directly through the membrane, uneven charge, as well as no
net charge. Polar drugs will dissolve in polar solvents such as water but
not in non-polar solvents such as oil. (Like dissolves like)
Ion: Drugs that have a net electrical charge (+ or -). Ions are unable to
cross membranes, therefore not absorbed.
5. pH-dependent ionization
Weak acid or weak base is determined by the pH of the drugs medium.
Acid: Proton donor; when an acid gives up a proton it is negatively
charged.
Base: Proton acceptor, base takes proton it is now positively charged.
The process of receiving or donating a proton is called Ionization.
6. Ion-trapping: When the pH of a fluid differs from one side of the
membrane, drug molecules tend to accumulate on the side, which the pH
is, favors its ionization. Influences movement of the drug through the body
and the way it is excreted.
- Acidic drugs--- alkaline side
-Base drugs-----Acidic side
Example: Poisoning: By manipulating urinary pH, we can employ ion
trapping to draw toxic substances from the blood into the urine, thereby,
accelerating its removal.
4. How does this relate to drugs?
-Most drugs are weak bases, non-ionized, and absorbed in the
small intestines. (Aspirin is one of the few that is absorbed in the
stomach. Drugs must be non-ionized in order to be absorbed.
5. Absorption: Movement of drugs from its administration site into the blood
stream. Rate: How soon effects will begin. Amount: How intense the effect will be
Factors affecting drug absorption:
1. Rate of dissolution: How quickly the drug can dissolve
2. Surface area: larger surface area, quicker absorption, oral drugs are
usually absorbed in the small intestine because of the larger
surface area.
3. Blood flow: Greater concentration gradient, more rapid absorption
4. Lipid solubility: Highly lipid soluble drugs are absorbed more rapidly
than low-lipid soluble drugs.
5. Non-ionized drugs: Can be absorbed
6. pH partitioning: The pH difference between drug and fluid will have a
higher tendency to be ionized in the plasma.
7. Route: Enteral: GI track and Parenteral: Injection

Characteristics of Routes
ROUTES BARRIERS PATTERNS ADVANTAGES DISADVANTES
None
Instantaneous
-Rapid onset
IV
-Irreversible
- Precise control, -Large volumes
-Irritant drugs.

IM

Capillary wall

SQ
PO

Same as IM
Epithelial lining
GI wall and
capillary wall

Rapid with water

soluble, slow with
poor soluble
drugs

-Permits use poor

soluble drugs
-Permits the use of
depot preparations
(from where the drug is
absorbed slowly over
an extended period of
time.)

Slow and highly

variable

-Easy
-Inexpensive
-Ideal for self
administration
Potentially reversible

-Expensive
-Inconvenient
-Infection
-Embolism
-Drug must water
soluble
-Discomfort
-Inconvenient

-The variability.
Gastric acid can cause
inactivation of some
drugs.
Possible for nausea and
vomiting.
Must be conscience
and cooperative

When is Parenteral preferred of Oral administration?

1. Emergencies
2. Tight plasma drug level
3. Drug destroyed by oral administration
4. Drug causes severe local GI injury
5. Drug causes severe disorder with drugs that cannot cross membranes
6. Patient cannot/will not take drugs orally.
7. Treatment of systemic disorder with drugs cannot cross plasma
membranes.
Pharmaceutical Preparations for Oral Administration
1. Tablets: Same drug may very among manufacturer.
2. Enteric-coated preparations: Avoid antacids; varies with gastric
emptying time, protect stomach from drug that it inside, to be absorbed
in small intestines.
3. Sustained-release preparations: Dose dumping; bioavailability varies
more than tablets.

6. Bioavailability: The % of a drug dose that actually reaches circulation

chemically unchanged.
Parenteral Route: Highest bioavailability
Enteral/Oral: Low bioavailabilitydrug does not dissolve, enzymes metabolize it
before its absorbed, and the liver metabolizes by the liver during First Pass.

Feeding tubes: No enteric coatings, extended release, whole pill, or

uncrushable drugs will be given in a feeding tube.
Distribution: The movement of drugs throughout the body
A. Can be stored
B. Metabolized & excreted
C. Exert action
Location where the drugs can be moved:
A. Interstitium
B. Total body water
C. Plasma
D. Adipose Tissue
E. Muscle
F. Bone
Drug distribution is determined by there three factors:
A. Blood flow to tissue & organs: Drugs are carried by blood to tissue
and organs of the body.
a. Rate of distribution is determined by blood flow to the area.
Most tissue is well perfused.
b. Shock/heart failure, diabetes, blood flow issues, abscess &
tumors are conditions that affect blood flow.
B. Exiting the vascular system: Necessary for the drug to enter site to
produce an effect & undergo metabolic & excretions. Most drugs are
not effective in the bloodThey have to pass through the
capillary bed into the cell to be effective.
a. Drugs can form reversible bonds with various proteins.
b. Plasma albumin is the most abundant and important.
c. % Of drug bound to protein depends on strength of attraction to
albumin.
d. If you have a drug that is highly attracted to albuminyou are
restricting the amount of drug available for distribution in the
body.
e. Restricts drug distribution
f. Source of drug interactions

g. Drugs cannot exert action if bound to protein!

i. Usually no resistance when exiting typical capillary beds.
h. Drugs pass between capillary cells rather than through them.
Movement through the interstitial space is not hampered.
ii. Blood Brain Barrier: Refers to the specialized anatomy of the
nervous System Capillaries:

i.

Tight junction between the cells that compose the walls of

capillaries in the CNS.
j. Drug must be able to pass through cells of the capillary wall
k. Only drugs that are lipid soluble or have a transport system
can cross the BBB to a significant degree.
l. BBB is not fully developed at birth so infants are sensitive to
medication and vulnerable to toxins.
Placental drug transfer:
a. Membranes of the placenta do not constitute an absolute barrier
to the passage of drugs.
I. Movement determined in the same way as other membranes.
b. Risks with drug transfer:
i. Birth defects: mental retardation, gross malformations, low birth
weight.
ii. Mothers use of habitual opioids: Birth of drug-dependent baby
MUST BE MONITORED.
Protein Binding: pg. 38
a. Drugs can form reversible bonds with various proteins.
b. Plasma albumin is the most abundant and important of the proteins
to which drugs binds.
i.
Large molecule that always remains in the bloodstream.
1. Too large to squeeze through capillary walls and there is not
transport system.
2. Only unbound free drug molecules can leave the vascular
system.
3. Bound molecules are too large to fit through the pores in the
capillary wall.
c. Percentage of drug binding to albumin depends on strength of attraction to
albumin.
d. Albumin is the most prevalent protein in plasma and the most important
proteins to which drugs bind.
e. Only unbound (free drugs) molecules can leave the vascular system.
f. Bound molecules are too large to fit through the pores in the capillary wall.
g. If you have a drug that is highly attracted to albumin, you are restricting
the amount of drug available for distribution in the body.
a. Albumin doesnt have a lot of spaces for it to attach to, so albumin
cant get outtherefore drug attached to albumin cant leave
circulation and can cause toxicity.
h. Can be a source of drug interactions
1. Albumin doesnt have a lot of binding sites.
2. Drugs with the ability to bind to albumin compete for those
sitesbecause of this fact, one drug can replace another,
causing the concentration of the displaced drug to rise

3.
4.
5.
6.

thereforeincreasing the effect of the displaced drug-toxicity

can result. Pg. 37-38
Drug cannot exert action if bound to protein
Some drugs must enter the cells if to reach its site of action.
Most drugs must enter cell to undergo metabolism and
excretions.
Many drugs produce their effects by binding with
receptors on external surface of the cell membrane.
a. Meaning, some drugs do not need to cross the
cell membrane to act
Metabolism

7. This is also known as BIOTRANSFORMATION.

8. Defined as the enzymatic alteration of drug structure
9. Most often takes place in the liver by CYP enzymes. Read
38-39 about CYP enzyme families.
a. CYP enzymes inhibited by certain other drugs &
grapefruit juice and limes.
b. P450 is the hepatic microsomal enzyme system.
c. CYP- (C1,C2,C3) Metabolizes drugs, other 9
enzymes metabolism endogenous compounds
(steroid, fatty acids)
10. Biotransformation can also take place in the stomach,
intestine, and kidney.
Consequences of drug metabolism
11. Acceleration renal drug excretion: kidney major organ of
drug excretion. Unable to excrete drugs that are highly lipid
solubleconverting lipid soluble into water soluble for
quicker excretion. Kidneys excrete water-soluble drugs
quickly.
12. Drugs are converted from an active compound to an inactive
form of the drug.
13. Increased therapeutic action: metabolism can increase the
effectiveness for some drugs.
14. Activation of prodrugs : a compound that is
pharmacologically inactive when taken but converts into an
active form within the body.
15. Decreased toxicity: by converting drugs into inactive forms,
metabolism can decrease toxicity
16. Increased toxicity: Acetomophen is converted into a
hepatoxic metabolitethis is specific cause of liver damage
when overdosed.
Special considerations in Metabolism

Factors that can influence the rate at which drugs are

metabolized:
1. Age: babies are especially sensitive to drugs; the
liver cannot fully metabolize drugs until a year old.
2. Induction of drug-metabolized enzymes:
a. Some drugs cause the liver to increase
metabolism by synthesizing drugmetabolizing enzymesincreased
metabolism of other drugs as well,
necessitating increased dosages of that
drug.
-- Process of stimulation enzyme synthesis
is induction
3. First Pass effect: we discussed this in
absorptionrefers to rapid hepatic inactivation of
certain oral drugs. When oral drugs are absorbed in
the GI tractthey go directly to the liver by way of the
hepatic portal vein. If the liver is functioning well, that
drug will be metabolized completelytherefore
having no therapeutic effect. This drug would need to
be given another wayparenteralit goes directly
into systemic circulation and bypasses the liver. EX:
Nitroglycerin.
3. Nutritional status: Inadequate diets may cause a
lack of nutrients necessary for metabolism.
4. Competition between drugs: If two drugs are
metabolized in the same manner, they may be
competing for the factors necessary for
metabolismone or both could be metabolized,
and one or both could reach dangerous levels.
Intestinal First Pass: Important--when the liver metabolizes a
drug taken orally, thereby reducing the amount drug in the
bloodstream available for the intended use.
Intestinal CYP enzymes play a part:
-Asian Indians have less of the enzyme
-Citron inhibits the enzyme
Bacteria in the intestine also plays a part
- Metabolisms certain drugs and produces enzymes
- What happens if on antibiotics? Antibiotics can kill the
good normal bacteria flora.
Hepatic First-Pass Effect:
a. Rapid hepatic inactivation of certain oral drugs.

b. From GI tract, drugs are brought directly to liver via

hepatic portal vein.
c. Drug may be completely inactivated during this first pass.
These drugs are typically not given PO
Extraction Ratio
A. Higher ER: Low bioavailability
1. PO doses much higher than parenteral
2. Small changes in liver enzymes=big change in
amount of drug available
B. Lower ER: Higher bioavailability
1. Doses similar regardless of route
2. Changes in enzymes have little effect.
Excretion:
A. Defined as the removal of drugs from the body.
B. Drugs and their metabolites can exit the body through:
1. Urine, sweat, saliva, bile, breast milk, or expired air

Renal Route of Drug Excretion:

A. Steps in renal drug excretion
1. Glomerular filtration
a. Blood flows through the glomerular
capillaries, drugs and small molecules
are forced through pores of the capillary
wall.
b. Hydrostatic pressure in glomeruli capillaries
forces low MW drugs & metabolites into
urine in the renal tubules.
c. Large molecules & proteins bound drugs
are too large to undergo glomerular filtration
d. Drugs at a low molecular weight will go
through pores and filter into renal tubule.
e. Drugs that bind to albumin/protein, cant get
through because theyre too big, and can
accumulate in the body and produce toxic
levels.
2. Passive Tubular reabsorption
a. In distal tubule drug concentration in blood
are lower than in tubule. With this being
said, it will want to equalize and the drug
will be reabsorbed into the body.
b. Lipid-soluble drugs that were filtered into
the urine from the glomerular capillaries
move across membranes back into blood.

i. Should not take megadoses of

vitamins because it gets reabsorbed.
ii. Water-soluble drugs & metabolites (Ion & polar
compounds) remain in the urine and are excreted.
(Water-soluble drugs filter through urine.)
iii. Can happen in liver and kidney
1. Active tubular secretion:
a. Renal Tubules have pumps that actively
secrete large endogenous substances &
metabolites into urine.
b. ATS a rapid, high-capacity process. Even
protein bound metabolites that have been
conjugated by Phase II metabolism will
quickly dissociate from plasma proteins &
be eliminated by the kidney in a single pass
through the kidney.
i. Organic acid pump: pglycoprotein pump
ii. Actively forcing drugs to be
filtered into urine.
iii. Competition: One will be excreted,
and other will be absorbed or both
could get stuck and neither will be
absorbed
B. Factors that modify renal drug excretion
1. pH-dependent Ionization: The urine itself, the
medium in which the drug is in, the pH affected by
the drug.
a. Say its very acidic, and the drug itself is also acidic, instead of being
eliminated, it will stay it will stay in the body.
b. If one is basic, and the drug is acidic? It depends on drugs medium if it
will be absorbed or eliminated.
2. pH of urine
3. Competition for active tubular transport:
Competing for excretion, one will get through,
other one wont.
4. Age: Accumulate in kidney
iv. Full renal function at 1 year, under a
year, there is no proper excretion.
v. Older adults have declined in
function.
C. Creatinine Clearance
a. Is an estimate of the glomerular filtration rate

b. Produced of muscle metabolism

c. You can do a 24-hour urine, if creatinine of high, muscle is
being broke down for energy.
d. If creatinine is reduced, what does that mean for dose
adjustment? Kidneys are not excreting properly, so
decrease medication and decrease frequency of dose.
e. How do you measure how often a drug needs to be given?
By peak and trough levels.
f. Normal:
i. Men: 90-139 ml/min
ii. Women: 80-125 ml/min
g. Mild impairment: 50-80 ml/min
h. Moderate impairment: 10-50 ml/min
i. Severe impairment: less than 10 ml/min
j. Blood creatinine: If kidneys are impaired, creatinine will be
high.
k. Measured by mL per minute and patient body size.
Nonrenal Routes of Drug Excretion:
1. Breast Milk-Lipid soluble drugs enter breast milk easily.
a. If ingests megadoses of vitamins, baby gets them.
2. Other Nonrenal routes of excretion
a. Bile: Goes from bile, from liver, into duodenum, back into the portal
vein and back into circulation.
b. Enterohepatic recirculation/recycling
c. Lungs- especially anesthesia
d. Sweat/saliva- small amounts
Enterohepatic Recycling
a. Bacteria in the small intestine have enzymes that may hydrolyze some
of the drug conjugate back to the original drugor metabolite.
i. Because its bacteria, the bacterial floor in the intestines is
importantwhat happens to the length of time of the drug action? It
will be shorter because drug is recirculating.
ii. The deconjugated drug is absorbed from the gut lumen back to the
liver via the portal vein
iii. Instead of totally eliminating drug in the body, enzymes in the small
intestines, release free drug radicals into the circulation, that free
drug is fat solubleit is deposited in fat.
iv. What happens to length of time of the drug action?
v. What happens if patient is on antibiotics? Antibiotics will destroy
bacterial floor. Drug is affected.
vi. Zetia: goes through Enterohepatic cycle
Time course of Drug Responses:
A. Measure plasma drug levels to determine how much drug is in body.

B. Measure this because cannot measure at site of actionWe have these

different drugs, and specific parts of the body that we want them to act on
upon. We dont usually go to the affected organ to determine its
effectiveness. Certain lab levels will show appropriate drug responses.
C. When an epileptic patient takes phenytoin, we cannot routinely draw
samples of the brain to assess for adequate seizure control. Its not
necessary to measure drug concentration at actual site of action, in order
to have an objective basis for adjusting dosages.
D. Remember, drug must be therapeutic to exert action.
E. Need to know how much of drug is bound & how much is free. Whatever
drug is bound to an albumin, it cannot elicit its effect because its too big.
Therefore, whatever drug is free is what is able to elicit the therapeutic
response because it can either be dissolved, transported, etc., across or
through cell membrane.
F. What if malnourished? Time course of drug response is affected if patient
isnt able to metabolize drug.
Time course of drug response:
Terms:
A. Minimum effective concentration (MEC)- The plasma drug level below
which therapeutic effects will not occur.
B. Toxic concentration- Plasma level at which toxic effects begin.
C. Therapeutic rage-Falls between MEC & Toxic concentration; objective of
drug therapy is to remain in this range. If above the therapeutic range,
considered toxic.
i. Narrow: There is a small therapeutic ragemeaning toxicity and
MEC are very close. You have to monitor closely for labs, and side
effects often.
ii. Wide: Meaning the therapeutic rage of a drug is wide, so you dont
have to monitor as closely, etc.
-Example: 10mL 50 mL, wider range, not as much to
monitor.
Onset of drug action -time for a drug to reach plasma level where therapeutic
effects can occur.
Duration of drug action: How long plasma levels stay above MEC.
a. How long the therapeutic effect lasts. How long does it last?
Single-Dose Time course:
A. The duration of effects is determined largely by the combination of
metabolism and excitation. How long does it take the body to break it
down & excretions?
B. Drug levels above MEC- Therapeutic response will be maintained.
The duration of the therapeutic level is determined by metabolism.

We want the drug levels to stay in the middle to stay therapeutic- Take
times to get to this level if you given patient loading doses or
maintenance to keep it at this level.
Half-Life
Defined as the time required for the amount of drug in the body
to decreased by 50%.
Percentage vs. amount: a % - not a specific amount of drug
is lost during one half life.
Determines the dosing interval
Also important regarding drug reactions.
Zetia: 22 hour half-life. After 22 hours, half of that dose will be
eliminated from the body. How often would you give this
medication? Daily, because it has a half-life of 22 hours, not twice,
or three? Too often, concentration high, because half-life, it
determines the dosage.
Half-life: Gave a drug today, tomorrow when we go to give the dose
again, 50% of the drug has been eliminated from the body.
Percentage: 50%
Recommended: 10mL once daily. So 22 hours later, 5mL would be
left in circulation. Important to know the reaction of drug and
when to monitor.
Drugs Levels Produced with Repeated Doses:

The process by which plateau (steady) drug levels are

achieved. Steady drug level is achieved: Plateau
Occurs when amount of drug eliminated between doses= the
dose administered
Time to plateau
o When given in same dose, takes 4, half lives to reach
plateau
o Is independent of dose size
Zetia:
10/19: gave patient first dose of 10mg
10/20: 5mg +10mg= 15mg
10/21: 7.5mg +10mg= 17.5mg
10/22: 8.75mg + 10mg =18.75mg
10/23: 9.38mg +10mg= 19.38mg
10/24: 9.67mg + 10mg= 19.69mg ----- circulating is closest to
the initial dose.
As long as dosage remains constant, the time required to
reach plateau is independent of dosage size.
If kidney and liver are properly workingevery 24 it should get
50% eliminated.

Loading doses vs. maintenance doses

-Larger dose given initially to achieve plateau quickly (loading dose) Can
load dose (bolus) and use a PCA pump for maintenance.
-Followed by smaller doses (Maintenance doses) Can be a continuous
infusion for maintenances doses.
Decline from plateau
-Take 4 lives for 94% of drugs to be eliminated from body.
Haldol: Psych medication, big dose, once a week. Reduce size and frequency of
dose2mg for a regular dose, changed to 1mg in the morning, and 1mg at
nightThis eliminates the trough levels.

Loading dose: needed to get level of drug at a therapeutic level, after that take
maintenance doses.
Antibiotic IM: Faster, then patient can take the PO after that in a smaller dose to
maintain.
Will do antibiotics, digoxin (IV loading dose) Arrhythmias, CHF

Patient has DVT or PE: Need heparin at a therapeutic level, IV push and then
maintenance doses.
PTT: Narrow window, every 6 hours, monitor PTT levels.
Will take 4 doses to decline.

-Peak- Highest plasma drug level below toxic.

-If giving medication, when would we draw the peak?? Given at 10 (given slowly,
hour and a half) at 11:30 infusion should be finished.
-After medication administration is completed, thats when you would take peak
levels.
-The trough: want about 10. Needs to be between the MEC and toxic level.
You will draw trough before the next dose.
-If the trough is below the MEC? They will probably increase the dose.
-Peak is above 20? Doctor will decrease dose. Nausea vomiting for toxic digoxin
level hold dose for a day or decrease dose